update on ectodermal dysplasias clinical classification

�

CLINICAL REPORT

Update on Ectodermal Dysplasias ClinicalClassification
Nina Amalia Brancia Pagnan,1* and Atila Fernando Visinoni21Department of Genetics, Federal University of Parana, Curitiba, Parana, Brazil2Positivo University, Curitiba, Parana, Brazil
Manuscript Received: 29 October 2013; Manuscript Accepted: 14 April 2014

How to Cite this Article:Pagnan NAB, Visinoni AF. 2014. Update

on ectodermal dysplasias clinical

classification.

Am J Med Genet Part A 164A:2415–2423.

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. Freire-

Maia 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 theOMIM, PUBMED, and Science

Direct online databases. � 2014 Wiley Periodicals, Inc.

Key words: ectodermal dysplasias; ectodermal appendage

alteration; clinical classification

Conflict of interest: none.

Grant sponsor: National Foundation for Ectodermal Dysplasias.�Correspondence to:

Nina Amalia 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

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 differ-

ence between syndromes comes down to one or to a few features

[Brunner and van Driel, 2004].

The enormous clinical variability and the etiological heterogen-

ities, 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

[Makitie, 2011]. In this context, the classifications proposed by

many authors regarding different nosological groups such as the

arthrogryposis and the skeletal and ectodermal dysplasias [Freire-

Maia, 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

2014 Wiley Periodicals, Inc.

enable for the organization within extremely complex syndrome

groups.

The well-known clinical-based classification of ectodermal dys-

plasias (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

anupdate of the clinical classification and the inclusionofmolecular

data regarding the causative genes and their products. Many new

articles on ectodermal dysplasias have been published since then,

and anewupdatewas required so that relevant piecesof information

were added. This was the specific aim of the present work. In order

to check new articles and information on ectodermal dysplasias,

2415

TABLE I. Ectodermal Dysplasias of Group A (N¼ 163), Modified From Visinoni et al. [2009]

Ectodermal dysplasia (ED) Reference (OMIM, whenever available) Inheritance

Subgroup hair–teeth–nails–sweat glands. N¼ 38

1 Alopecia-contractures-dwarfism mental retardation syndrome 203550 AR

2 Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC;

Hay–Wells syndrome); Rapp–Hodgkin syndrome (129400) included

106260 AD

3 Anonychia with flexural pigmentation 106750 AD

4 AREDYLD (Acrorenal field defect, ED, and lipoatrophic diabetes) 207780 AR

5 Arthrogryposis and ED 601701 AR

6 Camarena syndrome Freire-Maia and Pinheiro [1984] AD?; XD?

7 Cleft lip/palate-ED syndrome (CLPED1; Zlotogora–Ogur syndrome;

Margarita Island syndrome)

225060 AR

8 Curly hair-acral keratoderma-caries syndrome van Steensel and van der Hout [2009] AD

9 Dyskeratosis congenita, AD (Dyskeratosis congenita, Scoggins type) 127550 AD

10 Dyskeratosis congenita, AR 224230 AR

11 Dyskeratosis congenita, X-linked (Zinsser–Cole–Engman syndrome) 305000 XR

12 Ectrodactyly, ED, and cleft lip/palate syndrome (EEC1) 129900 AD

13 Ectrodactyly, ED, and cleft lip/palate syndrome 3 (EEC3) 604292 AD

14 ED hypohidrotic, with acanthosis nigricans (Lelis syndrome) 608290 ?

15 ED-syndactyly syndrome 2 (EDSS2) 613576 AR

16 ED with natal teeth, Turnpenny type 601345 AD

17 ED, Caratinga type Montebelo et al. [1996] AD?; XD?

18 ED, hypohidrotic, with hypothyroidism and agenesis of the corpus

callosum

225040 AD?; AR?; XD?

19 Focal dermal hypoplasia (FDH) 305600 XD

20 Hypohidrotic ED, autosomal dominant (ADHED) 129490 AD

21 Hypohidrotic ED, autosomal recessive (ARHED) 224900 AR

22 Hypohidrotic ED, X-linked (XLHED; Christ–Siemens–Touraine syndrome;

CST syndrome)

305100 XR

23 Hypohidrotic ED with immune deficiency 300291 XD

24 Hypohidrotic ED with immunodeficiency, osteopetrosis, and

lymphedema (OLEDAID syndrome)

