CLINICAL REPORT

Update on Ectodermal Dysplasias Clinical Classification Nina Ama´lia Brancia Pagnan,1* and ´Atila Fernando Visinoni2 1

Department of Genetics, Federal University of Parana´, Curitiba, Parana´, Brazil Positivo University, Curitiba, Parana´, Brazil

2

Manuscript Received: 29 October 2013; Manuscript Accepted: 14 April 2014

Monogenic genetic disorders constitute a very large group of rare conditions, each of which is defined by a characteristic combination of phenotypic features. Their enormous clinical variability and their etiological heterogeneity may result in difficulties for the establishment of a syndromic diagnosis. In this context, classifications were proposed for different nosological groups, including ectodermal dysplasias. FreireMaia proposed a clinical based classification, but nowadays the need of connecting clinical and molecular data on EDs demands a re-evaluation of the knowledge and the formulation of a new classification approach. The aim of this article is to provide an update of an article published in 2009 in this Journal. In order to check for new articles and information on ectodermal dysplasias, we have consulted the OMIM, PUBMED, and Science Direct online databases. Ó 2014 Wiley Periodicals, Inc.

Key words: ectodermal dysplasias; ectodermal appendage alteration; clinical classification

INTRODUCTION Monogenic genetic disorders constitute a very large group of rare conditions, many of which are characterized by the presence of congenital malformation. Each of these malformation syndromes is defined by a combination of phenotypic features; and the overlapping among syndromes is the rule. Sometimes, the difference between syndromes comes down to one or to a few features [Brunner and van Driel, 2004]. The enormous clinical variability and the etiological heterogenities, associated with complicating factors such as incomplete penetrance and variable expressivity, may result in difficulties for the establishment of a syndromic diagnosis. In spite of such difficulties, a correct diagnosis is important for genetic counseling, treatment decisions, follow-up and long-term outcome forecast [Ma¨kitie, 2011]. In this context, the classifications proposed by many authors regarding different nosological groups such as the arthrogryposis and the skeletal and ectodermal dysplasias [FreireMaia, 1971, 1977; Hall, 1997; Warman et al., 2011] have emerged. The choice of clinical criteria allowed these clinical classifications to become useful tools for clinical practice and genetic counseling. Clinical-based classifications improve syndrome identification and

Ó 2014 Wiley Periodicals, Inc.

How to Cite this Article:

Pagnan NAB, Visinoni A´F. 2014. Update on ectodermal dysplasias clinical classification. Am J Med Genet Part A 164A:2415–2423.

enable for the organization within extremely complex syndrome groups. The well-known clinical-based classification of ectodermal dysplasias (EDs) proposed by Freire-Maia [1971, 1977] lies on the occurrence of alterations in hair, teeth, nails, and sweat glands, whose frequencies are 87.1%, 78.5%, 73%, and 37.4%, respectively. These alterations, referred to as “classical,” were numbered from one (1) to four (4), and the combination of at least two alterations gives rise to 11 subgroups within a single set named Group A. In Group A, the most studied and best-known ectodermal dysplasias are included. There are also ectodermal dysplasias characterized by the occurrence of one classical sign plus another ectodermal defect constituting Group B, according to Freire-Maia’s classification. Only four subgroups are possible within the B cluster of ectodermal dysplasias. In a previously published article [Visinoni et al., 2009], we extensively reviewed the EDs belonging to group A, which enabled an update of the clinical classification and the inclusion of molecular data regarding the causative genes and their products. Many new articles on ectodermal dysplasias have been published since then, and a new update was required so that relevant pieces of information were added. This was the specific aim of the present work. In order to check new articles and information on ectodermal dysplasias,

Conflict of interest: none. Grant sponsor: National Foundation for Ectodermal Dysplasias.  Correspondence to: Nina Ama´lia Brancia Pagnan, Department of Genetics, Federal University of Parana´, P.O. Box 19071, 81531-990 Curitiba, PR, Brazil. E-mail: [email protected], [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 6 August 2014 DOI 10.1002/ajmg.a.36616

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AMERICAN JOURNAL OF MEDICAL GENETICS PART A

TABLE I. Ectodermal Dysplasias of Group A (N ¼ 163), Modified From Visinoni et al. [2009]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44

