EIVIC voor CD-Rom · 1 Bartiméus Institute for the Visually Impaired, Zeist, The Netherlands 2 Faculty of Life Sciences, University of Manchester, United Kingdom 3 Department of

Chapter 5

The EEM syndrome, a ten year follow-up of two new patients

van Genderen MM1, Dixon MJ 2, Riemslag FCC 1,Stilma JS 3, Meire FM4

Submitted

1 Bartiméus Institute for the Visually Impaired, Zeist, The Netherlands

2 Faculty of Life Sciences, University of Manchester, United Kingdom3 Department of Ophthalmology, University Medical Center Utrecht, The Netherlands 4 University Children’s Hospital Koningin Fabiola, Brussel en University Hospital Gent, Belgium

ELECTROPHYSIOLOGY IN VISUALLY IMPAIRED CHILDREN MARIA MICHIELDE VAN GENDEREN


The EEM syndrome, a ten year follow-up of two

new patients

Abstract

The EEM syndrome (Ectrodactyly, Ectodermal Dysplasia, and MacularDystrophy) is a rare inherited disorder affecting the limbs, eyes, hair and teeth.Affected patients have hypotrichosis, malformations of the distal extremities suchas syndactyly and ectrodactyly, and retinal abnormalities mainly of the posteriorpole. In addition, there are narrow teeth, missing teeth, or both. Recently it wasascertained that EEM is caused by homozygous mutations in CDH3, encoding P-cadherin.We describe a brother and sister with the EEM syndrome, born from unaffectedparents. Of their four healthy siblings, one sister had teeth abnormalities, whichmay be a mild manifestation of the syndrome in a carrier. The patients already had extensive retinal abnormalities in infancy. The retinalappearance was consistent with a congenital abnormality of Bruch’s membrane,rather than a macular dystrophy. Follow-up of more than ten years showed mini-mal changes in fundoscopic appearance and visual functions. The ERG in bothchildren remained normal, indicating normal photoreceptor function.Ophthalmologically, the EEM syndrome appears distinct from hypotrichosis withmacular dystrophy (HJMD), a syndrome also caused by mutations in CDH3.

Key words

EEM syndrome, retinal dysplasia, ERG, Bruch’s membrane, HJMD, CDH3

Introduction

In 1956, Albrectsen and Svendsen described a previously unknown syndrome intwo Danish children, a brother and sister.1 The children had syndactyly, sparsehair, and retinal abnormalities interpreted as a retinal degeneration. Their psycho-motor development was normal. Ohdo2 first used the acronym EEM in 1983, in adescription of an inbred family with the syndrome. A total of twelve patients have been described so far, with significant clinicalvariability of the symptoms1-5 (Table 1). All patients had retinal abnormalities con-sisting of pigmentary alterations or atrophic lesions of the posterior pole, somealso had peripheral lesions. (Table 2). The visual functions of some patients

83


deteriorated over several years,4,5 while in others they seemed to be fairly stable.1,2,3

Several patients were born from consanguineous marriages,1,2,4 which suggestedautosomal recessive inheritance. A recent study by Kjaer6 of two previously reported families showed homozygousmutations in CDH3, encoding P-cadherin, to be the cause of EEM. P-cadherin isan important component in maintaining cell-cell adhesions at adherens junctionsthrough Ca2+ -dependent homophilic interactions.7 It is thought to be involved inthe regulation of both hair8 and retinal9 development.

In this report we describe two children, a brother and a sister, who presented withthe EEM syndrome. We first examined them as infants, and present follow-updata of more than 10 years on their visual functions, tested both psychophysicallyand electrophysiologically.

