Journal of Pediatric Ophthalmology and Strabismus

The Rieger Syndrome and a Chromosome 13 Deletion

Rena A Stathacopoulos; J Bronwyn Bateman; Robert S Sparkes; Robert S Hepler

Abstract

ABSTRACT

The Rieger syndrome, characterized by a prominent Schwalbe line, iris strands to the cornea, iris hypoplasia, dental abnormalities, facial malformations, and umbilical defects, is inherited in an autosomal dominant pattern. We studied a boy with the ocular features of the Rieger syndrome, micrognathia, and redundancy of the periumbilical skin. Chromosome analysis revealed an interstitial deletion of the long arm of chromosome 13 involving the distal region of band ql4 through band q31. As there was a previous report of the Rieger syndrome in a child with an interstitial deletion of chromosome 13(ql2,q22), we suggest that a gene for this disorder may be located in the segment ql4 to q22.

Abstract

ABSTRACT

The Rieger syndrome, characterized by a prominent Schwalbe line, iris strands to the cornea, iris hypoplasia, dental abnormalities, facial malformations, and umbilical defects, is inherited in an autosomal dominant pattern. We studied a boy with the ocular features of the Rieger syndrome, micrognathia, and redundancy of the periumbilical skin. Chromosome analysis revealed an interstitial deletion of the long arm of chromosome 13 involving the distal region of band ql4 through band q31. As there was a previous report of the Rieger syndrome in a child with an interstitial deletion of chromosome 13(ql2,q22), we suggest that a gene for this disorder may be located in the segment ql4 to q22.

Introduction

The Rieger syndrome, first described in 1934,1 is a congenital malformation characterized by a prominent Schwalbe line, iris strands to the cornea, iris hypoplasia in the eye, and monocular abnormalities usually including dental abnormalities, facial abnormalities, and umbilical defects. Uncommonly, it has been reported in association with chromosome abnormalities. We report a case of the Rieger syndrome occurring in a patient with an interstitial deletion of chromosome 13(ql4,q31) and review other cases of the Rieger syndrome associated with chromosome rearrangements. As an interstitial deletion of chromosome 13(ql2,q22) was described in a previous report, a gene for this disorder may be in the deleted segment ql4 to q22, the region common to both cases.

Case Report

The male patient was the product of a 39- week pregnancy and delivered vaginally. During the third trimester the mother took diphenhydramine hydrochloride and a combination of brompheniramine maléate, phenylephrine hydrochloride, and phenylpropanolamine hydrochloride. The patient's mother and father were 31 and 33 years of age, respectively, at the time of the patients birth and were nonconsanguineous. There was no family history of the Rieger syndrome or other significant disease, and examinations of the parents' eyes showed no evidence of iris hypoplasia, iris strands, or corectopia.

Just after birth generalized hypotonia, poor sucking, and excess mucous production were noted. At 6 weeks of age, the infant was 3900 gm in weight (3rd percentile), 54 cm in height ( 10-25th percentile), and had a head circumference of 40 cm (97th percentile). Micrognathia, large low-set ears, a high arched palate, redundancy of the periumbilical skin.

FIGURE IA: Iris hypoplasia and corectopia.

FIGURE IA: Iris hypoplasia and corectopia.

FIGURE 2: Chromosome analysis with trypsin-Giemsa banding. The right chromosome of pair 13, identified by the large arrow, has a deletion; the two small arrows beside the intact left chromosome of the pair indicate the margins of the deletion. The remainder of the chromosomes appear normal.

FIGURE 2: Chromosome analysis with trypsin-Giemsa banding. The right chromosome of pair 13, identified by the large arrow, has a deletion; the two small arrows beside the intact left chromosome of the pair indicate the margins of the deletion. The remainder of the chromosomes appear normal.

FIGURE 3: Chromosome analysis with reverse banding using BUdR incorporation demonstrates a deletion of chromosome 13 involving bands ql4 to q31. Both chromosome pairs shown are chromosome 13; the pair on the left is more extended. The large arrows indicate the chromosome of the pair with the deletion. The smaller arrows beside the intact chromosome of each pair indicate the margins of the deletion.

FIGURE 3: Chromosome analysis with reverse banding using BUdR incorporation demonstrates a deletion of chromosome 13 involving bands ql4 to q31. Both chromosome pairs shown are chromosome 13; the pair on the left is more extended. The large arrows indicate the chromosome of the pair with the deletion. The smaller arrows beside the intact chromosome of each pair indicate the margins of the deletion.

FIGURE IB: Slit-like transillumination defects of the cornea.

FIGURE IB: Slit-like transillumination defects of the cornea.

and bilateral inguinal hernias were evident; the inguinal hernias were repaired at 7 weeks of age.

