SOX2 anophthalmia syndrome

Abstract

Heterozygous, de novo, loss-of-function mutations in SOX2 have been shown to cause bilateral anophthalmia. Here we provide a detailed description of the clinical features associated with SOX2 mutations in the five individuals with reported mutations and four newly identified cases (including the first reported SOX2 missense mutation). The SOX2-associated ocular malformations are variable in type, but most often bilateral and severe. Of the nine patients, six had bilateral anophthalmia and two had anophthalmia with contralateral microphthalmia with sclerocornea. The remaining case had anophthalmia with contralateral microphthalmia, posterior cortical cataract and a dysplastic optic disc, and was the only patient to have measurable visual acuity. The relatively consistent extraocular phenotype observed includes: learning disability, seizures, brain malformation, specific motor abnormalities, male genital tract malformations, mild facial dysmorphism, and postnatal growth failure. Identifying SOX2 mutations from large cohorts of patients with structural eye defects has delineated a new, clinically-recognizable, multisystem disorder and has provided important insight into the developmental pathways critical for morphogenesis of the eye, brain, and male genital tract.

ANE syndrome caused by mutated RBM28 gene: a novel etiology of combined pituitary hormone deficiency

“…These genes are HESX1, PROP1, POU1F1, LHX3, LHX4, TBX19, SOX2, SOX3, TBCE, and OTX2 (4-6). Non-syndromic CPHD has been found to be caused by mutations in PROP1 and POU1F1 (7-9), while mutations in the other genes typically cause a syndromic subtype of CPHD, featuring septo-optic dysplasia (HESX1) (10), short stiff neck (LHX3) (11), cerebellar anomalies (LHX4) (12,13), mental retardation (SOX3) (14), anophthalmia, esophageal atresia, and genital anomalies (SOX2) (15,16), hypoparathyroidism-retardation and dysmorphism (TBCE) (5), and microphthalmia and anophthalmia (OTX2) (6). Associated neuroradiological findings, including anterior pituitary hypoplasia, absent infundibulum, and an ectopic posterior pituitary, may present in 50% of patients with CPHD (4).…”

A practical guide to the management of anophthalmia and microphthalmia

“…These include genes principally involved in ocular development, such as CHX10, many of which are involved in the development of substructures within the eye 19,21 and genes that are involved in eye and brain development including SOX2, OTX2, and PAX6. 20,[22][23][24][25][26] Several syndromic genes are involved in developing other organs in addition to the eye, including CHD7, the gene for CHARGE syndrome 27,28 and PTCH, the gene for Gorlin syndrome. 29 There is a complex interplay between the different eye development gene pathways, which allows their expression to be finely regulated 5,27,30 and begins to explain why there is such an overlap of the phenotypes associated with mutations of each gene.…”

Hypothalamic and pituitary development: novel insights into the aetiology

“…Similar to its murine counterpart, the human SOX2 gene is composed of a single exon encoding a 317 amino acid protein containing an N-terminal domain of unknown function, a DNAbinding HMG domain and a C-terminal transcriptional activation domain. Twelve heterozygous de novo mutations in SOX2 were previously reported in 14 human patients associated with bilateral anophthalmia or severe microphthalmia with additional abnormalities including developmental delay, learning difficulties, oesophageal atresia and genital abnormalities (45,(49)(50)(51)(52). All of these mutations occurred de novo and included five nonsense, four frameshift, one deletion and two missense mutations.…”