Svndro,ne of the month

Journal of Medical Getnetics 1987, 24, 659-663

Hypohidrotic ectodermal dysplasiaA CLARKERegional Genetics Advisory Service, Newcastle upon Tyne NE2 4AA.

Hypohidrotic ectodermal dysplasia (HED) is anuncommon X linked condition. The phenotypeincludes sparse scalp hair, largely absent body hair,deficiency of the eccrine sweat glands, and anodontiaor oligodontia with conical teeth (figs 1 to 3). Thereis often a distinctive facies, with prominence of theforehead, a depressed nasal bridge, prominent lips,and periorbital wrinkling and pigmentation. Sub-cutaneous fat is often diminished or absent, as arethe mucous glands in the respiratory tree and thegastrointestinal tract.HED was first described in 1848 by Thurnam,'

and later in the 19th century by Darwin.2 It wasassigned to the X chromosome in 1921 by Thadani,who later reported that the carrier females couldmanifest signs of the condition.4 The full signi-ficance of this was not appreciated until Mary Lyonhypothesised the random inactivation of one Xchromosome in each female cell early in embryo-genesis.

Incidence

HED is found in all racial groups and in all areas ofthe world. The incidence at birth was estimated byStevenson and Kerr,6 based on the prevalence ofHED in Oxfordshire: they suggested a rate of 1 per100 000 births. Personal experience would supportthis estimate.

Clouston"' and other authors" 12 have pointedout that hypohidrosis could result in impairedthermoregulation leading to hyperpyrexia andapparent cot death. The recurrent episodes ofhyperthermia or sepsis or both more usually resolvespontaneously and growth and developmentproceed normally.Temperature control in older children can be

helped by cool surroundings, drinking cool fluids,and taking cool showers or wearing wet T shirts(table). Some of the males also suffer in coldweather because of their reduced subcutaneous fat.The growth of boys with HED should be monitored

and short stature should not be regarded as being anatural consequence of HED: a few boys with HEDmay be subject to endocrine deficiencies. 13 Mentaldevelopment is generally normal and suggestions ofintellectual retardation are unfounded, but someboys do have speech problems. These may beassociated with difficulty in articulation caused byoligodontia and nasal obstruction, with hearingproblems from wax in the auditory canal, and with alack of social confidence resulting from the unusualfacies. The early fitting of artificial dentures, beforeprimary school age if the boy is willing, can help hisspeech and facial appearance as well as his nutrition.

Convulsions may occur in association with hyper-pyrexia in early childhood, but are uncommon,

Clinical course TABLE Cllinical approach to HED.

Infants may have dry, peeling skin at birth thatmakes them look dysmature. Some infants onlypresent later with oligodontia, but many havefeeding problems caused by crusts of nasal secret-ions that obstruct the nose. They may suffer fromfevers in hot weather, from recurrent chest infect-ions, and from eczema. Some infants with recurrentsepticaemia may benefit from prophylaxis withantibiotics. Reports of a primary immune deficiencyas a feature of HED have not been substantiated.7-Received for publication 23 April 1987.Revised version accepted for publication 22 May 1987.

Mortalitv in eiarls childhood 30"(1(higher in first affectcd sib, rnost dciaths occur in infancy)

Severe illncss in carlv childhood 51(including dea ths)

Control of body tcmperaturc: tepid spongitng. showers. cold drinlks. anti-pyretics. wet clothing.

Treatment and prophylaxis of infections.Feeding problems (7(0%): nasal crustittg (8X(X/, ) will oftcn contributc. I Icatcd

drinks and dry foods rnay causc difficultics.Monitor growth: short staiturc is not inesvitable atnd warrants full insXcstigatiot.Monitor speech and hcaring: artificial dcrItircs fitted before school maylltclp

speech. cotifidcnce. and nutrition.Asthma (65" atnd eczema (7(10 rcquire stantdard trea.timcints.Deficient lacrimal sccretions requirc cye drops.Genetic counselling and support.

