How to cite this article: Visinoni ÁF, Lisboa-Costa T, Pagnan NAB, Chautard-Freire-Maia EA. 2009. Ectodermal dysplasias: Clinical and molecular review. Am J Med Genet Part A 149A:1980–2002.
Ectodermal dysplasias: Clinical and molecular review†
Article first published online: 13 AUG 2009
Copyright © 2009 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A
Special Issue: Ankyloblepharon-Ectodermal Defects-Cleft Lip and/or Palate Syndrome and Ectodermal Dysplasias
Volume 149A, Issue 9, pages 1980–2002, September 2009
How to Cite
Visinoni, Á. F., Lisboa-Costa, T., Pagnan, N. A.B. and Chautard-Freire-Maia, E. A. (2009), Ectodermal dysplasias: Clinical and molecular review. Am. J. Med. Genet., 149A: 1980–2002. doi: 10.1002/ajmg.a.32864
- Issue published online: 20 AUG 2009
- Article first published online: 13 AUG 2009
- Manuscript Accepted: 9 MAR 2009
- Manuscript Received: 18 NOV 2008
- ectodermal dysplasias;
- ectodermal appendage alterations
- Top of page
- DEFINITION, CLASSIFICATION, AND REVISION OF ECTODERMAL DISPLASIAS
- MOLECULAR ASPECTS OF EDs
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.
- Top of page
- DEFINITION, CLASSIFICATION, AND REVISION OF ECTODERMAL DISPLASIAS
- MOLECULAR ASPECTS OF EDs
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
- Top of page
- DEFINITION, CLASSIFICATION, AND REVISION OF ECTODERMAL DISPLASIAS
- MOLECULAR ASPECTS OF EDs
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.
|Ectodermal dysplasia (ED)||Reference (OMIM, whenever available)||Inheritance|
|Subgroup hair-teeth-nails-sweat glands. N = 42, Single case = 4|
|1||Acrorenal field defect, ED, and lipoatrophic diabetes (AREDYLD)||207780||AR|
|2||Alopecia-contractures-dwarfism mental retardation syndrome||203550||AR|
|3||Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC; Hay–Wells syndrome)||106260||AD|
|4||Anonychia with flexural pigmentation||106750||AD|
|5||Arthrogryposis and ED||601701||AR|
|6||Camarena syndrome||Freire-Maia and Pinheiro 1984 (Pers. comm.)||AD?; XD?|
|7||Carey syndrome (Single case)||Freire-Maia and Pinheiro 1984 (Pers. comm.)||?|
|8||Cleft lip/palate-ED syndrome (CLPED1; Zlotogora–Oğur syndrome; Margarita Island syndrome)||225060||AR|
|9||Curly hair-acral keratoderma-caries syndrome||Van Steensel et al. 2001||AD|
|10||Dyskeratosis congenita, AD (Dyskeratosis congenita, Scoggins type)||127550||AD|
|11||Dyskeratosis congenita, AR||224230||AR|
|12||Dyskeratosis congenita, X-linked (Zinsser–Cole–Engman syndrome)||305000||XR|
|13||Ectrodactyly, ED, and cleft lip/palate syndrome (EEC1)||129900||AD|
|14||Ectrodactyly, ED, and cleft lip/palate syndrome 3 (EEC3)||604292||AD|
|15||ED hypohidrotic, with acanthosis nigricans (Lelis syndrome)||608290||?|
|16||ED with alopecia, onychodysplasia, hypohidrosis, keratoderma, abnormal teeth and deafness (Single case)||Akhyani and Kiavash 2007||AR?|
|17||ED with cardiac and skeletal abnormalities (Single case)||Lipson 1988||?|
|18||ED with mental retardation and syndactyly (Single case)||600906||AR?|
|19||ED with natal teeth, Turnpenny type||601345||AD|
|20||ED, Caratinga type||Montebelo et al. 1996||AD?; XD?|
|21||ED, hypohidrotic, with hypothyroidism and agenesis of the corpus callosum||225040||AD?; AR?; XD?|
|22||Focal dermal hypoplasia (FDH)||305600||XD|
|23||Hypohidrotic ED, autosomal dominant (ADHED)||129490||AD|
|24||Hypohidrotic ED, autosomal recessive (ARHED)||224900||AR|
|25||Hypohidrotic ED, X-linked (XLHED; Christ–Siemens–Touraine syndrome; CST syndrome)||305100||XR|
|26||Hypohidrotic ED with immune deficiency||300291||XD|
