medgenet twenty-four of the eec syndrome: clinical

Med Genet 1995;32:716-723

Twenty-four cases of the EEC syndrome:clinical presentation and management

P W Buss, H E Hughes, A Clarke

AbstractTwenty-four cases ofEEC syndrome were

identified as part of a nationwide study.Ectodermal dysplasia, by study definition,was present in all cases and hair and teethwere universally affected. Nail dysplasiawas present in 19 subjects (79%) and theskin was affected in 21 (87%). The presence

of hypohidrosis was not noted as a pre-

dominant feature in the syndrome and itsoccurrence appeared to depend on thepresence of all other features. Distal limbdefects from simple syndactyly to tetra-melic cleft hand and foot were identified,including preaxial anomalies. Orofacialclefting was identified in 14 cases (58%)and lacrimal duct anomaly in 21 (87%).

Significant clinical problems encoun-

tered were chiefly cosmetic or ophthal-mological, but conductive deafness andgenitourinary problems in some cases

required surgical intervention. Alteredself-image was also noted in some cases.

Multidisciplinary management is neces-

sary with the early involvement of theclinical geneticist.Developmentally, the EEC syndrome

and related disorders represent disordersof ectodermallmesodermal interaction.Candidate regions include 7q21.3, the"ectrodactyly" locus; other candidatesinclude developmental genes implicatedin the ectodermallmesodermal interactiveprocess.

(JMed Genet 1995;32:716-723)

drome has become more apparent as therecognised clinical spectrum of the EECsyndrome has continued to broaden. Kusterand Majewski7 reported eight members in twofamilies with the EEC syndrome with no limbdefects. Majewski and Kuster' later coined theterm "oligosymptomatic EEC syndrome" andsuggested that ectrodactyly was not mandatoryfor syndrome diagnosis. Penchaszadeh and deNegrotti9 had previously indicated that the lackof a major component in the syndrome shouldnot preclude diagnosis and subsequentlyWallis"0 reported a four generation family withEEC syndrome without orofacial clefting.Renal anomalies are also frequently reportedin the syndrome.1' Other reported anomaliesinclude choanal atresia,12 growth retarda-tion,1' and EEG abnormalities.'4 We undertooka clinical study of the EEC syndrome in theUK to delineate closely such aspects of thecondition in a defined population, althoughrecognising that complete ascertainment wouldnot be possible.

MethodsCase ascertainment was through a letter cir-culated to over 1000 clinicians (paediatricians,clinical geneticists, orthodontists, and plasticsurgeons) and the criteria for notification in-cluded cases with the following:(1) A definite or provisional diagnosis ofEEC

syndrome.(2) Ectodermal dysplasia with distal limb an-

omalies.(3) Ectodermal dysplasia with orofacial cleft-

ing, with/without distal limb anomalies.

Institute of MedicalGenetics,University of WalesCollege of Medicine,Heath Park,Cardiff CF4 4XN,UKP W BussH E HughesA Clarke

Correspondence to:Dr Buss.

Received 10 January 1995Revised version accepted forpublication 10 April 1995

The EEC syndrome is a multiple congenitalanomaly syndrome characterised by ec-

todermal dysplasia, distal limb anomaly, cleftlip and palate, and lacrimal duct anomalies.The acronym was first used by Rudiger et

al' describing a girl with trimelic ectrodactyly,ectodermal features involving hair, teeth,and nails, and bilateral cleft lip and palate.Cockayne2 had previously reported a case ofdacrocystitis and orofacial clefting and bothWalker and Clodius' and Rosselli and Gul-linetti4 described cases with anomalies similarto those described by Rudiger et al' with, inaddition, lacrimal duct anomalies.There exist numerous case reports of EEC

and phenotypically related syndromes. TheRapp-Hodgkin ectodermal dysplasia' and theankyloblepheron, ectodermal dysplasia, andclefting (AEC) syndrome6 are believed, bymany, to represent separate clinical entities.The overlap between these and the EEC syn-

