J Med Genet: first published as 10.1136/jmg.24.11.659 on 1 November 1987. Downloaded from

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Journal of Medical Getnetics 1987, 24, 659-663 Hypohidrotic ectodermal dysplasia A CLARKE Regional Genetics Advisory Service, Newcastle upon Tyne NE2 4AA.

Hypohidrotic ectodermal dysplasia (HED) is an Clouston"' and other authors" 12 have pointed uncommon X linked condition. The phenotype out that hypohidrosis could result in impaired includes sparse scalp hair, largely absent body hair, thermoregulation leading to hyperpyrexia and deficiency of the eccrine sweat glands, and anodontia apparent cot death. The recurrent episodes of or oligodontia with conical teeth (figs 1 to 3). There hyperthermia or sepsis or both more usually resolve is often a distinctive facies, with prominence of the spontaneously and growth and development forehead, a depressed nasal bridge, prominent lips, proceed normally. and periorbital wrinkling and pigmentation. Sub- Temperature control in older children can be cutaneous fat is often diminished or absent, as are helped by cool surroundings, drinking cool fluids, the mucous glands in the respiratory tree and the and taking cool showers or wearing wet T shirts gastrointestinal tract. (table). Some of the males also suffer in cold HED was first described in 1848 by Thurnam,' weather because of their reduced subcutaneous fat. and later in the 19th century by Darwin.2 It was The growth of boys with HED should be monitored assigned to the X chromosome in 1921 by Thadani, and short stature should not be regarded as being a who later reported that the carrier females could natural consequence of HED: a few boys with HED copyright. manifest signs of the condition.4 The full signi- may be subject to endocrine deficiencies. 13 Mental ficance of this was not appreciated until Mary Lyon development is generally normal and suggestions of hypothesised the random inactivation of one X intellectual retardation are unfounded, but some chromosome in each female cell early in embryo- boys do have speech problems. These may be genesis. associated with difficulty in articulation caused by oligodontia and nasal obstruction, with hearing Incidence problems from wax in the auditory canal, and with a lack of social confidence resulting from the unusual http://jmg.bmj.com/ HED is found in all racial groups and in all areas of facies. The early fitting of artificial dentures, before the world. The incidence at birth was estimated by primary school age if the boy is willing, can help his Stevenson and Kerr,6 based on the prevalence of speech and facial appearance as well as his nutrition. HED in Oxfordshire: they suggested a rate of 1 per Convulsions may occur in association with hyper- 100 000 births. Personal experience would support pyrexia in early childhood, but are uncommon, this estimate. on September 26, 2021 by guest. Protected Clinical course TABLE Cllinical approach to HED.

Infants may have dry, peeling skin at birth that Mortalitv in eiarls childhood 30"(1 makes (higher in first affectcd sib, rnost dciaths occur in infancy) them look dysmature. Some infants only Severe illncss in carlv childhood 51 present later with oligodontia, but many have (including deaths) feeding problems caused by crusts of nasal secret- Control of body tcmperaturc: tepid spongitng. showers. cold drinlks. anti- ions that obstruct the nose. They may suffer from pyretics. wet clothing. fevers in hot weather, from recurrent chest infect- Treatment and prophylaxis of infections. Feeding problems (7(0%): nasal crustittg (8X(X/, ) will oftcn contributc. I Icatcd ions, and from eczema. Some infants with recurrent drinks and dry foods rnay causc difficultics. septicaemia may benefit from prophylaxis with Monitor growth: short staiturc is not inesvitable atnd warrants full insXcstigatiot. Monitor speech and hcaring: artificial dcrItircs fitted before school maylltclp antibiotics. Reports of a primary immune deficiency speech. cotifidcnce. and nutrition. as a feature of HED have not been substantiated.7- Asthma (65" atnd eczema (7(10 rcquire stantdard trea.timcints. Deficient lacrimal sccretions requirc cye drops. Received for publication 23 April 1987. Genetic counselling and support. Revised version accepted for publication 22 May 1987. 659 J Med Genet: first published as 10.1136/jmg.24.11.659 on 1 November 1987. Downloaded from

