American Journal of Medical Genetics Part C (Semin. Med. Genet.

) 131C:45 51 (2004)

A r t i c l e

Ectodermal Dysplasias
PETER H. ITIN* AND SUSANNA K. FISTAROL

Ectodermal dysplasias are a large group of heritable conditions characterized by congenital defects of one or more ectodermal structures and their appendages: hair (hypotrichosis, partial, or total alopecia), nails (dystrophic, hypertrophic, abnormally keratinized), teeth (enamel defect or absent), and sweat glands (hypoplastic or aplastic). The ectodermal dysplasias, as a rule, are not pure one-layer diseases. Mesodermal and, rarely, endodermal dysplasias coexist. Embryogenesis exhibits distinct tissue organizational elds and specic interactions among the germ layers that may lead to a wide range of ectodermal dysplasias when genes important for development are mutated or otherwise altered in expression. Of the approximately 200 different ectodermal dysplasias, about 30 have been studied at the molecular level with identication of the causative gene. Freire-Maia and Pinheiro used the clinical aspects for their classication, and Priolo integrated molecular genetic and clinical aspects for her scheme. Those two more historical classication schemes have the difculty that, when applied strictly, several additional groups of diseases should be integrated within the term ectodermal dysplasias, e.g. keratodermas with skin or hair alterations or the ichthyoses with associated features. Such consequent classication would lead to an endless list of diseases and would be useless for the practical work. Recent evidence implicates a genetic defect in different pathways orchestrating ectodermal organogenesis. Modern molecular genetics will increasingly elucidate the basic defects of the different syndromes and yield more insight into the regulatory mechanisms of embryology. In this way, a reclassication of ectodermal dysplasias will be possible according to the function of their involved mutated genes. Lamartine recently proposed a helpful classication according to the functions of the genes discovered in different types of ectodermal dysplasias. Accordingly, the present overview categorizes the various ectodermal dysplasias into four major functional subgroups: cellcell communication and signaling, adhesion, transcription regulation, and development. 2004 Wiley-Liss, Inc. KEY WORDS: ectodermal dysplasias; embryology of the skin; classication; gene functions; patched; p63 and keratinization; eld theory

INTRODUCTION
Ectodermal dysplasias describe a large and complex group of disorders characterized by abnormal development of the skin and appendages (hair, nails, teeth, and sweat glands). They involve

Peter H. Itin is Professor of Dermatology and chairman of the Department of Dermatology in Aarau, Switzerland. In addition he is Associate Professor at the Department of Dermatology, University of Basel. One of the main eld of interest are genodermatoses. He is the clinical advisor of the Swiss group for dystrophic epidermolysis patients (DEBRA). Susanna K. Fistarol is a Dermatologist with a special interest in stomatology including the genetic syndromes. She is consultant in the Department of Dermatology in Aarau, Switzerland. *Correspondence to: Peter H. Itin, Department of Dermatology, Kantonsspital Aarau, 5001 Aarau, Switzerland. E-mail: peter.itin@unibas.ch DOI 10.1002/ajmg.c.30033

various organs developing from the primordial external germ layer. Ectodermal dysplasias may occur isolated or associated with other clinical manifestations. Most syndromic forms of ectodermal dysplasias are recognized by particular clinical features [Solomon and Keuer, 1980]. Danz [1793] described two boys with congenital atrichia and anodontia in 1793. Weech [1929] coined the designation ectodermal dysplasia and already recognized its heterogeneity. Solomon and Keuer emphasized that the term ectodermal dysplasia has to be limited to those conditions that are congenital, diffusely present, and nonprogressive. New forms of ectodermal dysplasias are continuously described garbane et al., 1998]. In recent [Me years, several ectodermal dysplasias were reported with marked overlapping phenotypes in disorders that were considered to be distinct [Bertola et al., 2000].

EPIDEMIOLOGY AND CLASSIFICATION

Although exact incidence data are missing, it is estimated that about 7 in 10,000 births are affected with a form of ectodermal dysplasia. The resulting functional impairments lead to numerous signs and symptoms (Table I). Ectodermal dysplasias may occur as sporadic conditions. However, all Mendelian modes of inheritance, autosomal dominant or recessive, X-linked dominant or recessive, are described. A rather large and comprehensive classication, with regular updates, was initiated by FreireMaia and Pinheiro based on clinical description [Freire-Maia and Pinheiro, 1984, 1988; Pinheiro and Freire-Maia, 1994]. They proposed two main groups specied as A and B. To group A belong all the entities which have defects in at least two of the classic ectodermal structures such as hair, teeth, nails, and sweat glands. Group B disorders have

