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The red face: Photogenodermatoses
The Red Face: Photogenodermatoses ERNST G. JUNG, MD
G
enodermatoses with a marked sun sensitivity are called photogenodermatoses. They are very rare diseases in which the photosensitivity is an early and constant symptom. The photosensitivity can be expressed as sun-induced eruptions of the exposed skin areas within hours and days, as light-induced tumor formation within years, or as both symptom complexes together. An enzymatic defect of known (xeroderma pigmentosum) or unknown character, impairing the defense against or the recovery from sun-induced skin damage, can be described as the result of a genetic defect (Table 1). In other examples (porphyrias), an inborn error of metabolism leads to accumulation of products that act as endogenous photosensitizers (Table 2). The main diseases following one or the other type of pathogenesis are presented as the main headings in this article.
Xeroderma Pigmentosum Xeroderma pigmentosum (Xl’) is a rare and heterogeneous group of diseases with distinct clinical characteristics. It is a unique biologic model of a disease with a congenital defect affecting the enzymatic system, enabling an error-free recovery of ultraviolet light (UV)-induced damages and therefore controlling the structural integrity of the nuclear DNA and its function.
Clinical Findings Xl’ is characterized by sensitivity to sunlight with a high rate of sun-induced malignancies of the exposed skin areas and impaired repair of UV-induced DNA damage.
From the Klinikum der Stadt Mannheim, Mannheim, Germany. Address correspondence to: Ernst G. Jung MD, Direktor der Hautklinik, Klinikum der Stadt Mannheim, D-6800 Mannheim 1, Postfach 100023, Germany.
0
1993 by Elsevier Science Publishing Co., Inc. 0738-081x/93/$6.00 l
The sun sensitivity is expressed as the ability to sunburn easily with or without blistering and a prolonged erythema not fading for weeks. Sun sensitivity can be measured by a low minimal erythema dose (MED) of UVB. Most patients also suffer from repeated actinic conjunctivitis and have photophobia. The tendency to sunburn and get conjunctivitis often subsides later in life. The skin symptoms appear on sun-exposed areas of the skin, with a delay of months to years after a single or repeated exposure to sunlight. Symptoms appear early in childhood and progress throughout life. Most patients manifest their first permanent alterations of the skin before 10 years of age. The first symptoms involve the pigment system of the skin. Some patients show a discrete dyschromia of the trunk, especially on the buttocks, as a primary and not irradiation-provoked, minor sign. The sun-induced alterations are first characterized by multiple freckles, increasing in size and attaining a variable intensity of pigmentation, ranging from light brown through all stages to black, and becoming irregular and larger in size. Hypopigmented macules are interspersed with pigmented and coalescent ones. Hyperpigmented macules may be present on the palms and soles as well as on the mucous membranes of the lips, the tongue, the conjunctivae, and the genitals. An additional and regular symptom is epidermal atrophy. The skin becomes dry, scaly, thin, and wrinkled. This is the case in all areas exposed to the sun, but especially on the face and the forearms. The dermal atrophy is less pronounced but sometimes rather evident as tightness and actinic elastosis interspersed with teleangiectatic veins. Wound healing is not impaired. The atrophy of the skin may induce microstoma, ectropion, and mutilation of the ears and of the fingertips by a continuous shrinkage process. The combination of dyschromia, atrophy, and telangiectasia, called poikiloderma, is very typical of XP. It is permanently progressive in expression and in expansion (Fig 1).
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Clinics in Dermatology 2993;11:275-281 Table 1. Photogenodermatoses Signs Xerodenna pigmentosum
Light sensitivity, skin malignancies
Cockayne syndrome
Dwartism, preaging, light sensitivity
Bloom syndrome
Growth retardation, telangiectasias, lightinduced (LE-like) erythema of the face, tumors in 50%
l
Genetics Autosomal recessive, heterogeneity (types A-G, v), - 1200 cases Autosomal recessive, heterogeneity, - 100 cases Autosomal recessive, - 160 cases
Defect*
_
Repair defects (UDS 1, CFA J) Fibroblasts are light sensitive (CFA J) Chromosome instability (SCE t)
UDS,unscheduled DNAsynthesis;CFA, colony-forming ability;33, sister chromatid exhange.
A subsequent and also very regular phase of the disease is characterized by the appearance of multiple benign and neoplastic tumors of the skin. Most of these tumors arise in poikilodermatic areas and increase in number and size throughout life, and many lead to exophytic exuberances as well as ulcerative mutilation. The first skin tumors appear in childhood or adolescence, months or years after poikiloderma has developed. Kerafibromas, toses, warty papilomas, keratoacanthomas, neurofibromas, angiofibromas, and angiomyomas may occur as benign tumors. The most common alterations are the precancerous lesions in the epidermis originating from keratinocytes (“carcinoma in situ”) with a plain or verrucous appearance, sometimes impressing as comu cutaneum or even mimicking scars. They appear in large numbers, forming reticular structures or covering large fields. Interspersed are bizarre-shaped, progressive, and deeply pigmented macules called lentigo maligna. These are precancerous lesions originating from melanocytes and located in the epidermal compartment. The precancerous lesions give origin to neoplastic Table 2. Congenital Metabolic
Diseases With Light Sensitivity Signs
Erythropoietic protoporphyria Porphyria congenita erythropoietica (porphyria congenita Gunther) Hartnup disease
tumors, perforating the basement membrane and invading the dermis and lower tissues. The keratinocyte-borne precancerous lesions are the precursors of basal cell carcinomas (BCC) and squamous cell carcinomas (SCC), whereas lentigo maligna turns to malignant melanomas (LMM). These tumors appear one after another or simultaneously and intermixed. They invade the skin and subjacent structures. The tumors lead to ulceration and destruction, as well as to functional impairment, especially on the face and hands (Fig 2). Bleeding and infections may follow. SCC and LMM have the tendency to metastasize in the lymph nodes and throughout the whole body. Several observers, however, have noted that metastases in XI’ are relatively rare and of late onset. SCC of the anterior portion of the tongue is observed to be more common in persons with Xl’ than in the general population and is probably related to occasional sun exposure. Noncutaneous neoplasms in Xl’ are infrequent, despite a significant increase in some rare primary brain tumors, Neurologic abnormalities have been described in 18.5% of 830 XI’ cases. Most neurologic signs, and the most important ones, were found in XP-A. The most se-
Genefics
Defect
Erythema, swelling, hematomas, pachydermia Erythema, blistering, atrophy and scars, skin malignancies
Autosomal dominant, heterogeneity, - 1000 families Autosomal recessive, - 100 cases
Ferrochelatase J
Pellagra-like dermatitis,
Autosomal recessive, - 70 cases
Inborn error of ammo acid metabolism
neurologic Impairment, sun sensitivity, cerebellar ataxia, renal aminoaciduria
Heme synthesis disturbed
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Clinics in Dermatology 1993;11:275-281 Table 3. Ophthalmologic Pigmentosum Patients
Findings in 21 Xeroderma
Alteration Dyspigmentation of the skin of the lids Telangiectases of the lids Telangiectases of the conjunctiva Atrophy of the lower lids and loss of cilia Dyspigmentation of the iris Papillomas of the lids Dysplasia and scarring of the cornea Dyspigmentation of the conjunctiva Pinguecula-lie tumors of the conjunctiva Ectropion Iris stroma atrophy Basal cell carcinoma of the lids
Figure 1. Xeroderma pigmentosum with freckling of the sunexposed forarm. One lent&o maligna is developing as a brown, irregularly shaped macule (lCyear-old woman, XP-D).
verely affected cases are classified as DeSanctisCacchione syndrome. They show the severe skin alterations of Xl’ complementation group A as well as dwarfism, hypogenitalism, microcephaly, and low intelligence. The neurologic symptoms such as hyporeflexia or areflexia of the tendons, spasticity, ataxia, and deafness have an onset in early infancy and are progressive. Discrete signs of minimal brain dysfunction as well as
Figure 2. Xeroderma pigmentosum with poikiloderma, atrophic scars, and multiple basal cell carcinomas, especially at the lower eyelid (47-year-old man, XP-VJ
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Number of Patients 21 21 18 10 10 9 8 8 7 6 5
minor neurologic abnormalities were found in selected cases of complementation groups B, C, F, and G. Periocular and ocular signs of light-induced damage can regularly be observed XI’ cases. The onset, the progression, and therefore the severity of these alterations depend on the light exposure and the expression of the repair defect. The first and most severe alterations are typically seen on the lower lid and the uncovered part of the iris. The differentiation of the ophthalmologic findings and their relative frequency are listed in Table 3. No UV-dependent alterations of the lens and fundus could be observed.1,2
Genetic Factors and Epidemiology The overall frequency of XP is approximately 4 cases in 1 million (1: 250,000), but even higher frequencies have been reported in defined areas, such as The Netherlands, Israel, and Japan (up to 10 to 25 per million). The gene frequency is calculated to be 1: 200. Xl’ is an autosomal recessive disease. The XP-A gene is located on chromosome 9, with different mutations in every family investigated, the XP-B gene on chromosome 2, and the XI’-D gene on chromosome 19. Consanguinity in parents occurs but is not consistent. The parents of affected individuals are obligate heterozygotes and, therefore, carriers of the defective gene. They are clinically normal and not especially sun sensitive. The prevalence of skin tumors, however, seems to be fourfold higher in XP heterozygotes than in normal, age-adjusted controls. The overall prevalence of skin tumors in the affected XP patients, however, is lOOO- to 5000-fold higher than in normal persons. Most well-documented XI’ cases belong to complementation groups A, C, D, and variants. These groups
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1993:11:275-282 Table 4. Heterogeneity Complementation group A B C D E F G Variant
of Xeroderma Pigmentosum Number of cases
LIDS* W
159
<5
3 91 52
10 10-47 25-60
13
40-70
16 7 130
(471 Cases, 1992) Skin symptoms
Severe, early Severe Moderate to severe Moderate Mild, late Moderate Moderate Mild, late
Predominant skin tumors
Neurologic symptoms ++ + _ -
see SCC + BCC LMM BCC
+ + -
BCC
Remarks DeSanctis - Cacchione syndrome 3X with CS 1X with CS 6X with TTD (no tumors) 2X with CS
l LIDS,unscheduled DNA synthesis; SCC, sclvamous cell cnrcinomo; KC, basal cell carcinoma; LMM, lent& malignu melanoma; TTD, ttichothiodysfrophy; syndrome.
occur worldwide, but their distribution is not even. Prenatal diagnosis can be done in cultured amniotic cells.
Complementation
Groups
The possibility of precisely defining XP subgroups by complementation analysis provides closer insights. The intrafamilial constancy of the complementation analysis is strong evidence that each complementation group lacks a specific gene product. Therefore, every XP group represents a genetic entity of its own with autosomal recessive transmission. Xl? is therefore a heterogenous group of at least eight distinct molecular defects leading to a common, or at least similar, clinical appearance of the skin after sun exposure.3,4 The clinical and biochemical features are relatively constant within each complementation group. Nevertheless, they show minor variations from one sibling to another, reflecting more or less the lifelong balance between the amount of light exposure and the consistency of a constant light protection with early onset. The clinical and molecular characteristics, however, show larger interfamilial variations within each complementation group, indicating that gene activity, gene product, and residual repair activity vary from one mutation to another. Of much greater significance and importance is the variation between complementation groups. Of the more than 1000 XP cases published to date, only 471 cases have been exactly analyzed and classified according to the eight subgroups (A-G and variants). These groups and the corresponding data are listed in Table 4. The residual repair capacity expressed as unscheduled DNA synthesis (UDS) and confirmed by complementary methods (postUV colony-forming ability and DNA-incising capacity) shows a clear correlation with the onset and the severity of the clinical symptoms.5 The analysis of XP complementation groups provides evidence for a particular tumor prevalence of some of these groups, as shown in Table 4. The mild XP-E and the
a,
&cknyne
variants regularly show BCC with great predominance. This is not at all exclusive, and SCC and LMM may also be found in some of the variants but at a significantly lower frequency. Most Xl’-A cases show multiple SCCs and, in lower frequency, BCCs. LMMs are very rare in these cases. The most striking phenomenon is the predominance and multiplicity of LMM in the XP-D group. Six Xl’-D cases are combined with another genetic trait affecting skin and hair, trichothiodystrophy (TTD). All six cases are affected with sun sensitivity and some skin symptoms of XP, but they did not, up to now, manifest any skin tumor. Another correlation of XP is of increasing interest, that with Cockayne’s syndrome (CS). Eight cases of XI’, of complementation groups B, C, D, and F, have been observed to also have CS, exclusively of complementation type C (Tables 4 and 5).
Treatment The early diagnosis-even prenatally by amniocentesis -in families with affected members and the lifelong protection from and avoidance of sun and ultraviolet exposure may prevent or at least delay many of the poikilodermatic and neoplastic alterations of the skin and eyes. Sun protection seems to be most essential during the first 5 years of life. Patients must be educated to protect themselves by adapting their lifestyles, by wearing protective clothing (and glasses), and by using sunscreens (UVB Table 5. Correlations
With Xeroderma Pigmentosum
Cockayne’s Syndrome with XP CS-A CS-B cs-c 3X 1X 2X 2X
Trichothiodystrophy with photosensitivity 6X with Xl’-D (no tumors)
with with with with
Xl’-B Xl’-C Xl’-D XP-G
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Clinics in DermatoZogy
protection). The early detection of cutaneous neoplasias is important for early surgical resection. This may be better in cases treated by repeated surgery than in those receiving X-ray treatment, although BCCs and SCCs in XI? are normally radiosensitive. Topical treatment with 5-fluorouracil (5-FU) creams and treatment with psoralens followed by UVA irradiation (PUVA) are not effective. Prophylactic treatment with systemic retinoids (0.5 mg etretinate per kilogram body weight) may have some cancer-protective effect, and these have been administered in some cases over a period of months to years. Nevertheless, patients should be followed regularly to detect and remove precancerous lesions and malignant tumors as early as possible.
Cockayne Syndrome Dwarfism with retinal atrophy and deafnessCockayne’s syndrome-is an autosomal recessive disease characterized by acute sun sensitivity, growth retardation beginning in the second year, premature aging, and progressive neurologic abnormalities. This very rare disease occurs predominantly in males. During the first or second year of life, the sun sensitivity and skin signs appear, followed by the cachectic dwarfism and progressive alterations of the eye, ear, and nervous system. About 100 patients have been described, and death usually occurs in the second or third decade of life from atheromatous vascular disease. Born at term, the children develop normally for the first few months. During the first or second year, the sun sensitivity appears as butterfly-like rashes of the face resembling lupus erythematosus. The recurrent erythematous rashes lead to pigmentary abnormality and atrophic scarring. Actinic keratoses and skin malignancies do not occur in these areas. Simultaneously with the first skin symptoms, growth retardation becomes apparent, leading to a cachectic dwarfism with rapid progression of premature aging and to many abnormalities of the skeleton such as microcephaly, prognathism, ankylosis, and contractures of the joints. The premature aging results in retinal atrophy and cataracts, deafness, and progressive mental deficit. The condition is fully developed by the age of 5 years. In this syndrome the lipid metabolism is unaltered; diabetes, porphyria, and renal dysfunction are not generally observed. The immune system is not primarily involved and the chromosomes show no constant instability. Cultured fibroblasts have decreased post-UV colony-forming ability (CFA) but normal rates of UV-induced UDS (excision repair of UV-induced thymine dimers). It is not yet clear whether or not the in vitro findings in fibroblasts correlate with the premature aging
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and sun sensitivity.6 Further studies have revealed a heterogeneity of three types of Cockayne syndrome, A, B, and C. In eight cases of CS, exclusively of type C, there was a correlation with Xl’, affecting patients with complementation group B, C, D, and F (Tables 4 and 5). There is no known treatment that influences the course of this condition.
Bloom’s Syndrome Facial telangiectasia of dwarfs, or Bloom’s syndrome, is an autosomal recessive condition resembling lupus erythematosus. It is characterized by sun hypersensitivity and growth retardation. The gene is located on chromosome 15. This very rare disease occurs in both sexes. Affected patients are born at term with reduced body weight and size. They have small narrow faces with prominent features. Many patients show cafe-au-lait spots. Growth is retarded, but intellectual and sexual development is normal. In male patients, spermatogenesis is absent. During the tirst years of life, these patients get butterfly-like telangiectatic erythemas of the face after sun exposure, sometimes associated with blister formation. Similar erythemas may also occur on other body regions. After repeated light-provoked erythematous rashes, the skin is marked by a reticular atrophy and papular elements with pigrnentary incontinence and a network of telangiectasias, resembling poikiloderma. Most patients with Bloom’s syndrome have an increased rate of infections and show diminished levels of immunoglobulins (IgG, IgA, IgM). In the lymphocytes and skin fibroblasts and in the bone marrow cells of these patients an increased number of chromosomal breaks and characteristic rearrangements can be shown. The spontaneous rate of sister chromatid exchanges (SCEs) is markedly increased. More than half of the patients die from acute leukemia or metastatic tumors of various origins. It is not clear whether the chromosomal instability must be evaluated as one symptom of the syndrome’s puzzle or if it is the first demonstrable sign of malignant transformation.7*8 Avoidance of sun exposure and protection by sunscreens may prevent skin rashes. An attempt has been made with in vitro storage of frozen bone marrow cells at the homologous repopulation of the bone marrow after whole-body x-ray treatment of leukemia.
Erythropoietic Protoporphyria Erythropoietic protoporphyria (EPP) is an autosomal dominant porphyric disease, in which the defect in porphyrin metabolism results in an accumulation of proto-
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porphyrin in the erythrocytes (fluorocytes), probably because of defective heme synthetase activity. Urine porphyrines are not elevated. The passage of protoporphyrin-loaded erythrocytes through the dermal vessels results in photohemolysis when skin is exposed to UVA and visible light. An endogenous photosensitivity reaction starts, with pain and burning within a few minutes. This is succeeded by erythema and edema (sometimes hemorrhagic) and, later, by vesicles and sores on the light-exposed areas, chiefly the nose, cheeks, chin, lips, and backs of the hands. The sores heal with small vermicular scars. After repeated eruptions, the skin on the hand and face gradually becomes yellow, gray, dull, and thickened (pachydermia). The symptoms start early in childhood and follow the patients as so-called “persistent solar urticaria” throughout life. The disease obviously is rather common. It is not provoked by drugs or alcohol. There is increasing evidence for genetic heterogeneity in EPP. Apart from the traditional autosomal dominant transmission in most families, there are a minority of families with autosomal recessive transmission. These data are supported by biochemical analysis of the defective enzyme in affected patients and in nonaffected heterozygotes. Evidence in given that more than one gene may be required for the expression of the disease.9 No causal therapy is known, but the oral administration of p-carotene during light exposure periods of the year can achieve symptomatic photoprotection in most patients. The individual dose has to be evaluated (25200 mg daily) with respect to the fact that tolerance to light begins only 2 to 4 weeks after initiation of the therapy. Despite the good tolerance of the medication, liver checks are recommended.
alopecia, but hypertrichosis often develops on the face and limbs. Splenectomy and transfusions may help for a while but it remains to be determined whether these treatments affect survival. At least in the unusual patient with late onset of the disease, oral management with p-carotene (25 -200 mg daily) may prevent sun-induced skin alterations.
Congenital
Hartnup Disease
Erythropoietic
Porphyria
(Giinther)
This autosomal recessive disease is very rare and occurs in both sexes. It is characterized by sun sensitivity with subsequent mutilating skin lesions and secondarily arising tumors, as well as by a complex defect of the porphyrin metabolism, with urinary excretion of large amounts of uroporphyrin I, as the leading metabolic symptom, and hemolytic anemia. No chromosomal abnormalities have been observed. Photosensitivity may appear in infancy in the form of erythema and blistering. These lesions ulcerate and heal with atrophic scars. Repeated episodes lead to severe deformity and mutilation of the nose, ears (Fig 3), eyes, and fingers, with the loss of nails and terminal phalanges. Tumors can arise in the mutilated tissue after years. Keratoconjunctivits and ectropion, as well as dyspigmentation, may occur. Lesions in the scalp end with scarring
Figure 3. Pachydermia, dyschromia, and mutilation of the ear in a 32-year-old man with porphyria congenita Giinther.
Hartnup disease is an autosomal recessive condition characterized by pellagra-like dermatitis in sun-exposed skin areas, intermittent cerebellar ataxia, and renal aminoaciduria. It is very rare, occurring equally in both sexes. During childhood the first symptoms appear after sun exposure and skin signs may disappear during life. More than 70 patients have been described, with the exclusion of asymptomatic cases. The first symptoms occur symmetrically on the sunexposed areas of the skin of the face, neck, hands, and lower legs. Scaly erythematous patches with infiltration persist for weeks and months. Acute dermatitis and blistering occur in addition after sun exposure, turning into crusts and scars. These changes together with marked hyperpigmentation present the aspect of classic pellagra. The dermatitis is aggravated by malnutrition and inter-
JUNG PHOTOGENODERMATOSES
Clinics in Dermatology 1993;12:275-281 current infections. Glossitis, cheilitis, and angular stomatitis are additional signs as is vulvovaginitis. The hair may be fine and fragile. Associated neurologic symptoms may parallel the skin rashes or follow them. Cerebellar ataxia develops in association with skin rashes or with infections. Nystagmus, ptosis, diplopia, muscular hypertonicity, and hyperreflexia have been observed as have signs of pyramidal involvement. The neurologic symptoms are fully reversible. Renal hyperaminoaciduria of a specific pattern is a constant and pathognomonic finding without any evidence of other renal dysfunction. In addition, there is an increase in the urinary and fecal excretion of indole and indican.‘O The peculiar pattern of symptoms and their reversibility can be explained by a disorder of tubular and intestinal transport of amino acids. There is a primary and very specific defect in the reabsorption of amino acids from the glomerular filtrate, resulting in a constant aminoaciduria of most of the monoamino monocarboxylic acids. The defect results in delayed and incomplete jejunal absorption of amino acids, mainly I-tryptophan. This explains the fecal loss of unabsorbed amino acids, either unchanged or metabolized by intestinal bacteria to indole and indican. The latter products can be absorbed in the intestine and may result, toxic as they are, in the variable and reversible neurologic symptoms. The lack of intestinally absorbed 1-tryptophan leads to a deficiency in its main metabolite, nicotinic acid, and results in the pellagra-like, sun-sensitive dermatitis. Differential diagnosis has to consider the group of porphyrias and the complex forms of dietary or drug-induced vitamin deficiencies, such as true pellagra and pellagroid. Avoidance of sun exposure and protection with sunscreens
are helpful.
Daily therapy
with 50 to 200 mg
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nicotinamide may improve the skin changes and some of the neurologic symptoms. Long-term oral neomycin treatment helps to sterilize the intestinal tract and therefore suppresses the bacterial formation of toxic products.
References 1. Fischer E, Thielmann HW, Neundijrfer B, et al. Xeroderma pigmentosum patients from Germany: Clinical symptoms and DNA repair characteristics. Arch Dermatol Res 1982;274:229 -47.
2. Jung
EG. Xeroderma 1986;25:629-33.
pigmentosum.
Int J Dermatol
3. Cleaver JE. Defective repair replication of DNA in xeroderma pigmentosum. Nature 1968;219:652-6.
4. De Weerd-Kastelein EA, Keijzer W, Bootsma D. Genetic heterogeneity of xeroderma pigmentosum demonstrated by somatic cell hybridization. Nature 1972;238:80-2.
5. Thielmann HW, Popanda 0, Edler L, et al. Clinical symptoms and DNA repair characteristics of xeroderma pigmentosum patients from Germany. Cancer Res 1991;51: 3456- 70.
6. Andrews AD, Barrett SF, Yoder FW, et al. Cockayne’s syndrome fibroblasts have increased sensitivity to ultraviolet light but normal rates of unscheduled DNA synthesis. J Invest Dermatol 1978;70:237-9.
7. Chaganti RSK, Schonberg S, German J. A manyfold increase in sister chromatid exchanges in Bloom’s syndrome lymphocytes. Proc Nat1 Acad Sci USA 1974;71:450812.
8. Dicken CH, Dewald G, Gordon H. Sister chromatid exchanges in Bloom’s 114:755-60.
syndrome.
Arch
Dermatol
1978;
9. Norris PG, Nunn AV, Hawk JLM, et al. Genetic heterogeneity in erythropoietic protoporphyria: A study of the enzymatic defect in nine affected families. J Invest Dermatol 1990;95:260-3. 10. Wilcken B, Brown DA. Natural history of Hartnup disease. Arch Dis Child 1977;52:38-40.
G
enodermatoses with a marked sun sensitivity are called photogenodermatoses. They are very rare diseases in which the photosensitivity is an early and constant symptom. The photosensitivity can be expressed as sun-induced eruptions of the exposed skin areas within hours and days, as light-induced tumor formation within years, or as both symptom complexes together. An enzymatic defect of known (xeroderma pigmentosum) or unknown character, impairing the defense against or the recovery from sun-induced skin damage, can be described as the result of a genetic defect (Table 1). In other examples (porphyrias), an inborn error of metabolism leads to accumulation of products that act as endogenous photosensitizers (Table 2). The main diseases following one or the other type of pathogenesis are presented as the main headings in this article.
Xeroderma Pigmentosum Xeroderma pigmentosum (Xl’) is a rare and heterogeneous group of diseases with distinct clinical characteristics. It is a unique biologic model of a disease with a congenital defect affecting the enzymatic system, enabling an error-free recovery of ultraviolet light (UV)-induced damages and therefore controlling the structural integrity of the nuclear DNA and its function.
Clinical Findings Xl’ is characterized by sensitivity to sunlight with a high rate of sun-induced malignancies of the exposed skin areas and impaired repair of UV-induced DNA damage.
From the Klinikum der Stadt Mannheim, Mannheim, Germany. Address correspondence to: Ernst G. Jung MD, Direktor der Hautklinik, Klinikum der Stadt Mannheim, D-6800 Mannheim 1, Postfach 100023, Germany.
0
1993 by Elsevier Science Publishing Co., Inc. 0738-081x/93/$6.00 l
The sun sensitivity is expressed as the ability to sunburn easily with or without blistering and a prolonged erythema not fading for weeks. Sun sensitivity can be measured by a low minimal erythema dose (MED) of UVB. Most patients also suffer from repeated actinic conjunctivitis and have photophobia. The tendency to sunburn and get conjunctivitis often subsides later in life. The skin symptoms appear on sun-exposed areas of the skin, with a delay of months to years after a single or repeated exposure to sunlight. Symptoms appear early in childhood and progress throughout life. Most patients manifest their first permanent alterations of the skin before 10 years of age. The first symptoms involve the pigment system of the skin. Some patients show a discrete dyschromia of the trunk, especially on the buttocks, as a primary and not irradiation-provoked, minor sign. The sun-induced alterations are first characterized by multiple freckles, increasing in size and attaining a variable intensity of pigmentation, ranging from light brown through all stages to black, and becoming irregular and larger in size. Hypopigmented macules are interspersed with pigmented and coalescent ones. Hyperpigmented macules may be present on the palms and soles as well as on the mucous membranes of the lips, the tongue, the conjunctivae, and the genitals. An additional and regular symptom is epidermal atrophy. The skin becomes dry, scaly, thin, and wrinkled. This is the case in all areas exposed to the sun, but especially on the face and the forearms. The dermal atrophy is less pronounced but sometimes rather evident as tightness and actinic elastosis interspersed with teleangiectatic veins. Wound healing is not impaired. The atrophy of the skin may induce microstoma, ectropion, and mutilation of the ears and of the fingertips by a continuous shrinkage process. The combination of dyschromia, atrophy, and telangiectasia, called poikiloderma, is very typical of XP. It is permanently progressive in expression and in expansion (Fig 1).
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Clinics in Dermatology 2993;11:275-281 Table 1. Photogenodermatoses Signs Xerodenna pigmentosum
Light sensitivity, skin malignancies
Cockayne syndrome
Dwartism, preaging, light sensitivity
Bloom syndrome
Growth retardation, telangiectasias, lightinduced (LE-like) erythema of the face, tumors in 50%
l
Genetics Autosomal recessive, heterogeneity (types A-G, v), - 1200 cases Autosomal recessive, heterogeneity, - 100 cases Autosomal recessive, - 160 cases
Defect*
_
Repair defects (UDS 1, CFA J) Fibroblasts are light sensitive (CFA J) Chromosome instability (SCE t)
UDS,unscheduled DNAsynthesis;CFA, colony-forming ability;33, sister chromatid exhange.
A subsequent and also very regular phase of the disease is characterized by the appearance of multiple benign and neoplastic tumors of the skin. Most of these tumors arise in poikilodermatic areas and increase in number and size throughout life, and many lead to exophytic exuberances as well as ulcerative mutilation. The first skin tumors appear in childhood or adolescence, months or years after poikiloderma has developed. Kerafibromas, toses, warty papilomas, keratoacanthomas, neurofibromas, angiofibromas, and angiomyomas may occur as benign tumors. The most common alterations are the precancerous lesions in the epidermis originating from keratinocytes (“carcinoma in situ”) with a plain or verrucous appearance, sometimes impressing as comu cutaneum or even mimicking scars. They appear in large numbers, forming reticular structures or covering large fields. Interspersed are bizarre-shaped, progressive, and deeply pigmented macules called lentigo maligna. These are precancerous lesions originating from melanocytes and located in the epidermal compartment. The precancerous lesions give origin to neoplastic Table 2. Congenital Metabolic
Diseases With Light Sensitivity Signs
Erythropoietic protoporphyria Porphyria congenita erythropoietica (porphyria congenita Gunther) Hartnup disease
tumors, perforating the basement membrane and invading the dermis and lower tissues. The keratinocyte-borne precancerous lesions are the precursors of basal cell carcinomas (BCC) and squamous cell carcinomas (SCC), whereas lentigo maligna turns to malignant melanomas (LMM). These tumors appear one after another or simultaneously and intermixed. They invade the skin and subjacent structures. The tumors lead to ulceration and destruction, as well as to functional impairment, especially on the face and hands (Fig 2). Bleeding and infections may follow. SCC and LMM have the tendency to metastasize in the lymph nodes and throughout the whole body. Several observers, however, have noted that metastases in XI’ are relatively rare and of late onset. SCC of the anterior portion of the tongue is observed to be more common in persons with Xl’ than in the general population and is probably related to occasional sun exposure. Noncutaneous neoplasms in Xl’ are infrequent, despite a significant increase in some rare primary brain tumors, Neurologic abnormalities have been described in 18.5% of 830 XI’ cases. Most neurologic signs, and the most important ones, were found in XP-A. The most se-
Genefics
Defect
Erythema, swelling, hematomas, pachydermia Erythema, blistering, atrophy and scars, skin malignancies
Autosomal dominant, heterogeneity, - 1000 families Autosomal recessive, - 100 cases
Ferrochelatase J
Pellagra-like dermatitis,
Autosomal recessive, - 70 cases
Inborn error of ammo acid metabolism
neurologic Impairment, sun sensitivity, cerebellar ataxia, renal aminoaciduria
Heme synthesis disturbed
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Clinics in Dermatology 1993;11:275-281 Table 3. Ophthalmologic Pigmentosum Patients
Findings in 21 Xeroderma
Alteration Dyspigmentation of the skin of the lids Telangiectases of the lids Telangiectases of the conjunctiva Atrophy of the lower lids and loss of cilia Dyspigmentation of the iris Papillomas of the lids Dysplasia and scarring of the cornea Dyspigmentation of the conjunctiva Pinguecula-lie tumors of the conjunctiva Ectropion Iris stroma atrophy Basal cell carcinoma of the lids
Figure 1. Xeroderma pigmentosum with freckling of the sunexposed forarm. One lent&o maligna is developing as a brown, irregularly shaped macule (lCyear-old woman, XP-D).
verely affected cases are classified as DeSanctisCacchione syndrome. They show the severe skin alterations of Xl’ complementation group A as well as dwarfism, hypogenitalism, microcephaly, and low intelligence. The neurologic symptoms such as hyporeflexia or areflexia of the tendons, spasticity, ataxia, and deafness have an onset in early infancy and are progressive. Discrete signs of minimal brain dysfunction as well as
Figure 2. Xeroderma pigmentosum with poikiloderma, atrophic scars, and multiple basal cell carcinomas, especially at the lower eyelid (47-year-old man, XP-VJ
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Number of Patients 21 21 18 10 10 9 8 8 7 6 5
minor neurologic abnormalities were found in selected cases of complementation groups B, C, F, and G. Periocular and ocular signs of light-induced damage can regularly be observed XI’ cases. The onset, the progression, and therefore the severity of these alterations depend on the light exposure and the expression of the repair defect. The first and most severe alterations are typically seen on the lower lid and the uncovered part of the iris. The differentiation of the ophthalmologic findings and their relative frequency are listed in Table 3. No UV-dependent alterations of the lens and fundus could be observed.1,2
Genetic Factors and Epidemiology The overall frequency of XP is approximately 4 cases in 1 million (1: 250,000), but even higher frequencies have been reported in defined areas, such as The Netherlands, Israel, and Japan (up to 10 to 25 per million). The gene frequency is calculated to be 1: 200. Xl’ is an autosomal recessive disease. The XP-A gene is located on chromosome 9, with different mutations in every family investigated, the XP-B gene on chromosome 2, and the XI’-D gene on chromosome 19. Consanguinity in parents occurs but is not consistent. The parents of affected individuals are obligate heterozygotes and, therefore, carriers of the defective gene. They are clinically normal and not especially sun sensitive. The prevalence of skin tumors, however, seems to be fourfold higher in XP heterozygotes than in normal, age-adjusted controls. The overall prevalence of skin tumors in the affected XP patients, however, is lOOO- to 5000-fold higher than in normal persons. Most well-documented XI’ cases belong to complementation groups A, C, D, and variants. These groups
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1993:11:275-282 Table 4. Heterogeneity Complementation group A B C D E F G Variant
of Xeroderma Pigmentosum Number of cases
LIDS* W
159
<5
3 91 52
10 10-47 25-60
13
40-70
16 7 130
(471 Cases, 1992) Skin symptoms
Severe, early Severe Moderate to severe Moderate Mild, late Moderate Moderate Mild, late
Predominant skin tumors
Neurologic symptoms ++ + _ -
see SCC + BCC LMM BCC
+ + -
BCC
Remarks DeSanctis - Cacchione syndrome 3X with CS 1X with CS 6X with TTD (no tumors) 2X with CS
l LIDS,unscheduled DNA synthesis; SCC, sclvamous cell cnrcinomo; KC, basal cell carcinoma; LMM, lent& malignu melanoma; TTD, ttichothiodysfrophy; syndrome.
occur worldwide, but their distribution is not even. Prenatal diagnosis can be done in cultured amniotic cells.
Complementation
Groups
The possibility of precisely defining XP subgroups by complementation analysis provides closer insights. The intrafamilial constancy of the complementation analysis is strong evidence that each complementation group lacks a specific gene product. Therefore, every XP group represents a genetic entity of its own with autosomal recessive transmission. Xl? is therefore a heterogenous group of at least eight distinct molecular defects leading to a common, or at least similar, clinical appearance of the skin after sun exposure.3,4 The clinical and biochemical features are relatively constant within each complementation group. Nevertheless, they show minor variations from one sibling to another, reflecting more or less the lifelong balance between the amount of light exposure and the consistency of a constant light protection with early onset. The clinical and molecular characteristics, however, show larger interfamilial variations within each complementation group, indicating that gene activity, gene product, and residual repair activity vary from one mutation to another. Of much greater significance and importance is the variation between complementation groups. Of the more than 1000 XP cases published to date, only 471 cases have been exactly analyzed and classified according to the eight subgroups (A-G and variants). These groups and the corresponding data are listed in Table 4. The residual repair capacity expressed as unscheduled DNA synthesis (UDS) and confirmed by complementary methods (postUV colony-forming ability and DNA-incising capacity) shows a clear correlation with the onset and the severity of the clinical symptoms.5 The analysis of XP complementation groups provides evidence for a particular tumor prevalence of some of these groups, as shown in Table 4. The mild XP-E and the
a,
&cknyne
variants regularly show BCC with great predominance. This is not at all exclusive, and SCC and LMM may also be found in some of the variants but at a significantly lower frequency. Most Xl’-A cases show multiple SCCs and, in lower frequency, BCCs. LMMs are very rare in these cases. The most striking phenomenon is the predominance and multiplicity of LMM in the XP-D group. Six Xl’-D cases are combined with another genetic trait affecting skin and hair, trichothiodystrophy (TTD). All six cases are affected with sun sensitivity and some skin symptoms of XP, but they did not, up to now, manifest any skin tumor. Another correlation of XP is of increasing interest, that with Cockayne’s syndrome (CS). Eight cases of XI’, of complementation groups B, C, D, and F, have been observed to also have CS, exclusively of complementation type C (Tables 4 and 5).
Treatment The early diagnosis-even prenatally by amniocentesis -in families with affected members and the lifelong protection from and avoidance of sun and ultraviolet exposure may prevent or at least delay many of the poikilodermatic and neoplastic alterations of the skin and eyes. Sun protection seems to be most essential during the first 5 years of life. Patients must be educated to protect themselves by adapting their lifestyles, by wearing protective clothing (and glasses), and by using sunscreens (UVB Table 5. Correlations
With Xeroderma Pigmentosum
Cockayne’s Syndrome with XP CS-A CS-B cs-c 3X 1X 2X 2X
Trichothiodystrophy with photosensitivity 6X with Xl’-D (no tumors)
with with with with
Xl’-B Xl’-C Xl’-D XP-G
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protection). The early detection of cutaneous neoplasias is important for early surgical resection. This may be better in cases treated by repeated surgery than in those receiving X-ray treatment, although BCCs and SCCs in XI? are normally radiosensitive. Topical treatment with 5-fluorouracil (5-FU) creams and treatment with psoralens followed by UVA irradiation (PUVA) are not effective. Prophylactic treatment with systemic retinoids (0.5 mg etretinate per kilogram body weight) may have some cancer-protective effect, and these have been administered in some cases over a period of months to years. Nevertheless, patients should be followed regularly to detect and remove precancerous lesions and malignant tumors as early as possible.
Cockayne Syndrome Dwarfism with retinal atrophy and deafnessCockayne’s syndrome-is an autosomal recessive disease characterized by acute sun sensitivity, growth retardation beginning in the second year, premature aging, and progressive neurologic abnormalities. This very rare disease occurs predominantly in males. During the first or second year of life, the sun sensitivity and skin signs appear, followed by the cachectic dwarfism and progressive alterations of the eye, ear, and nervous system. About 100 patients have been described, and death usually occurs in the second or third decade of life from atheromatous vascular disease. Born at term, the children develop normally for the first few months. During the first or second year, the sun sensitivity appears as butterfly-like rashes of the face resembling lupus erythematosus. The recurrent erythematous rashes lead to pigmentary abnormality and atrophic scarring. Actinic keratoses and skin malignancies do not occur in these areas. Simultaneously with the first skin symptoms, growth retardation becomes apparent, leading to a cachectic dwarfism with rapid progression of premature aging and to many abnormalities of the skeleton such as microcephaly, prognathism, ankylosis, and contractures of the joints. The premature aging results in retinal atrophy and cataracts, deafness, and progressive mental deficit. The condition is fully developed by the age of 5 years. In this syndrome the lipid metabolism is unaltered; diabetes, porphyria, and renal dysfunction are not generally observed. The immune system is not primarily involved and the chromosomes show no constant instability. Cultured fibroblasts have decreased post-UV colony-forming ability (CFA) but normal rates of UV-induced UDS (excision repair of UV-induced thymine dimers). It is not yet clear whether or not the in vitro findings in fibroblasts correlate with the premature aging
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and sun sensitivity.6 Further studies have revealed a heterogeneity of three types of Cockayne syndrome, A, B, and C. In eight cases of CS, exclusively of type C, there was a correlation with Xl’, affecting patients with complementation group B, C, D, and F (Tables 4 and 5). There is no known treatment that influences the course of this condition.
Bloom’s Syndrome Facial telangiectasia of dwarfs, or Bloom’s syndrome, is an autosomal recessive condition resembling lupus erythematosus. It is characterized by sun hypersensitivity and growth retardation. The gene is located on chromosome 15. This very rare disease occurs in both sexes. Affected patients are born at term with reduced body weight and size. They have small narrow faces with prominent features. Many patients show cafe-au-lait spots. Growth is retarded, but intellectual and sexual development is normal. In male patients, spermatogenesis is absent. During the tirst years of life, these patients get butterfly-like telangiectatic erythemas of the face after sun exposure, sometimes associated with blister formation. Similar erythemas may also occur on other body regions. After repeated light-provoked erythematous rashes, the skin is marked by a reticular atrophy and papular elements with pigrnentary incontinence and a network of telangiectasias, resembling poikiloderma. Most patients with Bloom’s syndrome have an increased rate of infections and show diminished levels of immunoglobulins (IgG, IgA, IgM). In the lymphocytes and skin fibroblasts and in the bone marrow cells of these patients an increased number of chromosomal breaks and characteristic rearrangements can be shown. The spontaneous rate of sister chromatid exchanges (SCEs) is markedly increased. More than half of the patients die from acute leukemia or metastatic tumors of various origins. It is not clear whether the chromosomal instability must be evaluated as one symptom of the syndrome’s puzzle or if it is the first demonstrable sign of malignant transformation.7*8 Avoidance of sun exposure and protection by sunscreens may prevent skin rashes. An attempt has been made with in vitro storage of frozen bone marrow cells at the homologous repopulation of the bone marrow after whole-body x-ray treatment of leukemia.
Erythropoietic Protoporphyria Erythropoietic protoporphyria (EPP) is an autosomal dominant porphyric disease, in which the defect in porphyrin metabolism results in an accumulation of proto-
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porphyrin in the erythrocytes (fluorocytes), probably because of defective heme synthetase activity. Urine porphyrines are not elevated. The passage of protoporphyrin-loaded erythrocytes through the dermal vessels results in photohemolysis when skin is exposed to UVA and visible light. An endogenous photosensitivity reaction starts, with pain and burning within a few minutes. This is succeeded by erythema and edema (sometimes hemorrhagic) and, later, by vesicles and sores on the light-exposed areas, chiefly the nose, cheeks, chin, lips, and backs of the hands. The sores heal with small vermicular scars. After repeated eruptions, the skin on the hand and face gradually becomes yellow, gray, dull, and thickened (pachydermia). The symptoms start early in childhood and follow the patients as so-called “persistent solar urticaria” throughout life. The disease obviously is rather common. It is not provoked by drugs or alcohol. There is increasing evidence for genetic heterogeneity in EPP. Apart from the traditional autosomal dominant transmission in most families, there are a minority of families with autosomal recessive transmission. These data are supported by biochemical analysis of the defective enzyme in affected patients and in nonaffected heterozygotes. Evidence in given that more than one gene may be required for the expression of the disease.9 No causal therapy is known, but the oral administration of p-carotene during light exposure periods of the year can achieve symptomatic photoprotection in most patients. The individual dose has to be evaluated (25200 mg daily) with respect to the fact that tolerance to light begins only 2 to 4 weeks after initiation of the therapy. Despite the good tolerance of the medication, liver checks are recommended.
alopecia, but hypertrichosis often develops on the face and limbs. Splenectomy and transfusions may help for a while but it remains to be determined whether these treatments affect survival. At least in the unusual patient with late onset of the disease, oral management with p-carotene (25 -200 mg daily) may prevent sun-induced skin alterations.