660 A Clarke occurring not very much more frequently than in the deficiency of lacrimation. Inadequate salivation general population. may also predispose to dental decay. Deficiency of saliva may necessitate the drinking Adolescents are often very self-conscious, but can of water with food, and eye drops may remedy any be reassured that men with HED lead entirely

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FIG 1 (a, b, c) Three males with X linked HED. (Courtesy ofthefamilies, and of the Medical Photography Departments, Coventry and Warwickshire Hospital and University Hospital of Wales.) Fig 1 (c) is also reproduced by kind permission ofthe Editor, Archives of Disease in Childhood. J Med Genet: first published as 10.1136/jmg.24.11.659 on 1 November 1987. Downloaded from

Hypohidrotic , todermal dtysplasia 661 normal social lives, although their occupation and distinguish the much less common, autosomal leisure activities sometimes need to be modified if recessive variety of HED that cannot be distinguished heat intolerance is a continuing problem. Once clinically.'7 In the isolated case, a search should be mixing in the world of adults, affected men generally made for manifesting female carriers. Other recessive find little problem with their appearance. They conditions whose phenotypes overlap are dis- should be advised to avoid industrial work in a dusty tinguished by severe nail dystrophy and normal atmosphere and not to smoke, because these sweating (Fried's tooth and nail syndrome), by factors may lead on to chronic obstructive airways normal teeth (hypohidrotic ectodermal dysplasia disease.'5 with hypothyroidism), or by mottled pigmentation of the skin, mental retardation, and absence of Differential diagnosis hypohidrosis (Berlin's syndrome). The rare Rosselli- Gulienetti syndrome includes features of ectodermal In their recent compendium, Freire'Maia and dysplasia, as well as facial clefts and popliteal Pinheirolb recognise 117 varieties of ectodermal pterygia. dysplasia, but only a few are likely to cause Dominant ectodermal disorders are also distin- confusion in diagnosis. The pedigree structure may guished by pedigree structure or by atypical features

(a) copyright. http://jmg.bmj.com/

FIG 2 Postmnortem photomicrographs of skin from male infant (a) abdomen, (b) scalp. Note absence ofsweat glands and paucity ofhair. (Courtesy of Dr J R Read, Castle Hill Hospital, North Humberside.) on September 26, 2021 by guest. Protected

(b) J Med Genet: first published as 10.1136/jmg.24.11.659 on 1 November 1987. Downloaded from

662 A ClulrA-.- nation alone, in fact, will reveal this proportion of carrierst' and more may be recognised by exami- nation of sweat pores.20 2 I have experienced considerable difficulty in interpreting the results of direct sweat pore counting (heavy housework can obliterate sweat pores) and prefer the whole back sweat test of Happle and Frosch22 to reveal the pattern of Lyonisation as manifest in the lines of Blaschko. Even this test, however, is not invariably correct, and may leave some residual doubt. Female heterozygotes may manifest patchiness of body or scalp hair, in addition to dental and sweating anomalies. Others suffer problems with heat intolerance, chest infections, and even failure to thrive in infancy; a very few have a facies Fri 3 Teeth ofmale with HED. (Courtesy of Mr P reminiscent of the affected males. These findings Crawford, Dental Hospital, Unil (etsit' of Wales College can be largely explained in terms of Lyonisation.234 of Medicine.) Classical linkage studies excluded close linkage to the loci for Xg25 and for G6PD.26 A female manifesting HED was described by Cohen et a127 and then by Cook28; she had an X;9 translocation in the isolated case. Thus, the EEC, AEC, and with the X breakpoint at Xql2. This has prompted Rapp-Hodgkin syndromes are characterised by several groups to use RFLP techniques to identify facial clefts and other abnornnalities. The features of DNA probes that recognise closely linked sequences Clouston's dominant hidrotiic ectodermal dysplasia on this region of the X.2 31 A consensus view would also include a severe nail dy,strophy. The dominant be that the HED locus lies close to the centromere,copyright. Basan syndrome is characterised by severe nail probably on proximal Xq; DXYSJ (recognised by dystrophy, simian creases, and absent dermato- pDP34) lies distal at 10 cM and DXS14 (recognised glyphics, in addition to hypiotrichosis, hypodontia, by probe 58-1) lies across the centromere on and hypohidrosis. The Zaniier-Roubicek syndrome proximal Xp at 7 to 10 cM. These loci are probably can be distinguished by the normal eyebrows and too distant to be useful alone in prenatal diagnosis. eyelashes, the transverse str^eaks in dental enamel, The locus DXS146 (recognised by the probe and the sparing of palmnoplan tar sweating. Koshiba's pTAK8) may lie closer to HED, but has been tricho-onychodental dysplasila has a distinct pattern studied in only a few families.3 http://jmg.bmj.com/ of dental malformation aLnd more severe nail Homology of HED with the murine 'tabby' dystrophy. The Lenz-Passar,ge HED is a condition mutation accords well with the comparative maps of almost identical to that under review, but said to be human and mouse X chromosomes,32 and these transmitted as an X linked dominant disorder with conditions map close to the loci for Menkes' disease more severe manifestation in males. and PGK in both species.

