Novel NFIX variant in a patient with Malan syndrome and associated Chiari type I malformation: a case report

Malan syndrome (MALNS) is a rare overgrowth disorder caused by pathogenic Nuclear Factor I × (NFIX) gene variants, and characterized by postnatal overgrowth, macrocephaly, developmental delay, intellectual disability and distinctive facial features. Chiari type I malformation (CMI), a condition where the cerebellar tonsils extend below the foramen magnum, has been observed in some patients with MALNS, although the exact relationship between these disorders remains unclear. The objective of this case report is to describe a novel NFIX variant in a patient with MALNS and associated CMI. This case adds to the literature on NFIX variants in patients with CMI and underscores the potential benefit of early genetic testing for diagnosis and management.

We describe a patient with clinical features consistent with MALNS, including macrocephaly, developmental delay, and typical craniofacial features. Brain Magnetic Resonance Imaging (MRI) revealed the presence of CMI. Genetic testing identified a novel heterozygous variant in NFIX, not previously described in the literature.

This case contributes to the clinical and molecular characterization of MALNS by linking a previously unreported NFIX variant to CMI. The case underlines the importance to take into account MALNS in patients presenting with overgrowth and CMI. Furthermore, we report a novel variant to improve diagnostic accuracy and genotype-phenotype correlation. Indeed, timely molecular diagnosis is essential to differentiate among overgrowth syndromes and to establish appropriate long-term clinical follow-up.