Ectodermal dysplasia (ED) Subgroup hair–teeth–nails–sweat glands. N ¼ 38 Alopecia-contractures-dwarfism mental retardation syndrome Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC; Hay–Wells syndrome); Rapp–Hodgkin syndrome (129400) included Anonychia with flexural pigmentation AREDYLD (Acrorenal field defect, ED, and lipoatrophic diabetes) Arthrogryposis and ED Camarena syndrome Cleft lip/palate-ED syndrome (CLPED1; Zlotogora–Ogur syndrome; Margarita Island syndrome) Curly hair-acral keratoderma-caries syndrome Dyskeratosis congenita, AD (Dyskeratosis congenita, Scoggins type) Dyskeratosis congenita, AR Dyskeratosis congenita, X-linked (Zinsser–Cole–Engman syndrome) Ectrodactyly, ED, and cleft lip/palate syndrome (EEC1) Ectrodactyly, ED, and cleft lip/palate syndrome 3 (EEC3) ED hypohidrotic, with acanthosis nigricans (Lelis syndrome) ED-syndactyly syndrome 2 (EDSS2) ED with natal teeth, Turnpenny type ED, Caratinga type ED, hypohidrotic, with hypothyroidism and agenesis of the corpus callosum Focal dermal hypoplasia (FDH) Hypohidrotic ED, autosomal dominant (ADHED) Hypohidrotic ED, autosomal recessive (ARHED) Hypohidrotic ED, X-linked (XLHED; Christ–Siemens–Touraine syndrome; CST syndrome) Hypohidrotic ED with immune deficiency Hypohidrotic ED with immunodeficiency, osteopetrosis, and lymphedema (OLEDAID syndrome) Hypomelanosis of Ito (HMI, Incontinentia pigmenti type I; IP1) Keratitis-ichthyosis-deafness syndrome, autosomal dominant (KID syndrome, AD) Keratitis-ichthyosis-deafness syndrome, autosomal recessive (KID syndrome, AR) Naegeli syndrome (Naegeli–Franceschetti–Jadassohn syndrome, NFJS) Odontoonychodermal dysplasia (OODD); Scho¨pf–Schulz–Passarge syndrome (224750) included Odontotrichomelic syndrome (tetramelic deficiencies, ectodermal dysplasia, deformed ears, and other abnormalities) Pachyonychia congenita, type 1 (PC1) Pachyonychia congenita, type 2 (PC2) Papillon–Lefevre syndrome Rosselli–Gulienetti syndrome Scalp-ear-nipple syndrome (Finlay–Marks syndrome; ED with adrenal cyst) Tricho-odonto-onychodysplasia with pili torti Tricho-onycho-dental dysplasia (TOD) Xeroderma-talipes-enamel defects (XTE) Subgroup hair–teeth–nails. N ¼ 34 Ackerman syndrome ADULT syndrome Arthrogryposis, ED, cleft lip/palate, and developmental delay Cardiofaciocutaneous syndrome (CFC) Cardiomyopathy, dilated, with woolly hair, and keratoderma (Carvajal syndrome) Clouston syndrome (ectodermal dysplasia, hidrotic, autosomal dominant)

Reference (OMIM, whenever available) 203550 106260 106750 207780 601701 Freire-Maia and Pinheiro [1984] 225060 van Steensel and van der Hout [2009] 127550 224230 305000 129900 604292 608290 613576 601345 Montebelo et al. [1996] 225040

Inheritance AR AD AD AR AR AD?; XD? AR AD AD AR XR AD AD ? AR AD AD?; XD? AD?; AR?; XD?

305600 129490 224900 305100

XD AD AR XR

300291 300301

XD XD

300337 148210

XD AD

242150

AR

161000

AD

257980

AR

273400

AR

167200 167210 245000 225000 181270; 129550

AD AD AR AR AD

Freire-Maia and Pinheiro [1984] Koshiba et al. [1978] Moynahan [1970]