Diagnostic criteriaFor the purpose of the study ectodermal dys-plasia was chosen as a mandatory feature insyndrome definition. Cases were also con-

sidered eligible for inclusion if at least one

family member had ectodermal dysplasia andthey also possessed: (1) a minimum of two

additional major signs (table 1); (2) absence ofa specific pointer towards one of the other

syndrome diagnoses; (3) a clear reason notto categorise them among one of the overlapsyndromes currently recognised as distinct. Ifin

Table 1 Major and minor anomalies in EEC syndrome(criteria for acceptance into the UK study)

Major Minor

Ectodermal dysplasia Renal anomaliesEctrodactyly DeafnessCleft lip/palate Mental retardationLacrimal duct anomalies Choanal atresia

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Twenty-four cases of the EEC syndrome: clinical presentation and management

Table 2 A summary of clinical findings in 24 cases of the syndrome

Syndrome component

Ectodermal dysplasia*Three componentsFour componentsFive components

Limb deficitCleft limb only (No of affected)

Cleft limb/syndactylySyndactyly onlyPreaxial

Orofacial cleftingCLP (unilateral)CLP (bilateral)CPCleft lip

Lacrimal duct anomalyUni/bilateral

DeafnessConductiveSensorineural

UG tract anomalyHypospadiasRefluxHydronephrosisOther

Case No

2, 3, 4, 61, 5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 22, 237, 20, 21 (all with hypohidrosis)

2(4), 4(4), 8(4), 9(4), 10(2), 11(4), 14(1), 16(1),18(4), 19(1), 20(4), 21(4), 22(4), 23(4)1, 5, 6, 7, 8, 17156 (absent thumb), 19 (small proximal thumbs)

1, 2, 4, 17, 19, 2112, 18, 20, 22, 237 (submucous), 16No cases

1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 17, 18, 19, 20,21, 22, 23, 24

2, 4, 6, 7, 16, 18, 19, 20, 21, 22No cases

71913, 21, 22, 2423 (reduced bladder volume)

Familial cases: 3, 4, 10, 11, 12, 14, 15, 23, 24.* Case 24 omitted owing to age at entry.

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ..............

Figure 1 The infant with EEC syndrome. Case 12 shows evidence of three majorfeatures of the syndrome. He has additional bilateral lacrimal duct anomalies.

a particular case clinical features (for example,ankyloblepheron, hypospadias, skin pigment-ation) suggested significant doubt, then thiscase was excluded from the study group despitesatisfying our first criterion.

Result of ascertainmentTwenty-nine replies indicated possible EECsyndrome. Three cases (following examination)had Rapp-Hodgkin ectodermal dysplasia andtwo cases had ankyloblepheron, ectodermaldysplasia, and clefting syndrome. Three casesclearly did not fit into our study criteria andthree cases, identified as cases of the EECsyndrome by clinical geneticists, were unwillingto participate. Eighteen cases met the inclusioncriteria and they and their immediate familieswere visited at home leading to a total as-certainment of 24 cases (in 18 families).

Clinical findings (table 2)The total group consisted of 16 males and eightfemales with ages ranging from 1 month to 52years and with mean birth weight for males atterm of2770 g (below 1 0th centile) and femalesof 3010 g (25th centile). Two males (cases 19and 22) and a female (case 24) were preterm,both with birth weights appropriate for gesta-tional age. Subsequent postnatal growth in allcases was satisfactory. By definition all casesshowed evidence of ectodermal involvement(however, no relatives- of probands were ex-cluded because of its absence). Distal limbdeficit was present in 21/24 (87-5%) (fig 1),facial clefting in 14/24 (58%), and lacrimalduct anomaly in 21/24 (87 5%).

ECTODERMAL DYSPLASIAFreire-Maia and Pinheiro'5 deemed that at leasttwo abnormal ectodermal components shouldbe present. Over three quarters of the cases inour study had four or five ectodermal featuresclinically apparent.

