Axenfeld-Rieger syndrome (ARS) is an autosomal dominant disease that manifests as anomalies of the anterior segment of the eye and systemic abnormalities [1]. In the eye, this condition is characterized by varying degrees of anterior segment dysgenesis and is associated with a high risk of glaucoma. Other associated systemic issues include cardiovascular outflow tract malformations, craniofacial abnormalities, and pituitary abnormalities that can cause severe endocrinological sequelae [2].

Genetically, mutations in FOXC1 on chromosome 6p25 and PITX2 on chromosome 4q25 have been identified in ARS patients [3, 4]. The prevalence of FOXC1 or PITX2 mutations in the affected probands ranges from 40% to 70% [5-7]. FOXC1 mutations are associated with only eye involvement, while PITX2 mutations often result in systemic abnormalities in addition to eye issues. Although the causative mutations have yet to be identified, 13q14 and 16q24 are known to contain loci of interest. A pediatric patient who was compound heterozygous for mutations in CYP1B1 showed characteristic anterior chamber anomalies and had an umbilical hernia [8-10].

PITX2, a member of the paired class of homeodomain transcription factors, is expressed in the corneal endothelium, stroma, iris, ciliary body, and sclera, which all originate from the neural crest. This transcription factor is known to affect the development of the periocular mesenchyme [8, 11]. A coding region frameshift as well as nonsense and missense mutations are thought to compromise the ability of PITX2 to bind to DNA. Copy number losses due to large chromosome rearrangements, small intragenic deletions, and a rare duplication have also been reported [12]. Here, we report a Korean family with clinical features of ARS carrying a novel c.300_301delinsT mutation in the PITX2 gene.

We found a novel PITX2 gene mutation (c.300_301delinsT) that appears to result in ARS through haploinsufficiency either due to a frameshift-mediated decay of mutant mRNA or production of mutant PITX2 protein, in a Korean family affected by autosomal dominant ARS. The spectrum of Axenfeld-Rieger malformations demonstrates locus heterogeneity with the involvement of 2 major genes, PITX2 and FOXC1 [13]. This is the first report of a PITX2 gene mutation associated with ARS in a Korean individual. To our knowledge, 7 cases of ARS have been reported in Korea in addition to the present 2 cases. In one of those cases, the diagnosis of ARS was confirmed by a molecular method, which showed a novel FOXC1 mutation [14-17]. The clinical features, including ocular and extraocular symptoms and molecular features, are described in Table 1.

The PITX2 gene is located on 4q25, and mutations have been identified in 10-60% of probands with ARS [8, 18]. Most commonly, coding region frameshifts and nonsense and missense mutations are present, which are thought to affect DNA binding. A small number of large chromosome rearrangements, small intragenic deletions, and a rare duplication resulting in copy number loss have also been described [12]. All individuals who inherit the ARS-associated PITX2 or FOXC1 alleles exhibit ocular symptoms, with full penetrance [2]. Compared to FOXC1 mutations, PITX2 mutations are more commonly associated with the extraocular systemic abnormalities of ARS. In our case, the patient and her mother had extraocular abnormalities such as dental anomalies with or without redundant periumbilical skin. On the basis of the systemic findings, we predicted a PITX2 mutation rather than a FOXC1 mutation, but sequenced both genes. Although gain-of-function mutations in PITX2 have been suggested to cause ARS, most intragenic PITX2 mutations are loss-of-function mutations that yield a protein defective in DNA binding or one that is unable to transactivate downstream genes, or both [12]. FOXC1 transcriptional activity is negatively regulated by PITX2, which explains how FOXC1 duplication and PITX2 deletion result in similar phenotypes [19].

Phenotypes of the novel PITX2 mutation (c.300_301delinsT) in this family were variable. Although only the patient and her parents were fully genetically evaluated, ocular or extraocular manifestations of ARS were present in seven of the family members (Fig. 1). The patient showed severe glaucoma, Peters' anomaly, and visual impairment and therefore, requires a trabeculectomy and corneal transplantation. However, although her mother shared the PITX2 gene mutation, her ocular symptoms were mild and could be controlled with eye drops. In ARS, varying degrees of anterior segment dysgenesis may be present, and careful examination of the features of the anterior segment is necessary to establish the diagnosis for each family member. Other systemic symptoms including cardiovascular outflow tract malformations, craniofacial abnormalities, and pituitary abnormalities were not typical in this family. However, dental anomalies and redundant periumbilical skin were observed.

In summary, we found a novel c.300_301delinsT mutation in PITX2 in a Korean family with ARS. We suggest that this PITX2 mutation causes typical ARS. Our results extend the spectrum of PITX2 mutations and highlight the role of PITX2 in the development and progression of ARS.