Review DOI: 10.6003/jtad.1374r1

Dermatologic Manifestations of Neurologic Disease

Ümit Türsen,* MD, Belma Türsen,** MD

Address: *Mersin University, Medical Faculty, Dermatology Department, **Mersin Hospital, Dermatology Department, Mersin, Turkey. E-mail: [email protected] * Corresponding Author: Dr Ümit Türsen, Mersin University, Medical Faculty, Dermatology Department, 33079- Mersin

Published: J Turk Acad Dermatol 2013; 7 (4): 1374r1. This article is available from: http://www.jtad.org/2013/4/jtad1374r1.pdf Key Words: Dermatology, manifestation, neurology

Abstract

Background: Many diseases present with both neurologic and dermatologic manifestations. Eight such clinical cases are presented, along with clinical photographs of the skin lesions, in the format of a self-evaluation. Each case is followed by a discussion and a brief review of the characteristic cutaneous and neurologic findings. The intent is to demonstrate classic dermatologic manifestations of diseases seen by neurologists.

Introduction light the more common skin changes that occur in association with stroke, peripheral Many disorders have a combination of neurologic and dermatologic findings in neuropathy, meningitis, encephalitis, malig- patients. This manuscript provides an nancy and HIV. overview of neurocutaneous disorders and organizes them into clinically relevant groups In addition, we cover the most frequently of use to the practicing physician. Many encountered neurocutaneous conditions and neurological conditions are accompanied by finally, we will remind the reader of skin skin changes, which frequently appear before changes associated with adverse reactions to the onset of the neurological symptoms. In drugs commonly used by neurologists. This some cases a rash may herald the start of an article aims to cover the most important and infectious process. In others, skin changes meaningful dermatological disorders that you may mirror pathological processes that are also occurring in the brain or peripheral may encounter within neurology. An ex- nerves. Careful examination of the skin can haustive list of all potential cutaneous findings therefore provide important clues when would not necessarily be useful in diagnosis making a neurological diagnosis, allowing early and management; rather, we aim to provide a treatment and avoiding unnecessary tests. practical selection of management altering Instead of presenting an exhaustive list of dermatological signs within the context of cutaneous manifestation of every neurological condition, we aim to provide practical common neurological presentations. We also knowledge for the non-dermatologist to aid review some commonly encountered neuro- neurological differential diagnosis. We high- cutaneous disorders, skins lesions at different

Page 1 of 19 (page number not for citation purposes) J Turk Acad Dermatol 2013; 7 (4): 1374r1. http://www.jtad.org/2013/4/jtad1374r1.pdf stages of HIV/AIDS and remind the reader of Telangiectasias are best seen on the lips, ton- important drug reactions [1,2]. gue, nose and fingers [1]. 4. Angiokeratomata: It is characterised by small red or black vascular malformations. A-Neurocutaneous Disorders Associated Fabry's disease is a rare X linked recessive With Stroke disorder caused by a deficit in the enzyme In young patients, the skin can provide im- α-galactosidase, resulting in deposition of portant clues as to the cause of stroke [1,2]. glycolipids in blood vessels and various or- There are some skin manifestations in pati- gans. There is multisystem involvement. ents with stroke as belows; Typically patients are male, presenting in childhood or early adolescence with painful 1.Livedo reticularis (Cutis marmorata): It neuropathy and in adulthood with ischae- is characterised by mottled red–blue disco- mic strokes. Discrete angiokeratomata ap- louration, net-like appearance, especially pear in a ‘bathing suit’ distribution early in over the legs, and exacerbated by cold. Livedo disease and usually before any neurological reticularis is not uncommon in young women symptoms [1]. and can be completely benign. However, it 5. Lax stretchy skin/hypermobility: Pseu- may indicate an underlying hyperviscosity doxanthoma elasticum is associated with syndrome or vasculitis. It appears in 25% of premature atherosclerosis and aneurysm those with systemic lupus erythematosus formation. It manifests cutaneously as patc- and antiphospholipid syndrome and is a hes of lax redundant skin like plucked chic- common association of vasculitis involving ken appearance, typically around the neck medium sized vessels like polyarteritis no- and inguinal folds. Arterial dissection and dosa and small sized vessels like cryoglobuli- aneurysm formation also occur in Ehlers– nemia. Sneddon's syndrome is characterised Danlos syndrome type IV as a result of de- by widespread livedo reticularis in associa- fective collagen, which causes thin trans- tion with multiple strokes. Here, patients lucent skin, easy bruising and joint hyper- tend to have high titres of antiphospholipid mobility [2]. antibodies and typically livedo reticularis de- 6. Xanthomata and xanthelasmata: It is velops several years before stroke. Patients characterised by yellow papules and plaques with polycythaemia may appear plethoric with cholesterol deposits [2]. and, in addition to livedo, often complain of itchy skin, especially when exposed to warm 7. Varicella zoster infections: On rare oc- water [3]. casions following trigeminal shingles, vari- cella zoster virus may infect arteries in close 2. Purpura: Purpura is non-blanching red or proximity to the trigeminal ganglion and purple macular lesions. A petechia is a small, cause ischaemic stroke [2]. less than 1-2 mm diameter, red or purple spot on the body, caused by a minor hemorr- 8. Diabetic skin manifestations: Dermato- hage. Purpura and petechia from bleeding be- logical examination can also provide clues to neath the skin are common in the older the more common risk factors for stroke. patient but may be significant in young pati- Dyslipidemia commonly manifests in the ents with stroke. Frequently, this indicates skin, especially familial forms. Neurologist small vessel vasculitis and platelet disorders, should look specifically for tendon xantho- including thrombotic thrombocytopenic pur- mata, xanthelasmata, eruptive xanthomata pura [2]. and palmar striae. And they do not forget to look for nicotine stained fingers and hair. 3. Telangiectasia: Telangiectasia is small Diabetes mellitus has many cutaneous mani- vascular lesions, prone to haemorrhage. He- festations, including necrobiosis lipoidica dia- reditary haemorrhagic telangiectasia is cha- beticorum (a well demarcated waxy yellow/ racterised by telangiectasia of the skin and brown plaque, usually on the shins, with sur- mucosal linings of the nose and gastrointes- face telangiectasia and ulceration), non-spe- tinal tract, with brain involvement in 10% of cific dermopathy (red/brown discolouration cases. Most patients complain of nosebleeds. often over the knees), blisters or acanthosis

Page 2 of 19 (page number not for citation purposes) J Turk Acad Dermatol 2013; 7 (4): 1374r1. http://www.jtad.org/2013/4/jtad1374r1.pdf nigricans (velvety pigmented skin in body the first event. Patients without antibodies, folds) [2]. who had recurrent abortions as their first event, were at lowest risk. The study reported that recurrent events are of the same type as Antiphospholipid Syndrome the presenting symptom. Therefore, initial cli- Antiphospholipid syndrome is a hypercoagu- nical features can help predict the prognosis lable state resulting from antibodies that ne- of the disorder. Specific clinical features tend utralize anionic phospholipids on endothelial to cluster during the course of the disease. A cells and platelets. It is a multisystemic disor- variety of therapies have been tried. Use of der, and patients may present with a wide long-term anticoagulants to maintain the in- range of neurologic manifestations, fetal loss, ternational normalized ratio at 3 or greater mild thrombocytopenia, valvular heart di- may help prevent recurring thromboembo- sease, and livedo reticularis. Antiphospholi- lism. Aspirin is of clinical benefit and may pid syndrome is associated strongly with help decrease the incidence of fetal loss in systemic lupus erythematosus (SLE) and pa- some patients. Plasmapheresis and cyclop- tients with SLE are considered to have secon- hosphamide have been used. Ancrod (purified dary antiphospholipid syndrome. The term pit viper venom) has been used successfully primary antiphospholipid syndrome is reser- in one patient. A review of clinical and labo- ved for cases of unknown etiology. The disor- ratory characteristics of 50 patients by Asher- der is characterized by high titers of anti- son et al described a 70% survival rate in phospholipid antibodies (APLA), ie, lupus an- patients treated with anticoagulation, stero- ticoagulant and anticardiolipin antibodies. ids, and treatments that decrease antiphosp- Studies suggest that antibodies are not direc- holipid antibodies, such as plasmapheresis ted against phospholipids but are directed at and/or intravenous IgG. Statins have been phospholipid-binding proteins such as B2- used in antiphospholipid syndrome because glycoprotein I and prothrombin. The cuta- of their antithrombotic, anti-inflammatory, neous manifestations most commonly seen and pleiotropic effects on vascular endothe- include livedo reticularis and leg ulceration. lium. Statins may block the antiphospholi- Livedo reticularis is a mottled, bluish, netlike pid-induced endothelial cell activation, which discoloration that changes from red-blue to is thought to be a mechanism of thrombus deep blue on cold exposure. This nonspecific formation in antiphospholipid syndrome [4]. reaction pattern has been reported in other disorders, such as polyarteritis nodosa, Sneddon Syndrome cryoglobulinemia, disseminated intravascular coagulation, and endocarditis. Other cuta- Sneddon syndrome is characterized by livedo neous manifestations, including acrocyanosis reticularis and multiple strokes resulting in (Raynaud-like phenomenon) and Degos ma- dementia. Antiphospholipid antibodies and lignant atrophic papulosis, are rare findings. anti–B2-glycoprotein antibodies also have Neurologic complications may be misdiagno- been detected in some patients with this di- sed as multiple sclerosis. Clinical findings in- sorder. The cutaneous manifestation of livedo clude multiinfarct dementia, focal deficit, reticularis may precede the cerebrovascular epilepsy, and recurrent stroke. Transitory we- episodes, thus alerting the clinician[5]. akness, vertigo, ataxia, and dysarthria may occur. Neurocognitive defects including de- mentia, atypical migraines, depression, and B- Neurocutaneous Disorders Associated delusional states also have been reported [4]. With Peripheral Neuropathy Research to predict outcome in patients with Many neuropathies are associated with skin antiphospholipid syndrome has shown that changes. Some reflect underlying vitamin de- patients with elevated IgG have increased risk ficiencies (B12, niacin) while others suggest of recurrent thrombotic events. Tektonidou et microvascular damage (angiokeratoma, dia- al predicted that risk of a second event was betes mellitus, lupus erythematosus, am- highest in patients with B2-glycoprotein I an- yloid, small vessel vasculitis) or infection tibodies in whom autoimmune hemolysis was (Lyme disease, syphilis, leprosy).

