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As genodermatoses: uma visão geral

Autor: Teresa S Wright, MD, FAAD, FAAP
Editores de seção: Helen V Firth, DM, FRCP, FMedSci, Jennifer L Hand, MD
Editor-adjunto: Rosamaria Corona, MD, DSc
Todos os tópicos são atualizados conforme novas evidências se tornam disponíveis e nosso processo de
revisão por pares é concluído.
Revisão da literatura atualizada até: novembro de 2021. | Última atualização deste tópico: 21 de julho de
2020.
INTRODUÇÃO
As genodermatoses são um grande grupo de doenças hereditárias com manifestações

cutâneas. Muitos desses distúrbios são raros. No entanto, o reconhecimento de seus
achados cutâneos é importante não apenas para o início da terapia apropriada, mas
também para a detecção de outras anormalidades associadas, incluindo malignidade,
nessas doenças frequentemente multissistêmicas [ 1-3 ].
Uma visão geral das genodermatoses é apresentada aqui. Os recursos online que
fornecem informações gerais sobre esses distúrbios incluem Orphanet e Herança
Mendeliana Online no Homem (OMIM) .
TRANSTORNOS COM POTENCIAL MALIGNOS
Este grupo de genodermatoses é de particular importância devido à associação de

achados cutâneos com o desenvolvimento de neoplasias, tanto cutâneas como não
cutâneas ( tabela 1) Os exemplos incluem a síndrome do nevo basocelular, a síndrome
de Gardner, a síndrome de Peutz-Jeghers (PJS) e o xeroderma pigmentoso (XP).
Síndrome do nevo basocelular - A síndrome do nevo basocelular (síndrome do

carcinoma basocelular nevóide, síndrome de Gorlin, MIM # 109400) é um distúrbio raro
de herança autossômica dominante que resulta de mutações germinativas do gene
patched humano ( PTCH ). (Consulte "Síndrome do carcinoma de células basais nevóides
(síndrome de Gorlin)" .)
Os pacientes afetados apresentam anomalias de desenvolvimento e tumores pós-natais,

especialmente carcinomas basocelulares múltiplos (CBCs), geralmente por volta dos 35
anos. A maioria tem as seguintes características clínicas:
● Macrocefalia, protuberância frontal e hipertelorismo.
● Costelas bífidas.
● Palmar e corrosão plantar ( Imagem 1)
● Ceratocistos odontogênicos, especialmente na mandíbula, que geralmente se

desenvolvem na adolescência e normalmente são o sinal de apresentação da
doença.
● Meduloblastoma em 3 a 5 por cento; meningioma ocorre raramente. (Consulte

"Epidemiologia, patogênese e características clínicas do carcinoma basocelular" .)
A aparência histológica dos CBCs na síndrome do nevo basocelular não difere daquela
observada em casos esporádicos. O diagnóstico deve ser suspeitado em pacientes que
apresentam múltiplos CBCs, especialmente em idade precoce.
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 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 ichthyosis".)
● (See "Recessive 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 phakomatoses, may present with a variety
of neurologic and cutaneous findings. Examples include the neurofibromatoses and
tuberous sclerosis complex.
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 [55]. 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)
Neurofibromatosis type 2 — Neurofibromatosis type 2 (NF2) is the central form of

neurofibromatosis and 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 [56]. 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 [57]. (See "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 [58,59]. TSC is caused by mutations in one of two genes: TSC1, which encodes
hamartin, and TSC2, which encodes tuberin. (See "Tuberous sclerosis complex: Genetics,
clinical features, and diagnosis".)
It is estimated that more than 95 percent of patients with TSC have one of the
characteristic skin lesions [59]. 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) [59].
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 (PXE) and focal dermal hypoplasia are less common connective tissue disorders
with prominent skin abnormalities.
● (See "Focal dermal hypoplasia (Goltz syndrome)".)

● (See "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes".)
● (See "Overview of the management of Ehlers-Danlos syndromes".)
● (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related
disorders".)
● (See "Management of Marfan syndrome and related disorders".)
● (See "Osteogenesis imperfecta: An overview".)
Pseudoxanthoma elasticum — Pseudoxanthoma elasticum (PXE, also called Grönblad-

Strandberg syndrome, MIM #264800 and #177850) is a genetic disorder of abnormal
elastic tissue (fragmentation of elastic fibers) and calcification. Inherited forms are
autosomal recessive, but sporadic forms have been observed [60]. The underlying defect
is a mutation in the ABCC6 gene on chromosome 16 that encodes an ATP-binding cassette
transporter [61-63].
The onset of the disorder varies from childhood to early adulthood, although the
characteristic skin findings may be subtle in children. The primary organ systems involved
include the skin, eyes, and cardiovascular systems; gastrointestinal bleeding also can
occur [64-66].
Progressive skin lesions develop in 80 percent of individuals before age 20 years. The
characteristic skin findings are 2 to 5 mm yellow to orange papules, which may coalesce
into irregularly shaped plaques surrounded by normal skin. Because such lesions have a
pebbly appearance and are yellow, they are named pseudoxanthomas. The texture of the
skin has been likened to plucked-chicken skin. Lesions occur most commonly in flexural
areas, such as the neck and axillary folds, periumbilical region, and on the inner lower lip (
picture 12A-D). The involved skin may eventually become lax and redundant.
The primary ocular finding is that of angioid streaks, representing tears in Bruch's
membrane, but this finding is seen in other disorders as well ( picture 12E). Macular
degeneration and retinal deformities contribute to loss of central vision. Severe vision loss
occurs in 3 to 8 percent of patients.
Common cardiovascular manifestations include accelerated atherosclerosis, which is

thought to result from calcification of the internal elastic laminae. These changes can
result in myocardial infarction, cerebrovascular disease, and renovascular hypertension at
a young age and result in a shortened life expectancy.
The diagnosis of PXE is based upon the clinical appearance and findings on histologic
examination of lesional skin. Treatment consists of close ophthalmologic management,
monitoring and treatment of any cardiovascular symptoms, and dietary consultation.
Because of the risk of ocular disease, patients should be educated to avoid contact sports
and straining (eg, weight lifting) [66]. They should be referred for genetic counseling.
X-LINKED DOMINANT DISORDERS
Incontinentia pigmenti (IP), focal dermal hypoplasia, congenital hemidysplasia with

ichthyosiform erythroderma and limb defects (CHILD syndrome, MIM #308050), and
chondrodysplasia punctata (Conradi-Hünermann-Happle syndrome, MIM #302960) are
examples of X-linked dominant disorders with cutaneous manifestations [67,68].
● (See "Overview and classification of the inherited ichthyoses", section on 'X-linked

dominant disorders'.)
● (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) [69]. 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-related disorders".)
SUMMARY
● 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 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.)
● Keratins form the cytoskeleton in epithelial cells. Disorders of keratinization include

the ichthyosiform dermatoses ( table 2 and picture 13A-C), palmoplantar
keratodermas, pachyonychia congenita ( picture 4), and Darier disease (
picture 5A-B). (See 'Disorders of keratinization' above.)
● 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 14A-B). (See 'Epidermolysis
bullosa' above.)
● Congenital defects in melanin synthesis lead to pigmentation disorders. 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.)
● 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.)
● Multisystem inherited connective tissue disorders include Ehlers-Danlos syndrome,

Marfan syndrome, osteogenesis imperfecta, and pseudoxanthoma elasticum (
picture 12A-B, 12E). (See 'Disorders of connective tissue' above.)
● X-linked disorders with cutaneous manifestations include incontinentia pigmenti (

picture 15) and focal dermal hypoplasia ( picture 16). (See 'X-linked dominant
disorders' above.)
● 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.)
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Topic 3004 Version 34.0
GRAPHICS
Genodermatoses associated with malignancy
Inheritance/
Key clinical features
pathogenesis
Basal Cell Autosomal Multiple basal cell carcinomas. Other features include
Nevus dominant odontogenic cysts of the jaw, palmoplantar pits, bifid ribs and
Syndrome other skeletal abnormalities. Common CNS abnormalites
Mutation of the
(Nevoid Basal include calcification of the falx cerebri and bridging of the sella
tumor
Cell turcica. Extracutaneous tumors, including medulloblastomas,
suppressor
Carcinoma meningiomas, and ovarian fibrosarcomas, are also associated
gene patched
Syndrome, with the syndrome.
(PTC)
Gorlin
Syndrome)
Gardner Autosomal Triad of familial adenomatous polyposis, benign osteomas, and

Syndrome dominant skin and soft tissue tumors. Multiple epidermoid cysts are the
most characteristic skin finding. Desmoid tumors may also be
Mutation of
seen. Congenital hypertrophy of the retinal pigmented
tumor
epithelium is a reliable and early marker of disease. Colon
suppressor
cancer develops in all affected individuals requiring
gene APC
prophylactic colectomy.
Peutz-Jegher Autosomal Dark periorificial and acral freckling most markedly on the lips;
Syndrome dominant patients develop hamartomatous polyps of GI tract which may
give rise to cancer. Also associated with increased risk of early
Mutation of
adenocarcinomas of the breast, cervix, pancreas, uterus and
tumor
ovaries.
suppressor
gene STK11
Xeroderma Autosomal Increased photosensitivity, development of cutaneous

