American Journal of Medical Genetics 107:38–42 (2002)

Craniosynostosis, Ectopia Lentis, and CongenitalHeart Defects: Further Delineation of an AutosomalDominant Syndrome With Incomplete Penetrance

Nada L. Quercia and Ahmad S. Teebi*The Hospital for Sick Children, Division of Clinical and Metabolic Genetics, Toronto, Ontario, Canada

The association of craniosynostosis withectopia lentis is extremely rare. This wasrecently reported in monozygotic twin sis-ters, supporting a genetic etiology for thissyndromic association. We report on femalefirst cousins once removed who were bornwith unilateral coronal synostosis. One cou-sin also had peripheral pulmonic branchstenosis at birth and was later found to haveectopia lentis and severe myopia. The othercousin had an atrial septal defect, mitralvalve prolapse, and only mild myopia. Theirintelligence is normal. The inheritance islikely autosomal dominant with variableexpression and incomplete penetrance andfurther defines this syndrome to includecongenital heart defects. These findings willhave important implications for geneticcounseling. ß 2001 Wiley-Liss, Inc.

KEY WORDS: craniosynostosis; ectopialentis; peripheral pulmo-nic branch stenosis

INTRODUCTION

The craniosynostoses are an etiologically and patho-genetically heterogenous group of disorders whichinvolve premature closure of the cranial sutures.Craniosynostosis may occur in nonsyndromic or syn-dromic forms [Cohen et al., 1997].

Ectopia lentis is defined as the displacement of thecrystalline lens of the eye. Ectopia lentis may also occurin isolation or as a part of multisystem hereditarydisorders, including Marfan syndrome, homocysti-

nuria, Weill-Marchesani syndrome, hyperlysinemia,and sulfite oxidase deficiency [Nelson and Maumenee,1982].

The association of craniosynostosis with ectopialentis is extremely rare. A review of the literaturerevealed three reports of the occurrence of craniosy-nostosis with ectopia lentis; two of these were sporadicin nature [Pesme et al., 1950; Reichel et al., 1992].Recently, Cruysberg et al. [1999] reported on mono-zygotic twin sisters with craniosynostosis and ectopialentis, supporting a genetic etiology for this association.The authors hypothesized that the occurrence ofcraniosynostosis and ectopia lentis in their case wasmost likely due to an autosomal dominant newmutation.

We observed the association of craniosynostosis,ectopia lentis, and a congenital heart defect in anindividual whose first cousin once removed also hadcraniosynostosis and congenital heart defects.

CLINICAL REPORTS

Patient 1 (IV:1) was born at full term following anuneventful pregnancy. On examination shortly afterbirth, she was noted to have plagiocephaly with markedrecession of the supraorbital ridge, a small orbit on theleft side, flat frontal bone, and ridging over the coronalsuture (Fig. 1). There was deviation of the nasal rootand compensatory bulging of the right frontal bone. Askull X-ray confirmed unilateral left coronal synostosis.At 4 months old, she was found to have bilateral dis-located lenses and some iridodonesis present in theright eye. The lenses were both found to be dislocatedapproximately half-way across the pupil medially andslightly downward. Refraction was ÿ10 spheres bilat-erally. At 6 months of age she was noted to have aGrade I–II/VI systolic ejection murmur which radiatedalong the left sternal border into the neck. Chest X-rayat 6 months gave the impression of mild cardiomegalywith a calculated CT ratio of 64%. The pulmonaryvascular markings were normal. An electrocardiogramshowed incomplete right bundle branch block andborderline left ventricular hypertrophy for age. A 2Dechocardiogram showed a structurally normal heart. Aslight turbulence was noted across both the pulmonaryvalve and the aortic valve, but the greatest source of

*Correspondence to: Dr. Ahmad S. Teebi, Division of Clinical &Metabolic Genetics, The Hospital for Sick Children, 555 Uni-versity Ave., Toronto, Ontario, M5G 1X8, Canada.E-mail: ateebi@sickkids.on.ca

