Am J Med Genet C Semin Med Genet. 2025 Aug 17. doi: 10.1002/ajmg.c.32150. Online ahead of print.
ABSTRACT
Myhre syndrome is a rare connective tissue disorder characterized by skeletal, cardiopulmonary, dermatologic, neurocognitive changes, and a predisposition to exaggerated fibrosis in response to mechanical stress. We report monozygotic male twins with Myhre syndrome caused by the recurrent SMAD4 gain-of-function variant c.1498A>G (p.Ile500Val), identified by targeted next-generation sequencing of peripheral blood. Proband 1 presented at age 37 years for evaluation of symptomatic aortic stenosis. Clinical recognition of Myhre syndrome prompted deferral of transesophageal echocardiography, and molecular diagnosis informed subsequent conservative management. His co-twin, Proband 2, underwent posterior pharyngeal flap surgery and right-heart catheterization with pulmonary artery stenting in childhood; later, he developed progressive pulmonary arterial hypertension and died at 31 years. We report on the differing outcomes of the twins and the possibility that invasive airway and cardiac procedures may have accelerated fibro-proliferative complications of Proband 2. Early recognition of Myhre syndrome allows selection of alternatives to high-risk procedures, longitudinal monitoring, and may reduce morbidity and mortality.
PMID:40820266 | DOI:10.1002/ajmg.c.32150