Figure 2 Dental x ray of case 14 shows oligodontia (reduced number of teeth) and thosepresent are taurodontic (have widened tooth pulp).

TEETHThe teeth were universally affected althoughhistorically the primary dentition was usuallycomplete though not always morphologicallynormal. The dentition of three cases under 1year of age could not be adequately assessed.Abnormalities noted in secondary dentition in-cluded microdontia and oligodontia. The teethwere not as conical as in cases ofXHED, beingmore often straight edged with gaps. Dentalcaries was universally present and usuallysevere. Where x rays had been visualised tau-rodontism (deepened pulp space) was a con-sistent finding (fig 2).

HAIRHair was affected in all cases, generally beinglight in colour (as were eyelashes) and coarseand dry in 18/23 (78%). In five cases it waspoorly formed, sparse, and extremely slowgrowing (fig 3). Affected postpubertal males

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Figure 3 Case 6 with evidence of severe hair dysplasiaand loss, leading to sparse, "downy", soft hair qualityrather than to coarse, dry hair seen in most cases.

tended to have less body hair than usual (par-ticularly on the limbs) but facial and axillaryhair grew normally. A gradual tendency forincrease in hair pigmentation with age wasnoted in several cases.

NAILSNineteen cases (79%) had nail dystrophy. Nailswere slow growing, transversely ridged andpitted, and showed varying degrees of con-cavity. Such findings could be readily visualisedwith magnification using a hand lens.

SKINClinical problems were often minor but werenoted in 21 cases (87%). One case was severelyaffected (case 10). Dry, scaled skin on theextremities was the most common mani-festation, occasionally also present around theneck. Notably other flexures were spared. Pain-ful fissuring in interdigital webs and finger pulpswas reported in a number ofcases; this occurredon the feet of case 23. Case 12 had major skinproblems at birth (fig 4) though as a clinicalproblem this was diminishing. His grandfather(case 10) had ichthyosiform erythroderma"6affecting his neck with Candidal superinfectioninfection. Case 2 showed evidence of solarkeratosis in the third decade as well as recurringCandidal paronychia. He was also noted tohave recurring precancerous scrotal skin le-sions. In most cases a pale complexion wasnoted with two cases (cases 7 and 20) havingan almost albinoid appearance.

SWEATINGReduced sweating did not manifest as a majorproblem. Three cases (13%) (case 24 not as-sessed) had symptomatic hypohidrosis. Allthree, however, reported scalp sweating inparticularly warm conditions. Those withsymptomatic hypohidrosis possessed all majorfeatures of the syndrome.

LIMB ANOMALYThis was identified in 21 cases (87%) ofwhom12 (57%) had tetramelic involvement (10 pos-sessing tetramelic cleft limb). Six cases had acentral ray deficit in the upper limbs combinedwith syndactyly of the toes. Eight cases (38%)had asymmetry of the limb defect with thesame number possessing at least one limb withisolated syndactyly. Two cases (9%) had pre-axial anomalies, one with a unilateral absentthumb (case 6) and one with two small prox-imally placed thumbs (case 19). The digitsmost commonly involved in syndactyly weredigits three and four, in both upper and lowerlimbs.'7

Functional impairment was usually not asignificant problem provided opposition couldbe attained. Some cases had had surgery closingwide cleft hands, or to separate a syndactyly.Obtaining suitably wide fitting shoes was afrequently encountered problem. The 16 par-ents of eight isolated cases were examined andno subtle manifestations were found in thelimbs.

,...........

..

;... ~~~~~~~~~~~~~~~~..,ia

Figure 4 Case 12, an early clinical clue, dry skin atbirth despite prematurity. In this case dry, scaly skinremained throughout childhood.

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OROFACIAL CLEFTINGThirteen cases had orofacial clefting. Five(38%) had bilateral cleft lip and palate and sixpossessed unilateral cleft lip and palate. Twocases had a central cleft palate, submucous inone (case 7). All cases with cleft palate hadnasal quality of speech indicating velo-pharyngeal incompetence.