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1. Hyper/hypopigmentation, especially in Neurologic complications of type 1 and type sun-exposed areas. Pigmentary changes are 2 diabetes mellitus are similar; the most com- seen in leprosy, syphilis and pellagra. Leprosy mon is peripheral neuropathy. Other impor- remains a common cause of neuropathy in tant complications of diabetes result from South America, East Africa and the Indian accelerated atherosclerosis that places pa- subcontinent. Tuberculoid leprosy is charac- tients at high risk for cerebrovascular acci- terised by anaesthetic hypopigmented lesions dents, hypertension, and cardiovascular whereas lepromatous leprosy results in cuta- disease. Associated cutaneous manifestati- neous nodules containing massive numbers ons of diabetes include necrobiosis lipoidica of Mycobacterium leprae. Neurological com- diabeticorum (NLD), acanthosis nigricans, plications associated with syphilis usually and bullous diabeticorum. NLD occurs in present in secondary or tertiary disease. Pri- 0.3% of patients, and one study by Little et al mary syphilis is typically characterised by a reported 0.8% prevalence in 82% of patients painless, firm ulcerated lesion (chancre) 3–90 with type 1 diabetes. NLD is 3 times more days after infection and secondary syphilis, common in women, and 60% of patients with 4–10 weeks later, with a diffuse macular or NLD have diabetes. Screen patients with NLD papular rash which often involves the palms for diabetes. Lesions start as sharply demar- and soles. cated erythematous papules that become well circumscribed and annular and most com- 2. Erythema nodosum: It is characterised monly occur pretibially. Lesions progress to by tender red nodules, appearing on the form shiny yellow-brown plaques with central shins. Erythema nodosum may indicate early atrophy and telangiectases. Control of diabe- lupus erytematosus or sarcoidosis. tes does not necessarily result in remission of 3. Photosensitivity, in sun exposed areas: NLD. Treatment consists of occlusive dres- Photosensitivity is a feature of lupus and oc- sing, topical steroids, aspirin, dipyridamole, curs in pellagra. pentoxifylline, and whirlpool therapy. Intrale- sional steroids have been used but can cause 4. Purpura and Raynaud's phenomenon: tissue breakdown. Reports have shown mar- Purpura is characterised by non-blanching ked improvement using 0.05% tretinoin red or purple lesions (<3 mm=petechiae). cream applied before bed. Topically applied Raynaud phenomenon manifests as recur- bovine collagen also may enhance wound rent vasospasm of the fingers and toes and healing. New treatment strategies include usually occurs in response to stress or cold cyclosporin A, infliximab, or tacrolimus, exposure. In this phenomenon fingers and which can be used topically or systemically. toes go white, blue, then red. Small vessel vasculitis may cause polyneuropathy or mo- Acanthosis nigricans can be seen in a variety noneuritis multiplex and is frequently asso- of disorders. More severe forms are associa- ciated with skin changes, which include a ted with malignant disease, and milder forms non-blanching purpuric rash, livedo reticula- can occur in obesity and in patients with in- ris and Raynaud's phenomenon. sulin resistance, despite the absence of overt diabetes. Characteristic skin changes include 5. Erythema chronicum migrans: It is cha- velvety hyperpigmented plaques in the neck racterised by an expanding, annular rash. In and axillary regions, and patients often com- Lyme disease, 80% of patients develop a cir- plain of dirty skin. More severe forms of cular expanding, flat or slightly elevated le- acanthosis nigricans can become generalized sion (erythema chronicum migrans) at the over the knuckles, extensor surfaces, and site of a tick bite, which is painless. Neurolo- may involve mucosal surfaces. A rare cuta- gical symptoms develop in approximately 15– neous finding in diabetes is bullous diabe- 20% of cases [1, 2]. ticorum. These tense bullae can arise spontaneously on the distal extremities. The bullae are subepidermal, with the plane Diabetes Mellitus of separation at the basement membrane Diabetes mellitus is the most common syste- zone above the basal lamina, and heal wit- mic endocrine disorder; an increasing num- hout scarring. They may be chronic and re- ber of patients are diagnosed each year. current, especially in older patients. Only 100

Page 4 of 19 (page number not for citation purposes) J Turk Acad Dermatol 2013; 7 (4): 1374r1. http://www.jtad.org/2013/4/jtad1374r1.pdf cases have been reported in the past 70 untreated patients. Patients with human leu- years, but according to a report by Lipsky et kocyte antigen D4 haplotype may be at in- al of 12 patients in an 8-year period, this di- creased risk for chronic arthritis resulting sorder may be underdiagnosed [1, 2]. from Lyme disease. Carditis, conduction ab- normalities, and heart blocks also may occur. Antibiotics are 90% curative in the early sta- Lyme Disease ges but become less effective as the disease Lyme disease was first described in 1975 in progresses. Consider prescribing doxycycline Lyme, Connecticut. Currently, more than (100 mg bid) or amoxicillin (500 mg tid) for 90% of cases occur in the northern hemisp- 14-21 days, or 28 days if arthritis is present. here. Lyme disease is a multisystemic disor- For patients with carditis or neurologic com- der caused by the spirochete Borrelia plications, ceftriaxone (2 g IV qd) for 14-21 burgdorferi transmitted by a tick bite. During days is recommended. In pregnant patients, the bite, the risk of transmission increases use amoxicillin (500 mg PO tid) for 21 days. with the duration of the tick's attachment. If they are allergic to penicillin, use azith- The degree of engorgement seen in the tick is romycin (500 mg PO qd) for 7-10 days [6]. a rough measure of the risk of transmission. Cutaneous manifestations occur in 65-80% Arsenic Poisoning of patients. Erythema chronicum migrans Arsenic is a tasteless and odorless substance (ECM) begins as a small papule, commonly at and often is used in insecticides, fabric dyes, the site of the tick bite. The lesion progresses the tanning of animal hides, and certain prin- centrifugally over weeks and can become ting processes. Contaminated drinking water large. Central clearing gives the lesion the can be a common source of chronic exposure. typical bull's-eye appearance. The area can At one time, arsenic was used medically to irritate the patient, and regional lymphade- treat disorders such as psoriasis. Many cases nopathy may develop. Secondary lesions have of arsenic poisoning occur each year as a re- been reported and usually are multiple eryt- sult of accidental or industrial mishaps, and hematous macules with central clearing, si- its characteristics and availability make it a milar to ECM but smaller. A bluish-red popular choice for intentional poisoning. Cu- solitary nodule as borrelial lymphocytoma taneous manifestations include hyperpig- may develop at the site of the tick bite or at a mentation occurring in a guttate pattern with distant location such as the ear, nose, scro- increased pigment in the areola and inguinal tum, or areola region. Acrodermatitis chro- folds. Mees lines are transverse bands of leu- nica atrophicans consists of atrophic, konychia and can occur 2-3 weeks after an edematous, bluish-red plaques on the exten- acute poisoning or in persons with chronic sor aspect of the lower legs and elbows and exposure. Associated neurologic effects in- most commonly occurs in women. These may clude subacute sensorimotor polyneuro- resemble scleroderma or lichen sclerosus6. pathy, convulsions and, in severely affected More than 50% of patients have a migrating patients, coma and death. Treatment begins peripheral neuropathy, usually occurring 2- by removing the offending agent and by chela- 3 months after the onset of infection. The ting with British antilewisite (BAL). BAL (2,3- term neuroborreliosis describes the many dimercaprol) is a traditional chelating agent neurologic complications that occur, such as that has been used clinically in arsenic poiso- lymphocytic meningitis, cranial neuritis, fa- ning since 1949. In humans and experimental cial palsy, ophthalmoplegia, trigeminal neu- models, the antidotal efficacy of BAL has been ralgia, vestibular neuritis, and paralysis. shown to be most effective when administered Neurologic complications cannot be excluded immediately after the exposure [1, 2]. on the basis of a negative cerebral spinal fluid antibody analyses. Late complications, occur- ring after 1 year, are chronic peripheral neu- C- Neurocutaneous Disorders Associated ropathy, MS-like demyelinating disease, with Meningitis and Encephalitis dementia, and extreme fatigue. Arthritis in one to a few large joints is a common manife- Determining whether a patient has infective station and develops in as many as 70% of or non-infective meningitis/encephalitis can

