The Genodermatoses - An Overview - UpToDate

You might also like

Download as pdf or txt
Download as pdf or txt
You are on page 1of 89

Official reprint from UpToDate®

www.uptodate.com © 2021 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

The genodermatoses: An overview


Author: Teresa S Wright, MD, FAAD, FAAP
Section Editors: Helen V Firth, DM, FRCP, FMedSci, Jennifer L Hand, MD
Deputy Editor: Rosamaria Corona, MD, DSc

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Nov 2021. | This topic last updated: Jul 21, 2020.

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


"Epidemiology, pathogenesis, and clinical features of basal cell carcinoma".)

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

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.)

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

REFERENCES

1. Spitz JL. Genodermatoses: A Full-Color Clinical Guide to Genetic Skin Disorders,


Williams & Wilkins, New York 1996.

2. Sybert VP. Genetic Skin Disorders, Oxford University Press, New York 1997.
3. Reyes MA, Eisen DB. Inherited syndromes. Dermatol Ther 2010; 23:606.

4. Perniciaro C. Gardner's syndrome. Dermatol Clin 1995; 13:51.


5. Griffith CD, Bisset WH. Peutz-Jeghers syndrome. Arch Dis Child 1980; 55:866.

6. Scott RJ, Crooks R, Meldrum CJ, et al. Mutation analysis of the STK11/LKB1 gene
and clinical characteristics of an Australian series of Peutz-Jeghers syndrome
patients. Clin Genet 2002; 62:282.

7. Utsunomiya J, Gocho H, Miyanaga T, et al. Peutz-Jeghers syndrome: its natural


course and management. Johns Hopkins Med J 1975; 136:71.

8. Toro JR, Nickerson ML, Wei MH, et al. Mutations in the fumarate hydratase gene
cause hereditary leiomyomatosis and renal cell cancer in families in North
America. Am J Hum Genet 2003; 73:95.

9. Menko FH, Maher ER, Schmidt LS, et al. Hereditary leiomyomatosis and renal
cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Fam Cancer
2014; 13:637.
10. DiGiovanna JJ, Kraemer KH. Shining a light on xeroderma pigmentosum. J Invest
Dermatol 2012; 132:785.

11. Porter RM, Lane EB. Phenotypes, genotypes and their contribution to
understanding keratin function. Trends Genet 2003; 19:278.

12. Roop D. Defects in the barrier. Science 1995; 267:474.


13. McLean WH, Moore CB. Keratin disorders: from gene to therapy. Hum Mol
Genet 2011; 20:R189.
14. Oji V, Tadini G, Akiyama M, et al. Revised nomenclature and classification of
:
inherited ichthyoses: results of the First Ichthyosis Consensus Conference in
Sorèze 2009. J Am Acad Dermatol 2010; 63:607.

15. Itin PH, Lautenschlager S. Palmoplantar keratoderma and associated


syndromes. Semin Dermatol 1995; 14:152.
16. Lucker GP, Van de Kerkhof PC, Steijlen PM. The hereditary palmoplantar
keratoses: an updated review and classification. Br J Dermatol 1994; 131:1.

17. Hereditary disorders of cornification. In: Hurwitz Clinical Pediatric Dermatology:


A Textbook of Skin Disorders of Childhood and Adolescence, 3rd ed, Paller AS,
Mancini AJ (Eds), W.B. Elsevier Saunders, Philadelphia 2006. p.107.
18. Wilson NJ, O'Toole EA, Milstone LM, et al. The molecular genetic analysis of the
expanding pachyonychia congenita case collection. Br J Dermatol 2014;
171:343.
19. Shah S, Boen M, Kenner-Bell B, et al. Pachyonychia congenita in pediatric
patients: natural history, features, and impact. JAMA Dermatol 2014; 150:146.
20. Eliason MJ, Leachman SA, Feng BJ, et al. A review of the clinical phenotype of
254 patients with genetically confirmed pachyonychia congenita. J Am Acad
Dermatol 2012; 67:680.
21. Sakuntabhai A, Ruiz-Perez V, Carter S, et al. Mutations in ATP2A2, encoding a
Ca2+ pump, cause Darier disease. Nat Genet 1999; 21:271.
22. Ringpfeil F, Raus A, DiGiovanna JJ, et al. Darier disease--novel mutations in
ATP2A2 and genotype-phenotype correlation. Exp Dermatol 2001; 10:19.
23. Burge S. Darier's disease--the clinical features and pathogenesis. Clin Exp
Dermatol 1994; 19:193.

24. Burge SM, Wilkinson JD. Darier-White disease: a review of the clinical features in
163 patients. J Am Acad Dermatol 1992; 27:40.

25. 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.

