Brook E. Tlougan and Amy S. Paller
SELECTED GENETIC DISORDERS OF THE SKIN
During the last decade, our understanding of the molecular bases for genetic disorders of the skin has expanded tremendously. Identifying the gene mutations that lead to phenotypic manifestations facilitates prenatal diagnosis using molecular techniques. For some disorders, this information has translated into early trials of gene therapy or the development of new pharmacologic therapy based on manipulation of gene product levels.
THE ICHTHYOSES AND ICHTHYOSIFORM DISORDERS
Named for the Greek term meaning “fishlike scales,” this heterogeneous group of disorders is characterized by the predominant clinical feature of visible accumulation of scale. FIRST (Foundation for Ichthyosis and Related Skin Types) is a national support group for patients with the ichthyoses and other disorders with thickening of epidermis (http://www.scalyskin.org). During the past decade, the underlying molecular basis for many of the ichthyotic disorders has been discovered, and many can be diagnosed prenatally through molecular analysis of genomic DNA obtained by chorionic villus sampling or amniocentesis. In general, therapy for these disorders is similar and is based on disease severity and tolerance rather than the specific type. During the neonatal and early infantile period, however, therapy should be limited to the frequent application of bland emollients, since use of topical medications with keratolytic agents during the first 6 months of life is usually unnecessary and risks significant absorption of potentially toxic substances (eg, absorption of lactic acid, salicylic acid).
Scaling in the genetic forms is usually either present at birth or has its onset within the first few years of life. Rarely, nongenetic causes lead to ichthyosis in pediatric patients. Causes of acquired ichthyosis include hypothyroidism, chronic renal insufficiency, malignancy (particularly lymphoma), malabsorption syndromes, essential fatty acid deficiency, sarcoidosis, and certain drugs (particularly hypocholesterolemic agents).
Ichthyosis vulgaris is the most common form of the ichthyoses.1,2 It is now known to result from mutations in the gene encoding filaggrin, a gene also recently implicated in atopic dermatitis. Approximately 1 in 20 Northern European individuals carry a mutation on 1 allele and have a mild form; homozygotes have a much more severe form. Thus, the disorder is not autosomal dominant, as was once thought, but is semidominant. Regardless of severity, the onset of scaling in ichthyosis vulgaris tends to be after 3 months of age and may become more prominent later during childhood or at puberty. Fine, white scales, often without much erythema, predominate on the exterior surfaces of the extremities, especially the legs (Fig. 360-1). There is an increased prominence of palmoplantar markings (hyperlinear palms) owing to mild to moderate thickening of the palms and soles. The majority of patients with ichthyosis vulgaris show a reduced granular layer of skin with decreased conversion of profilaggrin to filaggrin, the major protein in keratohyalin granules. The risk of atopic dermatitis is increased in patients with ichthyosis vulgaris, suggesting an important role of the defective epidermal barrier in the development of the dermatitis.
Recessive X-linked ichthyosis occurs in 1 of 2000 to 6000 boys. Scaling is often more pronounced than in ichthyosis vulgaris, and scales tend to be larger and darker; the trunk is usually involved, but palms and soles are unaffected.1,2 The antecubital and popliteal flexures are usually spared, whereas the neck and periauricular areas are affected. The disease is caused by the absence of the microsomal enzyme steroid sulfatase (arylsulfatase C). Because of the deficiency of fetal placental steroid sulfatase, the first clue to diagnosis may be failure to initiate labor or of having labor progress in the pregnant mother. Abnormalities of the genitalia, particularly undescended testes, have been described in approximately 10% of patients. Minute, asymptomatic corneal opacities are present in half of adult patients. Diagnosis can be confirmed by measurement of enzyme activity in fibroblasts, leukocytes, amniocytes, or scales or by measurement of substrate (cholesterol sulfate) accumulation in scales or blood. The majority of cases result from deletion of the gene, which can be detected by fluorescent in situ hybridization (FISH) analysis. Approximately 10% of affected individuals have contiguous gene deletion with associated hypogonadism, anosmia, and mental retardation.
FIGURE 360-1. The scaling of patients with ichthyosis vulgaris is most severe on the lower extremities and during cold months. The palms and soles tend to be thickened as well in this semidominant common skin disorder. (Source: Courtesy of Amy Paller, MD.)
Epidermolytic hyperkeratosis, or bullous congenital ichthyosiform erythroderma, is an autosomal dominant trait in which large areas of denuded skin are typically present at birth, often suggesting a mechanobullous disease rather than a form of ichthyosis. The disease may be localized and mild or generalized and severe. A milder form, often with more superficial blistering and thinner scaling (ichthyosis bullosa of Siemens), results from mutations in keratin 2e, encoding keratin intermediate filaments expressed in the upper half of the epidermis. A more severe form with thicker scaling (bullous congenital ichthyosiform erythroderma of Brocq) is usually caused by mutations in either the keratin 1 or keratin 10 gene, which is expressed in the immediate suprabasal areas. By infancy, scaling becomes more conspicuous. Blistering occurs less frequently with advancing age, is often focal, and may be caused by secondary staphylococcal infection. Although the disorder is generalized, scaling is particularly verrucous in intertriginous areas and overlying joints. The degree of associated erythroderma and palmoplantar keratoderma is variable. Treatment of this disorder with keratolytics or retinoids is often complicated by the propensity of these agents to increase skin fragility. The mosaic form of epidermolytic hyperkeratosis presents as epidermal nevi with linear streaks of thickening of skin, often with increased pigmentation, following Blaschko lines (the lines of embryologic development of ectoderm).