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drastically change early management. Many ganglia and can reactivate years later as her- patients with an infectious aetiology develop pes zoster. More than 300,000 cases of zoster skin signs before the causative organism is are seen in the United States every year. proven on culture or on serological testing. Crops of diffuse, painful, pruritic vesicles and papules that occur in a dermatomal distribu- 1. Purpura and petechiae: A petechial rash tion characterize zoster. The disease is self-li- in a sick child indicates meningococcal me- miting and usually resolves within 2-3 weeks. ningitis until proven otherwise. Cutaneous manifestations are present in al- 2. Maculopapular rash: These lesions are most all cases of zoster. The phrase "dewdrops characterised by blanching, flat macules and on a rose petal" describes the appearance of raised papules. Rocky Mountain spotted the vesicles on an erythematous base. The af- fever, a tick-borne rickettsial illness, presents fected dermatome is painful to the touch, and with some type of rash in 90% of cases. Typi- prodromal pain may precede the development cally macules appear on the wrists, ankles of visible lesions. Although zoster can occur and forearms 4 days after the tick bite. By anywhere along the neural axis, thoracic der- day 6, approximately half of patients have de- matomes are affected most commonly, follo- veloped a characteristic red spotted, petechial wed by the face. Southern blot analysis and rash, which in most cases affects just the in situ hybridization has detected the virus in palms and soles. Leptospirosis also presents human trigeminal and thoracic ganglia. Poly- with a maculopapular rash in 50% of cases merase chain reaction (PCR) analysis further and, when occurring with jaundice and re- confirms the clinical findings of thoracic and cent exposure to contaminated water, is trigeminal dermatomes as the most common highly suggestive. site of reactivation [7, 8]. Non-infectious causes including Behçet's di- Zoster occurring in the ophthalmic division of sease, sarcoidosis, small vessel vasculitis and the trigeminal nerve may result in keratitis, a Sjögren's syndrome also result in skin chan- potential cause of blindness. Immediately ges. These changes not only guide the physi- refer these patients to an ophthalmologist for cian on further investigations but may prove slit lamp examination. Of patients with opht- invaluable if seeking a histological diagnosis. halmic nerve zoster, two thirds have eye in- The neurologists should look for; volvement, especially when vesicles occur on • Mouth/genital ulcers the side of the nose, indicating involvement of the nasociliary nerve (Hutchinson sign). • Erythema nodosum Other complications can develop following va- • Lupus pernio: This lesions are characteri- ricella or zoster infections. Ramsay-Hunt sed by raised indurated, purple, papules and syndrome is the reactivation of the virus in plaques appearing on nose, ears, cheeks and the seventh cranial nerve, causing one-sided fingers. facial weakness combined with lesions of the ipsilateral external ear, herpes zoster oticus, • Skin metastases or zoster of the hard palate. Ophthalmople- Patients with Behçet's disease all develop gia, optic neuritis, and other cranial neuro- mouth ulcers, whereas only 25% of those pathies may develop. Arm weakness and, less with sarcoidosis have cutaneous disease in- frequently, diaphragmatic paralysis may cluding erythema nodosum and lupus pernio. occur with cervical zoster. Leg weakness with Sweet's syndrome is characterised by painful bladder and bowel dysfunction may occur red papules and plaques, and frequently oc- with lumbosacral zoster. Rarely, myelitis or curs with leukaemia [1,2]. encephalitis occurs after the development of skin lesions. Recently, studies have shown that infection of blood vessels by the virus D. Neurocutaneous Disorders of Viral Origin causes encephalitis. Granulomatous arteritis results from large vessel arterial disease and 1. Herpes Varicella Zoster occurs mainly in immunocompetent patients. Varicella-zoster virus is a herpes virus that Encephalitis resulting from small vessel di- causes a primary infection of varicella. The sease occurs exclusively in immunodeficient virus is latent in cranial nerve and dorsal root patients. Long-term use of low-dose steroids

Page 6 of 19 (page number not for citation purposes) J Turk Acad Dermatol 2013; 7 (4): 1374r1. http://www.jtad.org/2013/4/jtad1374r1.pdf may cause an increased susceptibility to ride, adenosine monophosphate, and levo- myelitis and encephalitis [7, 8]. dopa with benserazide. Different therapies have been tried to treat postherpetic neural- Treatment of zoster includes the following: gia. Tricyclic antidepressants and anticonvul- Analgesic and famciclovir, valacyclovir (1000 sants have provided relief to some patients. mg tid) or oral acyclovir (800 mg 5 times per Steroids may help by reducing inflammation. d) for 7 days to decrease new lesions. Treat- Topical aspirin, capsaicin, and anesthetic ment is ideally started within 3 days of rash agents may help relieve pain [7, 8]. appearance. Zoster is common in older pati- ents, especially those older than age 60 years. Of patients who have had chickenpox, 2% de- 2 - HIV and AIDS velop zoster. Patients who develop chicken- pox younger than age 1 year are predisposed NHIV and AIDS cause skin involvement in to develop zoster before age 60 years. Millions 90% of patients. This often precedes neurolo- of children worldwide have received the vari- gical symptoms, which in turn appear in 75% cella vaccine, and vaccination is recommen- of cases. Skin lesions are due to opportunis- ded by the American Academy of Pediatrics. tic infections, tumours and adverse drug re- Vaccine prevents the primary infection; ho- actions. wever, the virus remains latent, and vaccina- 1. Seroconversion: 50% of those infected with tion does not prevent later development of HIV develop acute retroviral syndrome 2–4 zoster. Pediatric herpes zoster has been re- weeks after exposure. Following a short flu- ported in children who received the vaccine like illness, a generalised maculopapular rash or who had clinical chickenpox at a very develops. young age. A vaccine (Zostavax) has been approved by the US Food and Drug Adminis- 2. Established HIV (CD4 cell count 200– tration for the prevention of herpes zoster in 500/mm3): individuals age 50 years and older. In a ran- a. Bacterial infections: Folliculitis, cellulitis, domized, double-blinded controlled trial, the impetigo, abscesses and bacillary angiomato- zoster vaccine reduced the burden of illness sis for individuals aged 60 years or older by 61.1%, decreased the incidence of postherpe- b. Fungal infections: Candidiasis, pityriasis tic neuralgia by 66.5%, and reduced the inci- versicolor and seborrhoeic eczema: Intrac- dence by 51.3%. In March 2011, the Food table seborrhoeic dermatitis may be the first and Drug Administration (FDA) lowered the cutaneous manifestation of HIV and often in approved age for use of Zostavax to 50-59 patients with AIDS associated dementia or years. Zostavax was already approved for use CNS disease. in individuals aged 60 years or older. Zosta- c. Viral infections: Molluscum contagiosum, vax significantly reduced the risk of develo- oral hairy leukoplakia, herpes zoster (shin- ping zoster by approximately 70%. The most gles), viral warts, and herpes simplex may common complication of zoster is postherpe- occur in patients with HIV positive. tic neuralgia. Pain often is debilitating and can persist indefinitely. A prognostic factor is d. Infestations: Norwegian scabies age, and this complication usually does not T cell dysfunction and altered immunity allow occur in immunocompetent patients younger opportunistic infections and promote tumour than 50 years. After age 60 years, more than growth. Staphylococcal skin infections may 40% of patients develop postherpetic neural- seed haematogenously and cause spinal epi- gia. Optimal therapy for prevention has not dural abscess. Infection with Bartonella spe- been established. Although controlled trials cies may cause meningitis or encephalitis, have not shown oral antiviral drugs to be ef- and often manifests cutaneously as bacillary fective, such medications are administered angiomatosis. Viral infections may also cause empirically to patients older than 60 years. encephalitis and frequently cause skin di- Studies of other therapeutic options have sease in HIV. Herpes simplex infections las- been initiated to discover how to prevent ting for more than a month are common and postherpetic neuralgia and include steroids, herpes zoster may be recurrent or multi-der- interferon alfa-n3, amantadine hydrochlo- matomal. Epstein Barr virus causes oral hairy

