Photosensitivity Disorders in Children

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Photosensitivity disorders in children

Part I

Rattanavalai Chantorn, MD,a HenryW.Lim,MD,b and Tor A. Shwayder, MDb Bangkok, Thailand, and Detroit, Michigan

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1093.e1 1093.e2 Chantorn, Lim, and Shwayder JAM ACAD DERMATOL DECEMBER 2012

Photosensitivity disorders in children encompass a diverse group of diseases. Compared to adult patients, underlying systemic disorders, including genetic or metabolic defects, are common causes in pediatric photosensitivity disorders. Photosensitivity in a child should be suspected if the child develops a sunburn reaction in sun-exposed sites after limited sun exposure. Diagnosis of a photodermatosis is made based on careful history taking and a physical examination. Early recognition and prompt diagnosis are essential to minimize long-term complications associated with inadequate photoprotection. In part I of this continuing medical education article, immunologically mediated photodermatoses, photodermatoses caused by exogenous photosensitizers, and the cutaneous porphyrias will be covered. ( J Am Acad Dermatol 2012;67:1093.e1-18.)

Key words: children; photodermatoses; photosensitivity; phototesting; polymorphous light eruption; porphyrias.

Ultraviolet (UV) radiation Photodermatoses have their and visible light are portions CAPSULE SUMMARY action spectrum in the UVA of the spectrum of electro- and/or UVB and/or visible magnetic radiation, which is d Photodermatoses in children are much light range. UVA light is in- classified by wavelength less common than those in adults. volved in the majority of drug- induced photosensitivity (Table I). Ultraviolet C d The most common pediatric (UVC) light or germicidal ra- photodermatosis is polymorphous light reactions. diation (200-290 nm) is ab- eruption, followed by erythropoietic Photosensitivity can be sorbed completely by the protoporphyria. defined as an abnormal or ozone layer and does not adverse reaction of the skin d Photoprotection is the mainstay of reach the earth’s surface at to UV or visible radiation. It management, although for some, there sea level. Ultraviolet A (UVA) usually follows exposure to are additional specific treatment options. light has been divided into sunlight, but rarely artificial UVAI (340-400 nm) and light sources may be also UVAII (320-340 nm). Because responsible. Similar to of the proximity of the wavelength range of UVAII adults, photosensitivity in children encompasses a to ultraviolet B (UVB) light, as compared to UVAI, the diverse group of diseases. Many of them are the biologic properties of UVAII are closer to that of UVB. result of genetic or metabolic defects, and others may The depth of penetration of UV radiation into the indicate an underlying systemic disorder. skin depends on the wavelength. The longer wave- Photosensitivity in a child should be suspected if length UVA easily reaches the reticular dermis; shorter the child develops a sunburn reaction, swelling, or wavelength UVB light is absorbed in the epidermis and intense pruritus after limited sun exposure or de- little reaches the papillary dermis. Even though only velops an eruption, skin fragility, or scarring pre- 2% to 3% of UV radiation from the sun reaches the dominantly in sun-exposed areas (face, the V of the earth’s surface, there are well described physiologic neck, and the dorsal surfaces of the hands and arms). and pathologic cutaneous effects of UVexposure. UVB Photosensitivity disorders in children can be is the major spectrum responsible for cutaneous ery- classified into 4 main categories: (1) immunologi- themaorsunburn response, whileUVAelicits a tanning cally mediated photodermatoses (IMPs; previously response.Recently, visiblelighthas been also shown to called idiopathic photodermatoses); (2) drug- or induce a tanning response that is more persistent than chemical-induced photosensitivity; (3) hereditary that induced by UVAI.1 Both UVA and UVB exposures photodermatoses; and (4) photoaggravated derma- 2 are known to generate metalloproteinases and to toses (Table II). induce immunosuppression, and they therefore play The incidence of photodermatoses in the pedi- 3-5 a role in photoaging and photocarcinogenesis. atric population is much lower than in adults. A

From the Department of Pediatrics,a Faculty of Medicine Siriraj Reprint requests: Tor A. Shwayder, MD, FAAP, FAAD, Director, Hospital, Mahidol University, Bangkok, Thailand, and the De- Pediatric Dermatology, Henry Ford Hospital, 3031 W Grand partment of Dermatology,b Henry Ford Hospital, Detroit, Blvd, Ste 800, Detroit, MI 48202. E-mail: [email protected]. Michigan. 0190-9622/$36.00 Funding sources: None. JAM ACAD DERMATOL Chantorn, Lim, and Shwayder 1093.e3 VOLUME 67, NUMBER 6

d The physical examination should include Abbreviations used: careful observation on the distribution and AP: actinic prurigo morphology of lesions CEP: congenital erythropoietic porphyria d As appropriate, plasma porphyrins, autoim- EPP: erythropoietic protoporphyria HC: hereditary coproporphyria mune profile, a skin biopsy specimen, and HV: hydroa vacciniforme phototesting may be useful IMP: immunologically mediated photodermatosis As in adults, the diagnosis of photodermatoses in JSE: juvenile spring eruption MED: minimal erythemal dose children is made based on careful history taking and NB-UVB: narrowband UVB physical examination (Fig 1). Questions should PCT: porphyria cutanea tarda include the age of onset of lesions, season of the PMLE: polymorphous light eruption SLE: systemic lupus erythematosus eruption, timing of development of lesions or symp- SU: solar urticaria toms after sun exposure, the nature of the lesions, UV: ultraviolet duration of the eruption, exposure to potential VP: variegate porphyria photosensitizers (both topical or systemic), systemic reviews particularly those suggestive of autoimmune disorder, and family history of photosensitivity and summary of the distribution of photosensitivity consanguinity. Because UVB light is filtered out by 3-5 disorders in children as reported in the literature window glass, the development of an eruption after 3 is shown in Table III. Jansen reported 95 (26%) exposure to window glassefiltered sunlight would cases of a total 370 patients with photosensitivity indicate action spectra in the UVA and/or visible light disorders started before 15 years of age. Eighty-two range. Patients with suspected photosensitivity percent of these cases were diagnosed as polymor- should undergo a thorough physical examination, phous light eruptions (PMLEs), and the remaining with a focus on the distribution of lesions, including registered patients in this study had xeroderma the areas of sparing. In a photosensitivity disorder, pigmentosum (XP), erythropoietic protoporphyria relatively photoprotected sites, such as the upper (EPP), systemic lupus erythematosus (SLE), and eyelids, the postauricular area (Wilkinson’s triangle), 4 pellagra. A study by Horkay et al collected 83 and submental area, nasolabial folds and neck folds, childhood-onset photodermatosis patients evalu- the volar aspect of the wrist, and the antecubital ated between 1967 and 2006 in Debrecen, fossae tend to be spared. The morphology of the Hungary, and found that the vast majority of pho- lesions may be helpful, such as urticarial lesions tosensitivity cases in children were PMLEs, similar to suggesting acute lesion of EPP or solar urticaria (SU), the result of the previous report. However, Horkay and atrophic scarring which could be associated with 4 et al found that the second most common cause EPP and hydroa vacciniforme (HV). was EPP. The latest literature in pediatric photo- Initial investigations should include a complete 5 dermatoses, published by Ten Berge et al, also blood cell count and autoimmune proﬁle, if appro- reported that PMLE was the most common diagnosis priate, particularly in patients with systemic mani- (39% of patients). Interestingly, 23% of the patients festation, such as arthritis or myalgia. Screening had photosensitivity associated with atopic plasma porphyrin levels and, if available, spectro- dermatitis, and an equal percentage had EPP. ﬂuorimetric scanning of plasma porphyrins are Photosensitivity induced by systemic or topical recommended if one of the cutaneous porphyrias agents is relatively rare in children, but it has (CPs) is suspected. If screening plasma porphyrins become increasingly common in recent years be- are elevated, a quantitative porphyrin assay to cause of the wide use of photosensitizers in the determine biochemical defects in the erythrocytes, environment. plasma, urine, and/or stool should be performed. Skin biopsy specimens for routine histopathology DIAGNOSTIC STEPS IN CHILDREN may be helpful in some diseases, such PMLE, HV, SUSPECTED PHOTOSENSITIVITY and actinic prurigo. Phototesting is necessary in a DISORDERS minority of cases. It can be helpful in determining Key points the cause of an acquired photodermatosis. d History taking should include age of onset, Evaluation of growth parameters, developmental seasonality, timing of development of le- milestones, systemic involvement, and neurologic sions or symptoms after sun exposure, du- abnormalities are also helpful for identifying pa- ration of the eruption, exposure to tients with genodermatoses associated with photo- photosensitizers, and family history sensitivity. Chromosomal analysis and molecular 1093.e4 Chantorn, Lim, and Shwayder JAM ACAD DERMATOL DECEMBER 2012

