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Keywords:

  • ectodermal dysplasias;
  • ectodermal appendage alterations

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DEFINITION, CLASSIFICATION, AND REVISION OF ECTODERMAL DISPLASIAS
  5. MOLECULAR ASPECTS OF EDs
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES

Ectodermal dysplasias (EDs) as defined by Freire-Maia [Freire-Maia (1971); Hum Hered 21: 309–312; Freire-Maia (1977); Acta Genet Med Gemellol 26: 121–131] are congenital disorders characterized by alterations in two or more ectodermal structures, at least one of these involving alterations in hair, teeth, nails, or sweat glands. Suggestions for a new definition and, consequently, for a new classification of EDs have being proposed lately, mainly with the purpose of connecting clinical knowledge with recent discoveries of gene mutations responsible for about 30% of EDs. The aim of this review was to update the clinical classification of EDs with recent molecular (64 genes and 3 chromosome regions) and clinical data, mainly of EDs of the A group (N = 186), in order to contribute information for the evaluation of the ED definition proposed by Freire-Maia. Our conclusion is that the combination of both procedures—clinical and molecular—only brings advantages for a deeper knowledge of EDs. First, it allows a rapid diagnosis that may become even more precise whenever DNA exams are available. Secondly, the comprehension of the biological mechanisms that cause EDs is needed for the design of efficient prevention and treatment approaches. © 2009 Wiley-Liss, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DEFINITION, CLASSIFICATION, AND REVISION OF ECTODERMAL DISPLASIAS
  5. MOLECULAR ASPECTS OF EDs
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES

Ectodermal dysplasias (EDs) as defined by Freire-Maia 1971, 1977 are congenital disorders characterized by alterations in two or more ectodermal structures, at least involving one in hair, teeth, nails, or sweat glands. Suggestions for a new definition and, consequently, for a new classification of EDs have being proposed. The main reason for the present situation seems to be the need to integrate clinical knowledge with recent discoveries in the molecular area which led to the identification of genes encoding about 30% of EDs. In March 2008, an International Conference for Ectodermal Dysplasias Classification, sponsored mainly by the National Foundation for Ectodermal Dysplasias and the Medical University of South Carolina, was held in Charleston with the aim of initiating discussions in order to arrive at a consensus for EDs definition and classification. In this event, gene function-based classifications were also discussed. However, none of these classifications seemed to solve the present problem, as only 62 clinically different EDs have already a gene (64 genes) or a chromosome region (3 regions) assigned to them.

The aim of the present study is to update the clinical classification established by Freire-Maia with recent molecular and clinical data, mainly of EDs of the A group, in order to evaluate Freire-Maia's ED definition and also offer information for future discussions. Some EDs of the B group were included in this review whenever molecular information was available.

DEFINITION, CLASSIFICATION, AND REVISION OF ECTODERMAL DISPLASIAS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DEFINITION, CLASSIFICATION, AND REVISION OF ECTODERMAL DISPLASIAS
  5. MOLECULAR ASPECTS OF EDs
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES

In our opinion, the definition of this nosologic group, as proposed by Freire-Maia 1971, 1977, continues to be appropriate as it imposes clear limits for what is considered an ED and also generates a classification of the different entities in well delineated groups and subgroups.

It is important to emphasize that an ED should have a genetic cause and that the four cited classical structures are affected in the following decreasing order of frequency: hair, teeth, nails, and sweat glands, associated or not with alterations in other ectodermal appendages. This order establishes the criterion for the EDs classification as will be shown as follows.

According to Freire-Maia's classification, EDs are divided into two categories: Group A which comprises all the entities with disturbances in two or more of the classical structures, and Group B which includes those with alterations in only one of these structures plus another ectodermal defect.

The A group is subdivided into 11 subgroups, according to the involved structures: 1-2-3-4 (hair-teeth-nails-sweat glands); 1-2-3 (hair-teeth-nails); 1-2-4 (hair-teeth-sweat glands); 1-3-4 (hair-nails-sweat glands); 2-3-4 (teeth-nails-sweat glands); 1-2 (hair-teeth); 1-3 (hair-nails); 1-4 (hair-sweat glands); 2-3 (teeth-nails); 2-4 (teeth-sweat glands); 3-4 (nails-sweat glands). Similarly, entities belonging to Group B are classified with the same criteria into four subgroups with number 5 added at the end, indicating that another ectodermal defect is present: 1-5, 2-5, 3-5, and 4-5.

Other structures of ectodermal origin that may also be involved in EDs are: mammary glands, thyroid gland, thymus, anterior pituitary, adrenal medulla, central nervous system, external ear, melanocytes, cornea, conjunctiva, lacrimal gland and lacrimal duct [see Irvine, 2005] and Meibomian glands [Kaercher, 2004].

“Pure ectodermal dysplasias” are entities with only ectodermal signs without disturbances derivatives of other embryonic layers. On the other hand, “syndromes of ectodermal dysplasia and malformation” present ectodermal signs and also defects of another embryonic origin, such as cleft lip/palate [Freire-Maia and Pinheiro, 1984].

The definition of ED is used in sensu lato. EDs are simply groups of conditions presenting similar ectodermal signs: a subgroup includes conditions with defects in the same structures that may be affected in different ways [Freire-Maia and Pinheiro, 1988]. Consequently, the cardinal ectodermal signs in some EDs may not be the most prominent defects in the clinical picture. For instance, in Ellis–van Creveld syndrome, an ED of the 1-2-3 subgroup, the osseous anomalies (short-limb dwarfism, club foot, genua valga, poly/syndactyly) are clinically more relevant than the ectodermal alterations. Other examples of this situation are pycnodysostosis, and Costello, Barber–Say and otopalatodigital syndromes.

Some conditions that lie within this broad definition are often excluded from ED classifications, for example, pachyonychia congenita, incontinentia pigmenti, and dyskeratosis congenita. These entities are EDs by definition, but common practice has considered them separate entities [Irvine, 2005]. However, there is no impediment for a disturbance to belong to more than one clinical classification. For instance, a clear ED also associated with an immunologic problem may be classified as an ED by a dermatologist or as an immune disturbance when the patient is examined by an immunologist. This fact may facilitate a multidisciplinary approach to the patient, focusing the relevant aspects of each medical specialization.

The other classifications which are being proposed [Priolo et al., 2000; Priolo and Laganà, 2001; Lamartine, 2003; Itin and Fistarol, 2004] use molecular knowledge as the starting point. Our opinion is that a classification based on gene function or other molecular aspects is no doubt of utmost importance. However, this type of knowledge is not yet available for most EDs and, furthermore, members of the clinical team involved with EDs (pediatricians, dermatologists, ophthalmologists, dentists, physiotherapists, and other professionals), when examining a patient with ED, need at first a clear method of diagnosis, and only afterwards may use information concerned with cause.

This is the reason why we consider the co-existence of two different ED classifications acceptable. The clinical classification will clearly delineate the condition and allow a rapid diagnosis. The classification based on molecular aspects is prone to continued additions and modifications due to new discoveries and will provide organized information to be used in new researches, such as those on metabolic pathways and embryonic signaling. For this reason, this type of classification is important for future studies, referring both to cause and to development of preventive and therapeutic procedures. Examples of the use of molecular knowledge for ED treatment can be found in Gaide and Schneider 2003 and Casal et al. 2007 who achieved the permanent correction of the phenotype of X-linked hypohidrotic ED (Christ–Siemens–Touraine syndrome) by the administration of a recombinant protein to mutant mice and dogs, respectively.

