Spectrum of Congenital Anomalies in Myhre Syndrome-Insights Into Effects Brought by Altered TGF-β Signaling via Gain-of-Function Variants in SMAD4

Myhre syndrome is a rare genetic disorder characterized by progressive multisystem involvement. Gain-of-function missense heterozygous variants affecting the Ile500 residue and Arg496 residue of the SMAD4 gene are implicated in this condition. In this article, we aim to understand the spectrum of congenital anomalies in Myhre syndrome by studying a cohort of previously unreported patients alongside published literature. Our analysis revealed that the musculoskeletal system was the most common system to be affected, followed by the cardiovascular system. Intrauterine growth restriction was the most reported intrauterine anomaly. Although there was no clear genotype–phenotype correlation, it appears that the Ile500Thr variant showed early multisystem involvement compared to other variants.