Pigmentosa recessive malignancies in early childhood. Associated ocular and
neurologic abnormalities.
Defective
excision repair
of UV-induced
DNA damage
Epidermolysis bullosa (EB) syndromes

Dowling Autosomal Presents at birth or in early infancy; bullae occur with mild
Meara EB dominant trauma, but lesions heal without scarring; mild or no mucosal
simplex involvement. Increased risk of basal cell carcinoma during mid-
Mutation of
adulthood.
keratin 5 or
keratin 14 gene
Herlitz Autosomal Onset at birth with widespread bullae and erosions with
junctional recessive nonhealing granulation tissue; absent nails, dysplastic teeth,
EB oral lesions.
Mutations in the
laminin alpha-3, Increased risk of squamous cell carcinoma beginning in
beta-3, or adolescence.
gamma-2 gene
Hallopeau- Autosomal Onset at birth; generalized bullae that heal with extensive
Siemens recessive scarring; repeated episodes may lead to contraction flexures at
recessive the knees and elbows and fusion of the digits; frequent
Mutation in the
dystrophic involvement of the mucous membranes.
collagen type VII
EB
alpha-1 gene Increased risk of malignant melanoma beginning in childhood
and squamous cell carcinoma beginning in adolescence.
Graphic 72060 Version 4.0

Palmar pits associated with nevoid basal cell
carcinoma syndrome
Palmar surface of hand showing 1 to 2 mm, sharply marginated,

depressed, red lesions (ie, palmar pits).
Reproduced with permission from: Fitzpatrick TB, Johnson RA, Wolff K, Suurmond D.
Color Atlas & Synopsis of Clinical Dermatology. Common & Serious Diseases. (4th Ed).
McGraw-Hill, New York 2001. pgs. 268 & 289. Copyright © 2001 McGraw-Hill.

Oral lesions in Peutz-Jeghers syndrome
Photograph shows the characteristic circumoral pigmentation in a

patient with the Peutz-Jeghers syndrome. The pigmentation may not
be obvious as in this patient, and it should always be sought
carefully in young patients presenting with unexplained
gastrointestinal bleeding, particularly if there is a family history of
such bleeding.
Reprinted with permission from Pounder RE, Allison MC, Dhillon AP. A Colour Atlas of
the Digestive System, Wolfe, London 1989 p. 118.

Cutaneous leiomyomatosis
(A) Clustered, pink cutaneous leiomyomatosis nodules on the central and upper back.
(B) Close-up image of nodules in panel A.
Courtesy of Edward W Cowen, MD, MHSc.

Generalized cutaneous leiomyomatosis. Hundreds of painful, small, red papules and nodules on
the leg.

Typical ovoid, pink, banal appearance of a single cutaneous leiomyomatosis lesion.

Pink/red, variably sized and shaped papules and nodules.

The ichthyoses
Inheritance
and Key clinical features
pathogenesis
Icthyosis vulgaris Autosomal Relatively common (1:250 to 1:300). Fine,
dominant white translucent scales predominantly on
extensor surfaces of extremities with sparing
Fillagrin defect
of flexures, palms, soles, and face.
resulting in a
Hyperlinear palms. Often associated with
retention
keratosis pilaris and atopy including eczema.
hyperkeratoses
Onset during childhood. Typically improves
(Normal with age.
epithelial
turnover)
X-linked ichthyosis (steroid X-linked recessive 1:6000 men. Failure to progress in labor in
sulfatase deficiency) mother of affected fetus (placental sulfatase
Steroid sulfatase
deficiency). Large brown "dirty" adherent
deficiency results
scales with relative sparing of flexures,
in cholesterol
palms, soles, and face. Asymptomatic
sulfate
corneal opacities (50 percent of adult males).
accumulation
12 to 15 percent incidence of cryptorchidism
and a retention
and independently increased risk of
hyperkeratoses
testicular cancer. Onset at two to six weeks.
(Normal Gradually worsens with age.
epithelial
turnover)
Lamellar ichthyosis Autosomal 1:300,000 live births. "Collodion baby" at

recessive birth (translucent taut parchment-like
membrane encasing infant, ectropion,
Transglutaminase
eclabium, generalized erythroderma;
deficiency
complications include sepsis, protein loss,
(Increased and electrolyte abnormalities). Children and
epithelial adults develop large brown polygonal scales
turnover) involving entire body surface, with increased
involvement in flexural folds. Palmoplantar
keratoderma, scarring alopecia, nail
dystrophy, and hypohidrosis with heat
intolerance frequently seen. Ectropion is also
almost always present.
Congenital ichthyosiform Autosomal "Collodion baby" at birth (see above).

erythroderma recessive Children and adults develop generalized
erythroderma with fine white scaling.
(Increased
Palmoplantar keratoderma, scarring
epithelial
alopecia, and persistent ectropion may also
turnover)
be seen.
Epidermolytic hichtyosis Autosomal Neonatal period with widespread blistering

(epidermolytic hyperkeratosis dominant and erythema. Later infancy and adulthood
or bullous congenital characterized by generalized hyperkeratosis
50 percent due to
ichthyosiform erythroderma) with dark scales and spiny ridges especially
spontaneous
pronounced flexurally. Denuded areas of
mutations of
skin where scales shed with full thickness
keratins 1 and 10
stratum corneum also seen. Focal bullae due
(Increased to secondary infection may also develop.
epithelial
turnover)
Harlequin ichthyosis Autosomal Massive armor-like plates of scale with deep

recessive fissures encasing fetus. Severe ectropion,
eclabium, deformed or absent ears, nose,
(Increased
fingers, toes. Infants are born stillborn or
epithelial
generally die shortly after birth due to
turnover)
respiratory and feeding compromise due to
constriction.

Pachyonychia congenita
Thickened, discolored nails are present in this patient with

pachyonychia congenita.
Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights

reserved.

Darier disease
Multiple yellow-brown, hyperkeratotic papules are present on the

chest.

reserved.

Darier disease
Multiple hyperpigmented, hyperkeratotic papules are on the chest.

reserved.

Darier disease
Distal notching and linear, red and white bands are present on the
nails.

reserved.

Epidermolysis bullosa
EB type Pathogenesis Key clinical features

EB simplex (most Autosomal dominant; most due to Typically presents at birth or early
common) mutations in genes for keratins 5 and infancy. Bullae with mild trauma, heal
14 expressed on epithelial cell without scarring. Most forms with
cytoskeleton mild or no mucosal involvement.
Chronic course but blistering tends to
Intraepidermal separation
decrease with age, usually normal
lifespan.
Junctional EB Autosomal recessive; mutation in More severe variant characterized by

genes encoding hemidesmosomal widespread bullae and erosions with
proteins such as laminin 5 resulting in nonhealing granulation tissue;
defective cell adhesion associated with absent nails,
dysplastic teeth, oral lesions, and
Intra-lamina lucida separation
pyloric stenosis. Death usually occurs
in early childhood due to malnutrition
or infection. Normal life expectancy in
patients with milder variant who
develop bullae, primarily on the
extremities, that may heal with
atrophic scarring.
Dystrophic EB Autosomal recessive and autosomal Onset at birth; generalized bullae,

dominant; type VII collagen mutation heal with extensive scarring, milia.
leading to defective anchoring fibrils Repeated episodes of severe
blistering and scarring lead to
Sub-basal lamina separation contraction flexures at knees and
elbows and fusion of digits ("mitten
deformities") of hands and feet. Oral,
GI, and ocular mucous membrane
involvement is also frequently seen
and can be severe. Risk of developing
squamous cell cancer within scars.
Patients often die in early adulthood
from complications such as infection
or severe malnutrition. Milder
phenotype seen with autosomal
dominant forms.
Kindler EB Autosomal recessive Blisters induced by mild trauma,

progressive poikiloderma, and skin
Separation at the level of the basal atrophy (particularly of the dorsal
keratinocytes, within the lamina hands and feet). Photosensitivity may
lucida, or sub-basal lamina separation or may not be present. Additional
features may include desquamative
gingivitis and strictures of the
esophagus, anus, vagina, and urethra.
Blistering and photosensitivity may
decrease with age.
EB: epidermolysis bullosa.

