The genodermatoses: An overview

INTRODUCTION — The genodermatoses are a large group of inherited disorders with skin manifestations. Many of these disorders are rare. However, the recognition of their skin findings is important not only for the initiation of appropriate therapy but also for the detection of other associated abnormalities, including malignancy, in these frequently multisystem disorders [1-3].

An overview of the genodermatoses is presented here. Online resources that provide general information about these disorders include Orphanet and Online Mendelian Inheritance in Man (OMIM).

DISORDERS WITH MALIGNANT POTENTIAL — This group of genodermatoses is of particular importance because of the association of skin findings with the development of malignancies, both cutaneous and noncutaneous (table 1). Examples include basal cell nevus syndrome, Gardner syndrome, Peutz-Jeghers syndrome (PJS), and xeroderma pigmentosum (XP).

Basal cell nevus syndrome — The basal cell nevus syndrome (nevoid basal cell carcinoma syndrome, Gorlin syndrome, MIM #109400) is a rare disorder of autosomal dominant inheritance that results from germline mutations of the human patched gene (PTCH). (See "Nevoid basal cell carcinoma syndrome (Gorlin syndrome)".)

Affected patients have both developmental anomalies and postnatal tumors, especially multiple basal cell carcinomas (BCCs), usually by age 35 years. Most have the following clinical features:

●Macrocephaly, frontal bossing, and hypertelorism.

●Bifid ribs.

●Palmar and plantar pitting (picture 1).

●Odontogenic keratocysts, especially in the mandible, which usually develop in adolescence and typically are the presenting sign of the disorder.

●Medulloblastoma in 3 to 5 percent; meningioma occurs infrequently. (See "Basal cell carcinoma: Epidemiology, pathogenesis, clinical features, and diagnosis".)

The histologic appearance of the BCCs in basal cell nevus syndrome does not differ from those seen in sporadic cases. The diagnosis should be suspected in patients who present with multiple BCCs, especially at an early age.

These patients require careful sun protection from infancy and regular skin surveillance by a dermatologist. Radiotherapy should be avoided due to the risk of inducing BCCs in the treatment fields.

Gardner syndrome — Gardner syndrome consists of familial adenomatous polyposis (FAP, MIM #175100) with associated extraintestinal manifestations [4]. It is inherited as an autosomal dominant disorder caused by mutations in the tumor suppressor gene, adenomatous polyposis coli (APC). (See "Gardner syndrome".)

The most characteristic skin feature is multiple epidermoid cysts. Other findings include desmoid tumors, lipomas, osteomas (especially of the mandible), supernumerary teeth, gastric polyps, and juvenile nasopharyngeal angiofibromas. Congenital hypertrophy of the retinal pigmented epithelium is a reliable and early marker of the disease when it is present. Prophylactic colectomy is recommended because of the nearly universal development of colorectal cancer in affected patients.

In addition to colorectal adenocarcinoma, patients with FAP are at risk for several extracolonic malignancies, including:

●Duodenal ampullary carcinoma

●Follicular or papillary thyroid cancer

●Childhood hepatoblastoma

●Gastric carcinoma

●Central nervous system (CNS) tumors (mostly medulloblastomas)

Peutz-Jeghers syndrome — Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant condition characterized by distinctive mucocutaneous pigmentations and multiple hamartomatous polyps in the gastrointestinal tract [5]. Most cases are associated with mutations in the tumor suppressor gene STK11 (serine/threonine kinase 11)/LKB1 [6]. (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management".)

The characteristic mucocutaneous pigmentations (lentigines) of PJS are present in more than 95 percent of patients and are caused by pigment-laden macrophages in the dermis. They are typically flat, blue-gray to brown spots 1 to 5 mm in size that look like freckles. However, the onset and location of PJS spots are different from those of freckles.

Lentigines occur most commonly on the lips and perioral region (94 percent), hands (74 percent), buccal mucosa (66 percent), and feet (62 percent) (picture 2) [7]. They also occur on the nose, perianal area, and genitals and are rarely found in the intestines. They usually occur during the first one to two years of life, increase in size and number over the ensuing years, and finally fade after puberty, with the exception of those on the buccal mucosa.

