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Background: Axenfeld-Rieger syndrome (ARS, OMIM:602482) is a genetic disease characterized by ocular and systemic features. Clinical features of ARS are highly variable among patients and associated with mutations of human PITX2 and FOXC1 genes. Herein, we present an ARS in two cases (proband and his mother) with a novel variant in the PITX2. Methods: A 3-month-old boy was admitted with an abnormal eye development at birth. Physical examination and ophthalmologic examination findings revealed an abnormal development of the anterior segments, ectropion of redundant skin in the umbilicus, single-sided deafness, teeth eruption failure, patent foramen ovale, and a mid-facial flattening. The proband's mother has been blind since the age of 12. We conducted genetic tests for the family via whole exome sequencing (WES) and quantitative PCR (qPCR) to identify the genetic etiology in the family. We also conducted a retrospective review of the ARS type I phenotype caused by the PITX2 mutations. Results: WES and qPCR results of the proband and his parents suggested that both the child and his mother carry a 1.31kbp deletion (chr4: g.111538559_111539864del [GRCh37]) spanned the exon 4 of PITX2, resulting in the typical and rare phenotype of ARS type I. It can conclude that truncating variants in the exon 3-4 of PITX2 are the more common mechanism to cause the malfunction of the gene with a broader phenotypic spectrum. Conclusion: The study has filled in a new clinical manifestation of the PITX2 and enriched the phenotype of ARS. The retrospective analysis of phenotype of PITX2 mutations provided a comprehensive understanding of the disease. [ABSTRACT FROM AUTHOR]

Axenfeld-Rieger syndrome is characterized by a spectrum of anterior segment dysgenesis involving neural-crest-derived tissues, most commonly secondary to mutations in the transcription factor genes PITX2 and FOXC1. Single retrospective case report. A full-term infant presented at 5 weeks of age with bilateral Peters anomaly and Axenfeld-Rieger syndrome, with development of atypical features of progressive corneal neovascularization and proliferative vitreoretinopathy. Despite surgical interventions, the patient progressed to bilateral phthisis bulbi by 22 months of age. Genetic testing revealed a novel de novo p.Leu212Valfs*39 mutation in PITX2, leading to loss of a C-terminal OAR domain that functions in transcriptional regulation. It is important to consider mutations in PITX2 in atypical cases of anterior segment dysgenesis that also present with abnormalities in the angiogenesis of the anterior and posterior segments. [ABSTRACT FROM AUTHOR]

Anterior segment dysgeneses are developmental anomalies of the anterior eye segment that can occur as isolated defects or as part of various syndromes. A subgroup is caused by abnormal embryonic neural crest development. The Axenfeld-Rieger syndrome is an umbrella term for a continuum of anterior segment dysgeneses of neural crest origin, characterized by the presence of the Axenfeld or Rieger eye malformation predisposing for glaucoma. Additionally, other structures of neural crest origin can be variably affected giving rise to a wide spectrum of associated extra-ocular malformations. Key clinical features comprise facial dysmorphism including mid-face and dental hypoplasia, hearing loss, cardiac anomalies, and involuted periumbilical skin. The Axenfeld-Rieger syndrome is genetically heterogeneous and about 16% of cases are caused by heterozygous mutations inFOXC1at 6p25.3, a transcription factor gene regulating neural crest cell development. There is considerable clinical overlap between the Axenfeld-Rieger syndrome and the 6p25 deletion syndrome, a microdeletion syndrome characterized by heterozygous loss ofFOXC1. In both syndromes,FOXC1haploinsufficiency seems to be pathogenic. Here, we review the clinical features and pathogenesis of the 6p25 deletion syndrome. [ABSTRACT FROM AUTHOR]