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A Clarke

occurring not very much more frequently than in thegeneral population.

Deficiency of saliva may necessitate the drinkingof water with food, and eye drops may remedy any

deficiency of lacrimation. Inadequate salivationmay also predispose to dental decay.

Adolescents are often very self-conscious, but canbe reassured that men with HED lead entirely

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FIG 1 (a, b, c) Three males with X linked HED. (Courtesy of the families, and of the Medical PhotographyDepartments, Coventry and Warwickshire Hospital and University Hospital of Wales.) Fig 1 (c) is alsoreproduced by kind permission of the Editor, Archives of Disease in Childhood.

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Hypohidrotic , todermal dtysplasia

normal social lives, although their occupation andleisure activities sometimes need to be modified ifheat intolerance is a continuing problem. Oncemixing in the world of adults, affected men generallyfind little problem with their appearance. Theyshould be advised to avoid industrial work in a dustyatmosphere and not to smoke, because thesefactors may lead on to chronic obstructive airwaysdisease.'5

Differential diagnosis

In their recent compendium, Freire'Maia andPinheirolb recognise 117 varieties of ectodermaldysplasia, but only a few are likely to causeconfusion in diagnosis. The pedigree structure may

distinguish the much less common, autosomalrecessive variety ofHED that cannot be distinguishedclinically.'7 In the isolated case, a search should bemade for manifesting female carriers. Other recessiveconditions whose phenotypes overlap are dis-tinguished by severe nail dystrophy and normalsweating (Fried's tooth and nail syndrome), bynormal teeth (hypohidrotic ectodermal dysplasiawith hypothyroidism), or by mottled pigmentationof the skin, mental retardation, and absence ofhypohidrosis (Berlin's syndrome). The rare Rosselli-Gulienetti syndrome includes features of ectodermaldysplasia, as well as facial clefts and poplitealpterygia.Dominant ectodermal disorders are also distin-

guished by pedigree structure or by atypical features

(a)

FIG 2 Postmnortem photomicrographs ofskin from male infant (a) abdomen, (b) scalp.Note absence ofsweat glands and paucityof hair. (Courtesy of Dr J R Read, Castle HillHospital, North Humberside.)

(b)

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662

nation alone, in fact, will reveal this proportion ofcarrierst' and more may be recognised by exami-nation of sweat pores.20 2 I have experiencedconsiderable difficulty in interpreting the results ofdirect sweat pore counting (heavy housework canobliterate sweat pores) and prefer the whole backsweat test of Happle and Frosch22 to reveal thepattern of Lyonisation as manifest in the lines ofBlaschko. Even this test, however, is not invariablycorrect, and may leave some residual doubt.Female heterozygotes may manifest patchiness of

body or scalp hair, in addition to dental andsweating anomalies. Others suffer problems withheat intolerance, chest infections, and even failureto thrive in infancy; a very few have a facies

(Courtesy ofMr P reminiscent of the affected males. These findings(etsit' of Wales College can be largely explained in terms of Lyonisation.234

Classical linkage studies excluded close linkage tothe loci for Xg25 and for G6PD.26 A femalemanifesting HED was described by Cohen et a127and then by Cook28; she had an X;9 translocation

the EEC, AEC, and with the X breakpoint at Xql2. This has promptedare characterised by several groups to use RFLP techniques to identify

nalities. The features of DNA probes that recognise closely linked sequencesic ectodermal dysplasia on this region of the X.2 31 A consensus view would,strophy. The dominant be that the HED locus lies close to the centromere,terised by severe nail probably on proximal Xq; DXYSJ (recognised byand absent dermato- pDP34) lies distal at 10 cM and DXS14 (recognised

iotrichosis, hypodontia, by probe 58-1) lies across the centromere onier-Roubicek syndrome proximal Xp at 7 to 10 cM. These loci are probablynormal eyebrows and too distant to be useful alone in prenatal diagnosis.