|27||Hypohidrotic ED with immunodeficiency, osteopetrosis, and lymphedema (OLEDAID syndrome)||300301||XD|
|28||Hypomelanosis of Ito (HMI, Incontinentia pigmenti type I; IP1)||300337||XD|
|29||Keratitis-ichthyosis-deafness syndrome, autosomal dominant (KID syndrome, AD)||148210||AD|
|30||Keratitis-ichthyosis-deafness syndrome, autosomal recessive (KID syndrome, AR)||242150||AR|
|31||Naegeli–Franceschetti–Jadassohn syndrome (NFJS)||161000||AD|
|32||Odontoonychodermal dysplasia (OODD)||257980||AR|
|34||Pachyonychia congenita, type 1 (PC1)||167200||AD|
|35||Pachyonychia congenita, type 2 (PC2)||167210||AD|
|39||Scalp-ear-nipple syndrome (Finlay–Marks syndrome; ED with adrenal cyst)||181270; 129550||AD|
|40||Tricho-odonto-onychodysplasia with pili torti||Freire-Maia and Pinheiro 1984 (Pers. comm.)||AD?; XD?|
|41||Tricho-onycho-dental dysplasia (TOD)||Koshiba et al. 1978||AD|
|42||Xeroderma-talipes-enamel defects (XTE)||Moynahan 1970||AR|
|Subgroup hair-teeth-nails. N = 43, Single cases = 10|
|45||Arthrogryposis, ED, cleft lip/palate, and developmental delay||301815||XR|
|46||Cardiofaciocutaneous syndrome (CFC)||115150||AD|
|48||Coffin–Siris syndrome||135900||AD?; AR?; XD?|
|50||Cranioectodermal dysplasia (Sensenbrenner syndrome)||218330||AR|
|52||Dolichocephaly, dental defects, trichodysplasia||Freire-Maia and Pinheiro 1984 (Pers. comm.)||AD|
|53||Ectodermal defect with skeletal abnormalities (Single case)||Wallace 1958||?|
|54||ED syndrome with distinctive facial appearance and preaxial polydactyly of feet (Single case)||129540||AD?|
|55||ED with pillous anomaly and syndactyly||Wiedemann et al. 1980||AR|
|56||ED with tetramelic deficiencies (Single case)||Freire-Maia and Pinheiro 1984 (Pers. comm.)||?|
|57||ED, cleft lip/palate, and severe cutaneous and osseous syndactyly and mental retardation (Single case)||Freihofer et al. 1997||?|
|58||ED, trichoodontoonychial type||129510||AD|
|59||Ellis–van Creveld syndrome (EVC)||225500||AR|
|61||Growth retardation, alopecia, pseudoanodontia, and optic atrophy (GAPO syndrome)||230740||AR|
|62||Hidrotic ED autosomal recessive (Fried's tooth and nail syndrome)||602401||AR|
|63||Hypoplasia of nails, malformations of hands and feet, curly hair, microdontia, seizures (Single case)||Cortes and Lacassie 1986||?|
|64||Hypotrichosis with pili bifurcati||Beemer et al. 1987||AR?|
|65||Incontinentia pigmenti (IP2)||308300||XD|
|66||Mesomelic dwarfism-skeletal abnormalities-ED (Single case)||Brunoni 1984||?|
|68||Odonto-onychodysplasia-alopecia||Pinheiro and Freire-Maia 1981||AR|
|69||Odontotrichoungual-digital-palmar syndrome||601957||AD?; XD?|
|70||Osteosclerosis and ED (Single case)||Côté and Katsantoni 1982||AR|
|71||Pilo-dento-ungular dysplasia with microcephaly (Single case)||Tajara et al. 1987||AR|
|72||Pineal hyperplasia, insulin-resistant diabetes mellitus, and somatic abnormalities||262190||AR|
|73||Rothmund–Thomson syndrome (RTS)||268400||AR|
|74||Šalamon–Miličevič syndrome (Single case)||Šalamon and Miličevič 1964||AR|
|75||Schinzel–Giedion midface-retraction syndrome||269150||AR?; AD?|
|78||Thumb deformity and alopecia||188150||AD|
|79||Trichodentoosseus syndrome (TDO)||190320||AD|
|80||Tricho-dermodysplasia-dental defects||Pinheiro et al. 1986||AD?; XD?|
|82||Tricho-odonto-onycho-dermal syndrome (Single case)||Pinheiro et al. 1981||?|
|83||Trichorhinophalangeal syndrome, type I (TRPS1)||190350||AD|
|84||Trichothiodystrophy, photosensitive (TTDP)||601675||AR|
|Subgroup hair-teeth-sweat glands. N = 10, Single cases = 2|