26. Intong LR, Murrell DF. Inherited epidermolysis bullosa: new diagnostic criteria
and classification. Clin Dermatol 2012; 30:70.

27. Disorders of pigmentation. In: Hurwitz Clinical Pediatric Dermatology: A Textbo


:
ok of Skin Disorders of Childhood and Adolescence, 3rd ed, Paller AS, Mancini
AJ (Eds), W.B. Elsevier Saunders, Philadelphia 2006. p.265.
28. Summers CG. Albinism: classification, clinical characteristics, and recent
findings. Optom Vis Sci 2009; 86:659.
29. Grønskov K, Ek J, Brondum-Nielsen K. Oculocutaneous albinism. Orphanet J
Rare Dis 2007; 2:43.
30. King RA, Hearing VJ, Dreel DJ, Oetting WS. Albinism. In: Metabolic and Molecular
Bases of Inherited Disease, 8th ed, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds),
McGraw-Hill, New York 2001. p.5587.
31. Spritz RA. Molecular genetics of oculocutaneous albinism. Hum Mol Genet
1994; 3 Spec No:1469.
32. Rosenberg T, Schwartz M. X-linked ocular albinism: prevalence and mutations--
a national study. Eur J Hum Genet 1998; 6:570.

33. van Dorp DB. Albinism, or the NOACH syndrome (the book of Enoch c.v. 1-20).
Clin Genet 1987; 31:228.

34. Albinism, ocular, type I;OA1. In: Online Mendelian Inheritance in Man. Johns Ho
pkins University. www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300500 (Access
ed on November 02, 2006).
35. Shen B, Samaraweera P, Rosenberg B, Orlow SJ. Ocular albinism type 1: more
than meets the eye. Pigment Cell Res 2001; 14:243.

36. Oetting WS. New insights into ocular albinism type 1 (OA1): Mutations and
polymorphisms of the OA1 gene. Hum Mutat 2002; 19:85.

37. O'Donnell FE Jr, Green WR, Fleischman JA, Hambrick GW. X-linked ocular
albinism in Blacks. Ocular albinism cum pigmento. Arch Ophthalmol 1978;
96:1189.

38. Shiono T, Tsunoda M, Chida Y, et al. X linked ocular albinism in Japanese


patients. Br J Ophthalmol 1995; 79:139.

39. Lyle WM, Sangster JO, Williams TD. Albinism: an update and review of the
literature. J Am Optom Assoc 1997; 68:623.

40. Winship I, Gericke G, Beighton P. X-linked inheritance of ocular albinism with


late-onset sensorineural deafness. Am J Med Genet 1984; 19:797.
:
41. Winship IM, Babaya M, Ramesar RS. X-linked ocular albinism and sensorineural
deafness: linkage to Xp22.3. Genomics 1993; 18:444.
42. Albinism, ocular, with sensorineural deafness. In: Online Mendelian Inheritance
in Man. Johns Hopkins University www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id
=103470 (Accessed on November 02, 2006).
43. Spritz RA. Piebaldism, Waardenburg syndrome, and related disorders of
melanocyte development. Semin Cutan Med Surg 1997; 16:15.
44. Syrris P, Heathcote K, Carrozzo R, et al. Human piebaldism: six novel mutations
of the proto-oncogene KIT. Hum Mutat 2002; 20:234.

45. Dourmishev AL, Dourmishev LA, Schwartz RA, Janniger CK. Waardenburg
syndrome. Int J Dermatol 1999; 38:656.

46. Read AP, Newton VE. Waardenburg syndrome. J Med Genet 1997; 34:656.
47. Nayak CS, Isaacson G. Worldwide distribution of Waardenburg syndrome. Ann
Otol Rhinol Laryngol 2003; 112:817.
48. Silan F, Zafer C, Onder I. Waardenburg syndrome in the Turkish deaf
population. Genet Couns 2006; 17:41.

49. Hart J, Miriyala K. Neural tube defects in Waardenburg syndrome: A case report
and review of the literature. Am J Med Genet A 2017; 173:2472.

50. Potterf SB, Furumura M, Dunn KJ, et al. Transcription factor hierarchy in
Waardenburg syndrome: regulation of MITF expression by SOX10 and PAX3.
Hum Genet 2000; 107:1.
51. Pingault V, Ente D, Dastot-Le Moal F, et al. Review and update of mutations
causing Waardenburg syndrome. Hum Mutat 2010; 31:391.

52. Edery P, Attié T, Amiel J, et al. Mutation of the endothelin-3 gene in the
Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome). Nat Genet
1996; 12:442.
53. McCallion AS, Chakravarti A. EDNRB/EDN3 and Hirschsprung disease type II.
Pigment Cell Res 2001; 14:161.

