SOX2 pathogenic variants with normal eyes: Expanding the phenotypic spectrum.

SOX2 pathogenic variants, though rare, constitute the most commonly known genetic cause of clinical anophthalmia and microphthalmia. However, patients without major ocular malformation, but with multi-system developmental disorders, have been reported, suggesting that the range of clinical phenotypes is broader than previously appreciated. We detail two patients with bilateral structurally normal eyes along with 11 other previously published patients. Our findings suggest that there is no obvious phenotypic or genotypic pattern that may help set apart patients with normal eyes. Our patients provide further evidence for broadening the phenotypic spectrum of SOX2 mutations and re-appraising the designation of SOX2 disorder as an anophthalmia/microphthalmia syndrome. We emphasize the importance of considering SOX2 pathogenic variants in the differential diagnoses of individuals with normal eyes, who may have varying combinations of features such as developmental delay, urogenital abnormalities, gastro-intestinal anomalies, pituitary dysfunction, midline structural anomalies, and complex movement disorders, seizures or other neurological issues.

Review of 37 patients with SOX2 pathogenic variants collected by the Anophthalmia/Microphthalmia Clinical Registry and DNA research study.

SOX2 variants and deletions are a common cause of anophthalmia and microphthalmia (A/M). This article presents data from a cohort of patients with SOX2 variants, some of whom have been followed for 20+ years. Medical records from patients enrolled in the A/M Research Registry and carrying SOX2 variants were reviewed. Thirty-seven patients were identified, ranging in age from infant to 30 years old. Eye anomalies were bilateral in 30 patients (81.1%), unilateral in 5 (13.5%), and absent in 2 (5.4%). Intellectual disability was present in all with data available and ranged from mild to profound. Seizures were noted in 18 of 27 (66.6%) patients, usually with abnormal brain MRIs (10/15, 66.7%). Growth issues were reported in 14 of 21 patients (66.7%) and 14 of 19 (73.7%) had gonadotropin deficiency. Genitourinary anomalies were seen in 15 of 19 (78.9%) male patients and 5 of 15 (33.3%) female patients. Patients with SOX2 nucleotide variants, whole gene deletions or translocations are typically affected with bilateral or unilateral microphthalmia and anophthalmia. Other associated features include intellectual disability, seizures, brain anomalies, growth hormone deficiency, gonadotropin deficiency, and genitourinary anomalies. Recommendations for newly diagnosed patients with SOX2 variants include eye exams, MRI of the brain and orbits, endocrine and neurology examinations. Since the clinical spectrum associated with SOX2 alleles has expanded beyond the originally reported phenotypes, we propose a broader term, SOX2-associated disorder, for this condition.