Table I. Electromagnetic radiation spectrum Table II. Classification of pediatric photodermatoses Waveband Wavelength range (nm) X-ray 0.1-1 Immunologically mediated photodermatoses Vacuum ultraviolet 10-200 Polymorphous light eruption Ultraviolet C 200-290 Juvenile spring eruption Ultraviolet B 290-320 Actinic prurigo Ultraviolet A 320-400 Hydroa vacciniforme UVAII 320-340 Solar urticaria UVAI 340-400 Drug- and chemical-induced photosensitivity Visible light 400-760 Exogenous Near infrared 760-1,000 Phototoxicity: systemic and topical Far infrared 1,000-100,000 Photoallergy: systemic and topical Microwaves and radiowaves [106 Endogenous: cutaneous porphyrias Hereditary photodermatoses Caused by defects in nucleotide excision repair Xeroderma pigmentosum genetic studies can conﬁrm the diagnosis in many Cockayne syndrome, including cerebro-oculo-facio- cases of hereditary photodermatoses. Phototesting, skeletal syndrome when practical, is helpful in many cases to deter- Trichothiodystrophy mine the action spectrum. Ultraviolet light sensitive syndrome In this review, we will discuss the prevalence, Caused by double strand break repair defects e clinical manifestations, pathogenesis, investigations, Rothmund Thomson syndrome Bloom syndrome and therapies of all pediatric photodermatoses. We Caused by abnormal chemical stubstances divided our review into 2 parts. Part I focuses on Smith-Lemli-Opitz syndrome immunologically mediated photodermatoses and Hartnup disease drug- and chemical-induced photosensitivity. Part Others II covers hereditary photodermatoses and photo- Kindler syndrome aggravated dermatoses. Photoaggravated dermatoses Atopic dermatitis IMMUNOLOGICALLY MEDIATED DariereWhite disease PHOTODERMATOSES Dermatitis herpetiformis Key point Herpes simplex infection Lupus erythematosus and neonatal lupus d Immunologically mediated photodermato- erythematosus ses include polymorphous light eruption, Juvenile dermatomyositis juvenile spring eruption, solar urticaria, hy- Pellagra droa vacciniforme, and actinic prurigo Psoriasis In children, IMPs, also previously known as idi- Seborrheic dermatitis opathic or primary photodermatoses, consist of Adapted from Lim and Hawk.2 PMLE, juvenile spring eruption (JSE), SU, HV, and AP. The exact pathophysiology of these IMPs has not d Management includes photoprotection and been clariﬁed. Immunologic mechanisms, autoim- hardening with narrowband UVB treatment munity, and genetic predisposition all seem to play a role.2 UV-induced endogenous photoantigens likely Prevalence. PMLE affects both adults and chil- represent the etiologic background of IMP; however, dren. A positive family history is reported in 3% to these antigens have not been identified. 56% of patients with PMLE.6 It has an inverse relation to latitude, with a prevalence in the adult population Polymorphous light eruption of approximately 21% in Scandinavian countries, Key points 10% to 15% in the United States, 5% in Australia, and d Polymorphous light eruption is the most 1% in Singapore7; the low prevalence in Australia common pediatric photodermatosis and Singapore may represent ‘‘hardening’’ occurring d Patients are less likely to be photoimmuno- in patients living in sunny climates. It predominantly suppressed after sun exposure; this results affects young females during the second and third in an enhanced immunologic response to decades of life; however, the age of onset in PMLE cutaneous neoantigens generated by sun may range from childhood to late adult life. Horkay exposure et al4 reported that 4% of 398 PMLE cases manifested JAM ACAD DERMATOL Chantorn, Lim, and Shwayder 1093.e5 VOLUME 67, NUMBER 6

