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Prevalence
The estimated frequency is around 1 in 800,000 individuals. MYHRS exhibits no significant sex-related differences in prevalence.

Main clinical features
Individuals with MYHRS (OMIM#139210) have distinctive dysmorphic facial features, skeletal deformities, intellectual disability (ID), proliferative and progressive fibrosis. Due to fibrosis, most patients usually experience joint stiffness, restrictive lung and cardiovascular disease, and thickening of the skin.

Molecular features
Heterozygous gain-of-function pathogenic variants in SMAD4(OMIM*600993) cause MYHRS. However, it should be noted that loss-of-function variants in this gene are associated with Juvenile Polyposis Syndrome (JPS) and Hereditary Hemorrhagic Telangiectasia (HHT), which are entirely distinct entities.

Inheritance and genetic counselling
MYHRS is inherited in an autosomal dominant manner. In most patients, the variant is identified as de novo, although familial cases have also begun to be reported. All de novomutations are of paternal origin, with a noted association with advanced paternal age. If one of the proband’s parents carries the pathogenic variant found in the proband, there is a 50% chance that the siblings may inherit the same pathogenic variant. If the SMAD4pathogenic variant identified in the proband is not detected in either parent, the recurrence risk for siblings is estimated to be 1–2%, due to the potential presence of parental gonadal mosaicism. If the pathogenic variant in the SMAD4gene is known in the family, prenatal and preimplantation genetic diagnosis options may also be offered.

Management
Currently, there is no cure for MYHRS. Supportive management aimed at enhancing quality of life, optimizing functional abilities, and minimizing complications is advised, preferably through coordinated multidisciplinary care provided by relevant specialists. All patients should have regular follow-ups to monitor their progress.