Letters to the Editor

IIdiopathicdiopathic acquiredacquired truetrue Abnormal keratinization of nail plate is a possible explanation for true leukonychia. In past, biopsy of a lleukonychia:eukonychia: A fewfew ccommentsomments toenail, having trauma-induced acquired leukonychia, revealed an abnormal parakeratotic strip in the lower 1/3rd of nail plate. Leukonychia occurs due to reflection Sir, of light by these parakeratotic cells and loss of nail plate Leukonychia is the most common dyschromia of transparency.[4] While hereditary true leukonychia nails. We would like to add on the information is persistent and resistant to treatment, it requires [1] to an interesting case reported by Arsiwala in genetic counselling to unearth other syndromes in a your journal. In most of such nail aberrations, family. Removal or treatment of a cause in acquired it is difficult to make complete diagnosis. True leukonychia may result in complete reversal of this hereditary leukonychia may be another diagnostic nail abnormality. possibility here. Variable expression and incomplete penetrance in total hereditary leukonychia have Since leukonychia is rarely associated with other been documented in past.[2] Leukonychia partialis is systemic findings, one can speculate that there will a subtle variant or phase of leukonychia totalis with be many more cases compared to anecdotal reports variable expression of same genetic defect.[2] Absence published sporadically. It is imperative to diagnose this of family history does not necessitate diagnosis rare and intriguing nail abnormality correctly because of acquired leukonychia. There have been reports leukonychia cause extensive cosmetic embarrassment documenting onset of hereditary leukonychia in to the patient. childhood, not necessarily at birth.[3] Moreover, it is highly unlikely that trauma may result in total AACKNOWLEDGMENTCKNOWLEDGMENT leukonychia in all finger nails simultaneously. While hereditary leukonychia is a rare condition and We wish to thank the patient of total leukonychia who made usually involves the entire nail, acquired type usually us search the literature for diagnosis. presents in childhood as leukonychia partialis (either punctata or transverse striae).[3] True leukonychia PPratikratik GGahalaut,ahalaut, NNitinitin MMishra,ishra, may occur as an isolated trait or it may be a marker of MMadhuradhur KantKant RastogiRastogi several clinical syndromes.[3] Department of Dermatology, Sri Ram Murti Smarak Institute of Medical Sciences, Bareilly, Uttar Pradesh, India A white appearance of nails can result from whitening of the nail plate due to alterations AAddressddress forfor correspondence:correspondence: Dr. Pratik Gahalaut, or dysfunctioning of nail matrix (true 69, Silver Estate, Bareilly - 243 006, Uttar Pradesh, India. E-mail: [email protected] leukonychia); the nail bed or other underlying tissue without any matrix dysfunction (apparent RREFERENCESEFERENCES leukonychia); or when nail plate alternation 1. Arsiwala SZ. Idiopathic acquired persistent true partial to total has an external origin, for example, in leukonychia. Indian J Dermatol Venereol Leprol 2012;78:107-8. onychomycosis (pseudoleukonychia).[4,5] 2. De D, Handa S. Hereditary leukonychia totalis. Indian J Dermatol Venereol Leprol 2007;73:355-7. 3. Rodríguez-Lojo R, Del Pozo J, Sacristán F, Barja J, Depending on the extent of each nail involved, Piñeyro-Molina F, Pérez-Varela L. Leukonychia total is true leukonychia may be totalis, subtotalis, or associated with multiple pilar cysts: Report of a five- partialis (involving less than 2/3rd of nail).[4] In generation family: FLOTCH syndrome? Eur J Dermatol 2011; rd 21:484-6. subtotal leukonychia, the proximal 2/3 of the nail 4. Tuzun Y, Karakus O. Leukonychia. J Turk Acad Dermatol is white.[5] Morphologically, leukonychia partialis 2009;3:93101[about 3 p.]. Available from: http://www. may again be divided into punctate, transverse, or jtad.org/2009/1/jtad93101r.pdf. [Last accessed on 2013 [4] Mar 1]. longitudinal types. Total or subtotal leukonychia is 5. Berker DAR, Baran R. Disorders of nails. In: Burns T, usually hereditary.[6] Breathnach S, Cox N, Griffiths C, editors. Rook’s Textbook

812 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Letters to the Editor

of Dermatology. 8th ed. Singapore: Wiley-Blackwell; 2010. age, sex, occupation, residential background, duration p. 65.15. and pattern of disease were recorded in case sheet 6. Tosti A, Piarccini BM. Biology of Nails and Nail Disorders. In: Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, after obtaining written informed consent. Personal Leffell DJ, editors. Fitzpatrick’s Dermatology in General or family history of atopy, present or past history Medicine. 7th ed. New York: McGraw Hill Medical; 2008. p. 782. of hypersensitivity and other dermatological and Access this article online systemic illness was also recorded. Those with atopy,

Quick Response Code: Website: hypersensitive reactions were excluded in order to www.ijdvl.com avoid false positive results. Cases were subjected to

DOI: patch testing as per the standard guidelines, taking 10.4103/0378-6323.120736 all necessary precautions. Patch test series used was Indian standard series (ISS), containing 25 allergens, PMID: ***** and approved by contact and occupational dermatitis forum of India. Patch testing with conventional ISS was undertaken for convenience of getting a variety of allergens combined in a single battery. We did not PPreliminaryreliminary experienceexperience ofof patchpatch select any particular occupational group or a specific patient group and so did not use any specific allergen ttestingesting aatt SSrinagar,rinagar, KKashmirashmir series. Reading and grading of positivity was carried out according to International Contact Dermatitis Research Group guidelines.[3] Sir, Allergic contact dermatitis (ACD), a delayed type of Out of 85 cases patch tested, 49 were males (57.6%) hypersensitivity reaction developing in sensitized and 36 females (42.4%), with age ranging from 5 years individuals after environmental exposure to allergens, to 72 years (mean age 40.47 years ± SD 14.84), is a challenging problem with considerable morbidity as described in Table 1. 51 (60%) cases were from [1,2] and economic impact. Prevention of contact with urban and 34 (40%) from rural background [Table 1]. the incriminating allergens forms the main component The duration of illness ranged from 10 days to of management of ACD, and patch testing is a useful 10 years (mean ± SD = 28.6 ± 36.20 months). [2] tool for detecting it. The exposure to allergens and the Dermatitis of hands and feet was seen in 45 (52.9%) type of allergens included in standard patch test series cases; non-specific pattern in 27 (37.8%), air borne varies considerably from area-to-area, depending on contact dermatitis (ABCD) in 10 (11.8%), and photo the local experience.[1] ACD in 3 (3.5%) cases.

We conducted the study with the aim of having Out of 85 cases patch tested, 33 (38.8%), 19 males and preliminary experience of patch testing in Kashmir, 14 females, showed positive reactions. 20 cases showed in the newly set-up contact dermatitis clinic of our positive reaction to one allergen and 13 to more than department. All consecutive clinically suspected one, giving a total of 56 reactions. Thirty-four positive cases of ACD of all age groups visiting the clinic over reactions were seen in males and 22 in females. a period of 7 months, from mid-May to mid-December Most common allergens identified were potassium 2012, were included in the study. Details regarding dichromate and nickel sulfate showing nine reactions

Table 1: Age, sex, residential distribution of cases Age group Males (%) Females (%) Total (n=85) (%) Rural (%) Urban (%) ≤10 years 01 01 02 00 02 11-30 years 09 17 26 (30.59) 15 11 31-50 years 27 12 39 (45.9) 12 27 51-70 years 11 06 17 06 11 ≥71 years 01 00 01 01 00 Total (n=85) 49 (57.6) 36 (42.4) 85 (100) 34 (40) 51 (60) Average age 40.47 (±14.84 SD) Average duration of illness 28.6 (±36.20 SD) months

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 813 Letters to the Editor

(16.1%) each. Cobalt chloride showed 6 (10.7%), The age, sex and duration of illness variables in our thiuram mix 5 (8.9%), P-phenylenediamine (PPD) study were similar to other studies.[1,2,4-7] 60% cases 4 (7.1%), and colophonium 4 (7.1%) reactions. were from urban background, probably because our hospital is located in the main city. Dermatitis of In males, the most common reactions were observed with hands and feet was the most common clinical pattern potassium dichromate showing nine reactions (26.5%), in our study, similar to some studies from India and followed by 5 (14.7%) with thiuram mix. In females, abroad[2] and different from other Indian studies where the most common allergen was nickel sulfate with ABCD is common.[7] nine reactions (40.9%), followed by 5 (22.7%) with cobalt chloride. Positive reaction exclusively in males Nearly 38.8% positive reaction in our study is similar to was seen with potassium dichromate, PPD, mercapto 32.3% by Akasya-Hillenbrand et al.;[6] however, differs mix, 2-mercaptobenzothiazole, nitrofurazone, from positive results of 63.5% by Davoudi et al.,[1] 59% lanolin alcohol, thiuram mix, black rubber mix, by Bajaj et al.,[2] 63% by Handa and Jindal[7] and 64.7% formaldehyde, and parthenolide. Positive reactions by Sudhashree et al.[8] The low positive percentage exclusive to females were due to benzocaine, nickel sulfate, and polyethylene glycol 400. No reaction was tested with ISS may be because of different exposure seen with petrolatum, paraben mix, gentamicin, epoxy patterns in our population than rest of the country. resin, p-chloro-m-cresol, and clioquinol. Overall present relevance rate was 55.4% (31 reactions out of The five most common allergens were potassium 56) and the results are summarized in Table 2. The dichromate and nickel sulfate, followed by cobalt occupational status of the study group and its relation chloride, thiuram mix, PPD and colophonium, similar with positive reaction is summarized in Table 3. to other studies.[1,2,4-8]

Table 2: Patch test results for each allergen of Indian standard series Allergen Positive results (n=56) Males (n=34) Females (n=22) Clinical relevance (%) (%) (%) (%) Petrolatum 100% 00 00 00 Potassium dichromate 0.5% pet 09 (16.1) 09 (26.5) 00 6 Neomycin sulfate 20% pet 02 (3.6) 01 (2.9) 01 (4.5) 1 Cobalt (II) chloride hexahydrate 1% pet 06 (10.7) 01 (2.9) 05 (22.7) 4 Benzocaine 6% pet 01 (1.8) 00 01 (4.5) P-phenylenediamine 1% pet 04 (7.1) 04 (11.8) 00 3 Paraben mix 16% pet 00 00 00 Nickel (II) sulfate hexahydrate 5% pet 09 (16.1) 00 09 (40.9) 7 Colophonium 20% pet 04 (7.1) 02 (5.9) 02 (9.1) 1 Gentamicin sulfate 20% pet 00 00 00 Mercapto mix 2% pet 01 (1.8) 01 (2.9) 00 Epoxy resin 1% pet 00 00 00 2-Mercapto benzothiazole 2% pet 02 (3.6) 02 (5.9) 00 1 Fragnance mix 2% pet 02 (3.6) 01 (2.9) 01 (4.5) 1 Nitrofurazone 1% pet 01 (1.8) 01 (2.9) 00 p-chloro-m-cresol 1% pet 00 00 00 Lanolin alcohol 30% pet 01 (1.8) 01 (2.9) 00 1 Myroxylon pereirae resin 25% pet 02 (3.6) 01 (2.9) 01 (4.5) 1 Thiuram mix 1% pet 05 (8.9) 05 (14.7) 00 2 Clioquinol 5% pet 00 00 00 Black rubber mix 0.6% pet 01 (1.8) 01 (2.9) 00 4-tert-Butyl phenol formaldehyde resin 1% pet 03 (5.4) 02 (5.9) 01 (4.5) 1 Formaldehyde 1% aq 01 (1.8) 01 (2.9) 00 1 Polyethylene glycol 400 100% 01 (1.8) 00 01 (4.5) Parthenolide 0.1% pet 01 (1.8) 01 (2.9) 00 1 Total 56 34 22 31 (55.4)

814 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Letters to the Editor

Table 3: Positive patch test reactions to various allergens in each occupational group Occupational group Number Allergen Positive reaction Total reactions Housewives 21 Nickel 5 15 Cobalt 4 Colophonium 2 Neomycin, myroxylon, benzocaine, PEG 1 each Service 21 PPD 4 12 Fragrance mix, thiuram 2 each Myroxylon, lanolin, black rubber, potassium dichromate 1 each Students 10 Nickel 2 4 Cobalt, PTBP 1 each Construction workers 8 Potassium dichromate 6 13 Thiuram mix, MBT 2 each Colophonium, Mercapto mix, nitrofurazone 1 Farmers 6 Potassium dichromate, thiuram, formaldehyde, 1 each 4 parthenolide Cottage Industry workers 6 PTBP 2 4 Potassium dichromate, cobalt 1 each Business 5 Colophonium, neomycin 1 each 2 Medical professional 5 Nickel 2 2 Unemployed 2 Automobile industry/driver 1 Total 85 56 56 PEG: Polyethylene glycol, PPD: P-phenylenediamine, PTBP: 4-tert-Butyl phenol, MBT: 2-Mercapto benzothiazole

In our study, all reactions to potassium dichromate, traditional, and cultural values in Kashmir causing thiuram mix, and PPD were seen exclusively different exposure patterns. We intend to carry forward in males and all reactions to nickel sulfate and the study in order to obtain larger data. most to cobalt (5 out of 6), in females, similar to other studies.[1,2,7,8] In Kashmir, most of the IIffatffat HHassan,assan, PParvaizarvaiz AAnwarnwar RRather,ather, construction and outdoor labor work is carried YYasmeenasmeen Jabeen,Jabeen, ZubairZubair A.A. Wani,Wani, HinahHinah Altaf,Altaf, out by males and females are not involved much NNuzhatunuzhatun Nisa,Nisa, UmarUmar Yaseen,Yaseen, FarhanFarhan RasoolRasool in outdoor work especially, construction (cement) Department of Dermatology, STD and Leprosy, Government Medical College, Srinagar, Jammu and Kashmir, India work. So all positive reactions to potassium dichromate in our study were found in males and AAddressddress forfor correspondence:correspondence: Prof. Iffat Hassan, no female was found positive because of the above Department of Dermatology, STD and Leprosy, Government reason. Medical College, Srinagar, Jammu and Kashmir, India. E-mail: [email protected]

We found only one positive reaction to parthenolide RREFERENCESEFERENCES than the high positive percentage seen in other Indian [2,7] 1. Davoudi M, Firoozabadi MR, Gorouhi F, Zarchi AK, Kashani MN, studies. The positivity to parthenolide does not Dowlati Y, et al. Patch testing in Iranian patients: A ten-year mean a definite implication of Parthenium weed experience. Indian J Dermatol 2006;51:250-4. for the ACD and does not have much sensitivity. 2. Bajaj AK, Saraswat A, Mukhija G, Rastogi S, Yadav S. Patch testing experience with 1000 patients. Indian J Dermatol Exposure level to Parthenium plant as such is very Venereol Leprol 2007;73:313-8. low in Kashmir, which could be the reason for low 3. Wilkinson DS, Fregert S, Magnusson B, Bandmann HJ, Calnan CD, Cronin E, et al. Terminology of contact dermatitis. positivity in this preliminary study. Acta Derm Venereol 1970;50:287-92. 4. Shenoi DS, Srinivas CR, Balachandran C. Results of patch In conclusion, this preliminary study conducted to testing with a standard series of allergens at Manipal. Indian J Dermatol Venereol Leprol 1994;60:133-5. experience the results of patch testing at our center 5. Narendra G, Srinivas CR. Patch testing with Indian standard reveals results generally similar to that of other centers, series. Indian J Dermatol Venereol Leprol 2002;68:281-2. 6. Akasya-Hillenbrand E, Ozkaya-Bayazit E. Patch test results both in country and abroad. Few differences, though, in 542 patients with suspected contact dermatitis in Turkey. may be because of different climatic conditions, Contact Dermatitis 2002;46:17-23.

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7. Handa S, Jindal R. Patch test results from a contact STD are disregarded in syndromic management. dermatitis clinic in North India. Indian J Dermatol Venereol Researchers found 49% asymptomatic patients among Leprol 2011;77:194-6. 8. Sudhashree VP, Parasuramalu BG, Rajanna MS. 295 attendees in a STD clinic among responders with A clinico-epidemiological study of allergens in patients with either genital ulcer disease or genital discharge.[4] STDs dermatitis. Indian J Dermatol Venereol Leprol 2006;72:235-7. increase the spread of human immunodeficiency Access this article online virus (HIV) 2-20 fold. Syndromic management fails

Quick Response Code: Website: to reduce the genital shedding of HIV and this has www.ijdvl.com been demonstrated by testing genital secretions for the [5] DOI: presence and concentrations of HIV. 10.4103/0378-6323.120737 Overuse of antibiotics is another area of concern PMID: ***** with syndromic management. Medicines are often prescribed unnecessarily to patients without disease.[6] Threat of antibiotic resistance looms large considering this perspective. The consistency of syndromic SSyndromicyndromic managementmanagement inin thethe management has also not been validated and varies from place-to-place. ccontrolontrol ofof ssexuallyexually transmittedtransmitted Syndromic management falls short of tackling the iinfections:nfections: TTimeime fforor a rrelookelook spiraling threat of spread of STD and with it HIV. Screening of patients, preferably laboratory based, among both high-risk and low-risk populations is Sir, the need of the hour. Behavior modification and Syndromic management involves identifying a group strategies based on epidemiological data should of signs and symptoms in a patient and advocating be combined with health education. Use of mobile treatment against the most common organism, which phones and the internet explosion can also be may be responsible. An effort to establish etiological utilized to enhance low-cost, highly engaging diagnosis of the disease before instituting therapy is and deeply permeating STD/HIV prevention and not required. treatment support interpolations at an incomparable pace.[7] Perhaps the time has come to look closely Vaginal discharge has been established as a syndrome. and seriously assess aggressive strategies such as However, it fails to diagnose and treat chlamydia mass treatment. In comparison with syndromic and gonorrhea though the two diseases may present management, single-round mass treatment had with this manifestation. 60-70% of gonococcal and a greater short-term impact on HIV (36 vs. 30% chlamydial infection are found to be asymptomatic.[1] over 2 years), but a smaller long-term impact (24 vs. Vaginal discharge usually visible during pregnancy 62% over 10 years). Mass treatment combined with or discharge seen in those on oral contraceptives improved treatment services led to a rapid and is physiological, but often reported apprehending sustained fall in HIV incidence (57% over 2 years; [6] sexually transmitted disease (STD). Other women have 70% over 10 years). The Piot-Fransen model of the misconception that vaginal discharge is normal and STD management depicting such mass treatment policy is based on data from underprivileged do not report to the clinics despite suffering morbid countries Uganda, Zaire, and Tanzania [Figure 1]. STD. Discharge from the vagina is thus not a suitable All consenting individuals in the reproductive age entry point in syndromic management. Genital ulcer group of 15-60 years can be offered single dose of disease included as part of syndromic diagnosis and azithromycin, ciprofloxacin, and metronidazole treatment is concerned only with the number of ulcers by health-care workers visiting each household. [2] healed and not whether the disease is cured. The health-care providers must then return after a specified time period to collect biological samples Symptomatic patients do not habitually report to the from the volunteers. These results of the prevalence STD clinics. Study among female sex workers reported of sexually transmitted infections and HIV must then only 12.7% women presenting with vaginal discharge. be compared with the projected values without such On examination, 51.7% were found to manifest intervention. Initial high-cost of such policy may discharge from vagina.[3] Asymptomatic patients of be cost effective in the long run as asymptomatic

816 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Letters to the Editor

AAddressddress forfor correspondence:correspondence: Dr. Sumit Sen, CG-75, Sector 2, Salt Lake, Kolkata - 700 091, West Bengal, India. E-mail: [email protected] RREFERENCESEFERENCES

1. Mabey D. Sexually transmitted diseases in developing countries. Trans R Soc Trop Med Hyg 1996;90:97-9. 2. Wasserheit JN. The significance and scope of reproductive tract infections among Third World women. Suppl Int J Gynecol Obstet 1989;3:145-68. 3. Desai VK, Kosambiya JK, Thakor HG, Umrigar DD, Khandwala BR, Bhuyan KK. Prevalence of sexually transmitted infections and performance of STI syndromes against aetiological diagnosis, in female sex workers of red light area in Surat, India. Sex Transm Infect 2003;79:111-5. 4. Wolday D, G-Mariam Z, Mohammed Z, Meles H, Messele T, Seme W, et al. Risk factors associated with failure of syndromic treatment of sexually transmitted diseases among women seeking primary care in Addis Ababa. Sex Transm Infect 2004;80:392-4. 5. Fleming DT, Wasserheit JN. From epidemiological synergy to public health policy and practice: The contribution of other sexually transmitted diseases to sexual transmission of HIV infection. Sex Transm Infect 1999;75:3-17. 6. Korenromp EL, Van Vliet C, Grosskurth H, Gavyole A, Van der Ploeg CP, Fransen L, et al. Model-based evaluation of single-round mass treatment of sexually transmitted diseases for HIV control in a rural African population. AIDS 2000;14:573-93. 7. Swendeman D, Rotheram-Borus MJ. Innovation in sexually transmitted disease and HIV prevention: Internet and mobile phone delivery vehicles for global diffusion. Curr Opin Psychiatry 2010;23:139-44. 8. Hayes R, Wawer M, Gray R, Whitworth J, Grosskurth H, Mabey D. Randomised trials of STD treatment for HIV prevention: Report of an international workshop. HIV/STD Trials Workshop Group. Genitourin Med 1997;73:432-43. Figure 1: Piot-Fransen model depicting effect of mass treatment on sexually transmitted disease Access this article online

Quick Response Code: Website: infections are treated, contact tracing is obviated, www.ijdvl.com treatment seeking behavior is not required and DOI: [8] compliance and treatment effectiveness is assured. 10.4103/0378-6323.120738 Antibiotic resistance may result and must be weighed PMID: against the benefits of such form of treatment. ***** Developing countries should evaluate such an approach through meticulous trials.

A combined approach of a single round of mass A ssimpleimple aandnd ccost-effectiveost-effective treatment with syndromic management and with extensive use of the media to educate the population ddeviceevice forfor mmobileobile ddermoscopyermoscopy may be the answer to impede the burgeoning threat of association and spread of STD and HIV. Sir, AACKNOWLEDGMENTSCKNOWLEDGMENTS We had earlier presented an article mentioning the use of a simple jeweller’s loupe as a dermoscopy [1] Professor Gobinda Chatterje, Head of the Department of device. Here, we present a modification by which Dermatology of our institute for his help in literature search. any smart-phone camera can be converted into a dermoscopy device. SSumitumit SSenen Department of Dermatology, IPGME and R and SSKM Hospitals, Some of the popular devices available in the Kolkata, West Bengal, India market for the same purpose are Canfield

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 817 Letters to the Editor dermscope® (Canfield scientific) and Handyscope® Like in the original method,[1] we used a simple (FotoFinder systems Gmbh) both of which can be jeweler’s loupe with ×10 magnification and a built-in attached to smart-phones and serve the purpose LED (Light-Emitting Diode) light. The loupe after of effective dermoscopy. These devices are extension was taped to the back of the smart-phone especially useful in the context of e-dermoscopy or with the lens approximating the lens of the teledermoscopy, in which dermoscopic images can smart-phone camera [Figure 1]. Alcohol gel was used also be transmitted along with the clinical images as the dermoscopy fluid. It should be noted that the for teleconsultations.[2] The main disadvantage of lesions were viewed through the fluid with a small gap these devices, in the context of use in developing between the loupe and the fluid. In other words, direct nations is the relatively high cost (starting from contact was minimal [Figure 2]. approximately 35,000INR/700USD). Moreover, most of these devices are compatible with only one The main advantages of this simple device are the very particular make of smart-phones, limiting its utility. low cost (less than 500 INR/10dollars for the loupe) and the fact that it can be attached to any smart-phone, Here, we present a simple device which can function making it more versatile. Since both the macro effectively as a mobile dermoscope and can be a images and the dermoscopic images can be taken cheap and useful tool in mobile-phone enabled with the same smart-phone, it becomes very easy to teledermoscopy. submit the images for teledermatology consultations. The obvious limitations are the lower quality of the dermoscopic images and the absence of polarized dermoscopy options. Further studies would be needed to validate such a tool for use for the diagnosis or triage of cases like melanoma. However, we suggest this only as a basic tool which could be an aid to mobile teledermatology especially, in rural settings and also effective in teaching students and clinicians the basics of dermoscopy, especially in the Indian context, where dermoscopy for diagnosis and triage of melanoma is not a major need.

FFerozeeroze Kaliyadan,Kaliyadan, K.K. T.T. AAshiqueshique1 Department of Dermatology, College of Medicine, King Faisal University, Hofuf, Al-Hassa, Saudi Arabia and Amrita Figure 1: Jeweler’s loupe attached to a HTC desire HD mobile Institute of Medical Sciences and Research Centre, Elamakkara, phone with cello-tape and visualization of a melanocytic nevus Kochi, 1Consultant Dermatologist, Alshifa Hospital, with the loupe Perinthalmanna, Kerala, India

a b c Figure 2: Melanocytic nevus over the fi nger (a) viewed with a jeweler’s loupe attached to a smartphone (b) and with a standard dermoscope-DERMLITE pro HRII attached to a Sony DSC W-350 camera (c)

818 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Letters to the Editor

AAddressddress forfor correspondence:correspondence: Dr. Feroze Kaliyadan, The second case was a 42-year-old, Indian woman, Department of Dermatology, College of Medicine, King Faisal skin type IV diagnosed with melasma 14 years back. University, Saudi Arabia, E-mail: [email protected] She was treated with modified Kligman’s formula containing 2% hydroquinone, 0.025% tretinoin, RREFERENCESEFERENCES 1% hydrocortisone, sunscreens, and glycolic acid

1. Kaliyadan F. Using a simple jeweler’s loupe as a dermoscopic peels. She continued use of skin lightening agents instrument. Indian J Dermatol Venereol Leprol 2011;77:617-20. unsupervised for 13 years, and presented with 2. Kroemer S, Frühauf J, Campbell TM, Massone C, Schwantzer G, worsening of her melasma. Soyer HP, et al. Mobile teledermatology for skin tumour screening: Diagnostic accuracy of clinical and dermoscopic image tele-evaluation using cellular phones. Br J Dermatol On clinical examination, both cases revealed grayish 2011;164:973-9. brown macules with interspersed “confetti like” Access this article online hypo-pigmented macular areas on the malar region, Quick Response Code: Website: a speckled pattern of pigmentation [Figure 1a-d] www.ijdvl.com and a coarse texture with pinpoint, dark brown DOI: papules, which were more appreciable on 10.4103/0378-6323.120740 palpation [Figure 1d]. In addition, case one, revealed PMID: erythema and fine telangiectasias on bilateral malar ***** areas, whereas case two revealed mild atrophy of the malar regions and a mild bluish black hue of bilateral zygomatic regions. There was no clinical or laboratory evidence of alkaptonuria in both cases. DDermoscopicermoscopic criteriacriteria forfor 3 mm punch biopsies taken from the pinpoint ddifferentiatingifferentiating exogenousexogenous papular lesions revealed characteristic short, stout, curvilinear, “banana-shaped,” ochre-colored fibers of oochronosischronosis fromfrom melasmamelasma varying thickness in the papillary dermis [Figure 1f]. Methylene blue staining showed dark blue staining of the ochronotic fibers [Figure 1e]. There was evidence Sir, of solar elastosis in both cases. Both cases were There has been a sudden rise in the number of reported clinical stage II as per Dogliotti staging.[4] Dermoscopic cases of exogenous ochronosis (EO),[1-3] and it may not be examination of both patients in areas with melasma as uncommon as previously thought. In the early stages, without ochronosis revealed an accentuation of the it is clinically difficult to distinguish EO from melasma. normal pseudo-rete of the facial skin. In areas with A worsening of pigmentation due to EO can lead to ochronosis, greyish brown dark amorphous structures paradoxical increased application of skin lightening in the perifollicular region and some obliterating the agents, further aggravating the condition. Thus, it is follicular openings were observed. The pattern was curvilinear and “worm like” in some areas [Figure 2]. essential to distinguish early EO from melasma. The There was a clear demarcation between melasma and gold standard for diagnosis of EO is a skin biopsy. exogenouss ochronosis on dermoscopy [Figure 3a-d]. Dermoscopy may be an important tool to differentiate EO from melasma, and may assist in choosing the EO is clinically characterized by an asymptomatic appropriate site for biopsy in suspected cases. Two cases hyperchromia of the skin, usually on the sun of EO following the use of skin lightening agents for the exposed areas of the face, back, and the extensor treatment of melasma are reported and dermoscopic criteria for diagnosis are being put forward. Table 1: Clinical setting where dermoscopy should be used as a screening test A 48-year-old Indian woman, Fitzpatricks skin type IV, Patients who have history of chronic hydroquinone usage presented with erythema, and gradual deterioration Facial hyperpigmentation not responding to treatment of her melasma. She was using sunscreens and skin Facial hyperpigmentation relapsing after initial improvement lightening agents containing 2% hydroquinone in Coarse texture of the skin on palpation an unsupervised manner since 8 years. She noted Presence of fi ne telangiectasia’s worsening of her melasma since the past 3 years. Hyperchromia with “speckling” or “reticulation”

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 819 Letters to the Editor

a b

e

c d f Figure 1: (a) Ochronosis in case 1 showing grayish brown macules with interspersed “confetti like” depigmented macular areas with erythema on the cheeks. (b) Close-up view showing speckled pattern of hyperpigmentation with a coarse texture and pinpoint, dark brown papules. (c) Bluish grey to brown macules and papules with interspersed “confetti like” depigmented macular areas. (d) Tiny pinpoint caviar like brown papules with telangiectasia. (e) Methylene blue staining showing ochronotic fi bers stained dark blue. (f) Characteristic short, stout, curvilinear, “banana-shaped,” ochre-colored fi bers of varying thickness in the papillary and upper dermis

Figure 2: Dermoscopic features of ochronosis showing dark a b c d brown globules, elongated and curvilinear-worm like structures Figure 3: (a) Ochronosis. (b) Sharp contrast between ochronosis conjoined together in a reticulate pattern of ochronosis in the upper half and melasma in the lower half. (c) Areas of melasma without ochronosis, showed accentuation of the normal surfaces of the extremities. Tan et al.[5] recently pseudo-rete pattern with a diffuse brown pigmentation. (d) Normal skin reported variable clinical presentations of EO. Due to its varied presentation and striking similarity to require a high index of suspicion in order to make a melasma, especially in the early stages, clinicians diagnosis [Table 1]. An early diagnosis is important as

820 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Letters to the Editor

Table 2: Comparison of dermoscopic features of melasma and exogenous ochronosis Dermoscopic criteria Melasma Exogenous ochronosis Global features Reticular pattern-accentuation of the normal pseudo-rete Diffuse brown background with blue-gray amorphous pattern of the facial skin sparing follicles and sweat areas obliterating some follicular openings gland openings Local features Dark brown multiple granules and globules sparing the Irregular, brown-gray globular, annular, and arciform follicles structures. “Worm-like” pattern White dots may be seen worsening of pigmentation may lead to application of A clinicopathological study, diagnosis and treatment. J Eur increased concentration of hydroquinone rather than Acad Dermatol Venereol 2011;25:842-50. 2. Ribas J, Schettini AP, Cavalcante Mde S. Exogenous ochronosis terminating it immediately. hydroquinone induced: A report of four cases. An Bras Dermatol 2010;85:699-703.