|87||Cleft lip/palate, ED, acral anomalies||Richieri-Costa et al. 1992||AR|
|88||Hypohidrotic ED with focal sweating||Gorlin 1988||AR?; XR?|
|89||Ichthyosis follicularis, atrichia, and photophobia syndrome (IFAP)||308205||XR|
|90||Johnson neuroectodermal syndrome||147770||AD|
|91||Lenz–Passarge dysplasia||Lenz 1963||XD|
|92||Leukomelanoderma, infantilism, mental retardation, hypodontia, hypotrichosis||246500||AR|
|93||Regional ED with total bilateral cleft (Single case)||Fára 1971||?|
|94||Ulnar–mammary syndrome (UMS)||181450||AD|
|95||Wesser-Vistnes ED with palatal paralysis (Single case)||Wesser and Wistnes 1969||?|
|Subgroup hair-nails-sweat glands. N = 8, Single cases = 4|
|96||Alopecia-onichodysplasia-hypohidrosis-deafness (Single case)||Freire-Maia et al. 1977||?|
|97||Alopecia-skin atrophy-anonychia-tongue defects||Sequeiros and Sack 1985||?|
|98||ED with digital and eye anomalies (Single case)||Viljoen and Winship 1988||?|
|99||ED with severe mental retardation (Single case)||Kirman 1955||?|
|100||ED, hypohidrotic, with hypothyroidism and ciliary dyskinesia (HEDH syndrome)||225050||AR|
|101||ED/skin fragility syndrome||604536||AR|
|102||Fischer-Volavsek syndrome||Fischer 1921||AD|
|103||Trichodysplasia-onychogryposis-hypohidrosis-cataract (Single case)||Freire-Maia et al. 1975||?|
|Subgroup teeth-nails-sweat glands. N = 2|
|105||Limb–mammary syndrome (LMS)||603543||AD|
|Subgroup hair-teeth. N = 32, Single cases = 3|
|106||Barber–Say syndrome||209885||AR?; AD?; XD?|
|109||Cataract, hypertrichosis, mental retardation syndrome (CAHMR syndrome)||211770||AR|
|110||Cerebellar ataxia and ED||212835||AR|
|111||Cleft lip/palate-oligodontia-syndactyly-hair defects||Martínez et al. 1987||AD?; XD?|
|112||Congenital atrichia, palmoplantar hyperkeratosis, mental retardation, and early loss of teeth||Steijlen et al. 1994||AR?|
|113||Craniotubular dysplasia with severe postnatal growth retardation, mental retardation, ED (Single case)||Nishimura et al. 1997||?|
|114||Distal arthrogryposis, ED and dilated cardiomyopathy (Single case)||Parker et al. 1998||AR?|
|116||ED and neurosensory deafness||224800||AR|
|117||ED, Cape Verde||Werninghaus 1993||AR|
|118||ED, ectrodactyly, and macular dystrophy (EEM syndrome)||225280||AR|
|119||Gingival fibromatosis with hypertrichosis||135400||AD|
|120||Gingival fibromatosis-sparse hair-malposition of teeth (Single case)||Jorgenson 1971||AR|
|122||Hallermann–Streiff syndrome (HSS)||234100||AR|
|124||Johanson-Blizzard syndrome (JBS)||243800||AR|
|125||Mental retardation, hypotrichosis, and syndactyly||Lopes and Marques-de-Faria 1996||AR?|
|126||Oculodentoosseous dysplasia, recessive||257850||AR|
|127||Oculodentodigital dysplasia (ODDD)||164200||AD|
|128||Orofaciodigital syndrome I (OFD1)||311200||XD|
|130||Pilodental dysplasia with refractive errors||262020||AR|
|131||Progeroid short stature with pigmented nevi (Mulvihill–Smith syndrome)||176690||AD|
|132||Rodrigues blindness (microphthalmia, microcornea, and sclerocornea with short stature and hair and dental abnormalities)||268320||AR|
|134||Trichodysplasia and amelogenesis imperfecta||Angelos and Jorgenson 1993||AD?; XD?|
|135||Uncombable hair, retinal pigmentary dystrophy, dental anomalies, and brachydactyly||191482||AD|
|136||Walbaum–Dehaene–Schlemmer syndrome||Walbaum et al. 1971||AR|
|137||Zunich neuroectodermal syndrome||280000||AR|
|Subgroup hair-nails. N = 26, Single cases = 2|
|138||Alopecia congenita with keratosis palmoplantaris||104100||AD|
|139||Alopecia, nail dystrophy, palmoplantar hyperkeratosis, keratitis, hearing difficulty and micrognathia (Single case)||Nakamura and Ishikawa 2007||?|
