Brief Clinical Report

Craniosynostosis Associated With Ectopia Lentis inMonozygotic Twin Sisters

Johan R.M. Cruysberg,1* Conny M.A. van Ravenswaaij-Arts,2 Alfred Pinckers,1 Roberto Roddi,3 andHan G. Brunner2

1Institute of Ophthalmology, University Hospital Nijmegen, Nijmegen, The Netherlands2Institute of Human Genetics, University Hospital Nijmegen, Nijmegen, The Netherlands3Institute of Plastic Surgery, Craniofacial Center, University Hospital Maastricht, Maastricht, The Netherlands

Ectopia lentis has rarely been reported tooccur in association with craniosynostosis,and this was found only in sporadic cases.We report on twin sisters who underwentsurgery for craniosynostosis and later on, atage 3 years, were found to have bilateral ec-topia lentis. Molecular studies yielded aprobability of monozygosity of more than0.98. Inheritance of the syndrome may beautosomal dominant, possibly due to a newmutation, autosomal recessive, or X-linkedwith male lethality. Am. J. Med. Genet. 82:201–205, 1999. © 1999 Wiley-Liss, Inc.

KEY WORDS: craniosynostosis; ectopia len-t is ; monozygotic twins ;scaphocephaly; trigono-cephaly; high myopia

INTRODUCTIONCraniosynostosis is an anomaly of the skull charac-

terized by premature closure of the sutures. Autosomaldominant and recessive inheritance, as well as isolatedcases, have been reported [Cohen, 1986]. Bilateral ec-topia lentis has rarely been reported as an ocular mani-festation of craniosynostosis [Pesme et al., 1950; Rei-chel et al., 1992]. Both reports were in sporadic cases.We observed the association of craniosynostosis andbilateral ectopia lentis in twin sisters.

CLINICAL REPORTPatient 1 (K.) the first of two twin girls, was born

following an uneventful pregnancy at 37 weeks. On ex-

amination at 7 months, this child had severe scapho-cephaly with frontal and occipital bossing. The skullcircumference was 44 cm (between 50th and 90th cen-tiles). A 3D-CT scan of the skull confirmed prematureclosure of the sagittal suture (Fig. 1). Surgical correc-tion of the craniosynostosis was performed when shewas 14 months old. Except for slightly retarded motordevelopment, i.e., walking without support at the ageof 22 months, psychomotor development was normal.

The parents had noticed subnormal vision and jelly-like movements of the iris (iridodonesis) when she was3 years old. Ocular examination at this age showedvisual acuity of 6/120 in the right eye and 6/24 in theleft eye. Measurement of refraction after cycloplegiashowed myopia and astigmatism (right eye: sph −4.254 cyl −1.5 axis 65° and left eye: sph −0.75 4 cyl −1.0axis 115°). External examination showed iridodonesisof both eyes. There was no strabismus or nystagmus.The pupils were central, with isocoria and normal re-actions to light. Slit lamp examination showed sublux-ated lenses with iridodonesis and phakokinesis. How-ever, the margins of the lenses were not visible due topoor pupillary dilatation with mydriatic and cyclople-gic eyedrops. A very small remnant of prepupillarymembrane was visible in both eyes. Corneas and lenseswere clear. There was no iris transillumination. Thefundus was normal in both eyes. Echography showedaxial lengths of 21 mm in both eyes. Physical exami-nation at 4 years demonstrated normal stature (height96 cm, 10th centile). There were no physical anomalies,except for hirsutism over the back and mildly hypoplas-tic toe nails. Joint laxity of elbows and knees was pres-ent.

Patient 2 (L.), the second twin, underwent surgicalcorrection of trigonocephaly due to synostosis of themetopic suture when she was 23 months old (Fig. 2).She also had a slightly retarded motor development,i.e., walking without support at the age of 22 months.