Received 23 February 2001; Accepted 5 September 2001

ß 2001 Wiley-Liss, Inc.DOI 10.1002/ajmg.10124

turbulence was a roughly 10-mm gradient into theleft pulmonary artery. The diagnosis of branch pul-monary stenosis was made. Surgical correction of thecraniosynostosis was performed at 7 months of age.Bilateral lens extraction was performed at 9 months ofage and bilateral mediorectus muscle recession forstrabismus was performed at 18 months. Psychomotordevelopment was normal. A follow-up heart ultrasoundat 3 years of age suggested mild peripheral pulmonaryartery narrowing. At 13 years of age, her height was162 cm (50th centile), OFC was 52 cm (just below the50th centile), inner canthal distance (ICD) was 3.8 cm(97th centile), outer canthal distance (OCD) was 9.5 cm(75–97th centile), and interpupillary distance (IPD)was 6.3 cm (97th centile). Her ears were normal butslightly small, with an ear length of 5.5 cm (3–25thcentile). She had a high forehead with a depression onthe left side of the head. She had bilateral epicanthalfolds and a slightly depressed nasal root. Her face wasasymmetrical and there was slight supraorbital depres-

sion on the left (Fig. 2a,b). Her hands and feet,including nails, were normal with only mild interdigitalwebbing bilaterally and a wide gap between the 4th and5th fingers bilaterally. Her mother was found to havethis on examination as well. Her joints were nothypermobile. No hirsutism was noted. She had a slightesotropia in primary position and there was moderateoveraction of the inferior obliques on side gaze. Hervisual acuity was correctable to right eye 20/100 andleft eye 20/30. Her refraction was OD þ5.75, þ2.25axis 120 and OS þ9.75, þ1.25 axis 90. She was ofnormal intelligence. A karyotype analysis was normal(46,XX, 450 level G-banding) as well; FISH for micro-deletion 22q was normal. Urine and plasma aminoacids and plasma urate levels were normal. Thenitroprusside test was negative. Mutation analysis ofthe P250R mutation in the FGFR3 gene was negative.Mutation analysis of the FGFR2 gene (exons IIIa andIIIc) was negative. The entire coding region of theTWIST gene was sequenced and no mutation wasdetected.

Patient 2 (III:3) was born at full term following anuneventful pregnancy. Unilateral coronal synostosis(right) was noted at 6 months of age on routine physicalexamination. She had ridging of the coronal sutureand depression of the right eyebrow. X-rays confirmedunilateral right coronal synostosis. She had surgicalcorrection of the right coronal synostosis at 8 monthsof age. At 2 years of age she had right inferior obliquemyectomy for strabismus of the right eye. Asidefrom ear tympanoplasties on three occasions, tonsil-lectomy and adenoidectomy, she had no other sur-geries. Psychological testing at 5 years of age wasnormal and developmental milestones were met ontime.

At 26 years of age her height was 163 cm (50thcentile) and OFC was 52.5 cm (50th centile). Her headshape was normal (Fig. 3a,b). ICD was 4 cm (97thcentile), IPD was 7 cm (> 97th centile), OCD was10.5 cm (> 97th centile). Her hands and feet, includingnails, were normal. She did not have joint hypermobi-lity or other physical anomalies. No hirsutism wasnoted. She was of normal intelligence. On ophthalmo-logical examination at 26 years of age she had myopiawith a best corrected vision of 20/25 in the right eye and25/25 in the left eye. She had right hypertropia andnystagmus. Intraocular pressure was 14 in both eyes.Fundi were normal. There was no evidence of lensdislocation. On cardiology examination at 26 years ofage she was found to have a clinically insignificantatrial septal defect of the secundum type and mitralvalve prolapse. Investigations included mutation ana-lysis of the FGFR3 gene for the P250R mutation, whichwas negative. As well, mutation analysis of the FGFR2gene (exons IIIa and IIIc) was negative.

FAMILY DATA

The family history was unremarkable for craniosy-nostosis, ectopia lentis, or cardiac abnormalities (Fig. 4).There was no consanguinity. The mother of Patient 1(III:2) was examined and found to have a normal head

Fig. 1. Patient 1 (IV:1) at 6 months of age, prior to surgical correction ofcraniosynostosis.