|140||Anonychia-onychodystrophy with hypoplasia or absence of distal phalanges (Cooks syndrome)||106995||AD|
|141||Autosomal recessive neurodegenerative disorder with trichorrhexis invaginata and ED||Gyure et al. 1992||AR?|
|142||Cartilage-hair hypoplasia (CHH)||250250||AR|
|143||Curly hair-ankyloblepharon-nail dysplasia syndrome (CHANDS)||214350||AR|
|144||ED hidrotic, Christianson–Fourie type||601375||AD|
|145||ED with skin anomalies and mental retardation||Halal et al. 1991||AR|
|146||ED, ‘pure’ hair-nail type||602032||AD?|
|147||Hair-nail dysplasia||Pinheiro and Freire-Maia 1992||AD|
|148||Hairy elbows (Hypertrichosis cubiti)||139600||AD|
|149||Hypotrichosis and nail dysplasia, hidrotic ED (Single case)||Harrison and Sinclair 2004||?|
|150||Ichthyosis and male hypogonadism||308200||XR?|
|151||Ichthyosis with alopecia, eclabion, ectropion, and mental retardation||242510||AR|
|152||Lymphedema-hypoparathyroidism syndrome||247410||AR?; XR?|
|154||Onychotrichodysplasia and neutropenia||258360||AR|
|155||Pili torti and onychodysplasia||Beare 1952||AD|
|156||Pili torti, alopecia and onychodysplasia||Calzavara-Pinton et al. 1991||AR|
|157||Polyposis, skin pigmentation, alopecia, and fingernail changes||175500||?|
|158||Popliteal pterygium syndrome, lethal type||263650||AR|
|159||Syndrome of accelerated skeletal maturation, failure to thrive and peculiar face (Marshall syndrome II)||Marshall et al. 1971||AR?; XR?|
|160||T-cell immunodeficiency, congenital alopecia, and nail dystrophy||601705||AR?|
|161||Trichomegaly with mental retardation, dwarfism, and pigmentary degeneration of retina||275400||AR|
|162||Tricho-onychodysplasia-xeroderma||Freire-Maia et al. 1985||AR|
|163||Trichothiodystrophy, nonphotosensitive 1 (TTDN1)||234050||AR|
|Subgroup hair-sweat glands. N = 5, Single case = 1|
|164||Dry skin and extranumerary areolae||Freire-Maia and Chautard-Freire-Maia 1990||AD|
|165||Focal facial dermal dysplasia (facial ED)||136500; 227260||AD|
|166||Short stature-kidney insufficiency-ophthalmological anomaly-growth retardation-ED (SKORED)||Greenstein et al. 1985||AR?; XR?|
|167||Tetra-amelia with ED and lacrimal duct abnormalities (Single case)||273390||AR|
|168||Tricho-facio-hypohidrotic syndrome||Antley et al. 1976||AR?; XR?|
|Subgroup teeth-nails. N = 13|
|169||Corneodermatoosseous syndrome (CDO syndrome)||122440||AD|
|170||Deafness, congenital, and onychodystrophy, autosomal dominant||124480||AD|
|171||Deafness, onychodystrophy, osteodystrophy, and mental retardation syndrome (DOOR syndrome)||220500||AR?; AD?|
|172||Dermatoosteolysis, Kirghizian type||221810||AR|
|173||Haim-Munk syndrome (HMS)||245010||AR|
|174||Hearing loss, sensorineural, with enamel hypoplasia and nail defects (Heimler syndrome)||234580||AR|
|175||Lacrimoauriculodentodigital syndrome (LADD)||149730||AD|
|177||Odonto-ungueal dysplasia||Pinheiro and Freire-Maia 1996||AD|
|178||Otopalatodigital syndrome, type I (OPD1)||311300||XD|
|180||Weyers acrofacial dysostosis||193530||AD|
|181||Williams–Beuren syndrome (WBS)||194050||AD|
|Subgroup teeth-sweat glands. N = 3|
|182||Hypohidrotic ED with mydriasis, iris atrophy, and mental retardation||Beyer et al. 1979||AD?|
|183||Kohlschutter–Tonz syndrome (epilepsy, dementia, and amelogenesis imperfecta)||226750||AR?; XR?|
|184||Marshall syndrome I||154780||AD|
|Subgroup nail-sweat glands. N = 2|
|185||ED, absent dermatoglyphic pattern, changes in nails, and simian crease||129200||AD|
|186||Pachyonychia congenita, recessive||260130||AR|