Table III. Summary of the frequencies of childhood quite rare; chills, headache, fever, and nausea have onset photosensitivity disorders been reported, but may have been the consequence of accompanying sunburn. No. of patients (%) Finland, Hungary, Netherlands, Disease 19815 20086 20107 Investigations Polymorphous light 78 (82.1) 38 (46) 22 (39) Histology. The basic features of the papular eruption form of PMLE include edema, focal spongiosis, and Erythropoietic 2 (2.1) 23 (28) 13 (23) occasionally small vesicles in the epidermis. protoporphyria Acanthosis, spongiosis, focal parakeratosis, and ba- Xeroderma 13 (13.7) 3 (4) 1 (2) sal vacuolization can be present. Moderate to dense pigmentosum perivascular lymphocytic inﬁltrate is seen in the Photosensitivity in — — 13 (23) papillary and middle dermis, comprised predomi- atopic dermatitis nantly of lymphocytes and, to a lesser degree, Photosensitive atopic — — 8 (14) neutrophils and eosinophils. Direct immunoﬂuores- dermatitis cence studies are negative. AD with coexistence — — 5 (9) Phototesting. PMLE Most PMLE patients have normal minimal erythemal doses (MEDs) to UVA and UVB Juvenile spring eruption — 7 (8) — 5,7 Systemic lupus 1 (1) 1 (1) 1 (2) and pigmentary responses to UVA. However, there erythematosus are several reports showing decreased MED values 9 Porphyria cutanea tarda — 4 (5) — either to UVA or UVB. Diagnosis can be confirmed Solar urticaria — 1 (1) 3 (5) by evaluating the patient after exposure to sunlight Hydroa vacciniforme — 2 (2) — or by performing provocative phototesting in the Phototoxic contact — 3 (4) — clinic. The latter can be performed by exposing the dermatitis skin either to multiples of MEDs or to suberythemo- Pellagra 1(1) 1 (1) — genic UV doses for 3 to 4 days followed by evaluation AD, Atopic dermatitis; PMLE, polymorphous light eruption. 1 to 2 days later for the development of characteristic PMLE lesions. Pathogenesis. A delayed-type hypersensitivity before 5 years of age and 10% between 6 and 14 (DTH) response to an endogenous, cutaneous UV- years of age. In a study from Scotland, 20% of the induced antigen has been considered in the patho- patients presented before 10 years of age,4 whereas genesis of PMLE.7 It has been reported that patients in Finland, approximately 25% of the cases occurred with PMLE are less likely to be photoimmunosup- before 15 years of age.3 pressed, resulting in an enhanced response to the Clinical manifestation. Eruptions in PMLE typ- cutaneous neoantigens generated after sun expo- ically develop within a few hours after sun exposure, sure.10,11 With repeated UV exposure, photoimmu- although less commonly they may appear within 20 nosuppression occurs in these patients; this explains to 30 minutes or 1 to 2 days after exposure.7 PMLE why patients tend to improve as the sunny season tends to be most severe at the beginning of the sunny progresses or with UV desensitization therapy. season and becomes less severe as the sunny season Differential diagnosis. The differential diagno- progresses (a phenomenon known as ‘‘hardening’’). sis of PMLE in children includes AD, SLE, EPP, SU, Patients present with a nonscarring pruritic eruption HV, and photosensitivity induced by exogenous on a sun-exposed area (Fig 2, A and B). There is a agents. Careful history taking, physical examination, wide spectrum of clinical presentation, ranging from and appropriate laboratory evaluations should help the common papular type to the relatively rare large in the diagnosis. papules, vesicular, plaque-like, urticarial, hemor- Management. Many PMLE patients are mildly rhagic, insect biteelike, and even erythema multi- affected. They can be satisfactorily controlled by formeetype variants. In darker skinned patients, proper photoprotection measures. Symptomatic pinhead papular eruption is the most common treatment, including the use of topical corticoste- morphology.8 In an individual patient, a single roids, is helpful once the lesions have developed. In morphologic feature tends to present with each young, otherwise healthy adults who go on short occurrence. Mild pruritus or a burning sensation winter holidays to a sunny region, a short course (5-7 may be experienced by affected subjects. The lesions days) of systemic corticosteroids (usually predni- are commonly symmetric, and in the absence of sone, 0.6-1 mg/kg/d) has been shown to be helpful additional sun exposure resolve completely over (level of evidence, IB).12 Although this regimen has several days. Associated systemic symptoms are not been studied in the pediatric age group, it should 1093.e6 Chantorn, Lim, and Shwayder JAM ACAD DERMATOL DECEMBER 2012

Fig 1. Algorithm for the evaluation of pediatric photodermatoses. be considered in severely affected patients. Prevalence. In a prevalence study of children in Individuals with recurrent attacks may require a New Zealand,13 the overall prevalence of juvenile course of prophylactic narrowband UVB (NB-UVB) spring eruption (JSE) was estimated to be 6.7%. The phototherapy or psoralen plus UVA light photother- most commonly affected site is the top of an ear that apy (PUVA; 3 times per week for 5 weeks; level of is not covered by hair. evidence, IB), done in the early spring.7 Because of Clinical manifestation. JSE is considered a lo- its known photocarcinogenicity, the use of PUVA in calized form of PMLE. This photodermatosis occurs children should be done with caution. Other thera- more commonly in boys than in girls, and particularly pies, such as antimalarial agents, beta-carotene, and between the ages of 5 and 12 years. The eruption nicotinamide are of uncertain efficacy. typically occurs in the spring and consists of pruritic erythematous papules that are usually conﬁned to Juvenile spring eruption the helix of the ears and that evolve into vesicles and Key points crusts and heal with minimal or no scarring. d Juvenile spring eruption is considered a variant of polymorphous light eruption Investigations d Juvenile spring eruption is most commonly Histology and phototesting. Stratigos et al14 seen on the top of the ears of young boys reported the results of histologic findings and JAM ACAD DERMATOL Chantorn, Lim, and Shwayder 1093.e7 VOLUME 67, NUMBER 6

careful use of narrowband ultraviolet B light hardening Prevalence. SU is an uncommon form of physical urticaria and is also a rare subtype of IMP. It has been described throughout the world. The age of onset of SU is variable. New cases have been described in ages ranging from 1 week old15 to the eighth decade of life.16 Most patients develop symptoms in young adulthood.16 Clinical manifestation. SU is characterized by the development of wheal and ﬂare, associated with pruritus and burning sensation, within 5 to 10 minutes after exposure to radiation. Individual lesions resolve within 24 hours. Headache, nausea, wheez- ing, dizziness, syncope, and, rarely, anaphylactic shock have been reported.17 The hardening effect has been observed in SU patients, but the mechanism of SU remains elusive.