Purpose: To report the presence of Axenfeld-Rieger spectrum in a case of 45,X Turner syndrome. Design: Non-interventional case report. Methods: A 13-year-old girl underwent complete genetic clinical evaluation comprising detailed family history taking with pedigree construction in addition to a thorough clinical examination and a number of investigations. A cytogenetic study, molecular testing for hidden Y-chromosome material, and a full ophthalmological assessment including slit lamp examination were also performed. Results: Physical examination revealed typical features of Turner syndrome: short stature, webbing of the neck with low posterior hairline, widely spaced nipples and lack of development of secondary sexual characteristics. Abdominal and pelvic ultrasound showed a horse-shoe kidney with double ureter, a hypoplastic uterus and bilateral streak ovaries. Mitral regurgitation was diagnosed on echocardiography. Chromosomal analysis revealed a 45,X Turner syndrome karyotype while the molecular study failed to demonstrate any occult Y chromosome derivative. The ophthalmological assessment revealed sclerocornea and Axenfeld anomaly with synechia. Conclusion: Few reported cases in the literature describe the coexistence of Axenfeld-Rieger spectrum and Turner syndrome. Our study adds to the evidence that ocular problems occur frequently in Turner syndrome. A routine ophthalmologic examination is recommended early in Turner syndrome to diagnose and treat confirmed abnormalities. Conversely, general examination and chromosomal analysis should be indicated in patients presenting with anterior chamber dysgenesis. [ABSTRACT FROM AUTHOR]

A patient with osteogenesis imperfecta (OI) and some features of Ehlers-Danlos syndrome had Rieger's anomaly and other associated ocular abnormalities. He carried a COL1A1 mutation (c.3313delA) that has only rarely been seen in OI. The association of ocular anterior chamber abnormalities with OI has not been reported previously, while OI with Ehlers-Danlos syndrome features has only been described in some kindreds. The patient had serious complications as a result of his ocular anomalies. We speculate that the course of his disease and, perhaps, its co-existence with OI could be exacerbated by his collagen type-I defect, although no causality can be established by this report of a single case. [ABSTRACT FROM AUTHOR]

Purpose: To determine the underlying genetic cause of Axenfeld-Rieger syndrome (ARS) in a three-generation family. Introduction: ARS is a multisystem, autosomal dominant disorder characterized by specific ocular and non-ocular anomalies sometimes caused by mutations in the transcription factor gene, PITX2. Methods: The three coding exons of the PITX2 gene, i.e., exons 2.3. and 4, in affected and unaffected subjects were amplified by polymerase chain reaction (PCR) and sequenced. The PCR products of exon 4 were subcloned and sequenced to confirm the nature of the mutation. Results: A deletion of thymine (T) 1261 was identified, creating a frameshift mutation in codon 227. This change is predicted to create 11 novel amino acids downstream, followed by premature truncation of the protein. Conclusions: This mutation highlights the functional importance of a conserved 14-amino acid sequence at the C-terminus of the protein thought to be important in repressing DNA binding and in protein-protein interactions. [ABSTRACT FROM AUTHOR]

We report a Japanese girl with the Conradi-Hünermann form of chondrodysplasia punctata and anterior segment malformations characteristic of Axenfeld-Rieger syndrome. The patient also had cataracts and unilateral optic atrophy. A possible role for homeobox-containing genes in the etiology of this type of chondrodysplasia punctata is suggested as an explanation for the coincidence of these two syndromes. [ABSTRACT FROM AUTHOR]

Iridogoniodysgenesis is an autosomal dominant disorder in which there are abnormalities in the development of the iris stroma and trabecular meshwork tissues commonly resulting in glaucoma. The unoperated eye from an affected member of a family with iridogoniodysgenesis syndrome (IGDS) was removed shortly after death. Histopathological studies showed an incomplete, normally positioned line of Schwalbe and iris stromal hypoplasia. The molecular basis underlying the disorder is a missense mutation in the RIEG gene at 4q25, mutations of which have been previously shown to cause Axenfeld-Rieger syndrome (ARS). Coupled with another report of a missense mutation of the RIEG gene in a family with IGDS, we suggest that these mutations may interfere less with gene function and thereby may be responsible for a milder phenotype than occurs in the more characteristic ARS. [ABSTRACT FROM AUTHOR]