2004 Wiley-Liss, Inc.

46

AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)

ARTICLE

TABLE I. Clinical Manifestations in the Ectodermal Dysplasias Skin alteration Supercial dry scaling skin at birth Dry and often hypopigmented skin Dermatitis resembling atopic skin disease Impaired sweat gland function Absence or reduction of sweating Hyperthermia under warm condition Abnormalities in hair follicles Sparse, curly, and fair hair Alopecia because of hypotrichosis or increased hair fragility Eyebrows or eyelashes absent/sparse or malformed Nail changes Leukonychia Dystrophic and malformed nails Dental changes Hypodontia or anodontia Malformed teeth with cone- or pegshaped aspect Prone to caries because of enamel defect or salivary gland malfunction with xerostomia Facial changes Dysmorphic features Numerous facial malformations Eye abnormalities Corneal dysplasias Cataract Displaced or stenotic lacrimal puncta Defective or decreased lacrimation

defects in only one of the four abovementioned structures, plus one other ectodermal defect such as anomaly of the ears, lips, or dermatoglyphics on palms

To group A belong all the entities which have defects in at least two of the classic ectodermal structures such as hair, teeth, nails, and sweat glands. Group B disorders have defects in only one of the four above-mentioned structures, plus one other ectodermal defect such as anomaly of the ears, lips, or dermatoglyphics on palms and soles.

and soles. A disease which features only ectodermal signs is named a pure ectodermal dysplasia. A combination of ectodermal signs with other anomalies is called an ectodermal dysplasia syndrome. Pure ectodermal dysplasias and ectodermal dysplasia syndromes form the large group of ectodermal syndromes sensu lato [Pinheiro and FreireMaia, 1994]. The diseases belonging to this rather broadly dened ectodermal dysplasias are also termed by the numbers corresponding to the basic affected structure (1, 2, 3, 4 hair, teeth, nails, and sweat glands) and by number 5 indicating other ectodermal defects such as malformation of ears, lips, and dermatoglyphics. As a result, conditions are labeled 15, 25, 35, or 45. The 192 known ectodermal dysplasias are classied into 11 subgroups [Freire-Maia et al., 2001]. The number of ectodermal dysplasias in each subgroup varies from one to 43. The numbers of conditions

due to autosomal dominant, autosomal recessive, and X-linked genes are 41, 52, and 8 respectively. In numerous diseases the cause is not known, and in 42 of them some signs of genetic etiology are present. In 21 entities, the exact genetic defect is described. An alternative nomenclature mentions the affected structures, such as tricho-odontic, tricho-onychial, and tricho-dyshidrotic. Classication of ectodermal dysplasias according to inheritance pattern and associated allelic variations in known genes is another possibility. Priolo and Lagana [2001] tried to use biological mechanisms that are important in the pathogenesis of ectodermal dysplasias for their classication. They coined two groups. Group 1 represented defects in developmental regulation and epithelialmesenchymal interactions, and group 2 included diseases with abnormalities concerning cytoskeleton maintenance and cell stability. Lamartine recently expanded the classication of ectodermal dysplasias by molecular and biochemical criteria. He proposed four major functional subgroups: cellcell communication and signaling, adhesion, transcription regulation, and development [Lamartine, 2003]. This will certainly be the most promising classication for the future.

CLINICAL FEATURES OF VARIOUS ECTODERMAL DYSPLASIAS

Patients may have abnormalities of the skin such as adermatoglyphia, reticular pigmentation, depigmentation, scaling, telangiectases, atrophy, or hyperkeratosis [Itin et al., 1993b]. In general the skin is dry and ne. Often alopecia is a feature of subtypes in ectodermal dysplasias. Hair is generally fair and scanty, sometimes brittle and uncombable [Itin et al., 1993a]. Body hair is often diminished or absent. Eyebrows and eyelashes may be lacking [Silengo et al., 2002]. Decreased tear production, cataracts, and strabismus may occur. Bilateral panuveitis in a child with hypohidrotic ectodermal dysplasia has been observed [Rodriguez et al., 2002]. Nails can be dystrophic, hyperconvex, or discolored such as in

ARTICLE

AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)

47

leukonychia congenita associated with keratoderma and deafness [Fistarol and Itin, 2002]. Sweat glands may be reduced or absent, but apocrine glands are in general normally formed. Oligodontia or anodontia are rather common. Rudimentary or conical teeth may be observed. Enamel defects often occur and lead to severe and early caries. Absent salivary glands may lead to xerostomia. Oral ndings include leukoplakia or cleft lip and palate. Common otolaryngologic manifestations include eczematoid skin changes, unusual facies, chronic infections such as rhinitis, pharyngitis, and otitis media, epistaxis, hearing loss, and dysphonia [Daniel et al., 2002].