Investigations Phototesting. Phototesting serves as a provocative measure and a means to determine the eliciting action spectrum and the minimal urticarial dose, all of which can be of help in management.17 Caution should be exercised when performing phototesing in exposing only small portions of the skin; in Fig 2. Polymorphous light eruption. A, A young white patients who are highly sensitive to UV or visible boy with widespread eruptions on the face. Note the light, unintended exposure of skin surface during erythema on the malar area and the bridge of the nose and phototesting may provoke an anaphylactic reaction. sparing of the upper eyelid. B, A 10-year-old boy of The majority of SU patients have broad-spectrum Mexican and white descent with erythematous papules sensitivity, particularly UVA and visible wave- and excoriation on extensor forearms and wrists after sun 16 exposure. bands. Less commonly, UVB and, rarely, infrared are responsible; the latter is probably more appro- priately classified as heat urticaria. phototesting in 4 individuals with JSE. Pathogenesis. SU represents an immediate type Histopathology revealed apoptotic cells and mild I or immunoglobulin E (IgE)-mediated hypersensi- spongiosis in the epidermis, intraepidermal and tivity reaction to electromagnetic radiation. It is subepidermal vesicles, and dermal mononuclear thought that a photoallergen is produced in the cell infiltrate. All patients had normal phototest skin after exposure to the action spectrum. This is results. then recognized by the speciﬁc IgE to this allergen Pathogenesis. The etiology of JSE remains un- on the surface of mast cells, causing degranulation known, although it is probably similar to PMLE. and the release of histamines and other mediators.18 Management. Photoprotection and sympto- Differential diagnosis. This includes PMLE, matic treatment are usually sufﬁcient for these EPP, and drug- or chemical-induced photosensitivity. patients. Management. Photoprotection is an important part of the management of SU. Relief of the symp- Solar urticaria toms can be achieved with topical corticosteroids or Key points oral antihistamines. Hardening by exposure to UVA d Solar urticaria is a rare pediatric has been well described.19 While PUVA has been photodermatosis used in adults, its use in children should be reserved d Solar urticaria represents a type I hypersen- as a last resort because of its potential ocular side sitivity response effects and long-term photocarcinogenicity. NB-UVB d The management of solar urticaria includes phototherapy is another treatment option (level of photoprotection, antihistamines, and the evidence, IIB)20; however, similar to phototesting, 1093.e8 Chantorn, Lim, and Shwayder JAM ACAD DERMATOL DECEMBER 2012 care should be taken that a low starting dose and very graduated increases in the dose are done because treatment may trigger a generalized eruption resulting in anaphylaxis. To further minimize the side effects, only sites that are normally exposed to sunlight should be treated. Beta-carotene, antimalarial drugs, plasmapheresis (removal of a circulating serum factor/photoallergen), systemic immunosuppressive agents, and intravenous immunoglobulin (IVIG)21 have been reported to be effective in limited studies in adults.17 Similar to PUVA, plasmapheresis, IVIG, and systemic immunosuppressive agents should be used with caution in children.

Hydroa vacciniforme Key points d Hydroa vacciniforme is a rare photodermatosis that occurs almost exclusively in children d After sun exposure, macules evolve into vesicles, which heal with varioliform scars d Association with latent EpsteineBarr virus infection has been reported d Management consists primarily of photoprotection Clinical manifestation. HV is a rare photosensitivity disorder occurring almost exclusively in children. It usually begins in childhood and resolves spontaneously by early adulthood.22,23 The mean age of onset is 8 years.22 Boys are more often affected than girls. The cutaneous lesions in HV follow a distinct clinical pattern. Recurrent crops of discrete Fig 3. Hydroa vacciniforme. A, A 7-year-old boy with 2- to 3-mm erythematous macules evolve into blisters vesicles and crusts on the malar area a few days after sun exposure. B, A boy with pox-like scars on the left cheek. hours to a day or two after sun exposure. Healing occurs within days, with umbilication followed by and thrombosis of the vessels. In fully developed crusting and pitted, varioliform scarring (Fig 3, A and lesions, histopathologic findings reveal necrosis of B). This condition tends to appear each summer in the epidermis and dermis with mononuclear cell children on uncovered parts of the body after expo- infiltrate. sure to sunlight. The face and dorsal surfaces of the Phototesting. Most patients show sensitivity to hands are most frequently affected. Itching and UVA radiation in monochromatic phototesting, burning and mild constitutional symptoms may occur which may induce papulovesicular lesions.22 a few hours before the outbreak of the cutaneous Pathogenesis. The pathophysiology of this dis- lesions. Uncommon presentations of HV include order has not been clarified. An association between ocular involvement (keratoconjunctivitis and uveitis) latent EpsteineBarr virus (EBV) infection and HV has and blistering of the lips. As in other photoderma- been reported.24 EBV infection has also been well toses, significant adverse effect on quality of life in described to be associated with HV-like lesions in children has been recently reported, with patients adults; these cases—some fatal—have been mostly 23 citing the inability to play outdoors as a major factor. reported from Mexico and Asian countries. It probably represents a different disease than that seen in Investigations children.24 Histology. Skin biopsy specimens of the early Differential diagnosis. This includes other blis- lesions reveal multilocular vesicles within the epi- tering photosensitive disorders, such as EPP, vesicu- dermis. The underlying dermis may present with an lar PMLE, bullous SLE, and porphyria cutanea tarda inflammatory infiltrate and also show hemorrhage (PCT). JAM ACAD DERMATOL Chantorn, Lim, and Shwayder 1093.e9 VOLUME 67, NUMBER 6

Management. Photoprotection is the important component of the management of HV. No treatment has been universally successful. Chloroquine (level of evidence, IV), beta-carotene (level of evidence, IV), and PUVA (level of evidence, IV) have been effective in some cases, while thalidomide and cyclosporine are of unknown efﬁcacy. In severe cases, systemic corticosteroid can also be used (level of evidence, IV).

Actinic prurigo Key points d Actinic prurigo is mostly seen in the Indian and Mestizo populations in Central and South America living at high altitudes, al- Fig 4. Actinic prurigo. Note the erythematous papules that though it has also been reported in whites have coalesced to form a plaque on the right cheek, V of and Asians the neck, and extensor surfaces of both distal arms and d Actinic prurigo has a strong association with forearms of an 8-year-old girl. human leukocyte antigen DRB1*0407 d Cheilitis and conjunctivitis are common the lips and the conjunctiva is common, and it causes d Thalidomide is the most consistently effec- cheilitis, conjunctivitis, and pseudopterygium. Both tive form of therapy the upper and lower lips can be affected, although it is found mainly on the lower lip.28 In addition, Prevalence. AP is most commonly seen in the alopecia of the eyebrows has also been reported in Indian and Mestizo (mixed ancestry) populations of association with AP. Spontaneous remission may Mexico and Central and South America, especially occur in adolescence, particularly in patients with individuals living at high altitudes ([1000 m above onset in childhood, but persistence is common.29 In sea level); however, it has also been described in Latin American patients living at high altitudes, white and Asian populations.25 There is a strong relocation to a lower altitude area may result in association with human leukocyte antigen (HLA) resolution of the disease. subtypes. HLA DRB1*0407 is most prevalent, and is found in at least 60% to 70% of patients, but only a small percentage of controls (4-8% of DR4-positive Investigations patients).25,26 HLADRB1*0401 is the second most Histology. The histology of skin lesions reveals a prevalent subtype, present in up to 20% of patients.27 nonspecific subacute or chronic dermatitis, thicken- Clinical manifestation. AP is characterized by ing of basement membrane, and dense dermal the presence of intensely itchy papules, plaques, and lymphocytic infiltrate. However, a biopsy specimen nodules, along with excoriations and scars on the of the lip or conjunctiva usually reveals germinal sun-exposed area. The onset is usually in childhood, centers, which is diagnostic.30 but it ranges from 2 to 43 years.25 The mean age of Phototesting. An Australian study by Crouch onset is \10 years of age in a study from the United et al25 found lowered MEDs in approximately 60% Kingdom,26 and at 4 to 5 years of age in the native of cases, with abnormal results in the UVA spectrum Amerindian population.28 Clinically, AP causes a in all cases. In contrast, Hojyo-Tomoka et al28 from variety of lesions papules, plaques, and nodules Mexico reported that their patients had abnormal (Fig 4). Some patients show secondary eczematiza- response to photoprovocative test to both UVA and tion and lichenification. Very shallow linear, flat, or UVB, and had normal MEDs to UVA and UVB. punctate scars may occur on the face. The eruptions Differential diagnosis. The diagnosis is gener- usually manifest on the face, neck, extensor fore- ally based on the clinical appearance and, if avail- arms, dorsal surfaces of the hands, and the upper able, histologic findings; induction of lesions by aspect of the chest. However, in patients described in repeated exposure to UVA or UVB can be performed the United Kingdom, covered sites, including the and may achieve a positive result. The presence of back and buttocks, have been reported to be af- mucosal and conjunctival involvement, persistence fected. Patients frequently complain about pruritus beyond 4 weeks, and residual scarring of skin throughout the year with an exacerbation of the distinguish actinic prurigo from PMLE. Other photo- symptoms during spring or summer. Involvement of dermatoses and photoaggrevated dermatoses, 1093.e10 Chantorn, Lim, and Shwayder JAM ACAD DERMATOL DECEMBER 2012