Craniosynostosis–Ectopia Lentis Syndrome 39

shape with OFC of 54 cm (50th centile) and a height of162 cm (50th centile). She had a space between her 4thand 5th fingers bilaterally, similar to that of herdaughter (IV:1). Her ICD was 3.5 cm (> 97th centile),IPD was 6.7 cm (>97th centile) and OCD was 11.0 cm(>97th centile). The sister of Patient 1 (IV:4) wasexamined and found to have a normal head shape andOFC of 50 cm (50th centile). The sister of Patient 2(III:4) was examined and found to have a normal headshape with OFC of 55 cm (50th centile) and a height of165 cm (below 75th centile). Her ICD was 3.5 cm(>97th centile), IPD was 6.2 cm (75–97th centile) andOCD was 10.5 cm (>97th centile). Individuals II:2 andII:3 were not available for examination but werereported to have a normal head shape and normalstature. Individual II:3 was also reported to have mildmyopia.

DISCUSSION

A review of the literature revealed three reports ofcraniosynostosis in association with ectopia lentis:Pesme et al. [1950] reported on a mentally retarded

male with oxycephaly and bilateral ectopia lentis;Reichel et al. [1992] reported on a male with oxyce-phaly, bilateral ectopia lentis, and total retinal detach-ment in one eye; Cruysberg et al. [1999] reported onmonozygotic twin sisters with craniosynostosis (onetwin had premature closure of the sagittal suture whilethe other twin had premature closure of the metopicsuture) and bilateral ectopia lentis. The cases reportedby Pesme et al. [1950] and Reichel et al. [1992] weresporadic. The report of Cruysberg et al. [1999] supportsa genetic cause for this association. The authorshypothesized that the inheritance may have beenautosomal recessive or, more likely, an autosomaldominant new mutation.

Physical examination and genetic studies were doneto rule out a recognizable craniosynostosis syndromein this family. Craniosynostosis syndromes previouslyclassified on the basis of their clinical findings arenow being defined at the molecular level. In particular,mutations in the fibroblast growth factor receptors(FGFRs) have been identified causally in a numberof craniosynostosis syndromes such as Crouzon(FGFR2,3), Apert (FGFR2), and Pfeiffer (FGFR1,

Fig. 2. Patient 1 (IV:1) at 13 years of age.

40 Quercia and Teebi

FGFR2, FGFR3) syndromes [Schell et al., 1995; Rut-land et al., 1995; Wilkie et al., 1995; Bellus et al., 1996].A single mutation in the FGFR3 gene (Pro250Arg) hasbeen identified in patients with nonsyndromic coronalcraniosynostosis and is most often found in familialcoronal craniosynostosis [Gripp et al., 1998; Lajeunieet al., 1999; Muenke et al., 1997; Reardon et al., 1997].Most patients with Saethre-Chotzen syndrome havemutations in the TWIST gene, although some with anoverlapping phenotype have mutations in the FGFR3gene [Howard et al., 1997; Ghouzzi et al., 1997]. In ourpatients, mutations in the FGFR2, FGFR3, and TWISTgenes were not identified. Furthermore, our patientsdid not have limb abnormalities, ear abnormalities, ormental retardation.

Marfan syndrome, Weill-Marchesani syndrome, andhomocystinuria are disorders characterized by ectopialentis and skeletal anomalies [Nelson et al., 1982].Aside from ectopia lentis in Patient 1 and mitral valveprolapse in Patient 2, our patients did not havemanifestations of Marfan syndrome. Normal statureand limbs in our family rules out Weill-Marchesani

syndrome. In addition, craniosynostosis, which is afeature in our patients, is not among the manifestationsin these syndromes. Metabolic investigations in Patient1 ruled out homocystinuria.

It is possible that the individuals in the familyreported here share the same features by chance orthat the two cousins have different disorders; however,based on the previously reported cases it is likely thatthe association of craniosynostosis and ectopia lentis issyndromic. The additional finding of congenital heartdefects in our case has not been previously reported inassociation with both craniosynostosis and ectopialentis and may be part of the spectrum of thissyndrome. The finding of the relatively common mitralvalve prolapse in one cousin may be fortuitous. Never-theless, the presence of coronal synostosis in firstcousins once removed in this family supports the notionthat this is an autosomal dominant condition withincomplete penetrance and wide phenotypic variability.This will have important implications for geneticcounseling. At this time, precise predictions regardingthe potential full spectrum of the phenotype in at-risk

Fig. 3. Patient 2 (III:3) at 26 years of age.

Craniosynostosis–Ectopia Lentis Syndrome 41

future offspring for the probands is not possible.Identification and reporting of other families withsimilar features may help to further delineate thissyndrome.

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Fig. 4. Pedigree.

42 Quercia and Teebi