This review lists 186 EDs of the A group (Table I). Considering previous reviews, some entities were added and others were lumped together in view of clinical similarity. Adopting a rigorous procedure that excludes 26 EDs observed in only one patient and those whose knowledge was obtained only by personal communication [see Freire-Maia and Pinheiro, 1984], the classification includes 157 different entities. An updated review of the genes involved in EDs is also shown.

Table I. Ectodermal Dysplasias of the A Group (N = 186, Single Cases = 26)
 Ectodermal dysplasia (ED)Reference (OMIM, whenever available)Inheritance
  1. AR, autosomal recessive; AD, autosomal dominant; XD, X-linked dominant; XR, X-linked recessive; Pers. comm., personal communication.

Subgroup hair-teeth-nails-sweat glands. N = 42, Single case = 4
1Acrorenal field defect, ED, and lipoatrophic diabetes (AREDYLD)207780AR
2Alopecia-contractures-dwarfism mental retardation syndrome203550AR
3Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC; Hay–Wells syndrome)106260AD
4Anonychia with flexural pigmentation106750AD
5Arthrogryposis and ED601701AR
6Camarena syndromeFreire-Maia and Pinheiro 1984 (Pers. comm.)AD?; XD?
7Carey syndrome (Single case)Freire-Maia and Pinheiro 1984 (Pers. comm.)?
8Cleft lip/palate-ED syndrome (CLPED1; Zlotogora–Oğur syndrome; Margarita Island syndrome)225060AR
9Curly hair-acral keratoderma-caries syndromeVan Steensel et al. 2001AD
10Dyskeratosis congenita, AD (Dyskeratosis congenita, Scoggins type)127550AD
11Dyskeratosis congenita, AR224230AR
12Dyskeratosis congenita, X-linked (Zinsser–Cole–Engman syndrome)305000XR
13Ectrodactyly, ED, and cleft lip/palate syndrome (EEC1)129900AD
14Ectrodactyly, ED, and cleft lip/palate syndrome 3 (EEC3)604292AD
15ED hypohidrotic, with acanthosis nigricans (Lelis syndrome)608290?
16ED with alopecia, onychodysplasia, hypohidrosis, keratoderma, abnormal teeth and deafness (Single case)Akhyani and Kiavash 2007AR?
17ED with cardiac and skeletal abnormalities (Single case)Lipson 1988?
18ED with mental retardation and syndactyly (Single case)600906AR?
19ED with natal teeth, Turnpenny type601345AD
20ED, Caratinga typeMontebelo et al. 1996AD?; XD?
21ED, hypohidrotic, with hypothyroidism and agenesis of the corpus callosum225040AD?; AR?; XD?
22Focal dermal hypoplasia (FDH)305600XD
23Hypohidrotic ED, autosomal dominant (ADHED)129490AD
24Hypohidrotic ED, autosomal recessive (ARHED)224900AR
25Hypohidrotic ED, X-linked (XLHED; Christ–Siemens–Touraine syndrome; CST syndrome)305100XR
26Hypohidrotic ED with immune deficiency300291XD
27Hypohidrotic ED with immunodeficiency, osteopetrosis, and lymphedema (OLEDAID syndrome)300301XD
28Hypomelanosis of Ito (HMI, Incontinentia pigmenti type I; IP1)300337XD
29Keratitis-ichthyosis-deafness syndrome, autosomal dominant (KID syndrome, AD)148210AD
30Keratitis-ichthyosis-deafness syndrome, autosomal recessive (KID syndrome, AR)242150AR
31Naegeli–Franceschetti–Jadassohn syndrome (NFJS)161000AD
32Odontoonychodermal dysplasia (OODD)257980AR
33Odontotrichomelic syndrome273400AR
34Pachyonychia congenita, type 1 (PC1)167200AD
35Pachyonychia congenita, type 2 (PC2)167210AD
36Papillon–Lefèvre syndrome245000AR
37Rapp–Hodgkin syndrome129400AD
38Rosselli–Gulienetti syndrome225000AR
39Scalp-ear-nipple syndrome (Finlay–Marks syndrome; ED with adrenal cyst)181270; 129550AD
40Tricho-odonto-onychodysplasia with pili tortiFreire-Maia and Pinheiro 1984 (Pers. comm.)AD?; XD?
41Tricho-onycho-dental dysplasia (TOD)Koshiba et al. 1978AD
42Xeroderma-talipes-enamel defects (XTE)Moynahan 1970AR
Subgroup hair-teeth-nails. N = 43, Single cases = 10
43Ackerman syndrome200970AR
44ADULT syndrome103285AD
45Arthrogryposis, ED, cleft lip/palate, and developmental delay301815XR
46Cardiofaciocutaneous syndrome (CFC)115150AD
47Clouston syndrome129500AD
48Coffin–Siris syndrome135900AD?; AR?; XD?
49Costello syndrome218040AR
50Cranioectodermal dysplasia (Sensenbrenner syndrome)218330AR
51Dermoodontodysplasia125640AD
52Dolichocephaly, dental defects, trichodysplasiaFreire-Maia and Pinheiro 1984 (Pers. comm.)AD
53Ectodermal defect with skeletal abnormalities (Single case)Wallace 1958?
54ED syndrome with distinctive facial appearance and preaxial polydactyly of feet (Single case)129540AD?
55ED with pillous anomaly and syndactylyWiedemann et al. 1980AR
56ED with tetramelic deficiencies (Single case)Freire-Maia and Pinheiro 1984 (Pers. comm.)?
57ED, cleft lip/palate, and severe cutaneous and osseous syndactyly and mental retardation (Single case)Freihofer et al. 1997?
58ED, trichoodontoonychial type129510AD
59Ellis–van Creveld syndrome (EVC)225500AR
60GOMBO syndrome233270AR
61Growth retardation, alopecia, pseudoanodontia, and optic atrophy (GAPO syndrome)230740AR
62Hidrotic ED autosomal recessive (Fried's tooth and nail syndrome)602401AR
63Hypoplasia of nails, malformations of hands and feet, curly hair, microdontia, seizures (Single case)Cortes and Lacassie 1986?
64Hypotrichosis with pili bifurcatiBeemer et al. 1987AR?
65Incontinentia pigmenti (IP2)308300XD
66Mesomelic dwarfism-skeletal abnormalities-ED (Single case)Brunoni 1984?
67Oculotrichodysplasia (OTD)257960AR
68Odonto-onychodysplasia-alopeciaPinheiro and Freire-Maia 1981AR
69Odontotrichoungual-digital-palmar syndrome601957AD?; XD?
70Osteosclerosis and ED (Single case)Côté and Katsantoni 1982AR
71Pilo-dento-ungular dysplasia with microcephaly (Single case)Tajara et al. 1987AR
72Pineal hyperplasia, insulin-resistant diabetes mellitus, and somatic abnormalities262190AR
73Rothmund–Thomson syndrome (RTS)268400AR
74Šalamon–Miličevič syndrome (Single case)Šalamon and Miličevič 1964AR
75Schinzel–Giedion midface-retraction syndrome269150AR?; AD?
76Schöpf–Schulz–Passarge syndrome224750AR
77Sener syndrome606156?
78Thumb deformity and alopecia188150AD
79Trichodentoosseus syndrome (TDO)190320AD
80Tricho-dermodysplasia-dental defectsPinheiro et al. 1986AD?; XD?
81Trichoodontoonychial dysplasia275450AR?
82Tricho-odonto-onycho-dermal syndrome (Single case)Pinheiro et al. 1981?
83Trichorhinophalangeal syndrome, type I (TRPS1)190350AD
84Trichothiodystrophy, photosensitive (TTDP)601675AR
85Witkop syndrome189500AD
Subgroup hair-teeth-sweat glands. N = 10, Single cases = 2
86Böök syndrome112300AD
87Cleft lip/palate, ED, acral anomaliesRichieri-Costa et al. 1992AR
88Hypohidrotic ED with focal sweatingGorlin 1988AR?; XR?
89Ichthyosis follicularis, atrichia, and photophobia syndrome (IFAP)308205XR
90Johnson neuroectodermal syndrome147770AD
91Lenz–Passarge dysplasiaLenz 1963XD