[3] 3. Charlín R, Barcaui CB, Kac BK, Soares DB, Charlín et al. reported dermoscopic features of two Rabello-Fonseca R, Azulay-Abulafia L. Hydroquinone-induced patients with EO, wherein they observed blue-gray exogenous ochronosis: A report of four cases and usefulness of amorphous areas obliterating some follicular openings. dermoscopy. Int J Dermatol 2008;47:19-23. [6] 4. Dogliotti M, Leibowitz M. Granulomatous ochronosis – Gil et al. reported the dermoscopic features as A cosmetic-induced skin disorder in Blacks. S Afr Med J irregular, brown-gray, globular, annular, and arciform 1979;56:757-60. structures. This was confirmed using a reflectance 5. Tan SK. Exogenous ochronosis – A diagnostic challenge. J Cosmet Dermatol 2010;9:313-7. [7] confocal microscope. Berman et al. reported dark 6. Gil I, Segura S, Martínez-Escala E, Lloreta J, Puig S, Vélez M, et al. brown globules and globular-like structures on a Dermoscopic and reflectance confocal microscopic features of diffuse brown background, in patients having EO, exogenous ochronosis. Arch Dermatol 2010;146:1021-5. 7. Berman B, Ricotti C, Vieira M, Amini S. Differentiation of whereas those with melasma demonstrated a fine exogenous ochronosis from melasma by dermoscopy. J Am brown reticular pattern on a background of a faint Acad Dermatol. 2009;60(Suppl 1):AB2. light brown structure less area. Our dermoscopic Access this article online findings were similar to previously reported findings. Quick Response Code: Website: In addition, we observed a characteristic “worm-like” www.ijdvl.com pattern. Thus, the dermoscopic features of EO are clearly distinct from melasma [Table 2]. DOI: 10.4103/0378-6323.120741

Hence, dermoscopy can be employed as a rapid screening PMID: ***** test for EO. The clinical presence of coarse texture of the skin, fine telangiectasias and hyperchromia with “speckling” or “reticulation”[3] should alert the clinician to resort to a dermoscopic examination, particularly in LLEOPARDEOPARD ssyndromeyndrome withwith patients who are reluctant to get a facial biopsy. WWolff-Parkinson-Whiteolff-Parkinson-White ssyndromeyndrome To conclude, dermoscopy can be used as a rapid, non-invasive tool to detect EO, and may be a useful oonn eelectrocardiographylectrocardiography guide in the selection for the appropriate site for biopsy in patients with pre-existing melasma. Sir, LEOPARD syndrome (LS) is a rare complex of NNitiiti KKhunger,hunger, RRajatajat KKandhariandhari multisystemic congenital abnormalities characterized Department of Dermatology and STD, V.M. Medical College and by lentigenes, electrocardiographic (ECG) Safdarjang Hospital, New Delhi, India abnormalities, ocular hypertelorism, pulmonary AAddressddress forfor correspondence:correspondence: Dr. Niti Khunger, valvular stenosis, abnormalities of genitalia, Department of Dermatology and STD, V.M. Medical College and retardation of growth, and deafness (sensorineural). Safdarjang Hospital, New Delhi - 110 029, India. This neuro-cardio-facial-cutaneous genetic syndrome E-mail: [email protected] is mostly an autosomal-dominant disorder, caused RREFERENCESEFERENCES by germ line missense mutation in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2, 1. Tan SK. Exogenous ochronosis in ethnic Chinese Asians: located on chromosome 12q22.[1]

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A 16-year-old girl, the third child of nonconsanguineous and hormonal profile were all within the usual limits. parents, presented to us with numerous tiny Ultrasound study showed normal genitourinary hyperpigmented spots scattered over face, trunk, and system. limbs, admixed with multiple, bigger, hyperpigmented flat discrete lesions. They started appearing at the age On cutaneous examination, the girl had numerous of 6 and have been progressively increasing in number lentigines with scattered distribution over face, since then but have always remained asymptomatic chest, back, axillae, abdomen and thighs, admixed and nonremitting. She also gave history of chest with multiple discrete hyperpigmented café-au-lait deformity since birth, but denied history of any macules. Histopathological examination of the syncopal attacks, dyspnea, and cyanosis. There was suspected lentigines showed an increased number no history of deafness, abnormalities of genitalia, or of melanocytes with regular distribution of melanin secondary sexual characteristics. Her deceased father in the basal layer with elongation of rete ridges into had similar cutaneous lesions all over his trunk and the dermis, confirming the diagnosis of lentigen had died a sudden death at the age of 42, due to an simplex. unknown cause. No one else in the family, including her two siblings, is similarly affected. According to criteria proposed by Voron et al., to diagnose LS, the patient must have lentiginosis along On general examination, she was stunted for age, with a with at least two of the minor criteria, which are height of 100 cm (below 95th percentile for her age) and cardiac structural or ECG abnormalities, genitourinary had significant scoliotic deformity of thoracic spines abnormalities, endocrinal abnormalities, neurologic with winging of scapula and mild pectus excavatum. defects, cephalofacial dysmorphism, shortness of stature, skeletal abnormalities, and other cutaneous She also had ocular telorism with a broad nasal abnormalities. If lentigines are absent, three other root [Figure 1]. Clinically, cardiac examination was clinical features must be present.[3] LS is characterized unremarkable, but electrocardiogram showed left axis by highly variable phenotypic expressivity [Table 1]. deviation, shortened PR interval (106 ms), widened Other syndromes with lentigines that need to QRS interval (130 ms), with a slurred upstroke (delta be differentiated from LS are Cronkhite-Canada wave) suggestive of Wolff-Parkinson-White (WPW) syndrome, Carney complex and Bandler syndrome. syndrome, which is an anomalous accessory Noonan syndrome is another syndrome that shares connection between atria and ventricles which results many features with LS and careful differentiation in acceleration of passage of impulse from atria to between the two syndromes is important, because ventricle[2] [Figure 2]. Echocardiography showed no distinct mutations in the same PTPN11 gene has also structural or functional abnormalities. Visual and been attributed for Noonan syndrome which usually auditory brainstem response testing was normal. Her present with typical facial dysmorphism and clinical routine biochemical parameters, coagulation profile, features like short-webbed neck, cryptorchidism in

b

a c Figure 2: Electrocardiogram showing left axis deviation, shortened Figure 1: (a) A 16-year-old girl with lentiginosis on face and neck PR interval (106 ms), widened QRS interval (130 ms) with a slurred with multiple café-au-lait macules. (b) Same girl with a broad nasal upstroke (delta wave) suggestive of Wolff-Parkinson-White root and hypertelorism. (c) Shows scoliosis of thoracic and lumbar Syndrome, with nonspecifi c ST-T changes in the anteroseptal spines in the same patient and inferior leads

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Table 1: Clinical manifestations of LEOPARD syndrome in general population is estimated to be 0.15-0.25%. Cutaneous lesions: Lentiginosis (100%).[4] Whether this ECG abnormality is coincidental or part Seen in 100% of LS Café-au-lait macules (70-80%).[5] of a syndromic manifestation of single gene insult, patients.[4] that question remains to be answered and demands a Craniofacial Hypertelorism (50%).[4,5] mutation analysis. HCM, which is the most common dysmorphism: Seen in Broad nasal root.[3] 90% of LS patients.[5] Epicanthic folds.[3] structural cardiac anomaly seen in association with Triangular shape face. LS, can be a potential cause of sudden death in a few Prognathism.[3] and could be suspected as the cause of her father’s [5] Low set ears. sudden death. Left axis deviation, which is the most Ptosis.[5] High palatal arch.[3] common ECG abnormalities seen in this syndrome, Cardiac (structural Hypertrophic cardiomyopathy (HCM) has been reported in one-third of patients; the rest have abnormalities): Seen in in 70%.[5] been described as premature ventricular contractions, [5] [5] 85% of LS patients. Pulmonary stenosis in 25%. paroxysmal atrial tachycardia, shortened PR interval Aortic and mitral valve defects in isolated [3] cases.[5] among others. Atrial myxomas.[6] [6] Aneurysm of large vessels. In general, the long-term prognosis of the LS patient ECG abnormalities: Axis deviation. (33%).[3] Seen in 80% of LS Short PR interval.[3] is favorable, but patients with cardiac abnormalities patients.[4] Left ventricular hemiblock.[3] need periodic assessment because, despite cardiac Bundle-branch block.[3] involvement, most patients of LS remain asymptomatic. Complete heart block.[3] Premature ventricular contraction.[3] According to some authors, LS patients have increased Paroxysmal atrial tachycardia.[3] melanocytic activity, secondary to an abnormal Skeletal abnormalities: Short stature (42%).[4] development of neural crest cells and increased [4] Seen in 60% of LS Pectus excavatum/pectus carinatum. -adrenergic effector activity in the myocardium.[8] patients.[4] Kyphoscoliosis.[3]  Absent ribs.[3] Abnormal elbow articulation.[3] SSangitaangita Ghosh,Ghosh, SoumikSoumik ChaudhuriChaudhuri1, Cervical spine fusion.[3] Winging scapula.[3] VVijayijay KKumarumar JainJain Neurological Mental retardation (35%).[4] Departments of Skin and Veneral Diseases, and 1Medicine, abnormalities: Sensorineural hearing loss (27%).[4] Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India 27-30% of LS Nystagmus.[3] patients[3,4] Hyposmia.[3] AAddressddress forfor correspondence:correspondence: Dr. Sangita Ghosh, Seizures.[3] 42/136, New Ballygunge Road, Kolkata - 700 039, Abnormalities of EEG West Bengal, India. Genitourinary Cryptorchidism.[4] E-mail: [email protected] abnormalities: 29% of Hypospadias.[4] LS patients.[3,4] Small penis.[4] RREFERENCESEFERENCES Missing ovaries.[3,4] Unilateral ovarian hypoplasia.[3] 1. Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG. Delayed menarche. PTPN11 (Shp2) mutations in LEOPARD syndrome have Delayed puberty. dominant negative, not activating, effects. J Biol Chem Agenesis of kidney and ureter. 2006;281:6785-92. [3] Hydroureter, double ureter. 2. Sethi KK, Dhall A, Chadha DS, Garg S, Malani SK, Mathew OP. Endocrine Hypogonadotropic hypogonadism.[4] WPW and preexcitation syndromes. J Assoc Physicians India abnormalities: Hypothyroidism 2007;55:10-5. Incidence not studied Low levels of FSH, LH in female 3. Voron DA, Hatfield HH, Kalkhoff RK. Multiple lentigines patients. syndrome. Case report and review of the literature. Am J Med Delayed puberty.[3] 1976;60:447-56. ECG: Electrocardiography, EEG: Electroencephalography, FSH: Follicle- 4. Colomb D, Morel JP. Multiple lentigines syndrome. Apropos stimulating hormone, LS: LEOPARD syndrome of 2 cases. Critical study of the LEOPARD syndrome. Ann Dermatol Venereol 1984;111:371-81. 5. Sarkozy A, Digilio MC, Dallapiccola B. LEOPARD syndrome. male child, increased bleeding and bruising history, Orphanet J Rare Dis 2008;3:13. lymphatic dysplasia, motor delay, and so on would 6. Limongelli G, Pacileo G, Marino B, Digilio MC, Sarkozy A, help diagnosing Noonan over LEOPARD in a similar Elliott P, et al. Prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD [7] clinical presentation. syndrome. Am J Cardiol 2007;100:736-41. 7. Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Our patient had lentiginosis, ocular hypertelorism, Kremer H, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat short stature, scoliosis with ECG changes suggestive Genet 2001;29:465-8. of WPW syndrome. The incidence of WPW syndrome 8. Tartaglia M, Martinelli S, Stella L, Bocchinfuso G, Flex E,

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Cordeddu V, et al. Diversity and functional consequences of pathergy test was positive. Hematological examination germline and somatic PTPN11 mutations in human disease. showed leukocytosis with neutrophilia and raised Am J Hum Genet 2006;78:279-90. erythrocyte sedimentation rate (ESR). Peripheral Access this article online smear examination showed neutrophilia with Quick Response Code: Website: toxic granules. Liver and renal function tests were www.ijdvl.com normal. Antinuclear antibody (ANA), perinuclear DOI: anti-neutrophil cytoplasmic antibodies (p-ANCA), 10.4103/0378-6323.120742 and cytoplasmic-ANCA (c-ANCA) were negative;

PMID: antistreptolysin O (ASO) titer was within normal ***** range. Skin biopsies were taken during each episodes of exacerbation (a total of five biopsies during 8 years of disease course) and review of all slides consistently showed dense lymphocytic infiltrate RRecurrentecurrent lymphocyticlymphocytic Sweet’sSweet’s in the dermis [Figure 3a and b], with few areas of perivascular pattern and no basal cell degeneration. ssyndromeyndrome Immunohistochemistry showed CD3 +ve [Figure 3c], CD20 −ve cells confirming T cell lineage with no other or atypical cells. Direct immunoflourescence (DIF) Sir, did not reveal any complement or immunoglobulin Sweet’s syndrome (SS), also known as acute febrile deposits in the vessels or dermoepidermal junction. neutrophilic dermatosis or Gomm-Button disease Bone marrow aspiration studies done repeatedly were is characterized by fever; acute onset of painful, of normal cytology. erythematous or plum-colored papules, plaques or nodules; peripheral neutrophil leukocytosis; and a Chest radiogram, ultrasonographic studies of dense neutrophilic infiltrate on histology, according abdomen and pelvis, and neurological evaluation were to the classical description.[1] But rare histological unremarkable. A detailed literature search was made, presentations with lymphocytic and histiocytic and based on the aforementioned findings a diagnosis infiltrate in patients with myelodysplasia have been of recurrent lymphocyte predominant SS was made reported.[2] and the present episode was managed with systemic steroids. The lesions completely subsided and she is Here, we report a case of recurrent skin eruption presently under follow-up. resembling SS associated with dermal lymphocytic infiltrate without underlying hematological Dr. Robert Douglas Sweet first described this entity abnormality. in eight women with a “distinctive and fairly severe illness” in 1964.[3] The name Gomm-Button disease A 40-year-old female presented with recurrent referred to the initial two patients with this condition.[1] episodes of red raised tender lesions over face, neck, Histopathological description of SS is a diffuse dermal forearms, and upper back of trunk of 8 years duration. infiltrate of mature neutrophils. Several studies suggest Each episode was associated with high grade and that there may be an admixture of lymphocytes and/or continuous fever. There was no history of malar eosinophils, either of which can be prominent in some rash or arthralgia or photosensitivity. Each time she cases.[1] was treated with systemic corticosteroids, lesions responded completely, but recurred after a symptom A unique clinicopathologic subset of nine SS free interval of 6-9 months. patients has recently been recognized where clinically diagnosed SS skin lesions showed an Cutaneous examination revealed multiple plum- initial lymphocytic infiltrate in the dermis (initial colored and erythematous edematous tender plaques SS) and late neutrophilic infiltrate (late SS) of size ranging from 1 × 1.5 to 3 × 4 cm size over face, after 24-96 months. All these patients developed neck, upper chest, upper back, and bilateral forearms myelodysplastic syndrome later on.[2] Literature with some lesions showing pseudovesiculation search revealed similar reports of lymphocytic [Figures 1 and 2]. No mucosal lesions were present. infiltrate occurring 2 months to 4 years prior to Systemic examination was within normal limits. The classical neutrophilic infiltrate.[4-6]

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Figure 1 : Plum-colored plaques on posterior aspect of hand and forearm Figure 2: Plum-colored plaque on forearm in 2004

a b c Figure 3: (a) Low power views showing dense dermal lymphocytic infi ltrate (H and E, ×40). (b) High power view showing dermal lymphocytic infi ltrate (H and E, ×400). (c) Most of the cells in the infi ltrate are positive for CD3 (immunohistochemistry, ×100)

‘Histiocytoid SS’ is a recently described histological We propose that there can be an atypical lymphocytic variant of SS with infiltration of histiocyte-like cells SS with typical clinical features which may recur, into the upper dermis. These cells are considered as not associated with myelodysplasia or hematological immature myeloid cells from the bone marrow in early malignancy and need to be considered as a distinct acute stage.[7] entity. No report of such a rare presentation is available from India. In our case, the clinical presentation during each episode was typical of SS, but with dense dermal KKunnummalunnummal Muhammed,Muhammed, KhaderKhader Anza,Anza, lymphocytic infiltrate. The possibilities of Jessner’s BBetsyetsy AAmbooken,mbooken, PPuravooruravoor JayasreeJayasree lymphocytic infiltrate (JLI), polymorphic light Department of Dermatology and Venereology, Government Medical College, Calicut, Kerala, India eruption (PMLE), and lupus erythematosus (LE) were ruled out with the characteristic clinical appearance, AAddressddress forfor correspondence:correspondence: Dr. Kunnummal Muhammed, presence of fever, absence of basal cell degeneration in Kunnummal House, Koroth School Road, Vatakara, Calicut - 673 101, Kerala, India. biopsy, and negative DIF. The bone marrow cytology E-mail: [email protected] was normal repeatedly. Unlike the previous reports, in our case there was no evidence of myelodysplasia RREFERENCESEFERENCES or hematological malignancy or other systemic 1. Cox NH, Jorizzo JL, Bourke JF, Savage CO. Vasculitis, illnesses even after detailed evaluation and the dermal neutrophilic dermatoses and related disorders. In: Burns T, infiltrate has remained lymphocytic for 8 years. The Breathnack S, Cox N, Griffiths C, editors. Rook's Textbook of Dermatology. 8th ed. Oxford: Blackwell Publishing; 2010. presence of neutrophils in the dermis might herald an p. 50.74-50.80. underlying malignant transformation and persistence 2. Vignon-Pennamen MD, Juilard C, Rybojad M, Wallach M, Daniel MT, Morel P, et al. Chronic recurrent lymphocytic of lymphocytes for years point to a benign nature of sweet’s syndrome as a predictive marker of myelodysplasia: disease. A report of 9 cases. Arch Dermatol 2006;142:1170-6.

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3. Sweet RD. An acute febrile neutrophilic dermatosis. Br J over denture can be given.[3] We hereby, describe the Dermatol 1964;76:349-56. oral management of a female child with HED using the 4. Wawrzycki B, Chodorowska S, Pietrzak A, Krasowska DW, Wasik S, Dyblec E, et al. Recurrent skin eruption in patient with flexible over denture. chronic lymphocytic leukemia and lymphocytic infiltrates of the dermis resembling Sweet’s syndrome. G Ital Dermatol Venereol 2011;146:487-92. A 7-year-old girl with HED reported with the 5. Evans AV, Sabroe RA, Liddell K, Russell-Jones R. Lymphocytic complaint of inability to masticate, unesthetic infiltrates as a presenting feature of Sweet’s syndrome with appearance and teasing from her peer group. Patient myelodysplasia and response to cyclophosphomide. Br J Dermatol 2002;146:1087-90. gave a history of decreased sweating, dry oral 6. Boeckler P, Noacco G, Maradeix S, Heid E, Lipsker D, Cribier B. mucosa and skin and raised body temperature. She Lymphocytic infiltrate of the dermis preceding typical Sweet’s was born of a normal delivery and her psychomotor syndrome. Ann Dermatol Venereol 2007;134:559-63. 7. Haung CF, Wu BY, Liaw FY, Wang WM, Chiag CP. Histiocytoid development was normal. Patient’s family history Sweet syndrome: Report of two cases and review of the revealed that the mother’s cousin brothers had similar literature. Dermatol Sin 2012;30:71-4. problems. Intra-oral examination revealed dry oral Access this article online mucosa, conical shaped teeth, oligodontia and thin

Quick Response Code: Website: alveolar ridges [Figure 1]. Extra-oral examination www.ijdvl.com showed sparse hair, frontal bossing, depressed nasal bridge, sunken cheeks and everted lips [Figure 1]. DOI: 10.4103/0378-6323.120743 Nails appeared normal. Systemic examinations were within the normal limit. Based on history and PMID: ***** clinical examination a diagnosis of HED was made. At the age of 7 years, skeletal maturity is incomplete hence flexible removable over dentures were given to reestablish occlusion, mastication, speech and FFunctionalunctional estheticesthetic rrehabilitationehabilitation esthetic [Figure 2]. Primary impressions of both jaws were made with irreversible hydrocolloid impression ooff a 77-year-female-year-female ppatientatient wwithith material. Custom trays were prepared and border molding was carried out with a heavy body polyvinyl hhereditaryereditary ectodermalectodermal dysplasiadysplasia siloxane material. The final impressions were made uusingsing fl eexiblexible ddentureenture with medium and light body type of rubber base impression material. Maxillo-mandibular relation was recorded and teeth were arranged according to a Sir, balanced occlusal scheme. Maxillary and mandibular Hypohidrotic ectodermal dysplasia (HED) is a prostheses were fabricated in Valplast resin by congenital syndrome characterized by sparse hair, injection molding technique. Prior to insertion, the oligodontia and reduced sweating.[1] It is caused valplast partial denture was immersed for a minute by mutation in the ectodysplasin A gene, which is in warm water. The heat exposure assures a very inherited as X linked recessive pattern. However, smooth initial insertion and allows the denture to less commonly HED is also caused by mutation in adapt to the underlying tissue. The dentures were ectodysplasin-A receptor or EDARADD gene, which then inserted in patient’s mouth [Figure 2]. Patient has an autosomal dominant or autosomal recessive was educated about proper insertion, removal and pattern of inheritance.[2,3] Expression of symptoms are hygiene of the over denture. Future visits were fully blown in affected males, but females are usually scheduled for 6 months to monitor bone growth and carrier.[2,3] Dental manifestations include conical for denture relining. or pegged shaped teeth, hypodontia or complete anodontia, delayed eruption of permanent teeth, thin Oral care: As there are many oral manifestations, alveolus ridge and dry oral mucous membrane.[1] there is no standard formula for dental treatment. Children with HED have problems with mastication, Treatment needs may include: Preventive measures speech, esthetic and psychology: Affecting their quality against caries, restorations of decayed teeth, partial of life.[1] To restore the lost functions and to improve dentures, over dentures, implant supported denture self-confidence removable partial denture, complete and timely orthodontic care. In the present case, the denture, implant supported complete denture and child was given flexible removable partial denture.

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a b

Figure 1: (a) Intra-oral photograph showing oligodontia and cone shaped teeth. (b) Clinical photograph showing dysmorphic facial features

The advantage of flexible partial denture: Improved Figure 2: Extra-oral photograph showing denture in place esthetic, exceptionally strong and flexible, good biocompatibility, free from an allergic reaction, does Individuals are advised to take frequent sip of water not irritate the oral mucosa and satisfy daily diet for through the day. the child.[4] Implant supported complete denture is avoided until adolescence because of increased risk RRiteshitesh KKalaskar,alaskar, AAshitashita KKalaskaralaskar1 of implant failure due to insufficient alveolar bone Departments of Pedodontics, Government Dental College and support. Secondly, there is a risk of trauma to tooth Hospital, 1Oral Medicine and Radiology, VSPM Dental College and germs and interferences in craniofacial growth.[5] Research Centre, Nagpur, Maharashtra, India

AAddressddress forfor correspondence:correspondence: Dr. Ritesh Kalaskar, Orthodontic care is one of the major concerns of Plot No. 68, Banerjee Layout, Bhagwan Nagar Road, families with children affected with HED. Because Nagpur - 440 027, Maharashtra, India. early orthodontic care in such children not only E-mail: [email protected] improves alignment of permanent teeth, but also RREFERENCESEFERENCES improves facial profile and prevent psychological trauma associated with this condition. Orthodontic 1. Bashyam MD, Chaudhary AK, Reddy EC, Reddy V, Acharya V, treatment using flexible dentures can enhance growth Nagarajaram HA, et al. A founder ectodysplasin A receptor (EDAR) mutation results in a high frequency of the autosomal process, maintain favorable maxillomandibular recessive form of hypohidrotic ectodermal dysplasia in India. relations and provide a permanent base for prosthetic Br J Dermatol 2012;166:819-29. 2. Cluzeau C, Hadj-Rabia S, Jambou M, Mansour S, Guigue P, rehabilitation. This type of combination treatment Masmoudi S, et al. Only four genes (EDA1, EDAR, EDARADD, ultimately benefits stomatognathic function, vertical and WNT10A) account for 90% of hypohidrotic/anhidrotic growth and enhance the facial appearance and ectodermal dysplasia cases. Hum Mutat 2011;32:70-2. 3. NaBadalung DP. Prosthodontic rehabilitation of an anhidrotic profile. In a recent case, authors have incorporated ectodermal dysplasia patient: A clinical report. J Prosthet Dent midline jackscrew in removing partial denture 1999;81:499-502. to enhance transverse growth and closure of 4. Aswegan AL, Josephson KD, Mowbray R, Pauli RM, Spritz RA, Williams MS. Autosomal dominant hypohidrotic ectodermal [5] midline diastema. However, combine delivery of dysplasia in a large family. Am J Med Genet 1997;72:462-7. orthodontic and prosthodontic treatment can lead 5. Ioannidou-Marathiotou I, Kotsiomiti E, Gioka C. The contribution of orthodontics to the prosthodontic treatment of to design compromise leading to compromised ectodermal dysplasia: A long-term clinical report. J Am Dent functional stability. Therefore, such patients require Assoc 2010;141:1340-5. close attention and require frequent replacement of Access this article online prosthesis. Quick Response Code: Website: www.ijdvl.com Patient and parents should be made aware of the importance of denture hygiene maintenance, use DOI: 10.4103/0378-6323.120744 of fluoride mouth rinses, application of lubricant to avoid drying, cracking of the oral mucosa and periodic PMID: ***** modification in dentures due to growth changes.