Gastrointestinal hamartomatous polyps are present in most patients with PJS, and patients may develop gastrointestinal malignancy. The risk of nongastrointestinal cancers, including adenocarcinomas of the breast, cervix, pancreas, uterus, and ovaries, is also increased.

Hereditary leiomyomatosis and renal cell cancer — Hereditary leiomyomatosis and renal cell cancer (HLRCC; MIM #150800) is caused by autosomal dominant, heterozygous mutations in the fumarate hydratase gene (FH) [8]. HLRCC presents in early adulthood with multiple cutaneous leiomyomas, most frequently on the trunk and extremities (picture 3A-D). Affected women frequently develop uterine leiomyomas at an early age. HLRCC is associated with an increased risk of early-onset, aggressive renal cancer [9]. (See "Hereditary leiomyomatosis and renal cell cancer (HLRCC)".)

Xeroderma pigmentosum — Xeroderma pigmentosum (XP) is a rare, autosomal recessive disorder caused by mutations in any of eight genes involved in the recognition and repair of ultraviolet radiation (UVR)-induced DNA damage [10]. XP is characterized by increased sensitivity to UVR, early development of pigmentary changes and UVR-induced skin and mucous membrane cancers (beginning in early childhood), and, in some patients, progressive neurodegeneration.

The pathogenesis, clinical manifestations, diagnosis, and management of XP are discussed in detail separately. (See "Xeroderma pigmentosum".)

Epidermolysis bullosa — Patients with particular subtypes of epidermolysis bullosa are at increased risk for cutaneous malignancy. (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features", section on 'Skin cancer'.)

DISORDERS OF KERATINIZATION — Keratins are intermediate filament proteins that form the cytoskeleton in all epithelial cells, including the stratified epithelium of the epidermis [11]. Keratins represent the major proteins produced by the keratinocyte, which is the primary cell type of the epidermis. The maturation of basal epidermal cells to the flattened cells that constitute the superficial stratum corneum is known as keratinization [12].

Over 50 genes that encode keratins have been identified in humans [13]. The phenotype resulting from a particular mutation depends upon the tissue-specific expression pattern of that keratin.

Ichthyoses — The ichthyoses are a diverse group of hereditary skin disorders characterized by the accumulation of "fish-like" scales resulting from abnormal epidermal cell kinetics or differentiation (table 2) [14]. The severity of the individual disorders ranges from asymptomatic to life threatening.

The cornerstone of therapy for all types is aggressive hydration of the skin with emollients. When tolerated, keratolytics also may be used. Severe or extensive involvement may require systemic retinoids.

Referral to a dermatologist is indicated when basic treatment measures, such as emollients, are not working, when there are complications related to the skin condition, or if the diagnosis is not clear. Biopsy is useful for certain types of ichthyoses or disorders of cornification.

The major types of inherited ichthyoses are reviewed separately. Information for patients and families/caregivers is available on the website of the Foundation for Ichthyosis and Related Skin Types.

●(See "Overview and classification of the inherited ichthyoses".)

●(See "Autosomal recessive congenital ichthyoses".)

●(See "X-linked ichthyosis".)

●(See "Keratinopathic ichthyoses".)

●(See "Netherton syndrome".)

●(See "Sjögren-Larsson syndrome".)

Palmoplantar keratodermas — These disorders share the common feature of palmar and plantar hyperkeratosis that manifests as thickening and scaling of the palms and soles. The general underlying defect in the majority of the palmoplantar keratodermas is overproduction of a normal or an abnormal keratin in the palms and soles. The majority of cases are mild to moderate, without systemic problems and with autosomal dominant inheritance.

The keratodermas differ in their mode of inheritance, severity, and extent of involvement and associated features [15,16]. This is illustrated by the following examples of these disorders:

●Howel-Evans syndrome is a rare, autosomal dominant diffuse form with onset between 5 and 15 years of age [17]. It has been associated with the early development of esophageal cancer.

●Vohwinkel syndrome is a rare, autosomal dominant disorder in which patients may have autoamputation of the digits (pseudoainhum) and high-frequency hearing loss.