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.
|Ectodermal dysplasia (ED)||Reference (OMIM, whenever available)||Inheritance pattern||Hair||Teeth||Nails||Sweat glands||Other signs|
|Subgroup hair-teeth-nails-sweat glands|
|Curly hair-acral keratoderma-caries syndrome||Van Steensel et al. 2001||AD||Curly, dry and brittle hair; premature hair loss; sparse eyebrows and eyelashes||Partial loss of teeth due to caries||Yellow and thickening of finger and toe nails||Hypohidrosis||Skin: 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 type||Montebelo et al. 1996||AD?; XD?||Dysplastic||Altered||Dysplastic||Dyshidrosis|
|ED with alopecia, onychodysplasia, hypohidrosis, keratoderma, abnormal teeth and deafness (Single case)||Akhyani and Kiavash 2007||AR?||Sparse and fine scalp hair; sparse eyelashes, eyebrows, pubic and axillary hair; absence of terminal hairs on the trunk and limbs||Malformed||Finger and toenails with subungual hyperkeratosis, onycholysis and accentuation of longitudinal ridges; irregularities on the surface of nails||Hypohidrosis||Skin: dry and rough; palmoplantar keratoderma. Hearing: complete sensorineural deafness (right ear); parcial sensorineural deafness (left ear)|
|Arthrogryposis, ED, cleft lip/palate, and developmental delay||301815||XR||Scarce and fragile hair; pili torti||Absent; short and coniforms; delayed eruption||Hypoplasic||Normal||Skin: 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 syndrome||218040||AR||Short, sparse and curly scalp hair; thin in the anterior scalp; thick eyebrows||Widely spaced||Dystrophic; thin fingernails; small toenails||Normal||Skin: 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 retardation||Freihofer et al. 1997||?||Sparse and fine scalp hair; high frontal hair line; long eyelashes||Hypodontia||Dystrophic; synonychosis||Normal||Skin: 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 syndrome||601957||AD?; XD?||Dystrophic; hypochromic||Natal teeth; irregular eruption of secondary dentition; malocclusion||Dystrophic; absent||Normal||Face: 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 abnormalities||262190||AR||Hypertrichosis||Dysplastic; early dentition||Thick fingernails||Normal||Skin: dry; acanthosis nigricans. Face: prognathism; senile-appearing facies. Development: short stature. Other findings: insulin-resistant diabetes mellitus; pineal hyperplasia; phallic enlargement|
|Barber–Say syndrome||209885||AR?; AD?; XD?||Severe hypertrichosis; absent eyelashes; sparse eyebrows||Delayed eruption||Normal||Normal||Skin: 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 ED||212835||AR||Hypotrichosis; sparse body hair||Hypodontia||Normal||Normal||Face: triangular. Development: cerebellar ataxia; cerebellar atrophy; hyperreflexia|
|Congenital atrichia, palmoplantar hyperkeratosis, mental retardation, and early loss of teeth||Steijlen et al. 1994||AR?||Congenital atrichia; alopecia; short and fine scalp hair; sparse eyelashes and eyebrows; absent pubic and axillary hair||Dysplasic; premature loss||Normal||Normal||Skin: palmoplantar hyperkeratosis. Development: mental retardation|
|Craniotubular dysplasia with severe postnatal growth retardation, mental retardation, ED||Nishimura et al. 1997||?||Slow-growing||Enamel hypoplasia||Normal||Normal||Skin: 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. 1998||AR?||Sparse scalp hair, woolly, fine and hypopigmented; sparse eyelashes and eyebrows||Hypoplasic deciduous; enamel hypoplasia of the permanent teeth||Normal||Normal||Skin: 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 Verde||Werninghaus 1993||AR||High frontal hair line; sparse eyebrows and eyelashes||Enamel hypoplasia||Normal||Normal||Skin: multiple non pigmented spots|