300301 XD

25 Hypomelanosis of Ito (HMI, Incontinentia pigmenti type I; IP1) 300337 XD

26 Keratitis-ichthyosis-deafness syndrome, autosomal dominant

(KID syndrome, AD)

148210 AD

27 Keratitis-ichthyosis-deafness syndrome, autosomal recessive

(KID syndrome, AR)

242150 AR

28 Naegeli syndrome (Naegeli–Franceschetti–Jadassohn syndrome,

NFJS)

161000 AD

29 Odontoonychodermal dysplasia (OODD); Schopf–Schulz–Passarge

syndrome (224750) included

257980 AR

30 Odontotrichomelic syndrome (tetramelic deficiencies, ectodermal

dysplasia, deformed ears, and other abnormalities)

273400 AR

31 Pachyonychia congenita, type 1 (PC1) 167200 AD

32 Pachyonychia congenita, type 2 (PC2) 167210 AD

33 Papillon–Lefevre syndrome 245000 AR

34 Rosselli–Gulienetti syndrome 225000 AR

35 Scalp-ear-nipple syndrome (Finlay–Marks syndrome; ED with adrenal

cyst)

181270; 129550 AD

36 Tricho-odonto-onychodysplasia with pili torti Freire-Maia and Pinheiro [1984] AD?; XD?

37 Tricho-onycho-dental dysplasia (TOD) Koshiba et al. [1978] AD

38 Xeroderma-talipes-enamel defects (XTE) Moynahan [1970] AR

Subgroup hair–teeth–nails. N¼ 34

39 Ackerman syndrome 200970 AR

40 ADULT syndrome 103285 AD

41 Arthrogryposis, ED, cleft lip/palate, and developmental delay 301815 XR

42 Cardiofaciocutaneous syndrome (CFC) 115150 AD

43 Cardiomyopathy, dilated, with woolly hair, and keratoderma

(Carvajal syndrome)

605676 AR

44 Clouston syndrome (ectodermal dysplasia, hidrotic, autosomal

dominant)

129500 AD

2416 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

TABLE I. (Continued)

Ectodermal dysplasia (ED) Reference (OMIM, whenever available) Inheritance45 Coffin–Siris syndrome 135900 AD?; AR?; XD?

46 Costello syndrome 218040 AR

47 Cranioectodermal dysplasia (CED1, Sensenbrenner syndrome); CED2

(613610), CED3 (614099) and CED4 (614378) included

218330 AR

48 Dermoodontodysplasia 125640 AD

49 Dolichocephaly, dental defects, trichodysplasia Freire-Maia and Pinheiro [1984] AD

50 ED-syndactyly syndrome 1 (EDSS1); ED with pillous anomaly and

syndactyly (Wiedemann et al., 1978) included

613573 AR

51 ED, trichoodontoonychial type 129510 AD

52 Ellis–van Creveld syndrome (EVC) 225500 AR

53 GAPO syndrome (growth retardation, alopecia, pseudoanodontia, and

optic atrophy)

