Cartilage-hair hypoplasia syndrome (CHHS) is a rare autosomal recessive metaphyseal chondrodysplasia caused by mutations in the RMRP gene (chromosome 9p13). It features short-limbed dwarfism, sparse hair, and variable immune dysfunction, ranging from selective T cell lymphopenia to combined immunodeficiency, often with autoimmune phenomena and increased susceptibility to severe infections. The immune phenotype varies from leaky SCID to late-onset cytopenias and persistent viral infections. Hematopoietic stem cell transplantation (HSCT) is the curative option, though multisystem involvement complicates management.
Case 1: A prematurely born girl to non-consanguineous parents was hospitalized at 9 months with anemia and positive CMV IgM. During hospitalization, she developed pancytopenia with autoimmune hemolytic anemia confirmed by positive Coombs tests. Corticosteroids had limited effect. She had recurrent infections and hemolysis, requiring antibiotics, steroids, and immunoglobulin replacement. Persistent lymphopenia and refractory CMV viremia persisted despite ganciclovir. Immunophenotyping revealed total lymphocytes of 1,324/µL, with CD3 602/µL, CD4 190/µL (14 naïve cells [NC]), CD8 154/µL (3 NC), CD19 375/µL, and natural killer (NK) cells 104/µL. Genetic testing confirmed pathogenic RMRP variants (NR_003051.3:n.-24_-10dup / NR_003051.3)n.6C>T)). Currently, at 2 years old, CMV remains uncontrolled, and she awaits HSCT.
Case 2: Diagnosed prenatally with compound heterozygous RMRP variants (NR_003051.3:n.1_2insAGGACGTG / NR_003051.3:n.73A>G), newborn screening revealed very low T cell receptor excision circles (1), prompting early immunologic evaluation. Immunophenotyping showed moderate T cell lymphopenia (CD4: 607/µL, 265 NC) with preserved B and NK cells. She is asymptomatic on sulfamethoxazole–trimethoprim prophylaxis without infections. Both share phenotypic features: proportionate short stature, fine light-red hair, and metaphyseal dysplasia.
Despite overlapping clinical features and immunologic dysfunction, the early diagnosis in case 2—prior to the onset of infections or hematologic complications—may lead to a more favorable clinical trajectory, although long-term follow-up remains essential. In contrast, case 1 already presents a clear indication for HSCT due to progressive immune failure and viral persistence.