Table IV. Differentiating features of phototoxic and photoallergic reactions

Feature Phototoxic Photoallergic Clinical manifestations Occurrence after first exposure Yes No Onset of eruption after exposure Minutes to hours 24-48 hrs Dose of agents needed for Large Small reaction Cross reactivity with other agents None Common Clinical changes Similar to sunburn reaction Varied morphology, usually eczematous lesions Distribution Exposed skin only Exposed skin, may spread to unexposed area Histologic findings Necrotic keratinocytes, epidermal Spongiotic dermatitis degeneration, and dermal inflammation Pathophysiology Direct tissue injury Cell-mediated immune response Diagnosis Topical agent Clinical Photopatch test Systemic agent Clinical and phototest Clinical and phototest; possibly photopatch test

Adapted from Lim.31 including HV, EPP, SLE, and atopic dermatitis with d Phytophotodermatitis is the most common photosensitivity need to be considered. History, type seen in children physical examination, and appropriate blood tests d Identification and avoidance of the photo- can usually differentiate AP from these other sensitizer is treatment of choice conditions. In contrast to adults, photosensitive disorders Management. Photoprotection, including the caused by exogenous sensitizers are relatively rare use of sunglasses and photoprotective lip balms, is in pediatric populations. Exogenous photosensi- the most important factor in the treatment of AP. tizers may reach the skin by topical or systemic Topical corticosteroids, emollients, and oral antihis- routes. Pathophysiologically, it can be divided into tamines may be helpful for pruritus. Other treat- phototoxicity and photoallergy, although clinically, ments, such as antimalarial agents, beta-carotene, it may not always be possible to differentiate be- vitamin E, and pentoxyphillin are of uncertain effi- tween the two. Comparison between phototoxicity cacy. UV-based therapy, both NB-UVB (level of and photoallergy is shown in Table IV.31 evidence, III) and PUVA (level of evidence, III) can Almost all exogenous photochemical reactions be efficacious in clearing and preventing new lesions 29 are induced by UVA radiation. This is important in some patients. Currently, thalidomide (level of because such radiation penetrates window glass. evidence, III) is the most effective treatment in the UVA is also present in lamps used in tanning booth, majority of patients with AP. The dose of thalidomide lamps used in nail salons for acrylic lacquer harden- in children is 50 to 100 mg per day, with maintenance 28 ing (though only in relatively low doses), in dentist achievable with doses as low as 50 mg per week. offices for bonding, and in small amounts in light Some patients are able to stop the drug without a emitted by photocopy machines and uncovered need for ongoing therapy. The main side effects of fluorescent bulbs. Patients may therefore have reac- thalidomide are teratogenic effects and peripheral tions while driving in a car with closed windows or neuropathy; the former is not an issue for prepubes- while using a tanning salon. Another important cent children, and the latter rarely occurs in children. clinical implication is that NB-UVB phototherapy is relative safe for most patients who are taking photo- sensitizing medications; this is because the light DRUG- AND CHEMICAL-INDUCED source used emits practically no UVA. PHOTOSENSITIVITY Plant-induced photosensitivity (phytophotoder- Photosensitivity by exogenous sensitizers matitis) is the most common phototoxic reaction of Key points children.32 Citrus fruit, especially lemons and limes, d Photosensitivity by exogenous sensitizers along with parsnips, carrots, dill, parsley, figs, are rarely seen in the pediatric population meadow grass, giant hogweed, wheat, clover, JAM ACAD DERMATOL Chantorn, Lim, and Shwayder 1093.e11 VOLUME 67, NUMBER 6

is needed until this is done. Good broad spectrum sunscreens need to be used because the action spectrum is in the UVA range.

