Recessive <scp><i>MYH3</i></scp> variants cause “Contractures, pterygia, and variable skeletal fusions syndrome <scp>1B</scp>” mimicking Escobar variant multiple pterygium syndrome
Anna H. Hakonen, Johanna Lehtonen, Sirpa Kivirikko, Riikka Keski‐Filppula, Jukka S. Moilanen, Reetta Kivisaari, Henrikki Almusa, Eveliina Jakkula, Janna Saarela, Kristiina Avela, Kristiina Aittomäki
Abstract
The multiple pterygium syndromes (MPS) are rare disorders with disease severity ranging from lethal to milder forms. The nonlethal Escobar variant MPS (EVMPS) is characterized by multiple pterygia and arthrogryposis, as well as various additional features including congenital anomalies. The genetic etiology of EVMPS is heterogeneous and the diagnosis has been based either on the detection of pathogenic CHRNG variants (~23% of patients), or suggestive clinical features. We describe four patients with a clinical suspicion of EVMPS who manifested with multiple pterygia, mild flexion contractures of several joints, and vertebral anomalies. We revealed recessively inherited MYH3 variants as the underlying cause in all patients: two novel variants, c.1053C>G, p.(Tyr351Ter) and c.3102+5G>C, as compound heterozygous with the hypomorphic MYH3 variant c.-9+1G>A. Recessive MYH3 variants have been previously associated with spondylocarpotarsal synostosis syndrome. Our findings now highlight multiple pterygia as an important feature in patients with recessive MYH3 variants. Based on all patients with recessive MYH3 variants reported up to date, we consider that this disease entity should be designated as "Contractures, pterygia, and variable skeletal fusions syndrome 1B," as recently suggested by OMIM. Our findings underline the importance of analyzing MYH3 in the differential diagnosis of EVMPS, particularly as the hypomorphic MYH3 variant might remain undetected by routine exome sequencing.