54. Pingault V, Bondurand N, Kuhlbrodt K, et al. SOX10 mutations in patients with


Waardenburg-Hirschsprung disease. Nat Genet 1998; 18:171.

55. Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and
:
multidisciplinary management of neurofibromatosis 1 and neurofibromatosis
2. JAMA 1997; 278:51.

56. Hurwitz S. Clinical Pediatric Dermatology, 2nd ed, WB Saunders, Philadelphia 19


93.

57. Lim JY, Kim H, Kim YH, et al. Merlin suppresses the SRE-dependent transcription
by inhibiting the activation of Ras-ERK pathway. Biochem Biophys Res Commun
2003; 302:238.

58. Kwiatkowski DJ, Short MP. Tuberous sclerosis. Arch Dermatol 1994; 130:348.
59. Webb DW, Clarke A, Fryer A, Osborne JP. The cutaneous features of tuberous
sclerosis: a population study. Br J Dermatol 1996; 135:1.
60. Ringpfeil F, McGuigan K, Fuchsel L, et al. Pseudoxanthoma elasticum is a
recessive disease characterized by compound heterozygosity. J Invest Dermatol
2006; 126:782.
61. Le Saux O, Urban Z, Tschuch C, et al. Mutations in a gene encoding an ABC
transporter cause pseudoxanthoma elasticum. Nat Genet 2000; 25:223.
62. Ringpfeil F, Lebwohl MG, Christiano AM, Uitto J. Pseudoxanthoma elasticum:
mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette
(ABC) transporter. Proc Natl Acad Sci U S A 2000; 97:6001.
63. Bergen AA, Plomp AS, Schuurman EJ, et al. Mutations in ABCC6 cause
pseudoxanthoma elasticum. Nat Genet 2000; 25:228.
64. Sherer DW, Sapadin AN, Lebwohl MG. Pseudoxanthoma elasticum: an update.
Dermatology 1999; 199:3.
65. Engelman MW, Fliegelman MT. Pseudoxanthoma elasticum. Cutis 1978; 21:837.

66. Laube S, Moss C. Pseudoxanthoma elasticum. Arch Dis Child 2005; 90:754.

67. Hardelin JP, Levilliers J, del Castillo I, et al. X chromosome-linked Kallmann


syndrome: stop mutations validate the candidate gene. Proc Natl Acad Sci U S A
1992; 89:8190.
68. Happle R. X-linked dominant chondrodysplasia punctata. Review of literature
and report of a case. Hum Genet 1979; 53:65.
69. Wright JT, Grange DK, Fete M. Hypohidrotic ectodermal dysplasia. In: GeneRevie
ws, Adam MP, Ardinger HH, Pagon RA, et al (Eds), University of Washington, Sea
:
ttle, 1993.
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
Syndrome and other skeletal abnormalities. Common CNS
Mutation of the
(Nevoid Basal abnormalites include calcification of the falx cerebri and
tumor
Cell bridging of the sella turcica. Extracutaneous tumors,
suppressor
Carcinoma including medulloblastomas, meningiomas, and ovarian
gene patched
Syndrome, fibrosarcomas, are also associated with the syndrome.
(PTC)
Gorlin
Syndrome)

Gardner Autosomal Triad of familial adenomatous polyposis, benign


Syndrome dominant osteomas, and skin and soft tissue tumors. Multiple
epidermoid cysts are the most characteristic skin finding.
Mutation of
Desmoid tumors may also be seen. Congenital
tumor
hypertrophy of the retinal pigmented epithelium is a
suppressor
reliable and early marker of disease. Colon cancer
gene APC
develops in all affected individuals requiring prophylactic
colectomy.

Peutz-Jegher Autosomal Dark periorificial and acral freckling most markedly on


Syndrome dominant the lips; patients develop hamartomatous polyps of GI
tract which may give rise to cancer. Also associated with
Mutation of
increased risk of early adenocarcinomas of the breast,
tumor
cervix, pancreas, uterus and 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
:
Meara EB dominant mild trauma, but lesions heal without scarring; mild or no
simplex mucosal involvement. Increased risk of basal cell
Mutation of
carcinoma during mid-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
EB teeth, 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
recessive flexures at the knees and elbows and fusion of the digits;
Mutation in the
dystrophic frequent 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.

Graphic 72687 Version 4.0


:
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.

Graphic 80815 Version 4.0


:
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.

Graphic 100293 Version 2.0


:
Cutaneous leiomyomatosis

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

Courtesy of Edward W Cowen, MD, MHSc.

Graphic 100296 Version 2.0


:
Cutaneous leiomyomatosis

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

Courtesy of Edward W Cowen, MD, MHSc.

Graphic 100292 Version 2.0


:
Cutaneous leiomyomatosis

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

Courtesy of Edward W Cowen, MD, MHSc.