●Papillon-Lefèvre syndrome is an autosomal recessive condition that presents in the first six months of life. Patients often have severe periodontitis, leading to early dental loss.

The clinical presentation, diagnosis, and management of palmoplantar keratodermas are reviewed in detail elsewhere. (See "Palmoplantar keratoderma".)

Pachyonychia congenita — Pachyonychia congenita (PC) is an autosomal dominant disorder caused by mutations in the genes that encode keratins (KRT6A, KRT6B, KRT6C, KRT16, and KRT17), the type I and II intermediate filament proteins that form a cytoskeletal network in all epithelial cells [18]. Affected patients present with thickened, discolored nails of the fingers and toes (picture 4). These changes are present at birth in approximately 50 percent of the affected children [19]. Palmar and plantar hyperkeratoses and hyperhidrosis, follicular keratoses of the knees and elbows, and oral leukoplakia may develop within the first decade of life. Thickened nails and plantar hyperkeratoses may be extremely painful [20].

The pathogenesis, clinical manifestations, diagnosis, and management of PC are discussed in detail separately. (See "Pachyonychia congenita".)

Darier disease — Darier disease, also known as Darier-White disease or keratosis follicularis (MIM #124200), is an autosomal dominant disorder caused by mutations in the gene encoding the sarco/endoplasmic reticulum Ca(+2)-ATPase [21]. This results in loss of adhesion between epidermal cells and abnormal keratinization. The disorder is a relatively common genodermatosis with a frequency of up to 1 in 36,000 individuals [22].

The disorder typically presents in the second decade of life with hyperkeratotic, yellow-brown, greasy-appearing papules that coalesce into verrucous-like plaques (picture 5A-B) [23,24]. The lesions are often pruritic and frequently become purulent and malodorous, especially if infected. Typical sites of involvement are in a seborrheic distribution: trunk, face, scalp, and groin. Nails may demonstrate red/white vertical stripes, subungual hyperkeratosis, and notching of the distal nail margins (picture 6). Palmar keratosis and pits often are present.

The course of the illness is chronic and persistent, with characteristic worsening in summer months. Darier disease is discussed in detail separately. (See "Darier disease".)

GENETIC BLISTERING DISORDERS — These disorders result from abnormalities in the cohesion of the layers of the epidermis. They result in separation of the layers in response to minimal injury.

Epidermolysis bullosa — Epidermolysis bullosa (EB) constitutes a clinically and genetically heterogeneous group of rare inherited disorders characterized by marked skin and mucosal fragility caused by mutations in skin structural proteins. There are four major types of EB, based upon the ultrastructural level of tissue cleavage in the skin: EB simplex, junctional EB, dystrophic EB, and Kindler EB (table 3) [25,26]. Many subtypes have been identified based upon clinical, pathophysiologic, and molecular criteria (table 4A-D).

The clinical features, diagnosis, and management of EB are discussed in detail separately. (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features" and "Diagnosis of epidermolysis bullosa" and "Overview of the management of epidermolysis bullosa".)

PIGMENTATION DISORDERS — Melanin, a black or brown pigment formed from tyrosine, is responsible for the color of skin and hair [27]. Melanin is synthesized in melanocytes, which are specialized, dendritic secretory cells derived from the neural crest. These cells migrate to the basal layer of the epidermis during embryogenesis. The presence of melanin in the epidermis helps provide protection from ultraviolet radiation.

Disorders include decreased and excessive pigmentation. Diagnosis is based on the clinical features in most cases, although some may be clarified with molecular testing. (See "Congenital and inherited hyperpigmentation disorders".)

Oculocutaneous albinism — Oculocutaneous albinism (OCA) is a group of rare genetic disorders of melanin biosynthesis inherited in an autosomal recessive pattern [28,29]. There are seven types of OCA caused by mutations in different genes (table 5). Although all types share absent or reduced pigmentation of the hair, skin, and eyes, the clinical phenotypes vary along a broad spectrum of disease severity.

The pathogenesis, clinical manifestations, diagnosis, and management of OCA are discussed in detail separately. (See "Oculocutaneous albinism".)

Ocular albinism — Ocular albinism is albinism in which the hypopigmentation is primarily limited to the eyes [30,31]. It is less common than oculocutaneous albinism.