Genetic aspects References on September 26, 2021 by guest. Protected Thurnam J. Two cases in which the skin, hair and teeth werc The sex linked inheritance of HED, probably the very imperfectly developed. Proc R Med Cliir Soc (Lotid) commonest ectodermal dysplasia, has long been t848;31 :71-82. recognised. The molecular defect, however, has not 2 Darwin C. The variation of animals anid plants unider doinesti- been elucidated; the suggestion that low parathyroid cation. 2nd cd (revised). London: John Murray. 1888. 3 Thadani KI. A toothless type of man. J Hered 1921;12:87-8. hormone levels9 may be a primary feature of the 4 Thadani KI. The toothless man of Sind. J Hered 1934;25:483-4. condition has not been substantiated. Another s Lyon MF. Gene action in the X-chromosome of the mousc. suggestion, of genetic heterogeneity with several X Nature 1961;190:372-3. linked loci involved,t6 is also unsupported by 6 Stevenson AC, Kerr CB. On the distributions of frequencies of mutation to genes determining harmful traits in man. Mutat Res evidence, although gene localisation for the Lenz- 1967 ;4:339-52. Passarge dysplasia has not been attempted. Clinical 7 Davis JR, Solomon LM. Cellular immunodeficiency in anhi- heterogeneity, however, does exist both within and drotic ectodermal dysplasia. Acta Derm Venereol (Stockh) 1976; between families. 56:115-20. 8 Takeda E, Kuroda Y, Watanabe T, et al. Cytidine 5'- Female carriers may be identified in at least 70% diphosphate reductase and thymidine kinase activities in phyto- of cases by clinical examination.t8 Dental exami- hemagglutinin-stimulated lymphocytes of normal subjects of J Med Genet: first published as 10.1136/jmg.24.11.659 on 1 November 1987. Downloaded from

