Expanding the phenotype of males with OFD1 pathogenic variants-a case report and literature review

Pathogenic variants in the OFD1 gene have been classically associated with the Orofaciodigital syndrome type 1 in females, a condition previously considered to be X-linked dominant with male embryonic lethality. However, an increasing number of males with pathogenic OFD1 variants who survived beyond the neonatal period have now been reported in the literature. Although each new report has added to the ever-broadening spectrum of clinical findings seen in males, many questions about genotype-phenotype correlations and disease mechanism remain. Herein, we describe a 9-year-old male child with a novel hemizygous pathogenic OFD1 variant identified by exome sequencing and a unique combination of findings, not previously reported, including presence of both a hypothalamic hamartoma and the molar tooth sign. His clinical features overlap multiple ciliopathy phenotypes, blurring the boundaries of distinct ciliopathy gene-disease relationships. This case provides further evidence for the consideration of a broad OFD1-relateddisorder spectrum in affected males rather than multiple distinct phenotypes. Additionally, a review of previously published cases of the disorder in males support the inclusion of the OFD1 gene in the differential diagnosis and work up for all individuals who present with primary ciliopathy-type features, regardless of their gender. We also highlight current information about OFD1 variant types and pathogenesis and explore how these could mechanistically drive some of the observed phenotypic differences.