Myhre syndrome due to a recurrent SMAD4 p.Arg496Cys variant in a 17-year-old boy: clinical and neuroimaging findings

Background: Myhre syndrome (OMIM #139210) is a rare autosomal dominant connective tissue disorder caused by recurrent gain-of-function variants in SMAD4, leading to dysregulated TGF-β/SMAD signalling. Affected individuals present with short stature, developmental delay, progressive joint contractures, thickened skin, facial dysmorphism, and variable cardiovascular and respiratory involvement.

Case Presentation: We report a 17-year-old boy with a de novo SMAD4 c.1486C>T (p.Arg496Cys) variant, a recurrent pathogenic hotspot associated with Myhre syndrome. He was born at term after an uncomplicated pregnancy, with early feeding difficulties and poor weight gain. Autism spectrum disorder was diagnosed at 2 years of age, with severe language delay and minimal speech by 7 years. Current features include global developmental delay, severe speech disorder, ADHD, autism, epilepsy controlled with carbamazepine, aggression, sleep disturbance (managed with clonidine), short stature (3rd centile), macrocephaly (>98th centile), short fingers, cutaneous syndactyly of toes, prognathism, pica, constipation alternating with diarrhoea, hyperkeratosis, and mouth breathing. He entered puberty spontaneously. MRI brain demonstrated a solitary focus of T2/FLAIR hyperintensity in the right frontal white matter, isointense to grey matter on inversion recovery, consistent with possible grey matter heterotopia.

Discussion: This case highlights the neurodevelopmental and systemic phenotype associated with SMAD4 p.Arg496Cys, expanding the clinical spectrum of Myhre syndrome to include epilepsy and possible neuronal migration abnormality. Management remains supportive and multidisciplinary. Although no disease-modifying therapy exists, TGF-β pathway modulation is of interest; losartan has shown benefit in related TGF-β-driven disorders (e.g., Marfan syndrome), while sirolimus has theoretical potential through antifibrotic effects, but neither has been trialled in Myhre syndrome.

Conclusion: This report adds to the clinical spectrum of Myhre syndrome and underscores the importance of ongoing surveillance for emerging targeted therapies.