AD?; XD? AD AR

200970 103285 301815 115150 605676

AR AD XR AD AR

129500

AD

PAGNAN AND VISINONI

2417 TABLE I. (Continued )

45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91

Ectodermal dysplasia (ED) Coffin–Siris syndrome Costello syndrome Cranioectodermal dysplasia (CED1, Sensenbrenner syndrome); CED2 (613610), CED3 (614099) and CED4 (614378) included Dermoodontodysplasia Dolichocephaly, dental defects, trichodysplasia ED-syndactyly syndrome 1 (EDSS1); ED with pillous anomaly and syndactyly (Wiedemann et al., 1978) included ED, trichoodontoonychial type Ellis–van Creveld syndrome (EVC) GAPO syndrome (growth retardation, alopecia, pseudoanodontia, and optic atrophy) GOMBO syndrome Hidrotic ED autosomal recessive (Fried’s tooth and nail syndrome) Hypotrichosis with pili bifurcate Incontinentia pigmenti (IP2) Oculotrichodysplasia (OTD) Odonto-onychodysplasia-alopecia Odontotrichoungual-digital-palmar syndrome Pineal hyperplasia, insulin-resistant diabetes mellitus, and somatic abnormalities Rothmund–Thomson syndrome (RTS) Schinzel–Giedion midface-retraction syndrome Sener syndrome Split-hand/foot malformation (SHFM1); SHFM3 (246560), SHFM4 (605289), and SHFM5 (606708) included Thumb deformity and alopecia Trichodentoosseus syndrome (TDO) Tricho-dermodysplasia-dental defects Trichoodontoonychial dysplasia with bone deficiency Trichorhinophalangeal syndrome, type I (TRPS1) Trichothiodystrophy, photosensitive (TTDP) Witkop syndrome Subgroup hair–teeth–sweat glands. N ¼ 8 Bo¨¨ok syndrome Cleft lip/palate, ED, acral anomalies Hypohidrotic ED with focal sweating IFAP syndrome with or without bresheck syndrome (Ichthyosis follicularis, atrichia, and photophobia syndrome) Johnson neuroectodermal syndrome Lenz–Passarge dysplasia Leukomelanoderma, infantilism, mental retardation, hypodontia, hypotrichosis Ulnar-mammary syndrome (UMS) Subgroup hair–nails–sweat glands. N ¼ 4 Alopecia-skin atrophy-anonychia-tongue defects ED, hypohidrotic, with hypothyroidism and ciliary dyskinesia (HEDH syndrome) ED/skin fragility syndrome Fischer–Volavsek syndrome Subgroup teeth–nails–sweat glands. N ¼ 2 Ameloonychohypohidrotic syndrome Limb-mammary syndrome (LMS) Subgroup hair–teeth. N ¼ 29 Barber–Say syndrome Blepharocheilodontic syndrome Brachymetapody-anodontia-hypotrichosis-albinoidism CAHMR syndrome (Cataract, hypertrichosis, mental retardation syndrome) Cerebellar ataxia and ED

Reference (OMIM, whenever available) 135900 218040 218330

Inheritance AD?; AR?; XD? AR AR

125640 Freire-Maia and Pinheiro [1984] 613573

AD AD AR

129510 225500 230740

AD AR AR

233270 602401 Beemer et al. [1987f] 308300 257960 Pinheiro and Freira Maia [1981] 601957 262190

AR AR AR? XD AR AR AD?; XD? AR

268400 269150 606156 183600

AR AR?; AD? ? AD

188150 190320 Pinheiro et al. [1986] 275450 190350 601675 189500

AD AD AD?; XD? AR? AD AR AD

112300 Richieri-Costa et al. [1992] Gorlin [1988] 308205

AD AR AR?; XR? XR

147770 Lenz [1963] 246500

AD XD AR

181450

AD

Sequeiros and Sack [1985] 225050

? AR

604536 Fischer [1921]

AR AD

104570 603543

AD AD

209885 119580 211370 211770

AR?; AD?; XD? AD AR AR

212835

AR

2418

AMERICAN JOURNAL OF MEDICAL GENETICS PART A TABLE I. (Continued )

