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Rieger syndrome is associatedwith PAX6 deletionRuth Riise1, Kari Storhaug2 and Karen Brøndum-Nielsen3

Central Hospital of Hedmark1, Hamar, Norway, TAKO Centre, Faculty ofDentistry2, University of Oslo, Norway, Department of Medical Genetics3,John F Kennedy Institute, Glostrup, Denmark

ABSTRACT.Purpose: Rieger syndrome is an autosomal dominant condition defined by an-terior segment dysgenesis in combination with facial, dental, skeletal and um-bilical abnormalities. To date Rieger syndrome has been associated with muta-tions in the PITX2 gene at chromosome 4q25 and a second locus has been foundat chromosome 13q14.Methods: We describe a Rieger syndrome case with all the typical dysmorphicfeatures and the molecular genetic finding by use of FISH analysis of the PAX6gene.Results: An eight-year-old girl had iris stroma hypoplasia, corectopia and irido-goniodysgenesis. She had an underdeveloped premaxilla and a congenital ab-sence of nine teeth in the maxilla. The front teeth in the mandible were peg-shaped and all teeth were small. There was failure of involution of the periumbil-ical skin. FISH analysis using probes for the PAX6 gene showed a small de-letion for the PAX6 gene on one homologue of chromosome 11.Conclusion: Rieger syndrome can – in addition to PITX2 gene mutations andabnormalities at chromosome 13q14 – be associated with PAX6 gene abnor-malities.

Key words: Rieger syndrome – Rieger anomaly – anterior segment dysgenesis – iris atrophy –glaucoma – PAX6 deletion – dental anomalies – facial anomalies.

Acta Ophthalmol. Scand. 2001: 79: 201–203Copyright c Acta Ophthalmol Scand 2000. ISSN 1395-3907

Rieger syndrome is a rare autosomaldominant disorder comprising iris

stromal hypoplasia, and strands of iristissue crossing the anterior chamberangle (Rieger-Axenfeld anomaly).Schwalbe’s line may be anteriorly de-placed (Posterior Embryotoxon). In ad-dition to these anomalies of the anteriorchamber of the eye Rieger syndrome in-cludes midface hypoplasia, hypodontia,peg-shaped teeth and redundant perium-bilical skin. Several other ocular and sys-temic findings can occur (Winter & Ba-raitser 1996).

Rieger originally described the typicalocular features in a mother and her twochildren (Rieger 1935) and later noticedthe coincidence of the ocular and dentalanomalies (Rieger 1941). Glaucoma has

for a long time been known as a compli-cation to the anterior segment dysgenesis(Brændstrup 1948) and is estimated tooccur in 50% of patients by the age 20years (Traboulsi 1998).

One Rieger syndrome gene, PITX2 onchromosome 4q25 has been cloned (Sem-ina et al. 1996) and another locus wasidentified on chromosome 13q14 (Phillipset al. 1996). To our knowledge, however,abnormalities of the PAX6 gene have notpreviously been documented in patientswith Rieger syndrome.

Case ReportWe describe an eight-year-old girl whohas healthy non-related parents. Sixweeks old she was referred to the Depart-ment of Ophthalmology because of co-

rectopia in the right eye. Both eyes weremicrophthalmic and had hypoplasia ofthe iris stroma. In the right eye the pupilwas deplaced downwards and nasally andthere were two defects upwards in theperiphery of the iris. She has been treatedwith mydriatics in the right eye and visualacuity and the intraocular pressure havebeen measured regularly.

As she grew up she was noted to havea flat midface with hypoplasia of the pre-maxilla (Fig. 1).

Her inner canthal distance is 34 mm(age-specific normal range 23–35 mm(Møller 1997)). Corrected visual acuity inthe right eye is 0.5 and in the left 1.0.Corneal diameter is 9 mm in the right eyeand 11 mm in the left eye. Axial length is19.5 mm in right and 19.8 mm in left eye.Intraocular pressure is 7 mmHg in theright and 9 mm in the left eye. There ishypoplasia of the irisstroma in both eyes

Fig. 1. An underdeveloped premaxilla in aneight-year-old girl with Rieger syndrome.

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Figs. 2 and 3. Iris atrophy in both eyes and corectopia downwards nasally with two radial defects upwards in the right iris in an eight year-old girlwith Rieger syndrome.

Fig. 4. Congenital absence of front teeth in the maxilla and peg-shaped Fig. 5. Failure of involution of the periumbilical skin in an eight-year-front teeth in the mandible in an eight-year-old girl with Rieger syn- old girl with Rieger syndrome.drome.

with corectopia downwards nasally andtwo radial holes upwards in the right iriswhile the left eye has a central placed pu-pil (Figs. 2 and 3).

Gonioscopy shows an extremely nar-row anterior chamber angle in the righteye while strands of iris tissue in the lefteye traverse the trabecular meshwork.

In the maxilla two of the primary (51and 61) and seven of her permanent teeth(15, 13, 12, 11, 21, 23 and 25) have notdeveloped. The incisors in the mandibleare peg-shaped and all teeth are small(Fig. 4). There is no involution of the per-iumbilical skin (Fig. 5).

By conventional cytogenetic analysiswe have found a normal female karyo-type 46,XX, but FISH (fluorescent in-situhybridization) analysis with a probe forthe PAX6-gene showed a deletion en-compassing the PAX6 gene on one homo-logue of chromosome 11 (Fig. 6). The de-

letion does not include the Wilm’s tu-mour gene (WT1).

FISH analysis of her parents showedno deletion for the PAX6 gene.

DiscussionThe ocular features found in our Riegersyndrome patient have been described fordecades and the appropriate treatment ofthe accompanying glaucoma has beendiscussed (Brændstrup 1948; Heckenlive-ly et al. 1982).

The dental anomalies in our patientare also similar to what has been de-scribed previously (Childers & Wright1986).

The involved structures are derivedfrom the neural crest (Larsen 1997) andit is therefore natural to consider the ab-normalities in Rieger syndrome as due to

an abnormal migration or differentiationof these cells (Lang & Fleischer-Peters1989).

However, the phenotype varies for theocular features (Perveen et al. 2000).

Fig. 6. Deletion on one homologue of thechromosome 11 shown by FISH (fluorescentin-situ hybridization) analysis with probes forthe PAX6 gene.

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Also additional systemic manifes-tations such as cardiovascular anomalies(Mammi et al. 1998) and anomalies ofthe gut (Crowford 1967) have been foundin Rieger syndrome patients.

Genetic heterogeneity has been docu-mented with association to both chromo-some 4 (Semina et al. 1996) and chromo-some 13 (Phillips et al. 1996). However,to our knowledge, this is the first timethat the PAX6 gene on chromosome 11has been associated with Rieger syn-drome.

Hitherto the PAX6 gene mutationshave been found in aniridia (Ton et al.1992; Glaser et al. 1992; Hanson et al.1994; Grønskov et al. 1999) and Peters’anomaly (Hanson et al. 1994). But alsomore atypical ocular phenotypes havebeen described (Hanson et al. 1999).

We conclude that Rieger syndrome hasa heterogeneous aetiology and can be as-sociated with at least 3 different genes:The PITX2 gene on chromosome 4, agene located at chromosome 13 and thePAX6 gene on chromosome 11.

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Received on October 27th, 2000.Accepted on December 18th, 2000.

Corresponding author:

Ruth RiiseDepartment of OphthalmologyCentral Hospital of HedmarkN-2326 HamarNorway