92Leukomelanoderma, infantilism, mental retardation, hypodontia, hypotrichosis246500AR
93Regional ED with total bilateral cleft (Single case)Fára 1971?
94Ulnar–mammary syndrome (UMS)181450AD
95Wesser-Vistnes ED with palatal paralysis (Single case)Wesser and Wistnes 1969?
Subgroup hair-nails-sweat glands. N = 8, Single cases = 4
96Alopecia-onichodysplasia-hypohidrosis-deafness (Single case)Freire-Maia et al. 1977?
97Alopecia-skin atrophy-anonychia-tongue defectsSequeiros and Sack 1985?
98ED with digital and eye anomalies (Single case)Viljoen and Winship 1988?
99ED with severe mental retardation (Single case)Kirman 1955?
100ED, hypohidrotic, with hypothyroidism and ciliary dyskinesia (HEDH syndrome)225050AR
101ED/skin fragility syndrome604536AR
102Fischer-Volavsek syndromeFischer 1921AD
103Trichodysplasia-onychogryposis-hypohidrosis-cataract (Single case)Freire-Maia et al. 1975?
Subgroup teeth-nails-sweat glands. N = 2
104Ameloonychohypohidrotic syndrome104570AD
105Limb–mammary syndrome (LMS)603543AD
Subgroup hair-teeth. N = 32, Single cases = 3
106Barber–Say syndrome209885AR?; AD?; XD?
107Blepharocheilodontic syndrome119580AD
108Brachymetapody-anodontia-hypotrichosis-albinoidism211370AR
109Cataract, hypertrichosis, mental retardation syndrome (CAHMR syndrome)211770AR
110Cerebellar ataxia and ED212835AR
111Cleft lip/palate-oligodontia-syndactyly-hair defectsMartínez et al. 1987AD?; XD?
112Congenital atrichia, palmoplantar hyperkeratosis, mental retardation, and early loss of teethSteijlen et al. 1994AR?
113Craniotubular dysplasia with severe postnatal growth retardation, mental retardation, ED (Single case)Nishimura et al. 1997?
114Distal arthrogryposis, ED and dilated cardiomyopathy (Single case)Parker et al. 1998AR?
115Dubowitz syndrome223370AR
116ED and neurosensory deafness224800AR
117ED, Cape VerdeWerninghaus 1993AR
118ED, ectrodactyly, and macular dystrophy (EEM syndrome)225280AR
119Gingival fibromatosis with hypertrichosis135400AD
120Gingival fibromatosis-sparse hair-malposition of teeth (Single case)Jorgenson 1971AR
121Gorlin-Chaudhry-Moss syndrome233500AR
122Hallermann–Streiff syndrome (HSS)234100AR
123Hypertrichosis universalis145700AD
124Johanson-Blizzard syndrome (JBS)243800AR
125Mental retardation, hypotrichosis, and syndactylyLopes and Marques-de-Faria 1996AR?
126Oculodentoosseous dysplasia, recessive257850AR
127Oculodentodigital dysplasia (ODDD)164200AD
128Orofaciodigital syndrome I (OFD1)311200XD
129Pili torti261900AR
130Pilodental dysplasia with refractive errors262020AR
131Progeroid short stature with pigmented nevi (Mulvihill–Smith syndrome)176690AD
132Rodrigues blindness (microphthalmia, microcornea, and sclerocornea with short stature and hair and dental abnormalities)268320AR
133Trichodental dysplasia601453AD
134Trichodysplasia and amelogenesis imperfectaAngelos and Jorgenson 1993AD?; XD?
135Uncombable hair, retinal pigmentary dystrophy, dental anomalies, and brachydactyly191482AD
136Walbaum–Dehaene–Schlemmer syndromeWalbaum et al. 1971AR
137Zunich neuroectodermal syndrome280000AR
Subgroup hair-nails. N = 26, Single cases = 2
138Alopecia congenita with keratosis palmoplantaris104100AD
139Alopecia, nail dystrophy, palmoplantar hyperkeratosis, keratitis, hearing difficulty and micrognathia (Single case)Nakamura and Ishikawa 2007?
140Anonychia-onychodystrophy with hypoplasia or absence of distal phalanges (Cooks syndrome)106995AD
141Autosomal recessive neurodegenerative disorder with trichorrhexis invaginata and EDGyure et al. 1992AR?
142Cartilage-hair hypoplasia (CHH)250250AR
143Curly hair-ankyloblepharon-nail dysplasia syndrome (CHANDS)214350AR
144ED hidrotic, Christianson–Fourie type601375AD
145ED with skin anomalies and mental retardationHalal et al. 1991AR
146ED, ‘pure’ hair-nail type602032AD?
147Hair-nail dysplasiaPinheiro and Freire-Maia 1992AD
148Hairy elbows (Hypertrichosis cubiti)139600AD
149Hypotrichosis and nail dysplasia, hidrotic ED (Single case)Harrison and Sinclair 2004?
150Ichthyosis and male hypogonadism308200XR?
151Ichthyosis with alopecia, eclabion, ectropion, and mental retardation242510AR
152Lymphedema-hypoparathyroidism syndrome247410AR?; XR?
153Monilethrix158000AD
154Onychotrichodysplasia and neutropenia258360AR
155Pili torti and onychodysplasiaBeare 1952AD
156Pili torti, alopecia and onychodysplasiaCalzavara-Pinton et al. 1991AR
157Polyposis, skin pigmentation, alopecia, and fingernail changes175500?
158Popliteal pterygium syndrome, lethal type263650AR
159Syndrome of accelerated skeletal maturation, failure to thrive and peculiar face (Marshall syndrome II)Marshall et al. 1971AR?; XR?
160T-cell immunodeficiency, congenital alopecia, and nail dystrophy601705AR?
161Trichomegaly with mental retardation, dwarfism, and pigmentary degeneration of retina275400AR
162Tricho-onychodysplasia-xerodermaFreire-Maia et al. 1985AR
163Trichothiodystrophy, nonphotosensitive 1 (TTDN1)234050AR
Subgroup hair-sweat glands. N = 5, Single case = 1
164Dry skin and extranumerary areolaeFreire-Maia and Chautard-Freire-Maia 1990AD
165Focal facial dermal dysplasia (facial ED)136500; 227260AD
166Short stature-kidney insufficiency-ophthalmological anomaly-growth retardation-ED (SKORED)Greenstein et al. 1985AR?; XR?
167Tetra-amelia with ED and lacrimal duct abnormalities (Single case)273390AR
168Tricho-facio-hypohidrotic syndromeAntley et al. 1976AR?; XR?
Subgroup teeth-nails. N = 13
169Corneodermatoosseous syndrome (CDO syndrome)122440AD
170Deafness, congenital, and onychodystrophy, autosomal dominant124480AD
171Deafness, onychodystrophy, osteodystrophy, and mental retardation syndrome (DOOR syndrome)220500AR?; AD?
172Dermatoosteolysis, Kirghizian type221810AR
173Haim-Munk syndrome (HMS)245010AR
174Hearing loss, sensorineural, with enamel hypoplasia and nail defects (Heimler syndrome)234580AR
175Lacrimoauriculodentodigital syndrome (LADD)149730AD
176Odontomicronychial dysplasia601319AR
177Odonto-ungueal dysplasiaPinheiro and Freire-Maia 1996AD
178Otopalatodigital syndrome, type I (OPD1)311300XD
179Pycnodysostosis265800AR
180Weyers acrofacial dysostosis193530AD
181Williams–Beuren syndrome (WBS)194050AD
Subgroup teeth-sweat glands. N = 3
182Hypohidrotic ED with mydriasis, iris atrophy, and mental retardationBeyer et al. 1979AD?
183Kohlschutter–Tonz syndrome (epilepsy, dementia, and amelogenesis imperfecta)226750AR?; XR?
184Marshall syndrome I154780AD
Subgroup nail-sweat glands. N = 2
185ED, absent dermatoglyphic pattern, changes in nails, and simian crease129200AD
186Pachyonychia congenita, recessive260130AR