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various ages and patients with immunodcficiency. Pedi(atr Res women hetcrozygotes for X-linkcd hypohidrotic ectodermal 1984;18:691-6. dysplasia. Clini Geniet 23 1985:27:468-71. Sodcrholm AL. Kaitila 1. Expression of X-linked hvpohidrotic Kerr CB. Wells RS. Cooper KE. Gene effcct in cirricrs of ectoderm-al dysplasia in six males and in their mothcrs. Cli,t anhidrotic cctodermal dysplasia. J Med Getiet Gentet 24 1966:3:169-76. 1985;28: 136-44. Passargc E. Fries E. X chromosome inactivation in X-linked Clouston HR. The major forms of hcreditary ectodermal hypohidrotic ectodermal dysplasia. Natuire 1973:245:58-9. dysplasia. Cant Med Assoc J 1939;40:1-7. Simpson JL. Allen FH Jr. New, M. German J. Absencc of close Mills J. Anhidrotie ectodermal dysplasia presenting as a pyrexia linkage bctween the locus for Xg and the locus for inhidrotic of undetermined origin in the neonatal period. Postgrad Med J ectodermal dysplasia. Vox Satng 1969:17:465-7. 1967:44:193-4. 2- Filippi G. Rinaldi A. Crisponi G. et ail. X-maipping in man: Salisburv DM. Stothcrs JK. livpohidrotie ectodermal dysplasia evidence against measurable linkage heteen inhidrotic ecto- and suddcn infant death. Lancet 1981 J: 153-4. dermal dysplasia and G6PD deficiency. J Med Geniet 1979:16: '3 Pabst (IF. Groth 0. McCoy EE. Ilypohidrotic ectodermal 223-4. dysplasia with hypothyroidism. J Pediatr 1981:;98:223-7. 27 Cohen MM. Lin CC. Syhert V. Orecchio EJ. Two human X- 14 Tanner BA. Intellectual funetioning and ectodermal dysplasia. autosome translocations identified h' iautoradiography and Pediatrics 1985X;75:126. fluorescencc. Ain J Humn Geniet Bcahrs JO. 1972:24:583-97. Lillington GA. Rosan R. et al. Anhidrotic ccto- 2-Is Gerald PS. Brown JA. Report of the committec on the genetic dermal dysplasia: prcdisposition to bronchial discisc. Ann constitution of the X chromosome. HGMI. Cs'togenet Cell lItterti Med 1971:74:92-6. Geniet 1974:,13:29-34. Ih Freire-Maia N. Pinheiro M. Ectoderinal ds'splasias: a clinical -9 MacDermot KD. Winter RM. Malcolm S. Gene localisation of anid genetic studsv. New York: Alan R Liss. 1984. X-linked hypohidrotic ectodermal dvsplasia (C-S-T svndrome). 17 Passarge E. Fries E. Autosomal recessive hypohidrotic ccto- Humn Genet 1986;74:172-3. dermal dysplasia with subclinical manifestation in the hetero- 30 Clarke A. Sarfarazi M. Thomas NST. et al. X-linkcd hvpo- zygote. Birth Defects 1977:XIII(3C):95-100. hidrotic ectodermal dysplasia: DNA prohe linkage analysis and x Pinheiro M. Ideriha MT. Chautard-Freire-Maia EA. et al. gene localization. Humn Geniet 1987;75:378-80(. Christ-Sicmens-Tourainc syndrome. Invcstigations on two large 3 Kolvraa S. Kruse TA. Jensen PKA. et al. Close linkage Brazilian a kindreds with new estimate of the manifestation rate between X-linked ectodermal dysplasia and a cloned DNA among carriers. Humn Geniet 1981:57:428-31. a two '9 sequence detecting allele restriction fragmcnt length Nakata M. Koshiba f1. Eto IH. Nanee WE. A genetic study of polymorphism in the region Xpl l-q12. Humn Genet 1986; anodontia in X-linkcd hypohidrotic ectodermal dysplasia. Ain J 74:284-7. Humn Geotet 1980:,32:908-19. 32 Bucklc VJ. Edwards JH. Evans EP. et a!. Comparative maps of

20 copyright. Frias JL. Smith DW. Diminished sweat pores in hypohidrotic human and mouse X chromosomes. HGM8. Cst'ogenet C(ell ectodermal dysplasia: a new method for issessmcnt. J Pediatr Geniet 1968;72:6(06-1(. 1985;40:594.-5. 21 Kleinebrecht J. Dcgenhardt KH. Grubisic A. et al. Swcat pore Correspondence and requests for reprints to counts in cctodcrmal dvsplasias. Hun Gen1et 1981(:57:437-9. Dr A Clarke, Regional Genetics Advisory Service, 22 Happle R. Frosch PJ. Manifestation of the lines of Blaschko in 19 Claremont Place, Newcastle upon Tyne NE2 4AA. http://jmg.bmj.com/ on September 26, 2021 by guest. Protected