Endogenous chemical-induced photosensitivity: The porphyrias Key points d While all cutaneous porphyrias have been reported in the pediatric population, the most common ones are erythropoietic protoporphyria and congenital erythropoietic Fig 5. Phytophotodermatitis. A 9-year-old boy with a porphyria linear hyperpigmented streak on the right arm a few d Cutaneous manifestations range from a days after exposure to lime and sunlight. burning and stinging sensation, edema, skin fragility, and blisters to scarring d Because the action spectrum is in the visible cocklebur, buttercups, Shepherd’s purse, pigweed, light range, only physical photoprotection is and celery contain furocoumarin, a phototoxic an effective form of photoprotection agent. The UV-induced eruption usually begins the day after exposure to the furocoumarin and sunlight, The porphyrias are a group of inherited and ranges in severity from mild erythema to severe acquired disorders that are caused by a specific blistering, and eventuates in a characteristic hyper- enzymatic defect in the heme biosynthesis pathway pigmentation. Linear streaks of hyperpigmentation, (Fig 6).35 Heme is assembled from simple precursors particularly on the face, chest, hands, and lower (glycine and succinyl coenzyme A synthetase) in an legs of children, are characteristic (Fig 5). 8-step pathway. Each step is catalyzed by a different Hyperpigmentation occurs over 1 to 2 weeks and enzyme. In CPs, enzyme deficiency results in an can persist for 6 to 12 months.33 accumulation of tetrapyrrole heme precursors, por- The incidence of phototoxic reaction and the phyrinogens, which are spontaneously oxidized to frequency of reactions to drugs used in childhood the corresponding porphyrins. The toxic profile of are unknown. In all likelihood, the most common the accumulate intermediate determines the variety drugs responsible for this type of reaction in pediat- of clinical features, ranging from acute neurovisceral ric patients are antibiotics, including sulfonamides, attacks, skin lesions, or liver disease. Most enzyme quinolones, and tetracyclines. Systemic phototoxic defects represent partial deficiency, because a com- agents include systemic antibacterial agents (pre- plete enzyme deficiency along the heme pathway is dominantly doxycycline, tetracyclines, sulfona- not compatible with life.36 mides, nalidixic acid, and fluoroquinolones), Heme synthesis starts in the mitochondria; the antifungal preparations (griseofulvin), sulfonylurea subsequent steps, from deamination, tetrapyrrole hypoglycemic agents, furosemide, nonsteroidal an- ring formation, to successive decarboxylation to tiinflammatory agents, amiodarone, quinine, isonia- 4-carboxyl porphyrinogen (coproporphyrinogen) zid, and thiazide diuretics. As a personal gestalt on take place in the cytoplasm. The final stages occur the incidence of photoedrug interactions in child- in the mitochondria (Fig 6). Heme is mostly pro- hood, in 2 of our practices (Drs Shwayder and Lim) duced in the erythrocytes for hemoglobin synthesis of [30 years each, we have seen 1 case of and in the hepatocytes for synthesis of cytochromes tetracycline-induced phototoxicity and no others. and hemoproteins. With regard to photoallergic reactions, organic UV Porphyrias are commonly classified as either he- filters used in sunscreens are currently the leading patic or erythropoietic, depending on the principal cause. Some of the commonly reported UV filters organ in which heme precursors accumulate. causing photoallergic reaction are octocrylene, Alternatively, they can be classified as acute por- benzophenone-3, and butyl methoxydibenzoylme- phyrias, CPs, and rare recessive porphyrias accord- thane.34 It should be noted that considering the ing to the type of clinical presentations.35 However, extensive use of sunscreens worldwide, the fre- some have both acute neurovisceral and cutaneous quency of photoallergy secondary to UV filters is manifestations. uncommon. Porphyrins, the oxidized products of heme The first line of treatment is removal of the precursor-porphyrinogens, are potent photosensi- photosensitizer; restriction of UV radiation exposure tizers responsible for photosensitivity in patients 1093.e12 Chantorn, Lim, and Shwayder JAM ACAD DERMATOL DECEMBER 2012

Fig 6. Heme biosysthetic pathway and sites of enzymatic defect in cutaneous porphyrias. ALA, Aminolevulinic acid; CEP, congenital erythropoietic porphyria; CP III oxidase, coproporphyrinogen oxidase; EPP, erythropoietic protoporphyria; HC, hereditary coproporphyria; HEP, hepatoerythropoietic porphyria; PBG, porphobilinogen; PCT, porphyria cutanea tarda; PP III oxidase, protoporphyrinogen oxidase; URO decarboxylase, uroporphyrinogen decarboxylase; URO III synthetase, uroporphyrinogen III synthase; VP, variegate porphyria. with CPs. The major action spectrum of the porphy- soluble, does not diffuse further than the endothelial rins ranges from 400 to 405 nm (the Sorbet band), lining of the blood vessels. Therefore, the phototoxic with a minor action spectrum range at 600 to 650 nm reaction causes endothelial necrosis in the papillary (visible red); this is the reason commercially avail- dermis, resulting in the typical pain and edema of able sunscreens, which only protect against UVB EPP. and UVA, are not helpful for patients with CPs. In the subsequent paragraphs, we will focus on Dihydroxyacetone, an agent responsible for sunless porphyrias with cutaneous involvements that can be tanning, has a proven beneﬁt in blocking longer UVA present in childhood: congenital erythropoietic por- and visible light. It can provide excellent protection phyria (CEP), EPP, PCT, hepatoerythropoietic por- in cases of CPs.37 Cutaneous presentations in porphyria (HEP), hereditary coproporphyria (HC), and phyrias range from acute burning pain and edema variegate porphyria (VP). within a few minutes after sun exposure in EPP to chronic skin fragility and blistering of the Congenital erythropoietic porphyria sun-exposed area without obvious relation to sun Key points exposure, such as in PCT. These varied clinical d Congenital erythropoietic porphyria is the manifestations result from the difference in water 38 most frequent of the rare autosomal reces- solubility in the intermediate porphyrins. The se- sive porphyrias, and the most disfiguring quential decarboxylations—from uroporphyrinogen d It presents with dark colored urine, severe (8-carboxyl porphyrinogen) to coproporphyrinogen photosensitivity and scarring, and may lead (4-carboxyl porphyrinogen) and to protoporphyrin- to the development of hepatosplenomegaly ogen (2-carboxyl porphyrinogen)—are associated and hemolytic anemia with a progressive decrease in the water solubility of d Bone marrow or stem cell transplantation is the porphyrinogens. In PCT, water-soluble uropor- curative phyrin diffuses throughout the skin up to the dermoepidermal junction, so the light-induced reac- CEP, also known as Gunther€ disease, is a rare tion occurs in the papillary dermis, resulting in skin autosomal recessive disease; however, it is the most fragility and blisters. In contrast, in EPP, protopor- frequent of the rare recessive porphyrias. It is the phyrin accumulates in erythrocytes, and, being lipid most severe disﬁguring form of porphyrias; it is JAM ACAD DERMATOL Chantorn, Lim, and Shwayder 1093.e13 VOLUME 67, NUMBER 6

