Endocrine Abstracts

Background: Syndromic Disorders/Differences of Sex Development (DSD) represent a subgroup of DSD characterized by genital atypia associated with additional clinical features such as intellectual disability or neurodevelopmental delay, short stature or weight-for-height deficit, major congenital anomalies, or dysmorphic features. While establishing a molecular diagnosis in DSD is often challenging, it becomes more difficult in syndromic cases due to phenotypic overlap and multisystem involvement. Despite the use of Whole Exome Sequencing (WES), many cases initially remain unsolved because variants may occur in genes whose disease associations were recognized only after the initial analysis. This highlights the importance of periodic reanalysis of exome data as knowledge of gene–disease associations continue to grow.

Methods: In 1993, a full-term newborn presented at 44 days of life with ambiguous genitalia and multiple syndromic features, including craniofacial dysmorphisms, clinodactyly, congenital heart defects, and pulmonary and ocular anomalies. Genital examination revealed a 1.5-cm phallus with chordee, perineal hypospadias, partial fusion of labioscrotal folds, and non-palpable gonads (Prader grade III; External Genitalia Score 2.5). Karyotype was 46,XY. Initial genetic evaluation, including Sanger sequencing of known DSD-associated genes, was inconclusive. WES performed in 2016 also failed to identify pathogenic variants. Following recent reports of novel gene–disease associations in DSD, the original WES data were reprocessed and reanalyzed.

Results: Reanalysis of the patient’s WES data identified a heterozygous c.1745C>A variant in exon 12 of the MYRF gene, resulting in the nonsense variant p.Ser582*. The variant is predicted to generate a truncated protein lacking the transcription factor domain. To date, this variant has not been reported in the literature.

Conclusion: This report describes a patient whose initial WES analysis was inconclusive; however, recently described associations between MYRF and DSD enabled the identification of a pathogenic variant upon exome reanalysis years later. Notably, the molecular diagnosis was established more than 30 years after the patient’s initial clinical evaluation, reflecting advances in genomic knowledge and its application in clinical practice. This case highlights the crucial role of periodic genetic data reinterpretation and clinical persistence in resolving the molecular etiology in Syndromic DSD.