Lumping of EDs Previously Considered as Different Entities

The lumping of conditions here referred was proposed in recent publications and/or is already available at Online Mendelian Inheritance in Man, OMIM (http://www.ncbi.nlm.nih.gov/omim).

The Zanier–Roubicek syndrome [Zanier and Roubicek, 1976] is the AD form of hypohidrotic ectodermal dysplasia (ADHED, OMIM 129490), caused by mutations in the EDAR or EDARADD genes.

The syndrome previously known as ectrodactyly, ED, and cleft lip/palate syndrome 2 (EEC2, OMIM 602077) was recently incorporated into EEC3 (OMIM 604292). Furthermore, Irvine 2005 suggests clinical similarity between EEC1 (OMIM 129900) and ectrodactyly, ED without cleft lip/palate (OMIM 129810) because the latter was observed in only one family and the absence of cleft lip/palate may be due to variable expressivity.

The EDs Margarita Island type and Zlotogora–Oğur syndrome are now considered the same condition: cleft lip/palate-ED syndrome (CLPED1, OMIM 225060), and the previous Zlotogora–Oğur syndrome number (OMIM 225000) belongs now to another ED (Rosselli–Gulienetti syndrome).

Nonphotosensitive trichothiodystrophy (TTD, OMIM 234050) includes two other EDs: Sabinas brittle hair syndrome (OMIM 211390) and trichorrhexis nodosa syndrome (Pollitt syndrome, OMIM 275550).

Winter 1993 stated that the patient described by Eronen et al. 1985 excreted large amounts of 2-oxoglutarate, which is found in the DOOR syndrome and suggested that the Eronen syndrome (digitorenocerebral syndrome, OMIM 222760) is identical to the DOOR syndrome (OMIM 220500). However, the two OMIM numbers are still conserved.

Ward and Moss 1994 suggested and Kaplan et al. 1995 concluded that the Setleis (OMIM 227260) and Brauer (OMIM 136500) forms of focal facial dermal dysplasia may be the same entity inherited in an AD inheritance pattern with variable expressivity [Kaplan et al., 1995; Masuno et al., 1995]. Irvine 2005 also suggests this possibility and we agree with this opinion.

Martino et al. 1992 suggested that dermotrichic syndrome [Freire-Maia and Pinheiro, 1984] and ichthyosis follicularis, atrichia, and photophobia syndrome (IFAP syndrome, OMIM 308205) may be the expression of the same X-linked gene, due to pleiotropy of a single gene or a contiguous gene syndrome. Irvine 2005 agrees that these may be the same entity.

Due to clinical similarity, the tricho-odonto-onycho-hypohidrotic dysplasia with cataract [Cole et al., 1945] may be Rothmund–Thomson syndrome (OMIM 268400). The study by Cole et al. 1945 is included in this OMIM entry.

ED with adrenal cyst (OMIM 129550) was studied in a patient and his mother by Tuffli and Laxova 1983 and was reported as a new ED, clinically characterized by aplasia cutis verticis, hypohidrosis, nipple hypoplasia, onychodysplasia and delayed dental eruption with minor tooth anomalies plus a large left adrenal cyst. Despite the presence of adrenal cyst, Edwards et al. 1994 suggested that this ED is in fact a case of scalp-ear-nipple syndrome (Finlay–Marks syndrome, OMIM 181270). We think that this suggestion cannot be ignored.

Lumping of EDs Suggested by the Present Review

Overlapping clinical manifestations may impair the differentiation of some EDs. This fact is aggravated by the low incidence of EDs, some of which having been observed only in a single family. Owing to the occurrence of a sign not yet mentioned in similar EDs already described, some of these patients were considered new entities. Considering that EDs show variable expression, it is possible that some of them belong to EDs already established. The following entities may illustrate this possibility.

Fried tooth and nail syndrome [Fried, 1977] is a hidrotic ED that seems to overlap with Witkop syndrome (OMIM 189500) which presents an AD inheritance pattern. The clinical similarities are evident and the first disturbance was observed in only two first cousin patients. As Fried syndrome occurred in a family with a high inbreeding coefficient, AR inheritance was suggested and led Fried 1977 to consider it as a new syndrome. Two other entities are also similar to these syndromes: Hidrotic ED with AR expression (OMIM 602401), observed in three generations of a Lebanese family with consanguineous marriages; and congenital absence of teeth with taurodontia and sparse hair (OMIM 272980) with unclear inheritance pattern and taurodontia as a sole sign. Considering the AR inheritance pattern, we suggest that Fried syndrome may be the same entity as hidrotic ED whereas Witkop syndrome represents another entity. As the inheritance pattern of absence of teeth with taurodontia and sparse hair is not clear and taurodontia may represent variable expressivity, this ED may belong either to Witkop or to Fried syndrome.

Similarities are found between tricho-onycho-dental dysplasia (TOD) [Koshiba et al., 1978] and tricho-odonto-onychodysplasia with pili torti [Carey, 1982; personal communication to Freire-Maia and Pinheiro, 1984] and refer to patients observed in a unique family and to a single patient, respectively.

The following EDs present similar signs: tricho-dermodysplasia-dental defects [Pinheiro et al., 1986], tricho-odonto-onycho-dermal syndrome [Pinheiro et al., 1981] and trichoodontoonychial dysplasia (OMIM 275450) all of them observed in only one family. Until their cause is discovered we cannot be sure if these EDs are really only one entity. Furthermore, dermoodonto dysplasia (OMIM 125640) and ED, trichoodontoonychial type (OMIM 129510) show clinical signs similar to these three EDs, despite the different suggested AD pattern with incomplete penetrance and variable expressivity [Lyngstadaas et al., 1996].