Ocular albinism type 1 (OA1, MIM #300500), also known as Nettleship-Falls ocular albinism, is the most common form of ocular albinism and has X-linked recessive inheritance. It has an estimated prevalence of 1 in 50,000 to 150,000 live births [32,33].

The clinical manifestations of OA1 are variable. In affected males, clinical features may include mild cutaneous hypopigmentation, hypopigmentation of the iris and retina, foveal hypoplasia, prominent choroidal vessels, nystagmus, strabismus, head nodding, photophobia, impaired vision, and abnormal crossing of the optic fibers resulting in deficient stereoscopic vision [31,34,35]. Female carriers may have a patchy distribution of retinal pigmentation resulting from X-inactivation [31,36].

OA1 is diagnosed by careful analysis of the family pedigree for X-linked inheritance and/or molecular analysis of the OA1 gene [36]. The severity of OA1 appears to be related to ethnic background, with individuals from lightly pigmented racial groups more severely affected than those from darkly pigmented groups [37-39]. Life expectancy is normal [30].

OA1 has been associated with late-onset sensorineural deafness. This form (OASD; MIM 300650) is probably a contiguous gene defect that includes the OA1 gene [40,41]. Another form of ocular albinism with sensorineural deafness has been linked to chromosome 11 and has autosomal recessive inheritance; this form is also known as Waardenburg syndrome type 2 (MIM 103470) [42]. (See 'Waardenburg syndrome' below.)

Ocular albinism type 2 (OA2, MIM #300600), also known as Forsius-Eriksson type ocular albinism and Aland Island eye disease, is a rare, X-linked disorder with clinical manifestations that include nystagmus, myopia, astigmatism, foveal hypoplasia, reduced visual acuity, pigmentary changes in the retina, and changes in color vision; the optic nerves are normal [30].

Piebaldism — Piebaldism (piebald trait) is a rare, autosomal dominant disorder in which cell proliferation and migration of neural crest-derived melanoblasts are defective. This leads to an abnormal distribution of melanocytes during embryogenesis and results in patchy areas of depigmentation [43]. The disorder is caused by mutations in the cell-surface receptor tyrosine kinase gene (KIT) [44].

Affected patients have patches of depigmented skin, with hyperpigmented borders occurring principally on the midforehead, neck, anterior trunk, and midextremities (picture 7A-C). Normal pigmentation occurs on the hands, feet, back, shoulders, and hips. A white forelock is a common finding. The depigmentation is stable and permanent. Patients with piebaldism are generally otherwise healthy and have normal life spans.

The pathogenesis, clinical manifestations, diagnosis, and management of piebaldism are discussed in detail separately. (See "Piebaldism".)

Waardenburg syndrome — Waardenburg syndrome is an autosomal dominant inherited pigmentary disorder in which abnormal distribution of melanocytes during embryogenesis results in patchy areas of depigmentation [43,45,46]. Several forms of Waardenburg syndrome are described. All have the clinical features of type 1, which is characterized by a piebald-like distribution of patchy depigmentation of the hair and skin. Other distinctive noncutaneous features include pigmentary abnormalities of the iris (heterochromia irides) and a broad nasal root, secondary to lateral displacement of the inner canthi of the eyes (picture 8). Congenital deafness occurs in one in five patients with Waardenburg syndrome, and, conversely, an estimated 2 to 7 percent of cases of congenital deafness result from the disorder [47,48]. Occasional findings in Waardenburg syndrome type 1 include cleft lip and palate and neural tube defects (eg, spina bifida, myelomeningocele) [49].

Waardenburg syndrome type 1 (MIM #193500) and type 3 (MIM #148820) are caused by mutations in the gene for one of three transcription factors (PAX3), whereas type 2 (MIM #193510) is caused by mutations in the transcription factor MITF [50,51]. Waardenburg syndrome type 4 (MIM #277580) also has features of Hirschsprung disease. This type is a result of biallelic mutation in the genes for the endothelin-B receptor (EDNRB) or its ligand endothelin-B (EDN3) [52,53] or heterozygous mutation in the SOX10 gene [54]. (See "Congenital aganglionic megacolon (Hirschsprung disease)".)