|Mental retardation, hypotrichosis, and syndactyly||Lopes and Marques-de-Faria 1996||AR?||Hypotrichosis; sparse scalp hair and eyebrows; fine and dry scalp hair||Earlier eruption||Normal||Normal||Face: 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)||176690||AD||Mild hypotrichosis in shoulders and extremities||Hypodontia; short and irregular; taurodontia; enamel defects; hypoplastic deciduous||Normal||Normal||Skin: 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)||268320||AR||Hypotrichosis; fine and sparse scalp hair||Malformed and malaligned||Normal||Normal||Face: dysmorphic; narrow nasal bridge with marked distal flaring; short upper lip; prominent ears. Eyes: blindness; microphthalmia; microcornea; sclerocornea. Development: mental retardation; short stature|
|Alopecia, nail dystrophy, palmoplantar hyperkeratosis, keratitis, hearing difficulty and micrognathia (Single case)||Nakamura and Ishikawa 2007||?||Alopecic regions on the scalp; scant eyelashes and eyebrows||Normal||Longitudinal fissures and distal onycholysis in fingernails and in toenails||Normal||Skin: 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 ED||Gyure et al. 1992||AR?||Sparse, short and fine scalp hair; trichorrhexis invaginata; scarce eyelashes and eyebrows||Normal||Hypoplasic or absent||Normal||Skin: 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 dysplasia||Pinheiro and Freire-Maia 1992||AD||Variable hypotrichosis; fine, sparse and fragile scalp hair; structural hair alterations||Normal||Short, fragile and spooned nails; mild dystrophy||Normal|
|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 nodosa||Normal||Dystrophic in all digits; distal onycholysis; shortened nail plate; loss of the cuticle||Normal|
|T-cell immunodeficiency, congenital alopecia, and nail dystrophy||601705||AR?||Congenital alopecia||Normal||Ridging and pitting of all nails||Normal||Other findings: severe T-cell immunodeficiency|
|Subgroup hair-sweat glands|
|Tetra-amelia with ED and lacrimal duct abnormalities (Single case)||273390||AR||Hypotrichosis; absent eyebrows, eyelashes and scalp hair||Normal||Normal||Hyperthermia||Face: 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|
|Haim-Munk syndrome (HMS)||245010||AR||Normal||Severe periodontitis; brittle teeth||Onichogryposis; atrophic alterations||Normal||Skin: palmoplantar hyperkeratosis; scaly and erythematosus patches. Limbs: pes planus; arachnodactyly; acroosteolysis; deformity of distal phalanges|
|Odonto-ungueal dysplasia||Pinheiro and Freire-Maia 1996||AD||Normal||Persistence of deciduous; hypodontia; enamel hypoplasia; microdontia; peg shaped incisors and canine teeth||Short, fine and fragile||Normal|
|Otopalatodigital syndrome, type I (OPD1)||311300||XD||Normal||Hypodontia||Short and dystrophic||Normal||Face: 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|
|Pycnodysostosis||265800||AR||Normal||Hypodontia; delayed eruption; persistence of deciduous teeth||Dysplastic; brittle||Normal||Face: 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)||194050||AD||Normal||Hypodontia; microdontia||Hypoplastic; short nails||Normal||Face: 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
- Top of page
- DEFINITION, CLASSIFICATION, AND REVISION OF ECTODERMAL DISPLASIAS
- MOLECULAR ASPECTS OF EDs
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.
