Psychotic Features in Myhre Syndrome: Evidence for Broader Neuropsychiatric Surveillance

Myhre syndrome is a rare genetic disorder caused by pathogenic variants in SMAD4. The neurocognitive profile may include intellectual disability and developmental delay across a wide spectrum of domains. Four individuals with Myhre syndrome and psychosis and/or schizophrenia have been reported. We discuss three additional individuals (one briefly mentioned in a review of patients with Myhre syndrome) with SMAD4 pathogenic variants at codon Arg496Cys (two cases) and codon Ile500Val (one case). All had social challenges and variable developmental delays. They presented with acute-onset psychosis and were diagnosed with either psychosis, not otherwise specified, or psychosis associated with bipolar disorder. The seven individuals (5 female, 2 male) ranged in age from 13 to 24 years (mean 18.7 years) and had variable responses to pharmacologic and behavioral interventions. The underlying mechanism of psychosis in Myhre syndrome may be due to disruptions in the TGF-β signaling pathway, which involves the interactions of TGF-β family members and SMAD proteins, including SMAD4. Although additional cases are needed to verify our observations, psychosis may be a component of the neurodevelopmental phenotype of Myhre syndrome, highlighting the importance of rapid psychiatric evaluation and intervention.