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(Investigative Ophthalmology and Visual Science. 2000;41:2456-2460.)
© 2000 by The Association for Research in Vision and Ophthalmology, Inc.

Phenotypic Variability and Asymmetry of Rieger Syndrome Associated with PITX2 Mutations

Rahat Perveen1, I. Christopher Lloyd2, Jill Clayton–Smith1, Amanda Churchill3, Veronica van Heyningen4, Isabel Hanson4, David Taylor5, Carole McKeown6, Maurice Super7, Bronwyn Kerr7, Robin Winter8 and Graeme C. M. Black1,2

1 From the University Department of Medical Genetics and Regional Genetics Service, St. Mary’s Hospital and 2 Manchester Royal Eye Hospital, Manchester; 3 Department of Ophthalmology, St. James’ Hospital, Leeds; 4 Medical Research Council Development Unit, Edinburgh; 5 Department of Ophthalmology and 6 Unit for Clinical Genetics, Great Ormond Street Hospital for Children National Health Service Trust, London; 7 West Midlands Regional Clinical Genetics Service, Clinical Genetics Unit, Birmingham Women’s Hospital, Birmingham; and 8 Department of Clinical Genetics, Royal Manchester Children’s Hospital, Manchester, United Kingdom.

PURPOSE. Rieger syndrome is an autosomal dominant condition characterized by a variable combination of anterior segment dysgenesis, dental anomalies, and umbilical hernia. To date, reports have shown mutations within the PITX2 gene associated with Rieger syndrome, iridogoniodysgenesis, and iris hypoplasia. The purposes of this study were to determine the range of expression and intrafamilial variability of PITX2 mutations in patients with anterior segment dysgenesis.

METHODS. Seventy-six patients with different forms of anterior segment dysgenesis were classified clinically. DNA was obtained and screened by means of polymerase chain reaction (PCR)–single-stranded conformation polymorphism (SSCP) and heteroduplex analysis followed by direct sequencing.

RESULTS. Eight of 76 patients had mutations within the PITX2 gene. Anterior segment phenotypes show wide variability and include a phenocopy of aniridia and Peters’, Rieger, and Axenfeld anomalies. Mutations include premature terminations and splice-site and homeobox mutations, confirming that haploinsufficiency the likely pathogenic mechanism in the majority of cases.

CONCLUSIONS. There is significant phenotypic variability in patients with PITX2 mutations, both within and between families. Developmental glaucoma is common. The umbilical and dental abnormalities are highly penetrant, define those at risk of carrying mutations in this gene, and guide mutation analysis. In addition, there is a range of other extraocular manifestations.




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