NEUROCUTANEOUS SYNDROMES — Neurocutaneous genetic disorders, also called phacomatoses, may present with a variety of neurologic and cutaneous findings. Examples include neurofibromatosis type 1 (NF1), NF2-related schwannomatosis (NF2), and tuberous sclerosis complex. The phacomatoses may be associated with increased risk of childhood cancer [55].

Neurofibromatosis type 1 — Neurofibromatosis type 1 (NF1), also known as von Recklinghausen's disease, is an autosomal dominant neurocutaneous disorder with nervous system, skeletal, and dermatologic manifestations [56]. It is caused by mutations in the NF1 gene, encoding the protein neurofibromin. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

The characteristic skin findings that contribute to establishing the diagnosis are:

●Six or more café-au-lait macules of greatest diameter >5 mm in prepubertal and >15 mm in postpubertal individuals (picture 9A)

●Two or more neurofibromas of any type or one plexiform neurofibroma (picture 9B)

●Freckling in the axillary or inguinal regions (Crowe sign) (picture 9C)

NF2-related schwannomatosis — NF2-related schwannomatosis (NF2) is characterized by bilateral vestibular schwannomas (acoustic neuromas), meningiomas of the brain, and schwannomas/neurilemmomas of the dorsal roots of the spinal cord. The disorder typically presents in the teens or soon after puberty with unilateral hearing loss. In contrast to NF1, café-au-lait spots in NF2 are typically few, large, and relatively light in color [57]. NF2 is caused by mutations in the gene encoding the intracellular membrane-associated protein neurofibromin-2 (NF-2), a tumor suppressor, which is also known as merlin [58]. (See "NF2-related schwannomatosis (formerly neurofibromatosis type 2)".)

Tuberous sclerosis complex — Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder that's skin findings are often the first clues to its diagnosis [59,60]. TSC is caused by mutations in one of two genes: TSC1, which encodes hamartin, and TSC2, which encodes tuberin. (See "Tuberous sclerosis complex: Clinical features".)

It is estimated that more than 95 percent of patients with TSC have one of the characteristic skin lesions [60]. The most common lesions are:

●Hypopigmented macules, also known as ash-leaf spots, which are usually elliptical in shape (picture 10A). These are often present at birth, although a Wood's lamp examination may be required to visualize them.

●Angiofibromas, previously called adenoma sebaceum, which typically involve the malar regions of the face (picture 10B) and usually become apparent by late childhood or early adolescence.

●Shagreen patches (connective tissue nevi), seen most commonly over the lower trunk.

●A distinctive brown, fibrous plaque on the forehead, which may be the first and most readily recognized feature of TSC to appear on physical examination of affected neonates and infants (picture 11) [60].

Ataxia-telangiectasia — Ataxia-telangiectasia (AT, also known as Louis-Bar syndrome) is an autosomal recessive disorder caused by mutations in the gene designated ATM (AT mutated). The ATM gene, which is expressed in all tissues in the body, is involved in the detection of DNA damage and plays an important role in cell cycle progression. The pathogenesis of AT is thought to be a defect in DNA repair resulting in increased sensitivity to ionizing radiation, immunodeficiency, and progressive cerebellar Purkinje cell death.

Patients with AT suffer from progressive cerebellar ataxia and other neurologic abnormalities, oculocutaneous telangiectasias, and immune deficiency. Associated features are an increased incidence of malignancy, radiation sensitivity, and diabetes mellitus caused by insulin resistance. (See "Ataxia-telangiectasia".)

VASCULAR DISORDERS — Inherited syndromes associated with cutaneous vascular abnormalities include ataxia-telangiectasia (AT) and hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome. These disorders are discussed separately. (See "Ataxia-telangiectasia" and "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)

DISORDERS OF CONNECTIVE TISSUE — Abnormalities of connective tissue are frequently expressed in the skin. Thus, multisystem inherited connective tissue disorders, such as Ehlers-Danlos syndrome, Marfan syndrome, and osteogenesis imperfecta, can be classified as genodermatoses. Pseudoxanthoma elasticum and focal dermal hypoplasia are less common connective tissue disorders with prominent skin abnormalities. These disorders are discussed separately.