Page 7 of 19 (page number not for citation purposes) J Turk Acad Dermatol 2013; 7 (4): 1374r1. http://www.jtad.org/2013/4/jtad1374r1.pdf leukoplakia while cytomegalovirus may cause men and women without regard to race or a maculopapular rash and painful polyradi- ethnic background [10]. culopathy. The National Institutes of Health (NIH) con- e. Other: Acne, atopic eczema, generalised sensus criteria for the diagnosis of NF1 re- pruritus and acquired ichthyosis can be seen quire 2 or more of the following: in patients with AIDS. • Café au lait macules larger than 5 mm in 3. AIDS (CD4 cell count <200/mm3): Tumo- diameter in prepubertal individuals and lar- urs such as Kaposi's sarcoma and lymphoma ger than 15 mm in diameter in postpubertal of the skin: Kaposi's sarcoma is associated individuals and numbering 6 or more with human herpes virus 8 and in addition to • Neurofibromas of any type or 1 plexiform cutaneous lesions may affect peripheral ner- neurofibroma and numbering 2 or more ves and the CNS. Neurological symptoms are variable, depending on location and whether • Axillary freckling (Crowe sign) or inguinal lesions cause infarction or haemorrhage. Cu- freckling taneous drug reactions are common in HIV, • Crowe sign, axillary freckling, in neurofib- especially with antibiotics including sulpho- romatosis type I. namides [9]. • Optic glioma • Lisch nodules (iris hamartomas; see image E-Inherited Neurocutaneous Disorders below) in more than 90% of patients younger than 6 years and numbering 2 or more Many neurocutaneous disorders have a gene- tic basis but in the absence of a strong family • Dysplasia of the sphenoid or thinning of history, neurologists need to be aware of the long bone cortex with or without pseudoarth- common cutaneous manifestations, especi- rosis ally in children presenting with seizures and • First-degree relative with NF1 [10] learning difficulties. In some cases, patients do not present until adulthood [1]. These criteria are useful in the clinical diag- nosis of NF1; however, some children younger than 8 years may not appear to have NF1 be- 1-Neurocutaneous Disorders with Autosomal cause of the late onset of the characteristic Dominant Phenotypes features used in the classification. a. Neurofibromatosis Type 1 Café au lait spots are characterised by flat patches of hyperpigmentation. Neurofibroma Half of new cases arise spontaneously with no is benign non-painful skin tumours that com- family history. Symptoms usually start in monly arise during puberty. They can also childhood with learning difficulties, seizures occur subcutaneously in 20% as painful rub- and visual disturbance due to optic nerve tu- bery tumours. Plexiform neurofibromata are mours. The diagnosis can be made on the diffuse, deep growths along nerve plexuses or basis of skin lesions with at least two of the dorsal nerve roots, which often cause neuro- following: café au lait macules (6+), neurofib- nal compression. Neurofibromas occur in al- romata (2+) or plexiform neurofibromta (1+), most all patients affected with NF1. axillary/inguinal freckling, optic glioma, Neurofibromas are benign tumors and almost Lisch nodules (2+), osseous lesion and first always involve cutaneous, subcutaneous, or degree relative with NF1. Although detectable dermal tissues. They comprise Schwann at birth, lesions usually increase in number cells, nerve fibers, fibroblasts, vascular ele- but fade in colour with advancing age. Neu- ments, mast cells, and myxoid matrix. Neu- rofibromatosis type 1 is an autosomal domi- rofibromas are classified into 4 types. The nant disorder. The gene locus is on band most common type is cutaneous neurofibro- 17q11.2, but spontaneous mutations occur mas. These neurofibromas are nonpainful, in approximately 50% of patients. As the soft, flesh-colored tumors that can range most common genetic disorder of the nervous from a few millimeters to 2 centimeters in dia- system, NF1 affects approximately 1 in 3000 meter. The underlying dermal defect allows people. NF1 occurs with equal frequency in reduction of the tumor with light pressure,

Page 8 of 19 (page number not for citation purposes) J Turk Acad Dermatol 2013; 7 (4): 1374r1. http://www.jtad.org/2013/4/jtad1374r1.pdf which is termed the buttonhole sign. Subcu- ging, neurofibrosarcoma is characterized by taneous neurofibromas occur in 20% of pati- a large heterogeneous tumor invading adja- ents and are painful, firm, rubbery tumors. cent structures. Other complications of NF1 Nodular plexiform neurofibromas comprise a include congenital glaucoma, hydrocephalus, large network of subcutaneous neurofibro- seizures, learning disabilities, psychosocial mas that occur along nerve plexuses or dorsal difficulties, and endocrine disturbances. nerve roots. As a result of their location, these Hypertension can occur in NF1 and may re- tumors cause severe neurologic deficits. Dif- sult from a pheochromocytoma or renal ar- fuse plexiform neurofibromas occur in appro- tery stenosis. Pheochromocytoma occurs in ximately 5% of patients and are considered 0.1-5.7% of patients with NF1 and is more specific to NF1. They usually are congenital common in adults. Other endocrine distur- and may have overlying hyperpigmentation bances, such as growth hormone deficiency, and hypertrichosis. These tumors are highly short stature, and precocious puberty, have vascular and may involve deep structures been reported in patients with NF1. Case re- that erode bone and extend to visceral areas. ports of NF1 and juvenile xanthogranulomas These tumors are like icebergs; what appears have been associated with juvenile chronic small on the outside may be extensive on the myelogenous leukemia. Zvulunov et al found inside and involve vast regions of the medias- a 30- to 40-fold higher than expected rate for tinum or retroperitoneum. Of plexiform neu- the association of NF1 with juvenile xanthog- rofibromas, 5-6% can progress to malignant ranulomas and juvenile chronic myelogenous peripheral nerve sheath tumors or Triton tu- leukemia [10]. mors (a rare variant of malignant peripheral nerve sheath tumors), which are severely pa- inful and carry a poor prognosis [10]. b. Neurofibromatosis Type 2 Chromosome 17 encodes the tumor suppres- Neurofibromatosis type 2 is an autosomal do- sor neurofibromin. Neurofibromin suppresses minant disorder caused by mutation in the the products of ras by enhancing its guano- schwannoma tumor suppressor gene on sine triphosphatase activity, thus reducing bands 22q11-13.1. This gene codes for the requirement for nerve growth factor or schwannomin/merlin proteins, which are neurotrophins. The loss of neurofibromin, membrane-organizing proteins and may af- which is expressed in neurons, Schwann fect tumor suppressor activity at the cell cells, the adrenal medulla, and white blood membrane level. Evidence for interfamilial cli- cells, may contribute to tumor progression. nical variability and spontaneous mutations Patients are at risk for developing numerous exists in 50-70% of patients. NF2 is less com- benign and malignant tumors. CNS neo- plasms are of particular concern in patients mon than NF1, occurring in 1 in 35,000 live with NF1. Optic gliomas are the most com- births without regard to sex, race, or ethnic mon CNS tumors, occur in approximately background. The neurologic hallmark of NF2 15% of patients, and may result in blindness is the development of bilateral vestibular if left untreated. Other associated CNS neo- schwannomas that are not associated with plasms are astrocytomas, vestibular schwan- NF1. Skin lesions are less frequent in NF2 alt- nomas (acoustic neuroma), and, less often, hough some patients have skin tumours that ependymomas and meningiomas. Non-CNS resemble neurofibromata and café au lait tumors associated with NF1 include neuro- spots. Freckling is unusual. The NIH Consen- fibrosarcoma, rhabdomyosarcoma, pheochro- sus Developmental Conferences provide gui- mocytoma, Wilms tumor, nonlymphocytic delines for use of the term neurofibromatosis childhood leukemia, and visceral neurofib- type 2. They suggest the term vestibular roma. Neurofibrosarcoma is the main cause schwannoma in place of the term acoustic of death of NF1 patients younger than 40 neuroma to reflect the anatomic site of the years. It may develop de novo or from sarco- tumor. Evidence suggests that 2 subtypes of matous degeneration of a preexisting plexi- NF2 exist, which are (1) a milder variant form neurofibroma. It should be suspected in (Gardner) resulting from missense and splice- patients with new onset of symptoms or in site germ-line mutations and (2) a severe va- patients with changing symptoms. At ima- riant (Wishart) resulting from frameshift and