LACRIMAL DUCT INVOLVEMENTTwenty-one cases (87%) had had lacrimal ductproblems, usually bilateral, causing mostdifficulty in infancy. Epiphora and recent re-current infections were commonly reported re-flecting varying degrees of nasolacrimal ductobstruction, Meibomian gland dysfunction,and reduced tear production. Four cases (cases5, 10, 20, and 22) had severe visual impairmentfrom chronic corneal scarring (cases 6 and20 are registered partially sighted). Infectionsreduced in number with age and followingoperative procedures. Case 5 required cornealgrafting (which to date has been successful)and case 11 required urgent surgical in-tervention and corneal grafting following ananterior chamber haemorrhage.

HEARINGTen of 23 cases (44%) reported a degree ofhearing loss. In the seven cases where audio-grams were examined a conductive deficit wasobserved. In no case was the hearing loss sen-sorineural in origin. Many cases reported im-pacted cerumen as a transient cause of hearingdeficit, but those with persistent deficit con-sistently reported episodes of recurrent otitismedia in childhood and had a repaired orofacialcleft. Case 2 had required surgery for chole-steatoma.

GENITOURINARY ANOMALIESFourteen cases (58%) had had a renal ultra-sound scan performed before our survey andsix (42%) had a problem. Anomalies includedglandular hypospadias (case 7), ureteric reflux(case 19), and hydronephrosis (cases 13 and24) which led to unilateral nephrectomy in case13 and ureterostomy in case 24. Cases 7 and9 had recurrent urinary tract infections andsubsequent ultrasound scans were normal(although more detailed radiological in-vestigations had not been performed). Case 23reported long term dysuria and frequency andwas shown to have a thick walled, very smallvolume bladder. Similar symptoms were re-ported at 2 years by the parents of case 17.

DEVELOPMENTNo affected subject had mental retardationor evidence of developmental delay. Languagemilestones were normal despite some havingmoderate hearing impairment. All affectedpeople attended normal schools. A formal in-tellectual and behavioural assessment was notundertaken. Occupations of the affected adultswere varied, from postman to clerk/typist toprofessional artist.

OTHER REPORTED PROBLEMSTwo cases (cases 7 and 22) reported difficultieswith eating dry food, probably related to alteredsalivary gland function and frequent fluids wererequired while eating. Case 7 (with associatedhypohidrosis) refused warm drinks in infancy.Postpubertal females reported normal breastdevelopment. Case 15 had poorly defined are-olae and nipples; her father (case 13) also hadthis. Cases 11 and 23 elected not to breast feedbecause of hypoplastic nipples. An additionalreason for case 11 was the facial cleft in heraffected child.

In those families where prenatal diagnosiswas considered, all parents were aware of a50% risk. The fetus of case 23 was noted tohave marked renal dilatation but normal faceand limbs on high resolution scanning. Con-firmation of disease status was, however, pos-sible within several weeks of delivery. Fetallimb anomalies were detected at 22 weeks'gestation in case 10.Many cases experienced frustration at ap-

parent late recognition of the syndrome. Forexample case 22 (with all four major ma-nifestations) was not offered appropriatecounselling until he was 20 years of age.Psychologically most cases appeared to copewith their condition well. Most were self-con-fident and had developed good interpersonalcommunication skills. Affected adults did ex-press unhappiness with their body image,wished for public acceptability, and recalledparticularly unhappy adolescent years. In ad-dition the persistent hiding of hands was acommon behavioural trait.

FAMILY HISTORIESThe four families in this study, although small,clearly show the autosomal dominant natureof this condition. Variability in expression wasobserved both within and between families.The family with cases 3 and 4 manifested thegene purely as ectodermal dysplasia (case 3).This was also evident in a second family (case13). Only one three generational family wasascertained. Case 24 had no orofacial or limbaspects of the syndrome, unlike her mother. Asib of case 18 had isolated ulnar hypoplasiabut no other signs. This was deemed to beinteresting but a possibly unrelated occurrence.In nine isolated cases both parents were ex-amined and were normal, and a total of threenormal children were born to isolated cases.Karyotype analysis of one affected memberfrom each family was normal as was analysisof seven isolated cases.