Lamellar ichthyosis and nonbullous congenital ichthyosiform erythroderma are now considered distinct disorders based on clinical characteristics and underlying molecular basis. Both are usually autosomal recessive conditions that almost always present at birth as a collodion baby (Fig. 360-2), a phenotype characterized by taut, shiny skin that has been likened to cellophane (collodion).1,2 This “membrane” leads to eversion of the eyelids (ectropion) and of the lips (eclabium), digital contractures, and, rarely, restricted respiration. In severely affected patients, the cartilaginous portions of the nose and ears may be underdeveloped. Collodion babies should be kept in a moist environment (such as a humidified Isolette), with application of emollients and attention to the increased risks of temperature instability, fluid and electrolyte imbalance (especially hypernatremic dehydration), and infection. The membrane is shed during the first weeks of life. Although most collodion babies eventually adopt the typical characteristics of patients with either lamellar ichthyosis or CIE, some patients show a normal phenotype (lamellar exfoliation of the newborn) or other ichthyosiform disorder.
Within a few months after clearance of the collodion membrane, babies with lamellar ichthyosis show scales that are large, platelike, and hyperpigmented, particularly in patients with darker skin. Underlying erythroderma is minimal, but ectropion and alopecia may be severe. Mutations in the transporter protein ABCA12 may cause lamellar ichthyosis or, when more severe, harlequin ichthyosis. Mutations in genes that encode keratinocyte transglutaminase I, transporter protein ABCA12, FLJ39501, and ichthyin may underlie lamellar ichthyosis. In contrast, infants with nonbullous congenital icthyosiform erythroderma have scales that are lighter in color and finer than those of infants with lamellar ichthyosis. Underlying erythroderma is greater, and alopecia and ectropion may be associated. Not uncommonly, these patients have associated neurologic abnormalities, and this phenotype may be part of other multisystem conditions, such as the neutral lipid storage disease (Chanarin-Dorfman syndrome) or Netherton syndrome (see below). Biopsies show marked acanthosis of the epidermis with a moderately thickened stratum corneum. Several genes may be mutated in this disorder, most commonly involved are the genes encoding 12R lipoxygenase and lipoxygenase 3.
FIGURE 360-2. Collodion baby. Note the taut, shiny skin reminiscent of cellophane, seen with lamellar ichthyosis or nonbullous congenital ichthyosiform erythroderma. (Source: Courtesy of Amy Paller, MD.)
Harlequin ichthyosis is a rare, autosomal recessive trait caused by mutations in the lipid transporter ABCA12 in which affected infants are usually stillborn or die soon after birth from massive, hyperkeratotic plates that obstruct respiratory movements and feeding. Skin tautness and massive plates of scale produce grotesque facial features with severe ectropion and eclabion and mittenlike encasement of fingers and toes. In the rare survivors, the platelike scales are shed post-natally, and an intense exfoliative erythroderma ensues. In general, harlequin babies are treated with supportive therapy, including a humid environment, the aggressive use of emollients, and careful monitoring of fluid and electrolyte needs. Some advocate the use of systemic retinoids for patients who survive the first few weeks of life; it should be recognized, however, that the resultant phenotype with chronic use of retinoids will continue to be that of severe CIE.
Ichthyosis may occur as a component of a multisystemic disease. Netherton syndrome is an autosomal recessive trait caused by a mutation in the SPINK5 gene that encodes the serine proteinase inhibitor lymphoepithelial Kazal-type inhibitor (LEKTI). The syndrome is characterized by the triad of ichthyosis, brittle hair, and an atopic diathesis, often including hypersensitivity to food antigens. Patients usually have generalized exfoliative erythroderma during the neonatal period and early infancy, with failure to thrive, diarrhea, and hypernatremia. Later, an unusual migratory annular pattern of double-edged scaling predominates, called ichthyosis linearis circumflexa. Light microscopic examination of hairs shows a pathognomonic defect with intussusception of the hair shaft, called trichorrhexis invaginata (bamboo hair), which allows the diagnosis to be made.
Patients with trichothiodystrophy, or sulfur-deficient brittle hair, may show a variety of associated defects, including ichthyosis, retardation, and decreased fertility.3 Some patients show photosensitivity, with a severe defect in DNA excision and repair. Under polarizing microscopy, the hair from patients with this autosomal recessive disorder shows a pathognomonic tiger-tail banding pattern.
Sjögren-Larsson syndrome is a rare, autosomal-recessive trait characterized by the triad of ichthyosis, spasticity, and mental retardation. Ichthyosis is usually the presenting sign and patients present with pruritic skin that is thickened and may have a slightly yellow hue. Pathognomonic retinal “glistening dots” are present in most patients by one year of age. Dysplasia of the dental enamel can also be seen. The disorder is caused by a mutation in the ALDH3A2 gene, which causes a deficiency of fatty alcohol oxidoreductase.
Neutral lipid storage disease (Chanarin-Dorfman) is another autosomal-recessive disorder that results from mutation in the gene ABHD5. Patients are most commonly of Mediterranean descent and show a CIE-like ichthyosis. Systemic signs may include neurosensory deafness, cataracts, myopathy, fatty liver, and mild mental and growth retardation. The diagnosis can be confirmed by finding lipid droplets in circulating leukocytes.