Ocular examination at 3 years showed visual acuity

*Correspondence to: J.R.M. Cruysberg, M.D., Ph.D., Instituteof Ophthalmology, University Hospital Nijmegen, P.O. Box 9101,6500 HB Nijmegen, The Netherlands.

Received 15 July 1996; Accepted 12 December 1997

American Journal of Medical Genetics 82:201–205 (1999)

© 1999 Wiley-Liss, Inc.

of <6/120 in the right eye and <6/120 in the left eye.Measurement of refraction showed very high myopia(>20 diopters) in both eyes. External examination dem-onstrated iridodonesis, but no strabismus or nystag-

mus. Pupils were central, with isocoria and normal re-actions to light. Slit lamp examination showed iridodo-nesis, phakokinesis, and ectopia lentis in both eyes.The right lens was subluxated into the inferonasal di-

Fig. 1. 3D-CT scan of the skull of Patient 1 showing scaphocephaly and synostosis of sagittal suture. Seen from the side, the skull is elongated, withposterior occipital retrusion and excessive bulging of the frontal bones anteriorly.

202 Cruysberg et al.

rection and showed cortical opacity. The left lens wascompletely clear and subluxated inferotemporally (Fig.3). Very small remnants of the prepupillary membranewere visible bilaterally. Corneas were clear. There was

no iris transillumination. The fundus was normal inboth eyes. Echography showed axial lengths of 22 mmin both eyes.

Physical examination at 4 years showed normal stat-

Fig. 2. 3D-CT scan of the skull of Patient 2 showing trigonocephaly and synostosis of metopic suture. Note the characteristic keel shape of the foreheadin axial view, providing a contrast with the normal biparietal diameter. The mediofrontal angulation extends back as far as the anterior fontanel in theform of a ridge. This ridge, sometimes visible and palpable, corresponds to the fused metopic suture.

Craniosynostosis and Ectopia Lentis 203

ure (height 98 cm, 10th centile). Just like her sister, L.had hirsutism over the back, mild hyperlaxity of elbowsand knees, and hypoplastic toe nails.

Differential Diagnostic Studies

Homocystinuria and Marfan syndrome were ex-cluded by appropriate studies. Normal serum homocys-teine levels were found in both children. The childrenhad no marfanoid habitus (Fig. 4) and normal echocar-diographic findings. There were no cardiac valve ab-normalities and the diameter of the ascending and de-scending aorta was normal. X-ray examination of thecervical spine showed normal vertebrae. Chromosomeswere apparently normal 46,XX. Molecular investiga-tion of zygosity with six highly polymorphic markerslocated on different chromosomes yielded a probabilityof monozygosity of more than 0.98.

Family Studies

The family history was unremarkable for craniosyn-ostosis and ectopia lentis. The parents were not con-sanguineous. Ophthalmic examination of the parentsshowed no abnormal findings except unilateral myopia(sph−-3.0) in the left eye of the mother. Lenses andshape of the head were normal in both parents. Heightwas 170 cm (10th centile) in the father and 167 cm(50th centile) in the mother.

DISCUSSION

Craniosynostosis is characterized by premature fu-sion of one or more sutures of the skull, which leads todeformity of the skull and an abnormal head shape.Normally, the sutures close when the brain hasreached its final dimensions at the age of 2 years, start-ing with the metopic suture. Craniosynostosis may beisolated (e.g., oxycephaly) or part of a syndrome (e.g.,Crouzon syndrome). Syndromic craniosynostosis oc-curs with other primary defects of morphogenesis, andmay be hereditary or environmentally induced. Casesin which only one suture is prematurely fused arecalled simple synostosis. The deformity is characteris-tic for the type of suture which is involved [Cohen,1986]. Most cases of simple craniosynostosis are spo-radic.