Genotypic and phenotypic variants of epidermolysis bullosa simplex
(epidermolytic)
Site of Inheritance
cleavage Mutated gene
Subtypes Clinical features
within the Targeted gene
epidermis product
Suprabasal Acantholytic EBS Autosomal Five cases of lethal acantholytic

(EBS-acanth) recessive epidermolysis bullosa due to
(cytolysis of
DSP, JUP mutations in DSP and one due
suprabasal
Desmoplakin to JUP have been described [1-5]
keratinocytes;
intact blisters (absent), Generalized skin fragility with
usually not plakoglobin rapidly progressive
clinically evident; (absent) epidermolysis and large sheets
keratinocytes of detached skin with superficial
form numerous erosions at birth; skin
interdigitating detachment on hands and feet
cellular in a glove and stocking pattern;
protrusions; only complete disruption of the
few desmosomal epidermal barrier without intact
remnants blisters or vesicles; no excessive
present) granulation tissue
Universal alopecia (complete
absence of scalp hair, eyebrows,
eyelashes despite discrete
follicular openings on scalp),
nail loss, and neonatal teeth
Involvement of oropharynx,
gastrointestinal, genitourinary,
and respiratory tract with
extensive suprabasal
acantholytic separation
Demise in neonatal period [1]
Skin fragility Autosomal Generalized skin fragility with

syndromes recessive trauma-induced and
Desmoplakin DSP, JUP, PKP1 spontaneous superficial
deficiency Desmoplakin erosions from birth;
(EBS- (reduced), palmoplantar keratoderma with
desmoplakin; plakoglobin painful, often disabling fissures
skin fragility- (reduced), (walking, bearing weight); nail
woolly hair plakophilin-1 dystrophy; alopecia
syndrome) (absent or Chronic cheilitis, perioral scale,
Plakoglobin reduced) perioral and lingual fissures
deficiency Blepharitis, astigmatism
(EBS- Persistent abnormal hair
plakoglobin; (hypotrichosis, loss of
skin fragility- eyelashes, complete alopecia;
plakoglobin woolly hair)
deficiency) Esophageal strictures,
Plakophilin constipation
deficiency Growth retardation (usually
(EBS- below the third centile for
plakophilin; height and weight)
skin fragility-
Variable clinical features include
ectodermal
scattered scale-crust on the
dysplasia
trunk and limbs, follicular
syndrome)
hyperkeratosis, inflammatory
scaly plaques in flexures,
perianal erythema and erosions,
pruritus; reduced sweating;
dental caries; recurrent
systemic infections; chronic
diarrhea
EBS superficialis Unknown Blistering between stratum

corneum and granulosum
Superficial erosions with
scarring and milia formation
from birth or early infancy [6]
Acral peeling skin Autosomal Superficial painless skin peeling

syndrome [7] recessive (volar and dorsal aspects of
TGM5 hands, feet; elbows, knees)
Transglutaminase- Acral blisters, erosions at
5 birth/since infancy; pruritus
aggravated by heat, sweating,
humidity, mechanical trauma,
exposure to water
Spontaneous healing with
residual erythema, burning
sensation, pruritus, and
hyperpigmentation
No scarring or atrophy
Basal EBS, localized Autosomal Most common EBS subtype

(EBS-loc, former
(cytolysis of Weber-Cockayne) dominant Mainly limited, regional
basal KRT5, KRT14 involvement of palms and soles
keratinocytes) Keratin 5, keratin Clinical onset usually during
14 infancy or, rarely, early
adulthood
Extracutaneous manifestations
(other than clinically
insignificant blisters within oral
cavity during early childhood)
rare [8]
EBS, generalized Autosomal Generalized, peculiar

severe (former dominant herpetiform distribution
Dowling-Meara) KRT5, KRT14 (arcuate grouping) of blisters
Keratin 5, keratin from birth (typically and best
14 seen when patients have
relatively milder disease
activity [9] )
Atrophic scarring, milia
formation, confluent
palmoplantar hyperkeratosis,
nail manifestations
Often mucosal involvement
EBS, generalized Autosomal Widespread but less severe

intermediate dominant form that usually presents at
(includes former KRT5, KRT14, birth
Koebner) EXPH5, DYS, Rarely eye involvement
KLHL24
Keratin 5, keratin
14, exophilin 5,
dystonin, Kelch-
like family
member 24
EBS-MP (EBS with Autosomal Skin blistering with reticulate

mottled dominant brown skin pigmentation,
pigmentation) KRT5 keratoderma, nail dystrophy
Keratin 5 Pigmentary lesions usually
present in early childhood, but
may become less distinctive or
even imperceptible by adult
life [9]
EBS, migratory Autosomal Blistering lesions on hands,

circinate dominant legs, and feet from birth
KRT5 Annular migratory erythema
Keratin 5 with vesicles and crusts at the
advancing edge
Brown postinflammatory
hyperpigmentation
Improves in the first few years
of life
EBS with Autosomal Generalized blistering from

muscular recessive birth
dystrophy PLEC1 Atrophic scarring, milia
Plectin formation, nail dystrophy and
loss
Granulation tissue formation
and stenosis within respiratory
tract
Muscular dystrophy may either
be present on or shortly after
birth in a child with severe
generalized skin involvement
(usually appearing as "floppy"
babies who are unable to easily
lift their arms and legs), or, in
others, may arise insidiously in
later childhood or adulthood;
this variant harbors a higher
mortality rate from muscle
involvement [8]
EBS with pyloric Autosomal Gestational hydramnion

atresia recessive Generalized blistering of
PLEC1, ITGA6, variable severity from birth,
ITGB4 atrophic scarring [10-12]
Plectin, integrin- Association with aplasia cutis
alpha-6, integrin- congenita [13]
beta-4 Mucosal involvement (protein
losing enteropathy, diarrhea)
Enamel hypoplasia, caries
Anemia, growth retardation,
contractures, cryptorchidism,
high mortality
EBS, autosomal Autosomal Generalized blistering from

recessive K14 recessive birth (frequently anogenital),
KRT14 [14] ichthyosiform plaques; rarely
Keratin 14 milia formation or atrophic
scarring
Involvement of oral cavity
(caries) and genitourinary tract
Growth retardation,
constipation
EBS, Ogna type Autosomal Hemorrhagic blisters at

dominant predominantly acral sites from
PLEC1 birth
Plectin Onychogryphosis (markedly
curved and deformed nails
resembling ram's horns) [9]
EBS, autosomal Autosomal First described in three siblings

recessive- recessive born to first cousin parents [15]
exophilin 5 EXPH5 Disrupted keratinocyte
deficiency Exophilin-5 adhesion within the lower
(Rab27B GTPase epidermis with prominent skin
effector protein fragility at birth
Slac2-b) Generalized trauma-induced,
occasionally spontaneous scale,
partly hemorrhagic crusts and
intermittent skin
blistering/erosions; bruising
Healing with slightly atrophic
scars and mild pigmentary
mottling
No involvement of mucous
membranes, nails, and hair
Symptomatic improvement
within the first years of life with
occasional small blisters,
erosions, linear crusts at sites of
mechanical trauma as the main
feature
EBS, autosomal Autosomal Only one reported case [14]

recessive-BP230 recessive Generalized, lifelong but
deficiency DST/BPAG1-e relatively mild trauma-induced
Dystonin/coiled and spontaneous blistering
coil domain of (ankles, feet)
epithelial isoform Skin peeling; erosions,
of bullous hemorrhage
pemphigoid Nail dystrophy; normal hair
antigen-1 (BPAG1- growth
e) Healing with postinflammatory
hypo- and hyperpigmentation
No scarring, milia formation, or
mucosal blistering
Episodes of collapse; recurrent
bilateral headaches, transient
episodes of arm numbness and
weakness reported in index
patient may represent
manifestation of concomitant
neurologic diagnosis of
CADASIL syndrome
Recessive EBS Autosomal Twenty-six cases in three