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 827 Letters to the Editor

CCutaneousutaneous metastasismetastasis ofof anan 5 mm to 1 cm presenting over the suprapubic region, left inguinal region and inner aspect of left aadvanceddvanced prostateprostate cancercancer thigh [Figure 1]. These lesions were non-tender, firm in consistency and fixed to the overlying skin, but not to the underlying structures. Scrotum was normal, but Sir, penis was thick, edematous infiltrated and deformed Primary visceral malignancies uncommonly present in shape. Rest of the mucocutaneous examination was with skin involvement with a reported incidence unremarkable. Systemic examination of the patient between 2% and 9% and their presence is indicative was also normal. of an advanced disease and poor prognosis. The most common tumors to metastasize to skin are breast, lung, Routine investigations showed a hemoglobin of [1] colorectal, renal and ovarian carcinomas. Despite 7.8 g/dl and increased liver enzymes (serum glutamic the high incidence of prostatic cancer, cutaneous and oxaloacetic transaminase and serum glutamic pyruvic subcutaneous metastases of this cancer are extremely transaminase). Fine needle aspiration cytology rare, seen in <1% cases. We report a case of an elderly revealed adenocarcinomatous cells of uncertain male with carcinoma of the prostate with multiple origin. Excisional biopsy of one of the papules cutaneous metastases. revealed stratified squamous epidermis on the surface, with rows and prostate acini-like glandular structures A 70-year-old man presented with 1 month history of appearing due to the ectatic lymphatic spaces due to multiple skin colored to erythematous papulonodular the lymphangiectasia secondary to metastasis blocking lesions variable in size over the pubic region and lymphatics [Figure 2]. PSA level was also elevated. inner aspects of thigh. These lesions first appeared over the suprapubic area and progressively increased Radiographs of pelvis revealed diffuse osteosclerotic in size and involved inner aspects of thighs and left lesions. Chest radiograph as well as ultrasound inguinal region. These lesions were associated with abdomen were normal. Patient was subjected to discomfort, but were not associated with ulceration palliative care with radiotherapy to the pelvic bones. and bleeding. About a year back, he had presented to the emergency department with urinary retention. He Cutaneous metastases from internal malignancies was diagnosed to have carcinoma of the prostate and are relatively rare, seen in about 2-9% of his prostate-specific antigen (PSA) level was found to malignancies.[2] Cutaneous metastases occur more be 210 ng/ml. commonly with mammary, pulmonary, renal and colonic cancers and are seen in the advanced stage Transrectal ultrasound guided biopsy was carried of malignancy, associated with a poor prognosis. out, which revealed poorly differentiated prostatic Although carcinoma of the prostate is common, it is adenocarcinoma with a Gleason score of 9 in all the responsible for lesser than 1% of cutaneous metastases. 8 core biopsies performed. There was no perineural invasion or extraglandular extension. A staging bone Cutaneous metastases from prostatic carcinoma are scan was performed at the time of diagnosis, which usually asymptomatic and may occur at single or did not show any evidence of bony involvement. multiple sites.[3] The most common sites involved are the lower abdomen, genitalia and thighs.[4] Metastatic Patient underwent a complete androgen blockade with lesions are usually papules and nodules and they rarely Buserelin and Cyproterone acetate. Almost 1 year after ulcerate. They may have a zosteriform distribution the diagnosis, patient noted development of cutaneous or may appear as sclerodermoid lesions. Other rare lesions at the pubic region. These lesions were considered manifestations include priapism, penile metastasis, to be cutaneous metastases from the prostatic cancer. gynecomastia and breast metastasis. Skin metastases Patient also complained of multiple bone pains, loss of from prostatic cancer are an ominous finding and most weight and appetite. Repeat bone scan revealed multiple of the patients die within 6 months. metastatic lesions of pelvic bones. Although the mechanism of cutaneous involvement Cutaneous examination revealed multiple is not well-understood, suggested routes include erythematous dome shaped papueonodular lesions, embolization of vessels, dissemination through with a smooth shiny surface, varying in size from lymphatics and through perineural lymphatics.

828 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Letters to the Editor

Figure 1: Multiple erythematous dome shaped papulonodular Figure 2: Histopathological image of one of the papules revealing lesions, ranging in size from 5 mm to 1 cm prostate acini-like glandular structures appearing due to ectatic lymphatic spaces due to lymphangiectasia secondary to metastasis blocking lymphatics (H and E, ×40) Immunohistochemistry is an important tool in establishing organ of origin when histology is not conclusive.[5] A large majority of metastatic J Cutan Pathol 2004;31:419-30. 6. Sheridan T, Herawi M, Epstein JI, Illei PB. The role of P501S adenocarcinomas are P501S positive (99%). A small and PSA in the diagnosis of metastatic adenocarcinoma of the subset of metastatic prostatic adenocarcinoma shows prostate. Am J Surg Pathol 2007;31:1351-5. significant differences in staining intensity and extent Access this article online of PSA and P501S and therefore combined use of Quick Response Code: Website: these markers may result in increased sensitivity for www.ijdvl.com [6] detecting prostatic origin. Cutaneous metastases DOI: from a prostatic carcinoma signifies an advanced stage, 10.4103/0378-6323.120745 aggressive behavior and a grave prognosis, with disease PMID: specific survival lesser than 6 months. Thus, the ***** treatment at this stage is palliative care, which includes keeping the lesions dry and clean. Debridement is a good option for bleeding or crusting lesions. PPsoriaticsoriatic pplaqueslaques withwith MMohammadohammad AbidAbid Keen,Keen, IffatIffat HassanHassan Department of Dermatology, STD and Leprosy, lleukotrichia:eukotrichia: A nnovelovel oobservationbservation Government Medical College and Associated SMHS Hospital, Srinagar, Kashmir (J and K), India Sir, AAddressddress forfor correspondence:correspondence: Dr. Mohammad Abid Keen, Hair is an important skin appendage as changes in Iqbal Abad, KP Road, Near Masjid Usman, Anantnag - 192 101, Kashmir, India. hair color, volume and texture may be an indicator E-mail: [email protected] to many dermatological conditions. The myriad of RREFERENCESEFERENCES hair colors include shades of grey, yellow, brown, red and black, produced by combinations of two primary 1. Krathen RA, Orengo IF, Rosen T. Cutaneous metastasis: pigments, eumelanin and pheomelanin, in varying A meta-analysis of data. South Med J 2003;96:164-7. proportions. These pigments are derived from 2. Spencer PS, Helm TN. Skin metastases in cancer patients. Cutis 1987;39:119-21. melanocytes of the upper root of the hair bulb, which 3. Steinkraus V, Lange T, Abeck D, Mensing H, Ring J. Cutaneous imparts color to the hair cortex during the anagen metastases from carcinoma of the prostate. J Am Acad Dermatol phase of the hair cycle. 1995;32:665-6. 4. Jones C, Rosen T. Multiple red nodules on lower abdomen. Metastatic carcinoma of the prostate. Arch Dermatol The population density of melanocytes in the hair bulb 1992;128:1532, 1535. 5. Saeed S, Keehn CA, Morgan MB. Cutaneous metastasis: is much greater than in the epidermis (approximately A clinical, pathological, and immunohistochemical appraisal. one melanocyte to four basal keratinocytes in the

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 829 Letters to the Editor upper hair bulb compared with a ratio of 1:25 in which the psoriatic plaques improved but the hair color the basal layer of the epidermis).[1] Leukotrichia, remained unchanged. meaning “white hair”, is caused by a variety of genetic and acquired disorders culminating Psoriasis is a chronic, recurrent, T cell mediated in the loss of these hair bulb melanocytes. The disorder of keratinization; characterized by red, scaly, dermatological conditions usually associated sharply demarcated, indurated plaques particularly with leukotrichia include vitiligo, alopecia areata, affecting the extensors. The underlying mechanism Vogt-Koyanagi-Harada syndrome, Allezandrini is still debatable; though most of the recent literature syndrome, Piebaldism, Waardenburg syndrome, points to an immune mediated mechanism, implicating Tuberous sclerosis etc.[1] However, leukotrichia has Th17-type helper T cell.[2] never been reported on psoriatic plaques unless as a part of co-localized vitiligo. Several studies and case reports have documented the coexistence and co-localization of psoriasis and We present a case of 45-year-old, HIV negative male vitiligo.[3] Koebner’s phenomenon is common to both with generalized stable plaque psoriasis. the disorders.

The patient presented in dermatology OPD with history Increased level of tumor necrosis factor alpha (TNF-) of red, raised, scaly lesions all over the body for the has been demonstrated in both psoriatic plaques and last 15 years. He reported that the hair over the lesions perilesional skin of vitiligo patients. Even if we try to was initially black but five years ago, turned white explain the presence of white hair over the psoriatic rapidly over a span of three months. On examination, plaques through a similar mechanism, the selective well demarcated, variable sized, erythematous, destruction of follicular melanocytes with sparing of raised, indurated scaly plaques with leukotrichia epidermal melanocytes poses a mystery which is hard strictly restricted to the plaques were present over the to solve. The fact, that ‘follicular-melanin unit’ resides extremities. Hairs elsewhere were black [Figure 1]. in the immune privileged proximal anagen hair bulb,[4] Grattage test and Auspitz sign were positive. Skin biopsy makes this observation even more intriguing. Selective revealed hyperkeratosis, parakeratosis, suprapapillary loss of follicular melanocytes without concomitant thinning and elongation of rete ridges, which favored the destruction of epidermal melanocytes has only clinical diagnosis of psoriasis [Figure 2a]. Staining with been noticed in acute alopecia areata in which the HMB (Human melanin black) - 45 revealed scattered inflammation is concentrated in and around the bulbar melanocytes in the basal layer [Figure 2b and c]; this region of anagen hair follicles[5] ruled out co-localized vitiligo. Melanocytes were conspicuously absent from the hair follicles [Figure 2c Follicular pigmentation is governed by numerous intrinsic and d]. Methotrexate was started after routine hematological and biochemical investigations, following

a b a

c d Figure 2: (a) (H and E, ×40) - Hyperkeratosis, parakeratosis, suprapapillary thinning and elongation of rete ridges. c b (b-d) (HMB45 stain, ×100) - Presence of melanocytes in basal Figure 1: (a-c) Psoriatic plaques with white hair and surrounding layer of epidermis (2b, 2c) and absence of melanocytes in the black hair hair follicle (c and d)

830 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Letters to the Editor and extrinsic factors including hair cycle-dependent Access this article online changes, racial and gender differences, environmental Quick Response Code: Website: influences, genetic defects and age-associated changes. www.ijdvl.com Recently, there has been tremendous research DOI: to elucidate mechanisms of age related selective 10.4103/0378-6323.120746 destruction of follicular melanocytes, evidenced by graying of hair with sparing of epidermal melanocytes. PMID: ***** It has been observed that the follicular-melanin unit of greying hair is associated with increased melanocyte apoptosis and oxidative stress, which could be the result of impaired antioxidant mechanisms.[6] A similar free radical injury can possibly explain our finding of CCutaneousutaneous TT-cell-cell nnonon HHodgkinodgkin white hair in the psoriatic plaques, since psoriasis is an inflammatory disorder with increased cell turnover. llymphomaymphoma iinn a ppatientatient wwithith However, the fact that this observation has never been iidiopathicdiopathic CD4+CD4+ lymphocytopenialymphocytopenia reported previously in psoriasis, which is a relatively common disease, remains an enigma. Sir, Thus, this case is unique as the current knowledge Idiopathic CD4+ lymphocytopenia (ICL) is a rare of the pathogenesis of psoriasis fails to explain heterogenous condition, often detected in middle age, leukotrichia restricted to psoriatic plaques. Whether following the occurrence of an opportunistic infection this novel finding signifies any change in prognosis or in a person without known immunodeficiency or course of the disease in the relevant patient can only immunosuppression.[1] Here we report, a patient with be explained with advanced molecular and further ICL who presented with recurrent furuncles and who observational studies. subsequently developed cutaneous T-cell non-Hodgkin lymphoma (T-cell NHL). NNidhiidhi Jindal,Jindal, RichaRicha JindalJindal1, BBrahmitarahmita MMonga,onga, SSunitaunita SSinghingh2 A 33-year-old man attended the out-patient-department Departments of Skin and VD, and 2Pathology, PGIMS, Rohtak, of our hospital with an 8 month history of recurrent 1 Haryana, Pathology, St. Stephen Hospital, New Delhi, India furuncles distributed over scalp, lower limbs, and back

AAddressddress forfor correspondence:correspondence: Dr. Brahmita Monga, of trunk. His past medical history was insignificant and H-171, Ashok Vihar, Haryana - 110 052, Delhi, India. he was not on any drugs. Swab culture from furuncles E-mail: [email protected] confirmed staphylococcal infection. RREFERENCESEFERENCES A detailed evaluation for any underlying 1. Messenger AG, Berker DA, Sinclair RD. Disorders of hair. In: immunosuppression including a complete hemogram, Burns T, Breathnach S, Cox N, Griffiths C, editors. Rook’s liver, and renal function tests, random blood sugar, Textbook of Dermatology, 8th ed. West Sussex: Wiley Blackwell; 2010. p. 66.90-66.93. serum immunoglobulins, chest X-ray, and peripheral 2. Sabat R, Philipp S, Höflich C, Kreutzer S, Wallace E, smear were within normal limits. Serology for Asadullah K, et al. Immunopathogenesis of psoriasis. Exp Dermatol 2007;16:779-98. p24 antigen, HIV 1 and 2 and human T cell leukemia 3. Inamadar AC, Sampagavi VV, Athanikar SB, Patil MN, virus (HTLV) 1 and 2 antibodies, venereal diesease Deshmukh NS. Vitiligo and psoriasis: Coexistence with research laboratory (VDRL) test, hepatitis B antigen colocalization. Indian J Dermatol Venereol Leprol 2001;67:214-5. 4. Christoph T, Müller-Röver S, Audring H, Tobin DJ, Hermes B, (HBsAg), Anti HCV (hepatitis C virus) antibody Cotsarelis G, et al. The human hair follicle immune system: and antinuclear antibody were also negative. A low Cellular composition and immune privilege. Br J Dermatol CD4+ T-cell count of 186 cells/mm3 was the only 2000;142:862-73. 5. Messenger AG, Berker DA, Sinclair RD. Disorders of hair. In: abnormal finding. This can be a transient, non-specific Burns T, Breathnach S, Cox N, Griffiths C, editors. Rook’s observation in an infection and he was treated with th Textbook of Dermatology, 8 ed. West Sussex: Wiley Blackwell; appropriate antibiotics.[2] 2010. p. 66.33. 6. Arck PC, Overall R, Spatz K, Liezman C, Handjiski B, Klapp BF, et al. Towards a “free radical theory of graying”: Patient was re-evaluated after 3 months and his Melanocyte apoptosis in the aging human hair follicle is an indicator of oxidative stress induced tissue damage. FASEB skin lesions had all subsided, but the CD4 count J 2006;20:1567-9. was still low at 180 cells/mm3. A repeat clinical and

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 831 Letters to the Editor laboratory work up failed to detect any cause for infection. (3) Absence of any defined immunodeficiency the persistent lymphocytopenia. Hence, we arrived or therapy that can depress CD4 count.[3] at the final diagnosis of ICL.[3] As the cluster of differentiation (CD) 4 count was below 200, he was Various theories put forth to explain the etiology prescribed cotrimoxazole prophylaxis and was urged of ICL include diminished production of T cell to be under regular follow-up. precursors, accelerated T-cell apoptosis, biochemical failure of the CD3-T cell receptor pathway, defective He returned 1 year later with pruritic, infiltrated generation of tumour necrosis factor (TNF)- and papules, and plaques all over the body and significantly interferon (IFN)- and antibodies against CD4+ enlarged cervical, axillary, and inguinal lymph T cells.[3] Clinical picture varies from an asymptomatic nodes [Figure 1a]. CD4 count was 178 cells/mm3. laboratory abnormality to life threatening Again there was no evidence of retroviral infection. complications such as opportunistic infections and Ultrasound abdomen revealed hepatosplenomegaly neoplasms.[1] It is documented in one series that, and retroperitoneal lymphadenopathy. Biopsy from in about one fifth of patients, lymphocytopenia an enlarged cervical node showed loss of normal resolved within 3 years of diagnosis whereas in the architecture with moderate to marked infiltrate majority, most serious complications developed of atypical lymphocytes. Histology [Figure 1b] during the first 2 years of diagnosis.[1] Our patient of the skin lesions revealed dermal infiltrate of manifested T-cell NHL 1 year after the confirmation atypical lymphocytes without epidermotropism. of ICL. On immunohistochemistry, the tumour cells were CD3 +ve [Figure 2a], CD4 +ve [Figure 2b], Previous reports point to a predominance of CD8+ve [Figure 2c] and CD20–ve [Figure 2d] Burkitt’s and other B-cell lymphomas in ICL, but pointing to a diagnosis of cutaneous T-cell NHL. our patient developed T-cell NHL, which is a rare The patient was referred to Hemato-Oncology occurrence.[3,4] A T-cell lymphoma in the setting of Department, chemotherapy was initiated, but while CD4+ lymphocytopenia is hard to explain. A pathogen on chemotherapy he developed septicemia and specific, immune response driven, CD4+ T-cell succumbed to death. activation and turn-over is proposed to be the root cause of lymphocytopenia in ICL.[1] This constant CDC defined ICL in 1992 as (1) CD4+ T-lymphocyte activation may precipitate the monoclonal expansion level <300 cells/mm3 or <20% of total lymphocytes, of atypical cells in the remaining T-cell population. at a minimum of two separate time points, at least On searching the literature, we came across only one 6 weeks apart. (2) No serological evidence of HIV more instance of T-cell neoplasm in ICL and this was reported by Moradi et al. (angiocentric nasal T-cell lymphoma) in a 13-year-old boy.[5]

Current recommendations (including cotrimoxazole

a b

a b c Figure 1: (a) Enlarged cervical lymph node and infi ltrated skin d lesions. (b) Skin biopsy from the infi ltrated plaque showing dermal Figure 2: (a) Dermal infiltrate showing CD3 positivity infi ltrate of atypical cells without epidermotropism (H and E, ×100). (Immunohistochemistry, ×400). (b) Dermal infi ltrate showing Inset: High power view of the same showing dermal infi ltrate CD4 positivity (Immunohistochemistry, ×400). (c) Dermal infi ltrate composed of atypical cells with irregular outline, scanty cytoplasm showing CD8 positivity (Immunohistochemistry, ×100). (d) Dermal and hyperchromatic nuclei (H and E, ×400) infi ltrate showing CD20 negativity (Immunohistochemistry, ×100)

832 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Letters to the Editor prophylaxis) for the treatment of ICL are based mainly A ccasease ooff llinearinear iimmunoglobulinmmunoglobulin on the experience with HIV patients.[1] IFN- has been tried to boost the depressed CD4 levels.[3] a ddiseaseisease withwith dapsonedapsone hhypersensitivityypersensitivity andand itsits We report this case to stress the need to consider ICL, in any patient (with no known immunodeficiency) mmanagementanagement strategiesstrategies presenting with opportunistic infections. Had it not been diagnosed earlier, lymphocytopenia in our patient would have been attributed to the lymphoma. Sir, Meticulous documentation and analysis of the clinical Linear immunoglobulin A (IgA) disease is a rare features and disease progression in those affected, acquired autoimmune subepidermal vesiculobullous may help us to improve the diagnostic definition and disorder with an estimated prevalence of 0.5 per treatment options for this rare condition. 1,000,000 adults.[1] Drugs and infections have been reported to be associated.[2] We herein report a patient AACKNOWLEDGMENTSCKNOWLEDGMENTS of severe linear IgA disease with unusual therapeutic challenges. We express our sincere gratitude to Dr. Sunitha Balakrishnan, Asst. Professor, Department of Pathology A 27-year-old lady presented with fever of 7 days for the help in analysing the histopathology specimens. duration, followed 2 days later by multiple painful fluid-filled lesions over body. Dermatological NNajeebaajeeba Riyaz,Riyaz, SaritaSarita Sasidharanpillai,Sasidharanpillai, examination revealed multiple polysized, discrete AAnzanza KKhader,hader, JayasreeJayasree PuravoorPuravoor to confluent crusted plaques with vesicles along Department of Dermatology and Venereology, margins in generalized distribution (cluster of jewel Government Medical College, Kozhikode, Kerala, India appearance) [Figure 1]. Multiple hypopigmented macules and pustules were also present. Bulla spread AAddressddress forfor correspondence:correspondence: Dr. Sarita Sasidharanpillai, ‘Rohini’, Girish Nagar, Nallalom PO, Kozhikode - 673 027, and Nikolsky’s signs were negative. There was no Kerala, India. mucosal involvement. Clinical differential diagnosis E-mail: [email protected] of subcorneal pustular dermatosis, linear IgA disease, RREFERENCESEFERENCES and bullous pemphigoid was offered.

1. Zonios DI, Falloon J, Bennett JE, Shaw PA, Chaitt D, Baseler MW, Initial skin biopsy revealed subepidermal bulla with et al. Idiopathic CD4+ lymphocytopenia: Natural history and a neutrophilic infiltrate in the dermis [Figure 2]. prognostic factors. Blood 2008;112:287-94. 2. Laurence J. T-cell subsets in health, infectious disease, and Direct immunofluorescence showed deposition of idiopathic CD4+ T lymphocytopenia. Ann Intern Med IgA linearly along basement membrane. Patient was 1993;119:55-62. diagnosed as a case of linear IgA disease and was 3. Luo L, Li T. Idiopathic CD4 lymphocytopenia and opportunistic infection – An update. FEMS Immunol Med Microbiol started on oral dapsone 100 mg once daily. The lesions 2008;54:283-9. showed gradual resolution over 4 weeks. 4. Hanamura I, Wakita A, Harada S, Tsuboi K, Komatsu H, Banno S, et al. Idiopathic CD4+ T-lymphocytopenia in a non-Hodgkin’s lymphoma patient. Intern Med 1997;36:643-6. However after 4 weeks, patient reported back with 5. Moradi S, Chavoshzadeh Z, Izadyar M, Mahjoub F, Rezaei N. fever and extensive redness and scaling over body. Angiocentric nasal T-cell lymphoma in a patient withidiopathic On examination, patient was febrile, had icterus, CD4+ lymphocytopenia. Iran J Allergy Asthma Immunol 2009;8:215-8. and an extensive erythematous maculopapular rash. Investigations revealed serum bilirubin of 3.3 mg/dL, Access this article online alanine aminotransferase levels of 162 IU/L, and aspartate Quick Response Code: Website: aminotransferase levels of 92 IU/L with absolute www.ijdvl.com eosinophil count of 1383 cells/cm. Ultrasound abdomen DOI: revealed hepatosplenomegaly. Patient was diagnosed 10.4103/0378-6323.120748 to have dapsone-induced hypersensitivity syndrome PMID: and dapsone was stopped. Patient was started on oral ***** prednisolone 60 mg and colchicine 0.5 mg thrice daily.

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 833 Letters to the Editor

Figure 1: Annular skin lesions with vesicles on margins giving a cluster of jewels appearance Figure 2: Histopathology revealing classical subepidermal bulla with neutrophilic infi ltrate. ×40 (H and E, ×40)

In spite of this therapy, after 7 days, the bullous lesions heterogeneous and can mimic other blistering diseases relapsed and serum bilirubin levels began to rise. such as dermatitis herpetiformis, bullous pemphigoid, With two different problems of linear IgA dermatosis pemphigus vulgaris, epidermolysis bullosa acquisita, and dapsone hypersensitivity syndrome, intravenous and also other groups of disorders like erythema pulse methylprednisolone 1 g for 3 consecutive days multiforme, toxic epidermal necrolysis, systemic lupus was administered. The patient started improving on erythematosus, and erythema annulare centrifugum.[3] the 2nd day of pulse therapy. She was restarted on Linear IgA disease is a chronic relapsing condition with oral prednisolone 60 mg after completion of the pulse mild cutaneous manifestations usually. Our patient had therapy and colchicine was continued. very severe cutaneous involvement without mucosal involvement which is not seen very commonly. Two weeks later, patient developed multiple furuncles over the extremities. There was no evidence of any Dapsone is the most effective drug in managing immunosuppression in the form of diabetes, human this condition with excellent initial responses and immunodeficiency virus infection, or any other long-term remissions being reported.[4] Colchicine, associated disorders. The patient was started on thalidomide, cyclosporine, niacinamide, antibiotics oral linezolid 600 mg twice daily, prednisolone was like sulfonamides and amoxicillin are also reported tapered by 10 mg every 2 weeks, and colchicine was to be effective.[5] Oral steroids have been combined continued. The furuncles regressed in duration of one with dapsone for better results in recalcitrant cases. week. When tapering of oral prednisolone had reached However, use of pulsed steroids in heavy intravenous 20 mg after 4 weeks, patient again started developing doses has not been described previously. Dapsone multiple fluid-filled lesions over extremities similar hypersensitivity syndrome being concomitantly to the initial episode. Repeat skin biopsy and direct managed with severe linear IgA disease is another immunofluorescence showed typical features of linear therapeutic challenge not faced very often. IgA dermatoses and patient was restarted on full dose of prednisolone 60 mg and colchicine was stopped. Herein, we had a patient of severe cutaneous linear The skin lesions gradually started resolving and liver IgA disease who had various therapeutic challenges function tests also became normal after 8 weeks. The in the form of dapsone hypersensitivity syndrome steroids were continued with progressively tapering and nonresponse to colchicine. She was in the doses for a total duration of further 12 weeks after reproductive age group and hence thalidomide was which all the skin lesions resolved, not leaving contraindicated. Corticosteroids seemed to be any trace of pigmentation or scars. The patient has the only panacea whenever she got into trouble presently been followed-up for 6 months during which and even pulsed steroids had to be given. Such she has had no recurrence. unusual therapeutic requirements in a case of linear IgA disease have rarely been mentioned in The clinical presentation of linear IgA disease can be literature.

834 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Letters to the Editor

RRajeshajesh Verma,Verma, BijuBiju Vasudevan,Vasudevan, AmitabhAmitabh Sagar,Sagar, 3. Dippel E, Orfanos CE, Zouboulis C. Linear IgA dermatosis presenting with erythema annulare centrifugum lesions: VVijendranijendran Pragasam,Pragasam, PrabalPrabal Deb,Deb, Report of three cases in adults. J Eur Acad Dermatol Venereol GGyaltshenyaltshen CChodenhoden 2001;15:167-70. Departments of Dermatology, Command Hospital, Wanowrie, Pune, 4. Alajlan A, Al-Khawajah M, Al-Sheikh O, Al-Saif F, Al-Rasheed S, Maharashtra, India Al-Hoqail I, et al. Treatment of linear IgA bullous dermatosis of childhood with flucloxacillin. J Am Acad Dermatol 2006;54:652-6. AAddressddress forfor correspondence:correspondence: Dr. Biju Vasudevan, 5. Madnani NA, Khan KJ. Linear IgA bullous dermatosis of Department of Dermatology, Command Hospital (Southern childhood: Response to thalidomide. Indian J Dermatol Command), Wanowrie, Pune - 411 040, Maharashtra, India. Venereol Leprol 2010;76:427-9. E-mail: [email protected] Access this article online RREFERENCESEFERENCES Quick Response Code: Website: 1. Zillikens D, Wever S, Roth A, Weidenthaler-Barth B, www.ijdvl.com Hashimoto T, Brocker EB. Incidence of autoimmune DOI: subepidermal blistering dermatoses in a region of central 10.4103/0378-6323.120750 Germany. Arch Dermatol 1995;131:957-8. 2. Jheng-Wei L, Yi-Chin S, Wen-Hung C. Vancomycin-induced PMID: linear IgA bullous dermatosis mimicking toxic epidermal ***** necrolysis. Indian J Dermatol Venereol Leprol 2011;77:537.