The term ectopia lentis is used whenever the crys-talline lens is loose or out of place, irrespective of cause.Bilateral cases are usually of genetic origin and may

occur as an isolated lens anomaly (e.g., ectopia lentissimplex), as part of an ocular syndrome (e.g., ectopialentis et pupillae), or as part of a systemic disease (e.g.,homocystinuria) or syndrome (e.g., Marfan syndrome)[Nelson and Maumenee, 1982; Cruysberg and Pinck-ers, 1995]. In all causes of ectopia lentis, the commonfactor is that the zonular fibers are loose, disrupted, orabsent.

Common ocular manifestations of craniosynostosisinclude proptosis, papilledema, optic atrophy, and stra-bismus. Ectopia lentis has rarely been reported in iso-lated cases of craniosynostosis [Pesme et al., 1950; Rei-

Fig. 3. Ectopia lentis in Patient 2. Note that the right lens is subluxatedinto the inferonasal direction and the left lens into the inferotemporaldirection.

Fig. 4. Phenotypes of both children at ages 1 (A) and 4 (B) years.

204 Cruysberg et al.

chel et al., 1992]. Reichel et al. [1992] reported on thecase of a 23-year-old man with craniosynostosis, spe-cifically oxycephaly, associated with bilateral ectopialentis and unilateral total retinal detachment. Bilat-eral ectopia lentis previously was reported in a men-tally retarded 6-year-old boy with craniosynostosis andscaphocephaly [Pesme et al., 1950]. This latter patientshowed characteristics of Crouzon syndrome such asproptosis and divergent strabismus. However, in a se-ries of 22 patients with Crouzon syndrome, not one hada dislocated lens [Nelson and Maumenee, 1982], andno further examples of this association have been re-ported.

Marfan syndrome, homocystinuria, and Weill-Marchesani syndrome are well-known hereditary dis-orders characterized by ectopia lentis and skeletalanomalies [Nelson and Maumenee, 1982]. However,these disorders were ruled out in our patients.

Shprintzen and Goldberg [1982] described two unre-lated boys with manifestations of the Marfan syndromeand craniosynostosis. These boys had arachnodactyly,camptodactyly, micrognathia, exophthalmos, abnormalpinnae, pectus carinatum or excavatum, mitral valveprolapse, and multiple abdominal herniae. They werementally retarded. Furlong et al. [1987] also reported apatient with marfanoid habitus and craniosynostosis.This male patient had typical findings of Marfan syn-drome, including dolichostenomelia, scoliosis, pectuscarinatum, dilated aortic root, myopia, and recurrentinguinal herniae. He died from aortic dissection. Thispatient also had scaphocephaly due to prematureclosure of the sagittal suture. However, he had no ec-topia lentis, but did have ptosis and spondylolisthesis.Except for the ectopia lentis, myopia, and joint laxity,our twin sisters had no manifestations of Marfansyndrome. There was no tall stature, no arachnodac-tyly, and no cardiac manifestations. Besides, our pa-tients do not have the same facial traits as thepatients of Shprintzen and Goldberg [1982], and ofFurlong et al. [1987], thereby ruling out these diagnos-tic possibilities.

The combination of craniosynostosis, joint laxity, andhypoplastic nails has been described in cranioectoder-mal dysplasia [Young, 1989; Gorlin et al., 1990]. How-ever, other characteristic manifestations of that syn-drome, like sparse slow-growing hair, microdontia, ashort narrow thorax, short limbs with brachydactyly,clinodactyly, and syndactyly, were lacking in our pa-tients. Myopia and hypermetropia have been reportedin cranioectodermal dysplasia, but not ectopia lentis.

We present two siblings with craniosynostosis andbilateral ectopia lentis. The occurrence of highly simi-lar associated findings in monozygotic twins supports agenetic cause, although environmental factors cannotbe ruled out. Inheritance may be autosomal recessiveor, even more likely, autosomal dominant, presumablyderived from a new mutation.

ACKNOWLEDGMENT

We gratefully acknowledge Professor R.M. Winter,Institute of Child Health, London, for his advice.

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