|Chromosome||Gene||Gene functiona||Protein or gene product||Ectodermal dysplasia (ED)||OMIM/Reference|
|Xp11.23||PORCN||O||Five isoforms (PORCA–PORCE)||Focal dermal hypoplasia||305600|
|Xp22.3-p22.2||OFD1||?||OFD1 protein||Orofaciodigital syndrome 1||311200|
|Xq28||NEMO||S||IKK-γ||Incontinentia pigmenti 2;||308300|
|Hypohidrotic ED with immune deficiency||300291|
|Xq28||DKC1||O||Dyskerin||Dyskeratosis congenita, X-linked||305000|
|Xq28||FLNA||O||Filamin A||Otopalatodigital syndrome (OPD1)||311300|
|1p21||COL11A1||O||Collagen XI alpha 1||Marshall syndrome||154780|
|1q32||PKP1||A||Plakophilin 1||ED/skin fragility syndrome.||604536|
|1q42.2-q43||EDARADD||S||Ectodysplasin-A receptor adapter||ADHED and ARHED||129490, 224900|
|2q11-q13||EDAR||S||Ectodysplasin-A receptor||ADHED and ARHED||129490, 224900|
|2q21||ERCC3||O||Excision-repair cross-complementing rodent repair deficiency, complementation group 3||Trichothiodystrophy||601675|
|2q35||WNT10A||S||Wingless-type MMTV integration site family, member 10A||Odontoonychodermal dysplasia (OODD)||257980|
|3q21-q28||TERC||O||Telomerase RNA component||Dyskeratosis congenita, AD||127550|
|3q27||TP63||R||p63 (p73-like)||ADULT syndrome||103285|
|Ectrodactyly, ED, cleft lip/palate syndrome 3 (EEC3)||604292|
|Rapp–Hodgkin syndrome (RHS)||129400|
|4p16||EVC and EVC2||R||EVC||Ellis–van Creveld||225500|
|Weyers acrofacial dysostosis||193530|
|4p16.3||FGFR3||S||Fibroblast growth factor receptor-3||Lacrimoauriculodentodigital syndrome||149730|
|5p13-p12||FGF10||S||Fibroblast growth factor-10||Lacrimoauriculodentodigital syndrome||149730|
|5p15.33||TERT||O||Telomerase reverse transcriptase||Dyskeratosis congenita, AD||127550|
|6p25.3||TGF2H5||O||General transcription factor IIH, polypeptide 5||Trichothiodystrophy||601675|
|6q21-q23.2||GJA1||S||Connexin 43||Oculodentodigital dysplasia (ODDD)||164200|
|7p14||TTDN1 (C7ORF11)||O||TTD non-photosensitive 1 protein||Trichothiodystrophy, nonphotosensitive 1 (TTDN1)||234050|
|7q11.2-q21.3||EEC1||Ectrodactyly, ED, cleft lip/palate syndrome 1 (EEC1)||129900|
|7q11.2||ELN||O||Elastin||Williams–Beuren syndrome (WBS)||194050|
|7q11.23||RFC2||?||Replication factor C2||Williams–Beuren syndrome||194050|
|CYLN2||?||Cytoplasmic linker 2||Williams–Beuren syndrome||194050|
|LIMK1||R||LIM domain kinase 1||Williams–Beuren syndrome||194050|
|GTF2IRD1||R||GTF21 repeat domain-containing protein 1||Williams–Beuren syndrome||194050|
|GTF2I||R||General transcription factor II-I (BTK-associated protein)||Williams–Beuren syndrome||194050|
|7q32||MEK2||O||Mitogen-activated protein kinase kinase 2||Cardiofaciocutaneous syndrome (CFC)||115150|
|7q34||BRAF||O||p21s protein||Cardiofaciocutaneous syndrome||115150|
|7q36||SHH||D||Sonic Hedgehog||SMMCI syndromeb||147250|
|8q24.12||TRPS1||R||Zinc finger transcription factor||Trichorhinophalangeal syndrome||190350|
|8q24.3||RECQL4||O||DNA helicase, RecQ-like 4||Rothmund–Thomson syndrome||268400|