Page 9 of 19 (page number not for citation purposes) J Turk Acad Dermatol 2013; 7 (4): 1374r1. http://www.jtad.org/2013/4/jtad1374r1.pdf nonsense mutations. Onset of the disorder childhood. Skin involvement occurs in 75% of frequently appears at age 15-30 years [11]. patients and is also early. Tuberous sclerosis is an autosomal dominant disorder in appro- Diagnostic criteria for NF2 include the follo- ximately 50% of patients; in the remaining wing: 50% of patients, the disorder occurs as a re- • Bilateral vestibular schwannomas (visua- sult of spontaneous mutation. In 1908, Vogt lized with CT scan or MRI) first described tuberous sclerosis as a triad of • A first-degree relative with the disease plus mental retardation, epilepsy, and adenoma a unilateral vestibular schwannoma before sebaceum; however, this triad is present in age 30 years less than one third of patients. The term epi- loia indicates epilepsy, low intelligence, and • Any 2 of the following: neurofibroma, me- adenoma. In tuberous sclerosis, 2 gene loci ningioma, glioma, schwannoma, or juvenile have been identified, TSC1 and TSC2. TSC1 posterior subcapsular opacity [11] has been mapped to band 9q34, which codes Cutaneous manifestations in NF2 are less for a 130-kd protein (termed hamartin) and common than NF1. Of patients with NF2, two is a probable tumor suppressor gene. TSC2 thirds have a skin manifestation. Neurofibro- has been mapped to band 16q13.3 and codes mas occur less commonly than in NF1. Plexi- for an amino acid protein (termed tuberin), form neurofibromas are unusual, and café au which has a region of homology with the lait macules tend to be fewer and lighter in GTPase-activating protein GAP3. GTPase re- pigmentation; only 8% of NF2 patients have gulates cell proliferation, and current studies more than 3 macules. Axillary or inguinal suggest tuberin may mediate this activity. freckling is not present. Cutaneous and sub- The genetic heterogeneity produces subtle cutaneous flat or spherical schwannomas differences in the phenotype. This may be often occur on peripheral nerves. Most com- explained by the function of hamartin and tu- monly, schwannomas are superficial raised berin as part of the same intracellular path- papules with overlying pigment and hair. way. Prevalence has been estimated to range Subcutaneous spherical nodular schwanno- from 1 case per 5,800 population to 1 case mas occur on peripheral nerves of the limbs per 10,000 population, occurring equally bet- and trunk and often can be palpated [11]. ween males and females of all races. Expres- sion is highly variable among families [12]. The most common neurologic finding is the presence of vestibular schwannomas; howe- In tuberous sclerosis, angiofibroma, Shagreen ver, schwannomas may occur on any of the patches, Ash leaf macules and periungual fib- cranial nerves except for the olfactory nerve. roma are seen as cutaneous manifestations. Pressure on the vestibulocochlear and facial Cutaneous manifestations associated with tu- nerve complex can cause symptoms of hea- berous sclerosis may be present at birth. In ring loss with intermittent tinnitus, unsteady approximately 87% of patients, congenital gait, and facial weakness. Advise patients to hypopigmented macules are found. These ash- avoid swimming under water, especially leaf macules are the earliest and most cha- alone, because of the association with under- racteristic finding and can be accentuated on water disorientation. Other tumors of the Wood lamp examination. Polygonal macules CNS occur in NF2, such as intracranial and are the most common type. Another type is spinal meningiomas, astrocytomas, and Confetti macules, which are 1 to 3 mm, hypo- ependymomas. Ocular manifestations in- pigmented, and spotlike macules commonly clude juvenile posterior subcapsular lenticu- located on the pretibial area. Melanocytes are lar opacity, retinal hamartomas, optic disk present in the macules; however, their trans- glioma, and optic nerve meningioma. Lisch fer and synthesis are impaired. Shagreen nodules are not associated with NF2 [11]. patch, a connective tissue nevus, may occur on the trunk, most often in the lumbosacral c. Tuberous sclerosis region. Shagreen patch is a 1- to 10-cm, flat, Tuberous sclerosis also has an autosomal do- flesh-colored plaque with an orange peel ap- minant pattern of inheritance but two-thirds pearance. Facial angiofibromas are diagnostic of cases arise spontaneously. Seizures, lear- of tuberous sclerosis and usually appear in ning difficulties and autism develop in early children aged 4-10 years. These typically are

Page 10 of 19 (page number not for citation purposes) J Turk Acad Dermatol 2013; 7 (4): 1374r1. http://www.jtad.org/2013/4/jtad1374r1.pdf firm, smooth, red-to-pink papules consisting obvious frontal bossing, hypertelorism, bifid of hyperplastic blood vessels and collagen, oc- ribs, and bone abnormalities of the spine and curring on the nasolabial folds, cheeks, and fingers. As the child ages, jaw cysts, palmar chin. Successful treatment of facial angiofibro- pitting, and basal cell carcinomas become ap- mas has been reported with podophyllin, but parent. Nevoid basal cell carcinoma this should be considered experimental. Su- syndrome results from mutation causing an bungual and periungual fibromas are firm inactivation of the patched gene, a tumor flesh-colored fibromas in the nail matrix or bed suppressor gene, in the hedgehog pathway. that result in destruction of the nail plate. Koe- Epidemiologic studies have demonstrated nen tumors are common in tuberous sclerosis, that sunlight, and particularly UV radiation, and surgical excision is curative. Other asso- are key risk factors for developing basal cell ciated cutaneous findings include fibrous pla- carcinomas. This explains the low frequency ques on the face, café au lait macules, and of these lesions in African Americans, owing port-wine hemangiomas [13]. to the protective action of melanin pigmenta- tion. Multiple basal cell carcinomas present Neurologic symptoms often are the first pre- as tan-brown papules on the face, neck, and senting sign and begin as focal or generalized trunk. Palmoplantar pits are 2- to 3-mm eryt- seizures. Infantile spasms, tonic-clonic seizu- hematous pits occurring on the palms and res, and complex partial and myoclonic sei- soles. Other cutaneous findings are epider- zures are the most common forms. Of moid cysts and milia [14]. children with infantile spasms, 10% have tu- berous sclerosis. Cortical tubers are charac- Key neurologic abnormalities are calcification teristic to tuberous sclerosis. These are of the falx cerebri, hydrocephalus internus, potatolike nodules of glial proliferation occur- agenesis of the corpus callosum, medullob- ring anywhere in the cortex, ganglia, or ven- lastoma, and occasionally, mental retarda- tricle walls. Other CNS findings include tion. Common features include odontogenic mental retardation, subependymal hamarto- keratocysts, jaw cysts (usually occurring in mas, paraventricular calcifications, and giant the maxilla), ovarian fibromas, fibrosarcoma, cell astrocytomas. Over time, subependymal strabismus, and congenital blindness. An nodules and cortical tubers can become cal- unusual finding of combined hamartoma of cified. Tuberous sclerosis is a multisystemic the retina and retinal pigment epithelium disease. Retinal hamartomas (phacomata) are also has been reported [14]. white streaks on the retina seen on fundus- copic examination. Renal involvement usually begins in infancy, and 75% of patients have e. Variegate Porphyria angiomyolipomas. Simple renal cysts may ap- Variegate porphyria is an autosomal domi- pear spontaneously. Oral pathology consists nant acute hepatic porphyria, due to a defici- of enamel pits and gingival fibromas. Effects ency of protoporphyrinogen oxidase activity, on the musculoskeletal system are seen in the penultimate enzyme in the heme biosynt- phalangeal cysts and periosteal thickening. hetic pathway. The disease is termed varie- Lung cysts may occur. Rhabdomyomas occur gate because it can manifest with in 50% of patients, usually in infancy, and neurological symptomatology, cutaneous may regress spontaneously with age. Pulmo- photosensitivity, or both. Variegate porphyria nary lymphangiomyomatosis, a proliferation has been recently cloned and mapped to the of smooth muscle cells, can occur in women protoporphyrinogen oxidase gene on bands with tuberous sclerosis. A few reports exist of 1q22-23. The disorder is termed South Afri- infants with a white forelock who later were can porphyria because it occurs frequently in diagnosed with tuberous sclerosis [13]. white South Africans of Boer descent with an incidence of 1 case per 330. Genealogic stu- dies show that all are descendants of Gerrit d. Nevoid Basal Cell Carcinoma Syndrome Jansz and Ariaantje Jacobs who married at Nevoid basal cell carcinoma syndrome is an the Cape of Good Hope in 1688. Similar foun- autosomal dominant disorder with a gene der effects explain the high prevalence of va- locus at bands 9q22-31 and a variable exp- riegate porphyria in Finland, and links have ressivity. The disorder begins at birth with been hypothesized to the houses of Stuart,

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Hanover, and Prussia. Symptoms begin in the neural deafness) syndrome is an autosomal second or third decade of life as a result of a dominant disorder with high penetrance and deficiency of protoporphyrinogen oxidase, the variable expressivity. Gorlin first described enzyme that catalyzes the oxidation of proto- the condition. This disease was also known porphyrinogen IX to protoporphyrin IX in the as multiple lentigines syndrome, cardiocuta- heme pathway. This results in the accumula- neous syndrome, Moynahan syndrome, len- tion of protoporphyrinogen, porphyrins, and tiginosis profuse, and progressive porphyrin precursors [15]. cardiomyopathic lentiginosis. About 200 pa- tients have been reported worldwide, but the Cutaneous manifestations are present in 80% real incidence of LEOPARD syndrome has not of patients. The extent of skin findings varies been assessed. Mutations in the PTPN11 (hence the name) and is identical to findings gene, are known to be mutated in persons in porphyria cutanea tarda. Vesicles, bulla, with Noonan syndrome, has been demonstra- and ulcers are found primarily on light-expo- ted in patients with LEOPARD syndrome [16]. sed skin. Increased skin fragility with chronic scarring, milia on fingers and hands, hyper- The most prominent cutaneous findings in pigmentation in photodistributed patterns, LEOPARD syndrome are the lentigines that sclerodermoid plaques, dystrophic calcificati- begin at birth and increase with age. These ons, photo-onycholysis and hypertrichosis lentigines are multiple 1- to 2-mm, flat, dark- are common [15]. brown patches in a general distribution, spa- ring mucous membranes. Areas of Acute attacks are seen in approximately 50% hypopigmentation in places where previous of patients and cause neuropsychiatric, gastro- lentigines existed also may be a key feature. intestinal, and cardiovascular manifestations Unlike freckles, the lentigines have an increa- as a result of the increase in porphobilinogen sed number of melanocytes and large pig- (PBG) and aminolevulinic acid (ALA). Acute at- ment granules that are unrelated to sun tacks also are associated with other hepatic exposure. Some patients lack lentigines, porphyrias, such as acute intermittent which makes the diagnosis difficult. Other porphyria and hereditary coproporphyria. key dermatologic findings include café noir During attacks, symptoms include delirium, and café au lait spots. Hypotonia is common colicky abdominal pain, dark urine, axonal in the newborn and can result in delayed neuropathy that can mimic Guillain-Barré psychomotor development. Mild learning dif- syndrome, seizures, coma, tachycardia, and ficulties are reported in about 30% of the hypertension. Attacks in all 3 porphyrias are cases. Sensorineural deafness occurs in 15- precipitated by increases in hepatic ALA 25% of reported cases and can be profound. synthase, eg, by drugs that increase cytoch- Once the diagnosis is made, screen the child rome P450 or by starvation dieting. Labora- for sensorineural deafness and start approp- tory analysis in variegate porphyria can be riate therapy as soon as possible to avoid helpful. ALA and PBG can be found in the later difficulties with speech and phonation. urine only during acute attacks and fluoresce Mild mental retardation, disturbed EEG wave a pink-to-red color. Accordingly, the Watson- activity, and diffuse encephalopathy also may Schwartz test for PBG is positive only during be present [16]. acute attacks. Stool porphyrin levels are ele- vated markedly (including between attacks), g. Von Hippel–Lindau syndrome with protoporphyrin in greater proportion Von Hippel–Lindau syndrome, a rare autoso- than coproporphyrin. Plasma porphyrin le- mal dominant condition associated with he- vels are elevated, and fluorescence at 626 nm mangioblastoma in the cerebellum, spinal is diagnostic [15]. cord, kidney and retina, can be associated with café au lait spots [17]. f. LEOPARD Syndrome h. Osler-Weber-Rendu disease (Hereditary hemorrhagic telangiectasia) LEOPARD (lentigines, electrocardiographic conduction abnormalities, ocular hypertelo- Patients with Osler-Weber-Rendu disease rism, pulmonary stenosis, abnormal genitalia have multiple telangiectasias on the face, in males, retardation of growth, and sensori- hands, palmoplantar, and subungual regi-

