Axenfeld-Rieger syndrome is an autosomal dominant disorder of morphogenesis that results in abnormal development of the anterior segment of the eye, and results in blindness from glaucoma in approximately 50% of affected individuals (Fitch and Kaback, 1978). Systemic ... Axenfeld-Rieger syndrome is an autosomal dominant disorder of morphogenesis that results in abnormal development of the anterior segment of the eye, and results in blindness from glaucoma in approximately 50% of affected individuals (Fitch and Kaback, 1978). Systemic anomalies have also been associated, including dental hypoplasia, failure of involution of periumbilical skin, and maxillary hypoplasia (Alkemade, 1969). See 109120 for a form of Axenfeld-Rieger syndrome associated with partially absent eye muscles, hydrocephalus, and skeletal abnormalities. Axenfeld-Rieger anomaly has also been observed in some patients with small vessel disease of the brain, see 607595. A closely related ocular disorder, iridogoniodysgenesis, can also be caused by mutation in the FOXC1 and PITX2 genes; see IRID1 (601631) and IRID2 (137600), respectively. - Genetic Heterogeneity of Axenfeld-Rieger Syndrome Linkage studies indicate that a second type of Axenfeld-Rieger syndrome maps to chromosome 13q14 (RIEG2; 601499). A third form of Axenfeld-Rieger syndrome (RIEG3; 602482) is caused by mutation in the FOXC1 gene (601090) on chromosome 6p25.
Hypodontia with malformation of the anterior chamber of the eye was recognized as a dominantly inherited disorder by Rieger (1935, 1941). The ocular features are microcornea with opacity, hypoplasia of the iris, and anterior synechiae. In 5 generations ... Hypodontia with malformation of the anterior chamber of the eye was recognized as a dominantly inherited disorder by Rieger (1935, 1941). The ocular features are microcornea with opacity, hypoplasia of the iris, and anterior synechiae. In 5 generations of a family, Busch et al. (1960) found myotonic dystrophy as a consistently associated feature. Others have not found myotonia. Pearce and Kerr (1965) studied a large kindred with many affected members and emphasized the variability in expression of the syndrome. A less well-known component of this syndrome is anal stenosis (Crawford, 1967; Brailey, 1890). Alkemade (1969) amply confirmed autosomal dominant inheritance. He pointed out characteristic facies consisting of broad nasal root with telecanthus and maxillary hypoplasia with protruding lower lip. A mother and 2 of her 3 children had severe developmental anomalies of the iris, associated with maldevelopment of the ear and maxilla, umbilical hernia and anal stenosis. Glaucoma occurred in all 3 patients. It is doubtful that Axenfeld anomaly (defects limited to the peripheral anterior segment of the eye) should be considered a separate entity. It is one feature of Rieger syndrome. Feingold et al. (1969) observed 6 cases in 3 generations with male-to-male transmission. De Hauwere et al. (1973) proposed that Rieger anomaly (peripheral abnormalities of the anterior segment with additional changes in the iris) with orbital hypertelorism and psychomotor retardation is a separate syndrome; see 109120. Jorgenson et al. (1978) pointed out that 'failure of involution of the periumbilical skin' is a cardinal feature. Surgery for umbilical hernia had been performed in several. Friedman (1985) described the distinctive umbilical changes of Aarskog syndrome, Rieger syndrome, and Robinow syndrome. He quoted the famous monograph on the umbilicus by Cullen (1916) which has illustrations by Max Broedel. Toppare et al. (1995) in Turkey measured the length of the periumbilical skin in 304 newborn babies. On the cranial side of the base of the umbilical cord the skin measured 12.36 (SD 3.23) mm and the caudal umbilical skin measured 8.76 (SD 3.10) mm on the average. Toppare et al. (1995) suggested that if the cranial skin measurement is greater than 2 standard deviations beyond the mean, i.e., greater than 18.82 mm, Rieger syndrome should be considered. Chisholm and Chudley (1983) reported a kindred with affected persons in 4 generations. Iridogoniodysgenesis was present in 10 persons, of whom 5 had established glaucoma. Somatic malformations were present in 5 persons in the third and fourth generations who did not have iridogoniodysgenesis. Nonocular features included characteristic facies (maxillary hypoplasia, short philtrum, and protruding lower lip of mild prognathism), dental anomalies (microdontia, hypodontia, and cone-shaped teeth), failure of involution of the umbilicus (often treated surgically in the neonatal period because of confusion with umbilical hernia), surgery for inguinal hernia in 8 persons, and hypospadias present in 4 males. Brooks et al. (1989) described Rieger anomaly together with other anomalies and suggested that it represented a previously unreported syndrome. The patient, a sporadic case born to nonconsanguineous, young parents, had bilateral microcondyles and bilateral choanal atresia as well as anal atresia, scoliosis, kyphosis, and short stature. Dental findings included severe enamel hypoplasia, conical and misshapen teeth, hypodontia, and impactions. The maxilla and mandible were underdeveloped. Chromosome studies were not reported. Brooks et al. (1989) suggested that this 'new' syndrome be called the short-FRAME syndrome for short stature, facial anomalies, Rieger anomaly, midline anomalies, and enamel defects.
Semina et al. (1996) isolated the novel homeobox gene PITX2 (601542), which they designated RIEG, and identified 6 mutations in this gene (601542.0001-601542.0006) in individuals with Rieger syndrome.
PITX2 and DLX2 (126255) are transcription markers observed ... Semina et al. (1996) isolated the novel homeobox gene PITX2 (601542), which they designated RIEG, and identified 6 mutations in this gene (601542.0001-601542.0006) in individuals with Rieger syndrome. PITX2 and DLX2 (126255) are transcription markers observed during early tooth development. Espinoza et al. (2002) demonstrated that PITX2 binds to bicoid and bicoid-like elements in the DLX2 promoter and activates this promoter 30-fold in Chinese hamster ovary cells. Mutations in PITX2 associated with Axenfeld-Rieger syndrome provided the first link of this homeodomain transcription factor to tooth development. One mutation produces Axenfeld-Rieger syndrome with iris hypoplasia but without tooth anomalies; this allele has a similar DNA binding specificity compared to wildtype PITX2 and transactivates the DLX2 promoter. In contrast, a different PITX2 mutation produces Rieger syndrome with the full spectrum of developmental anomalies, including tooth anomalies; this allele is unable to transactivate the DLX2 promoter. Since DLX2 expression is required for tooth and craniofacial development, the lack of tooth anomalies in the patient with iris hypoplasia may be due to the residual activity of this mutant in activating the DLX2 promoter. The authors proposed a molecular mechanism for tooth development involving DLX2 gene expression in Axenfeld-Rieger patients. Lines et al. (2002) reviewed the molecular genetics of Axenfeld-Rieger malformations, including the roles of PITX2 and FOXC1 (601090) in human disease and mouse models.