INTRODUCTION: Down syndrome is the most frequent autosomal aneuploidy in live newborns. Between 40% to 100% of patients with Down syndrome may present with an associated ophthalmological abnormality. There are historical reports where a possible association of microphthalmia and anophthalmia with Down syndrome was been proposed, however these studies were performed before the use of sequencing and molecular testing, therefore, other possible monogenic causes were not ruled out.

CASE PRESENTATION: A 10-month-old male patient with Down syndrome due to regular trisomy, also presented with syndromic bilateral microphthalmia associated with a pathogenic variant in the SOX2 gene. Both diseases were independent and the patient had a history of risk factors for advanced maternal and paternal age.

CONCLUSIONS: The relationship between advanced maternal age and nondisjunction during oogenesis, predisposing to autosomal aneuploidies, has long been known. However, it is important to note that defects in spermatogenesis have been postulated to induce single nucleotide variants that cause autosomal dominant pathologies. These variants may increase with paternal age because the exonuclease activity of the polymerase enzyme, which corrects the most paired bases, decreases with aging. Due to the history of advanced paternal age at the birth and conception of the patient, independent monogenic microphthalmia was suspected and confirmed. This report and the literature review suggest that microphthalmia is not part of the spectrum of ophthalmic abnormalities in Down syndrome; therefore, the presence of microphthalmia in future cases with Down syndrome warrants ruling out independent monogenic conditions distinct from the chromosomal syndrome.

KEYWORDS: Down syndrome, Ocular malformations, Microphthalmia and anophthalmia spectrum, Massively Parallel Sequencing, Advanced paternal age.