230740 AR

54 GOMBO syndrome 233270 AR

55 Hidrotic ED autosomal recessive (Fried’s tooth and nail syndrome) 602401 AR

56 Hypotrichosis with pili bifurcate Beemer et al. [1987f] AR?

57 Incontinentia pigmenti (IP2) 308300 XD

58 Oculotrichodysplasia (OTD) 257960 AR

59 Odonto-onychodysplasia-alopecia Pinheiro and Freira Maia [1981] AR

60 Odontotrichoungual-digital-palmar syndrome 601957 AD?; XD?

61 Pineal hyperplasia, insulin-resistant diabetes mellitus, and somatic

abnormalities

262190 AR

62 Rothmund–Thomson syndrome (RTS) 268400 AR

63 Schinzel–Giedion midface-retraction syndrome 269150 AR?; AD?

64 Sener syndrome 606156 ?

65 Split-hand/foot malformation (SHFM1); SHFM3 (246560), SHFM4

(605289), and SHFM5 (606708) included

183600 AD

66 Thumb deformity and alopecia 188150 AD

67 Trichodentoosseus syndrome (TDO) 190320 AD

68 Tricho-dermodysplasia-dental defects Pinheiro et al. [1986] AD?; XD?

69 Trichoodontoonychial dysplasia with bone deficiency 275450 AR?

70 Trichorhinophalangeal syndrome, type I (TRPS1) 190350 AD

71 Trichothiodystrophy, photosensitive (TTDP) 601675 AR

72 Witkop syndrome 189500 AD

Subgroup hair–teeth–sweat glands. N¼ 8

73 Book syndrome 112300 AD

74 Cleft lip/palate, ED, acral anomalies Richieri-Costa et al. [1992] AR

75 Hypohidrotic ED with focal sweating Gorlin [1988] AR?; XR?

76 IFAP syndrome with or without bresheck syndrome (Ichthyosis

follicularis, atrichia, and photophobia syndrome)

308205 XR

77 Johnson neuroectodermal syndrome 147770 AD

78 Lenz–Passarge dysplasia Lenz [1963] XD

79 Leukomelanoderma, infantilism, mental retardation, hypodontia,

hypotrichosis

246500 AR

80 Ulnar-mammary syndrome (UMS) 181450 AD

Subgroup hair–nails–sweat glands. N¼ 4

81 Alopecia-skin atrophy-anonychia-tongue defects Sequeiros and Sack [1985] ?

82 ED, hypohidrotic, with hypothyroidism and ciliary dyskinesia (HEDH

syndrome)

225050 AR

83 ED/skin fragility syndrome 604536 AR

84 Fischer–Volavsek syndrome Fischer [1921] AD

Subgroup teeth–nails–sweat glands. N¼ 2

85 Ameloonychohypohidrotic syndrome 104570 AD

86 Limb-mammary syndrome (LMS) 603543 AD

Subgroup hair–teeth. N¼ 29

87 Barber–Say syndrome 209885 AR?; AD?; XD?

88 Blepharocheilodontic syndrome 119580 AD

89 Brachymetapody-anodontia-hypotrichosis-albinoidism 211370 AR

90 CAHMR syndrome (Cataract, hypertrichosis, mental retardation

syndrome)

211770 AR

91 Cerebellar ataxia and ED 212835 AR

PAGNAN AND VISINONI 2417


Ectodermal dysplasia (ED) Reference (OMIM, whenever available) Inheritance92 Cleft lip/palate-oligodontia-syndactyly-hair defects Martınez et al. [1987] AD?; XD?

93 Coloboma, congenital heart disease, ichthyosiform dermatosis, mental

retardation, and ear anomalies syndrome (CHIME, Zunich

neuroectodermal syndrome)

280000 AR

94 Congenital atrichia, palmoplantar hyperkeratosis, mental retardation,

and early loss of teeth

Steijlen et al. [1994] AR?

95 Dubowitz syndrome 223370 AR

96 ED and neurosensory deafness 224800 AR

97 ED, Cape Verde Werninghaus [1993] AR

98 EEM syndrome (ED, ectrodactyly, and macular dystrophy);

Hypotrichosis, congenital, with juvenile macular dystrophy (HJMD,

601553) included

225280 AR

99 Gorlin–Chaudhry–Moss syndrome 233500 AR

100 Hallermann–Streiff syndrome (HSS) 234100 AR

101 Hypertrichosis terminalis, generalized, with our without gingival

hyperplasia (Gingival fibromatosis with hypertrichosis)

135400 AD

102 Hypertrichosis universalis 145700 AD

103 Johanson–Blizzard syndrome (JBS) 243800 AR

104 Mental retardation, hypotrichosis, and syndactyly Lopes and Marques-de-Faria [1996] AR?

105 Oculodentoosseous dysplasia, recessive 257850 AR

106 Oculodentodigital dysplasia (ODDD) 164200 AD

107 Orofaciodigital syndrome I (OFD1) 311200 XD

108 Pili torti, early onset 261900 AR

109 Pilodental dysplasia with refractive errors 262020 AR

110 Progeroid short stature with pigmented nevi (Mulvihill–Smith

syndrome)

176690 AD

111 Rodrigues blindness (Microphthalmia, microcornea, and sclerocornea

with short stature and hair and dental abnormalities)

268320 AR

112 Trichodental dysplasia 601453 AD

113 Trichodysplasia and amelogenesis imperfect Angelos and Jorgenson [1993] AD?; XD?

114 Uncombable hair, retinal pigmentary dystrophy, dental anomalies, and

brachydactyly

191482 AD

115 Walbaum–Dehaene–Schlemmer syndrome Walbaum et al. [1971] AR

Subgroup hair–nails. N¼ 25

116 Anonychia-onychodystrophy with hypoplasia or absence of distal

phalanges (Cooks syndrome)

106995 AD

117 Autosomal recessive neurodegenerative disorder with trichorrhexis

invaginata and ED

Gyure et al. [1992] AR?