The patient was diagnosed as having celiac disease at 3 months and placed on a gluten-free diet. An intermittent left exotropia developed at 5 months of age. Neurologic examination at 19 months revealed delayed psychomotor development and signs consistent with a chronic, nonprogressive, generalized central nervous system disease. At that time, a left exotropia, iris atrophy, and diffuse pigmentary mottling of the retinal pigment epithelium were noted on ocular examination.

When the patient was 21 weeks of age, chromosomal analysis with trypsin-Giemsa banding revealed a partial deletion of the long arm of chromosome 13. Thereafter, he underwent routine ocular examinations for retinoblastoma.

On his most recent ocular examination at age 13 years, he had myopic astigmatism with a best corrected visual acuity of 20/50 in the right eye and 20/40 in the left eye, a prominent and anteriorly displaced Schwalbe line nasally, iris hypoplasia, slit-like transillumination defects of the iris, irregular pupils (Figure 1 A & B), left nasolacrimal obstruction, and mildly dysplastic optic nerve heads. The patient was too uncooperative for gonioscopy.

CHROMOSOME ANALYSIS: Chromosomal analysis at 21 weeks of age with trypsin-Giemsa banding revealed a 46,XY, 13q- karyotype with an interstitial deletion (Figure 2). Repeat chromosome analysis in 1981 when he was 10 years of age with reverse banding using BUdR incorporation demonstrated a deletion of chromosome 13 involving bands ql4 to q31 in which most of band ql4 appeared to be intact (Figure 3). He had a 1-1 esterase D phenotype with normal enzyme activity (75.7 units). Chromosome analysis of both parents revealed normal karyotypes.

Discussion

The Rieger syndrome, characterized by a prominent Schwalbe line with attached iris strands, iris hypoplasia, and variable systemic abnormalities, is a congenital malformation usually inherited in an autosomal dominant pattern. Other ocular abnormalities include glaucoma in 60% of affected individuals,2 corectopia,2 iris pigment epithelial defects,2 microcornea,2 corneal opacities,24 and cataracts.2·87 Uncommonly, other ocular malformations have been reported (Table 1).

Table

TABLE 1RARE ASSOCIATIONS OF OCULAR MALFORMATIONS WITH THE RIEGER SYNDROME

TABLE 1

RARE ASSOCIATIONS OF OCULAR MALFORMATIONS WITH THE RIEGER SYNDROME

Table

TABLE 2UNCOMMONLY REPORTED ASSOCIATIONS OF SYSTEMIC MALFORMATIONS WITH THE RIEGER SYNDROME

TABLE 2

UNCOMMONLY REPORTED ASSOCIATIONS OF SYSTEMIC MALFORMATIONS WITH THE RIEGER SYNDROME

Table

TABLE 3CHROMOSOME ABNORMALITIES REPORTED IN ASSOCIATION WITH THE RIEGER SYNDROME

TABLE 3

CHROMOSOME ABNORMALITIES REPORTED IN ASSOCIATION WITH THE RIEGER SYNDROME

Although a wide variety of systemic abnormalities have been associated with the syndrome, dental abnormalities,29·12·13 specifically anodontia, oligodontia, and microdontia; facial dysmorphism,2·12 including maxillary hypoplasia, micrognathia, and hypertelorism; and redundancy of the periumbilical skin12·14 are relatively consistent features. Hypospadias is common in affected males.12·14 Empty sella turcica,15 enlarged sella turcica,16 growth hormone deficiencies,8·17 and related abnormalities are less common. Other rare and possibly fortuitous associations are listed in Table 2.

Uncommonly, the Rieger syndrome has been associated with chromosome abnormalities; we found 16 reported cases in the literature. We feel that only seven of these cases, including the subject of this report, meet the generally accepted criteria for the Rieger syndrome; these are itemized in Table 3. Tabbara et al26 described a patient with the Rieger syndrome and an isochromosome of the long arm of chromosome 6. However, both parents were deceased. As no relatives were examined, one cannot exclude the possibility that this case simply represents a dominantly inherited disorder. Heinemann et al27 reported a patient with the Rieger syndrome and a pericentric inversion of chromosome 6. The father carried the same chromosome abnormality and had a prominent Schwalbe line with iris mounds. None of the father's relatives were examined, however. This case could also represent a dominantly inherited disorder, the chromosome abnormality being a forfuitous occurrence. The remaining five cases seem to represent associations between the Rieger syndrome and a chromosome abnormality.