Three entities that deserve comparison are: ED with natal teeth Turnpenny type (OMIM 601345), ED with acanthosis nigricans (Lelis syndrome, OMIM 608290) and Clouston syndrome (OMIM 129500). Patients with Lelis syndrome present hypohidrosis and hyperkeratosis palmoplantaris whereas the Turnpenny type does not manifest these signs. Clouston syndrome shows hyperkeratosis as in Lelis syndrome and resembles Turnpenny type in normal hidrosis what stresses the similarities among these three syndromes. Considering that the gene responsible for Clouston syndrome has already been found, DNA analysis in patients with the two other syndromes could determine if they represent the same entity.

The two forms of hypomelanosis of Ito (X-linked and AD) are shown in OMIM as incontinentia pigmenti (IP1; OMIM 300337). In our opinion, The X-linked form is actually IP1, but the AD hypomelanosis of Ito is the Naegeli–Franceschetti–Jadassohn syndrome (OMIM 161000).

EDs of the A Group Not Included in Previous Reviews

The last revision by Pinheiro and Freire-Maia 1994 listed 154 entities of the A group. A note published by Freire-Maia et al. 2001 reports a total of 192 different EDs without naming them. On the other hand, Irvine 2005 reviewed 141 EDs, 6 belonging to the B group. Examining these reviews and comparing to EDs descriptions from the literature, 28 entities were included in the A group and their main clinical signs are shown in Table II.

Table II. Ectodermal Dysplasias (N = 28) Not Included in Previous Rewiews
Ectodermal dysplasia (ED)Reference (OMIM, whenever available)Inheritance patternHairTeethNailsSweat glandsOther signs
Subgroup hair-teeth-nails-sweat glands
 Curly hair-acral keratoderma-caries syndromeVan Steensel et al. 2001ADCurly, dry and brittle hair; premature hair loss; sparse eyebrows and eyelashesPartial loss of teeth due to cariesYellow and thickening of finger and toe nailsHypohidrosisSkin: keratoderma with a reticulate dark pattern on the tips of the fingers and toes. Face: flattening of the malar region and frontal bossing
 ED, Caratinga typeMontebelo et al. 1996AD?; XD?DysplasticAlteredDysplasticDyshidrosis 
 ED with alopecia, onychodysplasia, hypohidrosis, keratoderma, abnormal teeth and deafness (Single case)Akhyani and Kiavash 2007AR?Sparse and fine scalp hair; sparse eyelashes, eyebrows, pubic and axillary hair; absence of terminal hairs on the trunk and limbsMalformedFinger and toenails with subungual hyperkeratosis, onycholysis and accentuation of longitudinal ridges; irregularities on the surface of nailsHypohidrosisSkin: dry and rough; palmoplantar keratoderma. Hearing: complete sensorineural deafness (right ear); parcial sensorineural deafness (left ear)
Subgroup hair-teeth-nails
 Arthrogryposis, ED, cleft lip/palate, and developmental delay301815XRScarce and fragile hair; pili tortiAbsent; short and coniforms; delayed eruptionHypoplasicNormalSkin: hyperpigmentation; dry and squamous on the scalp. Face: blepharophimosis; cleft lip/palate; micrognathia. Eyes: hypoplastic nasolacrimal ducts; hypoplastic; bilateral ptosis. Limbs: severe congenital contractures. Development: psychomotor and growth impairment
 Costello syndrome218040ARShort, sparse and curly scalp hair; thin in the anterior scalp; thick eyebrowsWidely spacedDystrophic; thin fingernails; small toenailsNormalSkin: loose (neck, palms, soles, and fingers) dark and with palmoplantar hyperkeratosis. Face: epicanthal folds; papillomata around the mouth and nares; depressed nasal bridge; thick lips; aged facial appearance. Eyes: strabismus. Development: mental retardation; short stature. Limbs: hyperextensible fingers. Other findings: large earlobes; macrocephaly; polyhydramnios; cardiomyopathy; skeletal deformities; feeding problems; verrucal lesions around the anus
 ED, cleft lip/palate, and severe cutaneous and osseous syndactyly and mental retardationFreihofer et al. 1997?Sparse and fine scalp hair; high frontal hair line; long eyelashesHypodontiaDystrophic; synonychosisNormalSkin: dry; ichthyosiform alterations in neck and legs. Face: cleft lip/palate, frontal bossing, nasal anomalies; hypoplasia of the maxilla; prominent lower lip. Hearing: deafness. Eyes: lagophthalmos; slanted palpebral fissures
 Odontotrichoungual-digital-palmar syndrome601957AD?; XD?Dystrophic; hypochromicNatal teeth; irregular eruption of secondary dentition; malocclusionDystrophic; absentNormalFace: prognathism; thick lips. Limbs: cutaneous syndactyly; brachydactyly; hypoplasia of the distal phalanges of the toes; transverse palmar creases
 Pineal hyperplasia, insulin-resistan + diabetes mellitus, and somatic abnormalities262190ARHypertrichosisDysplastic; early dentitionThick fingernailsNormalSkin: dry; acanthosis nigricans. Face: prognathism; senile-appearing facies. Development: short stature. Other findings: insulin-resistant diabetes mellitus; pineal hyperplasia; phallic enlargement
Subgroup hair-teeth
Barber–Say syndrome209885AR?; AD?; XD?Severe hypertrichosis; absent eyelashes; sparse eyebrowsDelayed eruptionNormalNormalSkin: redundant and lax; atrophic; absent or hypoplastic nipples. Face: macrostomia; small ears; bulbous and long nose; micrognathia; ectropion; telecanthus. Eyes: hypertelorism. Development: mental retardation; delayed speech development; low birth weight. Other findings: hypospadias; absence of mammary glands; senile facies.
 Cerebellar ataxia and ED212835ARHypotrichosis; sparse body hairHypodontiaNormalNormalFace: triangular. Development: cerebellar ataxia; cerebellar atrophy; hyperreflexia
 Congenital atrichia, palmoplantar hyperkeratosis, mental retardation, and early loss of teethSteijlen et al. 1994AR?Congenital atrichia; alopecia; short and fine scalp hair; sparse eyelashes and eyebrows; absent pubic and axillary hairDysplasic; premature lossNormalNormalSkin: palmoplantar hyperkeratosis. Development: mental retardation
 Craniotubular dysplasia with severe postnatal growth retardation, mental retardation, EDNishimura et al. 1997?Slow-growingEnamel hypoplasiaNormalNormalSkin: lax; thin; hyperelastic. Face: ample nasal root; broad auricular pavilions; thick lips; micrognathia. Limbs: hypoplastic distal phalanges. Development: mental retardation; severe growth retardation; hypotonia. Other findings: broad head; sclerosis in the skull base and in face bones; thick ribs; generalized osteopenia
 Distal arthrogryposis, ED, and dilated cardiomyopathy (Single case)Parker et al. 1998AR?Sparse scalp hair, woolly, fine and hypopigmented; sparse eyelashes and eyebrowsHypoplasic deciduous; enamel hypoplasia of the permanent teethNormalNormalSkin: dry; palmar creases not well defined. Face: upward-slanting palpebral fissures; epicanthus; hypoplasia of the median face; micrognathia; short neck. Limbs: distal arthrogryposis; small thumbs; moderate ulnar deviation. Development: moderate motor delay. Other findings: cardiomyopathy; kyphosis
 ED, Cape VerdeWerninghaus 1993ARHigh frontal hair line; sparse eyebrows and eyelashesEnamel hypoplasiaNormalNormalSkin: multiple non pigmented spots
 Mental retardation, hypotrichosis, and syndactylyLopes and Marques-de-Faria 1996AR?Hypotrichosis; sparse scalp hair and eyebrows; fine and dry scalp hairEarlier eruptionNormalNormalFace: round; prominent forehead, cheeks and ears; upward-slanting palpebral fissures. Limbs: syndactyly of fingers; hypoplasia of median and distal phalanges. Development: delayed motor development; mental retardation. Other findings: kyphosis
 Progeroid short stature with pigmented nevi (Mulvihill–Smith syndrome)176690ADMild hypotrichosis in shoulders and extremitiesHypodontia; short and irregular; taurodontia; enamel defects; hypoplastic deciduousNormalNormalSkin: dry; multiple pigmented nevi. Face: lack of facial subcutaneous fat; bird-like face. Eyes: visual loss; hypertelorism; keratoconus. Hearing: deafness. Limbs: reduced joint mobility. Development: mental retardation; dwarfism; short stature; delayed puberty. Other findings: thoracic scoliosis; hypospadias; bicuspid aortic valve with mild aortic stenosis; immunodeficiency; microcephaly; hepatomegaly
 Rodrigues blindness (microphthalmia, microcornea, and sclerocornea with short stature and hair and dental abnormalities)268320ARHypotrichosis; fine and sparse scalp hairMalformed and malalignedNormalNormalFace: dysmorphic; narrow nasal bridge with marked distal flaring; short upper lip; prominent ears. Eyes: blindness; microphthalmia; microcornea; sclerocornea. Development: mental retardation; short stature
Subgroup hair-nails
 Alopecia, nail dystrophy, palmoplantar hyperkeratosis, keratitis, hearing difficulty and micrognathia (Single case)Nakamura and Ishikawa 2007?Alopecic regions on the scalp; scant eyelashes and eyebrowsNormalLongitudinal fissures and distal onycholysis in fingernails and in toenailsNormalSkin: hyperkeratosis on palms and soles. Face: micrognathia. Hearing: conductive hearing difficulties progressed in both ears. Eyes: keratitis
 Autosomal recessive neurodegenerative disorder with trichorrhexis invaginata and EDGyure et al. 1992AR?Sparse, short and fine scalp hair; trichorrhexis invaginata; scarce eyelashes and eyebrowsNormalHypoplasic or absentNormalSkin: dry; desquamation; undeveloped dermal ridges; squamous in the scalp and in the back; subcutaneous tissue reduction; single palmar crease. Eyes: vision impairment; opacity of cornea; nystagmus. Limbs: pes cavus; hammer toes. Development: hypotonus; absence or redution of reflexes; delayed development; EEG alterations; late response to pain; seizure. Other findings: high narrow palate; breathing difficulties; umbilical hernia; inguinal hernia
 Hair-nail dysplasiaPinheiro and Freire-Maia 1992ADVariable hypotrichosis; fine, sparse and fragile scalp hair; structural hair alterationsNormalShort, fragile and spooned nails; mild dystrophyNormal 
 Hypotrichosis and nail dysplasia, hidrotic ED (Single case)Harrison and Sinclair 2004?Short, sparse scalp hair with decreased number of follicles; absent eyebrows; short eyelashes; trichorrhexis nodosaNormalDystrophic in all digits; distal onycholysis; shortened nail plate; loss of the cuticleNormal 
 T-cell immunodeficiency, congenital alopecia, and nail dystrophy601705AR?Congenital alopeciaNormalRidging and pitting of all nailsNormalOther findings: severe T-cell immunodeficiency
Subgroup hair-sweat glands
 Tetra-amelia with ED and lacrimal duct abnormalities (Single case)273390ARHypotrichosis; absent eyebrows, eyelashes and scalp hairNormalNormalHyperthermiaFace: large downturned mouth; prominent and bulbous nose; bilateral preauricular pits; upward-slanting palpebral fissures. Eyes: lack of lacrimal openings; hypoplastic lacrimal ducts; sacs opening toward the exterior. Limbs: tetra-amelia. Development: mental retardation. Other findings: cryptorchidism; persistent constipation; dehydration; high narrow palate
Subgroup teeth-nails
 Haim-Munk syndrome (HMS)245010ARNormalSevere periodontitis; brittle teethOnichogryposis; atrophic alterationsNormalSkin: palmoplantar hyperkeratosis; scaly and erythematosus patches. Limbs: pes planus; arachnodactyly; acroosteolysis; deformity of distal phalanges
 Odonto-ungueal dysplasiaPinheiro and Freire-Maia 1996ADNormalPersistence of deciduous; hypodontia; enamel hypoplasia; microdontia; peg shaped incisors and canine teethShort, fine and fragileNormal 
 Otopalatodigital syndrome, type I (OPD1)311300XDNormalHypodontiaShort and dystrophicNormalFace: hypertelorism; frontal bossing; broad nasal root. Hearing: conductive hearing loss. Limbs: brachydactyly; clinodactyly; wide-spaced toes; broad thumbs and big toes; limited elbow extension. Development: mental retardation; short stature. Other findings: cleft palate; pectus excavatum; scoliosis; osteochondrodysplasia
 Pycnodysostosis265800ARNormalHypodontia; delayed eruption; persistence of deciduous teethDysplastic; brittleNormalFace: hypoplasia of median face; hypoplasic mandible. Limbs: brachydactyly; acroosteolysis. Development: short stature. Other findings: brachycephaly; hypoplasic clavicle; hypoplasic acetabulum; hip dislocation; wide cranial sutures; bone fragility; hepatosplenomegaly; anemia; craniostenosis
 Williams–Beuren syndrome (WBS)194050ADNormalHypodontia; microdontiaHypoplastic; short nailsNormalFace: elfin facies. Eyes: stellate iris pattern. Limbs: hallux valgus; radioulnar synostosis. Development: mental retardation; short stature. Other findings: supravalvular aortic stenosis; peripheral pulmonary arterial stenoses; renal abnormalities; hoarse voice; pectus excavatum; scypho scoliosis; diverticulitis; inguinal hernia; hypercalcemia; arterial hypertension