^eaks in dental enamel, The locus DXS146 (recognised by the probetar sweating. Koshiba's pTAK8) may lie closer to HED, but has beenla has a distinct pattern studied in only a few families.3Lnd more severe nail Homology of HED with the murine 'tabby'ge HED is a condition mutation accords well with the comparative maps ofr review, but said to be human and mouse X chromosomes,32 and thesedominant disorder with conditions map close to the loci for Menkes' diseasein males. and PGK in both species.

References

Thurnam J. Two cases in which the skin, hair and teeth wercvery imperfectly developed. Proc R Med Cliir Soc (Lotid)t848;31 :71-82.

2 Darwin C. The variation of animals anid plants unider doinesti-cation. 2nd cd (revised). London: John Murray. 1888.

3 Thadani KI. A toothless type of man. J Hered 1921;12:87-8.4 Thadani KI. The toothless man of Sind. J Hered 1934;25:483-4.s Lyon MF. Gene action in the X-chromosome of the mousc.Nature 1961;190:372-3.

6 Stevenson AC, Kerr CB. On the distributions of frequencies ofmutation to genes determining harmful traits in man. Mutat Res1967 ;4:339-52.

7 Davis JR, Solomon LM. Cellular immunodeficiency in anhi-drotic ectodermal dysplasia. Acta Derm Venereol (Stockh) 1976;56:115-20.

8 Takeda E, Kuroda Y, Watanabe T, et al. Cytidine 5'-diphosphate reductase and thymidine kinase activities in phyto-hemagglutinin-stimulated lymphocytes of normal subjects of

Fri 3 Teeth ofmale with HED.Crawford, Dental Hospital, Unilof Medicine.)

in the isolated case. Thus,Rapp-Hodgkin syndromesfacial clefts and other abnornClouston's dominant hidrotialso include a severe nail dyBasan syndrome is characdystrophy, simian creases,glyphics, in addition to hypand hypohidrosis. The Zanican be distinguished by theeyelashes, the transverse strand the sparing of palmnoplantricho-onychodental dysplasiof dental malformation adystrophy. The Lenz-Passar,almost identical to that undetransmitted as an X linkedmore severe manifestation

Genetic aspects

The sex linked inheritance of HED, probably thecommonest ectodermal dysplasia, has long beenrecognised. The molecular defect, however, has notbeen elucidated; the suggestion that low parathyroidhormone levels9 may be a primary feature of thecondition has not been substantiated. Anothersuggestion, of genetic heterogeneity with several Xlinked loci involved,t6 is also unsupported byevidence, although gene localisation for the Lenz-Passarge dysplasia has not been attempted. Clinicalheterogeneity, however, does exist both within andbetween families.Female carriers may be identified in at least 70%

of cases by clinical examination.t8 Dental exami-

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it-ipohidrotic ectodermal dysplasia

various ages and patients with immunodcficiency. Pedi(atr Res1984;18:691-6.Sodcrholm AL. Kaitila 1. Expression of X-linked hvpohidroticectoderm-al dysplasia in six males and in their mothcrs. Cli,tGentet 1985;28: 136-44.Clouston HR. The major forms of hcreditary ectodermaldysplasia. Cant Med Assoc J 1939;40:1-7.Mills J. Anhidrotie ectodermal dysplasia presenting as a pyrexiaof undetermined origin in the neonatal period. Postgrad Med J1967:44:193-4.Salisburv DM. Stothcrs JK. livpohidrotie ectodermal dysplasiaand suddcn infant death. Lancet 1981 J: 153-4.

'3 Pabst (IF. Groth 0. McCoy EE. Ilypohidrotic ectodermaldysplasia with hypothyroidism. J Pediatr 1981:;98:223-7.