Conradi-Hünermann syndrome, or chondrodysplasia punctata, is most commonly an X-linked dominant trait with lethality in males unless in a mosaic form. At birth, patients with Conradi-Hünermann syndrome show bands of ichthyosiform erythroderma that follow lines of Blaschko, reflecting the random activation of the mutant X chromosome. During infancy, these bands resolve, leaving follicular atrophoderma. Systemic signs include focal cataracts and asymmetric limb reduction defects with stippled epiphyses (chondrodysplasia punctata).
CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) is also an X-linked dominant trait caused by a mutation in the NSDHL gene. The ichthyosis and limb defects with epiphyseal stippling are predominantly unilateral.
The triad of progressive scarring keratitis, ichthyosis, and neurosensory deafness characterizes KID syndrome, a rare disorder with dominant and recessive forms that is caused by mutations in genes encoding connexins. Patients often show generalized keratotic plaques, palmoplantar keratoderma, and alopecia.
Darier disease, or keratosis follicularis, is an autosomal dominant trait caused by a mutation in ATP2A2, which encodes SERCA2b, an intracellular calcium pump ATPase. The skin eruption frequently follows intense sun exposure, most commonly in the second decade of life. Greasy keratotic papules show a predilection for seborrheic areas on the face, scalp, neck, upper chest, and back but may occur on extremities or may show a striking photodistribution. Lesions on flexural sites tend to coalesce to form erythematous, eroded plaques. Small keratotic papules and pits are found on palms and soles. Nails are short, fragile, and may show red and white longitudinal streaks as well as v-shaped distal nail nicks. The oral mucosa has a pebbly quality, particularly along gingival margins. The histopathologic appearance of biopsy sections is diagnostic .
PALMOPLANTAR KERATODERMAS
Palmoplantar keratodermas constitute a large group of predominantly autosomal dominant disorders in which the disorder of cornification is largely but not exclusively limited to palms and soles.4,5 The nonepidermolytic and epidermolytic hyperkeratotic types are most common and result from mutations in keratin 1 (and sometimes 6 or 16) and 9 genes, respectively. Hyperkeratosis may be diffuse or limited to papules or even linear bands, as in the striateform of palmoplantar keratoderma. In some forms, particularly Vohwinkel syndrome constriction of the terminal digits may lead to mutilating changes. If keratoses are focal or are accompanied by painful erosions, tyrosinemia type II (Richner-Hanhart syndrome) should be excluded. Other features of this autosomal recessive trait are keratitis and sometimes mental retardation. Dietary restriction of tyrosine and phenylalanine is indicated. The Papillon-Lefèvre syndrome is a recessive trait with diffuse keratoderma and periodontitis leading to premature loss of teeth. In treatment of keratoderma, keratolytics may be used followed by paring. Occasionally, one of the synthetic retinoids (isotretinoin or acitretin) is indicated to preserve function.
DISORDERS OF PIGMENTATION
The genetic basis for albinism in most patients is a mutation either in the gene that codes for tyrosinase, important for melanin synthesis (tyrosinase-negative albinism), or in the gene that codes for P protein (tyrosinase-positive albinism), leading to abnormal transport of melanin to keratinocytes. As a result, children with albinism, an autosomal recessive group of disorders, have decreased pigmentation of the skin, hair, and eyes, along with photophobia, nystagmus, and reduced visual acuity.6,7 Patients with all forms of oculocutaneous albinism must consistently avoid sunlight, use full-spectrum sun protectants, and wear protective clothing (long sleeves, brimmed hat, UV-filtering glasses) to prevent the development of cutaneous malignancy. The National Organization for Albinism and Hypopigmentation (NOAH) has a Web site (http://www.albinism.org) and provides support for families.
The Hermansky-Pudlak syndrome is a rare, autosomal recessive disorder7 characterized by a triad of decreased pigmentation, mild bleeding diathesis, and tissue storage of ceroid material.
Chédiak-Higashi and Griscelli syndromes are autosomal recessive disorders which result from mutations in LYST and myosin Va. The skin and hair assume a pigment-diluted, silvery sheen because of the accumulation of giant melanosomes with inability to transport the melanin granules to epidermal cells. Both disorders may show evidence of immunodeficiency, with the development of an “accelerated phase” by early childhood, which leads to the proliferation of atypical lymphocytes and histiocytes, multiorgan infiltration, and pancytopenia. Without successful bone marrow transplantation, most patients with Chédiak-Higashi or Griscelli syndrome die during this accelerated phase. Patients may develop neurologic deficits, particularly in Chédiak-Higashi syndrome and in type I Gris-celli syndrome. Patients with type II Griscelli syndrome (caused by mutations in Rab27a) are at particularly high risk for hemophagocytic lymphohistiocytosis.
Children with piebaldism display discrete patches of depigmentation involving the central forehead, anterior trunk, and midportions of the upper and lower extremities.7 A midline white forelock is characteristic. Absent or grossly abnormal melanocytes are seen in the involved skin. The condition is inherited as an autosomal dominant trait owing to mutations in the c-kit protooncogene, which directs melanoblast proliferation, migration, and differentiation.
Waardenburg syndrome is also an autosomal dominant disorder associated with mutations in PAX 3, with depigmentation of hair, skin, and irides. Its phenotypic manifestations are most commonly lateral displacement of the inner canthi (dystopia canthorum), broad nasal root, and confluent eyebrows. Patients without the facial features may have mutations in the MITF gene (type 2), and patients with associated Hirschsprung disease (type 4) may have autosomal recessive mutations in 1 of 4 other genes encoding endothelin, endothelin receptor, Slug, or Sox 10. Sensorineural hearing loss occurs overall in 20% of patients and indicates the critical role of pigment in directing development of hearing.
