Roifman Syndrome: A Gene Within a Gene—First Report in Latin America

Introduction Roifman syndrome is a rare multisystemic disorder characterized by growth retardation, microcephaly, cognitive impairment, spondyloepiphyseal dysplasia, and immunodeficiency (classified as combined immunodeficiency with syndromic features). To date, only 31 cases have been described in the medical literature. Case Presentation We present the case of a 2-year-old female from a genetically isolated community, with no known consanguinity or relevant family history. She presented with three episodes of severe pneumonia (without microbiological isolates). Upon admission, she showed growth retardation, microcephaly, facial dysmorphism, short limbs, and hypotonia. Given the suspicion of an inborn error of immunity, workup revealed CD8+ and CD19+ lymphopenia, decreased IgM levels, and defective natural killer cell degranulation. Ultrasound imaging showed a hypoplastic thymus. A genetic panel identified a homozygous pathogenic variant in the RNU4ATAC gene: n.16G>A. The patient began replacement therapy with subcutaneous immunoglobulin, with favorable clinical evolution and no new infections to date. Extended immunophenotyping and parental segregation studies are currently being planned. Discussion The U12 spliceosome machinery plays a critical role in cell proliferation, differentiation, and growth. One of its essential components is the small nuclear RNA U4atac, encoded within the CLASP1 gene. Mutations in RNU4ATAC are associated with Roifman syndrome. The n.16G>A variant has been rarely reported and, to our knowledge, never before in Latin America. Previous cases typically exhibit B cell and memory B cell lymphopenia—a finding shared with our patient. Notably, however, our case also demonstrated CD8+ lymphopenia and isolated low IgM, potentially suggesting a distinct immunologic phenotype associated with this specific variant. Conclusions Inborn errors of immunity present with a broad clinical spectrum. Syndromic immunodeficiencies should be considered in patients with multisystem involvement. A comprehensive diagnostic approach that includes genetic testing enables accurate phenotype characterization, improves clinical outcomes, and informs on familial recurrence risks.