due to stabilizing recessive reports from China, Israel, and
mutations in the KLHL-24 the United Kingdom
ubiquitin ligase Kelch-like family Quite marked birth traumas,
enzyme that member 24 especially the lower limbs
processes Early involvement of trunk and
KRT14 [16-18] arms
Heal with subtle atrophic
scarring
Nail defects
Oral ulceration
Not much dyspigmentation
Transient milia
Alopecia ±
EBS: epidermolysis bullosa simplex; CADASIL: cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy.
References:
1. Jonkman MF, Pasmooij AM, Pasmans SG, et al. Loss of desmoplakin tail causes lethal acantholytic Epidermolysis
bullosa. Am J HumGenet 2005; 77:653.
2. Hobbs RP, Han SY, van der Zwaag PA, et al. Insights from a desmoplakin mutation identified in lethal acantholytic
epidermolysis bullosa. J Invest Dermatol 2010; 130:2680.
3. Kim SJ, Ko JM, Shin SH, et al. Korean Monozygotic Twins with Lethal Acantholytic Epidermolysis Bullosa Caused by
Two Novel DSP Mutations. Ann Clin Lab Sci 2017; 47:213.
4. Bolling MC, Veenstra MJ, Jonkman MF, et al. Lethal acantholytic epidermolysis bullosa due to a novel homozygous
deletion in DSP: Expanding the phenotype and implications for desmoplakin function in skin and heart. Br J
Dermatol 2010; 162:1388.
5. Pigors M, Kiritsi D, Krümpelmann S, et al. Lack of plakoglobin leads to lethal congenital epidermolysis bullosa: a
novel clinico-genetic entity. Hum Mol Genet 2011; 20:1811.
6. Fine JD, Johnson L, Wright T. Epidermolysis bullosa simplex superficialis. A new variant of epidermolysis bullosa
characterized by subcorneal skin cleavage mimicking peeling skin syndrome. Arch Dermatol 1989; 125:633.
7. Kiritsi D, Cosgarea I, Franzke CW, et al. Acral peeling skin syndrome with TGM5 gene mutations may resemble
epidermolysis bullosa simplex in young individuals. J Invest Dermatol 2010; 130:1741.
8. Lanschuetzer CM, Fine JD. Classification and molecular basis of hereditary epidermolysis. In: Life with Epidermolysis
Bullosa (EB): Etiology, diagnosis, multidisciplinary care and therapy, Fine JD, Hintner H (Eds), Springer, Vienna, New
York 2008. p.6.
9. Fine JD. General cutaneous manifestations. In: Life with Epidermolysis Bullosa (EB): Etiology, diagnosis,
multidisciplinary care and therapy, Fine JD, Hintner H (Eds), Springer, Vienna, New York 2008. p.99.
10. Mellerio JE, Pulkkinen L, McMillan JR, et al. Pyloric atresia-junctional epidermolysis bullosa syndrome: Mutations in
the integrin beta4 gene (ITGB4) in two unrelated patients with mild disease. Br J Dermatol 1998; 139:862.
11. Nakano A, Pulkkinen L, Murrell D, et al. Epidermolysis bullosa with congenital pyloric atresia: novel mutations in the
beta 4 integrin gene (ITGB4) and genotype/phenotype correlations. Pediatr Res 2001; 49:618.
12. Pulkkinen L, Kim DU, Uitto J. Epidermolysis bullosa with pyloric atresia: Novel mutations in the beta4 integrin gene
(ITGB4). Am J Pathol 1998; 152:157.
13. Maman E, Maor E, Kachko L, Carmi R. Epidermolysis bullosa, pyloric atresia, aplasia cutis congenita:
Histopathological delineation of an autosomal recessive disease. Am J Med Genet 1998; 78:127.
14. Groves RW, Liu L, Dopping-Hepenstal PJ, et al. A homozygous nonsense mutation within the dystonin gene coding
for the coiled-coil domain of the epithelial isoform of BPAG1 underlies a new subtype of autosomal recessive
epidermolysis bullosa simplex. J Invest Dermatol 2010; 130:1551.
15. McGrath JA, Stone KL, Begum R, et al. Germline Mutation in EXPH5 Implicates the Rab27B Effector Protein Slac2-b in
Inherited Skin Fragility. Am J Hum Genet 2012; 91:1115.
16. He Y, Maier K, Leppert J, et al. Monoallelic mutations in the translation initiation codon of KLHL24 cause skin
fragility. Am J Hum Genet 2016; 99:1395.
17. Lin Z, Li S, Feng C, et al. Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin
fragility. Nat Genet 2016; 48:1508.
18. Lee JYW, Liu L, Hsu CK, et al. Mutations in KLHL24 Add to the Molecular Heterogeneity of Epidermolysis Bullosa
Simplex. J Invest Dermatol 2017; 137:1378.

Genotypic and phenotypic variants of junctional epidermolysis bullosa
(lucidolytic)
Inheritance
Mutated
gene
Subtype Clinical features
Targeted
gene
product
JEB, generalized Autosomal Varying degrees of mechanical fragility at birth with

severe recessive generalized, recurrent, often persistent blistering, erosions,
(formerly Herlitz) and crusting covering not only particularly exposed skin
LAMA3, LAMB3,
areas (like palms and soles) but most or almost all of the
LAMC2
body surface
Laminin-
Periungual inflammation, onychodystrophy, and nail loss
alpha-3 chain
Exuberant granulation tissue, often periorificial
of laminin-332
Involvement of oral cavity (blisters, erosions); teeth (enamel
Laminin-beta- hypoplasia, excessive caries); gastrointestinal (protein-
3 chain of losing enteropathy, diarrhea), respiratory, and genitourinary
laminin-332 tract; conjunctivae
Laminin-
Anemia, growth retardation, high lethality (survival past one
gamma-2
year of age uncommon)
chain of
laminin-332
JEB, generalized Autosomal Generalized blistering from birth, atrophic scarring, milia;
intermediate recessive "male-pattern" alopecia; nail dystrophy and loss
(formerly non- Involvement of oral cavity and teeth (excessive caries, teeth
COL17A1,
Herlitz) loss, enamel hypoplasia); gastrointestinal, respiratory, and
LAMA3, LAMB3,
LAMC2 genitourinary tract; conjunctivae
Anemia, growth retardation, protein losing
Type XVII
enteropathy, diarrhea
collagen
Laminin-
alpha-3 chain
of laminin-332
Laminin-beta-
3 chain of
laminin-332
Laminin-
gamma-2
chain of
laminin-332
JEB, localized Autosomal Localized disease of lesser extent and lesser severity, onset
recessive at birth; milia, nail dystrophy, and loss
COL17A1, Involvement of oral cavity and teeth (excessive caries,

ITGB4, LAMA3, enamel hypoplasia)
LAMB3, LAMC2 Extensive atrophic scarring, hair loss, anemia, impairments
of growth and development, ocular abnormalities or
Type XVII
alterations affecting gastrointestinal, genitourinary,
collagen
and respiratory tract mostly absent [1]
Integrin-beta-
4
Laminin-
alpha-3 chain
of laminin-332
Laminin-beta-
3 chain of
laminin-332
Laminin-
gamma-2
chain of
laminin-332
JEB with pyloric Autosomal Gestational hydramnion

atresia recessive Generalized and profound blistering from birth, occasionally
ITGA6, ITGB4 age-associated amelioration; atrophic scarring; nail
dystrophy and loss
Integrin-
Association with aplasia cutis congenita
alpha-6
Enamel hypoplasia
Integrin-beta-
Pyloric atresia
4
Congenital genitourinary malformations
Sporadically rudimentary ear anlage
JEB, inversa Autosomal Blistering predominantly located in intertriginous

recessive areas/sites, typically displaying an overall extent that
exceeds that observed in patients with JEB, localized [1]
LAMA3, LAMB3,
LAMC2 Atrophic scarring, milia, hypo-/hyperpigmentation,
dystrophic (or absent) nails
Laminin-
Moderate oral mucosal lesions; dental enamel hypoplasia,
alpha-3 chain
caries and gastrointestinal abnormalities to a lesser extent
of laminin-332
as compared with other JEB variants
Laminin-beta-
3 chain of
laminin-332
Laminin-
gamma-2
chain of
laminin-332
JEB, late onset Autosomal Mild form of JEB developing in young adulthood or later
recessive Dystrophic (or absent) nails, dental enamel hypoplasia and
COL17A1 caries to a lesser severity than JEB, generalized intermediate
Hyperhidrosis
Type XVII
Absence of dermatoglyphs on fingers, palms, toes, and
collagen
soles
JEB-LOC Autosomal High incidence in Punjab

(laryngo-onycho- recessive Minimal skin blistering, erosions
cutaneous) Extensive aberrant production of granulation tissue with
LAMA3A
syndrome [2-11] delayed healing, atrophic scarring
Laminin-
Involvement of larynx (altered cry) at birth or later, skin
alpha-3a
(face, nuchal) and conjunctiva (granulomatous papules,
chain of
symblepharon) in infancy
laminin-332
Nail dystrophy and loss
Enamel hypoplasia, caries
High childhood mortality due to laryngeal, gastrointestinal,
and urethral strictures
JEB with Autosomal Congenital nephrotic syndrome (small kidneys, atrophic

respiratory and recessive glomeruli, focal segmental glomerulosclerosis, diffuse
renal interstitial fibrosis, tubular atrophy and loss)
ITGA3
involvement Interstitial lung disease (tachypnea, respiratory distress,
(JEB-RR) [10-12] Integrin- cyanosis in first days of life; secondary aspiration with
alpha-3 respiratory tract infections)
Mild skin fragility (small blisters and erosions beginning at
age of two to four months
Fine and sparse scalp hair, eyebrows, eyelashes
Nail dystrophy, distal onycholysis
Delayed reepithelialization; healing with residual erythema
No scarring; no mucosal involvement
JEB: junctional epidermolysis bullosa.
References:
1. Fine JD, Eady RA, Bauer EA, et al. The classification of inherited epidermolysis bullosa (EB): Report of the Third
International Consensus Meeting on Diagnosis and Classification of EB. J Am Acad Dermatol 2008; 58:931.
2. Shabbir G, Hassan M, Kazmi A. Laryngo-onycho-cutaneous syndrome: A study of 22 cases. Biomedica 1986; 2:15.
3. Ainsworth JR, Spencer AF, Dudgeon J, et al. Laryngeal and ocular granulation tissue formation in two Punjabi
children: LOGIC syndrome. Eye (Lond) 1991; 5:717.
4. Ainsworth JR, Shabbir G, Spencer AF, Cockburn F. Multisystem disorder of Punjabi children exhibiting spontaneous
dermal and submucosal granulation tissue formation: LOGIC syndrome. Clin Dysmorphol 1992; 1:3.
5. Phillips RJ, Atherton DJ, Gibbs ML, et al. Laryngo-onycho-cutaneous syndrome: An inherited epithelial defect. Arch
Dis Child 1994; 70:319.
6. Murrell DF, Hamil K, Pfendner E, et al. Is Laryngo-Onycho-Cutaneous Syndrome a form of junctional epidermolysis
bullosa? Oral paper. Australasian College of Dermatologists' Spring Meeting, Cairns, Australia, September 2005.
7. Figueira EC, Crotty A, Challinor CJ, et al. Granulation tissue in the eyelid margin and conjunctiva in junctional
epidermolysis bullosa with features of laryngo-onycho-cutaneous syndrome. Clin Exp Ophthalmol 2007; 25:163.
8. Hamil K, Uitto J, Figueira EC, et al. Novel N-terminal mutation in LAMA3a isoform causing late-onset Herlitz
junctional epidermolysis bullosa with features of laryngo-onycho-cutaneous syndrome. Poster. Society for
Investigative Dermatology, Los Angeles, CA, May 2007.
9. Cohn HI, Murrell DF. Laryngo-onycho-cutaneous syndrome. Dermatol Clin 2010; 28:89.
10. Nicolaou N, Margadant C, Lilen MR, et al. Gain of glycosylation in integrin α3 causes lung disease and nephrotic
syndrome. J Clin Invest 2012; 122:4375.
11. Yalcin EG, He Y, Orhan D, et al. Crucial role of posttranslational modifications of integrin α3 in interstitial lung
disease and nephrotic syndrome. Hum Mol Genet 2015; 24:3679.
12. Has C, Spartà G, Kiritsi D, et al. Integrin α3 mutations with kidney, lung, and skin disease. N Engl J Med 2012;
366:1508.