Several reports are unlikely to represent an association between the Rieger syndrome and a chromosomal rearrangement. In 1968, Dark and Kirkham4 described a single case of the Rieger syndrome in a patient with Down's syndrome. As three generations of the family had the Rieger syndrome, the patient's ocular findings probably are an expression of an autosomal dominant gene and are unrelated to the trisomy 21. Nielsen and Tranebjaerg32 reported a patient with the Rieger syndrome and partial monosomy 21q22.2; the patient's eyes had congenital peripheral corneal opacities with anterior synechia e bilaterally, a small central corneal opacity, "a white membrane lining the limbus at the inner cornea," and a central lenticular opacification in the right eye. We believe the described features are more consistent with the Peter anomaly.

Nielsen and Tranebjaerg32 also cited several articles as describing the Rieger syndrome associated with chromosomal abnormalities.3335 However, none of the authors of the cited articles made the diagnosis of the Rieger syndrome. Four patients with trisomy 13 were described as such; however, upon review, we do not feel that the reported patients demonstrated an association between trisomy 13 and the Rieger syndrome.33 Another citation indicated an association with trisomy 18 in three patients; although all had corneal opacities there were no descriptions of a prominent Schwalbe line or iris abnormalities in any of these patients.34 One case of trisomy 9 was cited by Nielsen and Tranebjaerg, but the described ocular findings seemed most consistent with the Peter anomaly.35

Table

TABLE 4MALFORMATION ASSOCIATED WITH INTERSTITIAL DELETIONS OF THE LONG ARMS OF CHROMOSOME 13

TABLE 4

MALFORMATION ASSOCIATED WITH INTERSTITIAL DELETIONS OF THE LONG ARMS OF CHROMOSOME 13

Of the seven reports in Table 3, two, including our present account, involve the Rieger syndrome in patients with interstitial deletions of chromosome 13. Both cases had manifestations consistent with previous reports of the 13q- syndrome. The patient described by Akazawa et al29 had micrognathia, mental retardation, and retinoblastoma. Similarly, our patient had micrognathia and mental retardation, as well as low-set ears, a high arched palate, and strabismus. Both patients exhibit features consistent with the 13q- syndrome, the manifestations of which are described in Table 4. Our patient also had redundancy of the periumbilical skin which has not been associated with the 13q- syndrome.

The autosomal dominant gene for retinoblastoma and the gene for the enzyme esterase D are both located in band 13ql4.38 In our patient most of band ql4, including the gene for retinoblastoma, appears to be intact on the basis of reverse banding of the chromosomes and a normal esterase D activity. In the patient described by Akazawa et al,29 the entire ql4 band was deleted, probably accounting for the patient's bilateral retinoblastomas (Figure 4).

The chromosomal location of the autosomal dominant gene for the Rieger syndrome has not been established. As both the Rieger syndrome and interstitial deletions are uncommon events, the simultaneous occurrence of both by chance seems unlikely. Although multiple chromosome rearrangements reportedly have been associated with the Rieger syndrome, the two cases associated with a chromosome 13 abnormality are suggestive of a gene location. As both patients with interstitial deletions of chromosome 13 were lacking the region from the distal portion of band ql4 through q22, we suggest that a gene for the Rieger syndrome may be located in the region ql4 to q22 of chromosome 13. In view of the reports of other chromosomal rearrangements, it is also possible that more than one gene encodes for the Rieger syndrome. Genetic linkage analysis with restriction fragment length polymorphisms, identified by DNA probes specific for the long arm of chromosome 13, in a family with the Rieger syndrome may localize the gene. We recommend that patients with sporadic forms of the Rieger syndrome associated with mental retardation or other malformations undergo chromosomal analysis.

FIGURE 4: Diagram of chromosome 13. The large arrows indicate the margins of the deletion in our patient. The small arrows indicate the margins of the deletion in the patient described byAkazawa and his colleagues. The region common to both cases is the distal region of band ql4 through band q22.

FIGURE 4: Diagram of chromosome 13. The large arrows indicate the margins of the deletion in our patient. The small arrows indicate the margins of the deletion in the patient described byAkazawa and his colleagues. The region common to both cases is the distal region of band ql4 through band q22.

References

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TABLE 1

RARE ASSOCIATIONS OF OCULAR MALFORMATIONS WITH THE RIEGER SYNDROME

TABLE 2

UNCOMMONLY REPORTED ASSOCIATIONS OF SYSTEMIC MALFORMATIONS WITH THE RIEGER SYNDROME

TABLE 3

CHROMOSOME ABNORMALITIES REPORTED IN ASSOCIATION WITH THE RIEGER SYNDROME

TABLE 4

MALFORMATION ASSOCIATED WITH INTERSTITIAL DELETIONS OF THE LONG ARMS OF CHROMOSOME 13

10.3928/0191-3913-19870701-12

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