118 Cartilage-hair hypoplasia (CHH) 250250 AR

119 Curly hair-ankyloblepharon-nail dysplasia syndrome (CHANDS) 214350 AR

120 ED hidrotic, Christianson–Fourie type 601375 AD

121 ED with skin anomalies and mental retardation Halal et al. [1991] AR

122 ED, “pure” hair-nail type 602032 AD?

123 Hair-nail dysplasia Pinheiro and Freire-Maia [1992] AD

124 Hairy elbows (hypertrichosis cubiti) 139600 AD

125 Ichthyosis and male hypogonadism 308200 XR?

126 Ichthyosis with alopecia, eclabion, ectropion, and mental retardation 242510 AR

127 Lymphedema-hypoparathyroidism syndrome 247410 AR?; XR?

128 Monilethrix 158000 AD

129 Onychotrichodysplasia and neutropenia 258360 AR

130 Palmoplantar keratoderma and congenital alopecia, autosomal

dominant (alopecia congenita with keratosis palmoplantaris)

104100 AD

131 Pili torti and onychodysplasia Beare [1952] AD

132 Pili torti, alopecia and onychodysplasia Calzavara-Pinton et al. [1991] AR

133 Polyposis, skin pigmentation, alopecia, and fingernail changes 175500 ?

134 Popliteal pterygium syndrome, lethal type 263650 AR

135 Short stature, onychodysplasia, facial dysmorphism, and

hypotrichosis syndrome (SOFT syndrome)

Sarig et al. [2012] AR

136 Syndrome of accelerated skeletal maturation, failure to thrive and

peculiar face (Marshall syndrome II)

Marshall et al. [1971] AR?; XR?



Ectodermal dysplasia (ED) Reference (OMIM, whenever available) Inheritance137 T-cell immunodeficiency, congenital alopecia, and nail dystrophy 601705 AR?

138 Trichomegaly with mental retardation, dwarfism, and pigmentary

degeneration of retina

275400 AR

139 Tricho-onychodysplasia-xeroderma Freire-Maia et al. [1985] AR

140 Trichothiodystrophy, nonphotosensitive 1 (TTDN1) 234050 AR

Subgroup hair–sweat glands. N¼ 4

141 Dry skin and extranumerary areolae Freire-Maia and Chautard-Freire-Maia [1990] AD

142 Focal facial dermal dysplasia (Brauer syndrome); Facial ED (Setleis

syndrome, 227260) included

136500 AD

143 Short stature-kidney insufficiency-ophthalmological anomaly-growth

retardation-ED (SKORED)

Greenstein et al. [1985] AR?; XR?

144 Tricho-facio-hypohidrotic syndrome Antley et al. [1976] AR?; XR?

Subgroup teeth–nails. N¼ 14

145 Corneodermatoosseous syndrome (CDO syndrome) 122440 AD

146 Deafness, congenital, and onychodystrophy, autosomal dominant 124480 AD

147 Deafness, onychodystrophy, osteodystrophy, and mental retardation

syndrome (DOOR syndrome)

220500 AR?; AD?

148 Dermatoosteolysis, Kirghizian type 221810 AR

149 Haim–Munk syndrome (HMS) 245010 AR

150 Hearing loss, sensorineural, with enamel hypoplasia and nail defects

(Heimler syndrome)

234580 AR

151 Khan et al. chondroectodermal dysplasia Khan et al. [2012] AR

152 Lacrimoauriculodentodigital syndrome (LADD) 149730 AD

153 Odontomicronychial dysplasia 601319 AR

154 Odonto-ungueal dysplasia Pinheiro and Freire-Maia [1996] AD

155 Otopalatodigital syndrome, type I (OPD1) 311300 XD

156 Pycnodysostosis 265800 AR

157 Weyers acrofacial dysostosis 193530 AD

158 Williams–Beuren syndrome (WBS) 194050 AD

Subgroup teeth–sweat glands. N¼ 3

159 Hypohidrotic ED with mydriasis, iris atrophy, and mental retardation Beyer et al. [1979] AD?

160 Kohlschutter–Tonz syndrome (epilepsy, dementia, and amelogenesis

imperfecta)