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ons. Epistaxis is common in approximately develop gradually. Intelligence may be normal 80% of patients, and neurologic complications in early childhood but progressively deterio- include vascular lesions of the brain and/or rates. Immunodeficiency results in an inabi- spinal cord. The mutated genes are HHT1 and lity to mount sufficient immune response. HHT2; both endoglin and activin are tumor Recurrent viral and bacterial infections occur growth factor-beta receptors that play a role in in 80% of patients and are the most common vessel wall integrity. Piebald trait with neuro- cause of death resulting from respiratory fai- logic defects presents as a white forelock and lure. Patients lack helper T cells, but supp- depigmented patches with spots of hyperpig- ressor T cells are normal. Immunoglobulin A mentation on the anterior body, sparing the (IgA) is absent in 75% of patients, immunog- hands and feet. Patients have cerebellar ataxia, lobulin E (IgE) in 85%, and immunoglobulin varying degrees of mental retardation, and pos- G (IgG) is low. Alpha-fetoprotein and carcino- sible hearing loss [18]. embryonic antigen are elevated and may be useful in the diagnosis. Endocrine disorders associated with AT include ovarian agenesis, 2. Neurocutaneous Syndromes with Auto- testicular hypoplasia, and insulin-resistant somal Recessive Phenotypes diabetes.The ATM gene is a nuclear protein important in the detection and repair of da- Autosomal recessive phenotypes typically are maged DNA. Defects in the gene result in an more severe than those with autosomal domi- increased susceptibility to malignancy. Ma- nant traits and commonly are associated with lignant neoplasms occur in 10-15% of AT pa- enzyme deficiency [1, 2]. tients; most common are lymphoreticular a. Ataxia-telangiectasia neoplasm and leukemia [19]. Ataxia–telangiectasia (AT; Louis-Bar syndrome) is an autosomal recessive condition characte- b. Sjögren-Larsson Syndrome rised by progressive ataxia, variable immuno- deficiency and telangiectasia, which occur over Sjögren-Larsson syndrome (SLS) is a rare au- the cheeks, eyelids, neck, ears, backs of hands tosomal recessive disorder characterized by a and conjunctivae. Ataxia-telangiectasia is an triad of intellectual disability, spastic diplegia autosomal recessive disorder characterized by or tetraplegia, and congenital ichthyosis with progressive cerebellar ataxia, oculocutaneous associated ocular features, which include pig- telangiectasia, abnormalities in cellular and mentary changes in the retina. Linkage to humoral immunity, and recurrent viral and arm 17q has been reported in Swedish pedig- bacterial infections. The gene for AT has been rees. Lacour et al show linkage of chromo- localized to bands 11q22-23 and is termed some 17 in families from different ethnic the ATM gene. The disorder occurs with equal origins; thus providing evidence of a single frequency in males and females and in app- gene locus. SLS is caused by mutations in the roximately 1 in 80,000-100,000 live births ALDH3A2 gene, causing a deficiency in fatty [19]. alcohol oxidoreductase, which catalyzes the oxidation of medium- and long-chain fatty Patients present with distinctive cutaneous acids. The disorder begins at birth with gene- manifestations. Telangiectasias develop when ralized ichthyosis and erythroderma. As the patients are aged 3-6 years and are noted child ages, the scale becomes darker without first on the bulbar conjunctiva and ears. erythema and is more pronounced around Later, they appear on the flexor surface of the the umbilicus, neck, and flexures, typically arms, eyelids, malar area of the face, and sparing the face. Hyperkeratosis of the palms upper chest. Granulomas, café au lait macu- and soles and marked pruritus are common. les, graying hair, and progeria can occur. The Atypical retinal pigment degeneration in the presenting symptom is cerebellar ataxia be- macula (glistening dots) usually is seen after ginning in the second year, when the child the first year [20]. begins to walk. Choreic and athetoid move- ments, progressive nystagmus, slurred spe- Neurologic symptoms and signs appear du- ech, dystonia, dysarthria, oculomotor ring the first 1-2 years of life and consist of apraxia, impassive facies, decreased deep delay in reaching motor milestones due to tendon reflexes, and distal muscular atrophy spastic diplegia or, much less commonly,

Page 13 of 19 (page number not for citation purposes) J Turk Acad Dermatol 2013; 7 (4): 1374r1. http://www.jtad.org/2013/4/jtad1374r1.pdf spastic tetraplegia. Approximately half the pa- IKKy have been found to cause expression of tients are nonambulatory, and most others re- the disorder. Few affected males have been quire braces or crutches to walk. Seizures documented, and most had Klinefelter occur in about 40% of patients. Cognitive defi- syndrome (47,XXY). The disorder was descri- cits are equally divided among those with mild, bed as early as 1906; Bloch and Sulzberger moderate, or profound retardation, but rare pa- were credited with fully describing IP in 1928. tients have been found with normal intellect. Skin lesions arranged in a linear pattern, Delayed speech and dysarthria are common. A ocular defects, dental, and neurologic abnor- distinctive ophthalmologic finding is the pre- malities characterize IP. More than 700 cases sence of retinal crystalline inclusions, so-called have been reported, with a 97% female pre- glistening white dots, surrounding the fovea. dominance [24]. Although all SLS patients do not have the reti- nal inclusions, their presence is pathognomo- Characteristic cutaneous findings begin at nic for SLS. Photophobia and myopia are also birth and occur in 4 stages. In stage 1; The often present. Brain MRI reveals white matter vesicular stage occurs from birth to 2 weeks. disease and MR spectroscopy identifies an Infants present with inflammatory vesicles unusual lipid peak in myelin [20]. and bullae in a linear pattern on the extremi- ties, trunk, and scalp. Recurrent crops of c. Multiple sulfatase deficiency erythematous macules and papules may This is a neurodegenerative disorder that erupt for weeks. Skin biopsy at this stage re- progresses to death early in childhood. Child- veals increased eosinophils. In Stage 2: The ren with this disorder are unable to degrade verrucous stage occurs from 2-6 weeks, with various sulfatases like steroid sulfatase, hyperkeratotic streaks, pustules, and papu- which results in mild ichthyosis. Neurologic les occurring exclusively on the extremities. complications result from myelin deteriora- In Stage 3: The hyperpigmentation stage oc- tion, causing unsteady gait, deterioration in curs from 3-6 months and is characterized by speech, and blindness [21]. marbled swirls of hyperpigmentation along Blaschko lines. In Stage 4: The hypopigmen- d. Hartnup disease tation stage occurs in adult women, when fol- Hartnup disease is a disorder of amino acid licular atrophy and hypopigmentation replace transportation with resulting decreased ab- hyperpigmented swirls. Of patients, 50% pre- sorption of tryptophan. Cutaneous manife- sent in stage 1 at birth and 90% by age 2 stations include photosensitivity and the weeks. Stage 2 lesions occur in approximately pellagra-like skin changes of photodistributed 70% of patients. In a small percentage of pa- erythema and scale. Progressive cerebellar tients, the hyperpigmentation is present at ataxia and psychiatric disturbances are com- birth. Other cutaneous findings include scar- mon. Urinalysis shows aminoaciduria and ring alopecia in 30% of patients, nail tryptophan derivatives [22]. dystrophy in 5-10%, and peg teeth in 66%. e. Tangier disease Subungual tumors, keratotic tumors, and more rarely, squamous cell carcinoma also It is a rare autosomal recessive deficiency have been reported [24]. syndrome. The disease results from a defici- ency of high-density lipoproteins, causing CNS findings occur in more than 30% of pa- orange-yellow papules, xanthomatous papu- tients; seizures are the most common. Other les, and recurrent neuropathy [23]. findings include cerebral ischemia, cerebral edema, brain atrophy, and gyral dysplasia. Gross neurologic findings associated with IP 3. Other Inherited Neurocutaneous Syndromes include mental retardation, spastic paralysis, cortical blindness, and paresis. Ocular mani- a. Incontinentia Pigmenti festations occur in 25-35% of patients and in- Incontinentia pigmenti (IP; Bloch-Sulzberger clude strabismus, cataracts, retinal detach- syndrome) is an X-linked dominant disorder ments, optic atrophy, retrolental mass, and lethal to male patients. The disorder has been vitreous hemorrhage. In particular, note the linked to the gene locus Xq28 in a number of retinal vascular abnormalities with secondary studies. Recently, mutations in the NEMO/ blindness [24].