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 835 Resident’s PPatchatch ttestingesting iinn ccutaneousutaneous aadversedverse drugdrug reactions:reactions: Page MMethodology,ethodology, interpretation,interpretation, andand clinicalclinical relevancerelevance

VVikramikram KK.. MMahajan,ahajan, SanjivSanjiv HandaHanda1

IINTRODUCTIONNTRODUCTION nearly similar to skin tests have limited availability/ applicability in routine clinical practice. An increased Adverse drug reaction is a noxious and unintended focus has been witnessed in recent years on the utility response to a drug at normal doses used in of drug patch test in cutaneous adverse drug reactions humans for prophylaxis, diagnosis or therapy of since it is easy to perform, relatively safe, and the only a disease or for the modification of physiological in-vivo challenge test available. Hence, it becomes function (WHO).[1] Cutaneous adverse drug reactions imperative to revisit methodology, interpretation, and are a frequent problem in clinical practice and clinical relevance of drug patch testing. comprise 1-2% of outdoor and 5-10% of indoor patients in dermatology practice.[2] It is often difficult MMECHANISMSECHANISMS OFOF ADVERSEADVERSE DDRUGRUG RREACTIONSEACTIONS to pinpoint the offending drug from temporal correlation/history alone as most affected patients It will be prudent here to recapitulate briefly the are on multiple medications, and the clinical picture mechanisms involved in adverse drug reactions. is often not diagnostic. Although, re-challenge/ The majority (nearly 95%) of adverse drug reactions provocation tests, intradermal tests or skin prick are Type A (augmented) reactions which are tests are of significant value in identifying the culprit dose-dependent and predictable from the primary and drug, they are time consuming, need expertise or secondary drug pharmacology while Type B (Bizarre) may even re-precipitate life-threatening adverse drug reactions are idiosyncratic, unpredictable from drug reaction that may raise ethical issues. Availability pharmacology, and determined by patient-specific of basophil degranulation/lymphocyte activation susceptibility factors.[3] They can be “non-immune tests remains limited, has low sensitivity/specificity mediated (drug intolerance)” due to inadequate and may even be negative during acute stage of drug or imperfect metabolic detoxification leading to hypersensitivity. Radioallergosorbent test for drug hemolysis, bone marrow toxicity or neurotoxicity specific IgE, histamine release test, and passive from toxic metabolites or “pseudo-allergic” due to hemagglutination test with sensitivity/specificity histamine, leukotrienes, or other mediators released

Department of Dermatology, Venereology and Leprosy, from direct basophil/mast cell de-granulation. Dr. R. P. Government Medical College, Kangra, (Tanda), These are often difficult to distinguish from Himachal Pradesh, 1Postgraduate Institute of Medical Education true immunologically mediated immediate type and Research, Chandigarh, India allergic responses (e.g., asthma, anaphylaxis, and

AAddressddress forfor correspondence:correspondence: Dr. Vikram K. Mahajan, urticaria/angioedema-like reactions due to drugs Department of Dermatology, Venereology and Leprosy, like opiates, muscle relaxants or radio contrast Dr. R. P. Government Medical College, Kangra, (Tanda) - 176 001, media). Table 1 lists four main classes of immune Himachal Pradesh, India. E-mail: [email protected] effecter mechanisms involved in immune mediated

Access this article online Type B (immunologic) reactions which are relevant for drug patch testing.[3] Quick Response Code: Website: www.ijdvl.com BBASICASIC PRINCIPLES,PRINCIPLES, MMETHODOLOGY,ETHODOLOGY, AANDND RREPORTINGEPORTING DOI: OOFF RRESULTSESULTS 10.4103/0378-6323.120751

PMID: The basic principles and methodology for drug patch ***** test remains same as that in patch testing for contact

How to cite this article: Mahajan VK, Handa S. Patch testing in cutaneous adverse drug reactions: Methodology, interpretation, and clinical relevance. Indian J Dermatol Venereol Leprol 2013;79:836-41. Received: December, 2012. Accepted: February, 2013. Source of Support: Nil. Confl ict of Interest: None declared.

836 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Mahajan and Handa Patch testing in cutaneous adverse drug reactions

Table 1: Type B (immunologic) reactions Type of hypersensitivity Immune effector mechanism Clinical manifestation Remarks Type 1 (immediate or IgE bound to surface of mast cells or Urticaria/angioedema, asthma, Skin/prick test and anaphylactic) basophils. antigen (Ag) binding causes anaphylaxis intradermal test (with 15-min mast cell degranulation, release of response) will detect it except histamine and other mediators in pseudo-allergic types Type 2 Antibodies (Abs) to Ag determinants on cell Pemphigus, neutropenia, Skin manifestation is rare and (cytotoxic) surface are target for IgG/IgM Abs. Cells/ thrombocytopenia, hemolysis mainly as pemphigus tissues damaged by activated complement or by binding to cells through Fcr receptors, and activate cytotoxic killing, e.g., by K cells Type 3 Circulating immune complex deposited Hypersensitivity vasculitis, Skin tests are of no value (immune complex) in vascular beds or on tissue surfaces, Henoch-Schonlein purpura complement is activated, neutrophils attracted and their products damage tissues Type 4 T-lymphocytes (CD4 or CD8) producing Can be elicited by patch (delayed type) different patterns of cytokines and/or testing or intradermal test cytotoxic factors read after 48 h Type 4a Th1-Tc1 cells: IFN-g, TNF-a Contact dermatitis, tuberculin reaction Type 4b Th2 cells: IL-4/-13, IL-5, Eosinophils Maculopapular rash, exanthema with eosinophilia Type 4c Cytotoxic T-cells: Perforin, Granzyme-B, Contact dermatitis, Granulysin maculopapular drug rash, Stevens-Johnson syndrome, Toxic epidermal necrosis Type 4d T-cells: CXCL-8, GM-CSF, neutrophils Acute generalized exanthematous pustulosis Modifi ed after Friedman and Ardern-Jones.[3] Abs: Antibodies, TNF-: Tumor necrosis factor-, dermatitis. The T-cells get activated by adaptive (SJS-TEN), intertriginous/flexural exanthem less immune mechanism from hapten-antigen presenting affected skin sites may remain negative while, initially cells (APCs) and human leukocyte antigen (HLA) affected skin sites elicit more positive responses and complex (HLA-class I and/or II). For this, drug molecule should be selected for patch testing.[4,5] The patient or the metabolite becomes a hapten that binds with is instructed to leave the patches in place for next protein to form an antigen which then is processed by 48 h (2 days), avoid rubbing, scratching, or wetting APCs. Once T-helper cells get activated, they proliferate them. Patches are removed and marked clearly to produce clones of memory/effector T-cells with and responses are read 1-2 h after letting the skin specificity for that immunogen with ability to activate regain its normal contour and the non-specific skin immune effector mechanism (immunological memory) irritation subsides. Patch test results can be negative or they in turn help B cells to produce antibodies (IgA, on day 2 (D2) but, positive when read on day 4 (D4). IgG, IgE). It requires 7-10 days to develop immunological Readings should be made at 20 min for urticaria or memory (sensitization phase) meaning thereby that anaphylaxis-like immediate adverse drug reactions one must have continuous exposure for this much from betalactam antibiotics, neomycin, gentamycin, period to the offending drug for tissue damaging bacitracin, diclofenac. For drug photo-patch test, hypersensitivity to develop (elicitation phase). performed in drug induced photodermatitis, photo Re-exposure to the culprit drug will elicit similar allergic/toxic reactions, two sets of patch tests are clinical reaction pattern in previously sensitized applied. One set of drug photo-patch test is irradiated individuals. This is the background principle for drug with ultraviolet (UV)-A (5 or 10 J/cm2) at 24 or 48 h (D1 patch testing. or D2).[6] It will be pertinent to mention here that the protocol for reading of patch test results in cases of Finn chamber method is used for drug patch testing and FDE is not different.[7] For obvious reasons treatment test units are applied over non-hairy, upper back after with systemic corticosteroids or immunosuppressive cleansing with ethanol without rubbing [Figure 1]. drugs is required to be stopped at least 1 month before For drug reactions such as fixed drug eruptions (FDE), patch testing.[6] Similarly, topical corticosteroids Stevens-Johnson syndrome-toxic epidermal necrolysis should not be used over test sites for at least 2 weeks

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 837 Mahajan and Handa Patch testing in cutaneous adverse drug reactions prior to the patch test; topical corticosteroids applied Clinical types of cutaneous adverse reactions in large doses even away from the test site may have As not all cutaneous adverse reactions will elicit same effect as low doses of systemic corticosteroids.[8] positive results, drug patch testing is suitable Strong UV-exposure (e.g., exposure at seaside) prior for investigating only a select type of drug to drug patch testing will diminish test reactivity.[6] reactions [Table 2]. Figures 2-4 depict serious clinical However, anti-histamines do not interfere with test forms of adverse cutaneous drug reactions and potential results and can be allowed during/prior to drug patch cases of drug patch testing. A review of published testing (cf skin prick test). reports suggests that, drug patch testing is particularly useful in cases of acute generalized exanthematous The results are then read at D2, at D3 and another pustulosis (AGEP, ≥50%), maculopapular drug reading is made at D7 if initial results are negative. rash (50-60%), anticonvulsant hypersensitivity Results are reported according to International [9] Contact Dermatitis Research Group criteria as: No Table 2: Drug patch test recommended as fi rst line reaction (0), Doubtful reaction; faint erythema (?), weak investigation positive; palpable erythema, infiltration, papules (1+), Valuable in Reported positive strong positive [Figure 1d]; erythema, infiltration, results[2,5,10-15] % papules, vesicles (2+), extreme positive reaction; Acute generalized exanthematous pustulosis ≥50 intense erythema and infiltration and coalescing Maculopapular (exanthematous) drug rash 50-60 vesicles (3+), irritant reaction (IR) of different types, Anticonvulsant hypersensitivity syndrome 70 and not tested (NT). Drug rash, eosinophilia, and systemic ≥72 symptoms SJS-TEN from anticonvulsants, sulfonamides, 100 SSPECIFICPECIFIC IISSUESSSUES ABOUTABOUT DRUGDRUG PPATCHATCH TTESTINGESTING NSAIDs Betalactam antibiotics (ampicillin, amoxycillin) 39-54 The selection of a patient for drug patch testing is sensitivity important as the final results depend upon a number of NSAIDs induced fi xed drug eruptions 40-87 factors (vide infra) which can influence interpretation Contact and systemic contact dermatitis, and ≥87 photocontact sensitivity and usefulness of this procedure. Less valuable in Urticaria, pruritus, vasculitis, SJS-TEN due to allopurinol, acute phase of DRESS (due to unavailable clear skin for patch testing or iatrogenic immunosuppression) NSAIDs: Non-steroidal anti-infl ammatory drugs, SJS-TEN: Stevens-Johnson syndrome-toxic epidermal necrolysis, DRESS: Drug rash, eosinophilia, and systemic symptoms

b

a b a c d Figure 2: A patient of generalized exanthematous drug rash of Figure 1: Finn chambers, 8 mm diameter and 0.5 mm deep, made anticonvulsant hypersensitivity syndrome (from carbamazapine) of stiff aluminum and placed on a strip of adhesive (micropore®) characterized by moderate fever, facial and peri-orbital edema, and tape (a); and placed over upper back with a uniform pressure prominently pruritic maculopapular rash that occurred during fi rst applied in below upward direction for tight apposition to the 2 weeks of drug intake (may appear even 10-14 days after stopping skin (b); multiple test preparations placed in Finn chambers and it). She also eventuated to AGEP (note: Pustular lesions over the way they appear after application (c); A strong positive (2+) face); it can also progress to DRESS if multi-organ involvement, reaction (d) lymphadenopathy and eosinophilia develop

838 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Mahajan and Handa Patch testing in cutaneous adverse drug reactions

a b Figure 4: A patient of Stevens-Johnson syndrome-toxic a b epidermal necrolysis overlap (from diclofenac) showing macular Figure 3: A patient of Stevens-Johnson syndrome (from erythema, blisters, and detachment of epidermis from the phenytoin) showing macular erythema, blisters, and detachment dermis (between > 10% and 30% body surface area) and mucosae, of skin (involving 10% body surface area) and mucosae inset shows lesions over back (a); atypical targetoid spots are (a); atypical targetoid spots and bullae are also seen over face also seen over chest. SJS eventuate through SJS-TEN overlap and beyond large lesion over trunk (b) may develop more serious toxic epidermal necrolysis with wide-spread (>30% body surface area) skin/mucosal detachment and multi-organ involvement (b) syndrome (70%), drug rash, eosinophilia, and systemic symptoms (DRESS, ≥72%), and SJS-TEN (up to 100%), Table 3: Putative drugs for patch testing betalactam antibiotics (ampicillin, amoxycillin) Anticonvulsants sensitivity (39-54%), non-steroidal anti-inflammatory Carbamazapine drugs (NSAIDs) induced FDE (40-87%), contact Phenytoin and systemic contact dermatitis, and photocontact Phenobarbitone sensitivity (≥87%).[2,5,10-15] On the other hand, it is less Lamotrigine valuable in cases of immediate type of drug reactions, Sodium valporate pruritus, vasculitis, some cases of SJS-TEN (e.g., due Non-steroidal anti-infl ammatory drugs Paracetamol to allopurinol), and photodermatitis from systemic Diclofenac [2,5,12,13,16] drugs. Patch testing is more reliable for Piroxicam (tenoxicam, meloxicam, lornoxicam) eczematous type and (systemic) contact dermatitis or Celecoxib, etoricoxib anti-convulsant hypersensitivity reactions, which in Metamizole most instances is due to anti-convulsants, NSAIDs, Ketoprofen, ibuprofen sulfonamides or betalactum antibiotics.[15] Naproxen Nimisulide Betalactam antibiotics Putative drug(s) Amoxicillin The most immunologic (Type B) drug reactions Ampicillin are due to anti-convulsants (carbamazapine, Non-Betalactam antimicrobials phenytoin, phenobarbitone, or lamotrigine), Sulfonamides including co-trimoxazole sulfones, sulfonamides, and co-trimaxozole, NSAIDs Quinolones (ciprofl oxacin, norfl oxacin, moxifl oxacin) (paracetamol, diclofenac, piroxicam, metamizole), Doxycycline monohydrate betalactum antibiotics (amoxicillin, ampicillin), and Cephalosporins (cefadroxil, cephalaxin) Miscellaneous tetrazepam.[3-5,10,13] The list of putative drugs is expanding Cetirizine, levocetirizine by the day; allopurinol, minocycline, nevirapine, abacavir Iodinated contrast media are few recent additions. Less common causes of drug Heparin derivatives reactions are due to acyclovir, valaciclovir, diazepam, Glucocorticoids clobazam, terbinafine, fluoroquinolones, paracetamol, Pseudoephedrine glucocorticoids, pseudoephedrine, heparin, captopril, Tetrazepam and radio contrast media.[5,7,17] Although, allopurinol Acyclovir, valacyclovir Clobazam, diazepam has emerged second most common (first being anticonvulsants) cause of SJS-TEN, patch test is usually negative.[12,18] Table 3 lists some common drugs used Test preparations, test vehicles, and controls for drug patch testing, however, there is no consensus Pure drug form should be used for patch testing protocol that includes all drugs for testing. whenever possible in concentrations of 1-10% in

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 839 Mahajan and Handa Patch testing in cutaneous adverse drug reactions petrolatum, water or alcohol.[3,5,11,19] Alternatively, CCLINICALLINICAL RRELEVANCEELEVANCE liquid preparations or powder obtained from capsules or pulverized tablets/pills can be used The overall sensitivity of drug patch test is low between at concentrations up to 30% or as is.[3] Drugs like 11% and 38% and the clinical usefulness varies across carbamazapine, pseudoephedrine, acyclovir may studies depending upon putative drug(s) and clinical re-elicit drug reaction during patch test therefore it features of the cutaneous adverse drug reaction.[8,22] is recommended to use 1% dilution and up to 10% Although positive reactions have high predictive value, when initial responses are negative.[3] Excipients, gel false-positive reactions are not uncommon. They may jacket of the capsule (as is), etc., are also required to be due to IRs, which are frequent with drugs like sodium be included for patch testing. Although petrolatum valproate even in 1% concentration[14] or from cross remains the most preferred vehicle irrespective of reaction between drugs themselves, within their own the nature of test substance, it is crucial to use water metabolites, or the metabolite of one drug and that of and alcohol as vehicles additionally for preparing another. Cross reactivity is frequent especially among test substances in view of frequent false-negative aromatic anti-convulsants (carbamazapine, phenytoin, reactions from petrolatum. It is recommended to phenobarbitone), lamotrigine and valproic acid,[23] use petrolatum for betalactams, carbamazapine, among betalactum antibiotics,[8] acyclovir, valaciclovir celecoxib, and other NSAIDs, water for acyclovir, and famcyclovir,[17,24] and oxicams.[25] gancyclovir, or alcohol for corticosteroids and steroid hormones to avoid false-negative results.[11,17,20,21] It False-negative drug patch test reactions are not will be appropriate to test using all the vehicles as uncommon especially in patient having non-immune more validation is needed for optimal vehicles and drug reactions, when patch test drug has poor test concentrations. percutaneous absorption, e.g. allopurinol,[18] in the absence of concomitant factors like drug-virus (human Controls are important for high predictive value of herpes virus 6, HIV) interactions or the metabolite positive results and to exclude irritant reactions. The responsible for eliciting T-cell-dependent adverse test substances need to be tested in healthy control reaction is not formed in the skin.[3] Wrong selection of subjects before actual testing. Similarly, vehicle used vehicle, inadequate drug concentration and exposure in preparation of test substances is also included for time, and inappropriate timing for drug patch test patch testing for the same reasons. are some of other possible reasons for false-negative reactions. Time interval between adverse drug reaction and patch test While specificity and negative predictive value of Although, there is some consensus of opinion that skin drug patch test is not yet determined, false-positive prick tests and intradermal tests should be performed results need to be considered for final interpretation with the offending drug after resolution of clinical of the results. Predictive value of negative reactions is signs and symptoms, clearance of the drugs used for low and will not automatically exclude the offending the treatment of the adverse reaction, the offending drug. Barbaud et al.[11] observed 58% positive results on drug or its metabolites from blood circulation or at intradermal drug test among 60 patients with cutaneous least 3 weeks later, there exists some difference of adverse drug reactions having negative patch test with opinion to carry out patch testing to identify the the suspected drug. It suggests that skin prick test and/ incriminating drug. The European Network on Drug or intradermal test will be useful when patch testing Allergy recommends drug patch testing between is negative. They also recommend immediate reading 3 weeks and 3 months and according to European in urticaria-like drug reactions and delayed reading in Society of Contact Dermatitis it is best to test at other cutaneous drug reactions for accuracy. 6 weeks to 6 months after the complete resolution of clinical signs and symptoms.[22] As it is not known CCOMMENTSOMMENTS whether positive results will persist or last longer, it is advisable to perform drug patch test within 6 months Patch testing should preferably be performed on after cutaneous adverse drug reaction has subsided a previously involved skin or else a false-negative completely and the patient is off any kind of treatment result is likely. Similarly, some locations may be that may interfere with the results.[20] inappropriate for patch testing and discretion must be

840 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Mahajan and Handa Patch testing in cutaneous adverse drug reactions practiced. Drug patch tests can be particularly helpful Papa G, et al. Diagnosing nonimmediate reactions to penicillins in determining the culprit drug in eczematous drug by in vivo tests. Int Arch Allergy Immunol 2002;129:169-74. 9. Fischer T, Maibach HI. Patch testing in allergic contact reaction, systemic contact dermatitis, maculopapular dermatitis: An update. Sem Dermatol 1986;5:214-24. drug rash, DRESS, FDE and sometimes in SJS-TEN. It 10. Wolkenstein P, Chosidow O, Fléchet ML, Robbiola O, Paul M, Dumé L, et al. Patch testing in severe cutaneous adverse drug is easy to perform and any commercial drug can be reactions, including Stevens-Johnson syndrome and toxic used for testing (cf intradermal/prick tests). Adverse epidermal necrolysis. Contact Dermatitis 1996;35:234-6. reactions to drug patch test are rare and it has been 11. Barbaud A, Reichert-Penetrat S, Tréchot P, Jacquin-Petit MA, [26] Ehlinger A, Noirez V, et al. The use of skin testing in the used safely in children as well. However, possible investigation of cutaneous adverse drug reactions. Br J Dermatol precipitation of acute drug reaction, sensitization 1998;139:49-58. for cross reacting drugs, and possibility of contact 12. Santiago F, Gonçalo M, Vieira R, Coelho S, Figueiredo A. Epicutaneous patch testing in drug hypersensitivity allergy are some of the issues of ethical importance. syndrome (DRESS). Contact Dermatitis 2010;62:47-53. Sometimes, drug patch test reactions occur earlier 13. Grandhe NP, Kaur I, Parsad D, Dogra S. Role of patch than 2 days (e.g., after 24 h in abacavir), or as late as testing in antimicrobial drug eruptions. Contact Dermatitis 2004;50:259-61. 6-7 days after testing as in case of glucocorticosteroids 14. Vatve M, Sharma VK, Sawhney I, Kumar B. Evaluation of or betalactam antibiotics.[8] Additional readings of patch test in identification of causative agent in drug rashes results are highly desirable in such cases. In cases due to antiepileptics. Indian J Dermatol Venereol Leprol 2000;66:132-5. of negative patch test results, oral provocation test is 15. Gebhardt M, Wollina U. Allergy testing in serious cutaneous considered to be the only reliable method to identify drug reactions – Harmful or beneficial? Contact Dermatitis the culprit drug as in fixed drug eruption. In such a 1997;37:282-5. 16. Jindal N, Sharma NL, Mahajan VK, Shanker V, Tegta GR, situation, oral provocation is performed first with the Verma GK. Evaluation of photopatch test allergens for Indian least implicated drug followed by more likely causes. patients of photodermatitis: Preliminary results. Indian J A refractory period is also known especially in cases of Dermatol Venereol Leprol 2011;77:148-55. 17. Lammintausta K, Mäkelä L, Kalimo K. Rapid systemic FDE and a delay before and between patch testing and valaciclovir reaction subsequent to aciclovir contact allergy. oral provocation is recommended. Patch testing, alone Contact Dermatitis 2001;45:181. 18. Hamanaka H, Mizutani H, Nouchi N, Shimizu Y, Shimizu M. or in combination with oral provocation test, have a Allopurinol hypersensitivity syndrome: Hypersensitivity legitimate place in identifying the drug responsible for to oxypurinol but not allopurinol. Clin Exp Dermatol adverse reaction, especially, when multiple drugs are 1998;23:32-4. 19. Barbaud A. Skin testing in delayed reactions to drugs. Immunol used to check for cross-sensitivities to medications or Allergy Clin North Am 2009;29:517-35. to generate a list of safe drugs. 20. Barbaud A, Gonçalo M, Bruynzeel D, Bircher A, European Society of Contact Dermatitis. Guidelines for performing skin tests with drugs in the investigation of cutaneous adverse drug RREFERENCESEFERENCES reactions. Contact Dermatitis 2001;45:321-8. 21. Schuster J, Fabri M, Eming S, Hunzelmann N. Allergic drug 1. Edwards IR, Aronson JK. Adverse drug reactions: Definitions, eruption secondary to intravenous acyclovir. Acta Derm diagnosis, and management. Lancet 2000;356:1255-9. Venereol 2008;88:196-7. 2. Balachandran C, Shenoi SD, Sarkar D, Ravikumar BC. Patch 22. Gonçalo M, Oliveira HS, Monteiro C, Clerins I, Figueiredo A. tests in adverse cutaneous drug reaction. Indian J Dermatol Allergic and systemic contact dermatitis from estradiol. Contact Venereol Leprol 2002;68:13-5. Dermatitis 1999;40:58-9. 3. Friedmann PS, Ardern-Jones M. Patch testing in drug allergy. 23. Romano A, Viola M, Gaeta F, Rumi G, Maggioletti M. Patch Curr Opin Allergy Clin Immunol 2010;10:291-6. testing in non-immediate drug eruptions. Allergy Asthma Clin 4. Klein CE, Trautmann A, Zillikens D, Bröcker EB. Patch testing Immunol 2008;4:66-74. in an unusual case of toxic epidermal necrolysis. Contact 24. Mansur AT, Pekcan Yaşar S, Göktay F. Anticonvulsant Dermatitis 1995;33:448-9. hypersensitivity syndrome: Clinical and laboratory features. 5. Barbaud A. Drug patch testing in systemic cutaneous drug Int J Dermatol 2008;47:1184-9. allergy. Toxicology 2005;209:209-16. 25. Gonçalo M, Figueiredo A. Cross reactions among oxicams 6. Brockow K, Romano A, Blanca M, Ring J, Pichler W, Demoly P. in cutaneous adverse drug reactions. Contact Dermatitis General considerations for skin test procedures in the diagnosis 2002;46:S31. of drug hypersensitivity. Allergy 2002;57:45-51. 26. Buyuktiryaki AB, Bezirganoglu H, Sahiner UM, Yavuz ST, 7. Andrade P, Brinca A, Gonçalo M. Patch testing in fixed Tuncer A, Kara A, et al. Patch testing is an effective method drug eruptions – A 20-year review. Contact Dermatitis for the diagnosis of carbamazepine-induced drug reaction, 2011;65:195-201. eosinophilia and systemic symptoms (DRESS) syndrome in an 8. Romano A, Viola M, Mondino C, Pettinato R, Di Fonso M, 8-year-old girl. Australas J Dermatol 2012;53:274-7.

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 841 Focus SSystemicystemic sskinkin wwhitening/lighteninghitening/lightening agents:agents: WhatWhat isis tthehe eevidence?vidence?

MMunisamyunisamy Malathi,Malathi, DevinderDevinder M.M. ThappaThappa

IINTRODUCTIONNTRODUCTION are continuing to be introduced. A lot is known about topical skin whitening agents, but systemic skin The human skin color is one of the most perceptible whitening agents which are slowly gaining popularity phenotypic variations among humans and is do not have much evidence to their credit in the determined primarily by the type and amount of scientific literature. In this article, we have addressed melanin synthesized within melanosomes and the issues related to the use of these systemic skin the pattern of melanosome distribution within the whitening agents. melanocytes. Getting a lighter skin tone always draws a lot of interest, as for centuries, fair or light skin An overview of the pathway of melanin synthesis and color has been a symbol of prominence, superiority the site of action of the most commonly used systemic and higher social ranking. In India, attitudes towards skin whitening agent (glutathione [GSH]) is depicted skin color have developed over more than 2000 years in Figure 1. The mechanisms governing pheomelanin and reflect considerations of class and caste. Women to eumelanin balance are dependent on L-cysteine, especially Asian women are obsessed with fair skin GSH and tyrosinase related protein expression. and they would go to the ends of the earth to lighten Thus, as observed in the figure, the switching from their skin color as in most cases their marriage eumelanogenesis to pheomelanogenesis can be prospects or career opportunities are dominated by influenced by modifying the ratio between cysteine the hue of their skin. Hence, skin whitening products and GSH levels. Pheomelanogenesis preferentially are a half a billion dollar industry today capitalizing proceeds under conditions of high cysteine on the insecurity of these individuals and currently, concentrations and low tyrosinase activity.[1] skin lightening is one of the most common forms of potentially harmful body modification practices in the SSYSTEMICYSTEMIC SKINSKIN WHITENINGWHITENING AAGENTSGENTS AAVAILABLEVAILABLE IINN TTHEHE world. MMARKETARKET

A host of skin lightening agents are available in GSH dermatology and cosmetic market and newer agents The most commonly used systemic skin whitening agent is GSH used alone or in various combinations, Department of Dermatology and STD, Jawaharlal Institute of both as oral and intravenous formulations. GSH is Postgraduate Medical Education and Research, Puducherry, India an antioxidant synthesized in all mammalian cells AAddressddress forfor correspondence:correspondence: Dr. Devinder M. Thappa, from three amino acids-glutamate, cysteine, and Department of Dermatology and STD, Jawaharlal Institute glycine. It is also available naturally in watermelon, of Postgraduate Medical Education and Research, avocado, broccoli, spinach and tomatoes. GSH Puducherry - 605 006, India. E-mail: [email protected] exists in cells mostly in the reduced form (GSH)

Access this article online which is constantly oxidized forming oxidized GSH and its supply is replenished by the action of GSH Quick Response Code: Website: www.ijdvl.com reductase. GSH is involved in various biochemical processes especially those involving scavenging of DOI: free radicals and detoxification of toxic compounds, 10.4103/0378-6323.120752 it acts as coenzyme and helps in the transport of PMID: amino acids across the cell membranes.[1] Lower ***** GSH levels are implicated in many diseases and GSH

How to cite this article: Malathi M, Thappa DM. Systemic skin whitening/lightening agents: What is the evidence?. Indian J Dermatol Venereol Leprol 2013;79:842-6. Received: May, 2013. Accepted: June, 2013. Source of Support: Nil. Confl ict of Interest: None declared.