|9p21-p12||RMRP||O||Mitochondrial RNA-processing endoribonuclease||Cartilage-hair hypoplasia||250250|
|10p15||GATA3||R||GATA binding protein-3||Hypoparathyroidism, sensorineural deafness, and renal dysplasiab||146255|
|10q24.32–q25.1||Subgroup 1-3 EDc||Rafiq et al. 2005|
|10q26||FGFR2||S||Fibroblast growth factor receptor-2||Lacrimoauriculodentodigital syndrome||149730|
|11p15.5||HRAS||O||p21s protein||Costello syndrome||218040|
|11q14.1-q14.3||CTSC||O||Cathepsin C||Papillon–Lefèvre syndrome||245000|
|11q23-q24||PVRL1||A||Nectin 1||Cleft lip/palate-ED syndrome (CLPED1)||225060|
|12p12.1||KRAS2||O||p21s protein||Costello syndrome||218040|
|12q13||KRTHB1, KRTHB3, and KRTHB6||O||Keratins 81, 83, and 86||Monilethrix||158000|
|12q13||KRT6A and KRT6B||O||Keratins 6A and 6B||Pachyonychia congenita 1 and 2||167200, 167210|
|12q13||KRTHB5||O||Keratin 85||ED, ‘pure’ hair-nail type||602032|
|12q24.1||TBX3||?||Tbx 3||Ulnar–mammary syndrome||181450|
|13q11-q12||GJB2||S||Connexin 26||Palmoplantar keratoderma, with deafnessb||148350|
|Keratitis-ichthyosis-deafness syndrome, AD (KID, AD)||148210|
|Ichthyosis, hystrix-like, with deafness (HID syndrome)b||602540|
|13q12||GJB6||S||Connexin 30||Clouston syndrome||129500|
|14q12||TINF2||O||TRF1-interacting nuclear factor 2||Dyskeratosis congenita, AD||127550|
|15q14-q15||NOLA3||O||Nucleolar protein family A, member 3||Dyskeratosis congenita, AR||224230|
|15q15-q21.1||UBR1||O||Ubiquitin-protein ligase E3-alpha||Johanson-Blizzard syndrome||243800|
|15q21||MEK1||O||Mitogen-activated protein kinase kinase 1||Cardiofaciocutaneous syndrome||115150|
|ED, ectrodactyly, and macular dystrophy (EEM)||225280|
|17q11-q12||WHN||R||Winged-helix transcription factor||T-cell immunodeficiency, congenital alopecia, and nail dystrophy||601705|
|17q12-q21||KRT14||O||Keratin 14||Naegeli–Franceschetti–Jadassohn syndrome||161000|
|17q12-q21||KRT16 and KRT17||O||Keratins 16 and 17||Pachyonychia congenita 1 and 2||167200, 167210|
|17q21.3-q22||DLX3||D||Homeobox protein DLX-3||Trichodentoosseous syndrome||190320|
|18q22.1–22.3||Subgroup 1-2-3 EDc||Tariq et al. 2008|
|19p13.2||INSR||S||Insulin receptor||Pineal hyperplasia, insulin-resistant diabetes mellitus, and somatic abnormalities||262190|
|19q13.2-q13.3||ERCC2||O||DNA excision repair protein 2 (ERCC-2)||Trichothiodystrophy||601675|
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.
- Top of page
- DEFINITION, CLASSIFICATION, AND REVISION OF ECTODERMAL DISPLASIAS
- MOLECULAR ASPECTS OF EDs
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.
- Top of page
- DEFINITION, CLASSIFICATION, AND REVISION OF ECTODERMAL DISPLASIAS
- MOLECULAR ASPECTS OF EDs
We thank Dr. Marta Pinheiro and Dr. Carlos F. Salinas for the valuable critical reading of this manuscript and for fruitful discussions.
- Top of page
- DEFINITION, CLASSIFICATION, AND REVISION OF ECTODERMAL DISPLASIAS
- MOLECULAR ASPECTS OF EDs
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