DiscussionThe variability of the EEC phenotype has be-come increasingly apparent over the last dec-ade. The condition can appear as isolatedectodermal dysplasia in one family memberand then in a more fully developed state in asubsequent child.

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Cases 3 and 4

I Fg (3)

11 (4)

Cases 13-15

11

(15) (14)

D Ectodermaldysplasia

m Lacrimal ductL anomaly

Cases 10-12

11

III

Cases 23 and 24

(24)

Orofacialclefting

Ectrodactylylimb defect

A' Index case

Figure 5 Basic pedigrees showing small families and autosomal dominant inheritance.

INHERITANCEAlthough dominant inheritance is confirmedin the familial cases (fig 5), the small size ofthe families is difficult to explain. Families withisolated ectrodactyly may be extensive. There isalso no physiological reason to expect reducedreproductive fitness in EEC families. No cases

of recessive inheritance or parental con-

sanguinity were recorded. Pries et all8 referredto possible autosomal recessive inheritancewhen describing two affected sibs of apparentlyclinically normal parents and De Silva et all9reported similar findings. Both reports, how-ever, contain sparse data on parents and ger-

minal mosaicism or altered gene penetrancecannot be excluded. Clear parental con-

sanguinity was recorded in an isolated case byRogmanoli and Zunin.20

ECTODERMAL FEATURES

Ectodermal features were, by definition, pres-

ent in all cases. Secondary dentition was alwaysaffected. The frequently noted normal numberof deciduous teeth has been recorded byPsaume et al2' previously. Hair, althoughusually lightly pigmented, dry, and coarse, may

sometimes be sparse. Salinas and MarcosMontes22 suggested that there were specificpotentially diagnostic characteristics of hair inthe Rapp-Hodgkin syndrome using polarisinglight.22 Studies on hair morphology in EECsyndrome are currently being undertaken. Hy-pohidrosis is not a common or severe problemas in XHED, where the erroneous diagnosisof infection and subsequent placement of theneonate in an incubator may endanger life.23Abnormalities of eccrine glands may take a

number offorms and studies ofthese are neces-

sary in the EEC syndrome. Those cases withaltered hidrosis fulfilled all four major criteriaof the syndrome. Although this finding may

result from ascertainment bias it could alsosuggest that hypohidrosis in the EEC syndromeis dependent on the presence of all major fea-tures.

Skin and hair hypopigmentation have beendescribed previously and were frequently notedin our group. Severe skin problems were un-common however. Although dryness ofthe skinwas noted by many, it posed a clinical problemin just two cases. Reference has been made topremalignancies arising in cases of the EECsyndrome2425 and Clouston type ectodermaldysplasia.26 These reports are of significance inview of the premalignant biopsy reports ofulcerated scrotal skin in case 2.

OPHTHALMIC FEATURESFreid27 indicated that visual difficulties werepotentially the most serious clinical feature ofthe syndrome. Progressive visual loss and spon-taneous comeal perforation have been docu-mented as serious ocular complications of theEEC syndrome.28 Corneal scarring may resultfrom Meibomian gland dysfunction and alsofrom recurrent blepharitis which is more com-mon in infancy and ameliorated by operationsto improve lacrimal drainage. Case 11 sufferedspontaneous corneal perforation with severevisual impairment and both cases 5 and 11had corneal grafts functioning reasonably wellduring the early months.

