Review of Cutaneous Manifestations in Myhre Syndrome With Histopathological Analyses and Genotype–Phenotype Correlation

Myhre syndrome is a rare multisystem disorder characterized by distinctive facial features, hearing loss, and progressive fibrosis affecting the skin, joints, lungs, and cardiovascular system. It is caused by heterozygous pathogenic variants in the SMAD4 gene. In this review, we detail the cutaneous manifestations observed in two previously reported patients with genetically confirmed Myhre syndrome. While skin biopsies demonstrated pan-dermal thickening of collagen bundles, the immunohistochemical staining patterns were distinct from those seen in other inflammatory sclerosing disorders. Additionally, we conducted a comprehensive literature review of the cutaneous features associated with Myhre syndrome, identifying 175 patients with confirmed SMAD4 pathogenic variants. The most reported cutaneous finding was thickened or stiff skin (76%), followed by keratosis pilaris (22%) and impaired wound healing or abnormal scarring (18%). Genotype-phenotype analysis suggested a diagnostic delay in patients with the codon 496 variant, who were more frequently diagnosed in adulthood. This variant may also be associated with a milder cutaneous phenotype, highlighting the clinical heterogeneity of Myhre syndrome. These findings underscore the importance of recognizing cutaneous features as potential early diagnostic clues in patients with suspected Myhre syndrome.