Genotypic and phenotypic variants of dystrophic epidermolysis bullosa [1-3]
Inheritance
Mutated
gene
Subtype Clinical features
Targeted
gene
product
Dominant DEB
Dominant DEB, Autosomal Generalized blistering from birth, atrophic scarring,

generalized dominant dystrophic (or absent) nails; alopecia
COL7A1 "Albopapuloid" lesions (small, grouped, hypopigmented

papules usually on the lower back)
Type VII
Involvement of oral cavity, gastrointestinal and, rarely,
collagen
genitourinary tract
Dominant DEB, Autosomal Predilection of blistering for hands and feet from early
acral dominant, infancy, milia, atrophic scarring, dystrophic (or absent)
autosomal nails
recessive
COL7A1
Type VII
collagen
Dominant DEB, Autosomal Pretibial blistering from birth or early infancy,

pretibial dominant, involvement of hands and feet, milia, atrophic scarring;
autosomal dystrophic nails
recessive Lichen planus-like skin lesions
COL7A1
Type VII
collagen
Dominant DEB, Autosomal Generalized or localized erosions, blisters, milia, and

pruriginosa dominant, atrophic scars from infancy or later; dystrophic nails
autosomal Pronounced pruritus
recessive
COL7A1
Type VII
collagen
Dominant DEB, Autosomal Nail dystrophy or loss at birth or infancy without skin
nails only dominant involvement
COL7A1
Type VII
collagen
Dominant DEB, Autosomal Generalized blistering from birth or early infancy that
bullous dominant, improves dramatically over time
dermolysis of autosomal Milia, atrophic scarring; dystrophic nails
the newborn recessive
COL7A1
Type VII
collagen
Recessive DEB
Recessive DEB, Autosomal Generalized blistering from birth, atrophic scarring,

generalized recessive milia; sparse hair with scarring alopecia; dystrophic or
severe (formerly absent nails
COL7A1
recessive DEB- Acral pseudosyndactyly and contractures
Hallopeau- Type VII
Involvement of oral cavity (blisters, erosions, scarring,
Siemens) collagen
excessive caries, smooth tongue without papillae),
gastrointestinal (protein losing enteropathy) and
genitourinary tract (glomerulonephritis, IgA
nephropathy, chronic renal failure), conjunctivae
Tremendous risk for development of squamous cell
carcinomas
Cardiomyopathy, osteoporosis, anemia, impaired
growth, delayed puberty
Shortened life expectancy
Recessive DEB, Autosomal Generalized blistering at birth, continue to develop

generalized recessive throughout life; atrophic scarring, milia; nail dystrophy;
intermediate scarring alopecia
COL7A1
Pseudosyndactyly
Type VII
Increased risk for development of squamous cell
collagen
carcinomas
Involvement of oral cavity, gastrointestinal and
genitourinary tract, conjunctivae
Anemia, growth retardation
Recessive DEB, Autosomal Blistering predominantly located in intertriginous
inversa recessive lumbosacral, acral, and axial areas; milia, atrophic
scarring; nail dystrophy;
COL7A1
Involvement of oral cavity (caries), gastrointestinal and
Type VII
genitourinary tract
collagen
Stenosis of meatus acusticus externus
Anemia, growth retardation
Recessive DEB, Autosomal Pretibial blistering at birth or early infancy, involvement

pretibial recessive of hands and feet; milia; atrophic scarring; nail dystrophy
COL7A1 Lichen planus-like skin lesions
Type VII
collagen
Recessive DEB, Autosomal Blistering on hands and feet from early infancy, milia,
localized recessive atrophic scarring; nail dystrophy
COL7A1
Type VII
collagen
Recessive DEB, Autosomal Generalized or localized erosions, blisters, milia, and

pruriginosa recessive atrophic scars from infancy; dystrophic nails
COL7A1 Excessive pruritus
Type VII
collagen
Recessive DEB, Autosomal Pretibial and acral blistering at birth or from early
centripetalis recessive infancy, milia, atrophic scarring; nail dystrophy
COL7A1 Involvement of oral mucosa
Type VII
collagen
Recessive DEB, Autosomal Generalized blistering from birth or early infancy that
bullous recessive improves dramatically over time
dermolysis of Milia, atrophic scarring; dystrophic nails
COL7A1
the newborn
Type VII
collagen
DEB: dystrophic epidermolysis bullosa; IgA: immunoglobulin A.

References:
1. Dang N, Murrell DF. Mutation analysis and characterization of COL7A1 mutations with dystrophic epidermolysis
bullosa. Exp Dermatol 2008; 17:553.
2. Kim J, Loh CH, Murrell DF. Epidermolysis bullosa pruriginosa triggered by scabies infestation. J Dermatol 2013;
40:562.
3. Fine JD, Bruckner-Tuderman L, Eady RA. Inherited epidermolysis bullosa: updated recommendations on diagnosis
and classification. J Am Acad Dermatol 2014; 70:1103.

Genotypic and phenotypic characteristics of Kindler epidermolysis bullosa
Inheritance
Mutated gene
Site of cleavage Clinical features
Targeted gene
product
Intraepidermal, Autosomal Generalized blistering at birth, atrophic scarring,

junctional, or recessive skin fragility diminishes with advancing age;
sublamina densa poikiloderma
FERMT1 (KIND1)
Photosensitivity
Fermitin family
Pseudosyndactyly
homologue 1
Gingival hyperplasia, oral leukokeratosis, colitis,
(kindlin-1)
esophagitis
Involvement of genitourinary tract (genital
leukokeratosis)
Conjunctivitis, ectropium
Mental retardation
Bone malformations (mandibular abnormalities)
Increased risk of cutaneous squamous cell
carcinoma after age 30 years

Genetic classification of oculocutaneous albinism
Type of
MIM # Gene Locus Encoding function Comments
albinism
OCA1* 606933 TYR 11q14- Tyrosinase, which OCA1A: No

11q21 catalyzes several steps melanin
OCA1A 203100
in melanogenesis OCA1B: Varying
OCA1B 606952
amounts of
melanin are
present
OCA2 203200 OCA2 15q11.2- Melanosomal Common in sub-

(previously 15q12 membrane protein Saharan Africa due
called P to 2.7 kb deletion
gene) Includes brown
and rufous OCA
OCA3 203290 TYRP1 9p23 Stabilizes tyrosinase Previously called

and regulates red or rufous OCA
eumelanin production Common in Africa
OCA4 696574 SLC45A2 5p13.2 Membrane transport Minimal to near

(previously protein normal melanin
called Phenotype similar
MATP and to OCA2
AIM1) Common in Japan
OCA5 615312 Unknown 4q24 Unknown Described in a

Pakistani family
OCA6 609802 SLC24A5 15q21.1 Melanosome Described in a

maturation Chinese family
OCA7 615179 C10orf11 10q22.2- Melanocyte Described in

10q22.3 differentiation families on the
Faroe Islands
OCA8 Not DCT/TYRP2 13q32.1 Enzyme catalyst in Described in a

available melanogenesis French girl and a
North African
woman
OCA: oculocutaneous albinism.

* OCA1 includes previously described temperature-sensitive OCA, minimal pigment OCA, and
yellow OCA.
Original figure modified for this publication. From: Summers CG. Albinism. In: Taylor and Hoyt's Pediatric Ophthalmology
and Strabismus, 5th ed, Lambert SR, Lyons CJ (Eds), Elsevier, Atlanta 2017. Table used with the permission of Elsevier Inc.
All rights reserved.

Piebaldism
Patchy areas of depigmentation in a child with piebaldism.

reserved.

Piebaldism
A congenital depigmented patch with white hair is present on the

scalp and forehead of this man with piebaldism. The patient also
had depigmented patches on the trunk and extremities. Multiple
family members had similar lesions.
Copyright © Bernard Cohen, MD, Dermatlas; http://www.dermatlas.org.

Piebaldism
Multiple depigmented patches are present on the trunk and legs in

this patient with piebaldism.

reserved.

