Phenotypic variability and asymmetry of Rieger syndrome associated with PITX2 mutations.
OBJECTIVE
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.
University Department of Medical Genetics and Regional Genetics Service, St. Mary's Hospital, Manchester, United Kingdom.
R
R
Perveen
I C
IC
Lloyd
J
J
Clayton-Smith
A
A
Churchill
V
V
van Heyningen
I
I
Hanson
D
D
Taylor
C
C
McKeown
M
M
Super
B
B
Kerr
R
R
Winter
G C
GC
Black
D000869:Anterior Eye Segment / Q000002:abnormalities; D004252:DNA Mutational Analysis; D015785:Eye Diseases, Hereditary / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D020180:Heteroduplex Analysis; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007498:Iris / Q000002:abnormalities*; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins; D051761:Paired Box Transcription Factors; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*; D014603:Uveal Diseases / Q000235:genetics*; D000097577:Homeobox Protein PITX2
D005136:Eye Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D051761:Paired Box Transcription Factors; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C101485:homeobox protein PITX1; C433629:homeobox protein PITX3