226750 AR?; XR?

161 Marshall syndrome I 154780 AD

Subgroup nail–sweat glands. N¼ 2

162 Adermatoglyphia with congenital facial milia and acral blisters, digital

contractures, and nail abnormalities (ED, absent dermatoglyphic

pattern, changes in nails, and simian crease)

129200 AD

163 Pachyonychia congenita, autosomal recessive 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 theOMIM, PUBMED, and Science Direct online

databases.

RESULTS AND DISCUSSION

After the first International Conference on Ectodermal Dysplasias

Classification, held inCharleston(SouthCarolina) in 2008,we listed

186disorders inanarticlepublished ina special issueof theAmerican

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 con-

ditions (13.8%), and also because that bymentioning 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 ectoder-

mal 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 con-

ditions 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.

TABLE

II.Ectoderm

alDysplasias(N

¼7)Not

Included

inVisinoniet

al.[2009]

EDReference

Inheritance

Hair

Teeth

Nails

Sweatglands

Other

signs

Subgroup

hair–teeth–

nails–sw

eatglands

Cardiomyopathy,

dilated,

with

woolly

hairandkeratoderm

a(Carvajalsyndrom

e)

605676

ARWoolly,wavy,

wiryandauburn

hair;sparse

eyebrowsand

eyelashes

Hypodontia;

diminutiveupper

lateralincisors;

prepubertal

periodontitis;

prem

atureroot

resorption

ofprimaryteeth

Smalland

thickened

Hypohidrosis

Dilatedcardiomyopathyleading

tocongestiveheartfailure;

epidermolyticpalmoplantar

keratoderma

Subgroup

hair–teeth–

nails

Cranioectoderm

aldysplasia

(CED1,Sensenbrenner

syndrom

e);CED2(613610),

CED3(614099)andCED4

(614378)included

218330

ARSparse;fineandslow

-growing

hair

Hypodontia;

microdontia;

abnormally

shaped

Shortandbroad

Normal

Craniosynostosis;

microcephaly;hypoplasic

posteriorcorpuscallosum;

postnatal

grow

thretardation;narrowthorax

withpectusexcavatum;

shortlim

bs;brachydactyly;

nephropathy;photophobia

ED-syndactylysyndrom

e1

(EDSS1);ED

withpillous

anom

alyandsyndactyly

[Wiedemannet

al.,1978]

included

613573

ARSparse,coarse

andbreakable

scalpandbody

hair,

eyebrowsandeyelashes;

progressivehairloss;

alopecia;pillitorti

Enam

elhypoplasia;

peg-shaped;widely

spaced

Hypoplastic

Normal

Cutaneoussyndactyly;palmar

hyperkeratosis

ED-syndactylysyndrom

e2

(EDSS2)

613576

ARSparse

andslow

grow

ingscalp

hair;sparse

eyebrowsand

eyelashes,sparse

toabsent

armpitandpubichair;thinto

absentbody

hair;follicular

hyperkeratosis

Enam

elhypoplasia;

conical;widely

spaced

Hypoplastic;

thickened,flat,

andyellowish

ordiscolored

Hyperhidrosis

(hands,face,

andscalp)

Cutaneoussyndactyly;

palmoplantarkeratoderma;

hard

scalyskin;pointed

nose,

thin

upper

lips,and

largeprominentearpinnae;

cardiomegaly

Split-hand/foot

malform

ation

(SHFM

1);SH

FM3(246560),

SHFM

4(605289)and

SHFM

5(606708)included

183600

ADSparse;alopecia

Hypodontia

Dysplasic

Normal

Mentalretardation;

ectrodactyly;cleftlip/palate;

micrognathia;occasional

deafnessandcardiac

defects

Subgroup

hair–nails

Shortstature,onychodysplasia,

facial

dysm

orphism,and

hypotrichosissyndrom

e(SOFT

syndrom

e)

Sariget

al.