842 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Malathi and Thappa Systemic skin whitening/lightening agents

Figure 1: The pathway of melanin synthesis and the site of action of glutathione and cysteine, shifting the balance towards pheomelanin synthesis has been tried in the management of Alzheimer’s  Quenching of free radicals and peroxides that disease, Parkinson’s disease, multiple sclerosis, contribute to tyrosinase activation and melanin alcoholic hepatitis, atherosclerosis, acquired formation immunodeficiency syndrome, and chronic fatigue  Modulation of depigmenting abilities of syndrome. It has been commonly used to combat the melanocytotoxic agents. neuro- and nephrotoxicity associated with cisplatin chemotherapy[2] and this is the only Food and Drug GSH for skin whitening is available in both tablet and Administration (FDA) approved indication for the injectable form. When taken orally, GSH is hydrolyzed intravenous form of GSH. The role of GSH as a by intestinal and hepatic gamma-glutamyl transferase skin whitening agent was an accidental discovery resulting in reduced bioavailability. Even when large when skin whitening was noticed as a side effect oral doses were administered, it was found that most of large doses of GSH. This led to extensive studies of the absorbed GSH remains within the gut luminal establishing its role in melanogenesis and the recent cells and only small and transient increases of GSH use of GSH as systemic skin whitening agent. could be detected in the general circulation.[4] Thus, the effectiveness of exogenously administered GSH GSH exerts its action as skin whitening agent at is hindered by its instability when crossing cell various levels of melanogenesis which include the membranes and its rapid hydrolysis in the circulation following:[1,3] by gamma-glutamyltranspeptidase found on the  Interference with cellular transport of tyrosinase extracellular surfaces of cells.[5] On the contrary,  Direct inactivation of the enzyme tyrosinase by intravenous GSH delivers very high doses directly binding with the copper-containing active site into the systemic circulation, overloading the renal of the enzyme circulation.  Mediating the switch mechanism from eumelanin to phaeomelanin production Oral GSH is in the “generally regarded as safe” category as GSH is the major physiologic reservoir of FDA and is usually marketed as a food or dietary of cysteine and increase in cysteine levels supplement and hence it does not certainly need to results in switching of eumelanogenesis to be FDA or Bureau of Food and Drug (BFAD) approved. pheomelanogenesis [Figure 1] There are no provisions in the law for FDA to approve

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 843 Malathi and Thappa Systemic skin whitening/lightening agents dietary supplements for effectiveness before they than GSH and is BFAD approved.[9] Natural sources reach the consumer. However, FDA has banned the of L-cysteine include poultry, yogurt, egg yolks, red use of intravenous form of GSH for skin whitening peppers, garlic, onions, broccoli, Brussel sprouts, oats, in view of commonly reported side effects like skin and wheat germ. L-cysteine along with L-glutamic rashes, Stevens Johnson syndrome, toxic epidermal acid and glycine is the rate-limiting precursor in the necrolysis, derangement in thyroid and renal function synthesis of GSH peroxidase and has been found and severe abdominal pain.[6] that high concentrations of L-cysteine reduced the tyrosinase activity and produced more pheomelanin Till date there is only one study published in English by way of cysteinyl dihydroxyphenylalanine (DOPA), literature assessing the safety and efficacy of oral GSH the building block of pheomelanin [Figure 1]. The as a skin whitening agent.[3] It was a randomized, cysteinyl DOPAs can be formed in two ways-directly double-blind, two-arm, placebo-controlled study by nucleophilic addition of cysteine to DOPA conducted on 60 medical students in Thailand. quinone or indirectly from GSH DOPA by action of They found 500 mg/day orally administered GSH, gamma-glutamyl transferase and peptidase.[10-12] Hence for 4 weeks to cause significant skin whitening when L-cysteine peptide is promoted as skin whitening compared to placebo and they observed no significant agent but without much scientific evidence to support adverse events. However, there were many flaws in its use for this indication. the study-plasma GSH levels were not measured (as bioavailability of oral GSH is low), limited study Tranexemic acid period of 4 weeks, no follow-up to determine when the Tranexemic acid (trans-4-aminomethyl cyclohexane skin melanin indices return to their baseline values, carboxylic acid), a plasmin inhibitor, commonly used medical students were chosen (young, otherwise as a haemostatic agent owing to its antifibrolytic healthy population) and the study was conducted action is also promoted as a systemic skin whitening during their college time to ensure that sun exposures agent especially as oral or intradermal injections for were minimal. Hence, the results may be applicable to melasma. The skin whitening effects of tranexamic only young, otherwise healthy Asian individuals. acid was incidentally found when it was used in the treatment of aneurysmal subarachnoid hemorrhage. It The promoters of GSH promote it at a dose of 20 and is a synthetic derivative of lysine and its therapeutic 40 mg/kg/body weight/day which is divided into two role in melasma was first studied by Nijor as early as doses with a maintenance dose of 500 mg/day.[7] in 1979, but only limited data exist in the literature They claim that gradual systemic effect will be seen regarding its use in melasma. Plasmin, is a protease 1-3 months in medium brown skin, in 3-6 months in that enhances the intracellular release of arachidonic dark brown skin, in 6-12 months in very dark skin acid, a precursor of prostanoid, and also elevates and in 2 years are more in black skin. Injectable GSH alpha-melanocyte stimulating hormone (-MSH) is given at a dose of 900 mg weekly by intravenous processed from pro-opio-melanocortin. Both or intramuscular method and the sessions can be arachidonic acid and -MSH can activate melanin repeated 2-3 times a week. They claim skin whitening synthesis by melanocytes. Tranexemic acid by way to occur as early as 2-3 weeks.[7] of its antiplasmin activity depletes the keratinocyte pool of arachidonic acid involved in ultraviolet (UV) GSH is also combined with many other agents induced melanogenesis.[13-17] like vitamin C to increase its absorption, N-acetyl cysteine to boost its level, alpha lipoic acid and other It has been used at a low dose of 250 mg twice a day antioxidants like vitamin E and grape seed extract. for at least 3 months for the treatment of melasma and Some oral preparations have dangerous combinations found to be effective.[15] But, it is not safe to use it for a like monobenzone which causes irreversible long duration in view of its anti-hemorrhagic property depigmentation and hydroquinone which is banned resulting in side effects like venous thromboembolism, by FDA as a carcinogen.[8] myocardial infarction, cerebrovascular accidents and pulmonary embolism. It is contraindicated in L-cysteine peptide patients with acquired defective color vision, an active Another agent promoted for skin whitening is L-cysteine intravascular clotting condition, and hypersensitivity peptide, which is claimed to be 3-5 times more potent to tranexemic acid.[15] However, there is no scientific

844 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Malathi and Thappa Systemic skin whitening/lightening agents data available demonstrating the role of tranexemic Hence, well conducted studies, establishing the role acid as an overall skin whitening/lightening agent. of these agents in skin whitening and documenting It is even being promoted as intravenous injection adverse events is the need of the hour. for skin whitening at a dose of 500 mg every week for 1 or 2 months and 500 mg every month for PPROBLEMSROBLEMS WWITHITH SSYSTEMICYSTEMIC SSKINKIN WWHITENINGHITENING AAGENTSGENTS maintenance.[18] Tranexamic acid has been found to produce good synergistic effect when combined with As already mentioned above, these agents are not ascorbic acid or its derivatives and L-cysteine.[17] FDA approved for skin whitening and no scientific evidence exists for their use. In addition, the Miscellaneous agents injectable formulations are counterfeited and given Apart from these, large doses of vitamin C, hyaluronic by untrained people illegally and hence associated acid, epidermal growth factor and combinations of with the risk of sepsis, air embolism, transmission multiple natural extracts (natural collagen extracts, of human immunodeficiency virus, Hepatitis B, and bearberry extract, Glycyrrhiza glabra extract, use of non-sterile preparations that can lead to serious Lycopene, Kelp, olive leaf extract, hawthorn, jujube, infections. sea buckthorn, starch, coix seed, pearl extracts, etc.,) are also promoted for skin whitening in the form of food Another major question that remains unanswered as yet or dietary supplements with no scientific evidence. is that whether switching the normal machinery from eumelanin (which is protective against UV radiation) Nevertheless, there are few animal studies and to pheomelanin (which photosensitizes UV-induced in vitro studies demonstrating the role of natural deoxyribonucleic acid damage as observed in cultured extracts like irradiated green tea polyphenol,[19] human melanocytes) by an external agent for long proanthocyanidin-rich extract from grape seeds,[20] duration would result in an increased incidence of ellagic acid-rich pomegranate extract,[21] and coumarin skin cancers.[26,27] extracts from the plant Angelica dahurica,[22] in inhibiting melanogenesis resulting in skin whitening As a general rule, the promoters of the systemic skin thereby recommending these agents as oral preparations whitening agents list lactation, heart disease and for skin whitening. Procyanidins (pycnogenol, grape hypersensitivity as contraindications for all these seed extracts) and Polypodium leucotomos have been agents. Since there are not much human or animal found to effective and safe in the treatment of melasma studies advocating the role of these agents in skin and to prevent UV A induced pigmentary changes whitening, there is no data on the relative and absolute respectively.[23] But there are no trials demonstrating contraindications, the appropriate dosing schedule their efficacy in the treatment of post inflammatory and the long term side effects. pigmentation or in improving the general skin color. EECONOMICCONOMIC CCONSIDERATIONSONSIDERATIONS TTHEHE SCENARIOSCENARIO IINN IINDIANDIA In India, the dermatology market is worth In India, GSH is available as Dr. James GSH whitening 1642 crore rupees ($ 410 million) and fairness-directed pills[24] which contains 100% natural pure GSH with skin lightening cosmetic market (which are considered alpha T-acids costing 3500/- rupees for 60 capsules as ‘‘fast moving consumer goods’’) is 1000 crore of 1000 mg, I-Fair tablets[25] which contains GSH in ($ 250 million) resulting in a staggering 61% of the total combination with vitamin C, vitamin E, grape seed dermatology market.[28] Companies manufacturing skin extract, alpha lipoic acid, and glutanova 900 skin lightening products take advantage of the lax advertising whitening injections[10] which contains GSH with laws and make unsubstantiated claims about their vitamin C and collagen. These agents are being efficacy taking a horrendous toll on the consumers. advertised in the internet and currently there are no The high-end skin whitening products are often labeled market data available on the use of these agents by under the new quasi-pharmaceutical category called Indians. As mentioned in the introduction, most of cosmeceuticals – a hybrid entity with pharmaceutical Indian women’s marriage prospects are dominated by and cosmetic properties. This ambiguous labeling skin color paving way for irrational use of these agents strategy allows promoters of high-end skin whitening by these women and may result in untoward effects. and anti-aging products to make both pharmaceutical

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 845 Malathi and Thappa Systemic skin whitening/lightening agents and cosmetic claims. The marketing trends are designed 9. Perfect white skin whitening and anti-aging tablets. Available in such a way so as to blur the lines between cosmetics from: http://www.perfectwhiteaim.blogspot.in. [Last accessed on 2013 Apr 2]. and food categories and food and pharmaceutical 10. Smit NP, Van der Meulen H, Koerten HK, Kolb RM, categories, thereby helping in evading the regulatory Mommaas AM, Lentjes EG, et al. Melanogenesis in cultured melanocytes can be substantially influenced by L-tyrosine and constraints for these products, eventually enticing L-cysteine. J Invest Dermatol 1997;109:796-800. more consumers to consume these relatively expensive 11. del Marmol V, Ito S, Bouchard B, Libert A, Wakamatsu K, and poorly regulated products. Thus, their claims can Ghanem G, et al. Cysteine deprivation promotes eumelanogenesis in human melanoma cells. J Invest Dermatol neither be independently verified, nor can potential 1996;107:698-702. risks to consumers be assessed.[29] 12. Agrup G, Hansson C, Rorsman H, Rosengren E. The effect of cysteine on oxidation of tyrosine, DOPA, and cysteinyldopas. Arch Dermatol Res 1982;272:103-15. CCONCLUSIONONCLUSION 13. Ando H, Matsui MS, Ichihashi M. Quasi-drugs developed in Japan for the prevention or treatment of hyperpigmentary The desire for white and fair skin is a global disorders. Int J Mol Sci 2010;11:2566-75. 14. Tse TW, Hui E. Tranexamic acid: An important adjuvant in the phenomenon and it is being highly capitalized by treatment of melasma. J Cosmet Dermatol 2013;12:57-66. both the cosmetic and dermatologic industries. It is an 15. Karn D, S KC, Amatya A, Razouria EA, Timalsina M. Oral essential role of the dermatologist to make the public tranexamic acid for the treatment of melasma. Kathmandu Univ Med J (KUMJ) 2012;10:40-3. aware that skin lightening agents may progressively 16. Wu S, Shi H, Wu H, Yan S, Guo J, Sun Y, et al. Treatment of revert back the facultative color to the constitutive level melasma with oral administration of tranexamic acid. Aesthetic and normally this color change will not go beyond the Plast Surg 2012;36:964-70. 17. Tranexemic acid. Available from: http://www.mcbiotec.com/ constitutive level. If such a change is claimed, it should products/?type=detail & id=33. [Last accessed on 2013 Jun 17]. be considered to be dangerous as such alterations can 18. Beauty injections. Available from: http://www.beautyinjections. become non-reversible resulting in vitiligo and may com/products/Tranexamic-Acid.html. [Last accessed on 2013 Jun 17]. also predispose to other complications like skin cancer 19. An BJ, Kwak JH, Son JH, Park JM, Lee JY, Park TS, et al. as the normal biochemical processes are altered. Till Physiological activity of irradiated green tea polyphenol on the human skin. Am J Chin Med 2005;33:535-46. date, systemic skin whitening agents do not have 20. Yamakoshi J, Otsuka F, Sano A, Tokutake S, Saito M, much scientific evidence regarding their use and strict Kikuchi M, et al. Lightening effect on ultraviolet-induced laws should be enforced to ban the use of these agents pigmentation of guinea pig skin by oral administration of a proanthocyanidin-rich extract from grape seeds. Pigment Cell until well conducted randomized controlled trials are Res 2003;16:629-38. available ensuring the safety and efficacy of these agents. 21. Yoshimura M, Watanabe Y, Kasai K, Yamakoshi J, Koga T. Inhibitory effect of an ellagic acid-rich pomegranate extract on tyrosinase activity and ultraviolet-induced pigmentation. RREFERENCESEFERENCES Biosci Biotechnol Biochem 2005;69:2368-73. 22. Cho YH, Kim JH, Park SM, Lee BC, Pyo HB, Park HD. New 1. Villarama CD, Maibach HI. Glutathione as a depigmenting cosmetic agents for skin whitening from Angelica dahurica. agent: An overview. Int J Cosmet Sci 2005;27:147-53. J Cosmet Sci 2006;57:11-21. 2. Hospers GA, Eisenhauer EA, de Vries EG. The sulfhydryl 23. Konda S, Geria AN, Halder RM. New horizons in treating containing compounds WR-2721 and glutathione as radio- and disorders of hyperpigmentation in skin of color. Semin Cutan chemoprotective agents. A review, indications for use and Med Surg 2012;31:133-9. prospects. Br J Cancer 1999;80:629-38. 24. Skin whitening pills in India. Available from: http://www. 3. Arjinpathana N, Asawanonda P. Glutathione as an oral whitening drjamespills.blogspot.in/2013/01/glutanova-900-skin- agent: A randomized, double-blind, placebo-controlled study. whitening-injections.html. [Last accessed on 2013 Apr 28]. J Dermatolog Treat 2012;23:97-102. 25. I-Fair-Glutathione supplement with vitamin C for skin 4. Witschi A, Reddy S, Stofer B, Lauterburg BH. The systemic whitening. Available from: http://www.cosmonova.in/i_fair. availability of oral glutathione. Eur J Clin Pharmacol html. [Last accessed on 2013 Apr 28]. 1992;43:667-9. 26. Kvam E, Dahle J. Pigmented melanocytes are protected against 5. Hong SY, Gil HW, Yang JO, Lee EY, Kim HK, Kim SH, et al. ultraviolet-A-induced membrane damage. J Invest Dermatol Pharmacokinetics of glutathione and its metabolites in normal 2003;121:564-9. subjects. J Korean Med Sci 2005;20:721-6. 27. Wenczl E, Van der Schans GP, Roza L, Kolb RM, Timmerman AJ, 6. Injectable glutha not FDA-approved. Available from: http:// Smit NP, et al. (Pheo) melanin photosensitizes UVA-induced www.journal.com.ph/index.php/news/national/44605- DNA damage in cultured human melanocytes. J Invest Dermatol injectable-glutha-not-fda-approved. [Last accessed on 1998;111:678-82. 2013 Apr 2]. 28. Verma SB. Obsession with light skin – Shedding some light 7. Skin whitening pills. Available from: http://www. on use of skin lightening products in India. Int J Dermatol magicproducts.in. [Last accessed on 2013 Apr 2]. 2010;49:464-5. 8. Levitt J. The safety of hydroquinone: A dermatologist's 29. Mire A. The scientification of skin whitening and the response to the 2006 Federal Register. J Am Acad Dermatol entrepreneurial university-linked corporate scientific officer. 2007;57:854-72. Can J Sci Math Technol Educ 2012;12:272-9.

846 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Quiz PPainlessainless dellsdells onon thethe cheekcheek

A 30-year-old woman presented with a 15-year history of small cords and islands of basaloid cells that of two asymptomatic dells on her right cheek. There showed connection to the follicular infundibulum. was no history of preceding acne or inflammatory skin Tumor strands were surrounded by a desmoplastic disease. fibrous stroma [Figures 2 and 3]. Several keratinous cysts and foci of dystrophic calcification were also Dermatologic examination revealed two 0.5 cm and noted. Immunohistochemically, the tumor cells 0.3 cm-sized, sharply-demarcated, skin-colored stained positive with anti-pancytokeratin (CK), papules with cup-shaped central depressions, located on the zygomatic [Figure 1] and mandibular regions anti-CK15 and negative with anti-carcinoembryonic of the right cheek. On close inspection, follicular antigen (CEA), anti-CK7 and anti-epithelial plugging was evident. membrane antigen antibodies. The tumor was focally immunopositive for CK20 antibody, indicating the Histopathological examination displayed a partially presence of scattered Merkel cells. well-circumscribed tumor in the dermis with an overlying sharp depression. The tumor was composed WWHATHAT ISIS YOURYOUR DIAGNOSIS?DIAGNOSIS?

Figure 1: A well-circumscribed umbilicated patch on the right zygomatic region Figure 2: Thin cords and islands of basaloid cells in a dense fi brous stroma (H and E, ×100)

Figure 3: Closer view of Figure 2 (H and E, ×200)

How to cite this article: Duman D, Durmaz EÖ, Çetin ED, Yazar &, Şahin S. Painless dells on the cheek. Indian J Dermatol Venereol Leprol 2013;79:847-8. Received: March, 2013. Accepted: May, 2013. Source of Support: Nil. Confl ict of Interest: None declared.

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 847 Quiz

Answer Periodic Acid-Schiff (PAS) expressions may support Diagnosis: Desmoplastic trichoepithelioma a diagnosis of DTE and vice versa.[2-4] So far, CK20 is the most reliable immunohistochemical marker DDISCUSSIONISCUSSION in differentiating DTE from morphea-like BCC.[4] However, CK 20 expression in DTEs may be focal.[2-4] Desmoplastic trichoepithelioma (DTE) is a rarely encountered benign adnexal tumor with an estimated Once the diagnosis is established, DTE may be incidence of 2 in 10.000 skin biopsies.[1,2] The age clinically followed-up with an expectant policy.[1] range varies from 0 to 80. The lesion usually develops Cryotherapy, dermabrasion or laser surgery may pose on the face of a young woman (71-85%).[2] The cheek risks of recurrence and/or scar formation. Imiquimod is the most frequent site of affection (50%).[1-3] There is has been used in two cases as an adjunctive therapeutic a propensity for DTE development on the right side of measure, but without apparent benefit.[5] In equivocal the face.[2] DTE presents as an asymptomatic, solitary, cases, the best treatment is complete surgical annular, firm, white to yellowish papule or as a sclerotic excision.[1] If there is a consideration of microcystic plaque smaller than 2 cm. The lesion has a thread-like adnexal carcinoma or morphea-like BCC or if tissue raised and rolled border and a non-ulcerated central preservation is crucial, Mohs micrographic surgery dell.[1,2] The clinical appearance may be reminiscent of may be recommended.[1,2] basal cell carcinoma (BCC). DDenizeniz Duman,Duman, EmelEmel ÖztürkÖztürk DDurmaz,urmaz, The histologic portrait in previous reports encompasses EEmelmel DD.. ÇÇetinetin1, Şüükrükrü YYazarazar 2, SSedefedef Şahinahin narrow strands of basaloid cells, keratinous cysts and Departments of Dermatology, 1Pathology, and 2Plastic, Reconstructive desmoplastic stroma.[2] The well-demarcated solid and Aesthetic Surgery, Acıbadem University School of Medicine, Istanbul, Turkey tumor is situated symmetrically within the papillary and [2,3] reticular dermis. Small basaloid cells with prominent AAddressddress forfor correspondence:correspondence: Dr. Emel Öztürk Durmaz, oval nuclei and scant cytoplasm are arranged in slender Acıbadem Maslak Hospital, Büyükdere Caddesi 40, strands containing one to three rows of cells. There Maslak 34457, Istanbul, Turkey. is often a focal connection to the overlying epidermis E-mail: [email protected] through the follicular infundibulum. The stroma RREFERENCESEFERENCES surrounding the strands of basaloid cells consists of ample homogeneous eosinophilic collagen and multiple 1. Moynihan GD, Skrokov RA, Huh J, Pardes JB, Septon R. Desmoplastic trichoepithelioma. J Am Acad Dermatol horn cysts. There is no cleft between the nests of tumor 2011;64:438-9. cells and sclerotic stroma. While palisading is lacking, 2. Mamelak AJ, Goldberg LH, Katz TM, Graves JJ, Arnon O, epidermal hyperplasia may be noted.[2] Foreign body Kimyai-Asadi A. Desmoplastic trichoepithelioma. J Am Acad Dermatol 2010;62:102-6. granulomas from broken cysts, areas of calcification or 3. Jedrych J, Leffell D, McNiff JM. Desmoplastic trichoepithelioma ossification might be observed.[2,4] with perineural involvement: A series of seven cases. J Cutan Pathol 2012;39:317-23. 4. Costache M, Bresch M, Böer A. Desmoplastic trichoepithelioma The list of differential diagnostic considerations versus morphoeic basal cell carcinoma: A critical reappraisal embraces trichoadenoma, trichoepithelioma, of histomorphological and immunohistochemical criteria for syringoma, sebaceous hyperplasia, granuloma annulare, differentiation. Histopathology 2008;52:865-76. 5. Seo SH, Kim GW, Sung HW. Imiquimod as an adjuvant BCC, microcystic adnexal carcinoma and squamous treatment measure for desmoplastic trichoepithelioma. Ann cell carcinoma.[2] Differentiation from morphea-like Dermatol 2011;23:229-31. BCC may be extremely difficult, especially when a Access this article online lesion is sampled only in part. Immunohistochemical Quick Response Code: markers may help the pathologist to distinguish DTE Website: www.ijdvl.com and morphea-like BCC. In particular, identification of CK20-positive Merkel cells within the lesion, DOI: 10.4103/0378-6323.120754 the presence of CK15 expression in tumoral cells and CD34 expression in peritumoral stroma, along PMID: ***** with the absence of CEA androgen receptor and

848 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 e-IJDVL

For full text visit www.ijdvl.com (E-ISSN 0973-3922)

Net Letter 1 AArere ddermatologistsermatologists familiarfamiliar withwith acronyms?acronyms?

MMarkoviarković MMilica,ilica, IIvanovivanović BBranislavranislav1, BBjekijekić MMilan,ilan, SSipeticipetic SSandraandra2 City Institute for Skin and Venereal Diseases, Belgrade, 1Faculty of Philology, Belgrade University, Belgrade, 2Institute of Epidemiology, School of Medicine, Belgrade, Serbia

DOI: 10.4103/0378-6323.120756 - PMID: ****

How to cite this article: Milica M, Branislav I, Milan B, Sandra S. Are dermatologists familiar with acronyms?. Indian J Dermatol Venereol Leprol 2013;79:849. Net Letter 2 FFamilialamilial ccongenitalongenital generalizedgeneralized hypertrichosishypertrichosis

NNeerjaeerja Goel,Goel, SShalinihalini Rajaram,Rajaram, BindiyaBindiya Gupta,Gupta, KanikaKanika GuptaGupta Department of Obstetrics and Gynecology, UCMS and GTB Hospital, Dilshad Garden, Delhi, India

DOI: 10.4103/0378-6323.120757 - PMID: ****

How to cite this article: Goel N, Rajaram S, Gupta B, Gupta K. Familial congenital generalized hypertrichosis. Indian J Dermatol Venereol Leprol 2013;79:849. Net Letter 3 EEosinophilicosinophilic panniculitispanniculitis afterafter subcutaneoussubcutaneous administrationadministration ofof sodiumsodium hheparineparin

AAnana BBatalla,atalla, EElenalena RRosón,osón, CeliaCelia Posada,Posada, ÁngelesÁngeles FlórezFlórez Department of Dermatology, Pontevedra Hospital Complex, Pontevedra, Spain

DOI: 10.4103/0378-6323.120758 - PMID: ****

How to cite this article: Batalla A, Rosón E, Posada C, Flórez Á. Eosinophilic panniculitis after subcutaneous administration of sodium heparin. Indian J Dermatol Venereol Leprol 2013;79:849. Net Letter 4 DDee SSanctis-Cacchioneanctis-Cacchione syndromesyndrome HHemaema Mittal,Mittal, SSumitumit MMehndirattaehndiratta1, JJayaaya SShankarhankar KKaushik,aushik, TTusharushar GGodboleodbole Department of Pediatrics, UCMS and GTB Hospital, 1Lok Nayak Hospital, New Delhi, India

DOI: 10.4103/0378-6323.120760 - PMID: ****

How to cite this article: Mittal H, Mehndiratta S, Kaushik JS, Godbole T. De Sanctis-Cacchione syndrome. Indian J Dermatol Venereol Leprol 2013;79:849. Net Quiz EErythematousrythematous induratedindurated plaqueplaque lesionslesions onon thethe breastbreast BBilgeilge BBülbülülbül Şen,en, EEminemine NNurur RRifaioifaioğlu,lu, ÖÖzlemzlem EEkiz,kiz, TTümayümay ÖÖzgürzgür1, SSeçkineçkin AAkküçükkküçük2, MMehmetehmet Uğuurr İnnan,an, AAsenasena ÇiÇiğdemdem DoDoğramacramacı Departments of Dermatology, 1Pathology, 2General Surgery, Mustafa Kemal University School of Medicine, Hatay, Turkey

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vo l 79 | Issue 6 849 e-IJDVL

DOI: 10.4103/0378-6323.120761 - PMID: ****

How to cite this article: Şen BB, Rifaioğlu EN, Ekiz Ö, Özgür T, Akküçük S, İnan MU, et al. Erythematous indurated plaque lesions on the breast. Indian J Dermatol Venereol Leprol 2013;79:849.

A 50-year-old female patient, who had retraction of the right nipple for 2 years and erythema in the same breast for 2 months, was referred to our clinic. Mammography and breast ultrasonography performed at the time of onset of nipple retraction were normal. Dermatological examination revealed three erythematous, mildly indurated plaque lesions on the right breast, one of which involved the areola [Figure 1]. The nipple was retracted. The patient had no subjective complaints. The right axillary examination detected several lymphadenopathies, as confirmed by ultrasonography. The histopathological examination of the skin biopsy revealed islands of tumor cells in the dermal lymphatics [Figure 2]. These infiltrations consisted of round-shaped atypical cells with vesiculated nuclei and marked nucleoli. In immunohistochemical studies, strong positive staining by low-molecular weight keratin (LMWCK) and epithelial membrane antigen (EMA) and non-specific staining by vimentin have been detected.

WWHATHAT ISIS YOURYOUR DIAGNOSIS?DIAGNOSIS?