LIMB ANOMALIESWhile the central ray defect is the hallmark ofthe EEC syndrome its absence clearly does notexclude the diagnosis. In some cases isolatedsoft tissue syndactyly or thumb anomalies mayoccur. The coexistence of preaxial and centralray anomaly within the syndrome is an aspectwhich hitherto has not been much appreciated,

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although preaxial digital anomalies have fea-tured in the descriptions of trigger thumb8 andduplication.29 Preaxial anomalies also occur inthe LADD syndrome.30

OROFACIAL CLEFTING AND HEARINGTypically both lip and palate were cleft althougha single case of submucous cleft palate wasnoted. Successful repair was achieved in all butone case (case 7). Historically both conductiveand sensorineural hearing impairment havebeen described in the EEC syndrome. In onecase ear ossicles were absent on tympanotomy.3'All affected cases had a history of middle earinfection confirmed by review of seven audio-grams. Eight of the nine cases with hearingimpairment interestingly had orofacial clefts.Impacted cerumen was a common cause oftransient hearing loss generally (cf XHED).Despite several reported cases of sensorineuralhearing loss in EEC syndrome,32 33 no case wasnoted in our group. Structural pinnal anomalieshave been previously reported (usually downfolding)" 29 but are unusual, only one caseshowing an anomaly of the external ear (case5) which in this case was of the tragus andassociated with minor posterior rotation.

RENAL TRACTRollnick and Hoo34 suggested that renal tractinvolvement occurred in up to 50% of cases.This aspect of the EEC syndrome is not widelyappreciated by UK physicians. Fewer than halfof the cases ascertained had had a renal ultra-sound scan. Occasionally UG tract anomaliesmay be life threatening with two of our casesrequiring emergency surgery in the first fewweeks of life. Painful micturition with an as-sociated small volume bladder in case 23 wasnoted throughout childhood. Case 17 hasrecently noted similar symptoms. Severalmembers of a Dutch family have identicalsymptomatology (R C M Hennekam, personalcommunication).

GROWTH AND MENTAL DEVELOPMENTEEC syndrome has been described with severemental retardation' 25 and comparison with thesyndrome described by Bowen and Arm-strong35 has been made. The estimate of Ri-chiera-Costa et al6 that 15% of cases havemental retardation (a review of 41 cases) isalmost certainly an overestimate. Because thepresent study is cross sectional rather thanlongitudinal, our study of growth in the EECsyndrome has not been definitive. Low birthweight has only recently been suggested as aconsistent feature of the syndrome,37 but this isnot confirmed in our group. Adenohypophysealdysfunction has been described in EEC syn-drome'4 but this was not suggested by our data.

SALIVARY GLANDS AND CHOANAL ATRESIADental examination of case 7 showed absenceof Stensens duct. This resulted in difficultywith mastication and severe dental caries owing

to reduced oral pH. Pries et al'8 reported re-duced parotid secretions in a number of cases.No other cases had this problem. There werealso no cases with nasal problems indicatingtotal or partial nasal obstruction.

MANAGEMENT OF CASES OF EEC SYNDROMEThe management of cases requires multi-disciplinary action. Early syndrome diagnosiswill allow parents to gain access to accuratecounselling and in particular the reassuringinformation regarding the low risk of mentalhandicap. When faced with a case of EECsyndrome the paediatrician should coordinate amultidisciplinary management team includingplastic surgeon, ophthalmologist, and renalspecialist, etc. Children ideally should beplaced on prophylactic antibiotics until renalinvestigation has taken place. Early audiologicalassessment is necessary before distraction test-ing becomes possible. The geneticist shouldbe ideally involved at an early stage. Geneticcounselling of families with oligosymptomaticEEC syndrome may prove very difficult as theclinician is often making a diagnosis withoutthe complete clinical picture. Recurrence riskscan usually be given to such families, but asclinical manifestation may be broad, problemswith labelling are frequently encountered.3738The decision as to whether or not ectodermalinvolvement is present may be critical to diag-nosis and counselling. However, establishingthe presence of ectodermal involvement maynot be easy; a history of slow growing hair ornails maybe helpful. Magnification ofnails witha hand lens in the infant with EEC syndromelooking for definite transverse ridging, nail con-cavity, and pitting may provide useful clues asto the presence ofnail dystrophy. Interpretationof dental x rays in the infant is possible butalso not easy. Cases may sometimes present asapparent lacrimal duct anomalies with orofacialclefting or with limb anomalies. The presenceof recurrent ophthalmic infection or epiphorain infants with clefting or limb reduction/syn-dactyly indicates that subtle manifestations ofectodermal dysplasia should be sought.Managing cases is difficult from both prac-