Waardenburg syndrome
A white forelock, broad nasal root, and dystopia canthorum in the

parent, and heterochromatic irides in the child affected by
Waardenburg syndrome.
Reproduced with permission from: Nayak CS, Isaacson G. Worldwide distribution of

Waardenburg syndrome. Ann Otol Rhinol Laryngol 2003; 112:817. Copyright © 2003
Annals Publishing Company.

Neurofibromata and café-au-lait macules in a
patient with neurofibromatosis 1 (NF1)
Skin-colored and pink-tan, soft papules and nodules on the back are
neurofibromata. These lesions first appeared during late childhood.
The large, soft, ill-defined, subcutaneous nodule on the right lower
back is a plexiform neuroma. The café-au-lait macules appeared
earlier in childhood. A large one is visible on the middle lower back.
Reproduced with permission from: Fitzpatrick TB, Johnson RA, Wolff K, Suurmond D
(Eds). Color Atlas and Synopsis of Clinical Dermatology, 3 rd ed, McGraw-Hill, New
York. p.461. Copyright © 1997 The McGraw-Hill Companies.

Multiple neurofibromas in an adult patient with
neurofibromatosis type 1
Multiple papules and nodules consistent with neurofibromas are

present on the trunk.

reserved.

Axillary freckling in neurofibromatosis type 1
Multiple hyperpigmented macules are present in the axilla.

reserved.

Tuberous sclerosis complex
Hypomelanotic macule on the torso of a patient with tuberous

sclerosis complex.

Angiofibromas of the face presenting as erythematous papules in a

child with tuberous sclerosis complex.

Typical forehead fibrous plaque in a child with tuberous sclerosis.

Pseudoxanthoma elasticum
This woman with pseudoxanthoma elasticum has numerous yellow

asymptomatic papules on her neck and upper chest.
Copyright © Yahia Albaili, DO, Dermatlas; http://www.dermatlas.org.

Symmetric, confluent, yellow papules and redundant skin folds are

present in this 38-year-old woman. The characteristic plucked
chicken skin changes on the neck of patients with pseudoxanthoma
elasticum are seen. An eye examination showed the characteristic
angioid streaks.
Copyright © Rakhesh SV, MD, Dermatlas; http://www.dermatlas.org.

Yellow papules are present on the inner aspect of the lower lip.
Infiltration of the buccal mucosa of the lip is the most common
mucous membrane involvement in pseudoxanthoma elasticum.
Copyright © Franziska Ringpfeil, MD, Dermatlas; http://www.dermatlas.org.

Numerous confluent, yellow papules are present on the neck of this

patient with pseudoxanthoma elasticum.

reserved.

Angioid streaks
Typical angioid streaks in fundus of patient with pseudoxanthoma

elasticum.
Reproduced with permission from: Gold DH, Weingeist TA. Color Atlas of the Eye in
Systemic Disease. Lippincott Williams & Wilkins, Baltimore 2001. Copyright © 2001
Lippincott Williams & Wilkins.

Classification of ectodermal dysplasias
OMIM,
Ectodermal dysplasia (ED) whenever Inheritance
available
Subgroup hair-teeth-nails-sweat glands (n = 38)

Alopecia-contractures-dwarfism mental retardation 203550 AR
syndrome
Ankyloblepharon-ectodermal defects-cleft lip/palate 106260 AD

syndrome (AEC syndrome; Hay-Wells syndrome); Rapp-
Hodgkin syndrome (129400) included
Anonychia with flexural pigmentation 106750 AD
Acrorenal field defect, ED, and lipoatrophic diabetes 207780 AR

(AREDYLD)
Arthrogryposis and ED 601701 AR
Camarena syndrome [1] – AD?; XD?
Cleft lip/palate-ED syndrome (CLPED1 syndrome; 225060 AR

Zlotogora-Ogur syndrome; Margarita Island syndrome)
Curly hair-acral keratoderma-caries syndrome [2] – AD
Dyskeratosis congenita, AD (dyskeratosis congenita, 127550 AD

Scoggins type)
Dyskeratosis congenita, AR 224230 AR
Dyskeratosis congenita, X-linked (Zinsser-Cole-Engman 305000 XR

syndrome)
Ectrodactyly, ED, and cleft lip/palate syndrome (EEC1 129900 AD

syndrome)
Ectrodactyly, ED, and cleft lip/palate syndrome 3 (EEC3 604292 AD

syndrome)
ED hypohidrotic, with acanthosis nigricans (Lelis 608290 ?

syndrome)
ED-syndactyly syndrome 2 (EDSS2) 613576 AR
ED with natal teeth, Turnpenny type 601345 AD
ED, Caratinga type [3] – AD?; XD?
ED, hypohidrotic, with hypothyroidism and agenesis of 225040 AD?; AR?; XD?
the corpus callosum
Focal dermal hypoplasia (FDH) 305600 XD
Hypohidrotic ED, AD (ADHED) 129490 AD
Hypohidrotic ED, AR (ARHED) 224900 AR
Hypohidrotic ED, X-linked (XLHED; Christ-Siemens- 305100 XR

Touraine [CST] syndrome)
Hypohidrotic ED with immune deficiency 300291 XD
Hypohidrotic ED with immunodeficiency, osteopetrosis, 300301 XD

and lymphedema (OLEDAID syndrome)
Hypomelanosis of Ito (HMI, incontinentia pigmenti type 300337 XD

I [IP1])
Keratitis-ichthyosis-deafness syndrome, AD (KID 148210 AD

syndrome, AD)
Keratitis-ichthyosis-deafness syndrome, AR (KID 242150 AR

syndrome, AR)
Naegeli syndrome (Naegeli-Franceschetti-Jadassohn 161000 AD

syndrome [NFJS])
Odonto-onychodermal dysplasia (OODD); Schöpf- 257980 AR

Schulz-Passarge syndrome (224750) included
Odontotrichomelic syndrome (tetramelic deficiencies, 273400 AR

ED, deformed ears, and other abnormalities)
Pachyonychia congenita, type 1 (PC1) 167200 AD
Pachyonychia congenita, type 2 (PC2) 167210 AD
Papillon-Lefevre syndrome 245000 AR
Rosselli-Gulienetti syndrome 225000 AR
Scalp-ear-nipple syndrome (Finlay-Marks syndrome; ED 181270; 129550 AD

with adrenal cyst)
Tricho-odonto-onychodysplasia with pili torti [1] – AD?; XD?
Tricho-onycho-dental dysplasia (TOD) [4] – AD
Xeroderma-talipes-enamel defects (XTE) [5] – AR
Subgroup hair-teeth-nails (n = 34)

Ackerman syndrome 200970 AR
ADULT syndrome 103285 AD
Arthrogryposis, ED, cleft lip/palate, and developmental 301815 XR

delay
Cardiofaciocutaneous syndrome (CFC syndrome) 115150 AD
Cardiomyopathy, dilated, with woolly hair, and 605676 AR

keratoderma (Carvajal syndrome)
Clouston syndrome (ED, hidrotic, AD) 129500 AD
Coffin-Siris syndrome 135900 AD?; AR?; XD?
Costello syndrome 218040 AR
Cranioectodermal dysplasia (CED1; Sensenbrenner 218330 AR

syndrome); CED2 (613610), CED3 (614099), and CED4
(614378) included
Dermoodontodysplasia 125640 AD
Dolichocephaly, dental defects, trichodysplasia [1] – AD
ED-syndactyly syndrome 1 (EDSS1); ED with pillous 613573 AR

anomaly and syndactyly [6] included
ED, trichoodontoonychial type 129510 AD
Ellis-van Creveld syndrome (EVC) 225500 AR
Growth retardation, alopecia, pseudoanodontia, and 230740 AR

optic atrophy syndrome (GAPO syndrome)
GOMBO syndrome 233270 AR
Hidrotic ED, AR (Fried's tooth and nail syndrome) 602401 AR
Hypotrichosis with pili bifurcate [7] – AR?
Incontinentia pigmenti (IP2) 308300 XD
Oculotrichodysplasia (OTD) 257960 AR
Odonto-onychodysplasia-alopecia [8] – AR
Odontotrichoungual-digital-palmar syndrome 601957 AD?; XD?
Pineal hyperplasia, insulin-resistant diabetes mellitus, 262190 AR

and somatic abnormalities
Rothmund-Thomson syndrome (RTS syndrome) 268400 AR
Schinzel-Giedion midface-retraction syndrome 269150 AR?; AD?
Sener syndrome 606156 ?
Split-hand/foot malformation (SHFM1); SHFM3 183600 AD

(246560), SHFM4 (605289), and SHFM5 (606708)
included
Thumb deformity and alopecia 188150 AD
Trichodentoosseus syndrome (TDO) 190320 AD
Tricho-dermodysplasia-dental defects [9] – AD?; XD?
Trichoodontoonychial dysplasia with bone deficiency 275450 AR?
Trichorhinophalangeal syndrome, type I (TRPS1) 190350 AD
Trichothiodystrophy, photosensitive (TTDP) 601675 AR
Witkop syndrome 189500 AD
Subgroup hair-teeth-sweat glands (n = 8)