MOLECULAR BASIS OF ECTODERMAL DYSPLASIAS

Ectodermal dysplasias feature impaired development of ectodermal appendages. Their development is regulated by a sequence of inductive interactions between two adjacent tissue layers, the epithelium and the mesenchyme [Mikkola and Thesleff, 2003]. Recent evidence implicates a genetic defect in different pathways which orchestrate ectodermal organogenesis. Embryogenesis is regulated by a number of complex signaling cascades which are critical for normal development. One of the best investigated pathways is the sonic hedgehog, leading to interactions with the transcription factors within the Gli family. Dysregulation of the sonic hedgehogpatched gli pathway may lead to different diseases including some of the spectrum of ectodermal dysplasias [Villavicencio et al., 2000]. Ectodermal dysplasias caused by mutations of genes encoding cellcell signals Christ-Siemens-Touraine syndrome (OMIM 305100, Freire-Maia A 1-2-34) an X-linked condition, is the most common of the ectodermal dysplasias. However, autosomal dominant [Ho et al., 1999] and autosomal recessive [Munoz et al., 1997] forms have likewise been described. Christ-SiemensTouraine syndrome is characterized by

hypotrichosis with ne, slow-growing scalp and body hair, sparse eyebrows, hypohidrosis, nail anomalies, and hypodontia [Gilgenkrantz et al., 1989]. Pegshaped primary and secondary teeth are typical. Abnormal crown form and taurodontism was commonly seen radiologically [Crawford et al., 1991]. Decreased sweating leads to heat intolerance and enhances dryness of the skin. When this syndrome remains unrecognized, there is a 30% lethality rate during the rst 2 years of life [Clarke et al., 1987]. Sybert [1989] emphasized that scaling red skin in the neonate might be an important clue to early diagnosis of Christ-Siemens-Touraine syndrome. The children have heat intolerance with episodes of hyperpyrexia, which may result in seizures and neurologic damage. Affected persons show a distinctive facies with frontal bossing, depressed nasal bridge with a saddle nose, and large lower lips. Corneal and lenticular opacities or conductive hearing loss are uncommon features. However, absence of lacrimal puncta is a characteristic nding. The clinical ndings in female carriers of Christ-Siemens-Touraine syndrome have recently been delineated [Happle and Frosch, 1985; Cambiaghi et al., 2000]. The most impressive nding is the clinical evidence of the distribution of normal and abnormal skin along Blaschko lines in women. Four mouse mutants with similarity to hypohidrotic ectodermal dysplasia have been described (tabby, downless, sleek, crinkled). It has been shown that tabby is identical with ectodysplasin (EDA) and EDA-receptor was found to be mutated in the recessively inherited downless mice and in the dominant locus sleek [Mikkola and Thesleff, 2003]. Cloning of the crinkled gene revealed the signaling adapter protein EDARADD. Reduced epidermal growth factor receptor in X-linked hypohidrotic epidermal dysplasia and in the mouse model tabby has been found [Vargas et al., 1996]. Interestingly, induction of sweat glands by epidermal growth factor in murine X-linked anhidrotic ectodermal dysplasia was successful [Blecher et al., 1990].

The human gene maps to Xq12q13.1 and affects a transmembrane protein which is expressed by keratinocytes, hair follicles, and sweat glands. Kere et al. [1996] found ectodysplasin, a TNF ligand, to be the cause of the Xlinked hypohidrotic ectodermal dysplasia. The ectodysplasin pathway, a new TNF pathway, has an important function in embryonic development and especially in the formation of ectodermal structures. Ectodysplasin is a

The human gene maps to Xq12-q13.1 and affects a transmembrane protein which is expressed by keratinocytes, hair follicles, and sweat glands. Kere et al. [1996] found ectodysplasin, a TNF ligand, to be the cause of the X-linked hypohidrotic ectodermal dysplasia. The ectodysplasin pathway, a new TNF pathway, has an important function in embryonic development and especially in the formation of ectodermal structures.
membrane-bound protein with an extracellular protease cleavage site preceded by a long stalk and followed by a collagen domain and a C-terminal tumor necrosis factor homology domain. This domain is necessary for the function of the protein. Ectodysplasin forms homotrimers and is released by proteolytic shedding. Two closely related isoforms of ectodysplasin, EDA-1 and EDA-2 have been described. The two isoforms bind to two different receptors. EDA-1 binds to EDAR which is encoded by the human homologue of the mouse downless gene whereas EDA-2 is a specic ligand for an X-linked receptor (XEDAR), another related but distinct tumor necrosis factor receptor.