Figure 1: Three erythemateous plaques on the right breast, one Figure 2: Tumor islands consisted of atypical epithelium cells in involving the areola the lymphatics (H and E, ×200)

850 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Book Review

CCriticalritical CCareare inin DermatologyDermatology

Editiors: Arun C Inamadar and Aparna Palit Publisher: New Delhi: Jaypee Brother Medical Publishers (P) Ltd, India ISBN 978-81-924968-0-1 Edition: First 2013 Pages: 259 ISBN 978-93-5090-285-1 INR 795/-

The book ‘‘Critical Care in Dermatology’’ by Inamadar are incomplete, lack systematic presentation, and flow. and Palit is a valuable addition in critical care practice The text matter at places is disjointed. Also there is of Dermatology as an easy and handy document. It has repetition of texts at different places which could have a good description of common, uncommon, and rare been avoided. The skin biopsy has often been mentioned dermatological emergencies which Dermatologists as a rapid diagnostic technique which at many centers encounter in their clinical practice. There is a detailed is often not available for such purpose and there are no description of each dermatological emergency: how to histopathological details of the various conditions where recognize it; how to assess the severity and details of biopsy has been recommended or mentioned, to be of management. It also gives a good overview of general help to diagnosis the condition. At places, the tables measures in the management of these emergent situations, are appearing before the text which makes reading of which are of critical importance. There is a full chapter the book uneasy. Sometimes, tables appear at different dedicated to Fluid, Electrolyte and Nutrition Therapy places then the texts, leaving the readers wonders as to which is often a challenge for Dermatologists, since many why these could not have been placed close to the text. are not familiar with the finer details of these therapies and ‘‘Why a particular condition is an emergency’’ good for the detail of the monitoring techniques and procedures the beginners to recognize condition as an emergency during the management of these emergencies. The book and manage it appropriately. also describes sample collection methods from different sites in critically ill patients for appropriate diagnosis and Overall, the book may be of value to Dermatologists management. The issue of nursing care in Dermatological working in a hospital setting and for trainees. Reducing emergencies, which is an over-sighted aspect in the the number of tiny illustrations on the front page, management of such emergent situations, has been well avoiding shades of color on the top of each page and emphasized and appropriately detailed. The concept of slightly larger font-size of the text could have made the Dermatological Intensive Care Unit is well highlighted book more reader friendly. in the book with details of necessary equipments needed for such set-up. A dedicated chapter on the Drugs used KKaushalaushal K.K. VermaVerma in Dermatological Emergencies would also be handy Department of Dermatology and Venereology, for treating physicians, to critically review the different All India Institute of Medical Sciences, New Delhi - 110 029, India. aspects of the drugs including doses, adverse effects, drug E-mail: [email protected] interactions etc., Authors have also included a chapter on Drug Therapy in patients with renal and hepatic Access this article online impairment which may at times be the situations in these Quick Response Code: patients. A chapter on Drugs in Pregnancy and Lactation Website: appears to be an unnecessary avoidable intrusion in the www.ijdvl.com book. More appropriate would have been the inclusion of management of Dermatological Emergencies in Pregnant and Lactating women which may at times be complex and challenging. At places in the texts, the sentences

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 851 Current Best CCurrenturrent bestbest eevidencevidence fromfrom dermatologydermatology literatureliterature – Evidence PPartart I

Seilding V, Hoffmann JH, Enk AH, Hadaschik EN. Analysis • (Good) – skin symptoms ameliorated,; of high-dose intravenous immunoglobulin therapy in autoantibody titer: No change or lower titer, 16 patients with refractory autoimmune blistering skin • (Satisfactory) – skin symptoms unchanged; disease: High effi cacy and no serious adverse events. autoantibody titer: No change or higher titer, Acta Dermato-Venereol 2013;93:346-9. • (Unsatisfactory) – skin symptoms deteriorated; High-dose intravenous immunoglobulin (IVIG) autoantibody titer: No change or higher titer. have been shown to be effective in treating severe autoimmune diseases that are refractory to standard By the end of the 24-month observational period, most immunosuppressive therapy. Although considered of the patients were still receiving IVIG. The mean total effective and safe in treating autoimmune blistering number of cycles per patient was 38.6. Adverse events diseases, a clear evidence for its therapeutic effect were recorded in 87.5% of patients and in 56.3% of total besides case reports and case series is missing. infusion cycles. Headache (43.8%) and fatigue (43.8%) were the commonest side effects recorded. Only one A retrospective analysis of 16 patients (10 patients patient reported petechiae after a single infusion cycle. with pemphigus vulgaris, 3 with pemphigus foliaceus, Majority of patients had a very good score (43.8%, and one patient each with paraneoplastic pemphigus, bullous pemphigoid, and paraneoplastic bullous 75%, 61.5%, and 58.3%, respectively) in all of the four pemphigoid), refractory or relapsing disease under half-year periods. Also tapering of steroids up to a immunosuppressive combination therapy with at least mean reduction of 75.8% in starting dose was possible two immunosuppressive drugs and who had received without relapse in most patients. IVIG therapy for at least six full cycles, between January 2004 and July 2011 was done. The mean age and the Comment: IVIG is prepared from the pooled plasma mean duration from diagnosis to initiation of IVIG of donors. Although initially used in the treatment of therapy was 50.4 years and 40.8 months, respectively. primary immunodeficiency syndromes, recently its use Patients had a mean of 2.9 immunosuppressive drugs has been widely explored as an off-label indication in prior to initiation of IVIG therapy. High-dose IVIG a variety of autoimmune and inflammatory conditions was administered at a total dose of 2 g/kg body weight across multiple specialties. intravenously per cycle over 2 days after ruling out the contraindications. Patients received IVIG every Treatment of autoimmune bullous skin diseases can 4 weeks, and prior to discontinuation of IVIG the time often be challenging. The treatment options primarily between the cycles was extended to 5 or 6 weeks. comprise systemic corticosteroids and a variety of immunosuppressants. Current treatment strategies are Efficacy of IVIG therapy was assessed with changes effective in most cases, but side effects of long-term in skin symptoms, changes in autoantibody titers, immunosuppressive treatment are a limiting factor in and tapering of steroid dose. Laboratory blood tests some cases. including antibasement membrane antibodies and anti-intercellular epidermal antibodies were routinely In addition, few patients fail to respond or experience performed. To measure efficacy of IVIG therapy, a score frequent relapses. Some of the immunosuppressives for each 6 months during the total period of 24 months have a long latency before benefit begins. The situation was used: becomes all the more problematic in children for the • (Very good) – no skin symptoms; autoantibody fear of growth retardation. Secondary infection, which titer: No change or lower titer, may be either systemic or localized to the skin, may

How to cite this article: Citation will be included before issue gets online***

Received: August, 2013. Accepted: August, 2013. Sources of Support: Nil. Confl ict of Interest: None declared.

852 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Mangal and Kumaran Current best evidence from dermatology literature occur because of the use of immunosuppressants and niacinamide 4% and desonide 0.05% emulsions in the the presence of multiple erosions. Unlike most therapies treatment of axillary hyperpigmentation. for blistering disorders, IVIG is not immunosuppressive and has a favorable side effect profile. Twenty-four women aged 19-27 years with hyperpigmented axillae (phototypes III-V) were This has allowed its use to expand dramatically over randomly assigned to receive the study treatments the past decade. It is generally accepted that the in the axillary region. Improvement was assessed at use of IVIG should be limited to patients who (1) baseline, then clinically and by colorimetry 9 weeks fail conventional therapy; (2) have side effects or later. Quantitative evaluation including melanin, contraindications to conventional therapy that limits inflammatory infiltrates, NKI/BETEB, CD1a, CD68, its use; and/or (3) have rapidly progressive disease or and collagen type IV content was performed by progressive disease despite conventional therapy. histochemistry and immunohistochemistry, assisted by computerized morphometric analysis. This study demonstrates tapering of steroids up to a mean reduction of 75.8% from starting dose Both niacinamide and desonide induced significant without relapse in most patients. Most of the reports colorimetric improvement compared with placebo; utilizing IVIG at a dose of 2 gm/kg/cycle have shown however, desonide showed a better depigmenting a positive clinical outcome, decrease in pathogenic effect than niacinamide. A good to excellent response autoantibodies, and a steroid-sparing effect. was achieved in 24% of cases for niacinamide, 30% for desonide, and 6% for placebo. Side effects, It has been well documented that IVIG causes a rapid including local erythema, burning, pruritus, decline in pathogenic autoantibody levels following infection, and skin atrophy, were absent during the which there is often a rebound increase, as in trial. In addition to the associated inflammatory cell plasmapheresis. It has been hypothesized that use of infiltrates, a physical discontinuity of the epidermal IVIG along with rituximab or cyclophosphamide would basal membrane was found which improved after be more beneficial in causing decline in pathogenic exposure to both drugs and was more evident in the antibodies, suppressing the rebound increase and desonide group. providing a sustained long-term remission with relatively low infectious complication rates. Comment: Postinflammatory hyperpigmentation (PIH) is an acquired hypermelanosis occurring after In general, most published reports on IVIG have cutaneous inflammation or injury. It can arise in all been retrospective analysis. There is a paucity of skin types, but is more frequent in individuals with well-designed prospective trials. There is a need for darker skin (Fitzpatrick skin types IV to VI) as the randomized controlled trials for determining the melanocytes of darker-skinned individuals show an efficacy and adverse effects of IVIG in the treatment of exaggerated response to cutaneous injury. PIH can autoimmune bullous skin diseases. have a significant psychosocial impact, which is well supported by various epidemiological studies Castanedo-Cazares JP, Lárraga-Piñones G, Ehnis-Pérez A, that depict dyschromias. Axillary hyperpigmentation Fuentes-Ahumada C, Oros-Ovalle C, Smoller BR, et al. Topical has not been extensively studied due to its primarily niacinamide 4% and desonide 0.05% for treatment of cosmetic nature and lack of any major and significant axillary hyperpigmentation: A randomized, double-blind, health implications. It has been proposed that placebo-controlled study. Clin Cosmet Investig Dermatol axillary skin darkening is best defined as mild PIH, 2013;6:29-36. characterized by increased epidermal melanin Axillary hyperpigmentation is a frequent cause of production, following mild irritation or stimulation of cosmetic consultation among dark-skinned women the skin. The treatment of hyperpigmentation in these from tropical areas, including Latin America. patients has remained challenging for dermatologists. Currently, there is no widely accepted treatment for the disorder. It is usually treated with bleaching agents Axillary skin is distinctly different from those of other because it is considered a variant of inflammatory body sites, as it has reduced barrier integrity. Studies hyperpigmentation. This was a 9-week, randomized, have shown cholesterol, ceramide 3, and lactic acid double-blind, left–right axilla, placebo-controlled levels to be increased, and natural moisturizing factor trial study conducted to assess the efficacy of amounts to be lower, cornified envelopes to be smaller

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 853 Mangal and Kumaran Current best evidence from dermatology literature indicative of a shorter stratum corneum turnover, evaluation of hair growth, the three regions of interest compared with the volar forearm. of each axillary region were photodocumented at each visit with a handheld dermatoscope. Final Although the precise pathogenesis is unknown, it assessment was conducted 12 months after the last is thought to result from cytokines, inflammatory treatment by means of hair counts using close-up mediators, and reactive oxygen species. In some photographs. The primary endpoint was reduction individuals, the axillary skin may face additional in hair growth, analysed on an intention-to-treat challenges including leaching of lipids and proteins and last-observation-carried-forward basis (n = 30), from the stratum corneum by cleansing surfactants, or and secondary endpoints were patient-rated efficacy, additional irritation induced by shaving and plucking treatment-related pain, adverse effects, and treatment which further impairs the natural barrier to exogenous duration. irritants. Histological evaluation of female Filipino axillary skin has revealed that the trauma of underarm All participants completed the 3- and 6-month follow-up hair plucking is associated with melanosome leakage evaluations (visits 7 and 8), but only 25 volunteers into the dermis and hence increased pigmentation, as were available for the 12-month follow-up (visit 9). well as mononuclear cell and macrophage infiltration. Both devices significantly reduced hair counts. Mean reductions from baseline (3 and 12 months after This study reveals that niacinamide and desonide the last treatment) were 59.7% and 69.2% for DL have depigmenting properties in women with axillary and 42.4% and 52.7% for IPL treatment (P < 0·01), hyperpigmentation along with the added advantage respectively. DL treatment induced significantly more of improvement in the physical discontinuity of the pain [3.7 ± 2.1 (DL) vs 1.6 ± 1.4 (IPL); P < 0.01; VAS] epidermal basal membrane. However, multicentered but could be conducted faster [33.1 ± 3.8 s (DL) vs trials including a large number of patients would be 40.1 ± 5.0 s (IPL); P < 0.01]. No severe side effects helpful in providing a better interpretation. were observed for either therapy.

Klein A, Steinert S, Baeumler W, Landthaler M, Comment: Advances in laser technology have led to Babilas P. Photoepilation with a diode laser vs. intense the establishment of laser hair reduction as a safe pulsed light: A randomized, intrapatient left-to-right trial. modality for the treatment of unwanted hair on any Br J Dermatol 2013;168:1287-93. body part. An ideal patient has thick dark terminal Photoepilation with lasers or intense pulsed light (IPL, hair, white skin, and a normal hormonal status. There 590-1200 nm) sources is a widely used efficient and safe is a paucity of data regarding the safety and efficacy of treatment modality for the removal of unwanted hair. lasers in dark-skinned individuals. Devices currently in use work on the basis of the selective photothermal destruction of hair follicles, which is Studies in the past have compared diode and Nd: YAG based on the principle of selective photothermolysis. laser in terms of efficacy for hair reduction with This randomized controlled trial (RCT) was undertaken most of them showing DL to be more comfortable to compare the efficacy, side effects, and patient-rated and efficacious. However, without the use of topical efficacy of two popular light devices for hair removal, a anesthetics, patient preference might be based on pain diode laser (DL) and an IPL source. level during the treatment session.

IPL and DL treatments were evaluated in 30 Few studies done in the past have directly compared participants with a mean age of 33·7 years (skin types long-term outcomes of lasers with IPL with both the II–III) with unwanted axillary hair. Six treatments with lasers and light devices showing similar long-term each device were carried out at 4-week intervals. The efficacy contradicting the results of this study. Current two axillary regions of each patient were randomized long-term evidence on efficacy of IPL is sparse. Few to the two competing procedures. After each laser trials comparing diode with IPL have shown similar treatment, study subjects were evaluated for immediate efficacy at 6 months after treatment contrary to the side effects, such as burning, edema, and blistering. results in this study. A visual analog scale (VAS) ranging from 0 to 10 was used for the self-assessment of pain (0 = no pain, In this study, all sessions were repeated at 4-week 10 = maximum pain) at every treatment visit. The mean intervals. The resting phase for axillary hair tends to score for all six visits was obtained. For the quantitative be longer when compared with the scalp and beard

854 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Mangal and Kumaran Current best evidence from dermatology literature hair. Doing the sessions too frequently might lead Various therapeutic modalities are available for to a temporary suppression rather than destruction treatment of keloids. There is no consensus regarding of hair follicle. Controlled trials would be required the optimal or best management of keloids. Surgical to differentiate the hair reduction in the long term excision alone has been found to have a low success achieved when sessions are done at 4 weekly intervals rate with a high incidence of recurrence in previous versus increasing the gaps after second session. studies. Intralesional injection of corticosteroids is one of the mainstays in the management of earlobe Careta MF, Fortes AC, Messina MC, Maruta CW. keloids. Monotherapy with intralesional injection of Combined treatment of earlobe keloids with shaving, steroids has been found to alleviate the subjective cryosurgery, and intralesional steroid injection: A 1-year symptoms in most of the studies with variable success follow-up. Dermatol Surg 2013;39:734-8. in improving the objective symptoms. Earlobe keloids are benign, fibrous proliferations occurring in predisposed persons at sites of cutaneous In the recent literature, surgical excision along with injury (ear piercing, burns, or surgical procedures). adjuvant therapy is recommended. There is no Twelve consecutive patients with earlobe keloids were standardized protocol regarding the administration treated with a combination of surgery and cryosurgery. of intralesional corticosteroids. Some have advocated The surgical procedure consisted of shaving after local the instillation of steroids after removal of the sutures anesthesia leaving 1-2 mm of the remaining lesion at followed by weekly or fortnightly injections. Few have the borders. Cryosurgery (liquid nitrogen spray) of the also advocated the use of intralesional steroids prior to underlying tissue followed it. One cycle of freezing was surgical excision. performed (freezing time 60 s). Patients were evaluated 7 and 30 days after the surgical procedure. At day 30, Cryosurgery as monotherapy for the treatment of cases with persistent keloid lesion received adjuvant earlobe keloids has shown diverse results. The recently therapy with intralesional injection of triamcinolone introduced intralesional cryoneedle method has been acetonide (10-20 mg/mL). Monthly evaluation found to be simpler and safer to use, requiring less was done. The mean posttreatment follow-up was postoperative care. 12 months. Major response, moderate response, and failure was defined as 80%-100% reduction in keloid In this study, major response was observed in majority thickness, 50%-80% reduction in keloid thickness, of the cases at 1 year of follow-up with shaving, and improvement of less than 50% or complete relapse cryotherapy, and intralesional steroids. The success rate after treatment, respectively. of combination of surgery and triamcinolone acetonide injection has shown great variation across different After 1 year, major and moderate response were studies with some exhibiting unsatisfactory response. observed in 9 cases (75%) and 2 cases (16%), Here the treatment modality consists of three different respectively; 1 case had relapse 5 months after surgery. treatment techniques. The favorable response illustrated The number of intralesional triamcinolone injections probably reflects the synergism of the combinations. varied from none to 4. However, in a given patient, the location, size, depth, and duration of earlobe keloids are critical factors in Comments: Earlobe keloids are benign fibrous deciding the individualized modality of treatment. proliferations characterized by an excess of collagen deposition. They occur in predisposed individuals Although this study reveals good comprehensive at sites of trauma, ear piercing, burns, or surgical results, studies dealing with duration of keloids procedures. The incidence is higher in blacks and comparing with various treatment responses need to Asians when compared with Caucasians. be carried out.

They are commonly encountered in day-to-day clinical Poot AM, Diercks GF, Kramer D, Schepens I, practice and pose a challenging management problem Klunder G, Hashimoto T, et al. Laboratory diagnosis and distinctive cosmetic implications. Clinically, they of paraneoplastic pemphigus. Br J Dermatol 2013. appear as shiny, smooth, globular growths on one or both [In press] sides of the earlobe. Pruritus, pain, and paresthesias can Paraneoplastic pemphigus (PNP) is a multiorgan disease be another source of distress for some of these patients. characterized by antibodies against plakins, desmogleins,

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 855 Mangal and Kumaran Current best evidence from dermatology literature and the alpha-2-macroglobulin-like-1 (A2ML1) protein, and toxic epidermal necrolysis, hence demonstration in association with an underlying neoplasm. This of antiplakin antibodies alone is not sufficient to point study was undertaken to compare the diagnostic value toward the diagnosis of PNP. of different laboratory techniques in the serological IP has been found to be the most sensitive and specific diagnosis of PNP by performing immunoblotting, test for demonstrating antiplakin antibodies in ELISA for envoplakin (EP_ELISA), anti-Dsg1, anti-Dsg3, most of the studies, qualifying as a major diagnostic BP180, BP230, indirect immunofluorescence (IIF) on criteria for PNP. However, tedious nature, cost, and rat bladder, radioactive immunoprecipitation (IP), and lack of easy availability are the limiting factors. This a nonradioactive combined IP-immunoblot assay on the study shows sensitivity of radioactive IP assay to sera of 19 PNP (median age of 56.6 years) and 40 control be superior to IB, IIF on rat bladder, and EP-ELISA. Also, the nonradioactive IP showed marginally higher patients. The diagnosis of PNP was made if patients sensitivity than the radioactive IP. In the absence of IP, fulfilled the revised criteria proposed by Anhalt in 2004 combination of IB and rat bladder-IIF may be used as and Zimmerman in 2010. the first serological test for confirming the diagnosis of PNP. Sensitivities for anti-EP ELISA, rat bladder IIF, immunoblotting (IB), radioactive IP, and nonradioactive However, more studies with larger number of patients IP were 63%, 74%, 89%, 95%, and 100%, respectively, are required to support the findings, which would with specificities ranging from 86% to 100%. Low be of a substantial help in accurately diagnosing this sensitivity and specificity were observed with often-fatal disease with a myriad of variable cutaneous BP180- and BP230-ELISAs. morphologies and the morbidity of recalcitrant mucosal lesions. Comment: PNP is a distinct autoimmune blistering dermatosis occurring in association with various Moftah N, Moftah N, Abd-Elaziz G, Ahmed N, neoplasms. The clinical features consist of recalcitrant, Hamed Y, Ghannam B, et al. Mesotherapy using painful oral erosions that may be accompanied by dutasteride-containing preparation in treatment of polymorphic cutaneous eruptions and systemic female pattern hair loss: Photographic, morphometric involvement. It is characterized by the presence of and ultra structural evaluation. J Eur Acad Dermatol autoantibodies against desmoglein 3 (Dsg3) (130 kd), Venereol 2013;27:686-93. desmoglein 1 (Dsg1) (160 kd), envoplakin (210 kd), Female pattern hair loss (FPHL) is one of the most periplakin (190 kd), desmoplakin I (250 kd), common causes of hair loss, affecting 50% of women desmoplakin II (210 kd), bullous pemphigoid antigen 1 in the age of 50 years. Treatment of FPHL is frustrating (BPAG1) (230 kd), plectin (>400 kd), and a previously for both patients and doctors. This study including unidentified 170-kd protein which has recently been 126 female patients with FPHL was carried out to identified as A2ML1, a broad-range protease inhibitor evaluate the efficacy and safety of mesotherapy using expressed in stratified epithelia. dutasteride-containing preparation. The patients were classified into two groups: Group I (86 patients) (mean Histological findings vary considerably according age 34.1 ± 6.6 years) and group II (40 control to the clinical presentation and age of the lesions patients) (mean age 34.8 ± 7.2 years) injected with with predominant suprabasal acantholysis in dutasteride-containing preparation and saline, noninflammatory blisters, whereas interface and respectively. Patients received 12 sessions over lichenoid dermatitis in erythematous inflammatory a period of 16 weeks and were evaluated at the maculopapular lesions. DIF is negative in half of 18th week by photographic assessment, hair pull test, PNP patients and false negatives are also common, hair diameter, and patient self-assessment. Ultra attributable to lichenoid lesions and necrotic tissue in structural evaluation was done for three patients the mucosal biopsies. The presence of autoantibodies using five of the randomly epilated hairs from the to plakins is a characteristic feature with highest vertex as described by Wyatt and Riggott, before and specificity for envoplakin and periplakin followed by at the 18th week using scanning electron microscope. desmoplakins. Plakin autoantibodies, however, have Photographic improvement was seen in 62.8% of been found in other conditions such as pemphigus patients compared with 17.5% in control group. vulgaris, pemphigus foliaceous, erythema multiforme, Significant improvement in mean hair diameter and

856 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Mangal and Kumaran Current best evidence from dermatology literature decline in mean number of epilated hairs were seen in In this study, dutasteride administered by meso therapy group I. Side effects were minimal with no statistically demonstrated significant increases in target area hair significant difference between the two groups. Ultra count in comparison to placebo, as early as 12 and structural examination of pretreated hairs revealed 24 weeks. In few studies assessing the efficacy and absent cuticle in one patient and focal destruction of safety of five alpha inhibitors in androgenetic alopecia, the cuticle in the second patient, which reappeared in dutasteride was found to be superior to finasteride at both after therapy. There was a negative correlation 12 and 24 weeks in male pattern hair loss. Also, few between degree of improvement and duration of reports showed noteworthy response with dutasteride FPHL (P < 0.05). in patients with limited improvement after 6 months of finasteride. This study results reiterate the above Comment: FPHL is the most common cause findings. of alopecia in women characterized histologically by increased numbers of miniaturized hair follicles. Current treatment options are limited, and even Although medically benign, the impact is in positive responders a considerable time delay predominantly psychological leading to distress, low occurs before improvement is apparent. In cases of self-esteem, depression, and impaired quality of life in advanced alopecia (Ludwig grade III) and failure a significant number of affected females. with aforementioned medical therapies, surgical management remains an important option. Dutasteride The goal of treatment is to arrest the progression of may be considered as an additional treatment option, alopecia and stimulate new hair growth. Two main following further studies in cases of grade I and II FPHL. pharmacological options currently widely used are antiandrogens and minoxidil, which need to SSoniaonia Mangal,Mangal, MuthuMuthu SendhilSendhil KumaranKumaran be continued indefinitely to attain and maintain Department of Dermatology, Venereology and Leprology, response. Postgraduate Institute of Medical Education and Research, Chandigarh, India

Mesotherapy has gained a lot of attention in recent AAddressddress forfor correspondence:correspondence: Dr. M. Sendhil Kumaran, past; however, the scientific basis is not established. Department of Dermatology, Venereology and Leprology, The US FDA in view of lack of documented evidence Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012, India. has not yet approved it. On theoretical grounds, it E-mail: [email protected] can be hypothesized that dutasteride might be more efficacious than finasteride as the latter being a selective Access this article online inhibitor of type 2 isoenzyme of 5-alpha reductase has Quick Response Code: the capability to reduce serum dihydrotestosterone Website: levels by about 70%, whereas dutasteride inhibits www.ijdvl.com both isoenzymes inducing more than 90% reduction in the dihydrotestosterone levels. Longer half-life of dutasteride when compared with finasteride has been a limiting factor for the former’s use.

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 857 Current Best CCurrenturrent bestbest eevidencevidence fromfrom dermatologydermatology literatureliterature – Evidence PPartart IIII

Calabrò G, De Vita V, Patalano A, Mazzella C, Lo Conte V, group A resulted in significant overall lightening of the Antropoli C. Confi rmed effi cacy of topical nifedipine in skin compared with baseline and the control group. the treatment of facial wrinkles. J Dermatolog Treat The absence of de-pigmenting agents in the tested 2013; Early Online: 1-7. product suggests a possible role of nifedipine in skin There has been an ever-increasing demand for aesthetic lightening. No significant change in blood pressure procedures to reverse the effects of aging, particularly and heart rate were recorded during this study. in the facial area. Recently, topical nifedipine has been found to have anti-wrinkle effects. The aim of this study Comment: Both intrinsic and extrinsic factors was to confirm the anti-wrinkle efficacy and tolerability influence the aging process. Extrinsic factors include of a 0.5% nifedipine-based topical formulation. sun exposure, repetitive or exaggerated mimic expressions, gravity, and smoking. Reactive oxygen A randomized study was conducted in 20 healthy species (ROS), a byproduct of both environmentally female volunteers aged between 45-60 years with induced and intrinsic aging, lead to a cascade of moderate to moderately severe facial wrinkles and biochemical reactions within the skin, resulting in the Fitzpatricks skin phototypes II-IV. Ten volunteers production of matrix metalloproteinases (MMPs) and (group A) applied a cream containing nifedipine at a proinflammatory cytokines. Reduction in collagen concentration of 0.5%, hyaluronic acid, collagen, and and elastin and a loss in hydration are the main vitamin A and E, and the other 10 (group B) applied a structural changes in skin resulting from aging leading good moisturizer, containing hyaluronic acid, collagen, to wrinkling. Wrinkles can be divided into four main and vitamin A and E. Patients in both groups were types: Atrophic crinkling rhytids, permanent elastotic instructed to apply measured amounts (0.1 g) of topical creases, dynamic expression lines, and gravitational formulations on forehead, nose-geniene, periocular folds. Each type usually develops on specific and perilabial wrinkles, twice daily for 3 months after skin regions exhibiting distinct micro-anatomical washing the face with the same mild facial cleanser. All characteristics. However, the most important parameters were evaluated at baseline (T0), and then pathogenic mechanism is the chronic contraction of 30 (T1), 60 (T2), and 90 (T3) days later. The aesthetic mimic muscles. improvement was evaluated by a blinded investigator using the Wrinkle Severity Rating Scale (WSRS) with Nifedipine is a dihydropyridine-type calcium channel grade 1 indicating minimum severity and grade 5 blocker that blocks the transmembrane influx of indicating maximum severity. In group A, mean calcium ions into muscle cells inhibiting their WSRS scores at T1 (2.79), T2 (1.99), T3 (1.84) were contraction, thus accounting for its efficacy in the approximately 1.38, 1.93, and 2.09 times lower than treatment of facial wrinkles. In nifedipine group, there mean WSRS score at T0 (3.85), respectively. In group B, was a greater improvement in viscoelastic properties the mean WSRS score at T0 was 3.78, at T1 3.41, at of skin, and another significant effect observed T2 3.42, and at T3 3.36. Post-treatment WSRS score was skin lightening. Authors have not provided was significantly lower than the baseline WSRS score explanation for the observed skin lightening effect. only in the nifedipine group. Its poor percutaneous penetration combined with its rapid metabolism in the skin limits its systemic Improvement in skin hydration was found to be more absorption and side-effects. So, topical nifedipine in group A than in group B at the end of the study preparations can prove to be an economical, effective, period of 90 days. Also, the use of nifedipine cream in and convenient means of anti-wrinkle treatment.

How to cite this article: Citation will be included before issue gets online***

Received: July, 2013. Accepted: July, 2013. Sources of Support: Nil. Confl ict of Interest: None declared.