hyperbilirubinemia may lead to generalized blistering.41 When teeth erupt, they are dark colored, and fluoresce under examination with a Wood’s lamp because porphyrins bind to dental calcium phosphate (erythrodontia; Fig 8, A and B). Most patients have severe photosensitivity, leading to the recurrent eruption of vesicles and bullae filled with fluid that fluoresces pink and eventually resulting in mutilating ulceration, scarring, and loss of acral tissues (Fig 9, A and B). Other common clinical features include hypertrichosis of the face and extremities and hyperpigmentation (Fig 9, C ). Ocular involvement includes photophobia, corneal scarring, ulceration, ulcerative keratoconjunctivitis, and cataracts. The majority of patients have hemolytic anemia with associated hypersplenism. Bony involvements include osteodystrophia, combining osteolysis and osteoporosis; hypercellular bone marrow is present in most patients. These changes may lead to bone fragility and fracture. Biochemical studies show the marked elevation of uroporphyrin I and coproporphyrin I in circulating Fig 7. Congenital erythropoietic porphyria. A, Urine erythrocytes, bone marrow cells, plasma, urine, and stained on diaper from an infant with congenital erythro- feces. Exposure to a Wood’s lamp may reveal reddish poietic porphyria. B, Urine fluoresced pink under exam- orange porphyrin fluorescence in urine or aqueous ination with a Wood’s lamp. suspensions of feces; thin smears of peripheral erythrocytes glow red under a fluorescent micro- caused by the deficiency of uroporphyrinogen III scope. Patients have normochromic anemia with synthase (UROS). This deficiency results in a shift increased reticulocyte count. A skin biopsy specimen from production of III to production of I isomers of may be helpful, but may only differ in severity from uroporphyrinogen and coproporphyrinogen (Fig other forms of porphyria. Identification of responsi- 6).35 This leads to overproduction and excretion of ble mutations is helpful for genetic counseling, and the nonphysiologic and pathogenic isomer I of genotypeephenotype correlation can now be uroporphyrinogen and coproporphyrinogen. The achieved. Prenatal diagnosis is now available. human UROS gene has been assigned to the chro- Treatment consists of rigorous sun avoidance mosome region 10q25.3 to q26.3.36 Mutations in including avoidance of light through window glass, affected individuals are heterogenous. These include wearing protective clothing, and the use of opaque missense and nonsense mutations, large and small sunscreens containing nonmicronized titanium di- deletions and insertions, splicing defect, and intronic oxide or zinc oxide that block in the visible spec- branch mutations. However, a common missense trum. Beta-carotene has been used and shows some mutation, C73R (Cys / Arg at position 73), is photoprotective effect. Hypertransfusion and sple- identified in up to 40% of white patients; this muta- nectomy may be necessary in cases with severe tion is associated with \1% of UROS activity.39 In hemolytic anemia. Bone marrow and allogeneic addition, CEP cases associated with UROS deficiency stem cell transplantation (level of evidence, IV) secondary to a GATA-1 erythroidespecific transcrip- may correct all disease manifestations except eryth- tion factor gene mutation have also been reported.40 rodontia.42,43 The prognosis of the severe form of The disorder is characterized by the appearance CEP is poor. Death, when it occurs, is frequently of dark colored urine during infancy, which fluo- associated with hemolytic anemia. resces red upon exposure to a Wood’s lamp (Fig 7, A and B), severe photosensitivity that occurs during the Erythropoietic protoporphyria first 2 or 3 years of life, splenomegaly, and hemolytic Key points anemia. Affected cases become symptomatic in d Erythropoietic protoporphyria is the most infancy. Patients show signs of discomfort after sun common form of childhood porphyria exposure, although they cannot verbally communi- d Patients complain of a burning and stinging cate. Phototherapy during the neonatal period for sensation upon sun exposure 1093.e14 Chantorn, Lim, and Shwayder JAM ACAD DERMATOL DECEMBER 2012

Fig 8. Congenital erythropoietic porphyria. A, Teeth showing pink to brown color. B, The teeth fluoresce pink under examination with a Wood’s lamp because porphyrins bind to dental calcium phosphate (erythrodontia). (Photographs courtesy of Dr Wisuthsarewong, Bangkok, Thailand.)

d Inheritance is complex, with 2 molecular defects in the ferrochelatase gene d A much less common autosomal recessive form has been described, with a higher risk of severe liver disease EPP is the most common form of porphyria in childhood.3-5 It is caused by partial deficiency of the ferrochelatase (FECH) enzyme; clinical presentations appear only when FECH activity is \50% of normal function. EPP is an inherited disorder; however, the mode of inheritance is complex. The FECH gene has been cloned and mapped to the long arm of chromosome 18q21.3. EPP is almost always associated with 2 molecular defects. In about 94% of patients with overt disease, clinical expression usually requires coinheritance of a private FECH muta- tion44 and the low expression FECH*IVS3-48C allele. The effect of this coinheritance is to lower mito- chondrial ferrochelatase activity below a crucial threshold of about 35%.45 In a UK study, autosomal recessive EPP without an IVS3-48C allele has been identified, with a prevalence of 3%. Two of the 7 families with autosomal recessive EPP had liver disease, suggesting that this form of EPP carries a higher risk of severe liver disease than other forms of EPP.46 Accumulation of free protoporphyrin, mainly in erythrocytes and secondarily in other tissues (skin and liver) or biologic specimens (serum, bile, and feces), leads to painful photosensitivity and potential Fig 9. Congenital erythropoietic porphyria. A, A 10- liver complications. EPP usually becomes sympto- month-old white female with mutilating ulceration and matic between 1 and 6 years of age because of the scarring secondary to recurrent eruption of vesicles and photosensitivity. The average age of presentation is 4 bullae. B, Hypertrichosis on the face when the same patient years. Cutaneous photosensitivity in EPP usually was 28 months old (after bone marrow transplantation). presents with immediate painful reaction within d Thickening of the skin on the knuckles and minutes of sun exposure. There is severe burning subtle scarring on the bridge of the nose can pain, especially on the dorsal surfaces of the hands be seen and feet and the face, which is usually unresponsive JAM ACAD DERMATOL Chantorn, Lim, and Shwayder 1093.e15 VOLUME 67, NUMBER 6