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b. Sturge-Weber Syndrome years 1928-1929, it became the eighth-to- ninth highest cause of death in the United Sturge–Weber syndrome occurs sporadically States. Because of intensive fortification ef- and is associated with a red–purple area of forts in the United States, pellagra has be- skin discolouration as wine stain, usually come uncommon; however, it remains a over the ophthalmic division of the trigeminal public health issue in Africa, India, and nerve. Underlying the skin lesion, the lepto- China, and recent outbreaks were reported in meninges contain multiple angiomata and Angola at an asylum camp dependent on food over time the adjacent cortex becomes calci- distribution [26]. fied and may cause seizures. Sturge-Weber syndrome is not an inherited disorder, but it Pellagra continues to occur in the United Sta- has been reported to show prevalence among tes and commonly is associated with alcoho- relatives. Sturge-Weber syndrome is charac- lism and isoniazid therapy. Other possible terized by congenital facial port-wine stains causes include carcinoid tumors, Hartnup di- and leptomeningeal vascular angiomatosis. sease, hookworms, and medications such as Sporadic malformations most commonly azathioprine and 5-fluorouracil. Recognizing occur in the leptomeninges, facial capillaries, the clinical manifestations associated with and ocular vessels. Leptomeningeal angioma- pellagra is important, since the disorder is ea- tosis can present clinically as epilepsy, men- sily treated. The condition has been reported tal retardation, and hemiplegia [25]. in fad dieters and persons infected with HIV. Cutaneous manifestations occur in a photo- Newborns with port-wine stains have a 5-8% distributed pattern. Hand erythema in a glove risk of Sturge-Weber syndrome. In patients distribution is one of the first signs, and pa- with Sturge-Weber syndrome, the port-wine tients may complain of pruritus and burning, stain usually involves the ophthalmic and especially after sun exposure. Early facial le- maxillary division of the trigeminal nerve. The sions are erythematous scaly papules and macule is deep red, irregular-shaped, and of pustules and may resemble the malar rash vascular origin. The lesion's size varies, and seen in lupus erythematous. As the disorder it may involve the eyelid, face, and trunk. Alt- progresses, lesions become hard, dark, and hough striking, the size of the nevus does not thick plaques with painful fissures. Note that predict the degree of neurologic impairment. a striking demarcation exists between affec- Neurologic complications can begin as early ted and normal skin. A symmetric ring of le- as age 5 months with partial motor seizures sions around the neck as known Casal later progressing to more generalized seizu- necklace is a late finding [26]. res. Most neurologic complications, such as spastic hemiparesis, sensory defects, and ho- Episodes of mania, aggressive behavior, and monymous hemianopia, appear later in child- severe mood swings may occur. Neurologic hood and are contralateral to the nevus. At symptoms may be predominant in late stages approximately age 6-7 years, skull radiog- of the disease. Patients may experience pa- raphs reveal curved double outlines of the pa- resthesia, muscle weakness, and headaches. rietooccipital cortex, which is the classic Death occurs within 4-5 years if the patient tram-track calcification. Mental retardation is remains untreated. Focus treatment on die- present in approximately 55-92% of cases tary correction and daily supplements of 100- [25]. 300 mg of nicotinic acid. Once therapy has begun, skin lesions begin to heal within 24 hours [26]. F. Neurocutaneous Syndromes With Photosensitivity G.Neurologic Disorders With Important Pellagra Dermatologic Findings Pellagra is caused by dietary deficiency of nia- 1.Reflex Sympathetic Dystrophy cin, resulting in the 4 D 's: diarrhea, derma- titis, dementia, and eventually, death. Niacin Reflex sympathetic dystrophy (RSD) is a po- can be ingested or synthesized from large orly defined disorder often difficult to diag- quantities of dietary tryptophan. In the early nose. Symptoms of intolerable pain (out of 1900s, pellagra was prevalent, and during the proportion to clinical picture) develop follo-

Page 15 of 19 (page number not for citation purposes) J Turk Acad Dermatol 2013; 7 (4): 1374r1. http://www.jtad.org/2013/4/jtad1374r1.pdf wing an injury. In 50% of patients, the initial kers. Kemler et al reported spinal cord stimu- injury is a fracture, usually of the distal ext- lation to be safe and effective in decreasing remity. The sympathetic nervous system is pain associated with RSD. According to van believed to be a mediating factor in the early Hilten et al intrathecal baclofen, a type B stages of the disorder, but the exact role is GABA-receptor agonist, has relieved pain and unclear [27]. decreased spasms and dystonia in some pa- RSD can be divided into 3 stages, and each tients [27]. stage is characterized by dermatologic and neurologic findings. In early or acute stage, 2. Seborrheic Dermatitis patients are in severe pain, which often is described as a burning throbbing sensation. Seborrheic dermatitis is a common disorder The key finding is pain beyond that expected in the general population but has increased for the injury sustained. The pain can be in- incidence in certain neurologic disorders. duced easily by minor stimuli such as blo- Erythematous greasy scales and yellow pla- wing air, stress, and certain textures. In ques on the scalp, eyebrows, nasolabial folds, approximately 20% of patients, associated ears, and sternal area are characteristic. skin findings are edema, erythema, and Blepharitis is a common finding. The etiology warmth. In second or dystrophic stage occurs is unknown, but studies have described Pity- approximately 3 months after the injury and rosporum ovale as the causative agent. Pity- can last as long as 6 months. Pain begins to rosporum ovale is lipophilic yeast, and spread from the initial site and can occur patients with seborrheic dermatitis have sig- spontaneously. Skin becomes cool, clammy, nificantly higher amounts of it, as well as in- and pale. A faint cyanosis, decreased capil- creased skin lipids. Some associated lary refill, and/or livedo reticularis can be disorders are as follows: Patients with Parkin- present. If the affected area involves the nails, son disease can have severe cases of seborr- they can become dry and brittle. Hair in the heic dermatitis, usually involving the scalp area may become darker and grow faster. In and face. Facial paralysis resulting from stroke third or atrophic stage, This occurs approxi- or injury can result in seborrheic dermatitis, mately 8 months after the initial injury and usually occurring on the corresponding side. can be chronic. Patients may experience Other disorders including quadriplegia, poli- constant burning and increasing pain, resul- omyelitis and syringomyelia have an increased ting in disruption of sleep. Depression and incidence of seborrheic dermatitis. Immuno- anxiety may develop. Tissue damage progres- compromised patients like HIV patients are ses, and the skin appears shiny, dry, and especially at risk. Seborrheic dermatitis is mottled. Atrophic changes occur, and the pa- more common and more severe in persons in- tient may lose hair in the areas of previous fected with HIV, particularly in those with increased growth. Ridging of the nails and CD4 counts below 400 cells/μL, than in Beau lines may be present. Diffuse osteopo- uninfected persons, and it may regress with rosis (Sudeck atrophy) may occur because of highly active antiretroviral therapy. In HIV- increased absorption of bone [27]. infected patients, lesions are widespread and Diagnosis is primarily clinical; therefore, cu- markedly inflamed and oozing. The skin con- taneous manifestations can help the diagno- dition is rare in African blacks; when it oc- sis in patients without classic findings. Some curs in this population, it raises concern advocate sympathetic nerve block as a diag- about HIV infection. Seborrheic dermatitis nostic test. In chronic stages, a bone scan has been reported to be associated with seve- can reveal osteoporosis and a 3-phase scan ral conditions, including neuroleptic-induced often reveals abnormal absorption of bone. parkinsonism, familial amyloidosis with poly- Treatment begins with prevention. Promptly neuropathy, and trisomy 21, but these asso- immobilize patients with distal injuries. Once ciations have been poorly documented. diagnosed, no single effective therapy exists, Hyperinsulinism also has been associated and patients respond differently to proposed with seborrheic dermatitis and supports the treatments. Patients may benefit from inten- mycologic origin of the disorder [28]. In se- sive physical therapy, sympathetic blockade, borrheic dermatitis, effective treatments are calcitonin, or alpha-blockers and beta-bloc- available. Selenium sulfide, ketoconazole,