tical and psychological viewpoints. Severeectodermal manifestations can be helpedconsiderably by the use of wigs and cosmetics.Expert dental advice may preserve primaryteeth (encouraging mandibular growth).Simple emollients may be satisfactory for dryskin but the two cases with painful and severefissuring of the skin were both helped by cocoabutter based, unperfumed creams. Visual com-plications are particularly difficult to manage.Anticipation of recurrent infection in the earlyyears is necessary and artificial tears may alsobe protective if reduced lacrimal secretions isfound. Surgery for duct blockage is usuallynecessary. Little experience, even nationally,exists of corneal grafting (the specific cornealvascularisation in this syndrome is thought tomake long term successful grafting unlikely).

Prenatal diagnosis has been achieved39 butcases where a risk of fetal involvement existsmust be cautioned with regards to the potential

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Figure 6 The phenotypic Venn: a schematic representation of the EEC syndrome inrelation to other phenotypically related ectodermal dysplasias. OEEC= oligosymptomaticEEC syndrome; RHS= Rapp-Hodgkin syndrome; AEC= ankyloblepharon, ectodermaldysplasia, and clefting syndrome; ECMr= ectodermal dysplasia, cleft palate, and mentalretardation syndrome; LADD = lacrimoauricular-dento-digital syndrome; ECP=ectrodactyly-cleft palate syndrome.

difficulties in identifying affected fetuses in a

condition with such a variable presentation.Other syndromes with overlapping features,

such as the Rapp-Hodgkin syndrome and theAEC syndrome, have several features in com-

mon with the EEC syndrome but are thoughtto have distinctive characteristics. Rodini andRichiera-Costa40 discussed the clinical diag-nostic criteria in a review ofthe EEC syndrome,indicating that relatively minor differences be-tween the disorders confers separate syndromicstatus. In the authors' view this group of dis-orders can be considered as points on a pheno-typic Venn diagram (fig 6).

MOLECULAR CONSIDERATIONS

Embryologically, the cluster of features seen

in the EEC syndrome may be explained byanomalies of ectodermal/mesodermal in-teraction. The skin, nails, teeth, palate, limbs,salivary glands, and lacrimal duct have similardevelopmental profiles, developing either as

intrusions of embryonic ectoderm into un-

derlying mesenchyme or showing crucial re-

liance of ectoderm on underlying mesodermalsignalling. A rational aetiological classificationof the autosomal dominant ectodermal dys-plasias with distal limb deficit orofacial cleftingawaits the outcome of collaborative studieswhich may elucidate their molecular basis.Candidate chromosomal regions include7q21.3 (identified as a prime locus for ec-

trodactyly41), 7ql 1, and 9p2l (identified as

breakpoints in family with a translocation and

EEC syndrome).32 Other possible candidategenes for such a syndrome could include trans-forming growth factors alpha and beta (possiblyinvolved in palatogenesis42 43) and also ho-meobox genes (particularly MSX1 and MSX2,implicated in ectodermal mesodermal in-teraction in developing limbs,4445 teeth,46 andpalate47).

Contiguous genes may be involved in pro-ducing the EEC phenotype. Allelic hetero-geneity at a single locus could also explain theconsiderable overlap between the EEC andother syndromes. Until we have a clearer un-derstanding of the molecular basis of the EECsyndromes and similar disorders, difficulty willremain in their classification and hence in thepracticalities of making a firm diagnosis.

Dr Buss wishes to acknowledge that his work on EEC syndromewas undertaken while Action Research Training Fellow inMedical Genetics based at the Institute of Medical Genetics,UWCM, Cardiff.

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