Graphic 100291 Version 2.0


:
The ichthyoses

Inheritance
and Key clinical features
pathogenesis
Icthyosis vulgaris Autosomal Relatively common (1:250 to 1:300).
dominant Fine, white translucent scales
predominantly on extensor surfaces
Fillagrin defect
of extremities with sparing of
resulting in a
flexures, palms, soles, and face.
retention
Hyperlinear palms. Often associated
hyperkeratoses
with keratosis pilaris and atopy
(Normal including eczema. Onset during
epithelial childhood. Typically improves with
turnover) age.

X-linked ichthyosis (steroid X-linked recessive 1:6000 men. Failure to progress in


sulfatase deficiency) labor in mother of affected fetus
Steroid sulfatase
(placental sulfatase deficiency). Large
deficiency results
brown "dirty" adherent scales with
in cholesterol
relative sparing of flexures, palms,
sulfate
soles, and face. Asymptomatic corneal
accumulation
opacities (50 percent of adult males).
and a retention
12 to 15 percent incidence of
hyperkeratoses
cryptorchidism and independently
(Normal increased risk of testicular cancer.
epithelial Onset at two to six weeks. Gradually
turnover) worsens with age.

Lamellar ichthyosis Autosomal 1:300,000 live births. "Collodion baby"


recessive at birth (translucent taut parchment-
like membrane encasing infant,
Transglutaminase
ectropion, eclabium, generalized
deficiency
erythroderma; complications include
(Increased sepsis, protein loss, and electrolyte
epithelial abnormalities). Children and adults
turnover) develop large brown polygonal scales
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
(Increased
white scaling. Palmoplantar
epithelial
keratoderma, scarring alopecia, and
turnover)
persistent ectropion may also be
seen.

Epidermolytic hichtyosis Autosomal Neonatal period with widespread


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

Harlequin ichthyosis Autosomal Massive armor-like plates of scale


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

Graphic 71157 Version 5.0


:
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.

Graphic 52261 Version 5.0


:
Darier disease

Multiple yellow-brown, hyperkeratotic papules are present on the


chest.

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


reserved.

Graphic 56168 Version 7.0


:
Darier disease

Multiple hyperpigmented, hyperkeratotic papules are on the chest.

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


reserved.

Graphic 70000 Version 7.0


:
Darier disease

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

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


reserved.

Graphic 81865 Version 7.0


:
Epidermolysis bullosa

EB type Pathogenesis Key clinical features


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

Junctional EB Autosomal recessive; mutation in More severe variant characterized


genes encoding hemidesmosomal by widespread bullae and erosions
proteins such as laminin 5 resulting with nonhealing granulation tissue;
in 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.

Autosomal recessive and


Dystrophic EB Onset at birth; generalized bullae,
autosomal dominant; type VII
heal with extensive scarring, milia.
collagen mutation leading to
Repeated episodes of severe
defective anchoring fibrils
blistering and scarring lead to
contraction flexures at knees and
Sub-basal lamina separation
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 Blisters induced by mild trauma,
:
Autosomal recessive progressive poikiloderma, and skin
atrophy (particularly of the dorsal
Separation at the level of the basal
hands and feet). Photosensitivity
keratinocytes, within the lamina
may or may not be present.
lucida, or sub-basal lamina
Additional features may include
separation
desquamative gingivitis and
strictures of the esophagus, anus,
vagina, and urethra. Blistering and
photosensitivity may decrease with
age.

EB: epidermolysis bullosa.

Graphic 76897 Version 8.0


:
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


(EBS-acanth) recessive acantholytic epidermolysis
(cytolysis of
DSP, JUP bullosa due to mutations in
suprabasal
Desmoplakin DSP and one due to JUP
keratinocytes;
(absent), have been described [1-5]
intact blisters
usually not plakoglobin Generalized skin fragility
clinically (absent) with rapidly progressive
evident; epidermolysis and large
keratinocytes sheets of detached skin
form numerous with superficial erosions at
interdigitating birth; skin detachment on
cellular hands and feet in a glove
protrusions; and stocking pattern;
only few complete disruption of the
desmosomal epidermal barrier without
remnants intact blisters or vesicles;
present) no excessive 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
syndromes recessive with trauma-induced and
Desmoplakin DSP, JUP, PKP1 spontaneous superficial
deficiency Desmoplakin erosions from birth;
(EBS- (reduced), palmoplantar keratoderma
desmoplakin; plakoglobin with painful, often disabling
skin fragility- (reduced), fissures (walking, bearing
woolly hair plakophilin-1 weight); nail dystrophy;
syndrome) (absent or alopecia
Plakoglobin reduced) Chronic cheilitis, perioral
deficiency scale, perioral and lingual
(EBS- fissures
plakoglobin; Blepharitis, astigmatism
skin fragility- Persistent abnormal hair
plakoglobin (hypotrichosis, loss of
deficiency) eyelashes, complete
Plakophilin alopecia; woolly hair)
deficiency Esophageal strictures,
(EBS- constipation
plakophilin; Growth retardation (usually
skin fragility- below the third centile for
ectodermal height and weight)
dysplasia
Variable clinical features
syndrome)
include scattered scale-
crust on the trunk and
limbs, follicular
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 Autosomal Superficial painless skin
skin recessive peeling (volar and dorsal
syndrome [7] TGM5 aspects of hands, feet;
Transglutaminase- elbows, knees)
5 Acral blisters, erosions at
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 dominant Mainly limited, regional
(cytolysis of
Weber- KRT5, KRT14 involvement of palms and
basal
Cockayne) Keratin 5, keratin soles
keratinocytes)
14 Clinical onset usually during
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
Keratin 5, keratin blisters from birth (typically
14 and best 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
(includes former KRT5, KRT14, at birth
Koebner) EXPH5, DYS, Rarely eye involvement
KLHL24
Keratin 5, keratin
14, exophilin 5,
dystonin, Kelch-
like family
member 24

EBS-MP (EBS Autosomal Skin blistering with


with mottled dominant reticulate brown skin
pigmentation) KRT5 pigmentation,
Keratin 5 keratoderma, nail
dystrophy
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
Keratin 5 erythema 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
alpha-6, integrin- cutis 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
KRT14 [14] anogenital), ichthyosiform
Keratin 14 plaques; rarely 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
PLEC1 from birth
Plectin Onychogryphosis (markedly
curved and deformed nails
resembling ram's horns) [9]

EBS, autosomal Autosomal First described in three


recessive- recessive siblings born to first cousin
exophilin 5 EXPH5 parents [15]
deficiency Exophilin-5 Disrupted keratinocyte
(Rab27B GTPase adhesion within the lower
effector protein epidermis with prominent
Slac2-b) skin fragility at birth
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-
Dystonin/coiled induced and spontaneous
coil domain of blistering (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 recessive reports from China, Israel,
stabilizing KLHL-24 and the United Kingdom
mutations in the Kelch-like family Quite marked birth
ubiquitin ligase member 24 traumas, especially the
enzyme that lower limbs
processes Early involvement of trunk
KRT14 [16-18] and 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.

Graphic 77709 Version 10.0


:
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,
(formerly Herlitz) erosions, and crusting covering not only particularly
LAMA3, LAMB3,
exposed skin areas (like palms and soles) but most or
LAMC2
almost all of the body surface
Laminin-
Periungual inflammation, onychodystrophy, and nail
alpha-3 chain
loss
of laminin-332
Exuberant granulation tissue, often periorificial
Laminin-beta- Involvement of oral cavity (blisters, erosions); teeth
3 chain of (enamel hypoplasia, excessive caries);
laminin-332 gastrointestinal (protein-losing enteropathy,
Laminin- diarrhea), respiratory, and genitourinary tract;
gamma-2 conjunctivae
chain of
Anemia, growth retardation, high lethality (survival
laminin-332
past one year of age uncommon)

JEB, generalized Autosomal Generalized blistering from birth, atrophic scarring,


intermediate recessive milia; "male-pattern" alopecia; nail dystrophy and
(formerly non- loss
COL17A1,
Herlitz) Involvement of oral cavity and teeth (excessive
LAMA3, LAMB3,
LAMC2 caries, teeth loss, enamel hypoplasia);
gastrointestinal, respiratory, and genitourinary tract;
Type XVII
conjunctivae
collagen
Anemia, growth retardation, protein losing
Laminin-
enteropathy, diarrhea
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,
recessive onset at birth; milia, nail dystrophy, and loss

COL17A1, Involvement of oral cavity and teeth (excessive


ITGB4, LAMA3, caries, enamel hypoplasia)
LAMB3, LAMC2 Extensive atrophic scarring, hair loss, anemia,
impairments of growth and development, ocular
Type XVII
abnormalities or alterations affecting
collagen
gastrointestinal, genitourinary, and respiratory tract
Integrin-beta- mostly absent [1]
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,
ITGA6, ITGB4 occasionally 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,
LAMA3, LAMB3,
localized [1]
LAMC2
:
Laminin- Atrophic scarring, milia, hypo-/hyperpigmentation,
alpha-3 chain dystrophic (or absent) nails
of laminin-332 Moderate oral mucosal lesions; dental enamel
Laminin-beta- hypoplasia, caries and gastrointestinal abnormalities
3 chain of to a lesser extent as compared with other JEB
laminin-332 variants
Laminin-
gamma-2
chain of
laminin-332

JEB, late onset Autosomal Mild form of JEB developing in young adulthood or
recessive later

COL17A1 Dystrophic (or absent) nails, dental enamel


hypoplasia and caries to a lesser severity than JEB,
Type XVII
generalized intermediate
collagen
Hyperhidrosis
Absence of dermatoglyphs on fingers, palms, toes,
and soles

JEB-LOC Autosomal High incidence in Punjab


(laryngo-onycho- recessive Minimal skin blistering, erosions
cutaneous) Extensive aberrant production of granulation tissue
LAMA3A
syndrome [2-11] with delayed healing, atrophic scarring
Laminin-
Involvement of larynx (altered cry) at birth or later,
alpha-3a
skin (face, nuchal) and conjunctiva (granulomatous
chain of
papules, 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,


respiratory and recessive atrophic glomeruli, focal segmental
renal glomerulosclerosis, diffuse interstitial fibrosis,
ITGA3
involvement tubular atrophy and loss)
(JEB-RR) [10-12] Integrin-
Interstitial lung disease (tachypnea, respiratory
alpha-3
distress, cyanosis in first days of life; secondary
aspiration with 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.

Graphic 67202 Version 8.0


:
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,
collagen
rarely, genitourinary tract

Dominant DEB, Autosomal Predilection of blistering for hands and feet from
acral dominant, early infancy, milia, atrophic scarring, dystrophic (or
autosomal absent) 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
autosomal scarring; dystrophic nails
recessive Lichen planus-like skin lesions
COL7A1

Type VII
collagen

Dominant DEB, Autosomal Generalized or localized erosions, blisters, milia,


pruriginosa dominant, and atrophic scars from infancy or later; dystrophic
autosomal nails
:
recessive Pronounced pruritus

COL7A1

Type VII
collagen

Dominant DEB, Autosomal Nail dystrophy or loss at birth or infancy without


nails only dominant skin involvement

COL7A1

Type VII
collagen

Dominant DEB, Autosomal Generalized blistering from birth or early infancy


bullous dominant, that 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
severe or absent nails
COL7A1
(formerly Acral pseudosyndactyly and contractures
recessive DEB- Type VII
Involvement of oral cavity (blisters, erosions,
Hallopeau- collagen
scarring, excessive caries, smooth tongue without
Siemens) 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
intermediate dystrophy; scarring alopecia
COL7A1
:
Type VII Pseudosyndactyly
collagen Increased risk for development of squamous cell
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
Type VII
and genitourinary tract
collagen
Stenosis of meatus acusticus externus
Anemia, growth retardation

Recessive DEB, Autosomal Pretibial blistering at birth or early infancy,


pretibial recessive involvement 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,
localized recessive milia, atrophic scarring; nail dystrophy

COL7A1

Type VII
collagen

Recessive DEB, Autosomal Generalized or localized erosions, blisters, milia,


pruriginosa recessive and 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
bullous recessive that 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.

Graphic 55262 Version 4.0


:
Genotypic and phenotypic characteristics of Kindler epidermolysis
bullosa

Inheritance

Mutated
Site of cleavage gene Clinical features
Targeted
gene product

Intraepidermal, Autosomal Generalized blistering at birth, atrophic


junctional, or recessive scarring, skin fragility diminishes with
sublamina densa advancing age; poikiloderma
FERMT1 (KIND1)
Photosensitivity
Fermitin family
Pseudosyndactyly
homologue 1
Gingival hyperplasia, oral leukokeratosis,
(kindlin-1)
colitis, 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

Graphic 81536 Version 4.0


:
Genetic classification of oculocutaneous albinism

Type of Encoding
MIM # Gene Locus Comments
albinism function

OCA1* 606933 TYR 11q14- Tyrosinase, which OCA1A: No


OCA1A 203100 11q21 catalyzes several melanin
steps in OCA1B: Varying
OCA1B 606952 melanogenesis amounts of
melanin are
present

OCA2 203200 OCA2 15q11.2- Melanosomal Common in sub-


(previously 15q12 membrane protein Saharan Africa
called P due to 2.7 kb
gene) deletion
Includes brown
and rufous OCA

OCA3 203290 TYRP1 9p23 Stabilizes Previously called


tyrosinase and red or rufous
regulates OCA
eumelanin Common in
production Africa

OCA4 696574 SLC45A2 5p13.2 Membrane Minimal to near


(previously transport protein normal melanin
called Phenotype
MATP and similar 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.

Graphic 115427 Version 2.0


:
Piebaldism

Patchy areas of depigmentation in a child with piebaldism.

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


reserved.

Graphic 58857 Version 5.0


:
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.

Graphic 52591 Version 7.0


:
Piebaldism

Multiple depigmented patches are present on the trunk and legs in


this patient with piebaldism.

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


reserved.

Graphic 71514 Version 5.0


:
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.

Graphic 56776 Version 7.0


:
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.

Graphic 69606 Version 4.0


:
Multiple neurofibromas in an adult patient with
neurofibromatosis type 1

Multiple papules and nodules consistent with neurofibromas are


present on the trunk.

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


reserved.

Graphic 82613 Version 5.0


:
Axillary freckling in neurofibromatosis type 1

Multiple hyperpigmented macules are present in the axilla.

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


reserved.

Graphic 67532 Version 5.0


:
Tuberous sclerosis complex

Hypomelanotic macule on the torso of a patient with tuberous


sclerosis complex.

Graphic 61601 Version 8.0


:
Tuberous sclerosis complex

Angiofibromas of the face presenting as erythematous papules in a


child with tuberous sclerosis complex.

Graphic 54868 Version 5.0


:
Tuberous sclerosis complex

Typical forehead fibrous plaque in a child with tuberous sclerosis.

Graphic 78688 Version 3.0


:
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.

Graphic 80952 Version 7.0


:
Pseudoxanthoma elasticum

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.

Graphic 59135 Version 7.0


:
Pseudoxanthoma elasticum

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.

Graphic 70421 Version 7.0


:
Pseudoxanthoma elasticum

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


patient with pseudoxanthoma elasticum.

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


reserved.

Graphic 76225 Version 5.0


:
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.

Graphic 77863 Version 2.0


:
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- 305000 XR


Engman syndrome)

Ectrodactyly, ED, and cleft lip/palate syndrome 129900 AD


(EEC1 syndrome)

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


(EEC3 syndrome)

ED hypohidrotic, with acanthosis nigricans (Lelis 608290 ?


syndrome)

ED-syndactyly syndrome 2 (EDSS2) 613576 AR

ED with natal teeth, Turnpenny type 601345 AD

[3]
:
ED, Caratinga type [3] – AD?; XD?

ED, hypohidrotic, with hypothyroidism and agenesis 225040 AD?; AR?; XD?
of 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, 300301 XD


osteopetrosis, and lymphedema (OLEDAID
syndrome)

Hypomelanosis of Ito (HMI, incontinentia pigmenti 300337 XD


type 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 273400 AR


deficiencies, 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; 181270; 129550 AD


ED with adrenal cyst)

Tricho-odonto-onychodysplasia with pili torti [1] – AD?; XD?

Tricho-onycho-dental dysplasia (TOD) [4] – AD

[5]
:
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 301815 XR


developmental 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; 218330 AR


Sensenbrenner 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 613573 AR


pillous anomaly and syndactyly [6] included

ED, trichoodontoonychial type 129510 AD

Ellis-van Creveld syndrome (EVC) 225500 AR

Growth retardation, alopecia, pseudoanodontia, 230740 AR


and 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 262190 AR


mellitus, 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 275450 AR?


deficiency

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 246500 AR


retardation, 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


[14]
:
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- 211370 AR
albinoidism

Cataract, hypertrichosis, mental retardation 211770 AR


syndrome (CAHMR syndrome)

Cerebellar ataxia and ED 212835 AR

Cleft lip/palate-oligodontia-syndactyly-hair – AD?; XD?


defects [15]

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 225280 AR


(EEM 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 135400 AD


without gingival hyperplasia (gingival fibromatosis
with hypertrichosis)

Hypertrichosis universalis 145700 AD


:
Johanson-Blizzard syndrome (JBS) 243800 AR

Mental retardation, hypotrichosis, and – AR?


syndactyly [18]

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 176690 AD


(Mulvihill-Smith syndrome)

Rodrigues blindness (microphthalmia, microcornea, 268320 AR


and 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, 191482 AD


dental 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, 104100 AD


AD (alopecia congenita with keratosis
palmoplantaris)

Pili torti and onychodysplasia [24] – AD

Pili torti, alopecia, and onychodysplasia [25] – AR

Polyposis, skin pigmentation, alopecia, and 175500 ?


fingernail changes

Popliteal pterygium syndrome, lethal type 263650 AR

Short stature, onychodysplasia, facial – AR


dysmorphism, and hypotrichosis syndrome
(SOFT syndrome) [26]

Syndrome of accelerated skeletal maturation, – AR?; XR?


failure to thrive, and peculiar face (Marshall
syndrome II) [27]

T cell immunodeficiency, congenital alopecia, and 601705 AR?


nail dystrophy

Trichomegaly with mental retardation, dwarfism, 275400 AR


and 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); 136500 AD


facial 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 – AD?
mental retardation [34]

Kohlschutter-Tonz syndrome (epilepsy, dementia, 226750 AR?; XR?


and amelogenesis imperfecta)

Marshall syndrome I 154780 AD

Subgroup nail-sweat glands (n = 2)


Adermatoglyphia with congenital facial milia and 129200 AD
acral 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.