TUMOR SYNDROMES
Pediatric patients with the autosomal dominant type I neurofibromatosis (von Recklinghausen disease) usually show only multiple café au lait spots on examination.8-11 Six or more of these evenly brown-colored, sharply defined macules are present in more than 99% of patients. Additional café au lait spots may continue to appear during the first 5 years of life but by definition must be larger than 0.5 cm in diameter in the prepubertal child (1.5 cm in a postpubertal individual) to be counted for diagnosis. Definitive diagnosis requires the presence of other features, such as axillary freckling (Fig. 360-3); neurofibromatosis in a first-degree relative; pseudoarthrosis; plexi-form neurofibroma; sphenoid dysplasia; optic glioma or Lisch nodules (dome-shaped hyperpigmented iris hamartomas that are multiple, bilateral, and present in the majority of patients of school age and older). Two interacting genes, tuberin or hamartin, may be mutated to cause this disorder.
The plexiform neurofibromas often manifest during infancy and early childhood as a large café au lait spot, often irregular, with associated hypertrichosis. They can be deeply invasive, grow progressively, and be difficult to eradicate. Dermal neurofibromas present as soft sessile or pedunculated nodules, usually first apparent during puberty. Optic gliomas occur in 15% of patients but are not treated unless they are actively growing or causing clinical problems. Defective tumor suppression increases the risk of malignancy; central nervous system tumors and nonlymphocytic leukemias may appear during childhood and neurofibrosarcomas and malignant schwannomas after 20 years of age. Perhaps the most important reason for early diagnosis is the awareness that speech and learning disabilities occur in almost a third of patients.
Hypopigmented macules ranging from 1 to 4 cm in diameter are the most consistent cutaneous finding in tuberous sclerosis, an autosomal dominant neurocutaneous disorder.9,10 Macules are sometimes shaped like ash leaves (ash-leaf spots), but they may be round, oval, irregular, or confetti-like in configuration. The presence at birth of connective-tissue nevi (slightly elevated flesh-colored plaques with a rough or leathery surface, particularly on the forehead [fibrous forehead plaque]) may allow early definitive diagnosis. The plaques of collagenomas that occur in tuberous sclerosis are also known as “shagreen patches.” Numerous skin-colored to vascularized papules (adenoma sebaceum) appear on the central face during childhood in most patients with tuberous sclerosis (Fig. 360-4). Periungual, subungual, and gingival fibromas are not usually seen until puberty or adulthood. The majority of patients with tuberous sclerosis have seizures, often with onset by infancy, but 40% have normal intelligence. Tumors of the central nervous system, kidneys (angiomyolipomas), heart (rhabdomyomas), and eyes (retinal astrocytic hamartomas/phakomas) occur most commonly. The Tuberous Sclerosis Alliance (http://www.tsalliance.org) provides support to families.
FIGURE 360-3. Young children with multiple café au lait spots have cutaneous evidence of neurofibromatosis type I. The additional finding of freckling in the axillary area, as shown here, allows the diagnosis of neurofibromatosis type I to be made definitively. (Source: Courtesy of Amy Paller, MD.)
Basal cell nevus syndrome (Gorlin syndrome) is an autosomal dominant disorder caused by mutations in the patched gene that controls cell growth and patterning. Affected patients tend to develop basal cell carcinomas during childhood or early adulthood and to display dysmorphic facies (frontal bossing and hypertelorism), palmoplantar pits, a variety of skeletal defects (including the classic “bifid” ribs), and mental retardation.5,9 Cutaneous and visceral cysts are common, including painful cysts of the jaw that may become malignant. In addition to basal cell carcinomas, ovarian fibromas and carcinomas as well as medulloblastomas occur with increased frequency during childhood.
Peutz-Jeghers syndrome is an autosomal dominant defect characterized by gastrointestinal polyposes and hyperpigmented macules of the mucosae, perioral areas, fingers, and toes.5,9 In contrast, patients with Gardner syndromealso have gastrointestinal polyposes, but their characteristic cutaneous features are epidermal cysts and sometimes pilomatricomas. Patients with Gardner syndrome almost always develop colorectal carcinoma and have an increased risk of developing papillary adenocarcinoma of the thyroid (see Chapter 414).
OTHER NEUROCUTANEOUS DISORDERS
Incontinentia pigmenti is an X-linked dominant disorder caused by a NEMO gene mutation that is usually lethal in males.5,10-12 As a result, most affected patients are female, and affected mothers may report an increased frequency of miscarriages. Four overlapping stages are described: vesicular, verrucous, hyperpigmented, and hypopigmented/atrophic. Patterned blistering that follows the distribution of the lines of Blaschko (reflecting functional mosaicism) occurs in 96% of affected patients by 6 weeks of age (Fig. 360-5). Verrucous papules, similarly distributed, may be seen after the first several weeks and may persist for months. The hyperpigmented lines and swirls along the Blaschko lines typically appear during the first months of life and often persist for several years. About one fourth of patients develop the fourth stage of atrophic and/or hypopigmented streaks, which may also persist for several years. Cicatricial alopecia occurs in approximately one third of patients. Skin biopsy shows intraepidermal vesicles filled with eosinophils.
FIGURE 360-4. Tuberous sclerosis. Hallmarks include flesh-to-pink-colored papules and nodules appearing on the central face (adenoma sebaceum). (Source: Courtesy of Amy Paller, MD.)