14 Tanner BA. Intellectual funetioning and ectodermal dysplasia.Pediatrics 1985X;75:126.Bcahrs JO. Lillington GA. Rosan R. et al. Anhidrotic ccto-dermal dysplasia: prcdisposition to bronchial discisc. AnnlItterti Med 1971:74:92-6.

Ih Freire-Maia N. Pinheiro M. Ectoderinal ds'splasias: a clinicalanid genetic studsv. New York: Alan R Liss. 1984.

17 Passarge E. Fries E. Autosomal recessive hypohidrotic ccto-dermal dysplasia with subclinical manifestation in the hetero-zygote. Birth Defects 1977:XIII(3C):95-100.

x Pinheiro M. Ideriha MT. Chautard-Freire-Maia EA. et al.

Christ-Sicmens-Tourainc syndrome. Invcstigations on two largeBrazilian kindreds with a new estimate of the manifestation rateamong carriers. Humn Geniet 1981:57:428-31.

'9 Nakata M. Koshiba f1. Eto IH. Nanee WE. A genetic study ofanodontia in X-linkcd hypohidrotic ectodermal dysplasia. Ain JHumn Geotet 1980:,32:908-19.

20 Frias JL. Smith DW. Diminished sweat pores in hypohidroticectodermal dysplasia: a new method for issessmcnt. J Pediatr1968;72:6(06-1(.

21 Kleinebrecht J. Dcgenhardt KH. Grubisic A. et al. Swcat porecounts in cctodcrmal dvsplasias. Hun Gen1et 1981(:57:437-9.

22 Happle R. Frosch PJ. Manifestation of the lines of Blaschko in

women hetcrozygotes for X-linkcd hypohidrotic ectodermaldysplasia. Clini Geniet 1985:27:468-71.

23 Kerr CB. Wells RS. Cooper KE. Gene effcct in cirricrs ofanhidrotic cctodermal dysplasia. J Med Getiet 1966:3:169-76.24 Passargc E. Fries E. X chromosome inactivation in X-linkedhypohidrotic ectodermal dysplasia. Natuire 1973:245:58-9.Simpson JL. Allen FH Jr. New, M. German J. Absencc of closelinkage bctween the locus for Xg and the locus for inhidroticectodermal dysplasia. Vox Satng 1969:17:465-7.

2- Filippi G. Rinaldi A. Crisponi G. et ail. X-maipping in man:evidence against measurable linkage heteen inhidrotic ecto-dermal dysplasia and G6PD deficiency. J Med Geniet 1979:16:223-4.

27 Cohen MM. Lin CC. Syhert V. Orecchio EJ. Two human X-autosome translocations identified h' iautoradiography andfluorescencc. Ain J Humn Geniet 1972:24:583-97.

2-Is Gerald PS. Brown JA. Report of the committec on the geneticconstitution of the X chromosome. HGMI. Cs'togenet CellGeniet 1974:,13:29-34.

-9 MacDermot KD. Winter RM. Malcolm S. Gene localisation ofX-linked hypohidrotic ectodermal dvsplasia (C-S-T svndrome).Humn Genet 1986;74:172-3.

30 Clarke A. Sarfarazi M. Thomas NST. et al. X-linkcd hvpo-hidrotic ectodermal dysplasia: DNA prohe linkage analysis andgene localization. Humn Geniet 1987;75:378-80(.

3 Kolvraa S. Kruse TA. Jensen PKA. et al. Close linkagebetween X-linked ectodermal dysplasia and a cloned DNAsequence detecting a two allele restriction fragmcnt lengthpolymorphism in the region Xpl l-q12. Humn Genet 1986;74:284-7.

32 Bucklc VJ. Edwards JH. Evans EP. et a!. Comparative maps ofhuman and mouse X chromosomes. HGM8. Cst'ogenet C(ellGeniet 1985;40:594.-5.

Correspondence and requests for reprints toDr A Clarke, Regional Genetics Advisory Service,19 Claremont Place, Newcastle upon Tyne NE2 4AA.

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