48

AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)

ARTICLE

Recently it has been shown that EDAR also represses Lef-1/beta-catenin-dependent transcription, and this ability is defective in EDAR mutants associated with anhidrotic ectodermal dysplasia [Shindo and Chaudhary, 2004]. After the trimers are created at the membrane, the protein interacts with its receptor and induces the nuclear factor (NF-kB) pathway through the adapter protein EDARAD. NF-kB is primarily involved in inducing immune and inammatory responses and in regulating apoptosis. EDA mediates important signals for cell survival and growth and differentiation in epithelial and mesenchymal organs. Numerous genes encoding for different members of the EDA pathway are mutated in other syndromes in the spectrum of ectodermal dysplasias [Mikkola and Thesleff, 2003]. Mutations in the human homologue of mouse downless (dl) gene encoding the EDAR receptor cause autosomal dominant hypohidrotic ectodermal dysplasia (OMIM 129490) [Monreal et al., 1999]. Mutation in the adapter protein EDARADD is responsible for the autosomal recessive form of hypohidrotic ectodermal dysplasia (OMIM 224900). NEMO, a gene encoding IkB kinase, is a further important regulator of the NF-kB pathway. A novel X-linked disorder of immune deciency and hypohidrotic ectodermal dysplasia (ectodermal dysplasia of Zonana) has been described recently and was found to be allelic to incontinentia pigmenti Bloch-Sulzberger [Zonana et al., 2000]. A new subtype of anhidrotic ectodermal dysplasia with osteopetrosis and lymphedema has been found to be caused by impaired NFkB signaling [Do fnger et al., 2001]. The NF-kB transcription factor has an important role in the immune and inammatory responses, as well as in the control of apoptosis. Further important proteins for intercellular communication by forming gap-junctions are connexins which have been found to be involved in ectodermal dysplasias. Hidrotic ectodermal dysplasia or Clouston syndrome (OMIM 129500, Freire-Maia A, 1-23) is a rare autosomal dominant inherited

disease dened by generalized hypotrichosis, dystrophic nails, and palmoplantar keratoderma [Ando et al., 1988]. The causative gene of this syndrome is a mutated gap junction protein 6 which encodes connexin-30 [Smith et al., 2002]. Earlier reports of linkage of Clouston syndrome to chromosome 13q11-q12.1 have been conrmed, and a mutation in connexin-30 has been found [Lamartine et al., 2000]. Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness (KID) syndrome [Richard et al., 2002]. The clinical features are characterized by hyperkeratotic plaques with underlying erythema which has a tendency to fade over time [Traupe, 1990]. One type has a typical facial involvement with bizarre and sharply outlined verrucous hyperkeratotic plaques occurring also on elbows, knees, palms, and soles. The other phenotype shows more severe and diffuse involvement of the skin with scarring alopecia. Patients with KID syndrome have a high incidence of squamous cell cancer of the skin. The non-cutaneous features include bilateral neurosensory hearing impairment and vascularizing keratitis. Hearing loss is congenital but vascularizing keratitis develops during the natural course of the disease beginning with photophobia and ending in total blindness. Ectodermal Dysplasias Caused by Mutations of Genes Encoding for Adhesion Cell to cell junctions are formed by desmosomal plaque proteins. Desmosomal cadherins are important for the adhesion of neighboring cell membranes. Plakophilin 1 is a desmosomal plaque protein found primarily in epithelial tissues that frequently undergo mechanical stress [South, 2004]. Plakophilin 1 is absent in patients with the ectodermal-dysplasia skin fragility syndrome inherited in an autosomal recessive trait (OMIM 604536). In addition to repeated blistering at mechanical exposed skin regions, the patients show sparse hair, dystrophic nails, and abnormality of sweating [McGrath

et al., 1997]. With this knowledge preimplantation diagnosis of compound heterozygous mutations leading to ablation of plakophilin-1 ending in skin fragility ectodermal dysplasia syndrome has been performed [Thornhill et al., 2000]. Sprecher et al. [2001] found that hypotrichosis with juvenile macular degeneration is caused by a mutation in CDH3, encoding P-cadherin. In a further investigation, the same authors found that affected individuals of two large separate apparently unrelated families of Arab-Israeli origin were found to carry the same homozygous missense mutation (R503H) in exon 11 of the CDH3 gene. This mutation alters a Ca2-binding site in the fourth extracellular domain of P-cadherin [Indelman et al., 2003]. Margarita Island ectodermal dysplasia (ED4) is an autosomal recessive disorder characterized by facial anomalies, dental anomalies, hypotrichosis, palmoplantar hyperkeratosis, and dysplastic nails, syndactyly, and cleft lip/ cleft palate (OMIM 225060). PVRL1, which encodes nectin-1, an immunoglobulin (Ig)-related transmembrane cellcell adhesion molecule is part of the NAP cell adhesion system. Nectin-1 is also the principal cell surface receptor for alpha-herpes viruses [Suzuki et al., 2000]. Ectodermal Dysplasias Caused by Mutations of Genes Involved in the Regulation of Transcription Several genes important in the regulation of transcription are involved in some syndromes of ectodermal dysplasias. P63 is a transcription factor structurally related to the p53 tumor suppressor. While p53 is ubiquitously expressed, p63 is expressed specically in embryonic ectoderm and in the basal regenerative layers of epithelial tissues in the adult. Several dominant human syndromes have been mapped to chromosome 3q27 and are caused by mutations in the p63 gene. The p63 syndrome family includes the ectodermal dysplasia, ectrodactyly, cleft lip/palate syndrome (EEC), ankyloblepharon

ARTICLE

AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)

49

ectodermal dysplasia clefting syndrome (AEC), acro-dermato-ungual-lacrimaltooth (ADULT) syndrome, limb-mammary syndrome, and non-syndromic split hand/foot malformation.

Several dominant human syndromes have been mapped to chromosome 3q27 and are caused by mutations in the p63 gene. The p63 syndrome family includes the ectodermal dysplasia, ectrodactyly, cleft lip/palate syndrome (EEC), ankyloblepharon ectodermal dysplasia clefting syndrome (AEC), acro-dermato-unguallacrimal-tooth (ADULT) syndrome, limb-mammary syndrome, and non-syndromic split hand/foot malformation.

sulfur matrix proteins. Abnormalities in excision repair of ultraviolet damaged DNA exist in about half of the patients. Interestingly, in contrast to patients with xeroderma pigmentosum, no increased risk of skin cancers has been observed in patients with trichothiodystrophy. Three complementation groups have been characterized among photosensitive patients with trichothiodystrophy. Most patients have mutations on the two alleles of the XPD gene. Rarely, mutated XPB gene or an unidentied TTD-A gene may result in trichothiodystrophy. In UV-sensitive trichothiodystrophy patients, the TFIIH transcription factor containing XPB and XPD helicase activities necessary for both transcription initiation and DNA repair is

damaged (See Tsai and Tsao: The Genetics of Skin Cancer, in this issue). Beyond deciency in the NER pathway, it is hypothesized that basal transcription may be altered leading to decreased transcription of specic genes. Depressed RNA synthesis may be responsible for some clinical features, such as growth retardation, neurological abnormalities, and brittle hair and nails. Trichorhinophalangeal syndrome is inherited as an autosomal dominant trait and clinically characterized by growth retardation, craniofacial abnormalities, severe brachydactyly, sparse and slowgrowing hair, pear-shaped nose, elongated philtrum, and thin upper lip. In addition mental retardation and cartilaginous exostoses may occur depending

Ellis-Van Crefeld syndrome is a rare autosomal recessive skeletal dysplasia. The syndrome is characterized by chondrodystrophic dwarsm, postaxial polydactyly of the hands, hypoplastic nails, thin hair, and abnormal teeth. Congestive heart disease is present in more than one-half of homozygotes. The responsible gene belongs to the group of proteins with a potential transcription activity [Ruiz-Perez et al., 2003]. Trichothiodystrophy (TTD) is a heterogeneous group of autosomal recessive disorders with distinctive features of short, brittle hair and abnormally lowsulfur content [Itin et al., 2001]. The hair of patients with TTD is dry and sparse, and the hair shafts break easily with trauma. Within the spectrum of the trichothiodystrophy syndromes are numerous interrelated neuroectodermal disorders. The trichothiodystrophy syndromes show defective synthesis of high-

Figure 1. Patient with poikilodermia, aplastic radius, and premature aging as signs of Rothmund Thomson syndrome.

50

AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)

ARTICLE

on the type. The syndrome is caused by defects in the transcription factor GATA which mediates cell differentiation in several tissues [Malik et al., 2002]. Ectodermal Dysplasias Caused by Mutations of Other Genes Causative genes for ectodermal dysplasias include helicase proteins involved in DNA replication and repair. Some cases of Rothmund-Thomson syndrome are caused by mutations in the DNA helicase gene RECQL4 [Kitao et al., 1999]. This disease shows skin atrophy, pigmentation, and telangiectasia and frequently it is accompanied by juvenile cataract, saddle nose, congenital bone defects, disturbances of hair growth, and hypogonadism. Forearm reduction is quite common (Fig. 1A,B) [Wang et al., 2001]. Dyskeratosis congenita (Freire-Maia A 1-2-3-4) is a genetically heterogeneous disease [Cole et al., 1930; Drachtman and Alter, 1995]. Three different types of inheritance patterns have been documented [Drachtman and Alter, 1992]: most cases belong to the X-linked forms (OMIM 305000) but autosomal recessive (OMIM 224230) and autosomal dominant forms (OMIM 127550) have also been described. Dyskeratosis congenita is a rare genodermatosis with three main cutaneous features which include reticulated pigmentation, dystrophy of the nails, and leukoplakia of the mucous membranes. Additional important ndings are continuous lacrimation due to atresia of the lacrimal ducts, pancytopenia and, in many cases, testicular atrophy. A gene for dyskeratosis congenita (DKC1) has been assigned to the q28 region of the X chromosome. Autosomal dominant dyskeratosis congenita is associated with mutations in the RNA component of telomerase, hTERC, while X-linked dyskeratosis congenita is due to mutations in the gene encoding dyskerin, a protein implicated in both telomerase function and ribosomal RNA processing [Bessler et al., 2004]. The new concepts of functional cell biology and embryology enable a more logical reclassication of ectodermal dysplasias in the near future according

to the function of their involved mutated genes.

REFERENCES
Ando Y, Tanaka T, Horiguchi Y, Ikai K, Tomono H. 1988. Hidrotic ectodermal dysplasia: A clinical and ultrastructural observation. Dermatologica 176:205211. Bertola DR, Kim CA, Sugayama SMM, Albano LMJ, Utagawa CY, Gonzalez CH. 2000. AEC syndrome and CHAND syndrome: Further evidence of clinical overlapping in the ectodermal dysplasias. Pediatr Dermatol 17:218221. Bessler M, Wilson DB, Mason PJ. 2004. Dyskeratosis congenita and telomerase. Curr Opin Pediatr 16:2328. Blecher SR, Kapalanga J, Lalonde D. 1990. Induction of sweat glands by epidermal growth factor in murine X-linked anhidrotic ectodermal dysplasia. Nature 345:542 544. Cambiaghi S, Restano L, Paakkonen K, Caputo R, Kere J. 2000. Clinical ndings in mosaic carriers of hypohidrotic ectodermal dysplasia. Arch Dermatol 136:217224. Clarke A, Phillips DIM, Brown R, Harper PS. 1987. Clinical aspects of X-linked hypohidrotic ectodermal dysplasia. Arch Dis Child 62:989996. Cole HN, Rauschkolb JE, Toomey J. 1930. Dyskeratosis congenita with pigmentation, dystrophia unguis, and leukokeratosis oris. Arch Dermatol Syph 21:7195. Crawford PJM, Aldred MJ, Clarke A. 1991. Clinical and radiographic dental ndings in X linked hypohidrotic ectodermal dysplasia. J Med Genet 28:181185. Daniel E, McCurdy EA, Shashi V, McGuirt WFJr. 2002. Ectodermal dysplasia: Otolaryngologic manifestations and management. Laryngoscope 112:962967. Danz DFG. 1793. Sechste Bemerkung. Von Menschen ohne Haare und Za hne. Arch Geb Frauen Neugeb Kinderkr 4:684. Drachtman RA, Alter BP. 1992. Dyskeratosis congenita: clinical and genetic heterogeneity. Report of a new case and review of the literature. Am J Pediatr Hematol Oncol 14:297304. Drachtman RA, Alter BP. 1995. Dyskeratosis congenita. Dermatol Clinics 13:3339. Do fnger R, Smahi A, Bessia C, Geissmann F, Feinberg J, Durandy A, Bodemer C, Kenwrick S, Dupuis-Girod S, Blanche S, Wood P, Rabia SH, Headon DJ, Oberbeek PA, Le Deist F, Holland SM, Belani K, Kumararatne DS, Fischer A, Shapiro R, Conley ME, Reimund E, Kalhoff H, Abinum M, Munnich A, Israel A, Courtois G, Casanova JL. 2001. Xlinked anhidrotic ectodermal dysplasia with immunodeciency is caused by impaired NF-kB signaling. Nat Genet 27:277 285. Fistarol SK, Itin PH. 2002. Nail changes in genodermatoses. Eur J Dermatol 12:119 128. Freire-Maia N, Pinheiro M. 1984. Ectodermal dysplasias: A clinical and genetic study. New York: Alan R. Liss.

Freire-Maia N, Pinheiro M. 1988. Ectodermal dysplasiassome recollections and a classication. Birth Defects 24:314. Freire-Maia N, Lisboa-Costa T, Pagnan NAB. 2001. Ectodermal dysplasia: How many? Am J Med Genet 104:84. Gilgenkrantz S, Blanchet-Bardon C, Nazzaro V, Mujica P, Alembik Y. 1989. Hypohidrotic ectodermal dysplasia. Clinical study of a family of 30 over three generations. Hum Genet 81:120122. Happle R, Frosch PJ. 1985. Manifestations of the lines of Blaschko in women heterozygous for X-linked hypohidrotic ectodermal dysplasia. Clin Genet 27:468471. Ho L, Williams MS, Spritz RA. 1999. A gene for autosomal dominant hypohidrotic ectodermal dysplasia (EDA3) maps to chromosome 2q11-q13. Am J Hum Genet 62:1102 1106. Indelman M, Hamel CP, Bergman R, Nischal KK, Thompson D, Surget MO, Ramon M, Ganthos H, Miller B, Richard G, Lurie R, Leibu R, Russel-Eggitt I, Sprecher E. 2003. Phenotypic diversity and mutation spectrum in hypotrichosis with juvenile macular dystrophy. J Invest Dermatol 121:1217 1220. Itin PH, Bu hler U, Bu chner SA, Guggenheim R. 1993a. Pili trianguli et canaliculi: A distinctive hair shaft defect leading to uncombable hair. Dermatology 187:296298. Itin PH, Lautenschlager St, Meyer R, Mevorah B, Rui T. 1993b. Natural history of the NaegeliFranceschettiJadassohn syndrome and further delineation of the symptom complex. J Am Acad Dermatol 28:942 950. Itin PH, Sarasin A, Pittelkow MR. 2001. Trichothiodystrophy: Update on the sulfur-decient brittle hair syndromes. J Am Acad Dermatol 44:891920. Kere J, Srivastava AK, Montonen O, Zonana J, Thomas N, Ferguson B, Munoz F, Morgan D, Clarke A, Baybayan P, Chen EY, Ezer S, Saarialho-Kere U, De la Chapelle A, Schlessinger D. 1996. X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nature Genet 13:409416. Kitao S, Shimamoto A, Goto M, Miller RW, Smithson WA, Lindor NM, Furuichi Y. 1999. Mutations in RECQL4 cause a subset of cases of RothmundThomson syndrome. Nature Genet 22:8284. Lamartine J. 2003. Towards a new classication of ectodermal dysplasias. Clin Exp Dermatol 28:351355. Lamartine J, Essenfelder GM, Kibar Z, Lanneluc I, Callouet E, Laoudj D, Lemaitre G, Hand C, Hayick SJ, Zonana J, Antonarakis S, Radhakrishna U, Kelsell DP, Christianson AL, Pitaval A, Der Kaloustian V, Fraser C, Blanchet-Bardon C, Rouleau GU, Waksman G. 2000. Mutations in GJB6 cause hidrotic ectodermal dysplasia. Nat Genet 26:142144. Malik TH, Von Stechow D, Bronson RT, Shivdasani RA. 2002. Deletion of the GATA domain of TRPS1 causes an absence of facial hair and provides new insights into the bone disorder in inherited tricho-rhinophalangeal syndromes. Mol Cell Biol 24: 85928600.

ARTICLE

AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)

51

McGrath JA, McMillan JR, Shemanko CS, Runswick SK, Leigh IM, Lane EB, Garrod DR, Eady RAJ. 1997. Mutations in the plakophilin 1 gene result in ectodermal dysplasia/skin fragility syndrome. Nature Genet 17:240244. Mikkola ML, Thesleff I. 2003. Ectodysplasin signaling in development. Cytokine Growth Factor Rev 14:211224. Monreal AWM, Ferguson BM, Headon DJ, Street SL, Overbeek PA, Zonana J. 1999. Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nature Genet 22:366369. Munoz F, Lestringant G, Sybert V, Frydman M, Alswaini A, Frossard PM, Jorgenson R, Zonana J. 1997. Denitive evidence for an autosomal recessive form of hypohidrotic ectodermal dysplasia clinically indistinguishable from more common X-linked disorder. Am J Hum Genet 61:94100. garbane A, Noujeim Z, Fabre M, Der Me Kaloustian VM. 1998. New form of hidrotic ectodermal dysplasia in a Lebanese family. Am J Med Genet 75:196199. Pinheiro M, Freire-Maia N. 1994. Ectodermal dysplasias: A clinical classication and a causal review. Am J Med Genet 53:153162. Priolo M, Lagana C. 2001. Ectodermal dysplasias: A new clinicalgenetic classication. J Med Genet 38:579585. Richard G, Rouan F, Willoughby CE, Brown N, Chung P, Ryyna nen M, Jabs EW, Bale SJ, DiGiovanna JJ, Uitto J, Russell L. 2002. Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitisichthyosisdeafness syndrome. Am J Hum Genet 70:13411348. Rodriguez N, Eliott D, Garcia-Valenzuela E, Baker J. 2002. Bilateral panuveitis in a child with hypohidrotic ectodermal dysplasia. Am J Ophthalmol 134:443445.

Ruiz-Perez VL, Thompson SW, Blair HJ, Espinoza-Valdez C, Lapunzina P, Silva EO, Hamel JL, Gibbs JL, Young ID, Wright MJ, Goodship JA. 2003. Mutations in two nonhomologous genes in a head-to-head conguration cause Ellis-van Creveld syndrome. Am J Hum Genet 72:728732. Shindo M, Chaudhary PM. 2004. We present evidence that EDAR also represses Lef-1/ beta-catenin-dependent transcription and this ability is defective in EDAR mutants associated with anhidrotic ectodermal dysplasia. Biochem Biophys Res Commun 315:7378. Silengo M, Valenzise M, Sorasio L, Ferrero GB. 2002. Hair as a diagnostic tool in dysmorphology. Clin Genet 62:270272. Smith FJ, Morley SM, McLean WH. 2002. A novel connexin 30 mutation in Clouston syndrome. J Invest Dermatol 118:530533. Solomon LM, Keuer EJ. 1980. The ectodermal dysplasias. Problems of classication and some newer syndromes. Arch Dermatol 116:12951299. South AP. 2004. Plakophilin 1: An important stabilizer of desmosomes. Clin Exp Dermatol 29:161167. Sprecher E, Bergman R, Richard G, Lurie R, Shalev S, Petronius D, Shalata A, Anbinder Y, Leibu R, Perlman I, Cohen N, Szargel R. 2001. Hypotrichosis with juvenile macular dystrophy is caused by a mutation in CDH3, encoding P-cadherin. Nat Genet 29:134 136. Suzuki K, Hu D, Bustos T, Zlotogora J, RichieriCosta A, Helms JA, Spritz RA. 2000. Mutations of PVRL1, encoding a cellcell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia. Nat Genet 25:427430. Sybert VP. 1989. Scaling skin in the neonate: A clue to the early diagnosis of X-linked hypohidrotic ectodermal dysplasia (Christ

SiemensTouraine sundrome). J Pediatr 114: 600602. Thornhill AR, Pickering SJ, Whittock NV, Caller J, Bickerstaff HE, Handyside AH, Eady RA, Braude PR, McGrath JA. 2000. Preimplantation genetic diagnosis of compound heterozygous mutations leading to ablation of plakophilin-1 (PKP1) and resulting in skin fragility ectodermal dysplasia syndrome: A case report. Prenat Diagn 20:10551062. Traupe H. 1990. Not an ichthyosis at all: The keratitis, ichthyosis-like hyperkeratosis, and deafness (KID) syndrome In: Traupe H, editor. The ichthyoses. A guide to clinical diagnosis, genetic counseling, and therapy. Berlin, Heidelberg, New York: SpringerVerlag. pp 198202. Vargas GA, Fantino E, George-Nascimento C, Gargus JJ, Haigler HT. 1996. Reduced epidermal growth factor receptor expression in hypohidrotic ectodermal dysplasia and Tabby mice. J Clin Invest 97:24262432. Villavicencio EH, Walterhouse DO, Iannaccone PM. 2000. The sonic hedgehog-patched-gli pathway in human development. Am J Hum Genet 67:10471054. Wang LL, Levy ML, Lewis RA, Chintagumpala MM, Lev D, Rogers M, Plon SE. 2001. Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients. Am J Med Genet 102:1117. Weech AA. 1929. Hereditary ectodermal dysplasia (congenital ectodermal defect). A report of two cases. Am J Dis Child 37:766790. Zonana J, Elder ME, Schneider LC, Orlow SJ, Moss C, Golabi M, Shapira SK, Farndon PA, Wara DW, Emmal SA, Ferguson BM. 2000. A novel X-linked disorder of immune deciency and hypohidrotic ectodermal dysplasia is alleleic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). Am J Hum Genet 67:1555 1562.