Congenital
Hartnup Disease
Erythropoietic
Porphyria
(Giinther)
This autosomal recessive disease is very rare and occurs in both sexes. It is characterized by sun sensitivity with subsequent mutilating skin lesions and secondarily arising tumors, as well as by a complex defect of the porphyrin metabolism, with urinary excretion of large amounts of uroporphyrin I, as the leading metabolic symptom, and hemolytic anemia. No chromosomal abnormalities have been observed. Photosensitivity may appear in infancy in the form of erythema and blistering. These lesions ulcerate and heal with atrophic scars. Repeated episodes lead to severe deformity and mutilation of the nose, ears (Fig 3), eyes, and fingers, with the loss of nails and terminal phalanges. Tumors can arise in the mutilated tissue after years. Keratoconjunctivits and ectropion, as well as dyspigmentation, may occur. Lesions in the scalp end with scarring
Figure 3. Pachydermia, dyschromia, and mutilation of the ear in a 32-year-old man with porphyria congenita Giinther.
Hartnup disease is an autosomal recessive condition characterized by pellagra-like dermatitis in sun-exposed skin areas, intermittent cerebellar ataxia, and renal aminoaciduria. It is very rare, occurring equally in both sexes. During childhood the first symptoms appear after sun exposure and skin signs may disappear during life. More than 70 patients have been described, with the exclusion of asymptomatic cases. The first symptoms occur symmetrically on the sunexposed areas of the skin of the face, neck, hands, and lower legs. Scaly erythematous patches with infiltration persist for weeks and months. Acute dermatitis and blistering occur in addition after sun exposure, turning into crusts and scars. These changes together with marked hyperpigmentation present the aspect of classic pellagra. The dermatitis is aggravated by malnutrition and inter-
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Clinics in Dermatology 1993;12:275-281 current infections. Glossitis, cheilitis, and angular stomatitis are additional signs as is vulvovaginitis. The hair may be fine and fragile. Associated neurologic symptoms may parallel the skin rashes or follow them. Cerebellar ataxia develops in association with skin rashes or with infections. Nystagmus, ptosis, diplopia, muscular hypertonicity, and hyperreflexia have been observed as have signs of pyramidal involvement. The neurologic symptoms are fully reversible. Renal hyperaminoaciduria of a specific pattern is a constant and pathognomonic finding without any evidence of other renal dysfunction. In addition, there is an increase in the urinary and fecal excretion of indole and indican.‘O The peculiar pattern of symptoms and their reversibility can be explained by a disorder of tubular and intestinal transport of amino acids. There is a primary and very specific defect in the reabsorption of amino acids from the glomerular filtrate, resulting in a constant aminoaciduria of most of the monoamino monocarboxylic acids. The defect results in delayed and incomplete jejunal absorption of amino acids, mainly I-tryptophan. This explains the fecal loss of unabsorbed amino acids, either unchanged or metabolized by intestinal bacteria to indole and indican. The latter products can be absorbed in the intestine and may result, toxic as they are, in the variable and reversible neurologic symptoms. The lack of intestinally absorbed 1-tryptophan leads to a deficiency in its main metabolite, nicotinic acid, and results in the pellagra-like, sun-sensitive dermatitis. Differential diagnosis has to consider the group of porphyrias and the complex forms of dietary or drug-induced vitamin deficiencies, such as true pellagra and pellagroid. Avoidance of sun exposure and protection with sunscreens
are helpful.
Daily therapy
with 50 to 200 mg
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nicotinamide may improve the skin changes and some of the neurologic symptoms. Long-term oral neomycin treatment helps to sterilize the intestinal tract and therefore suppresses the bacterial formation of toxic products.
References 1. Fischer E, Thielmann HW, Neundijrfer B, et al. Xeroderma pigmentosum patients from Germany: Clinical symptoms and DNA repair characteristics. Arch Dermatol Res 1982;274:229 -47.
2. Jung
EG. Xeroderma 1986;25:629-33.
pigmentosum.
Int J Dermatol
3. Cleaver JE. Defective repair replication of DNA in xeroderma pigmentosum. Nature 1968;219:652-6.
4. De Weerd-Kastelein EA, Keijzer W, Bootsma D. Genetic heterogeneity of xeroderma pigmentosum demonstrated by somatic cell hybridization. Nature 1972;238:80-2.
5. Thielmann HW, Popanda 0, Edler L, et al. Clinical symptoms and DNA repair characteristics of xeroderma pigmentosum patients from Germany. Cancer Res 1991;51: 3456- 70.
6. Andrews AD, Barrett SF, Yoder FW, et al. Cockayne’s syndrome fibroblasts have increased sensitivity to ultraviolet light but normal rates of unscheduled DNA synthesis. J Invest Dermatol 1978;70:237-9.
7. Chaganti RSK, Schonberg S, German J. A manyfold increase in sister chromatid exchanges in Bloom’s syndrome lymphocytes. Proc Nat1 Acad Sci USA 1974;71:450812.
8. Dicken CH, Dewald G, Gordon H. Sister chromatid exchanges in Bloom’s 114:755-60.
syndrome.
Arch
Dermatol
1978;
9. Norris PG, Nunn AV, Hawk JLM, et al. Genetic heterogeneity in erythropoietic protoporphyria: A study of the enzymatic defect in nine affected families. J Invest Dermatol 1990;95:260-3. 10. Wilcken B, Brown DA. Natural history of Hartnup disease. Arch Dis Child 1977;52:38-40.