84


author sex hands feet hypotrichosis teeth

Albrectsen f syndactyly normal + small, widely spacedm ectrodactyly webbing + normal

Ohdo f syn/ ectrodactyly poly/syndactyly + nmf ectrodactyly syndactyly + small, widely spacedf syn/ ectrodactyly normal + nmm ectrodactyly syn/ ectrodactylyv + nmm ectrodactyly syn/ ectrodactyly + nm

Hayakawa f ectrodactyly nm + small, irregular, oligodontiaBalarin Silva m syndactyly nm + small, widely spaced

m webbing nm +Senecky f syndactyly nm + normal

m syndactyly nm + normalthis study f syn/ ectrodactyly normal + small, widely spaced, oligodontia

m syn/ ectrodactyly normal + small, widely spaced

f, female; m, male; nm not mentioned

Table 1. EEM syndrome, summary of clinical features (except ocular) of the 6 described families

Case report

Clinical findingsIn 1990, we saw a one year old girl, the fifth child of unrelated parents. She wasborn at term after an uneventful pregnancy, with a birth weight of 4180 gm. Shehad extensive abnormalities of both hands (see Figure 1). Her scalp hair was sparseand she had scanty, very blond eyelashes and eyebrows (Figure 2). When she grewolder, her dentist observed three missing teeth; furthermore her teeth were rathernarrow and widely spaced (Figure 3). Her mental development was normal. Thefindings in the girl were suggestive of the EEM syndrome.In 1992, her brother was born, also with features of the EEM syndrome withextensive hand malformations (see Figure 4). He also had very sparse scalp hairand very blond eyelashes and eyebrows. His teeth were widely spaced but normalin number. The girl had three older brothers and one older sister without any congenitalabnormalities, except for nine missing teeth in the sister.

85


VA1, visual acuity at first examination; VA2, visual acuity at follow up examination; M, of the macula; P, of the(mid)periphery; nm, not mentioned

Table 2. ocular features in the EEM syndrome

author VA1 VA2 fundus ElectrophysiologyOD OS (age) OD OS (age) RPE alterations atrophic lesions ERG EOG

Albrectsen 0.16 0.1 (6) M,P 0.12 (4) M,P

Ohdo nm (16) M Mnm (10) Mnm (39) M Mnm (45) M Mnm (42) M M

Hayakawa 0.07 0.01 (30) 0.03 0.01 (41) M M subnormal flatBalarin Silva 0.25 0.25 (23) 0.1 0.1 (33) M normal normal

0.3 0.3 (25) 0.3 0.1 (35) M normal normalSenecky nm (12) M M abnormal

nm (9) M M abnormalthis study 0.1 0.1 (1) 0.05 0.05 (4) M,P normal

0.08 0.08 (0.7) 0.05 0.05 (12) M,P normal normal

Ocular findingsOphthalmologic examination in the girl showed a visual acuity of 0.1, tested at ageone, two, and five with a test appropriate for age; her visual acuity was 0.06 at nineand fourteen years. She had a divergent squint and nystagmus. Color vision testingat age seven and thirteen was normal, as were her peripheral visual fields and darkadapted thresholds. Biomicroscopy was normal. Fundoscopy revealed normaldiscs and blood vessels. The retina showed severe pigmentary alterations andatrophic lesions in the macular area (Figure 5). Retinal pigment epithelium (RPE)disturbances were also observed in the midperiphery with hyperpigmentations,white deposits, and the aspect of peau d’orange (Figure 6). Subretinal fibrosis wasespecially noticed around the optic discs). Flash electroretinography (ERG)recordings according to ISCEV standards10 were made at age two, and repeated atage 14. The scotopic, mixed, and photopic responses of both recordings werewithin normal limits.The boy had a visual acuity of 0.08 at ten months of age, 0.1 at four and sevenyears, and 0.05 at ten and twelve years. He had a divergent squint and nystagmus.Color vision testing at seven and twelve years was normal, as were his peripheralvisual fields and dark adapted thresholds. Biomicroscopy was normal; fundoscopyshowed widespread pigmentary changes with the most obvious changes in themacular area. Discs and vessels were normal (Figure 7). ERG testing at age 12 showed normal scotopic, mixed and photopic responses.The electro-oculogram (EOG11) showed a normal Arden ratio of 2.0 in the righteye, and 2.4 in the left eye.