Böök syndrome 112300 AD
Cleft lip/palate, ED, acral anomalies [10] – AR
Hypohidrotic ED with focal sweating [11] – AR?; XR?
Ichthyosis follicularis, atrichia, and photophobia 308205 XR

syndrome with or without bresheck syndrome (IFAP
syndrome)
Johnson neuroectodermal syndrome 147770 AD
Lenz-Passarge dysplasia [12] – XD
Leukomelanoderma, infantilism, mental retardation, 246500 AR

hypodontia, hypotrichosis
Ulnar-mammary syndrome (UMS) 181450 AD
Subgroup hair-nails-sweat glands (n = 4)

Alopecia-skin atrophy-anonychia-tongue defects [13] – ?
ED, hypohidrotic, with hypothyroidism and ciliary 225050 AR

dyskinesia (HEDH syndrome)
ED/skin fragility syndrome 604536 AR
Fischer-Volavsek syndrome [14] – AD
Subgroup teeth-nails-sweat glands (n = 2)

Ameloonychohypohidrotic syndrome 104570 AD
Limb-mammary syndrome (LMS) 603543 AD
Subgroup hair-teeth (n = 29)

Barber-Say syndrome 209885 AR?; AD?; XD?
Blepharocheilodontic syndrome 119580 AD

Brachymetapody-anodontia-hypotrichosis-albinoidism 211370 AR
Cataract, hypertrichosis, mental retardation syndrome 211770 AR

(CAHMR syndrome)
Cerebellar ataxia and ED 212835 AR
Cleft lip/palate-oligodontia-syndactyly-hair defects [15] – AD?; XD?
Coloboma, congenital heart disease, ichthyosiform 280000 AR

dermatosis, mental retardation, and ear anomalies
syndrome (CHIME syndrome; Zunich neuroectodermal
syndrome)
Congenital atrichia, palmoplantar hyperkeratosis, – AR?

mental retardation, and early loss of teeth [16]
Dubowitz syndrome 223370 AR
ED and neurosensory deafness 224800 AR
ED, Cape Verde [17] – AR
ED, ectrodactyly, and macular dystrophy syndrome (EEM 225280 AR

syndrome); hypotrichosis, congenital, with juvenile
macular dystrophy (HJMD, 601553) included
Gorlin-Chaudhry-Moss syndrome 233500 AR
Hallermann-Streiff syndrome (HSS) 234100 AR
Hypertrichosis terminalis, generalized, with or without 135400 AD

gingival hyperplasia (gingival fibromatosis with
hypertrichosis)
Hypertrichosis universalis 145700 AD
Johanson-Blizzard syndrome (JBS) 243800 AR
Mental retardation, hypotrichosis, and syndactyly [18] – AR?
Oculodentoosseous dysplasia, AR 257850 AR
Oculodentodigital dysplasia (ODDD) 164200 AD
Orofaciodigital syndrome I (OFD1 syndrome) 311200 XD
Pili torti, early onset 261900 AR
Pilodental dysplasia with refractive errors 262020 AR
Progeroid short stature with pigmented nevi (Mulvihill- 176690 AD

Smith syndrome)
Rodrigues blindness (microphthalmia, microcornea, and 268320 AR

sclerocornea with short stature and hair and dental
abnormalities)
Trichodental dysplasia 601453 AD
Trichodysplasia and amelogenesis imperfect [19] – AD?; XD?
Uncombable hair, retinal pigmentary dystrophy, dental 191482 AD

anomalies, and brachydactyly
Walbaum-Dehaene-Schlemmer syndrome [20] – AR
Subgroup hair-nails (n = 25)

Anonychia-onychodystrophy with hypoplasia or 106995 AD
absence of distal phalanges (Cooks syndrome)
AR neurodegenerative disorder with trichorrhexis – AR?

invaginata and ED [21]
Cartilage-hair hypoplasia (CHH) 250250 AR
Curly hair-ankyloblepharon-nail dysplasia syndrome 214350 AR

(CHANDS)
ED hidrotic, Christianson-Fourie type 601375 AD
ED with skin anomalies and mental retardation [22] – AR
ED, "pure" hair-nail type 602032 AD?
Hair-nail dysplasia [23] – AD
Hairy elbows (hypertrichosis cubiti) 139600 AD
Ichthyosis and male hypogonadism 308200 XR?
Ichthyosis with alopecia, eclabion, ectropion, and 242510 AR

mental retardation
Lymphedema-hypoparathyroidism syndrome 247410 AR?; XR?
Monilethrix 158000 AD
Onychotrichodysplasia and neutropenia 258360 AR
Palmoplantar keratoderma and congenital alopecia, AD 104100 AD

(alopecia congenita with keratosis palmoplantaris)
Pili torti and onychodysplasia [24] – AD
Pili torti, alopecia, and onychodysplasia [25] – AR
Polyposis, skin pigmentation, alopecia, and fingernail 175500 ?

changes
Popliteal pterygium syndrome, lethal type 263650 AR
Short stature, onychodysplasia, facial dysmorphism, – AR

and hypotrichosis syndrome (SOFT syndrome) [26]
Syndrome of accelerated skeletal maturation, failure to – AR?; XR?
thrive, and peculiar face (Marshall syndrome II) [27]
T cell immunodeficiency, congenital alopecia, and nail 601705 AR?

dystrophy
Trichomegaly with mental retardation, dwarfism, and 275400 AR

pigmentary degeneration of retina
Tricho-onychodysplasia-xeroderma [28] – AR
Trichothiodystrophy, nonphotosensitive 1 (TTDN1) 234050 AR
Subgroup hair-sweat glands (n = 4)

Dry skin and extranumerary areolae [29] – AD
Focal facial dermal dysplasia (Brauer syndrome); facial 136500 AD

ED (Setleis syndrome, 227260) included
Short stature-kidney insufficiency-ophthalmological – AR?; XR?

anomaly-growth retardation-ED (SKORED) [30]
Tricho-facio-hypohidrotic syndrome [31] – AR?; XR?
Subgroup teeth-nails (n = 14)
Corneodermatoosseous syndrome (CDO syndrome) 122440 AD
Deafness, congenital, and onychodystrophy, AD 124480 AD
Deafness, onychodystrophy, osteodystrophy, and 220500 AR?; AD?

mental retardation syndrome (DOOR syndrome)
Dermatoosteolysis, Kirghizian type 221810 AR
Haim-Munk syndrome (HMS) 245010 AR
Hearing loss, sensorineural, with enamel hypoplasia 234580 AR

and nail defects (Heimler syndrome)
Khan et al. chondroectodermal dysplasia [32] – AR
Lacrimoauriculodentodigital syndrome (LADD 149730 AD

syndrome)
Odontomicronychial dysplasia 601319 AR
Odonto-ungueal dysplasia [33] – AD
Otopalatodigital syndrome, type I (OPD1 syndrome) 311300 XD
Pycnodysostosis 265800 AR
Weyers acrofacial dysostosis 193530 AD
Williams-Beuren syndrome (WBS) 194050 AD

Subgroup teeth-sweat glands (n = 3)
Hypohidrotic ED with mydriasis, iris atrophy, and mental – AD?
retardation [34]
Kohlschutter-Tonz syndrome (epilepsy, dementia, and 226750 AR?; XR?

amelogenesis imperfecta)
Marshall syndrome I 154780 AD
Subgroup nail-sweat glands (n = 2)