The cutaneous changes are of greatest importance as a marker for other noncutaneous abnormalities of incontinentia pigmenti. Delayed eruption of teeth, absent teeth, and malformed (peg or conical) teeth occur in almost two thirds of patients. Although the most common ophthalmologic abnormality is strabismus, the retinal neovascularization and detachment in patients with incontinentia pigmenti can lead to blindness in about 7% of patients. The occurrence of seizures during the neonatal period often leads to an erroneous diagnosis of herpes simplex infection. There is no relation between incontinentia pigmenti and incontinentia pigmenti achromians or hypomelanosis of Ito, a heterogeneous group of mosaic disorders with hypopigmented streaks and swirls along the Blaschko lines. The national support group for patients with incontinentia pigmenti can be e-mailed at nipf@pipeline.com.
Ataxia-telangiectasia is an autosomal recessive disorder5,9 that usually results from mutations in ATM, which prevents DNA synthesis from proceeding after irradiation damage. A milder form of the disorder can also be seen in patients with a mutation in the MREII gene. The early cerebellar ataxia in affected patients is followed by the development of telangiectasias on the bulbar conjunctival mucosae, usually beginning between 2 and 6 years of age. Telangiectasias may subsequently appear on the eyelids, nasal bridge, cheeks, ears, and flexural areas. Cutaneous granulomas that frequently ulcerate are difficult to eradicate. Other cutaneous features are loss of subcutaneous fat, sclerodermoid lesions, and cutaneous infections (due to thymic hypoplasia). Patients tend to show progressive neurologic deterioration and, variably, recurrent sinopulmonary infections related to immunodeficiency. Prenatal diagnosis has been possible using molecular techniques if the specific DNA defect in the family is identified.
FIGURE 360-5. Incontinentia pigmenti. Lines of Blaschko. (Source: Courtesy of Amy Paller, MD.)
Although boys with X-linked recessive Fabry disease (angiokeratoma corporis diffusum universale) usually present with unexplained fever, weakness, and/or acral paresthesias, the development of petechial lesions or keratotic vascular papules (angiokeratomas) during adolescence may allow the diagnosis to be made. The vascular lesions are predominantly distributed between the umbilicus and knees. Due to a deficiency in α-galactosidase A, patients progressively deposit ceramide-trihexoside in blood vessels. Later complications are angina pectoris, hypertension, renal failure, and an increased risk of cerebrovascular accidents.
Menkes syndrome is an X-linked recessive disorder caused by an abnormality in the ATP-dependent copper transporter, ATP7A. Patients have short, brittle, easily broken hairs that show pili torti (hair that twists 180°) by light microscopy. Characteristic facial features include sparse eyelashes and eyebrows and a “cupid’s bow” upper lip. Patients show progressive neurologic deterioration with seizures and retardation and tend to die during the first years of life. Other clinical manifestations include pigment dilution, degenerated elastic tissue, bladder diverticula, scurvy-like bone changes, and impaired temperature regulation.
EPIDERMOLYSIS BULLOSA
This heterogeneous group of genetically determined disorders results from structural defects that diminish the cohesive strength of skin, leading to blistering after mechanical trauma. At present, more than 15 genetically distinct forms have been recognized by their clinical features, histopathology, and inheritance patterns.11,13-15 Epidermolysis bullosa (EB) ranges in severity from forms that are lethal in infancy or are severely disabling and deforming to localized, mild disease. Prenatal diagnosis has been possible using molecular techniques if the specific DNA defect in the family is identified. Dystrophic Epidermolysis Bullosa Research Association of America (DEBRA) supports patients with all forms of epidermolysis bullosa; more information can be obtained at http://www.debra.org.
Epidermolysis bullosa is subdivided by ultrastructural and immunomapping characteristics into 3 major groups: EB simplex, in which the cleavage plane of the blister is through the basal epidermal cells; junctional or hemidesmosomal EB, in which the defect is in the hemidesmosome with the cleavage plane through the dermal-epidermal junction, causing blisters in the lamina lucida; and dystrophic EB, in which the cleavage plane lies below the basement membrane zone in the upper dermis. Defects in keratin genes 5 and 14, expressed in the basal layer of epidermis, cause all forms of EB simplex, and mutations in the gene encoding collagen VII, the major component of anchoring fibrils, underlie dystrophic EB. Junctional EB can result from defects in a variety of hemidesmosomal proteins, including 1 of the 3 chains of laminin 332 (EB letalis, most severe form), collagen XVII (generalized atrophic benign form), plectin (EB simplex with muscular dystrophy), and integrin subunits α6 and β4 (with pyloric atresia). Determination of the subtype of epidermolysis bullosa during the neonatal period is critical for prognostication and counseling but is very difficult based on clinical characteristics alone. A skin biopsy, preferably from the margin of an induced blister or a fresh blister, should be sent for immunomapping and immunomarker studies, which allow rapid diagnosis. In addition, other causes of widespread blistering in the newborn must be excluded (see Table 357-1).
EB simplex, characterized by blisters that heal without scarring or milia (small keratinaceous cysts), is almost always an autosomal dominant disorder. Blistering may be generalized with associated mucosal and nail involvement. In the mildest cases, the blistering is limited to the hands and feet, sites of maximal trauma. Although blistering may be extensive during the perinatal period, improvement with age is expected.
