Case Report: A new patient expanding the clinical spectrum of DOHH-associated syndrome with increased nuchal translucency, cardiomyopathy, hypoparathyroidism and mild intellectual disability.

Polyaminopathies are a family of rare genetic developmental disorders caused by pathogenic variants in genes involved in polyamine homeostasis and metabolism, and related biological pathways, including the hypusine biosynthesis pathway. DOHH is the enzyme catalyzing the last step of hypusine biosynthesis. DOHH-related disorders, caused by biallelic variants in the DOHH gene, were first described in 2022 in five patients exhibiting severe neurodevelopmental delay, congenital heart defects, and growth restriction. We report on a 10-year-old boy, the first child of consanguineous parents, whose clinical presentation began prenatally with increased nuchal translucency (7.5 mm), pericardial effusion and thickening of the right ventricular anterior wall. Postnatally, he developed dilated cardiomyopathy with left ventricular hypertrabeculation and hypoparathyroidism. Follow-up revealed delays in motor and cognitive milestones. Trio exome sequencing (ES) identified an inherited homozygous c.455C>T (p.Pro152Leu) pathogenic variant in DOHH. Review of the literature shows that our patient exhibits milder neurodevelopmental impairment and intellectual disability than previously described, and no growth restriction. Interestingly, this is the second report of increased prenatal nuchal translucency in DOHH-related disorders. As cardiomyopathy and hypoparathyroidism are being reported for the first time in this condition, additional cases are needed to corroborate or disprove this association. This case expands the phenotypic spectrum of DOHH-related disorders. It supports the diagnostic utility of exome sequencing in rare diseases, and highlights the importance of systematic bioinformatic reanalysis, long-term follow-up for accurate phenotypic characterization, and genetic counseling.