MTSS2-Related Disorder: Refining the Phenotype in Four New Cases and Literature Review.

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MTSS2 encodes a protein highly expressed in the central nervous system, with a crucial role in neurodevelopment. The de novo recurrent variant c.2011C>T (p.Arg671Trp) was first identified in 2022 as cause of Intellectual Developmental Disorder with ocular anomalies and distinctive facial features (OMIM#620086). We present clinical data about four new unrelated patients harboring the MTSS2 recurrent variant c.2011C>T (p.Arg671Trp). Common clinical features included developmental delay (particularly affecting language skills), mild intellectual disability, learning disabilities, microcephaly, non-specific brain MR findings and facial dysmorphisms. Other features were hypotonia, psychiatric disorders, generalized febrile or afebrile seizures with generalized epileptic anomalies on EEG, growth delay, skeletal anomalies, feeding difficulties (particularly affecting chewing), and poor coordination. Rare manifestations included hearing loss, ocular, gastrointestinal, genitourinary, and cardiovascular anomalies. To date, only six cases were documented in literature. Neurodevelopmental disorder with intellectual disability, microcephaly, and dysmorphisms are the main features of the disease. This study elaborates on the clinical manifestations, exploring the characterization of both neurologic and extra-neurologic comorbidities, proposing a possible association with cardiac and renal malformations. We suggest that MTSS2 could be linked to a predominantly neurological but multisystem disorder.