Multiple congenital anomalies-hypotonia-seizures syndrome 3 in a child with cerebellar ataxia and autism: evidence of phenotypic expansion

We report a 9-year-old male of Eastern European ancestry presenting with global psychomotor delay, atypical autism, and cerebellar ataxia. Clinical evaluation revealed features of cerebral palsy (cerebellar type), distal joint laxity, slurred cerebellar speech, and unstable gait. Additional findings included fragile nails, abnormal visual evoked potentials, and a history of feeding difficulties and gastrointestinal reflux during infancy. Neuroimaging demonstrated cerebellar atrophy, while EEG recordings showed variable abnormalities during early childhood. The patient achieved independent ambulation at 7 years of age. Laboratory assessment indicated anemia.
Whole-exome sequencing identified a homozygous pathogenic variant in PIGT [NM_015937.6:c.1582G>A p.(Val528Met)], consistent with multiple congenital anomalies-hypotonia-seizures syndrome 3 (MCAHS3) [MIM:615398]. Both parents were heterozygous carriers. The phenotype aligns with the clinical spectrum of MCAHS3, characterized by hypotonia, psychomotor retardation, and cerebellar hypoplasia. However, several features observed in this patient such as atypical autism, fragile nails, and anemia are not commonly reported in MCAHS3 and may represent an expansion of the phenotypic spectrum.
This case highlights the variability of MCAHS3 and underscores the importance of comprehensive genetic testing for accurate diagnosis, especially in patients with progressive cerebellar involvement and multisystemic features.