858 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Prashar and Yadav Current best evidence from dermatology literature

Further in-depth studies are needed to evaluate the bacillus-calmette-guérin (BCG) and exposure to anti-aging effects of topical nifedipine over longer non-tuberculous mycobacteria. A two-step test, also treatment period and its possible role not only in skin known as a booster PPD, has been suggested, in which rejuvenation, but also in the prevention of cutaneous a second PPD is administered 1-3 weeks after the aging by increasing skin hydration and elasticity. first to provoke an anamnestic response to reinforce weakened immune memory. This is useful in older Amerio P, Amoruso G, Bardazzi F, Campanati A, patients or in patients who are at high risk of infection Cassano N, Conti A, et al. Detection and management but show a negative result on the first PPD test. In vitro of latent tuberculosis infections before biologic therapy immunological tests for LTBI include QuantiFERON for psoriasis. J Dermatolog Treat 2013;24:305-11. and T-SPOT.TB, collectively referred to as IGRAs. The biologic agents are highly efficacious in the These assays correlate better with TB exposure, and treatment of psoriasis and psoriatic arthritis. However, they are not influenced by vaccination with BCG or their use is associated with an increased risk of previous exposure to non-tuberculous mycobacteria. developing active tuberculosis (TB). All patients should They also have a higher specificity. IGRAs employing be screened for latent tuberculosis infection (LTBI) prior a cocktail of antigens may be more sensitive than PPD to initiating therapy. This article reviews the current in immunosuppressed patients. recommendations for screening and chemoprophylaxis of LTBI in Italian psoriasis patients treated with biologics. A positive IGRA test is an indication for prophylactic treatment, independent from the results of other LTBI is defined by the presence of Mycobacterium tests. The situation is less clear when the IGRA and tuberculosis without clinical symptoms, and radiology results are negative, but the PPD is positive. bacteriological and radiographic signs of disease. In this case, it is necessary to carefully evaluate the Only about 10% of these patients develop active TB, individual situation. If the medical history does not immunosuppression being a major risk factor for suggest a risk, the PPD result is generally considered a activation. Among the anti-TNF- agents, the risk of probable false-positive, especially if there is a history LTBI activation is three to four times higher with the monoclonal antibodies (adalimumab, infliximab, and of BCG vaccination. However, chemoprophylaxis certolizumab) as compared to etanercept. There are no may still be initiated if a false-negative IGRA result is reports of LTBI reactivation with alefacept. The risk suspected. If the X-ray results are positive while the of LTBI with ustekinumab is lower than that observed other tests are negative, the patient should be referred with anti-TNF-  therapy. However, screening for LTBI to a pulmonologist for further evaluation. is recommended before starting any biologic therapy for psoriasis. For prophylactic treatment, in most cases, isoniazid at a dose of 300 mg/day for 9 months is recommended. According to the recommendations of an expert The combination of rifampicin/pyrazinamide is working group of Italian dermatologists, screening not recommended due to the risk of hepatotoxicity. process for LTBI includes taking complete medical Anti-TNF- therapy can be started at least 1 month history, chest X-ray (CXR), purified protein derivative after initiating prophylactic therapy. skin test (PPD), and interferon  release assays (IGRAs). History pertaining to age, TB vaccination, previous TB Comment: The advent of TNF- inhibitors as a infections, family history of TB, exposure to possible treatment modality in psoriasis is a significant step sources of infection, and any recent immunosuppressive forward in its management. However, a significant or long-term antibiotic therapy should be taken. CXR roadblock still remains due to the risk of developing should be performed in two projections and interpreted TB in patients with LTBI preventing the optimal by a radiologist (although US National Psoriasis utilization of this modality. Animal studies have Foundation consensus statement recommends an X-ray shown that TNF- inhibition impairs inflammatory only if immunologic tests are positive). Indurations cell trafficking and granuloma formation. Currently larger than 5 mm are considered positive in the PPD recommended screening for LTBI, typically, risk test. Although having good sensitivity, false negatives assessment, tuberculin skin testing (TST), and CXR can result from immunosuppression as a consequence used prior to anti-TNF- treatment can significantly of an autoimmune disease, medication, and age. reduce TB activation rates, but newer screening tests False positives test can result from vaccination with like IGRAs may enhance screening efficacy further.

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 859 Prashar and Yadav Current best evidence from dermatology literature

Patients positive on screening who are treated with number of false-positive TST results and the reduced isoniazid and subsequently receive anti-TNF- diagnostic specificity of the TST in BCG-vaccinated treatment still have approximately 19% risk for TB. populations may greatly diminish the value of traditional screening method of TST in psoriatic IGRA test has a better sensitivity and specificity than patients in India. TST needs to be combined with TST in detection of LTBI and is superior for predicting clinical history and supportive evidence from CXR TB infection, especially in immunosuppressed and IGRA’s to help decision-making while screening patients. In a country like India where BCG vaccination for LTBI in psoriasis patients being considered for is routinely administered to all in infancy, IGRA anti-TNF  therapy . test has still higher utility, and the requirement for TB chemoprophylaxis can be significantly reduced. Wolosker N, Campos JR, Kauffman P, Yazbek G, Neves S, A strategy of simultaneous testing to optimize Puech-Leao P. Use of oxybutynin for treating plantar diagnostic sensitivity is suggested in the clinical use hyperhidrosis. Int J Dermatol 2013;52:620-3. of biological drugs. IGRAs performed post-TST was Plantar hyperhidrosis (PLH) is an emotionally distressing elevated since day 3. So, it is advisable that when using condition. Several anti-cholinergic drugs have been tried a two-step screening strategy, it is better to perform an for its treatment in past, but their use is limited by their IGRA within 3 days after performing the TST. adverse effects. Oxybutynin is an anti-cholinergic drug, which is primarily used for treating urinary disorders A higher rate of TST positivity is found in patients of and diminished sudoresis is one of its side-effects. psoriasis being screened for LTBI than the corresponding The aim of this study was to evaluate the effectiveness inflammatory bowel disease (IBD) patients, which may and patient satisfaction with the use of oxybutynin be due to the priming of their clinically healthy skin when given at low doses for treating PLH. Thirty-five to overreact to a broad-spectrum of antigenic triggers, patients (aged between 18-71 years) with PLH were including M. tuberculosis derived antigens and also there treated with oxybutynin, of these 30 (female-26, male-4) is a higher degree of drug-induced immunosuppression completed the study. They also had hyperhidrosis at in patients of IBD. It seems reasonable to propose that other sites on the body, palmar in 25 (83.3%), axillary in injection of tuberculin antigens into the unaffected 13 (43.3%), craniofacial in 5 (16.6%), and thoracic and skin of patients with overt plaque psoriasis triggers abdominal in 5 (16.6%). During the first week, patients augmented inflammatory reactions resulting in stronger received 2.5 mg of oxybutynin once a day, 2.5 mg twice TST, and adherence to the widely accepted TST-based a day from the eighth to the 42nd day, and from the recommendations for the diagnosis of TB leads to 43rd day till the end of 12 weeks, 5 mg twice a day. overdiagnosis of LTBI in patients with plaque psoriasis. At the completion of 12 weeks of treatment, 70% of In countries, where TB prevalence is very high, the patients had moderate or great improvement in PLH criterion of LTBI diagnosis may be less valuable and more than 60% of patients showed improvement and the guiding principle for LTBI treatment may at all of the hyperhidrosis sites. Two-third of patients not be as strict as in the western countries. Unlike presented improvement in quality of life (QOL). active disease, monotherapy is often used in treating QOL was much better in 9 (30.0%), a little better in LTBI. The lower bacillary load in LTBI reduces the 11 (36.6%), and the same in 10 patients (33.3%). Dry chances of developing resistant mutants, although mouth was the most common side-effect (76.6%). this possibility cannot be fully excluded. Isoniazid Using 5 mg of oxybutynin per day, 66.6% of patients at a dose of 5 mg/kg (upto 300 mg/day) is used for either did not present dry mouth or only presented it chemoprophylaxis for a period of 9 months, and the mildly, which encouraged the patients to continue with anti-TNF therapy can be given at least 1 month after the treatment. Using 10 mg/d, this symptom increased initiating prophylactic therapy. but was tolerated well. Other side-effects reported were headache (10%) and urinary retention (6.6%); The screening protocols for LTBI need to be applied in however, they were not significant enough to lead to a way that there are less false positives so as to avoid discontinuation of treatment. denial of treatment to candidates who are eligible for anti-TNF- therapy. It should also be sensitive enough Comment: Hyperhidrosis is a disorder of excessive to identify patients at risk of LTBI activation. The sweating beyond what is expected for thermoregulatory tendency of patients with psoriasis to have higher needs and environmental conditions. Hyperhidrosis

860 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Prashar and Yadav Current best evidence from dermatology literature may be primary or secondary to medications or not willing for iontophoresis or BTX-A. It has been general medical conditions. Primary hyperhidrosis found to be effective with a minimum of side-effects. has an estimated prevalence of nearly 3% of the population. Topical therapy (20% aluminum chloride Tran KD, Wolverton JE, Soter NA. Methotrexate in solution, 15% aluminum chloride in 2-4% salicylic the treatment of pemphigus vulgaris: Experience in acid gel, and 0.5%, 1%, 2% glycopyrrolate) is generally 23 patients. Br J Dermatol 2013. [In press] considered first-line treatment for most cases of Pemphigus vulgaris (PV) is an autoimmune focal hyperhidrosis. Other topical agents such as mucocutaneous blistering disorder. The first-line glutaraldehyde, formaldehyde, and tannic acid are treatment for patients with PV consists of high-dose seldom used today due to irritancy, skin discoloration, glucocorticoids, which have greatly reduced the and the availability of better alternatives. For those mortality associated with this disease. This is a who fail such treatment, other options available are retrospective chart review of 23 patients of PV who iontophoresis, botulinum toxin A (BTX-A) injections were treated with methotrexate (MTX) between 2001 and surgical or video-assisted endoscopic thoracic and 2012. The primary objective was to evaluate the sympathectomy. But all these modalities have their efficacy of MTX in inducing clinical improvement in limitations. PV patients, as indicated by the drug’s steroid-sparing effect and also to determine if it could be effective as a Only limited data are available regarding the use of monotherapy in maintaining symptom control. oral medications in the management of hyperhidrosis. The various drugs tried include anti-cholinergic All the 23 patients included in the study (before drugs: glycopyrrolate (1-2 mg, once/twice daily), the initiation of methotrexate) were treated with oxybutynin (5-15 mg/day) and tolterodine (4 mg/day), prednisone at a mean maximum dose of 71 mg/day and alpha-2-agonists: clonidine (0.6-1.2 mg/d). (range 20 to 140 mg/day). Thirteen (56.5%) patients had received non-steroidal immunomodulators other Oxybutynin is primarily indicated for urge incontinence than MTX before. The mean dose of prednisone at where it is used in higher dosage (15 mg/d) and the time of initiation of MTX was 35 mg/day (range hence leading to a greater incidence of side-effects in 10 to 70 mg/day). The initial dose of MTX was 7.5 mg these patients. When used in low and progressively weekly, with increases of 5 to 7.5 mg weekly every 2 to increasing doses, it is found to be highly effective 8 weeks depending on the therapeutic response, until for hyperhidrosis with minimum side-effects. There a maximum dose of 15 to 25 mg weekly. Folic acid was improvement in hyperhidrosis at all the sites in at a dose of 1 mg/day was prescribed. Concomitant two-third of the patients. Potential side-effects of oral treatment with topical glucocorticoids such as anti-cholinergics include dry mouth, constipation, clobetasol propionate ointment, dexamethasone oral nausea, blurred vision, urinary retention, drowsiness, rinses and intralesional injections of triamcinolone and dizziness. The side effects of oxybutynin are acetonide 20 mg/mL was continued. Symptom control mild as compared to other anti-cholinergics. In was defined as either complete clearance of skin this study also, the side-effects were mild and lesions, or as “minimal disease activity” exemplified well tolerated by the patients. Because of its rapid by 1 to 2 new lesions every month that could be resorption (Tmax <1 hour), oxybutynin would also controlled with topical therapy and that were not be suitable for use ‘on demand,’ for example, in considered to cause considerable distress by the specific social situations that provoke hyperhidrosis. patient. In patients achieving symptom control after It is contraindicated in patients with urinary retention, addition of MTX, prednisone was tapered. Patients partial or complete obstruction of the gastrointestinal who were successfully weaned from prednisone were tract, paralytic ileus, gastroesophageal reflux disease, then put on tapering doses of MTX. uncontrolled narrow-angle glaucoma and also in those with hypersensitivity to the drug substance. Of the 23 patients included in this study, 2 (8.6%) Limitation of the study is that there was no follow up developed adverse events after initiation of MTX of the patients after the drug was stopped. Treatment requiring cessation of the drug, while 21 (91.3%) of plantar hyperhidrosis is challenging with each had improvement in blistering and were able to therapeutic modality having its own merits and reduce their dose of systemic corticosteroids. demerits. Treatment of PLH with oxybutynin is a good Sixteen (69.6%) patients were eventually weaned alternative in patients failing on topical treatment and completely off prednisone, with a mean time from

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 861 Prashar and Yadav Current best evidence from dermatology literature initiation of MTX to discontinuation of prednisone Most of the studies showing efficacy of MTX in PV of 18 months (range 7-30 months). Five (21.7%) have been retrospective case series. Previous studies patients experienced a partial steroid-sparing effect also suggest that a significant number of patients requiring a mean maintenance dose of prednisone of show clinical improvement with MTX and the 6.75 mg/day. One patient experienced no therapeutic drug has steroid-sparing effects. Further prolonged, benefit after 2 months of MTX reaching a maximum placebo-controlled or multiple-arm prospective dose of 25 mg/week. In the 16 patients who were clinical trials are needed in order to further assess the successfully weaned from prednisone, tapering of role of MTX in the treatment of PV. MTX dose was attempted in 14. Of these 14 patients, the weekly dose of MTX could not be reduced without Tse TW, Hui E. Tranexamic acid: An important adjuvant resulting in a flare of disease in 3 patients, MTX was in the treatment of melasma. J Cosmet Dermatol reduced to 8.75 mg/week (range 5 to 15 mg/week) in 2013;12:57-66. 8 patients, and 3 patients were eventually completely Melasma is a highly prevalent, chronic pigmentary tapered from MTX. Of the 3 patients who were disorder. Tranexamic acid (TA) is a plasmin inhibitor completely tapered off MTX, 2 remained in remission used to prevent abnormal fibrinolysis to reduce blood for a duration of 3 and 7 months, and the third was in loss. This article reviews the rationale use and safety remission lasting for 26 months. profile of TA as an adjuvant treatment in melasma.

These results were largely unchanged when compared TA has been tried in the treatment of melasma in the with the subgroup of patients who had previously oral, topical, and intradermal injection formulation. received other systemic immunomodulators. Eight studies using oral TA (0.5-1.5 g/day) in the treatment of melasma were reviewed. The response to Comment: High-dose systemic steroids are therapy was evaluated after 4-10 weeks of starting the considered the first-line of treatment for PV. drug. It was concluded that the usual effective dose of However, the appreciable morbidity associated TA in melasma can be 250 mg 2-3 times daily, which with systemic glucocorticoids has resulted in is much lower than the dose used to reduce excessive the use of other immunosuppressive drugs like bleeding. Clinical response was observed after a azathioprine, cyclophosphamide, mycophenolate period of at least 1 month. Side-effects in the form of mofetil, cyclosporine, and methotrexate. In addition, gastrointestinal upset and a decrease in the amount of dapsone, tetracyclines, plasmapheresis, intravenous menses were found in a minority of patients (3-4%). immunoglobulin (IVIg), and rituximab have been No change was found in the coagulation parameters. used successfully. Although good results have been Recurrence of melasma was seen after stopping reported with biological agents, their high cost is a treatment in a few patients. It was also found that the major limiting factor. duration of the therapy and not the higher dose made the treatment regime more effective. In this study, steroid dose could be reduced in 91% patients and in 69.6%, prednisone was completely Since systemic TA has potential side-effects, topical TA tapered. MTX is a safe and efficacious treatment for has been tried in melasma. Available data in literature patients with PV and should be included in the adjuvant on the efficacy of topical TA is scarce, and results therapy armamentarium. Another advantage is that it are conflicting. Some studies suggest that melasma is a relatively cheap and easily accessible drug with improves in significant number of patients with topical which dermatologists have a vast experience. MTX 2% TA emulsion when applied for 5-18 weeks and no generally has a delayed beneficial effect on oral lesions, side-effects were observed. While another study showed whereas the cutaneous lesions usually respond more that topical 5% TA when used for a 12-week period rapidly. In patients with severe to moderately severe caused more irritation to the applied area without PV, once the initial disease has been brought under any extra benefit. Recently, topical TA in liposome control using high doses of systemic corticosteroids, formulation has been developed to reduce irritation. MTX may be useful in maintaining that control, while allowing a lowering of the corticosteroid dose. It may One study has reported on the efficacy of intradermal even be successful in controlling the disease as a injections of TA. The study showed that 85 patients monotherapy, but it usually does not lead to complete who completed weekly intradermal injections of prolonged remission of the disease. TA, 0.05 ml TA (4 mg/mL) in the melasma lesion at

862 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Prashar and Yadav Current best evidence from dermatology literature

1 cm intervals for 12 weeks had significant decrease difficult to manage disorder of hyperpigmentation. It in the melasma area and severity index (MASI) from may also have some synergistic activity when used 8 weeks onward (8 rated good, 65 rated fair results). in combination with the other treatment modalities. No significant side-effect was noted. But, like other available treatment options, it is not uniformly effective in all the cases. It leads to Comment: The pathogenesis of melasma is multifactorial; improvement in pigmentation in many patients, genetic predisposition, UV light exposure and hormonal complete clearance in few, and recurrences can occur influences being the major etiologic factors. on stopping the treatment.

TA is a plasmin inhibitor used to prevent abnormal Carbo MA, Pastor MV, Nicolas BR, Sanjuan VP, fibrinolysis to reduce blood loss. It acts by attaching to Estebanez EQ, Carpio EG. Omalizumab in chronic the lysine-binding sites of plasmin and plasminogen. It urticaria: A retrospective series of 15 cases. Dermatol inhibits UV-induced plasmin activity in keratinocytes Ther 2013;26:257-9. by preventing the binding of plasminogen to the Chronic idiopathic or spontaneous urticaria (CU) keratinocytes, thus suppresses the production of affects around 0.1% of the population and can be prostaglandins (PGs) and UV-induced melanogenesis, highly distressing. It is defined by the presence of through the suppression of the epidermal plasmin daily or almost daily symptoms for more than 6 weeks. activity. Lesser free arachidonic acids and depleted Omalizumab is a monoclonal anti-IgE antibody production of PGs reduces the melanocyte approved for the treatment of severe allergic asthma tyrosinase activity. This might be the mechanism and is also being tried in CU. This is a retrospective for the effect of TA on melasma and improvement of case series of 15 patients with CU treated with post-inflammatory hyperpigmentation. Besides, it also omalizumab. Omalizumab was administered at a dose reverses melasma-related dermal changes, such as of 150-300 mg subcutaneously every 2-4 weeks; the vessel proliferation and increased number of mast cell. dosage used was adjusted according to total weight and serum IgE levels. Improvement was assessed In the majority of studies showing the efficacy of TA after 3 and 6 months of treatment. Complete response in melasma, the drug has been given orally. Although was defined as symptom disappearance that could be systemic TA has been reported to be safe for the followed by discontinuation of anti-histamines, and treatment of melasma, the risk-benefit study must be partial response as symptom improvement, but with done on a larger scale. The primary side-effects noted symptom worsening when attempting to discontinue with its use are gastrointestinal complaints (nausea, anti-histamines. After 3 months of treatment, diarrhea, and abdominal pain). There are also reports of 12 patients responded, with partial response in 9 and serious complications such as deep venous thrombosis, complete response in 3. At 6 months, 8 of 10 patients pulmonary embolism, cerebral artery thrombosis and continuing on omalizumab had a complete response embolism, and coronary artery thromboembolism. and 2 had a partial response. In patients discontinuing the drug, symptoms recurred after 5 weeks without There is limited published literature on the role of treatment. Only 2 patients reported dizziness or topical TA and intradermal TA injections in melasma. nausea after the injections. Topical TA may cause irritation and allergy. Therefore, novel topical TA liposome formulations have been Comments: The chronic types of urticaria are developed, but they are not yet commercially available. divided into physical urticaria (cold, delayed By injecting TA intradermally, it may be possible to pressure, vibratory urticaria, and urticaria factitia), treat the dermal and mixed-type melasma. Intralesional other urticaria types (aquagenic, cholinergic, microinjection of TA appears to be a potentially new contact urticaria, and exercise-induced urticaria/ and promising therapeutic tool that can be easily anaphylaxis), and spontaneous urticaria. Chronic performed in outpatient settings, with relatively rapid spontaneous urticarias may be idiopathic (55%) or results and without significant side-effects. autoimmune (45%) as defined by the presence of the immunoglobulin IgG against the alpha subunit of the Although many agents are available in the therapeutic high affinity IgE receptor, or IgG anti-IgE antibodies. options of melasma, its management is still challenging and recurrences are common. TA can The first-line drugs for the treatment of CU are second prove to be a useful adjunct in the treatment of this generation H1 anti-histamines. In non-responders, Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 863 Prashar and Yadav Current best evidence from dermatology literature the dose of the anti-histamine can be increased upto urticaria activity score. Few or no side-effects have been four-fold of the recommended dose or sedating H1 reported with omalizumab therapy. The most frequent anti-histamine/H2 anti-histamine may be added. adverse events noted are nausea, flu-like symptoms, The second-line therapies are doxepin, leukotriene diarrhea, nasopharyngitis, upper respiratory infection, receptor antagonist, corticosteroid (short-term only), and headache. Anaphylaxis has very rarely been dapsone, chloroquine, hydroxychloroquine, and reported (<0.1%). Omalizumab is an excellent sulfasalazine. The third-line treatments include treatment choice for severe treatment-refractory methotrexate, cyclosporine, mycophenolate mofetil, urticaria. It allows for a significant reduction in the omalizumab, autologous serum therapy, intravenous dose of anti-histamines, systemic steroids, and other immunoglobulin, and plasmapheresis. immunosuppressives in patients with CU, thus minimizing their side-effects. The drawbacks with this Omalizumab is a recombinant humanized anti-IgE-IgG therapy are the high cost, not uniformly effective in all monoclonal antibody approved for the treatment patients, prolonged treatment, and risk of recurrence of moderate to severe allergic asthma. It blocks the on stopping the treatment. Further studies should be high-affinity Fc receptor of IgE and also reduces the performed to confirm its efficacy in urticaria refractory expression of FcRI on circulating basophils and mast to the conventional treatment. cells, thus reducing their activation and histamine release. In addition to the anti-IgE mechanisms, it AAditiditi PPrashar,rashar, SSavitaavita YYadavadav also induces eosinophil apoptosis, downregulates Department of Dermatology, Venereology and Leprology, inflammatory cytokines IL-2, IL-4, IL-13, and PGIMER, Chandigarh, India TNF-alpha. This explains the successful results of AAddressddress forfor correspondence:correspondence: Dr. Savita Yadav, omalizumab in CU patients even with low levels of Department of Dermatology Venereology and Leprology, serum IgE. PGIMER, Chandigarh - 160 012, India. E-mail: [email protected]

Omalizumab has been shown to be effective in chronic Access this article online autoimmune urticaria, chronic idiopathic urticaria and Quick Response Code: various urticaria subtypes such as cholinergic, heat, Website: cold, solar, and delayed pressure urticaria. It is used www.ijdvl.com in doses of 150 mg or 300 mg subcutaneously every second or fourth week, depending on the weight and serum IgE levels. It has been found to be effective in restoring the patient’s quality of life and in reducing the

864 Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 Net Letter AArere ddermatologistsermatologists familiarfamiliar wwithith aacronyms?cronyms?

Sir, than 10 years of practice. Conversely, up to 79.2% Acronyms were initially introduced during the early dermatologists in the “good” knowledge group were 20th century, which places them among the relatively younger specialists who started to practice within new linguistic phenomena with wide spectrum of the past decade (P < 0.001). Moreover, their own definitions. The purpose of this study is to analyze the perception of fluency in speaking English (P < 0.05) current knowledge of Serbian dermatologists regarding is greater. Gender, type of practice (public vs. private) the recognition of acronyms and assessment of familiarity and the presence or absence of English language with selected acronyms among practicing dermatologists education, did not significantly differ between “good” with the practice experience of various duration. and “poor” acronym knowledge group.

The anonymous inquiry questionnaire containing Specific type of acronym was significant for the poetic letter with 10 hidden acronyms [Appendix 1] recognition process so in the "good" knowledge has been delivered to 52 certified practicing group, terms SAPHO, CHILD, LAMB, DRESS, and dermatologists. The final mixture of acronyms hidden KID were significantly more frequently detected in the text included 54-year-old up to 2-year-old by dermatologists. The most frequently detected acronym. Only 26.7% recognized more than 50% acronyms in both groups were LEOPARD and SAPHO, of the hidden acronyms [Figure 1]. Two groups respectively. emerged: The “poor” and “good” acronym knowledge group of dermatologists [Table 1]. Dermatologists According to the MedLine and PubMed database in the “poor” knowledge group were significantly search, more than 90 abbreviations were recorded in older with the higher mean age (P < 0.05), majority dermatology regarding the naming of dermatological of participants (85.7%) in this group had more diseases and syndromes (e.g. SSSS, AD, DLE). Some

Table 1: Characteristics of dermatovenereologists according to the number of recognized acronyms Characteristics 1-3 acronyms (group I) 4-7 acronyms (group II) P value Total number (45) 21 No (%) 24 No (%) Sex Male 5 23.8 3 12.5 Female 16 76.2 21 87.5 0.322* Age (mean±SD) 47.38±7.40 41.04±5.51 0.002 Years providing dermatovenereologists care <10 years 3 14.3 19 79.2 >10 years 18 85.7 5 20.8 0.000* Practice Public 16 76.2 22 91.7 Private 5 23.8 2 8.3 0.153* Learning english Yes 16 76.2 23 95.8 No 5 23.8 1 4.2 0.053* Own perceptions of knowledge in english Poor 8 38.1 5 20.8 Good 12 57.1 11 45.8 Excellent 1 4.8 8 33.3 0.050* *P value according χ2 test, **P value according t test, SD: Standard deviation

How to cite this article: Milica M, Branislav I, Milan B, Sandra S. Are dermatologists familiar with acronyms?. Indian J Dermatol Venereol Leprol 2013;79:849. Received: March, 2013. Accepted: March, 2013. Source of Support: This study was supported by the Ministry of Science and Technology of the Republic of Serbia, through Contract No 175402 (2011-2014). Confl ict of Interest: None declared. Net Letter

Figure 1: Distribution of dermatovenereologists according to the number of recognizable acronyms

of the commonly used acronyms describing diseases connections and hence familiarity with Greek goddess or syndromes in dermatology are (in alphabetical Sapho. order) AGEP, BIDS, CHILD, CLOVE, COIF, CREST, DRESS, EMPACT, HATS, ILVEN, KID, LAMB, Since, its cumbersome to memorize all the acronyms LEOPARD, MIDAS, NAME, PAN, PAPA, PHACES, and syndrome names (NAME, LAMB, LEOPARD, POEMS, REM, SACRAL, SAPHO, SDRIFE, TEN, and Carney syndrome) that refer to almost the same skin WILD. The first acronym used in dermatology, TEN lesions: Lentigines and/or ephelides and various appeared only 13 years after the offical acceptance of benign tumors, all of them being rare, only the oldest the exact acronym definition, and the rise of acronyms acronym LEOPARD was highly recognizable, which [5] in naming of dermatoses and syndromes continued emphasizes the significance of the clinical endpoint. during the past 6 decades.[1] The duration of acronym usage and interpretation in dermatology appeared to be important factor in Since, the dermatology is visual i.e descriptive medical recognition of “older” acronyms but only in case of specialty one could expect that the theory of visual a half-century old mnemonic words which holds word recognition would have the greatest impact primarily for LEOPARD. Similarly, there was complete on identification and memorization of acronyms.[2] ignorance of the 2 year old term WILD. This might well be supported by study on acronym “superiority effect” which presents that familiarity of a Influence of fluency in speaking English on acronym word (i.e., with pre-existing lexical representation) has recognition is evidenced in this survey. Word leopard even superior effect on recognition and memory than have the same written and pronounced version in orthographic regularity (effective spelling of the letter Serbian unlike the “animal” lamb, which remained [3] string) when it comes to visual word recognition. unrecognized by poor English speakers.

The acronymophyllia which appeared in other medical In conclusion, the strongest evidence stands for fields could have been easily avoided in dermatology positive causality between the amount of time spent on by using three simple rules when creating one: (1) the acronym usage in dermatology and the extent of visual acronym must have at least three letters and be easily word recognition, with significant positive influence pronounceable, (2) it has to make the communication of the recently gained knowledge through board exam easier, (3) and to be more readily recognized by the (not more than 10 years of practice), younger age of reader compared to the original phrase[4] adding the practicing dermatologist and fluency in English. familiarity as the most important characteristic. All acronyms elected in the study obey the proposed AACKNOWLEDGMENTCKNOWLEDGMENT rules: Surprisingly well- recognized acronym SAPHO could only be explained by Serbian-Greek historical This study was supported by the Ministry of Science and Net Letter

Appendix 1: Poetic letter with hidden acronyms RREFERENCESEFERENCES Dear Papa, 1. Patel CB, Rashid RM. Averting the proliferation of I went to the Zoo with our new teacher. Her name is Sapho, she acronymophilia in dermatology: Effectively avoiding is Greek. She took her own child, Alexander, with us. We saw ADCOMSUBORDCOMPHIBSPAC. J Am Acad Dermatol many wild animals, like tigers, wolves, lions and a leopard, but 2009;60:340-4. most of all I liked a pretty little lamb. I was wearing the red dress 2. Koriat A. Easy comes, easy goes? The link between learning you’ve bought me for my birthday and remembering and its exploitation in metacognition. Mem Zoo ticket was ten Euros Cognit 2008;36:416-28. All my love to mom and you, 3. Laszlo S, Federmeier KD. The acronym superiority effect. Psychon Bull Rev 2007;14:1158-63. Your kid Mary 4. Wren JD, Garner HR. Heuristics for identification of acronym-definition patterns within text: Towards an automated construction of comprehensive acronym-definition Technology of the Republic of Serbia, through Contract dictionaries. Methods Inf Med 2002;41:426-34. No 175402 (2011-2014). 5. Fred HL, Cheng TO. Acronymesis: The exploding misuse of acronyms. Tex Heart Inst J 2003;30:255-7.