MOLECULAR ASPECTS OF EDs

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DEFINITION, CLASSIFICATION, AND REVISION OF ECTODERMAL DISPLASIAS
  5. MOLECULAR ASPECTS OF EDs
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES

The recent discoveries of mutations responsible as cause of several EDs provide a better understanding of these conditions. Table III updates previous reviews [Priolo et al., 2000; Priolo and Laganà, 2001; Lamartine, 2003; Itin and Fistarol, 2004], adding almost 50 genes in those reported by Lamartine 2003, whose functional classification was followed. In some cases, one gene is responsible for the manifestation of a specific ED, for instance, mutations of the PKP1 gene (1q32) cause ED/skin fragility syndrome, and the PORCN gene (Xp11.23) is responsible for focal dermal hypoplasia. However, mutations in one gene cause clinically different EDs and mutations in different genes can determine the same ED entity, as will be discussed. Two conditions (Table III) for which only the clinical subgroups and chromosomal regions were assigned [Rafiq et al., 2005; Tariq et al., 2008] were not included in Table I, as they may represent previously described EDs.

Table III. Genes (N = 64) and Chromosomal Regions (N = 3) Responsible for 62 Different Ectodermal Dysplasias
ChromosomeGeneGene functionaProtein or gene productEctodermal dysplasia (ED)OMIM/Reference
  • a

    Gene function: S, cell–cell communication and signaling; R, regulation of transcription; A, adhesion; D, development; O, other; ?, not fully understood.