●(See "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes".)

●(See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders".)

●(See "Osteogenesis imperfecta: An overview".)

●(See "Pseudoxanthoma elasticum".)

●(See "Focal dermal hypoplasia (Goltz syndrome)".)

X-LINKED DOMINANT DISORDERS — Incontinentia pigmenti (IP), focal dermal hypoplasia, CHILD (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) syndrome (MIM #308050), and chondrodysplasia punctata (Conradi-Hünermann-Happle syndrome, MIM #302960) are examples of X-linked dominant disorders with cutaneous manifestations [61,62].

●(See "Overview and classification of the inherited ichthyoses", section on 'X-linked dominant disorders'.)

●(See "Focal dermal hypoplasia (Goltz syndrome)".)

●(See "Incontinentia pigmenti".)

ECTODERMAL DYSPLASIAS — The ectodermal dysplasias are a large group of inherited disorders that manifest as developmental anomalies in at least two of the structures derived from the embryonic ectoderm, with at least one involving the skin appendages (hair, nails, sweat glands) or teeth (table 6) [63]. The classic ectodermal dysplasias, including hypohidrotic ectodermal dysplasia, hypohidrotic ectodermal dysplasia with immune deficiency, and hidrotic ectodermal dysplasia; tumor protein p63-related disorders; and focal dermal hypoplasias are discussed separately.

●(See "Ectodermal dysplasias".)

●(See "Tumor protein p63 (TP63)-related ectodermal dysplasias".)

●(See "Focal dermal hypoplasia (Goltz syndrome)".)

SUMMARY

●Definition – The genodermatoses are a heterogeneous group of rare inherited single-gene disorders with skin manifestations. Recognition is important for the initiation of appropriate dermatologic therapy and detection of other associated abnormalities, including malignancy. (See 'Introduction' above.)

●Genodermatoses associated with cutaneous neoplasias – Genodermatoses associated with the development of cutaneous and noncutaneous malignancies include basal cell nevus syndrome (picture 1), Gardner syndrome, Peutz-Jeghers syndrome (PJS) (picture 2), and xeroderma pigmentosum (XP) (table 1). (See 'Disorders with malignant potential' above.)

●Disorders of keratinization – Disorders of keratinization include the ichthyosiform dermatoses (table 2 and picture 12A-C), palmoplantar keratodermas, pachyonychia congenita (picture 4), and Darier disease (picture 5A-B). (See 'Disorders of keratinization' above.)

●Blistering disorders – Abnormalities in the cohesion of the layers of the epidermis underlie the congenital blistering disorders (ie, the epidermolysis bullosa syndromes), in which blister formation occurs with little or no trauma (picture 13A-B). (See 'Epidermolysis bullosa' above.)

●Congenital defects of melanin synthesis – These include oculocutaneous albinism, a group of autosomal recessive disorders resulting in hypopigmentation of the hair, skin, and eyes (table 5); piebaldism; and Waardenburg syndrome (picture 8). (See 'Pigmentation disorders' above.)

●Neurocutaneous syndromes – Cutaneous findings are often a key to the diagnosis of the most common neurocutaneous syndromes: neurofibromatosis (picture 9A-C), tuberous sclerosis complex (TSC) (picture 10A-B), and ataxia-telangiectasia (AT). (See 'Neurocutaneous syndromes' above.)

●Connective tissue disorders – Multisystem inherited connective tissue disorders include Ehlers-Danlos syndrome, Marfan syndrome, osteogenesis imperfecta, and pseudoxanthoma elasticum (picture 14A-C). (See 'Disorders of connective tissue' above.)

●X-linked dominant disorders – X-linked disorders with cutaneous manifestations include incontinentia pigmenti (picture 15) and focal dermal hypoplasia (picture 16). (See 'X-linked dominant disorders' above.)

●Ectodermal dysplasias – The ectodermal dysplasias are a large group of inherited disorders that manifest as developmental anomalies in at least two of the structures derived from the embryonic ectoderm, with at least one involving the skin appendages (hair, nails, sweat glands) or teeth (table 6). (See 'Ectodermal dysplasias' above.)