MMarkoviarković MMilica,ilica, IIvanovivanović BBranislavranislav1, BBjekijekić MMilan,ilan, SSipeticipetic SSandraandra2 Access this article online City Institute for Skin and Venereal Diseases, Belgrade, 1Faculty of Quick Response Code: Website: Philology, Belgrade University, Belgrade, 2Institute of Epidemiology, www.ijdvl.com School of Medicine, Belgrade, Serbia DOI: AAddressddress forfor correspondence:correspondence: Dr. Marković Milica, 10.4103/0378-6323.120756 City Institute for Skin and Venereal Diseases, PMID: Džordža Vašingtona 17, Belgrade 11000, Serbia. ***** E-mail: [email protected] Net Letter FFamilialamilial ccongenitalongenital generalizedgeneralized hypertrichosishypertrichosis

Sir, Hair on chest and abdomen was sparse. There was Hypertrichosis is defined as an abnormal hair no hair on palms, soles and mucosal surfaces. Both growth resulting in an increase in body hair beyond breasts were normal and there was no clitoromegaly. the normal variation for a patient’s reference group; There were no associated dental anomalies, facial excluding androgen-induced hair growth. This should dysmorphism or gingival hyperplasia. Hormone be differentiated from hirsutism, which is increased levels were within range (Luteinizing Hormone hair growth in androgen dependent areas.[1] It is 4 IU/L, Follicle Stimulating Hormone 3.5 IU/L, usually a cosmetic problem, but may be associated Estradiol 54 pg/ml, Thyroid-Stimulating Hormone. with an underlying disorder that requires further 2.2 IU/ml and testosterone 0.9 ng/ml). Uterus and investigation. It has been classified into congenital and ovaries were normal on ultrasound. A diagnosis of acquired with further subdivision into generalized or congenital generalized familial hypertrichosis was localized hypertrichosis.[2] We present a rare case of made. Patient was counseled and referred for full body familial congenital generalized hypertrichosis, which laser treatment. However as she could not afford the on literature search has been reported in very few treatment, she continued with shaving and waxing. families worldwide. Congenital generalized hypertrichosis has terminal An 18-year-old girl, presented with profuse hair growth hair with typical phenotypic characteristics as over face, arms, legs and back since birth. Her thelarche described in our patient and has an autosomal or and menarche were normal and menstrual cycles were X-linked dominant pattern of inheritance, which regular with normal flow. There was no history of has been linked to chromosome x24-q27.1.[3] Various acne, weight gain or voice change. Both her mother mechanisms of hypertrichosis have been described; and maternal grandmother had a similar history of such as prolonged anagen phase of hair follicles, extensive body hair while her two sisters were normal. increased hair follicle density and abnormal vellus On examination, she was phenotypically female with a to terminal switch mechanism in normal vellus hair body mass index of 26. Extensive, soft, black terminal bearing areas.[2] Terminal hair is medullated, wider hair, 3-4 cm long was present on the face (shaved), than the inner root sheath of the follicle that produces arms, back, buttocks and lower limbs [Figures 1 and 2]. them and the follicle penetrates into the reticular Adult sexual hair was seen in axilla and pubic area. dermis. It can be easily differentiated from the softer

Figure 1: Excessive facial hair (shaved), side profi le Figure 2: Profuse hair on back

How to cite this article: Goel N, Rajaram S, Gupta B, Gupta K. Familial congenital generalized hypertrichosis. Indian J Dermatol Venereol Leprol 2013;79:849. Received: March, 2013. Accepted: May, 2013. Source of Support: Nil. Confl ict of Interest: None declared. Net Letter non-medullated lanugo and non-pigmented variably NNeerjaeerja Goel,Goel, SShalinihalini Rajaram,Rajaram, BindiyaBindiya Gupta,Gupta, medullated vellus hair.[4] Other forms of congenital KKanikaanika GuptaGupta syndromes with primary generalized hypertrichosis Department of Obstetrics and Gynecology, UCMS and GTB Hospital, are congenital hypertrichosis lanuginose (CHL), Dilshad Garden, Delhi, India gingival fibromatosis with hypertrichosis, AAddressddress forfor correspondence:correspondence: Dr. Bindiya Gupta, Cantu' syndrome and hypertrichosis, pigmentary Department of Obstetrics and Gynecology, UCMS and GTB retinopathy and facial anomalies syndrome.[2] In Hospital, Dilshad Garden, Delhi, India. CHL, the hair distribution is similar to generalized E-mail: [email protected] hypertrichosis except that there is uniform RREFERENCESEFERENCES overgrowth of soft lanugo hair with or without facial dysmorphisms (Ambras syndrome).[5] 1. Castelo Branco C, Cancelo MJ. Comprehensive clinical management of hirsutism. Gynecol Endocrinol 2010;26:484-93. 2. Wendelin DS, Pope DN, Mallory SB. Hypertrichosis. J Am Acad No single method of hair removal is appropriate for Dermatol 2003;48:161-79. all body locations or patients and the one adopted 3. Zhu H, Shang D, Sun M, Choi S, Liu Q, Hao J, et al. X-linked congenital hypertrichosis syndrome is associated with inter will depend on the character, area and amount of chromosomal insertions mediated by a human-specific hair growth as well as on the age of patient and their palindrome near SOX3. Am J Hum Genet 2011;88:819-26. personal preference. Techniques of hair removal can 4. Stenn KS, Paus R. Controls of hair follicle cycling. Physiol Rev 2001;81:449-94. [2] be temporary or permanent. Temporary methods can 5. Belengeanu V, Rozsnyai K, Gug C, Ba˘na˘˛teanu M, Farcaş S, be depilatory such as shaving, cutting or chemical Belengeanu A. Ambras syndrome: Report on two affected siblings depilators or epilatory such as plucking, waxing or with no prior family history. Clin Dysmorphol 2004;13:265-7. 6. Battle EF Jr. Advances in laser hair removal in skin of color. [2] tweezing. Patient continued to use these temporary J Drugs Dermatol 2011;10:1235-9. methods. Permanent methods of hair removal include electrolysis, thermolysis or laser treatment. The longer Access this article online wavelength Nd: YAG laser is considered safest in Quick Response Code: [6] Website: treating darker skin phototypes. www.ijdvl.com

Reporting such rare syndromes not only adds to the DOI: 10.4103/0378-6323.120757 database, but pooled data analysis may give us a better insight into patterns of inheritance, epidemiology and PMID: ***** associated symptoms. Net Letter EEosinophilicosinophilic panniculitispanniculitis afterafter subcutaneoussubcutaneous aadministrationdministration ofof sodiumsodium heparinheparin

Sir, interstitial inflammatory cell infiltrate composed Cutaneous side-effects of heparins are well-known. predominantly of eosinophils was evident. Mild Among them, nodule development is uncommon. overlying spongiosis was also identified. A diagnosis of Usually, these nodules reveal calcinosis cutis on cutaneous drug reaction with eosinophilic panniculitis histological examination. induced by heparin was made. Enoxaparin injections were discontinued, which resulted in cutaneous A 66-year-old woman presented with pruriginous improvement. A positive patch test to enoxaparin lesions on her abdomen, 25 days after initiating confirmed this diagnosis. oral acenocoumarol and subcutaneous enoxaparin for a pulmonary thromboembolism. On physical The incidence of skin lesions induced by subcutaneous examination, multiple tender, poorly delimited, heparin is unknown. Urticaria, angioedema, subcutaneous nodules at enoxaparin injection ecchymosis, cutaneous necrosis, cutaneous area were evident [Figure 1]. A biopsy and several induration and eczema-like lesions have been reported complementary studies were performed. Hemogram, secondary to heparin administration. Delayed-type erythrocyte sedimentation rate, serum chemistry hypersensitivity reactions appear to be the most including alpha-1-antitrypsin, lipase, tryptase, common mechanism to develop these cutaneous angiotensin I-converting enzyme, rheumatoid factor, lesions. The presence of nodules or panniculitis caused [1] thyroid hormone function, autoimmunity studies, by heparin has rarely been described. The majority urinalysis, chest X-ray and purified protein derivative of these patients presented with calcinosis cutis or test were all normal, except for slight eosinophilia subcutis on histological examination and only one with normal white cell count. Cutaneous biopsy case of eosinophilic panniculitis was reported. Most showed a mainly septal panniculitis [Figure 2]. The patients with nodules were receiving treatment with calcium non-fractionated heparins or low molecular inflammatory infiltrate was predominantly composed weight heparins (LMWH) containing calcium salts. of eosinophils, together with few lymphocytes and On the other hand, patients with calcinosis cutis histiocytes, within the thickened septa and lobules following subcutaneous heparin injection usually [Figure 3]. In the dermis, scant perivascular and

a b Figure 2: (a and b) Cutaneous drug reaction with eosinophilic panniculitis induced by heparin. Low power view showing Figure 1: Subcutaneous nodules in areas of heparin injection infl ammatory infi ltrate in the upper dermis, thickened septa and (abdomen) lobules (H and E, ×40)

How to cite this article: Batalla A, Rosón E, Posada C, Flórez Á. Eosinophilic panniculitis after subcutaneous administration of sodium heparin. Indian J Dermatol Venereol Leprol 2013;79:849. Received: March, 2013. Accepted: May, 2013. Source of Support: Nil. Confl ict of Interest: None declared. Net Letter

heparin.[1,5] Delayed-type hypersensitivity reactions have also been considered as the cause of these reactions.[5]

CCONCLUSIONONCLUSION

To the best of our knowledge, this is the first case of eosinophilic panniculitis induced by administration of LMWH containing sodium salts.

AAnana Batalla,Batalla, ElenaElena Rosón,Rosón, CeliaCelia Posada,Posada, ÁÁngelesngeles FlórezFlórez Department of Dermatology, Pontevedra Hospital Complex, Pontevedra, Spain Figure 3: Detail of numerous eosinophils (arrows) in the infl ammatory infi ltrate in the septum (H and E, ×200) AAddressddress forfor correspondence:correspondence: Dr. Ana Batalla, Department of Dermatology. Xestión Integrada suffered from vitamin D, parathyroid hormone or Pontevedra - Salnés. Hospital Provincial. C/ Dr. Loureiro Crespo, n2. CP 36002. Pontevedra, Spain. [2] calcium-phosphate disturbances. Nodules induced E-mail: [email protected] by sodium LMWH have also been found. Funt et al. observed nodules in 14 of 426 cancer patients RREFERENCESEFERENCES following dalteparin (heparin with sodium salts) 1. Yasuda M, Abe M, Yamanaka M, Amano H, Tamura A, Ishikawa O. injection. These authors described the radiological Eosinophilic panniculitis and hypereosinophilia caused by characteristics of these nodules, but histological hypersensitivity to calcium heparin. Eur J Dermatol 2010;20:401-2. studies were not performed.[3] 2. Campanelli A, Kaya G, Masouyé I, Borradori L. Calcifying panniculitis following subcutaneous injections of nadroparin-calcium in a patient with osteomalacia. Br J Regarding to acenocoumarol, the absence of reported Dermatol 2005;153:657-60. cases of panniculitis caused by this drug as well as the 3. Funt SA, Hidalgo A, Panicek DM. Subcutaneous nodules at the injection site of low-molecular-weight heparin: A mimic of involution of cutaneous lesions despite continuing with metastatic disease at CT. J Comput Assist Tomogr 2002;26:520-3. this treatment, helped us to exclude acenocoumarol as 4. Adame J, Cohen PR. Eosinophilic panniculitis: Diagnostic a possible cause of the lesions of our patient. considerations and evaluation. J Am Acad Dermatol 1996;34:229-34. 5. Masferrer E, Martin-Ezquerra G, Martínez-Escala E, Pujol RM, Eosinophilic panniculitis is a rare form of Giménez-Arnau A. Eosinophilic panniculitis triggered by panniculitis characterized by septal and lobular intramuscular penicillin and occupational setting. Allergy 2011;66:436-7. involvement with eosinophilic infiltration. It is believed to be a reactive process that has been Access this article online associated with a variety of systemic conditions such Quick Response Code: Website: as gnathostomiasis, leukocytoclastic vasculitis and www.ijdvl.com erythema nodosum.[4] In rare instances, eosinophilic panniculitis has been observed as a local phenomenon DOI: 10.4103/0378-6323.120758 induced by subcutaneous or intramuscular drug injections including apomorphine, specific PMID: ***** immunotherapy, benzathine penicillin and calcium Net Letter DDee SSanctis-Cacchioneanctis-Cacchione syndromesyndrome

Sir, and Tanner’s sexual maturity rating (SMR) of stage 2. De Sanctis-Cacchione syndrome (DSC) (MIM Examination of the central nervous system revealed #278800) is a rare autosomal recessive disorder that the child had spontaneous eye opening without with a gene map locus of 10q11, originally described focusing, motor response of localization to pain and as “xerodermic idiocy.”[1] DSC is characterized by incomprehensible vocal response. Fundus examination cutaneous photosensitivity, microcephaly, mental revealed the presence of salt and pepper retinopathy. retardation, short stature, hypogonadism, spasticity, Brainstem evoked auditory response revealed severe peripheral neuropathy and sensorineural deafness.[2] sensory-neural hearing loss. Pharyngeal reflex (gag In most of the cases in the literature, hypogonadism reflex) was weak suggestive of bulbar involvement. has been described, but we report a case of DSC with On examination, 3rd, 4th, 5th, 6th, 7th and 12th cranial intact gonadal functions. nerves were normal. Motor system examination showed a decrease in muscle bulk, increased tone, A 10-year-old boy presented with multiple episodes reduced power (1/5) and contractures at knee, ankle, of myoclonic seizures and progressive, rapid loss elbow and wrist joints. The elicitation of deep tendon of milestones, cognition, vision and hearing for the reflexes were masked by fixed contractures. There past 6 months. There was a history of persistent were no abnormal movements and no cerebellar or drooling of saliva, nasal regurgitation of feeds with meningeal signs. Examination of the abdominal, episodes of choking and coughing with attempted respiratory and cardiovascular systems revealed solid feeds. The child was confined to bed and gave no other abnormalities. Laboratory investigations no indications for thirst, hunger, bladder or bowel showed a normal hemoglobin (Hb 12.1 g/dl), serum needs. There was no response to auditory and visual creatinine (0.8 g/dl), serum albumin (3.5 g/dl), stimuli. Past history suggested dry and scaly skin and alanine aminotransferase (24 IU/L) and alkaline photosensitivity (since infancy) and developmental phosphatase (120 IU/L). Skeletal survey showed delay (developmental quotient 0.33; revised Denver a bone age of 11-12 years. Contrast-enhanced Developmental Scale II). The child was a third in computed tomography (brain) revealed dilated lateral birth order, product of a third degree consanguineous ventricles, atrophy of cerebral and cerebellar cortex marriage with high maternal (40 years) and and hydrocephalus (ex-vacuo) with no intracranial paternal (45 years) age, born at term with an uneventful calcifications [Figures 3 and 4]. Nerve conduction neonatal period. Other siblings were unaffected and velocity of upper and lower limb suggested axonal there was no family history of photosensitivity, seizures neuropathy. Electromyography revealed a decline in or mental retardation. On examination, the child was motor unit recruitment and other nonspecific changes. emaciated with a weight of 15 kg (<3rd percentile), Based on the constellation of above features, a diagnosis length of 122 cm (<3rd percentile), body mass index of DSC was established. of 10.1 (<3rd centile) and head circumference of 45 cm (<3rd percentile). Facial features were suggestive The child was advised protection from sun exposure of “Old man look” with an elongated face, micrognathia, by the use of protective clothing, eyeglasses, broad pinched nose and crowded caries teeth.The skin lesions spectrum sunscreens containing para-aminobenzoic were noted over the face, neck, upper chest and exposed acid esters and skin emollients. Seizures were parts of limbs and consisted of scaling, erythema, controlled with sodium valproate (25 mg/kg) and crusting with patches of hyperpigmentation [Figure 1]. lamotrigine mg/kg (2.5 mg/kg/day). Physiotherapy was He had fixed contractures of the ankle, knee, elbow initiated to prevent the worsening of contractures. and wrist joints [Figure 2]. The genitals, including the Child was on regular follow-up for next 6 months. penis and testes, were normal with a stretched penile Seizures were controlled with no further progression length of 4.5 cm (−2.5 standard deviation = 3.7 cm) of neurological illness.

How to cite this article: Mittal H, Mehndiratta S, Kaushik JS, Godbole T. De Sanctis-Cacchione syndrome. Indian J Dermatol Venereol Leprol 2013;79:849. Received: April, 2013. Accepted: June, 2013. Source of Support: Nil. Confl ict of Interest: None declared. Net Letter

a b Figure 2: (a and b) Contractures at elbow, wrist, knee and ankle along with lesions on upper chest, hands and legs Figure 1: Elongated face with erythema, scaling and crusted lesions

a b Figure 4: (a and b) Computed tomography scan of patient showing cortical and cerebellar atrophy with ex-vacuo hydrocephalus

in the neuronal cells resulting in neuronal death or dysfunction. Although neurological symptoms appear Figure 3: X-ray of skull Anterio-Posterior view showing prominent mastoids and no intracranial calcifi cations in the first two decades of life, late presentation in adults has also been reported.[5] The common Xeroderma pigmentosa (XP) results from defects neurological manifestations of DSC are progressive in the excision repair of ultraviolet (UV) induced neurological deterioration, peripheral neuropathy deoxyribonucleic acid (DNA) damage. Defects in and sensorineural deafness observed in 18% of nucleotide excision repair (NER) results in inherited cases.[6] Other manifestations include microcephaly, neurocutaneous syndromes such as XP, Cockayne choreoathetosis, cerebellar and extra pyramidal syndrome and trichothiodystrophy. There is a syndromes.[7] The late onset of neurological complaints complex relationship between NER mutations and and the relative preservation of gonads and sexual clinical features. Seven xeroderma pigmentosum maturity in our case depict sparing of cells from UV genes, XPA through XPG, have been identified. induced damage. Early intervention and appropriate Conversely, different mutations in one gene can lead to protection from sunlight started early in the illness different clinical disorders with variation in systemic could have a significant impact in delaying the involvement.[2,3] The gene locus implicated in DSC is onset of neurological symptoms. There are very few ERCC6, which is located at 10q11, which is also called cases reported with complete manifestations of this Cockayne syndrome-B gene.[4] syndrome. However, many patients have one or more of its neurological features. The features that favored a Among the variants of XP, patients with DSC have the diagnosis of DSC in our case were mental retardation, greatest UV sensitivity and the poorest DNA repair. microcephaly, cutaneous photosensitivity, stunting, The neurological manifestations in XP have been spasticity, contractures, sensorineural deafness and hypothesized to be secondary to defective DNA repair peripheral neuropathy. However, unlike the classical Net Letter

DSC, our child had normal gonads and sexual maturity AAddressddress forfor correspondence:correspondence: Dr. Sumit Mehndiratta, staging at the time of presentation. In the absence of Department of Pediatrics, Lok Nayak Hospital, New Delhi - 110 002, India. cataract, optic atrophy, skeletal dysplasia and basal E-mail: [email protected] ganglia calcifications, Cockayne syndrome was ruled out. RREFERENCESEFERENCES

1. De Sanctis C, Cacchione A. L’idiozia xerodermica. Riv Sper Diagnosis of DSC is mainly based on clinical features. Freniatr Med Leg Alien Ment 1932;56:269-92. Chromosomal breakage studies, complementation 2. Mishra OP, Tripathi AM, Katiyar GP. DeSanctis-Cacchione syndrome. Indian J Pediatr 1997;64:269-72. studies and gene sequencing to identify the specific gene 3. Kraemer KH, Patronas NJ, Schiffmann R, Brooks BP, Tamura D, complementation group are supportive. The mainstay of DiGiovanna JJ. Xeroderma pigmentosum, trichothiodystrophy treatment is adequate sun-protection and regular follow and Cockayne syndrome: A complex genotype-phenotype relationship. Neuroscience 2007;145:1388-96. up for the early detection of cutaneous malignancies. 4. Colella S, Nardo T, Botta E, Lehmann AR, Stefanini M. Identical This condition is not curable and lesser than 40% mutations in the CSB gene associated with either Cockayne patients with severe manifestations survive beyond the syndrome or the DeSanctis-cacchione variant of xeroderma pigmentosum. Hum Mol Genet 2000;9:1171-5. second decade of life. A multidisciplinary approach, 5. Robbins JH, Kraemer KH, Merchant SN, Brumback RA. involving a Neurologist and an Ophthalmologist, is Adult-onset xeroderma pigmentosum neurological required to deal with the associated conditions. A novel disease – Observations in an autopsy case. Clin Neuropathol 2002;21:18-23. approach to photo protection is to repair DNA damage 6. Kraemer KH, Lee MM, Scotto J. Xeroderma pigmentosum. after UV exposure by the delivery of a DNA repair Cutaneous, ocular, and neurologic abnormalities in enzyme into the skin by means of specially engineered 830 published cases. Arch Dermatol 1987;123:241-50. 7. El Fékih N, Fredj M, Aounallah-Skhiri H, Fazaa B, Zghal M, liposomes. T4 endonuclease V has been shown to Ridha Kamoun M. Neurological abnormalities in xeroderma repair cyclobutane pyrimidine dimers resulting pigmentosum. Rev Neurol (Paris) 2009;165:967-70. [8] 8. Yarosh DB, O’Connor A, Alas L, Potten C, Wolf P. Photoprotection from DNA damage. Gene therapy for XP is still in a by topical DNA repair enzymes: Molecular correlates of clinical theoretical and experimental stage. The earlier onset of studies. Photochem Photobiol 1999;69:136-40. disease is associated with a poorer prognosis. Parental counseling plays a significant role in the reduction of Access this article online future recurrence as prenatal diagnosis is possible by Quick Response Code: Website: amniocentesis or chorionic villous sampling. www.ijdvl.com

DOI: 1 HHemaema Mittal,Mittal, SSumitumit MMehndirattaehndiratta , 10.4103/0378-6323.120760 JJayaaya SShankarhankar Kaushik,Kaushik, TusharTushar GodboleGodbole PMID: 1 Department of Pediatrics, UCMS and GTB Hospital, Lok Nayak ***** Hospital, New Delhi, India Net Quiz EErythematousrythematous iinduratedndurated plaqueplaque lesionslesions onon thethe breastbreast

A 50-year-old female patient, who had retraction of the The histopathological examination of the skin right nipple for 2 years and erythema in the same breast biopsy revealed islands of tumor cells in the dermal for 2 months, was referred to our clinic. Mammography lymphatics [Figure 2]. These infiltrations consisted of and breast ultrasonography performed at the time of round-shaped atypical cells with vesiculated nuclei onset of nipple retraction were normal. Dermatological and marked nucleoli. In immunohistochemical examination revealed three erythematous, mildly studies, strong positive staining by low-molecular indurated plaque lesions on the right breast, one of weight keratin (LMWCK) and epithelial membrane which involved the areola [Figure 1]. The nipple was antigen (EMA) and non-specific staining by vimentin retracted. The patient had no subjective complaints. have been detected. The right axillary examination detected several lymphadenopathies, as confirmed by ultrasonography. WWHATHAT ISIS YOURYOUR DIAGNOSIS?DIAGNOSIS?

Figure 1: Three erythemateous plaques on the right breast, one Figure 2: Tumor islands consisted of atypical epithelium cells in involving the areola the lymphatics (H and E, ×200)

How to cite this article: Şen BB, Rifaioğlu EN, Ekiz Ö, Özgür T, Akküçük S, İnan MU, et al. Erythematous indurated plaque lesions on the breast. Indian J Dermatol Venereol Leprol 2013;79:849. Received: March, 2013. Accepted: May, 2013. Source of Support: Nil. Confl ict of Interest: None declared. Net Quiz

Answer: Carcinoma erysipeloides alone or in combination with radiotherapy represent the basic treatment options.[2] We also referred DDISCUSSIONISCUSSION our patient to the general surgery and oncology departments for planning the treatment of primary The rate of skin metastasis in internal malignancies tumor. varies from 0.7 to 10%.[1] The skin metastases may occur as a result of lymphogenous, hematogenous CCONCLUSIONONCLUSION spread, or direct invasion of surrounding tissue by tumor cells. Skin metastases usually occur as a While the skin metastases generally occur after the finding of the spread or the recurrence of internal diagnosis of primary tumor, they may also develop malignancies; however, they may rarely be an initial prior to diagnosis. The skin invasions can be clinically finding of an undetected malignancy. confused with other disorders. This may result in delayed diagnosis of the malignancy and decrease in Carcinoma erysipeloides (CE) is a rare cutaneous survival. Our case demonstrated the importance of metastasis, which results from the lymphatic spread non-specific skin lesions such as erythema in diagnosis of an inflammatory carcinoma. While it is mostly of breast cancer. Therefore, the dermatologists should related to breast cancer, it may also result from other be careful with respect to cutaneous metastases, tumors.[2-4] In our case, a solid mass lesion was also even if the patient’s medical history does not include detected in the right breast, and the biopsy performed malignancy. at the General Surgery Department was reported as invasive ductal carcinoma. BBilgeilge BBülbülülbül Şen,en, EEminemine NNurur RRifaioifaioğlu,lu, ÖÖzlemzlem EEkiz,kiz, TTümayümay ÖÖzgürzgür1, SSeçkineçkin AAkküçükkküçük2, In the differential diagnosis of CE, erysipelas, cellulitis, MMehmetehmet Uğurur İnan,nan, AsenaAsena ÇiÇiğdemdem DoDoğramacramacı radiation dermatitis, and contact dermatitis should Departments of Dermatology, 1Pathology, 2General Surgery, be considered. The exact diagnosis of CE is made by Mustafa Kemal University School of Medicine, Hatay, Turkey histopathology. The dermal lymphatic invasion is AAddressddress forfor correspondence:correspondence: Dr. Bilge Bülbül Şen, considered as the characteristic feature of CE. Department of Dermatology, Mustafa Kemal University, Tayfur Ata Sokmen Medical School, Serinyol, Antakya, Hatay 31005, Turkey. Other than breast cancer, nipple retraction may occur E-mail: [email protected] due to periductal mastitis, ductal ectasia, tuberculosis, RREFERENCESEFERENCES sarcoidosis, fungal infections, and granulomatous inflammatory diseases, including Wegener's 1. Krathen RA, Orengo IF, Rosen T. Cutaneous metastasis: granulomatosis and idiopathic granulomatosis lobular A meta-analysis of data. South Med J 2003;96:164-7. 2. Cox SE, Cruz PD Jr. A spectrum of inflammatory metastasis to mastitis.[5] In our case, nipple retraction began 2 years skin via lymphatics: Three cases of carcinoma erysipeloides. ago, and the laboratory examinations performed at J Am Acad Dermatol 1994;30:304-7. 3. Lee SY, Chang SE, Bae GY, Choi JH, Sung KJ, Moon KC, et al. that time revealed no pathology. Therefore, nipple Carcinoma erysipeloides associated with anaplastic thyroid retraction was not considered to be associated with carcinoma. Clin Exp Dermatol 2001;26:671-3. breast cancer. 4. Nikolaou V, Stratigos A, Frangia K, Nikolaidis I, Syrigos K. Carcinoma erysipeloides deriving from a primary cutaneous squamous cell carcinoma. Int J Dermatol 2011;50:754-6. In general, CE develops several months or years after 5. Nicholson BT, Harvey JA, Cohen MA. Nipple-areolar complex: the diagnosis of primary carcinoma. CE is an indicator Normal anatomy and benign and malignant processes. Radiographics 2009;29:509-23. of poor prognosis, and patients often die within few months of its diagnosis. CE developing as an initial Access this article online sign of undiagnosed tumor is rare.[2] Interestingly, in Quick Response Code: Website: our patient, CE was diagnosed before the diagnosis of www.ijdvl.com breast cancer. DOI: 10.4103/0378-6323.120761 In cases of CE, treatment of primary tumor is sufficient. Surgical treatment is not recommended. PMID: ***** Systemic chemotherapy and hormonal therapies Author Index 2013

Author Index will be added once issue gets online***

Indian Journal of Dermatology, Venereology, and Leprology | November-December 2013 | Vol 79 | Issue 6 877 Title Index 2013

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