Junctional forms of epidermolysis bullosa are all autosomal recessive in inheritance. Blistering is usually severe and occurs spontaneously or after trauma. Death caused by sepsis, sometimes in conjunction with hypoalbuminemia and anemia, often occurs before 6 months of age. Mucous membrane involvement is often severe, and hoarseness is characteristic. Survivors tend to be growth-retarded with chronic anemia, atrophic scarring, and highly vascularized granulation tissue at sites of chronic blistering. Nails slough easily, and dental enamel is hypoplastic, requiring capping.
An autosomal dominant form of dystrophic EB is characterized by blistering at localized areas (dorsal aspects of hands, elbows, and knees in particular) that heals with scarring and milia formation. Generalized blistering resulting in extensive scarring, and milia formation is the hallmark of the recessive form. Most affected patients survive the neonatal period.
Because of complex extracutaneous complications, an interdisciplinary approach encompassing pediatricians, dermatologists, nutritionists, ophthalmologists, dentists, urologists, otolaryngologists, and gastroenterologists is critical for the care of patients with recessive dystrophic EB. In addition to growth retardation, chronic anemia, and increased dental caries, intraoral scarring may lead to microstomia, ankyloglossia, and, occasionally, laryngeal stenosis. Esophageal blisters and ulcerations cause dysphagia, which contributes to the nutritional deficiencies. Strictures form commonly in the esophagus. Early placement of a gastrostomy tube is often recommended to provide additional nutrition for patients as well as to decrease the risk of esophageal trauma with eating. Painful blistering around the anal sphincter results in chronic constipation, particularly in recessive dystrophic EB. Stool softeners are essential in these patients, particularly because iron supplementation further hardens the stool. Conjunctival and corneal erosions may also occur; potential sequelae include symblepharon formation and corneal ulcerations or perforations. Recurrent urethral blistering in recessive dystrophic EB results in meatal stenosis and may lead to urinary retention and hydronephrosis.
After the first few years of life, the progressive scarring from blistering on the fingers and toes causes pseudosyndactyly (“mitten deformities”) of the hands and feet (Fig. 360-6), which may result in significant functional disability. Aggressive squamous cell carcinomas of the skin, oral cavity, stomach, esophagus, or bronchi may develop as early as the second decade in severe recessive dystrophic EB and are life threatening. Persistent ulcerations should be biopsied.
FIGURE 360-6. Generalized blistering in patients with recessive dystrophic epidermolysis bullosa results in scarring and milia formation. Patients show growth retardation and anemia and form “mitten deformities” of the distal extremities caused by scarring. (Source: Courtesy of Amy Paller, MD.)
To protect skin from trauma, tape and other adhesives should never be applied directly. Erosions may be covered with a nonadhesive dressing (eg, Vaseline-impregnated gauze, nonstick pads) and then wrapped in soft, bulky dressings. Bandages should be soaked or greased to disengage, never pulled off. Blisters should be decompressed daily by incision with a sterile blade to prevent lateral extension. Secondary infections, particularly with Staphylococcus aureus and Pseudomonas aeruginosa, are frequent and should be suspected if serous crusting is present. Maintenance of adequate nutrition is an important goal in the treatment of severely affected patients.
DISORDERS OF THE DERMIS
Ehlers-Danlos syndrome includes a group of 6 subtypes in which there is easy bruising, poor wound healing, and hyperextensibility of joints and/or skin.16 The skin has a soft texture and, although it is able to stretch easily, regains its normal appearance. Spread “fish-mouth” scars develop after trauma or surgery, and pseudotumor herniations of subcutaneous fat through atrophic dermal scars may be present, particularly on the lower extremities where bruising is easily seen and the thin skin leads to vessel prominence (Fig. 360-7). Mutations in the gene encoding perivascular dermal collagen type V are responsible for the most common classical type. Other types largely result from mutations in the synthesis of other dermal collagens. In patients with the vascular form, the skin may be particularly translucent; these patients have a high risk of vascular tears and aneurysms. The Ehlers-Danlos Syndrome Foundation can be accessed at http://www.ednf.org.
Cutis laxa is a disorder of generalized decreased or absent elastic tissue that manifests both genetic (autosomal recessive and autosomal dominant) and acquired forms. Loose pendulous folds of redundant skin may be present at birth (recessive form) or may develop later (dominant form).17 Patients with severe involvement frequently have pulmonary emphysema, joint dislocations, diverticula of the bladder or gastrointestinal tract, and inguinal or umbilical hernias. Mutations in the elastin gene have been described in patients with the dominant form, and mutations in fibulins 4 or 5 and a subunit of vesicular H+-ATPase have been noted in patients with the recessive form. The disorder is usually progressive and has a poor prognosis.
Focal dermal hypoplasia (Goltz syndrome) is inherited in X-linked dominant fashion, and 90% of patients are female.5,11 Cutaneous manifestations of this functionally mosaic condition include linear and swirled areas of skin hypoplasia, ulcerations, dyspigmentation, and yellowish nodules. A number of musculoskeletal, ocular, and dental anomalies may be present. Vertical striations in the long bones (osteopathia striata) are diagnostic when present.
Lipoid proteinosis is an autosomal recessive disorder ascribable to the deposition of hyaline material in the skin and other organ systems.17 The cutaneous manifestations usually develop during the first 2 years of life, sometimes manifesting as early erosions on the face and intertriginous areas. Waxy papules and nodules appear progressively during childhood, especially on the face and neck, with verrucous papules. A row of nodules at the free edge of the eyelid (string-of-pearls) is particularly characteristic, as is thickening of the tongue. The most common systemic manifestation is hoarseness caused by vocal cord infiltration.
Pseudoxanthoma elasticum (PXE) is a predominantly autosomal recessive disorder of elastic tissue17 due to a mutation in the ABCC6 gene encoding a cell transporter. Cutaneous lesions, which may begin during childhood, consist of grouped, yellowish papules that favor the axillae, groin, and neck. The areas of involvement may appear wrinkled, and their overall appearance has been likened to “plucked chicken skin.” Skin biopsy is diagnostic. Retinal angioid streaks (tears in the Bruch membrane) frequently develop, although it is central retinal defects that may interfere with vision. Widespread arterial involvement of elastic tissue degeneration and deposition of calcium may result in gastrointestinal bleeding, intermittent claudication, and angina pectoris. Support groups include the National Association for Pseudoxanthoma Elasticum (http://www.pxenape.org) and PXE International (http://www.pxe.org).
ECTODERMAL DYSPLASIAS AND OTHER PRIMARILY ECTODERMAL DISORDERS
In the ectodermal dysplasias, 2 or more ectodermally derived structures such as hair, nails, sweat glands, sebaceous glands, or teeth are poorly developed or absent. The National Foundation for Ectodermal Dysplasias can be accessed at http://www.nfed.org.
Hypohidrotic ectodermal dysplasia, usually an X-linked recessive trait caused by a mutation in ectodysplasin A or its receptor, is the most common form of ectodermal dysplasia.5,11,18 Phenotypic characteristics of female carriers may range from no evidence of involvement to extensive changes indistinguishable from those of affected male patients, depending on the extent of random activation of the X chromosome with the mutant gene through lyonization. The facies of patients with hypohidrotic ectodermal dysplasia are characteristic, with a frontal bossing, flat malar ridges, a depressed nasal root (saddle nose), thin upper lip, large pouting lower lip, small chin, and prominent ears. The mandible is underdeveloped, and partial anodontia with conical or pegged teeth is common. Both scalp and body hair is sparse, short, and hypopigmented. Periorbital wrinkling and hyperpigmentation is usually seen. The diminished or absent sweating leads to frequent fevers of unknown origin and heat stress. Poor secretion from other glandular structures results in a progressive erosion with drainage of the nasal mucosae, poor tearing, dry mouth, and increased frequency of otitis media and pneumonia. Patients have an increased frequency of atopy, particularly atopic dermatitis, and asthma. Early recognition of this disorder is key so that parents can be taught about external cooling, such as by dowsing with cool water, and the importance of dental care by 2 years of age to improve mastication, facial development, speech development, and appearance.
FIGURE 360-7. Ehlers-Danlos syndrome. The shins of this child showed chronic purplish-brown discoloration and wide scars. Palpation revealed several firm nodules underlying the discolored areas. (Source: Courtesy of Amy Paller, MD.)
The clinical findings of hidrotic ectodermal dysplasia (Clouston syndrome) include hair and nail hypoplasia in conjunction with palmoplantar keratoderma. Sweating is preserved. Ectodermal dysplasia of the hair and nails may also be associated with midfacial clefting in 3 autosomal dominant disorders: Rapp-Hodgkin syndrome, ectrodactyly–ectodermal dysplasia–clefting (EEC) syndrome (with claw deformities), and Hay-Wells syndrome (with varying degrees of persistent eyelid fusion, or ankyloblepharon). Dyskeratosis congenita is a rare, usually X-linked recessive disorder.5,9 Progressive nail dystrophy, often with eventual anonychia, is generally the first sign during early childhood.9 Mucosal leukoplakia, particularly of the tongue and buccal mucosa, also develops during childhood and may transform into squamous cell carcinomas after the second decade of life. Reticulated hyperpigmented macules and atrophy develop in sun-exposed sites, usually during teenage years. Pancytopenia with progressive bone marrow failure develops in many patients and may require bone marrow transplantation.
In monilethrix, the hair grows to 2 or 3 cm, then breaks off. With a hand lens, the “beaded” hair shaft is seen to undulate in width, and with light microscopy, areas of constriction lack a central medulla. Follicular prominence on the scalp and elsewhere is common. Pachyonychia congenita has been divided into 2 major subtypes, based on clinical manifestations.19 In all cases, the nails are thick and dystrophic in appearance owing to distal and subungual hyperkeratosis. The surface may be rough to smooth, but the nails tend to be discolored and show increased curvature. Secondary infection resulting from Staphylococcus aureus or Candida albicans infection is common. Palmoplantar keratoderma, hyperkeratotic plaques over the elbows and knees, and oral leukokeratosis, especially on the tongue, are associated features (type 1). Patients with mutations in keratins 6b and 17 (type 2 pachyonychia congenita), also expressed in adnexal structures, tend to develop myriad sebaceous cysts (steatocystoma multiplex or vellus hair cysts) and occasionally alopecia.