References: ​
1. Freire-Maia N, Pinherio M. Ectodermal Dysplasias: A Clinical and Genetic Study, Alan R Liss, New York 1984.
p.251.
2. van Steensel MA, van der Hout AH. Lelis syndrome may be a manifestation of hypohidrotic ectodermal
dysplasia. Am J Med Genet 2009; 149A:1612.
3. Montebelo Filho A, Freire AR, Pinheiro M, Freire-Maia N. Odonto-ungueal dysplasia: An apparently new
autosomal dominant ectodermal dysplasia. Braz J Genet 1996; 19:162.
4. Koshiba H, Kimura O, Nakata M, Witkop CJ Jr. Clinical, genetic, and histologic features of the
trichoonychodental [TOD] syndrome. Oral Surg 1978; 46:376.
5. Moynahan EJ. XTE syndrome (xeroderma, talipes and enamel defect): A new heredo-familial syndrome. Proc
R Soc Med 1970; 63:1.
6. Wiedemann HR, Grosse FR, Dibbern H. Características das síndromes em pediatria: Atlas de diagnostic
diferencial, Schattauer, São Paulo: Manole 1978.
7. Beemer FA, Bruynzell-Koomen C, Happle R. Two cases of hypotrichosis with pili bifurcati. Am J Med Genet
1987; 4:187.
8. Pinheiro M, Freire-Maia N. Ondoto-onicodisplasia com alopecia: Dois casos em uma irmandade. Ciênc Cult
1981; 33:696.
9. Pinheiro M, Freire-Maia DV, Miranda E, et al. Trichodermodysplasia with dental alternations: An apparently
new genetic ectodermal dysplasia of the tricho-odonto-onychial subgroup. Clin Genet 1986; 29:332.
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.
20. Walbaum R, Dehaene PH, Schlemmer H. Dysplasie ectodermique: Une forme autosomique récessive? Arch Fr
Pédiatr 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.
22. Halal F, Setton N, Wang NS. A distinct type of hidrotic ectodermal dysplasia. Am J Med Genet 1991; 38:552.
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.
26. Sarig O, Nahum S, Rapaport D, et al. Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis
syndrome is caused by a POC1A mutation. Am J Hum Genet 2012; 91:337.
27. Marshall RE, Graham CB, Scott CR, Smith DW. Syndrome of accelerated skeletal maturation and relative
failure to thrive: A newly recognized clinical growth disorder. J Pediatr 1971; 78:95.
28. Freire-Maia N, Pinheiro M, Fernandes-dos-Santos A. Trichoonychodysplasia with xeroderma, an apparently
hitherto 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.
31. Antely RM, Shields ED, Rosenberg GL, Bixler D. Hypohidrosis with sparse hair, short stature and normal
teeth and nails. Birth Defects Orig Artic Ser 1976; 12:136.
32. Khan B, Basit S, Touseef M, et al. A novel chondroectodermal dysplasia mapped to chromosome 2q24.1-
q31.1. Eur J 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).

Graphic 117077 Version 1.0


:
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

Graphic 61258 Version 2.0


:
X-linked ichthyosis

X-linked ichthyosis: legs, infant.

Reproduced with permission from: Stedman's Medical Dictionary. Copyright ©2008


Lippincott Williams & Wilkins.

Graphic 66723 Version 1.0


:
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.

Graphic 128200 Version 1.0


:
Epidermolysis bullosa simplex

Bullae are present on the hands of this infant with epidermolysis


bullosa simplex.

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


reserved.

Graphic 59364 Version 4.0


:
Epidermolysis bullosa simplex

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

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


reserved.

Graphic 73201 Version 5.0


:
Incontinentia pigmenti

Multiple erythematous papules, vesicles, and crusts are present in


linear streaks on the leg of this female infant.

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


reserved.

Graphic 58769 Version 6.0


:
Focal dermal hypoplasia

Multiple erythematous areas representing dermal hypoplasia are


present. Note the digital abnormalities involving the foot.

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


reserved.

Graphic 55714 Version 5.0


:
Contributor Disclosures
Teresa S Wright, MD, FAAD, FAAP No relevant financial relationship(s) with ineligible
companies to disclose. Helen V Firth, DM, FRCP, FMedSci No relevant financial relationship(s)
with ineligible companies to disclose. Jennifer L Hand, MD No relevant financial relationship(s)
with ineligible companies to disclose. Rosamaria Corona, MD, DSc No relevant financial
relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found,
these are addressed by vetting through a multi-level review process, and through requirements
for references to be provided to support the content. Appropriately referenced content is
required of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy


:

You might also like