  • b

    ED of the B group.

  • c

    ED characterized only as belonging to a subgroup without further delineation.

  • d

    Possibly determined by the PVRL1 gene.

Xp11.23PORCNOFive isoforms (PORCA–PORCE)Focal dermal hypoplasia305600
Xp22.3-p22.2OFD1?OFD1 proteinOrofaciodigital syndrome 1311200
Xq12-q13.1ED1SEctodysplasin-AXLHED (CST)305100
Xq28NEMOSIKK-γIncontinentia pigmenti 2;308300
    OLEDAID syndrome300301
    Hypohidrotic ED with immune deficiency300291
Xq28DKC1ODyskerinDyskeratosis congenita, X-linked305000
Xq28FLNAOFilamin AOtopalatodigital syndrome (OPD1)311300
1p21COL11A1OCollagen XI alpha 1Marshall syndrome154780
1q21CTSKOCathepsin KPycnodysostosis265800
1q32PKP1APlakophilin 1ED/skin fragility syndrome.604536
1q42.2-q43EDARADDSEctodysplasin-A receptor adapterADHED and ARHED129490, 224900
2q11-q13EDARSEctodysplasin-A receptorADHED and ARHED129490, 224900
2q21ERCC3OExcision-repair cross-complementing rodent repair deficiency, complementation group 3Trichothiodystrophy601675
2q35WNT10ASWingless-type MMTV integration site family, member 10AOdontoonychodermal dysplasia (OODD)257980
3q21-q28TERCOTelomerase RNA componentDyskeratosis congenita, AD127550
3q27TP63Rp63 (p73-like)ADULT syndrome103285
    Ectrodactyly, ED, cleft lip/palate syndrome 3 (EEC3)604292
    Limb–mammary syndrome603543
    Ankyloblepharon-ED106260
    SHFM4 syndromeb605289
    Rapp–Hodgkin syndrome (RHS)129400
4p16EVC and EVC2REVCEllis–van Creveld225500
    Weyers acrofacial dysostosis193530
4p16.1MSX1DMsx1Witkop syndrome189500
4p16.3FGFR3SFibroblast growth factor receptor-3Lacrimoauriculodentodigital syndrome149730
5p13-p12FGF10SFibroblast growth factor-10Lacrimoauriculodentodigital syndrome149730
5p15.33TERTOTelomerase reverse transcriptaseDyskeratosis congenita, AD127550
6p25.3TGF2H5OGeneral transcription factor IIH, polypeptide 5Trichothiodystrophy601675
6q21-q23.2GJA1SConnexin 43Oculodentodigital dysplasia (ODDD)164200
7p14TTDN1 (C7ORF11)OTTD non-photosensitive 1 proteinTrichothiodystrophy, nonphotosensitive 1 (TTDN1)234050
7q11.2-q21.3EEC1  Ectrodactyly, ED, cleft lip/palate syndrome 1 (EEC1)129900
7q11.2ELNOElastinWilliams–Beuren syndrome (WBS)194050
7q11.23RFC2?Replication factor C2Williams–Beuren syndrome194050
 CYLN2?Cytoplasmic linker 2Williams–Beuren syndrome194050
 LIMK1RLIM domain kinase 1Williams–Beuren syndrome194050
 GTF2IRD1RGTF21 repeat domain-containing protein 1Williams–Beuren syndrome194050
 GTF2IRGeneral transcription factor II-I (BTK-associated protein)Williams–Beuren syndrome194050
7q32MEK2OMitogen-activated protein kinase kinase 2Cardiofaciocutaneous syndrome (CFC)115150
7q32-q34   Coffin–Siris syndrome135900
7q34BRAFOp21s proteinCardiofaciocutaneous syndrome115150
7q36SHHDSonic HedgehogSMMCI syndromeb147250
8q24.12TRPS1RZinc finger transcription factorTrichorhinophalangeal syndrome190350
8q24.3RECQL4ODNA helicase, RecQ-like 4Rothmund–Thomson syndrome268400
9p21-p12RMRPOMitochondrial RNA-processing endoribonucleaseCartilage-hair hypoplasia250250
10p15GATA3RGATA binding protein-3Hypoparathyroidism, sensorineural deafness, and renal dysplasiab146255
10q24.32–q25.1   Subgroup 1-3 EDcRafiq et al. 2005
10q26FGFR2SFibroblast growth factor receptor-2Lacrimoauriculodentodigital syndrome149730
11p15.5HRASOp21s proteinCostello syndrome218040
11q14.1-q14.3CTSCOCathepsin CPapillon–Lefèvre syndrome245000
    Haim-Munk syndrome245010
11q23-q24PVRL1ANectin 1Cleft lip/palate-ED syndrome (CLPED1)225060
    Rosselli–Gulienetti syndrome225000
    Odontotrichomelic syndromed273400
12p12.1KRAS2Op21s proteinCostello syndrome218040
    Cardiofaciocutaneous syndrome115150
12q13KRTHB1, KRTHB3, and KRTHB6OKeratins 81, 83, and 86Monilethrix158000
12q13KRT6A and KRT6BOKeratins 6A and 6BPachyonychia congenita 1 and 2167200, 167210
12q13KRTHB5OKeratin 85ED, ‘pure’ hair-nail type602032
12q24.1TBX3?Tbx 3Ulnar–mammary syndrome181450
13q11-q12GJB2SConnexin 26Palmoplantar keratoderma, with deafnessb148350
    Keratitis-ichthyosis-deafness syndrome, AD (KID, AD)148210
    Ichthyosis, hystrix-like, with deafness (HID syndrome)b602540
13q12GJB6SConnexin 30Clouston syndrome129500
14q12TINF2OTRF1-interacting nuclear factor 2Dyskeratosis congenita, AD127550
15q14-q15NOLA3ONucleolar protein family A, member 3Dyskeratosis congenita, AR224230
15q15-q21.1UBR1OUbiquitin-protein ligase E3-alphaJohanson-Blizzard syndrome243800
15q21MEK1OMitogen-activated protein kinase kinase 1Cardiofaciocutaneous syndrome115150
16q22.1CDH3ACadherin-3HJMD syndromeb601553
    ED, ectrodactyly, and macular dystrophy (EEM)225280
17q11-q12WHNRWinged-helix transcription factorT-cell immunodeficiency, congenital alopecia, and nail dystrophy601705
17q12-q21KRT14OKeratin 14Naegeli–Franceschetti–Jadassohn syndrome161000
17q12-q21KRT16 and KRT17OKeratins 16 and 17Pachyonychia congenita 1 and 2167200, 167210
17q21.3-q22DLX3DHomeobox protein DLX-3Trichodentoosseous syndrome190320
18q22.1–22.3   Subgroup 1-2-3 EDcTariq et al. 2008
19p13.2INSRSInsulin receptorPineal hyperplasia, insulin-resistant diabetes mellitus, and somatic abnormalities262190
19q13.2-q13.3ERCC2ODNA excision repair protein 2 (ERCC-2)Trichothiodystrophy601675

One Gene—Different EDs

IKK-γ, encoded by the NEMO gene (Xq28), is an important regulator of the NF-κB pathway. Mutations in the NEMO gene cause hypohidrotic ED with immune deficiency (OMIM 300291), incontinentia pigmenti 2 (OMIM 308300) and hypohidrotic ED with immunodeficiency, osteopetrosis and lymphedema (OLEDAID syndrome, OMIM 300301).