[2012]

ARHypotrichosis;postpubertal

sparse

andshorthair

Normal

Hypoplastic

Normal

Shortstature;shortandthick

longbones;hypoplastic

pelvisandsacrum;

clinodactyly

and

brachydactyly;hypoplastic

distal

phalanges;peculiar

faces;sm

allears;high-

pitchedvoice

Subgroup

teeth–

nails

Khanet

al.chondroectodermal

dysplasia

Khanet

al.

[2012]

ARNormal

Absence

ofmandibular

centralincisors;

misshaped;

proeminent

Dysplastic;

enlarged

nail

bed;

hypertrophic

andconvex

shaped

Normal

Shortstature;osteopenia;with

breakable

bones;night

blindness;wateringeyes;

earinfections


TABLE III. Genes (N¼ 13a) and Chromosomal Regions (N¼ 6) Responsible for 15 Different Ectodermal Dysplasias Not Included inVisinoni et al. [2009]

Chromossome Gene Protein or gene product Ectodermal dysplasia (ED) OMIM/Refs

Xp22.12–p22.11 MBTPS2 Membrane-bound transcription

factor site-2 protease

IFAP syndrome with or without

bresheck syndrome

308205

1q23.3 PVRL4 Poliovirus receptor-related protein 4 ED-syndactyly syndrome 1

(EDSS1)

613573

2p24.1 WDR35 WD repeat-containing protein 35 Cranioectodermal dysplasia

(CED1–4)

218330, 613610, 614099, 614378

2q24.1–q31.1 Khan et al. chondroectodermal

dysplasia

Khan et al. [2012]

2q31 SHFM1, 3–5 syndrome 183600, 246560, 605289, 606708

2q37.3 TWIST2 Twist-related protein 2 Focal facial dermal dysplasia

(facial ED)

136500, 227260

3p21.2 POC1A Centriolar protein homolog A Short stature, onychodysplasia,

facial dysmorphism, and

hypotrichosis syndrome (SOFT)

Sarig et al. [2012]

3q21.3–q22.1 IFT122 Intraflagellar transport protein 122

homolog

Cranioectodermal dysplasia

(CED1–4)

218330, 613610, 614099, 614378

4p14 WDR19 WD repeat-containing protein 19 Cranioectodermal dysplasia

(CED1–4)

218330, 613610, 614099, 614378

6p24.3 DSP Desmoplakin Cardiomyopathy, dilated, with

woolly hair and keratoderma

(Carvajal syndrome)

605676

6q22.31 GJA1a Connexin 43 Oculodentodigital dysplasia

(ODDD)

164200

Hallermann–Streiff syndrome

(HSS)

234100

7p21.2–p14.3 ED syndactyly syndrome 2

(EDSS2)

613576

7q21.2–q21.3 SHFM1, 3–5 syndrome 183600, 246560, 605289, 606708

10q24 SHFM1, 3–5 syndrome 183600, 246560, 605289, 606708

14q24.3 IFT43 Intraflagellar transport protein 43

homolog

Cranioectodermal dysplasia

(CED1–4)

218330, 613610, 614099, 614378

16p13.3 ROGDI Protein rogdi homolog Kohlschutter–Tonz syndrome

(KTZS)

226750

17p11.2 PIGL N-acetylglucosaminyl-

phosphatidylinositol

de-N-acetylase

Coloboma, congenital heart

disease, ichthyosiform

dermatosis, mental

retardation, and ear anomalies

syndrome (CHIME)

280000

17q24.2–q24.3 Hypertrichosis terminalis,

generalized, with our without

gingival hyperplasia

135400

18q12.3 SETBP1 SET-binding protein Schinzel–Giedion midface

retraction synsdrome

269150

21q22.3 RIPK4 Receptor-interacting

serine-threonine-protein kinase 4

Popliteal pterygium syndrome,

lethal type

263650

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


With the description of new syndromes and the better delinea-

tionof the conditionsknown, 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 entitymay be separated in twoormore different conditions.

This lumping and splitting of syndromes as well as the reports of

previously undescribed conditionsmake the classifications dynam-

ic and modifiable by incorporating the new knowledge. For in-

stance, 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


(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 (Ectrodactyly-

ectodermal 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 (Car-

vajal 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, andhypotrichosis 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 thismanuscript and toDr. 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 partici-

pation in the “2012 International Conference on Ectodermal

Dysplasias Classification” held in Charleston, South Carolina, on

October 18–20.

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