Discussion

Including the two patients in this study, only fourteen patients, have beendescribed with the EEM syndrome since 1956.1-5 All patients had distal limbmalformations, hypotrichosis, and macular pigmentary changes; their visualacuities varied from 0.05 to 0.3. The reports showed significant clinical variabilityin the EEM phenotype (Table 1). Several patients had major hand malformationswith missing phalanges or even whole fingers; some also had foot abnormalities.In contrast, others had relatively minor hand abnormalities and normal feet. Ninepatients had teeth abnormalities. No relationship appears to exist between theextent of the hand malformations and the ocular features

The two siblings in this study are the first patients to have been examined ininfancy; at that time retinal abnormalities were already extensive. Follow-up of

86


87


Figure 1. Hand abnormalities of the girl at age one. The right hand showed missing distal phalanges of the second, third,and fourth fingers, a doubling of the proximal phalanx of the second, and syndactyly of the second and third fin-ger; the left hand had syndactyly of the first, second, third, and fourth finger and a doubling of the proximal phalanx of the second

Figure 2.Girl at age 7, showing hypotrichosis

88


Figure 3. Dental abnormalities of the girl. There are two missing upper incisors (1II and 2II), one missing lower incisor(4II). Furthermore the teeth are rather narrow and widely spaced.

Figure 4. Hands of the boy at nine months of age. The malformations of his right hand consisted of syndactyly of thethird and fourth fingers with missing distal phalanges. His left hand had syndactyly of the second and third fingers with a missing distal phalanx of the fourth finger.

more than 10 years showed only minimal changes in their retinal appearance. Thepatients had macular as well as peripheral RPE disturbances; the latter were alsodescribed in the original Danish family.1 The early presence of retinal abnor-malites indicates a congenital dysplasia rather than a retinal dystrophy. Thecongenital abnormality could well be associated with Bruch’s membrane pathologybecause of the similarities with the fundus appearance in severe pseudoxanthomaelasticum.12-14 The ERG in both children was normal, indicating normal photo-receptor function, which also argues against a retinal dystrophy.

Recently, it was ascertained that distinct CDH3 mutations cause EEM.6 CDH3mutations also cause hypotrichosis with juvenile macular dystrophy (HJMD),15-23 acondition closely resembling EEM, but without teeth or hand abnormalities.CDH3 encodes P-cadherin, one of the three classical (E-, N-, and P-) cadherins.Cadherins are a family of glycoproteins involved in Ca++-dependent cell-celladhesion. Classical cadherins play a major role in embryonic development, tissueformation, and cell growth and differentiation.24 In a mouse model, CDH3 isexpressed during embryonal development in craniofacial structures, and the foreand hind limbs.6

Since the initial identification of CDH3 mutation as the cause of HJMD, a total

89


Figure 6. Posterior pole of the boy with widespread pigmentarychanges, white deposits, and normal discs and vessels.

Figure 5. Posterior pole of the girl, showing severe pigmentaryalterations and atrophic lesions in the macular area,and subretinal fibrosis around the optic disc.

of seven mutations in 11 separate families have been reported.18-21 All mutationsseem to impair markedly the function of P-cadherin or result in the absence of functional P-cadherin expression. However, considerable phenotypic hetero-geneity and lack of phenotype-genotype correlation was found, even within singlefamilies carrying the same mutation, suggesting other, possibly genetic, modifiertraits.20

HJMD and EEM may represent phenotypic heterogeneity of the samesyndrome.6, 22 However, the ophthalmological abnormalities described in HJMDseem different from those in our patients. The retina in HJMD initially may looknormal,16 or have some asymptomatic pigmentary depositions confined to themacula,21 but subsequently a progressive macular degeneration develops, some-times even leading to legal blindness.15, 16, 18 Furthermore, the ERG in HJMD isoften already abnormal at a young age, indicating photoreceptor dysfunction.18-21

In contrast, the ERGs of our patients remained normal over a period of ten years. Follow-up on the ophthalmological features of EEM is described in three otherstudies;3-5 in one of those, the retinal appearance also hardly changed over a periodof ten years.4 On the other hand, the patients described by Balarin Silva andSenecky showed progression of their retinal lesions and deterioration ofelectrophysiological function. Remarkably, these patients had the least severe handabnormalities of the EEM families described, consisting only of syndactyly (seeTable 1). One could argue that these patients have a HJMD rather than an EEMphenotype, because of the absence of ectrodactyly, combined with progressivemacular degeneration with initially good vision. Support for this suggestion alsocomes from the fact that the mutation found in the Brazilian EEM kindred(829delG)6 is the same as previously found in a Turkish HJMD family.20 On theother hand, the Brazilian brothers did have small and widely spaced teeth. Noother HJMD patients have been described with teeth malformations, although theoften subtle dental abnormalities as seen in EEM may be overlooked withoutspecialist dental examination. The intermediate phenotype in this kindred maytherefore be an indication that HJMD and EEM are in fact one syndrome withphenotypic heterogeneity.

A function of P-cadherin in Bruch’s membrane development has not beendescribed, but P-cadherin mRNA is highly expressed in the retinal pigmentepithelium (RPE), 23 from which Bruch’s membrane is partly derived.25 In mice,loss of P-cadherin does not result in obvious hair or ophthalmologicalabnormalities. It has therefore been suggested that E-cadherin expression may be

90


turned on in P-cadherin null mice, or that RPE cells may express other cadherinswhich are capable of compensating for the loss of P-cadherin.23

E-cadherin may also play a role in determining the phenotypic differencesbetween HJMD and EEM.6 CDH1, encoding E-cadherin, is known to haveredundant functions. Compensation of CDH1 for the CDH3 loss of function mayultimately determine if a patient will have HJMD or EEM. Expression differencesand redundant functions of other cadherins may not only explain the differentphenotypes of HJMD and EEM, but also the phenotypic differences betweenhumans and mice carrying mutations in orthologous genes.18

In the study of Balarin Silva,4 a brother and a cousin of the patients had isolatedhand abnormalities. Kjaer6 describes mild bilateral syndactyly and widely spacedteeth in one heterozygous individual. In our study, one sister had teethabnormalities. These abnormalities in relatives may represent mild manifestationsof the syndrome in heterozygotes.

The siblings in this study are the thirteenth and fourteenth patient with EEM tobe described in 49 years, and the first ones in which the diagnosis was establishedin infancy. Molecular analysis of this family is currently under way.

Acknowledgements

We like to thank dr. J. van Twillert for his description of the teeth abnormalitiesand for the dental X-ray.

91


References

1. Albrectsen B, Svendsen IB. Hypotrichosis, syndactyly and retinal degeneration in two siblings.

Acta Derm Venereol 1956;2:96-101

2. Ohdo S, Hirayama K, Terawaki T. Association of ectodermal dysplasia, ectrodactyly, and

macular dystrophy: the EEM syndrome. J Med Genet 1983;20:52-57.

3. Hayakawa M, Kato K, Nakajima A, Yamauchi H. Association of ectodermal dysplasia,

ectrodactyly and macular dystrophy: EEM syndrome (case report). Ophthal Paediatr Genet

1989;10:287-292

4. Balarin Silva V, Simões AM, Marques-de-Faria AP. EEM syndrome report of a family and results

of a ten-year follow-up. Ophthalmic Genet 1999;20:95-99

5. Senecky Y, Halpern GJ, Attias J, Shohat M. Ectodermal dysplasia, ectrodactyly and macular

dystrophy (EEM syndrome) in siblings. Am J Med Genet 2001;101:195-197.

6. Kjaer KW, Hansen L, Schwabe GC, Marques-de Faria AP, Eiberg H, Mundlos S, Tommerup N,

Rosenberg T. Distinct CDH3 mutations cause ectodermal dysplasia, ectrodactyly, macular

dystrophy (EEM syndrome). J Med Genet 2005;42:292-8.

7. Yagi Y, Takeichi M: Cadherin superfamily genes: functions, genomic organization and

neurological diversity. Genes Dev 2000; 14:1169-1180.

8. Muller-Rover S, Tokura Y, Welker P, Furukawa F, Wakita H, Takigawa M, Paus R. E- and P-

cadherin expression during murine hair follicle morphogenesis and cycling. Exp Dermatol.

1999;8:237-246.

9. Riehl R, Johnson K, Bradley R, Grunwald GB, Cornel E, Lilienbaum A, Holt CE. Cadherin

function is required for axon outgrowth in retinal ganglion cells in vivo. Neuron.1996;17:837-

48.

10. Marmor MF, Zrenner E. Standard for clinical electroretinography (1994 update). Documenta

Ophthalmol 1995;89:199-210.

11. Marmor MF, Zrenner E. Standard for clinical electro-oculography. Documenta Ophthalmol

1993;85:115-124.

12. Giuffre G. The pathogenesis of peau d’orange and salmon spots. Metab pediatr Syst Ophthalmol

1987;10:95-98.

13. Shiraki K, Moriwaki M, Matsumoto M, Khono T, Miki T. Hypofluorescent spots in indocyanine

green angiography of peau d’orange and fundus. Int Ophthalmol 1997;21:43-50.

14. Lafaut BA, Leys AM, Scassellati-Sforzolini B, Priem H, De Laey J.J. Comparison of fluorescein

and indocyanine green angiography in angioid streaks. Graefes Arch Clin Exp Ophthalmol

1998;236:346-353.

15. Marren P. Wilson C. Dawber RP, Walshe MM. Hereditary hypotrichosis (Marie-Unna type) and

juvenile macular degeneration (Stargardt’s maculopathy). Clin Exp Dermatol 1992;17:189-191.

92


16. Souied E, Amalric P, Chauvet M-L, Chevalier C, Le Hoang P, Munnich A, Kaplan J. Unusual

association of juvenile macular dystrophy with congenital hypotrichosis: occurrence in two

siblings suggesting autosomal recessive inheritance. Ophthalmic Genet 1995;16:11-15.

17. Becker M, Rohrschneider K, Tilgen W, Weber BH, Volcker HE. Familial juvenile macular

dystrophy with congenital hypotrichosis capitis. Ophthalmologe 1998;95:233-240.

18. Sprecher E, Bergman R, Richard G, Lurie R, Shalev S, Petronius D, Shalata A, Anbinder Y,

Leibu R, Perlman I, Cohen N, Szargel R. Hypotrichosis with juvenile macular dystrophy is

caused by a mutation in CDH3, encoding P-cadherin. Nat Genet 2001;29:134-146.

19. Indelman M, Bergman R, Lurie R, Richard G, Miller B, Petronius D, Ciubutaro D, Leibu R,

Sprecher E. A missense mutation in CDH3, encoding P-cadherin, causes hypotrichosis with

juvenile macular dystrophy. J Invest Dermatol 2002;119:1210-1213.

20. Indelman M, Hamel CP, Bergman R, Nischal KK, Thompson D, Surget MO, Ramon M,

Ganthos H, Miller B, Richard G, Lurie R, Leibu R, Russel-Eggitt I, Sprecher E. Phenotypic

diversity and mutation spectrum in hypotrichosis with juvenile macular dystrophy. J Invest

Dermatol 2003; 121:1217-1220.

21. Indelman M, Leibu R, Jammal A, Bergman R, Sprecher E. Molecular basis of hypotrichosis with

juvenile macular dystrophy in two siblings. Br J Dermatol 2005;153:635-638.

22. Warburg M. Macular dystrophy and hypotrichosis: the EEM-Albrectsen syndrome. Ophthalmic

Genet 1995;16:177-178.

23. Xu L, Overbeek PA, Reneker LW. Systemic analysis of E-, N-, and P-cadherin expression in

mouse eye development. Exp Eye Res 2002;74:753-760.

24. Gumbiner BM. Cell adhesion: the molecular basis of tissue architecture and morphogenesis.

Cell 1996;84:345-57.

25. Takei Y, Ozanics V. Origin and development of Bruch's membrane in monkey fetuses: an

electron microscopic study. Invest Ophthalmol 1975;14:903-16

93



Documents

EIVIC voor CD-Rom · 1 Bartiméus Institute for the Visually Impaired, Zeist, The Netherlands 2 Faculty of Life Sciences, University of Manchester, United Kingdom 3 Department of