induces a tanning response, have been successfully used to increase sun tolerance in a pilot study.49 For patients with progressively deteriorating liver function, liver transplantation can be lifesaving. To prevent potentially severe phototoxic reaction in the exposed organs in the operating room, all surgeries need to be performed under a light source that emits minimally in the blue spectrum of the visible light, which is the major action spectrum of porphyrin- induced phototoxicity; shielding of organs and skin should be done if possible. Fig 10. Erytropoietic protoporphyria. A 12-year-old boy with vesicles and thickening of the skin over the knuckles. Porphyria cutanea tarda and hepatoerythropoietic porphyria to any analgesic drugs except cold air and cold water. Key points Crying upon exposure to sunlight frequently occurs d Porphyria cutanea tarda is the second most in young children. The burning pain is associated common porphyria in children; hepatoery- with erythema and edema in the exposed area, thropoietic porphyria is a homozygous form which could be followed by ecchymosis. of porphyria cutanea tarda Photoonycholysis may occur. Chronic lesions are d Cutaneous manifestations include skin fra- common, such as thickening of skin on the knuckles gility, blisters, and hypertrichosis and subtle scarring on the bridge of the nose (Fig 10). d In children, the treatment of choice is low Increased rugosity of the upper cutaneous lip can dose hydroxychloroquine also be seen. The severity of the photosensitivity may vary over the years. Hypochromic and microcytic PCT is the most common form of porphyria in anemia have been reported. Liver dysfunction can be adults and the second most common form in chil- identified in 10% to 20% of EPP patients. An increase dren. Heterozygous deficiency in uroporphyrinogen incidence of cholelithiasis is also present. In about decarboxylase causes PCT, whereas homozygous 2%, a rapidly progressing and irreversible cholestatic deficiency in this enzyme results in HEP. Estimated to liver failure develops.47 have an incidence of 1 in 25,000, PCT usually Laboratory findings include elevated free proto- presents during the third and fourth decades of life. porphyrin levels in circulating erythrocytes, plasma, Most patients have sporadic disease (type I, sporadic bone marrow cells, and feces. Because protopor- PCT), and the enzyme deficiency is limited to the phyrin is highly lipophillic, urinary porphyrin levels liver. About 20% to 30% of the patients have muta- are normal, unless the patient is in hepatic failure. tions in the gene for uroporphyrinogen decarboxyl- Examination of the peripheral blood smear under a ase enzyme (type II, familial form), resulting in fluorescence microscope reveals fluorescence of the approximately 50% reduction of the enzyme activity erythrocytes. Fluorescence of teeth and nails is not in all tissue.50 Another variant of PCT (type III) is present. Plasma fluorescence emission spectroscopy characterized by a family history of the disease shows a characteristic peak at 634 nm.35 although it is biochemically indistinguishable from Based on a systematic review, the available data sporadic PCT, with enzyme deficiency limited to the are insufficient to prove efficacy of any treatments liver. The familial subtype has an earlier onset and studied so far in EPP.48 The management of EPP is arises equally in both sexes; it is inherited in an dependent on photoprotection and the use of autosomal dominant manner with low penetrance. opaque sunscreens. The administration of beta- PCT always presents with cutaneous symptoms carotene (30-150 mg in children) may be only. Skin fragility is perhaps the most common considered, although its efficacy has been ques- presentation. Skin lesions in PCT are erosions, vesi- tioned. Other therapeutic approaches include cho- cles, or bullae on sun-exposed cutaneous surfaces, lestyramine (4 g/day), which helps prevent especially the dorsal aspects of the hands and fore- reabsorption of protoporphyrin excreted into the arms. The blisters vary markedly in size from 1 mm to intestinal lumen, and chenodeoxycholic acid 3 cm. Secondary infection may occur. The lesions (15 mg/kg/day), which is a primary bile acid and heal with hyperpigmentation; milia frequently help to inhibit the production of protoporphyrin in occur. Periorbital hypertrichosis and mottled hypo- the liver. Recently, subcutaneous implants of alfa- and hyperpigmentation are frequently present. melanocyte stimulating hormone analog, which Uncommonly, sclerodermoid skin changes may be 1093.e16 Chantorn, Lim, and Shwayder JAM ACAD DERMATOL DECEMBER 2012

observed; this is the only cutaneous manifestation of d Childhood onset of hereditary copropor- PCT that can be seen in the sun-exposed and also in phyria has only rarely been reported photoprotected sites. Rare ocular complications have been reported, such as ocular pain, photophobia, and HC is an autosomal dominant porphyria with perforation of sclera.51 HEP has similar but usually primary neurovisceral manifestations caused by the deficiency of coproporphyrinogen oxidase (CPO). more severe presentations; in some cases, it can result 36 in early onset sclerodermoid changes on fingers and Rare homozygous variants have been described. hands. Variable degrees of liver dysfunction are HC has almost always been described in adults. The few cases that presented during childhood were frequent in patients with this disorder. In adults, 54 PCT can be precipitated by, or associated with, iron initially mistaken for HV. overload, hepatitis C, alcoholic cirrhosis, hemodialy- The acute neurologic and abdominal attacks in sis, administration of estrogens, hydantoins, or gris- HC are generally identical to acute intermittent eofulvin, HIV infections, and hemochromatosis. porphyria but are usually less severe. Twenty to Confirmation of the clinical diagnosis of PCT can be thirty percent of patients are photosensitive; these made by increased levels of plasma, urinary and fecal patients have skin lesions resembling those of PCT. porphyrins, with a predominance of uroporphyrin The diagnosis is made after finding elevated levels of (8-carboxyl porphyrin) and 7 carboxyl porphyrin in coproporphyrin III in plasma, urine, and feces. plasma and urine, and isocoproporphyrin in feces. Treatment consists of the avoidance of agents Erythrocyte porphyrin levels are normal. Fluorescence known to induce acute neurovisceral attacks, espe- emission spectroscopy of plasma shows a character- cially drugs, including estrogen and progesterone. istic peak at 620 nm. A biopsy specimen of vesicular The avoidance of exposure to sunlight, sun- lesions reveals subepidermal bullae with dermal protective clothing, and the regular application of papillae arising irregularly from the floor of the bulla opaque sunscreens are mandatory. During an acute into its cavity (‘‘festooning’’). Periodic acideSchiff attack, precipitating factors must be identified; their positive material is deposited around blood vessels avoidance is a must. Neurologic symptoms like and sometimes at the dermoepidermal junction. abdominal pain, nausea, and vomiting should be As with other porphyrias, sun avoidance, the use treated symptomatically (eg, by the administration of of protective clothing, and the use of opaque sun- opioid analgesic drugs or chlorpromazine). The most important therapeutic step is the early intrave- screens are crucial to lessen skin symptoms. 55 Predisposing factors should be eliminated. In child- nous administration of hemin preparations. hood PCT, low-dose hydroxychloroquine treatment (3 mg/kg twice a week; level of evidence, IV) is Variegate porphyria widely used.52 Clinical improvement, which pre- Key points cedes biochemical improvement, is observed in 4 to d Patients with variegate porphyria have clin- 6 months. Urinary and plasma concentration of ical manifestations similar to those seen in porphyrin should be monitored every 3 months HC and usually returns to normal within 6 months.53 d Variegate porphyria is rarely seen in pediat- Liver function test should be monitored regularly ric patients (every few months or annually, depending on the degree of abnormality) in these patients. VP is an autosomal dominant disorder caused by Phlebotomy is the treatment of choice in adult cases, the decreased activity of protoporphyrinogen oxi- but it is difficult to perform in children. Therefore, it dase (PPO). This disease has its onset after puberty should be reserved for pediatric patients who do not and generally appears in the fourth to fifth decades respond to antimalarial agents. Spontaneous remis- of life; only a few cases in childhood have been sion with advancing age may occur. In adults, 5% to described.56 16% of patients with long-standing untreated disease Acute VP resembles acute intermittent porphyria and associated chronic active hepatitis develop he- in terms of neurovisceral clinical features. Sixty patocellular carcinoma. percent of adult patients manifest with cutaneous lesions.35 The cutaneous features of VP are similar to Hereditary coproporphyria those of PCT, but tend to be milder and less easily Key points provoked. Porphyrin profiles show the predomi- d Patients with hereditary coproporphyria nance of 4-carboxyl and 5-carboxyl porphyrins in present with neurovisceral complaints; 20% the urine, which contrast with the predominance of to 30% have skin lesions resembling those of 8-carboxyl porphyrin (uroporphyrin) and 7-carboxyl porphyria cutanea tarda porphyrin seen in PCT. Plasma fluorescence JAM ACAD DERMATOL Chantorn, Lim, and Shwayder 1093.e17 VOLUME 67, NUMBER 6

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