Adermatoglyphia with congenital facial milia and acral 129200 AD
blisters, digital contractures, and nail abnormalities (ED,
absent dermatoglyphic pattern, changes in nails, and
simian crease)
Pachyonychia congenita, AR 260130 AR
NOTE: The bold text highlights information not listed in an earlier article. [35]
AR: autosomal recessive; AD: autosomal dominant; ?: unknown; XD: X-linked dominant; XR: X-linked
recessive; ADULT: acro-dermato-ungual-lacrimal-tooth; GOMBO: growth retardation, ocular
abnormalities, microcephaly, brachydactyly, and oligophrenia.
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Am J Med Genet 2009; 149A:1612.
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10. Richieri-Costa A, Guion-Almeida ML, Freire-Maia N, Pinherio M. Autosomal recessive cleft lip/palate, ectodermal
dysplasia, and minor acral anomalies: Report of a Brazilian family. Am J Med Genet 1992; 44:158.
11. Gorlin RJ. Selected ectodermal dysplasias. In: Recent Advances in Ectodermal Dysplasias, Salinas CF, Optiz JM, Paul
NW (Eds), Alan R Liss, New York 1988. p.123.
12. Lenz W. Medical Genetics, University of Chicago Press, Chicago 1963. p. 214.
13. Sequeiros J, Sack GH. Linear skin atrophy, scarring alopecia, anonychia and tongue lesion: A "new" syndrome? Am J
Med Genet 1985; 21:669.
14. Fischer H. Familiar hereditäres vorkommen von keratoma palmare et plantare, nagelveränderungen,
haaranomalien und verdickung der endglieder der finger und zehen in 5 generationen. (Die beziehungen dieser
veränderungen zur inneren secretion). Dermatol Zeitschr 1921; 32:114.
15. Martínez BR, Monasterio LA, Pinheiro M, Freire-Maia N. Cleft lip/palate-oligodontia-syndactyly-hair alterations, a
new syndrome: Review of the conditions combining ectodermal dysplasia and cleft lip/palate. Am J Med Genet 1987;
27:23.
16. Steijlen PM, Neumann HA, Der-Kinderen DJ, et al. Congenital atrichia, palmoplantar hyperkeratosis, mental
retardation, and early loss of teeth in four siblings: A new syndrome? J Am Acad Dermatol 1994; 30:893.
17. Werninghaus K. Ectodermal dysplasia in Cape Verdian families. Arch Dermatol 1993; 129:515.
18. Lopes VL, Marques-de-Faria AP. Mental retardation, hypotrichosis and syndactyly: A new entity? Genet Couns 1996;
7:47.
19. Angelos G, Jorgenson RJ. Trichodysplasia and amelogenesis imperfecta. Oral Surg Oral Med Oral Pathol 1993; 75:86.
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1971; 28:435.
21. Gyure KA, Kurczynski TW, Gunning W, French BN. Autosomal recessive neurodegenerative disorder with trichorrhexis
invaginata and ectodermal dysplasia. Pediatr Neurol 1992; 8:469.
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23. Pinheiro M, Freire-Maia N. Hair-nail dysplasia – A new pure autosomal dominant ectodermal dysplasia. Clin Genet
1992; 41:296.
24. Beare JM. Congenital pilar defect showing features of pili torti. Br J Dermatol 1952; 64:366.
25. Calzavara-Pinton P, Carlino A, Benetti A, de Panfilis G. Pili torti and onychodysplasia. Report of previously
undescribed hidrotoic ectodermal dysplasia. Dermatology 1991; 182:184.
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syndrome is caused by a POC1A mutation. Am J Hum Genet 2012; 91:337.
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thrive: A newly recognized clinical growth disorder. J Pediatr 1971; 78:95.
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undescribed pure ectodermal dysplasia. Braz J Genet 1985; 8:775.
29. Freire-Maia N, Chautard-Freire-Maia EA. Dry skin extranumerrary areolae. Am J Med Genet 1990; 35:141.
30. Greenstein MA, Poole A, Urbanski M, Saal HM. Ectodermal dysplasia: A new form and consideration of possible
associations. Am J Hum Genet 1985; 37:56.
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nails. Birth Defects Orig Artic Ser 1976; 12:136.
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Med Genet 2012; 55:455.
33. Pinheiro M, Freire-Maia N. Odonto-ungueal dysplasia: An apparently new autosomal dominant ectodermal
dysplasia. Braz J Genet 1996; 19:633.
34. Beyer P, Grosshans E, Vetter JM, et al. Forme inhabituelle de dysplasia ectodermique hypohidrotique avec dês
glandes sudoripares em nombre apparemment normal, mais dysplasiques et dês anomalies morphologiques de la
peau. Pediatrie 1979; 34:341.
35. Visinoni AF, Lisboa-Costa T, Pagnan NA, Chautard-Freire-Maia EA. Ectodermal dysplasias: Clinical and molecular
review. Am J Med Genet A 2009; 149A:1980.
From: Pagnan NA, Visinon ÁF. Update on ectodermal dysplasias clinical classification. Am J Med Genet A 2014;
164A(10):2415-23. https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.a.36616. Copyright © 2014 Wiley Periodicals, Inc.
Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned by Wiley. Further
permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's
permissions department either via email: permissions@wiley.com or use the RightsLink service by clicking on the 'Request
Permission' link accompanying this article on Wiley Online Library (http://onlinelibrary.wiley.com).

Ichthyosis vulgaris
Skin with fine, white, adherent scale is present in this patient with
ichthyosis vulgaris.
Reproduced with permission from: Goodheart HP. Goodheart's Photoguide of

Common Skin Disorders, 2nd Edition, Lippincott Williams & Wilkins, Philadelphia
2003. Copyright © 2003 Lippincott Williams & Wilkins

X-linked ichthyosis
X-linked ichthyosis: legs, infant.
Reproduced with permission from: Stedman's Medical Dictionary. Copyright ©2008

Lippincott Williams & Wilkins.

Lamellar ichthyosis
Large, plate-like, diffuse scaling in a child with lamellar ichthyosis.
Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved.

Epidermolysis bullosa simplex
Bullae are present on the hands of this infant with epidermolysis

bullosa simplex.

reserved.

Epidermolysis bullosa simplex
Multiple erosions and bullae are present on the foot of this child
with epidermolysis bullosa simplex.

reserved.

Incontinentia pigmenti
Multiple erythematous papules, vesicles, and crusts are present in

linear streaks on the leg of this female infant.

reserved.

Focal dermal hypoplasia
Multiple erythematous areas representing dermal hypoplasia are

present. Note the digital abnormalities involving the foot.

reserved.

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As genodermatoses: uma visão geral

As genodermatoses são um grande grupo de doenças hereditárias com manifestações

TRANSTORNOS COM POTENCIAL MALIGNOS

Este grupo de genodermatoses é de particular importância devido à associação de

Síndrome do nevo basocelular - A síndrome do nevo basocelular (síndrome do

Os pacientes afetados apresentam anomalias de desenvolvimento e tumores pós-natais,

● Macrocefalia, protuberância frontal e hipertelorismo.

● Palmar e corrosão plantar ( Imagem 1)

● Ceratocistos odontogênicos, especialmente na mandíbula, que geralmente se

● Meduloblastoma em 3 a 5 por cento; meningioma ocorre raramente. (Consulte

Gardner syndrome — Gardner syndrome consists of familial adenomatous polyposis

● Duodenal ampullary carcinoma

Peutz-Jeghers syndrome — Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant

The characteristic mucocutaneous pigmentations (lentigines) of PJS are present in more

Hereditary leiomyomatosis and renal cell cancer — Hereditary leiomyomatosis and

Xeroderma pigmentosum — Xeroderma pigmentosum (XP) is a rare, autosomal

The pathogenesis, clinical manifestations, diagnosis, and management of XP are

Epidermolysis bullosa — Patients with particular subtypes of epidermolysis bullosa are at

Ichthyoses — The ichthyoses are a diverse group of hereditary skin disorders

Referral to a dermatologist is indicated when basic treatment measures, such as

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

Palmoplantar keratodermas — These disorders share the common feature of palmar

● Howel-Evans syndrome is a rare, autosomal dominant diffuse form with onset

● Vohwinkel syndrome is a rare, autosomal dominant disorder in which patients may

● Papillon-Lefèvre syndrome is an autosomal recessive condition that presents in the

The clinical presentation, diagnosis, and management of palmoplantar keratodermas are

The pathogenesis, clinical manifestations, diagnosis, and management of PC are

Darier disease — Darier disease, also known as Darier-White disease or keratosis

GENETIC BLISTERING DISORDERS

Epidermolysis bullosa — Epidermolysis bullosa (EB) constitutes a clinically and

Disorders include decreased and excessive pigmentation. Diagnosis is based on the

Oculocutaneous albinism — Oculocutaneous albinism (OCA) is a group of rare genetic

The pathogenesis, clinical manifestations, diagnosis, and management of OCA are

Ocular albinism — Ocular albinism is albinism in which the hypopigmentation is primarily

Piebaldism — Piebaldism (piebald trait) is a rare, autosomal dominant disorder in which

Affected patients have patches of depigmented skin, with hyperpigmented borders

The pathogenesis, clinical manifestations, diagnosis, and management of piebaldism are

Waardenburg syndrome — Waardenburg syndrome is an autosomal dominant inherited

Neurofibromatosis type 1 — Neurofibromatosis type 1 (NF1), also known as von

● Two or more neurofibromas of any type or one plexiform neurofibroma (

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

Neurofibromatosis type 2 — Neurofibromatosis type 2 (NF2) is the central form of

Tuberous sclerosis complex — Tuberous sclerosis complex (TSC) is an autosomal

● Angiofibromas, previously called adenoma sebaceum, which typically involve the

Ataxia-telangiectasia — Ataxia-telangiectasia (AT, also known as Louis-Bar syndrome) is

Inherited syndromes associated with cutaneous vascular abnormalities include ataxia-

DISORDERS OF CONNECTIVE TISSUE

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

Pseudoxanthoma elasticum — Pseudoxanthoma elasticum (PXE, also called Grönblad-

Common cardiovascular manifestations include accelerated atherosclerosis, which is

X-LINKED DOMINANT DISORDERS

Incontinentia pigmenti (IP), focal dermal hypoplasia, congenital hemidysplasia with

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

● (See "Ectodermal dysplasias".)

● The genodermatoses are a heterogeneous group of rare inherited single-gene

● Genodermatoses associated with the development of cutaneous and noncutaneous

● Keratins form the cytoskeleton in epithelial cells. Disorders of keratinization include

● Congenital defects in melanin synthesis lead to pigmentation disorders. These

● Multisystem inherited connective tissue disorders include Ehlers-Danlos syndrome,

● X-linked disorders with cutaneous manifestations include incontinentia pigmenti (

Use of UpToDate is subject to the Subscription and License Agreement.

19. Shah S, Boen M, Kenner-Bell B, et al. Pachyonychia congenita in pediatric patients: