British ournal of Ophthalmology 1995; 79: 135-138

Ectopia lentis et pupillae syndrome in threegenerations

J RM Cruysberg, A Pinckers

Institute ofOphthalmology,University HospitalNijmegen, Nijmegen,the NetherlandsJ RM CruysbergA Pinckers

Correspondence to:J RM Cruysberg, MD,Institute of Ophthalmology,University HospitalNijmegen, PO Box 9101,6500 HB Nijmegen, theNetherlands.Accepted for publication5 September 1994

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AbstractIn nine members from three generationsand in a distant relative, at least threesignificant characteristics of the ectopialentis et pupillae syndrome were estab-lished including ectopia lentis, ectopiapupiilae, persistent pupillary membrane,iris transillumination, and poor pupillarydilatation. All patients developed bilateralcataract before the age of 40 years, andtwo patients presented with intermittentacute intraocular hypertensive crises. Notonly the high number of patients in onefamily, but also the occurrence in threegenerations is very exceptional for theectopia lentis et pupiilae syndrome.Although the syndrome is said to be in-herited in an autosomal recessive mode,in this family, a mother to son and amother to daughter transmission werepresent. Pedigree analysis yielded argu-ments in favour ofan autosomal domian tinheritance with reduced penetrance. Abiochemical correlation was not identi-fied.(Br_J Ophthalmol 1995; 79: 135-138)

Ectopia lentis et pupillae (ELP) is a congenitalhereditary disorder in which there is displace-ment of the lenses and the pupils, associatedwith other ocular anomalies, but withoutsystemic manifestations.1-16 The condition isusually bilateral, with the lenses and pupils dis-placed in opposite directions. However, amarked variability in expression is observedbetween the two eyes of a patient and amongaffected members of a family.13 16 The ELPsyndrome must be differentiated from dis-placement of the pupillary position (corec-topia) as a result of intraocular surgery, orother progressive ocular disorders - forexample, essential iris atrophy, Chandler'ssyndrome, Rieger's syndrome, and intraocularinflammation. 17We examined a patient with classic ELP

syndrome and studied the family because themother of the proposita was also affected.

Patients and methodsThe proposita (VII-24), a 36-year-old woman,presenting with congenital bilateral ectopialentis et pupillae, asked for genetic counselling

10 25Figure 1 Pedigree ofafamily with ectopia lentis et pupiUae syndrome in three generations, showing 10 affected patients. The spouses of unaffectedfamilymembers (VII-32 and VII-63) were examined andfound to be normal.

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Table 1 Findings in patients with the ectopia lentis et pupillae syndrome

Generation VI VI VI VI VI VII VII VII VIII VIIIPatient No 2 4 10 11 12 10 21 24 10 25Sex (MIF) F F M F F F M F F M

Eye (RIL) R L R L R L R L R L R L R L R L R L R L

Ectopialentis + + + + + + + + + + + + + + + + + + + +Ectopiapupillae - - + + - - + + - - + + + + - - + +Pupillarymembrane - - # # + + + + . . . . . . . . + + +Iristransillumination # # # # + + + + - + + + + + + - - + +Poor pupillary dilatation # # # # + + + + # # # # + + + + # # + +Prominentirisprocesses # # # # - - # # - # # - # # # #Axial length # # # # # 25 24 23 21 21 21 21 30 31 23 24 20 20 21 21Cornealdiameter(mm) # # # # 11 12 # # # 11 11 12 11 11 10 10 11 12 11 11Corneal radius (mm) # # # # 7-7 7-7 # # 7-4 7-4 # # 7-9 7-9 8-0 79 7-3 7-2 7-6 7-7Cataract # # # # + + + + + + + + + + + + + + + +Glaucoma + + + + + + + + + + - + + - +Retinal detachment - - + - + - - + - - +Uveitis - - - - + + - + +Poorvision (<6/20) + + + + + - + + + - + + + + + + + +

-=Condition absent; + =condition present; #=condition not examined.

because several members of her family hadpoor vision. She was diagnosed elsewhere ashaving Rieger's syndrome. The patient andher relatives underwent complete ophthalmicexaminations, including measurement of therefractive error by subjective techniques (inadults) or cycloplegic retinoscopy (inchildren), corrected visual acuity measure-ment, slit-lamp biomicroscopy of the anteriorsegment before and after pupillary dilatation,ophthalmoscopy, and applanation tonometry.If ectopia lentis was diagnosed, measurementof the corneal diameter (ruler), corneal curva-ture (Javal ophthalmometer), and axial length(A scan ultrasonography) were performed.Photographic documentation was performedas previously described.18 Several members ofthe family had already been examined in ourdepartment. At the time of this study, the twooldest aunts of the proposita were deceased. Agenealogical study was performed in order tosearch for consanguinity between the parentsand maternal grandparents of the proposita.Later on, a distant relative (VIII-25) alsopresented with congenital bilateral ELP, andthe genealogical study was extended. Anumber of patients underwent elaborategeneral examinations in order to rule outsystemic and metabolic disorders, such asMarfan's syndrome and homocystinuria.

ResultsIn one family, we observed 10 patients with acongenital syndrome characterised by bilateral

Table 2 Clinicalfindings in the ectopia lentis et pupillaesyndrome in affected members of one family

No ofabnormal patientslCondition No ofexamined patients %

Ectopia lentis 10/10 100Ectopia pupillae 5/10 50Persistent pupillary membrane 4/9 44Iris transillumination 6/8 75Poor pupillary dilatanon 5/5 100Cataract 8/8 100

Before age 20 years 3/8 38At age 40 years 8/8 100

Glaucoma 7/10 70Retinal detachment 4/10 40Uveitis 2/10 20Poor vision (<6/20) 10/10 100

ectopia lentis, and associated abnormalities ofthe pupil (ectopia pupillae, persistent pupillarymembrane, poor pupillary dilatation) and iris(iris transillumination, excentric circularfolds). Other ocular complications (cataract,glaucoma, uveitis, retinal detachment), highmyopia, and poor vision were also seen.Systemic abnormalities were not found. Thefamily pedigree is shown in Figure 1 andthe clinical features are summarised inTables 1 and 2. The proposita (Figure 2;VII-24), her brother (VII-21), mother (VI-4),a maternal aunt (VI-1 1), and a distant relative(VIII-25) all had classic ELP syndrome,whereas other family members showed ectopialentis associated with other major signs of thesyndrome. In one case (VI-10), the persistentpupillary membrane was so dense that surgerywas needed to open the pupil. All the patientsdiagnosed as ELP had a history of poor vision.There was no history of poor vision in thegrandparents (V-1 and V-2) of the proposita.The syndrome was present in five patients ofgeneration VI, in three patients of generationVII, and in two patients of generation VIII.One affected female (VI-2) had an affecteddaughter, whereas another affected female(VI-4) transmitted the trait to a son and adaughter. The spouses of the unaffected familymembers, VII-32 and VII-63, were examinedand found to be normal.The maternal grandparents of the proposita

were consanguineous. In fact there was con-sanguinity in three successive generations, butconsanguinity of the parents of the propositacould not be demonstrated (Fig 1). The greatgrandparents, but not the parents of the distantrelative (VIII-25), were consanguineous.None of the affected family members

had any systemic abnormalities related todisorders associated with ectopia lentis. Inthree patients, homocystinuria was ruled outwith certainty by serum evaluation in thefasting state and after methionine loading.One patient (VII- 1 0) underwent extensiveinvestigations for metabolic disease: therewere no abnormal findings of the aminoacids, organic acids, purines, pyrimidines,mucopolysaccharides, oligosaccharides, neur-aminic acid, galactitol, and sorbitol in plasmaand urine.

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137Ectopia lentis et pupillae syndrome in three generations

Figure 2 Patient (VII-24;proposita) with classicectopia lentis et pupillaesyndrome (top), showingupward displaced eccentricpupils (middle), downwarddisplaced subluxated lensesand poor pupillarydilatation (bottom). Onlythe superior edge of the leftlens is visible (arrows).

DiscussionThe patients of this study fulfil the criteria forthe diagnosis ELP syndrome: in five patients,the characteristic picture of bilateral ectopialentis with congenital ectopia of oval or slit-shaped pupils was present. In the remainingfive patients there were, in addition to bilateralectopia lentis, a number of symptoms whichare described in the studies of the ELP syn-drome as significant, such as transilluminationof the iris periphery,13 16 a dense pupillarymembrane,6 1316 poor pupillary dilatationdespite repeated phamacological attempts,13-16high axial myopia,4 16 poor vision,14 16 a highprevalence of ocular complications at young

age - for example, cataract,3 13 glaucoma,4uveitis, retinal detachment,4 and lack of sys-temic disorders known to be associated withectopia lentis.19

Other causes of ectopia pupillae were ruledout. Ectopia pupillae simplex (EPS) usually isinherited as an autosomal dominant traitwithout ectopia lentis. Rieger's syndrome ischaracterised by a prominent Schwalbe's lineall around the corneal periphery. There is oftenhypoplasia of the iris stroma with through andthrough holes in the iris, causing polycoria andcorectopia (ectopia pupillae). Marked corec-

topia is almost always unilateral in progressiveessential iris atrophy, a subtype of the irido-corneal endothelial (ICE) syndrome, which

includes disorders of the comeal endotheliumwith varying degree of endothelialisation of theanterior chamber angle and iris surface.

Ectopia lentis simplex (ELS) is inherited asan autosomal dominant trait, but the existenceof an autosomal recessive form also has beenreported.2022 Dominantly inherited ectopialentis simplex is usually bilateral and sym-metrical, with the lenses dislocated upwardand laterally, but without ectopic pupils.23None of our patients showed clinical signs of

Marfan's syndrome, in which ectopia lentis iscommonly present and iris transilluminationhas been documented clinically.24 As withectopia lentis simplex, our patients showedlenticular myopia, amblyopia, cataract,glaucoma, retinal detachment, and poorvision. Compared with other authors16 ourpatients show a remarkably high prevalence ofcataract before the age of 40 years. Inter-mittent acute intraocular hypertensive crisesoccurred in two affected members of genera-tion VI. Enlarged corneal diameters13 16 werenot found. Microspherophakia, anothersymptom sometimes described in the ELPsyndrome,13 was not found.

In some respects the presented family isunique. Ten patients with the ELP syndromein one pedigree is exceptional. Most pedigreescontain three,5 6 8 12-14 16 sometimes four,4 andrarely five patients.1 Because the presence of

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Table 3 Ectopia lentis et pupillae syndrome in the literature

Number Number Number Male! Ectopia Ectoptaof of of female Patients! lentis pupillae

Reference pedigrees generations patients ratio pedigree (eyes) (eyes)

Siemens (cited)' 13/13Siemens' 1 1 5 1/4 5 10 10Waardenburg' 1 1 1 0/1 1 2 2Fecht4 1 1 4 3/1 4 6 2Franceschetti5 2 1 5 4/1 2, 3 9 7Crebbin6 1 1 1 1/0 1 2 2Diethelm8 1 1 2 1/1 2 4 2Walls and Heath"' 1 2 3 0/3 3 5 2Townes"2 1 1 2 2/0 2 4 4Leubbers etal"3 3 1 6 3/3 1,2,3 12 8Cross'4 1 1 2 2/0 2 4 4Goldberg'6 8 1 16 11/5 1, 2, 3 30 19Present study 1 3 10 3/7 10 20 10Total 44/39 108 72

ectopic pupils is a selection criterion for thediagnosis of ELP syndrome, the pedigreeswith only one affected patient for obviousreasons will show a 100% prevalence of ectopiapupillae. However, many studies show that ifthere are more patients in one family, ectopiapupillae is not an obligatory sign.4 5 8 10 13 16 Inpedigrees with the ELP syndrome, the numberof eyes with ectopia lentis presenting withsignificant ectopia pupillae is near 50%,4 5 13 16but may vary from 330/O4 to 100%.12 14 The50% ectopic pupils that we found in our studyis in accordance with these data.

Another exceptional finding in our studyis the presence of the ELP syndrome inthree generations. In ELP pedigrees from theliterature (Table 3), the syndrome was

present in only one generation in 20 pedi-grees. 1 2 4 8 12-14 16 This was also the case in1 1 pedigrees published before 1920 and citedby Siemens.1 ELP is inherited as a recessivetrait.5 11 Fran9ois11 summarised publicationsfrom 1885 to 1947 and noted that consan-

guinity has been reported in many studies. Henoted further that there were no exceptions tothe concept of an autosomal recessive inheri-tance. An autosomal recessive inheritance oftheELP syndrome is suggested by the occurrencein several siblings of one generation, consan-guinity,2 4 5 14 15 and an equal distributionbetween males and females. Extensive search ofthe literature resulted in only two pedigrees withmore than one affected generation. In the reportof Walls and Heath,10 two generations were

affected, suggesting a dominant inheritance: a

female with ELP had a son with normal pupilsbut with ectopia lentis in one eye; her twin sisterhad ectopia lentis in both eyes. Strebel andSteiger in 1915 reported the occurrence ofELPin four generations, in combination with myopiaand cardiac disease.' 2

In our pedigree, the inheritance of the ELPsyndrome is not unequivocal. There are argu-ments in favour of an autosomal recessiveinheritance, because the parents of theproposita are consanguineous and, by history,not affected. In addition the parents of thepatients VIII--10 and VIIII-25 were not affected.Furthermore five affected individuals (VI-10,VI-12, VII-10, VII-21, VII-24) had 24 normalchildren. However, arguments for a dominantinheritance are found in the fact that twoaffected persons had three affected children,and that the ELP syndrome occurred in three

generations. Pseudodominance could not beproved despite extensive genealogical investi-gations. A possible explanation is that in ourpedigree the ELP syndrome is transmitted asan autosomal dominant trait with reducedpenetrance and variable expression.A strict distinction into an autosomal reces-

sive inherited ELP syndrome, an autosomaldominant inherited ectopia pupillae syndromeor an autosomal dominant inherited ectopialentis syndrome, is in our opinion too artificialand probably no longer justified. In order tosolve the many questions, we must go back tothe genetic mechanisms involved in thedevelopment of both lens and iris. Waarden-burg25 wrote in 1932: 'it is very likely that therecessive ectopia lentis syndrome and theectopia pupillae et lentis syndrome, at least in anumber of cases, have a common geneticorigin.' Whatever the transmission, theaffected members of the pedigree we presenthere are suffering from a common geneticdefect.Supported by a grant from the Stichting ResearchfondsOogheelkunde.

1 Siemens HW, Ueber die Aetiologie der Ectopia lentis etpupillae nebst einigen allgemeinen Bemerkungen uberVererbung bei Augenleiden. Graefes Arch K/in ExpOphthalmol 1920; 109: 359-83.

2 Waardenburg PJ. Over het erfelijkheidsmoment bij deaangeboren verplaatsing van de pupil en lens. Genetica1924; 6: 337-82.

3 Zeeman WPC. Ueber ectopia pupillae et lentis congenita.K/in Monatsbl Augenheilkd 1925; 74: 325-38.

4 Fecht W. Ueber familiare Linsenluxation. Z Augenheilkd1927; 62: 162-8.

5 Franceschetti A. Ectopia lentis et pupillae congenita alsrezessives Erbleiden und ihre Manifestierung durchKonsanguinitat. K/in Monastbl Augenheilkd 1927; 78:351-62.

6 Crebbin AR. Persistent pupillary membrane and congenitalectopia lentis. Am Y Ophthalmol 1929; 12: 87-90.

7 Clarke CC. Ectopia lentis. A pathologic and clinical study.Arch Ophthalmol 1939; 21: 124-53.

8 Diethelm W. Ueber Ectopia lentis ohne Arachnodaktylieund ihre Beziehungen zur Ectopia lentis et pupillae.Ophthalmologica 1947; 114: 16-32.

9 Lund A, Sjontoft F. Congenital ectopia lentis. ActaOphthalmol 1950; 29: 33-48.

10 Walls GL, Heath GG. Dominant ectopia lentis et pupillae.AmJHum Genet 1959; 11: 166-8.

11 Frangois J. Hereditary in ophthalmology. St Louis: Mosby,1961: 161-4.

12 Townes PL. Ectopia lentis et pupillae. Arch Ophthalmol1976;94:1126-8.

13 Luebbers JA, Goldberg MF, Herbst R, Hattenhauer J,Maumenee AE. Iris transillumination and variableexpression in ectopia lentis et pupillae. Am Y Ophthalmol1977; 83: 647-56.

14 Cross HE. Ectopia lentis et pupillae. AmJ Ophthalmol 1979;88: 381-4.

15 L'Abbate A, Santorelli P, Pesando P. Ectopia della lenta edella pupilla. Valutazione clinica in 4 casi con follow up di26 anni. Boll Ocul 1984; 63: 3-4, 157-66.

16 Goldberg MF. Clinical manifestations of ectopia lentiset pupillae in 16 patients. Ophthalmology 1988; 95:1080-7.

17 Cross HE, Maumenee AE. Progressive, spontaneousdissolution of the iris. Surv Ophthalmol 1973; 18:186-99.

18 Aandekerk AL, Cruysberg, JRM. Photography of ectopialentis. YAudiovis Media Med 1987; 10: 87-9.

19 Nelson LB, Maumenee IH. Ectopia lentis. Surv Ophthalmol1982; 27: 143-60.

20 McKusick VA. Primordial dwarfism and ectopia lentis.AmJ Hum Genet 1955; 7: 189-98.

21 Ruiz C, Rivas F, Villar-Calvo VM, Serrano-Lucas JI,Cantui JM. Familial simple ectopia lentis; a probableautosomal recessive form. Ophthalmic Paediatr Genet1986; 7. 81-4.

22 Al-Salem M. Autosomal recessive ectopia lentis in two Arabfamily pedigrees. Ophthalmic Paediat Genet 1990; 11:123-7.

23 Falls HF, Cotterman CW. Genetic studies on ectopia lentis.A pedigree of simple ectopia of the lens. Arch Ophthalmol1943; 30: 610-20.

24 Maumenee IH. The eye in the Marfan syndrome. TransAmOphthalmol Soc 1981; 79: 684-733.

25 Waardenburg PJ. Das menschliche Auge und seine Erbanlage.The Hague: Mardinus Nijhof, 1932: 315.

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