Page 16 of 19 (page number not for citation purposes) J Turk Acad Dermatol 2013; 7 (4): 1374r1. http://www.jtad.org/2013/4/jtad1374r1.pdf and tar shampoos control symptoms well. Cor- pituitary disease. In acromegaly, the skin be- ticosteroid scalp solutions can help decrease comes oily with excess hair growth. Also skin the inflammation that commonly occurs. Cal- tags and deep, hard skin creases are noted cineurin inhibitors, such as tacrolimus oint- [1]. ment, work well for treatment of the face. Thyroid dysfunction may result in myxoe- Warm compresses and gentle cleaning with dema, the skin being cool and doughy with mild baby shampoo help relieve blepharitis. hair loss, or in thyrotoxicosis when it is Mild steroids, and in infection, steroids in com- warm, flushed and moist. In Cushing's di- bination with antimicrobial preparations, are sease there may be skin atrophy, bruising, effective. Ultraviolet B phototherapy is someti- acne and striae. Hypopituitarism leads to dry, mes considered as an option for extensive or scaly, hairless and finely wrinkled skin [1]. recalcitrant seborrheic dermatitis, but it has not been studied in randomized trials [28]. 4. Drug reactions Adverse drug reactions causing rashes are not uncommon in neurology, especially when 3. Malignancy prescribing antiepileptic drugs. Stevens– Melanoma is undoubtedly the most likely of Johnson syndrome, toxic epidermal necroly- any skin malignancy to metastasise to the sis and antiepileptic hypersensitivity brain. Primary intracranial melanoma can syndrome are non-allergic hypersensitivity arise from the leptomeninges or dura mater, reactions which may occur following carba- and accounts for less than 1% of melanomas. mazepine, lamotrigine, phenobarbital, pheny- Any incidental skin lesion suspicious of me- toin, sodium valproate or primidone, lanoma should be urgently referred to a der- especially if used in combination. Presenta- matologist [1]. tion is usually within the first 60 days and may occur in 5% of patients starting carba- Dermatomyositis is associated with malig- mazepine or lamotrigine. There is a strong as- nancy in 20% of patients; skin disease is the sociation between the HLA B*1502 allele in initial manifestation in around a third of Asian patients3 who often develop Stevens– these. Muscle disease is more variable but Johnson syndrome and toxic epidermal nec- importantly, both manifestations tend to rolysis with carbamazepine; genotyping is occur before any signs of malignancy. In der- advocated in some centres [1, 2]. matologic examination, there are photosensi- tivity ecpecially in sun exposed areas, Stevens–Johnson syndrome presents acutely heliotrope rash as periorbital purple discolou- with fever, sore throat and burning eyes. Mu- ration and swelling, Gottron's papules as cous membranes, especially around the purple flat topped plaques over the knuckles, mouth, eyes and lips, become blistered. This elbows or knees, urticarial lesions as itchy is followed by a widespread erythematous rash, usually over the face and neck, subcu- rash, which within hours becomes confluent taneous calcification as firm subcutaneous and sheets off to leave eroded surfaces similar papules or nodules, commonly associated to burns. Other organs may also be involved with trauma and best seen over the elbows, and patients often develop hepatitis, nephri- knees, buttocks and hands, and nail fold te- tis, pneumonitis and myocarditis. More wi- langiectasia [2]. despread involvement (>30% of body surface area) results in toxic epidermal necrolysis, Central nervous system involvement occurs which can be fatal if complicated by dehydra- in around 10% of patients with non-Hodg- tion or secondary sepsis. Early identification kin's lymphoma. In non-Hodgkin's lymphoma and immediate withdrawal of the suspected ichthyosis as dry, thickened, scaly or flaky drug improves outcome, and dermatological skin, paraneoplastic pemphigus as stomatitis advice should be sought while supportive tre- and blistering on the trunk and limbs, and atment is instigated. In antiepileptic hyper- also acquired hypertrichosis lanuginosa as sensitivity syndrome, patients have systemic rapid growth of long, fine, lanugo-type hair, and cutaneous features of Stevens–Johnson particularly on the face could be observed [1]. syndrome and toxic epidermal necrolysis but Skin changes often mirror changes in hor- without mucosal involvement or skin desqua- mone levels and may be the first indication of mation. Other serious cutaneous and syste-

Page 17 of 19 (page number not for citation purposes) J Turk Acad Dermatol 2013; 7 (4): 1374r1. http://www.jtad.org/2013/4/jtad1374r1.pdf mic acute drug reactions associated with an- 6. Potok OV, Brassard A. Lyme borreliosis: an update tiepileptics include acute fixed drug reacti- for Canadian dermatologists. J Cutan Med Surg 2013; 17: 13-21. PMID: 23364145 ons, phototoxic reactions and porphyric exacerbations. Maculopapular rashes and ur- 7. Gagliardi AM, Gomes Silva BN, Torloni MR, Soares BG. Vaccines for preventing herpes zoster in older ticaria are more common and resolve once adults. Cochrane Database Syst Rev 2012; 10: the drug is stopped. Intravenous immunoglo- CD008858. PMID: 23076951 bulin is commonly used to treat neurological 8. Thakur R, Philip AG. Chronic pain perspectives: Trea- conditions and may cause skin problems. A ting herpes zoster and postherpetic neuralgia: an evi- blistering eczematous reaction, usually on dence-based approach. J Fam Pract 2012; 61: 9-15. the palms, may spread to involve the whole PMID: 23000670 body 8–10 days after starting treatment. This 9. Alkali NH, Bwala SA, Nyandaiti YW, Danesi MA. Neu- can take up to a month to resolve although roAIDS in sub-Saharan Africa: a clinical review. Ann Afr Med 2013; 12: 1-10. PMID: 23480988 topical and oral steroids can expedite reco- very. Alopecia and urticaria have also been 10. Ghalayani P, Saberi Z, Sardari F. Dent Res J 2012; 9: 483-488. PMID: 23162593 reported [1, 2]. 11. Ko JY, Kim JE, Kim YH, Ro YS. Cutaneous plexiform schwannomas in a patient with neurofibromatosis type 2. Ann Dermatol 2009; 21: 402-405. PMID: Summary 20523833 Neurologists should examine a neurological 12. Wataya-Kaneda M, Tanaka M, Hamasaki T, Kata- yama I. Trends in the prevalence of tuberous sclero- patient, have a careful look at their skin. For sis complex manifestations: an epidemiological study young patients with stroke, think about pos- of 166 Japanese patients. PLoS One 2013 17; 8: sible causes of vessel damage, bleeding or e63910. PMID: 23691114 disturbed blood flow. For patients with me- 13. Rodrigues DA, Gomes CM, Costa IM.Tuberous scle- ningitis/encephalitis neurlogist should ask rosis complex. An Bras Dermatol 2012; 87: 184-196. whether this be infective or part of a systemic PMID: 22570021 illness or, in the case of neuropathy, could 14. Kiran NK, Tilak Raj TN, Mukunda KS, Rajashekar this be nutritional. Neurological symptoms Reddy V. Nevoid basal cell carcinoma syndrome (Gor- lin-Goltz syndrome). Contemp Clin Dent 2012; 3: frequently result in a new diagnosis of HIV in- 514-518. PMID: 23633824 fection and neurologists should do skin exa- 15. Chow KM, Hui CF, Lam CW, Morgan RR, Whatley mination. They should also remember that SD, Kay R, Wong KS.Clinical and genetic features of significant proportion of patients with neuro- variegate porphyria in a Chinese patient. Chin Med cutaneous syndromes have no family history J 2001; 114: 424-427. PMID: 11780470 and may present in adulthood. Rashes are 16. Martínez-Quintana E, Rodríguez-González F. LEO- common in patients starting antiepileptic PARD Syndrome: Clinical Features and Gene Muta- drugs and occasionally may be very serious tions. Mol Syndromol 2012; 3: 145-157. PMID: 23239957 indeed. 17. Wind JJ, Lonser RR. Management of von Hippel-Lin- dau disease-associated CNS lesions. Expert Rev Neu- rother 2011; 11: 1433-1441. PMID: 21955200 References 18. Damjanovich K, Langa C, Blanco FJ, McDonald J, 1. Warburton KL, Wakerley B. Dermatological clues to Botella LM, Bernabeu C, Wooderchak-Donahue W, neurological diagnoses. Pract Neurol 2011;11: 289– Stevenson DA, Bayrak-Toydemir P. 5'UTR mutations 295. PMID: 21921004 of ENG cause hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis 2011; 6: 85. PMID: 22192717 2. Burg G, Burg D. Skin symptoms in neurological di- seases. Ther Umsch 1995; 52: 243-250. PMID: 19. Huh HJ, Cho KH, Lee JE, Kwon MJ, Ki CS, Lee PH. 7754467 Identification of ATM Mutations in Korean Siblings with Ataxia-Telangiectasia. Ann Lab Med 2013; 33: 3. Herrero C, Guilabert A, Mascaró-Galy JM. Diagnosis 217-220. PMID: 23667852 and treatment of livedo reticularis on the legs. Actas Dermosifiliogr 2008; 99: 598-607. PMID: 19080891 20. Gupta SP, Mittal A, Maini B, Gupta S. Sjogren-Lars- son syndrome: A case report of a rare disease. Indian 4. Baz K, Türsen Ü, İkizoğlu G. Antifosfolipid antikor Dermatol Online J 2011; 2: 31-33. PMID: 23130213 sendromu. Türkiye Klinikleri J Dermatol 2001; 11, 174–180. 21. Maire I. A rare genetic disease: multiple sulfatase de- ficiency. Med Sci 2003; 19: 1056-1058. PMID: 5. Bolayir E, Yilmaz A, Kugu N, Erdogan H, Akyol M, 14648473 Akyuz A. Sneddon's syndrome: clinical and labora- tory analysis of 10 cases. Acta Med Okayama 2004; 22. Patel AB, Prabhu AS. Hartnup disease. Indian J Der- 58: 59-65. PMID: 15255506 matol 2008; 53: 31-32. PMID: 19967017

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