The TP63 gene, also known as TP73L (3q27) encodes several isoforms with divergent abilities to transactivate P53 reporter genes and induce apoptosis. Mutations in TP63 are responsible for the development of at least six different EDs: ADULT syndrome (OMIM 103285), EEC3 (OMIM 604292), limb–mammary syndrome (LMS, OMIM 603543), Hay–Wells syndrome (AEC, OMIM 106260), Rapp–Hodgkin syndrome (OMIM 129400) and split-hand/foot malformation 4 (SHFM4, OMIM 605289). This last ED belongs to the B group. The pattern of TP63 mutations in these syndromes indicates genotype–phenotype correlations (Brunner et al., 2002).

Nectin 1 is an adhesion molecule that is part of the NAP cell adhesion system and mutations in the PVRL1 gene (11q23-q24) may lead to three different EDs. Cleft lip/palate-ED syndrome (ED, Margarita Island type; Zlotogora–Oğur syndrome; OMIM 225060) is characterized by hypotrichosis, dental and facial anomalies, dysplastic nails, cleft lip/palate and palmoplantar hyperkeratosis. Rosselli–Gulienetti syndrome (OMIM 225000) is characterized by anhidrosis, hypotrichosis, microdontia, dysplasia of nails, cleft lip/palate, deformity of the fingers and toes, and malformation in the genitourinary system. Odontotrichomelic syndrome (OMIM 273400) has also the PVRL1 as its candidate gene.

Other genes are also responsible for more than one clinical type of EDs (EVC, EVC2, CTSC, KRAS2, GJB2, and CDH3) as shown in Table III.

Different Genes—One Clinical ED

The cardiofaciocutaneous syndrome (CFC, OMIM 115150) is caused by gain-of function mutations in 4 different genes BRAF (7q34), KRAS2 (12p12.1), MEK1 (15q21), and MEK2 (7q32), all belonging to the same RAS-extracellular signal-regulated kinase (ERK) pathway that regulates cell differentiation, proliferation, and apoptosis [Roberts et al., 2006]. The Costello syndrome (OMIM 218040) may also be caused by mutations in the KRAS2 gene and in the HRAS gene (11p15.5).

Ellis–van Creveld syndrome (OMIM 225500) may be caused by mutations in the EVC and EVC2 genes that code for an intracellular mediator of the hedgehog transduction signal pathway which is necessary for endochondral growth [Ruiz-Perez et al., 2007]. Ruiz-Perez et al. 2003 found that both genes are arranged in a divergent configuration with transcription start sites separated by 2624 bp in the human chromosome 4 (4p16). Shimada et al. 1989 and Platzer et al. 1997 gave examples of coregulation by a single promoter with bidirectional activity and Adachi and Lieber 2002 concluded that such head-to-head configurations may be common in the human genome.

Wang et al. 1999 reviewed published reports of Williams–Beuren syndrome (WBS, OMIM 194050) and noted that 33% of the patients had dys/hypoplastic nails and that 58% had dental anomalies, showing that this syndrome is an ED in some of the patients. Approximately 90% of WBS patients present a 2 Mb deletion in chromosome 7 (7q11.23) where the ELN, LIMK1, RFC2, CYLN2, GTF2IRD1, and GTF2I genes are located. Haploinsufficiency of these genes is responsible for WBS.

Dyskeratosis congenita presents three inheritance patterns. The X-linked (Xq28, OMIM 305000) and AR (15q14-q15, OMIM 224230) forms are each determined by a specific gene. On the other hand, the AD form (OMIM 127550) may be caused by mutations in the three following genes: TERC (3q21-q28) that codes for a telomerase RNA component; TERT (5p15.33) that determines a telomerase reverse transcriptase; and TINF (14q12) that codes for an interacting nuclear factor.

Monilethrix (OMIM 158000) is caused by mutations in genes responsible for hair keratin: KRTHB1, KRTHB3, and KRTHB6 (all in 12q13). The two pachyonychia congenita forms, type 1 (OMIM 167200) and type 2 (OMIM 167210) and the lacrimoauriculodentodigital syndrome (LADD, OMIM 149730) are other examples of EDs that may be caused by mutations located in different genes.

There is an unusual situation in which three hypohidrotic EDs (HED) show identical clinical manifestation but different inheritance patterns, being classified as separate entities: X-linked HED (OMIM 305100), autosomal dominant (ADHED, OMIM 129490) and autosomal recessive (ARHED, OMIM 224900). The clinical similarity of these forms of HED is related to the involvement of Ectodysplasin, EDAR (a member of the TNF receptor family), and EDARADD in the same signaling pathway. Ectodysplasin binds to its receptor EDAR which recruits the adapter protein EDARADD to transduce a signal and activate NF-κB via the IKK complex [Headon et al., 2001]. The XLHED form (OMIM 305100) is determined by mutations in the ED1 gene (EDA, Xq12-q13.1) that codes for ectodysplasin-A. Mutations in the EDAR gene (2q11-q13) which codes for the EDAR receptor cause both the autosomal forms: ARHED (OMIM 224900) and ADHED (OMIM 129490) [Monreal et al., 1999]. The EDARADD gene (1q42.2-q43) which determines the adaptor for the EDAR receptor may also cause hypohidrotic ED of the AR [Headon et al., 2001] and AD [Bal et al., 2007] inheritance patterns.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DEFINITION, CLASSIFICATION, AND REVISION OF ECTODERMAL DISPLASIAS
  5. MOLECULAR ASPECTS OF EDs
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES

It is important to have a clear and well delimited definition of EDs because it is the definition that gives the starting point for classifying these disturbances. The ED definition proposed by Freire-Maia 1971, 1977 has these requirements and generates a simple classification that is useful for diagnostic purposes.

Researches at the molecular level lead to the discovery of gene defects responsible for EDs and provide the causal diagnosis that may reduce the number of classified entities whenever EDs described as different clinical disturbances are shown to represent variable expressivity of the same ED.

The combination of both procedures—clinical and molecular—only brings advantages for a deeper knowledge on EDs. First, it allows a rapid diagnosis that may become even more precise whenever DNA exams are available. Secondly, the comprehension of the biological mechanisms that cause EDs is needed for the design of efficient prevention and treatment approaches.

All definitions and resulting classifications carry a degree of artificiality. Adding the fact that new discoveries are constantly made, it is evident that both definition and classification of EDs are dynamic and their re-evaluation is required from time to time. So, the number of EDs presented in this revision may be altered soon, new gene mutations conditioning these disturbances will continue to be identified and promising methods for prevention, diagnosis, and treatment will follow. Phenotype comparisons will continue to provide hints to interactions at the molecular level, leading to the discovery of new metabolic pathways. It is envisaged that with the increasing collaboration between researchers on fundamental biology and clinical aspects of EDs, using investigative procedures appropriate for each field, a clearer panorama of this nosologic group will be achieved in the early future.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DEFINITION, CLASSIFICATION, AND REVISION OF ECTODERMAL DISPLASIAS
  5. MOLECULAR ASPECTS OF EDs
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES

We thank Dr. Marta Pinheiro and Dr. Carlos F. Salinas for the valuable critical reading of this manuscript and for fruitful discussions.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DEFINITION, CLASSIFICATION, AND REVISION OF ECTODERMAL DISPLASIAS
  5. MOLECULAR ASPECTS OF EDs
  6. CONCLUSIONS
  7. Acknowledgements
  8. REFERENCES
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