92 93

94 95 96 97 98

99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136

Ectodermal dysplasia (ED) Cleft lip/palate-oligodontia-syndactyly-hair defects Coloboma, congenital heart disease, ichthyosiform dermatosis, mental retardation, and ear anomalies syndrome (CHIME, Zunich neuroectodermal syndrome) Congenital atrichia, palmoplantar hyperkeratosis, mental retardation, and early loss of teeth Dubowitz syndrome ED and neurosensory deafness ED, Cape Verde EEM syndrome (ED, ectrodactyly, and macular dystrophy); Hypotrichosis, congenital, with juvenile macular dystrophy (HJMD, 601553) included Gorlin–Chaudhry–Moss syndrome Hallermann–Streiff syndrome (HSS) Hypertrichosis terminalis, generalized, with our without gingival hyperplasia (Gingival fibromatosis with hypertrichosis) Hypertrichosis universalis Johanson–Blizzard syndrome (JBS) Mental retardation, hypotrichosis, and syndactyly Oculodentoosseous dysplasia, recessive Oculodentodigital dysplasia (ODDD) Orofaciodigital syndrome I (OFD1) Pili torti, early onset Pilodental dysplasia with refractive errors Progeroid short stature with pigmented nevi (Mulvihill–Smith syndrome) Rodrigues blindness (Microphthalmia, microcornea, and sclerocornea with short stature and hair and dental abnormalities) Trichodental dysplasia Trichodysplasia and amelogenesis imperfect Uncombable hair, retinal pigmentary dystrophy, dental anomalies, and brachydactyly Walbaum–Dehaene–Schlemmer syndrome Subgroup hair–nails. N ¼ 25 Anonychia-onychodystrophy with hypoplasia or absence of distal phalanges (Cooks syndrome) Autosomal recessive neurodegenerative disorder with trichorrhexis invaginata and ED Cartilage-hair hypoplasia (CHH) Curly hair-ankyloblepharon-nail dysplasia syndrome (CHANDS) ED hidrotic, Christianson–Fourie type ED with skin anomalies and mental retardation ED, “pure” hair-nail type Hair-nail dysplasia Hairy elbows (hypertrichosis cubiti) Ichthyosis and male hypogonadism Ichthyosis with alopecia, eclabion, ectropion, and mental retardation Lymphedema-hypoparathyroidism syndrome Monilethrix Onychotrichodysplasia and neutropenia Palmoplantar keratoderma and congenital alopecia, autosomal dominant (alopecia congenita with keratosis palmoplantaris) Pili torti and onychodysplasia Pili torti, alopecia and onychodysplasia Polyposis, skin pigmentation, alopecia, and fingernail changes Popliteal pterygium syndrome, lethal type Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis syndrome (SOFT syndrome) Syndrome of accelerated skeletal maturation, failure to thrive and peculiar face (Marshall syndrome II)

Reference (OMIM, whenever available) Martı´nez et al. [1987] 280000

Inheritance AD?; XD? AR

Steijlen et al. [1994]

AR?

223370 224800 Werninghaus [1993] 225280

AR AR AR AR

233500 234100 135400

AR AR AD

145700 243800 Lopes and Marques-de-Faria [1996] 257850 164200 311200 261900 262020 176690

AD AR AR? AR AD XD AR AR AD

268320

AR

601453 Angelos and Jorgenson [1993] 191482

AD AD?; XD? AD

Walbaum et al. [1971]

AR

106995

AD

Gyure et al. [1992]

AR?

250250 214350 601375 Halal et al. [1991] 602032 Pinheiro and Freire-Maia [1992] 139600 308200 242510 247410 158000 258360 104100 Beare [1952] Calzavara-Pinton et al. [1991] 175500 263650 Sarig et al. [2012] Marshall et al. [1971]

AR AR AD AR AD? AD AD XR? AR AR?; XR? AD AR AD AD AR ? AR AR AR?; XR?

PAGNAN AND VISINONI

2419 TABLE I. (Continued )

137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162

163

Ectodermal dysplasia (ED) T-cell immunodeficiency, congenital alopecia, and nail dystrophy Trichomegaly with mental retardation, dwarfism, and pigmentary degeneration of retina Tricho-onychodysplasia-xeroderma Trichothiodystrophy, nonphotosensitive 1 (TTDN1) Subgroup hair–sweat glands. N ¼ 4 Dry skin and extranumerary areolae Focal facial dermal dysplasia (Brauer syndrome); Facial ED (Setleis syndrome, 227260) included Short stature-kidney insufficiency-ophthalmological anomaly-growth retardation-ED (SKORED) Tricho-facio-hypohidrotic syndrome Subgroup teeth–nails. N ¼ 14 Corneodermatoosseous syndrome (CDO syndrome) Deafness, congenital, and onychodystrophy, autosomal dominant Deafness, onychodystrophy, osteodystrophy, and mental retardation syndrome (DOOR syndrome) Dermatoosteolysis, Kirghizian type Haim–Munk syndrome (HMS) Hearing loss, sensorineural, with enamel hypoplasia and nail defects (Heimler syndrome) Khan et al. chondroectodermal dysplasia Lacrimoauriculodentodigital syndrome (LADD) Odontomicronychial dysplasia Odonto-ungueal dysplasia Otopalatodigital syndrome, type I (OPD1) Pycnodysostosis Weyers acrofacial dysostosis Williams–Beuren syndrome (WBS) Subgroup teeth–sweat glands. N ¼ 3 Hypohidrotic ED with mydriasis, iris atrophy, and mental retardation Kohlschutter–Tonz syndrome (epilepsy, dementia, and amelogenesis imperfecta) Marshall syndrome I Subgroup nail–sweat glands. N ¼ 2 Adermatoglyphia with congenital facial milia and acral blisters, digital contractures, and nail abnormalities (ED, absent dermatoglyphic pattern, changes in nails, and simian crease) Pachyonychia congenita, autosomal recessive

Reference (OMIM, whenever available) 601705 275400

Inheritance AR? AR

Freire-Maia et al. [1985] 234050

AR AR

Freire-Maia and Chautard-Freire-Maia [1990] 136500

AD AD

Greenstein et al. [1985]

AR?; XR?

Antley et al. [1976]

AR?; XR?

122440 124480 220500

AD AD AR?; AD?

221810 245010 234580

AR AR AR

Khan et al. [2012] 149730 601319 Pinheiro and Freire-Maia [1996] 311300 265800 193530 194050

AR AD AR AD XD AR AD AD

Beyer et al. [1979] 226750

AD? AR?; XR?

154780

AD

129200

AD

260130

AR

Note: the bold text highlights information not listed in Visinoni et al. [2009]. AR, autosomal recessive; AD, autosomal dominant; XD, X-linked dominant; XR, X-linked recessive; ?, unknown.

we have consulted the OMIM, PUBMED, and Science Direct online databases.

RESULTS AND DISCUSSION After the first International Conference on Ectodermal Dysplasias Classification, held in Charleston (South Carolina) in 2008, we listed 186 disorders in an article published in a special issue of the American Journal of Medical Genetics [Visinoni et al., 2009]. Within this reported series of ectodermal dysplasias, descriptions of 26 single cases were included because of their significant frequency of conditions (13.8%), and also because that by mentioning these cases the description of similar patients could be encouraged, which could possibly help clarify some poorly understood clinical presentations.

Reviewing the data and following what was decided at the 2012 International Conference on Ectodermal Dysplasias Classification (Charleston, SC), we removed single cases from the list of ectodermal dysplasias. Table I provides a list of 163 dysplasias belonging to Group A. Besides the exclusion of the single cases and the inclusion of new EDs, new lumpings of conditions were added to this table, and the syndrome nomenclature was reviewed. For 78.5% of these conditions there is an OMIM entry, providing easy access to the more relevant information. The pattern of inheritance is also shown in Table I. It is remarkable that 39.9% are autosomal recessive, 33.7% are autosomal dominant, and 7.4% are X linked disorders. It is also noteworthy that the pattern of inheritance is not established in 19% of the ectodermal dysplasias.

Subgroup teeth–nails Khan et al. chondroectodermal dysplasia

Subgroup hair–nails Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis syndrome (SOFT syndrome)

Split-hand/foot malformation (SHFM1); SHFM3 (246560), SHFM4 (605289) and SHFM5 (606708) included

ED-syndactyly syndrome 1 (EDSS1); ED with pillous anomaly and syndactyly [Wiedemann et al., 1978] included ED-syndactyly syndrome 2 (EDSS2)

Subgroup hair–teeth–nails Cranioectodermal dysplasia (CED1, Sensenbrenner syndrome); CED2 (613610), CED3 (614099) and CED4 (614378) included

Khan et al. [2012]

Sarig et al. [2012]

AR

AR

AD

AR

613576

183600

AR

AR

AR

Inheritance

613573

218330

ED Reference Subgroup hair–teeth–nails–sweat glands Cardiomyopathy, dilated, with 605676 woolly hair and keratoderma (Carvajal syndrome)

Normal

Hypotrichosis; postpubertal sparse and short hair

Sparse, coarse and breakable scalp and body hair, eyebrows and eyelashes; progressive hair loss; alopecia; pilli torti Sparse and slow growing scalp hair; sparse eyebrows and eyelashes, sparse to absent armpit and pubic hair; thin to absent body hair; follicular hyperkeratosis Sparse; alopecia

Sparse; fine and slow-growing hair

Woolly, wavy, wiry and auburn hair; sparse eyebrows and eyelashes

Hair

Absence of mandibular central incisors; misshaped; proeminent

Normal

Hypodontia

Enamel hypoplasia; conical; widely spaced

Enamel hypoplasia; peg-shaped; widely spaced

Hypodontia; microdontia; abnormally shaped

Hypodontia; diminutive upper lateral incisors; prepubertal periodontitis; premature root resorption of primary teeth

Teeth

Dysplastic; enlarged nail bed; hypertrophic and convex shaped

Hypoplastic

Dysplasic

Hypoplastic; thickened, flat, and yellowish or discolored

Hypoplastic

Short and broad

Small and thickened

Nails

TABLE II. Ectodermal Dysplasias (N ¼ 7) Not Included in Visinoni et al. [2009]

Normal

Normal

Normal

Hyperhidrosis (hands, face, and scalp)

Normal

Normal

Hypohidrosis

Sweat glands

Short stature; osteopenia;with breakable bone´s; night blindness; watering eyes; ear infections

Short stature; short and thick long bones; hypoplastic pelvis and sacrum; clinodactyly and brachydactyly; hypoplastic distal phalanges; peculiar faces; small ears; highpitched voice

Cutaneous syndactyly; palmoplantar keratoderma; hard scaly skin; pointed nose, thin upper lips, and large prominent ear pinnae; cardiomegaly Mental retardation; ectrodactyly; cleft lip/palate; micrognathia; occasional deafness and cardiac defects

Craniosynostosis; microcephaly; hypoplasic posterior corpus callosum; postnatal growth retardation; narrow thorax with pectus excavatum; short limbs; brachydactyly; nephropathy; photophobia Cutaneous syndactyly; palmar hyperkeratosis

Dilated cardiomyopathy leading to congestive heart failure; epidermolytic palmoplantar keratoderma

Other signs

2420 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

PAGNAN AND VISINONI

2421

TABLE III. Genes (N ¼ 13a) and Chromosomal Regions (N ¼ 6) Responsible for 15 Different Ectodermal Dysplasias Not Included in Visinoni et al. [2009] Chromossome Xp22.12–p22.11

Gene MBTPS2

1q23.3

PVRL4

Protein or gene product Membrane-bound transcription factor site-2 protease Poliovirus receptor-related protein 4

2p24.1

WDR35

WD repeat-containing protein 35

2q24.1–q31.1 2q31 2q37.3

TWIST2

Twist-related protein 2

3p21.2

POC1A

Centriolar protein homolog A

3q21.3–q22.1

IFT122

4p14

WDR19

Intraflagellar transport protein 122 homolog WD repeat-containing protein 19

6p24.3

DSP

Desmoplakin

6q22.31

GJA1a

Connexin 43

7p21.2–p14.3 7q21.2–q21.3 10q24 14q24.3

IFT43

16p13.3

ROGDI

17p11.2

PIGL

Intraflagellar transport protein 43 homolog Protein rogdi homolog N-acetylglucosaminylphosphatidylinositol de-N-acetylase

17q24.2–q24.3

18q12.3

SETBP1

SET-binding protein

21q22.3

RIPK4

Receptor-interacting serine-threonine-protein kinase 4

a

Ectodermal dysplasia (ED) IFAP syndrome with or without bresheck syndrome ED-syndactyly syndrome 1 (EDSS1) Cranioectodermal dysplasia (CED1–4) Khan et al. chondroectodermal dysplasia SHFM1, 3–5 syndrome Focal facial dermal dysplasia (facial ED) Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis syndrome (SOFT) Cranioectodermal dysplasia (CED1–4) Cranioectodermal dysplasia (CED1–4) Cardiomyopathy, dilated, with woolly hair and keratoderma (Carvajal syndrome) Oculodentodigital dysplasia (ODDD) Hallermann–Streiff syndrome (HSS) ED syndactyly syndrome 2 (EDSS2) SHFM1, 3–5 syndrome SHFM1, 3–5 syndrome Cranioectodermal dysplasia (CED1–4) Kohlschutter–Tonz syndrome (KTZS) Coloboma, congenital heart disease, ichthyosiform dermatosis, mental retardation, and ear anomalies syndrome (CHIME) Hypertrichosis terminalis, generalized, with our without gingival hyperplasia Schinzel–Giedion midface retraction synsdrome Popliteal pterygium syndrome, lethal type