IMMUNODEFICIENCY DISORDERS
Primary genetic immunodeficiency disorders may manifest as persistent eczematous dermatitis, erythroderma, or recurrent skin infections or granulomas.20,21 In X-linked agammaglobulinemia, recurrent bacterial infections of the skin, particularly cellulitis and furunculosis, may be an important early sign of the disease. An atopic dermatitis-like rash occurs in many patients. Children with the severe combined immunodeficiency syndrome (SCID) may present in the newborn period with acute graft-versus-host disease as a result of maternal-fetal transfusion or transfusion of nonirradiated blood products. Omenn syndrome, a subtype of SCID, presents in infancy with scaling erythroderma associated with lymphadenopathy, hepatosplenomegaly, recurrent infections, and failure to thrive. The X-linked recessive Wiskott-Aldrich syndrome presents as a triad of severe eczematous dermatitis, recurrent bacterial skin infections, and thrombocytopenia with bleeding diathesis. Cutaneous manifestations of chronic granulomatous disease of childhood, a defect of phagocyte function inherited in both X-linked and autosomal recessive forms, include a chronic eczematous dermatitis, perianal abscesses, and aphthous stomatitis. Abnormalities of integrin function in leukocyte adhesion deficiency are associated with delayed separation of the umbilical cord, recurrent cutaneous infections often with draining sinus tracts, and periodontitis. Children with the hyperimmunoglobulin E syndrome have recurrent cutaneous staphylococcal or candidal infections in conjunction with often severe atopic dermatitis. The condition may present during infancy with vesicles and pustules, especially of the head and neck, which show eosinophilic folliculitis in biopsy sections. Serum IgE levels frequently exceeding 1000 mg/dL and peripheral eosinophilia is characteristically present. Patients may show dental and bone abnormalities, coarse facies, and almost always recurrent pulmonary infections.
PHOTOSENSITIVITY DISORDERS
The porphyrias are a group of disorders in which accumulation of by-products in heme metabolism lead to phototoxicity.22 The 2 forms of porphyria with cutaneous features and common onset during infancy and childhood are the rare autosomal recessive disorder, congenital erythropoietic porphyria (Gunther disease), and the more common autosomal dominant disorder, erythropoietic protoporphyria. Congenital erythropoietic porphyria results from a deficiency of uroporphyrinogen III cosynthase. Exposure to ultraviolet light results in a painful, vesiculobullous eruption, with red staining of the urine and teeth during infancy. Progressive scarring and deformity of the face and acral extremities, hyperpigmentation, and facial hypertrichosis occur. Hemolytic anemia and splenomegaly are associated. Successful bone marrow transplantation may reverse the cutaneous and hematologic features. Erythropoietic protoporphyria, a result of ferrochelatase deficiency, usually presents during the first decade of life with an exaggerated sunburn reaction to a relatively brief sun exposure. Although frank blistering is unusual, thickened, waxy skin and scars develop on the face and dorsum of the hands with recurrent episodes. Patients must be monitored for the development of cholelithiasis and hepatic failure, although these rarely occur. In addition to sun avoidance, the application of topical photoprotectants, and the use of sun-protective clothing, administration of β-carotene may be useful in decreasing episodes.
Xeroderma pigmentosum is an autosomal recessive group of disorders, most resulting from defective DNA excision repair.3,5,9 It usually presents in early childhood with exaggerated erythema after sun exposure. Numerous, often darkly pigmented freckles and lentigines develop on sun-exposed sites, and telangiectasias are also a feature. The malignant and premalignant lesions that may appear during childhood (actinic keratoses, keratoacanthomas, squamous cell carcinomas, basal cell epitheliomas, and melanomas) result from ultraviolet light–induced cellular mutations that cannot be repaired. Death in most patients is caused by a metastatic cutaneous malignancy, and many do not survive past childhood. Early recognition and rigorous avoidance of all sources of ultraviolet light is imperative. Some genetic forms are accompanied by neurologic abnormalities, with mental and growth retardation (De Sanctis-Cacchione syndrome).
Bloom syndrome is a rare, autosomal recessive disorder.5,9 Patients exhibit short stature, a severe blistering, photosensitive eruption, and an increased incidence of malignancy, especially leukemia.
Hartnup disease is caused by abnormal tryptophan transport and absorption. The principal cutaneous manifestation is a blistering eruption at sun-exposed sites, caused by a relative niacin deficiency.
Rothmund-Thomson syndrome (poikiloderma congenitale) is a rare autosomal recessive disorder that is characterized by the development of atrophy and telangiectasia (poikiloderma), primarily of sun-exposed sites, beginning during the first year of life.5,9 Other findings include a bullous photosensitive eruption, short stature, hypogonadism, cataracts, bone abnormalities, and an increased risk of sarcoma.
Cockayne syndrome is a rare autosomal recessive disorder that results from mutations in one of several excision-repair cross-complementing (ERCC) proteins.3,5 Patients present with short stature, mental retardation, and prematurely senile, birdlike facies. A photosensitive eruption with scaling, erythema, and scarring begins during the first few years of life.
DISORDERS OF PREMATURE AGING
Werner syndrome is an autosomal recessive disorder that results from mutations in WRN, a helicase. Signs of premature aging begin during teenage years and include cataracts, diabetes mellitus, severe vascular disease, and an increased risk of neoplasia. The most common cutaneous changes are graying of the hair (canities), shiny smooth skin (atrophy), alopecia, and distal cutaneous ulcerations related to inadequate tissue blood flow.
In progeria (Hutchinson-Gilford syndrome), a rare autosomal recessive disorder caused by mutations in the lamin A/C gene, signs of premature aging can occur by 1 year of age.23,24 Patients experience severe growth failure, an aged appearance, and a high incidence of atherosclerosis during the late childhood and early adolescent years. The skin is thin, and subcutaneous fat is deficient, leading to venous prominence. Other cutaneous manifestations are diffuse areas of inelastic skin resembling scleroderma, total alopecia, and nail dystrophy. Patients tend to have a squeaky voice, birdlike facies, and a peculiar hunched posture with shuffling gait. Death as a teenager is common, related to cardiovascular disease.