OMIM/Refs 308205 613573 218330, 613610, 614099, 614378 Khan et al. [2012] 183600, 246560, 605289, 606708 136500, 227260 Sarig et al. [2012]

218330, 613610, 614099, 614378 218330, 613610, 614099, 614378 605676

164200 234100 613576 183600, 246560, 605289, 606708 183600, 246560, 605289, 606708 218330, 613610, 614099, 614378 226750 280000

135400

269150 263650

The GJA1 gene was related only to Oculodentodigital dysplasia (ODDD) in Visinoni et al. [2009].

With the description of new syndromes and the better delineation of the conditions known, some syndromes initially described as different entities were considered variations of the same disorder. The opposite also occurs: descriptions considered as being the same clinical entity may be separated in two or more different conditions. This lumping and splitting of syndromes as well as the reports of previously undescribed conditions make the classifications dynam-

ic and modifiable by incorporating the new knowledge. For instance, the TP63-related syndromes, ankyloblepharon-ectodermal defects-cleft lip and palate (AEC or Hay–Wells syndrome, OMIM 106260) and the Rapp–Hodgkin syndrome (OMIM 129400) are now considered as being different phenotypic expressions of the same condition [Prontera et al., 2008; Clements et al., 2010]. Furthermore, Prontera et al. [2011] suggested that ADULT

2422 (OMIM 103285), Ectrodactyly, ED, and cleft lip/palate syndrome 3 (EEC3, OMIM 604292) and limb-mammary syndrome (LMS, OMIM 603543) may be clustered with AEC/Hay–Wells/Rapp– Hodgkin syndrome under the designation of ELA (Ectrodactylyectodermal dysplasia-cleft lip and palate, limb-mammary, and ADULT) syndrome. In the past 3 years, new descriptions of EDs have been published: Cardiomyopathy, dilated, with woolly hair and keratoderma (Carvajal syndrome, OMIM 605676); cranioectodermal dysplasias (CED1–4, OMIM 218330); ED-syndactyly syndromes 1 (EDSS1, OMIM 613573) and 2 (EDSS2, OMIM 613576); split-hand/ foot malformation (SHFM1, OMIM 183600); short stature, onychodysplasia, facial dysmorphism, and hypotrichosis syndrome (SOFT); and the chondroectodermal dysplasia described by Khan et al. [2012]. Table II shows these seven autosomal conditions; only one with dominant pattern. Today it is possible to connect 77 genes and nine chromosomal regions to 75 EDs. Taking into account that in 2009 the listing showed 64 genes and three chromosomal regions, it is evident that there has been a rapid evolution of the molecular knowledge in the past 3 years, with the addition of 13 genes and six chromosomal regions responsible for 15 EDs. Table III summarizes these new molecular findings (genes and their products plus chromosomal regions) and the related EDs.

CONCLUSION One of the aims of the Conferences on Ectodermal Dysplasias Classification was to discuss the definition of EDs and to review the criteria for a consensus classification. Clinical and molecular data should be integrated with the aid of bioinformatics tools and therefore informs clinical practice, genetic counseling and research, as well as patients and their families. The current paper provides an update of an article published in 2009 [Visinoni et al., 2009]. These new data are useful for the discussion towards a consensus classification of EDs.

ACKNOWLEDGMENTS We are very grateful to Dr. Eleidi Alice Chautard-Freire-Maia for the critical analysis of this manuscript and to Dr. Carlos Salinas and Dr. Mary Fete for their hospitality. We wish to thank the Medical University of South Carolina and the National Foundation for Ectodermal Dysplasias for their financial support on our participation in the “2012 International Conference on Ectodermal Dysplasias Classification” held in Charleston, South Carolina, on October 18–20.

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Update on ectodermal dysplasias clinical classification.

Monogenic genetic disorders constitute a very large group of rare conditions, each of which is defined by a characteristic combination of phenotypic f...
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