Humoral Immune Variability in Twin Sisters With SKIV2L-Associated Trichohepatoenteric Syndrome.

Trichohepatoenteric syndrome (THES) is a rare autosomal recessive disorder caused by pathogenic variants in tetratricopeptide repeat domain 37 (TTC37), designated THES-I, or Ski2-like RNA helicase (SKIV2L), designated THES-II, and characterized by infantile diarrhea, growth impairment, developmental delay, liver disease, hair abnormalities, and variable immune dysfunction. Although immunologic abnormalities have increasingly been recognized, the functional humoral phenotype of SKIV2L-associated THES remains incompletely characterized. We report twin sisters with compound heterozygous SKIV2L variants, consistent with THES-II, who underwent comprehensive immunologic evaluation after recurrent infections and concern for immune dysfunction. Both twins demonstrated persistently elevated serum immunoglobulin A concentrations, reduced memory B-cell populations, decreased plasmablasts, and predominantly nonprotective baseline pneumococcal antibody titers despite routine childhood immunization. However, selected quantitative and antigen-specific humoral findings differed between the twins. Twin 1 had infantile hypogammaglobulinemia that normalized by approximately three years of age without immunoglobulin replacement therapy but later demonstrated absent tetanus and diphtheria antibodies and a severely impaired response to pneumococcal polysaccharide vaccination, with protection against only 1 of 23 serotypes. Twin 2 never developed hypogammaglobulinemia and retained a protective diphtheria antibody response. However, tetanus antibody was absent and formal assessment of her polysaccharide vaccine responsiveness was limited by unavailable post-vaccination titers. These cases demonstrate intrafamilial variability in selected humoral immune features despite a shared disease-causing genotype and show that clinically important antibody dysfunction may not be apparent from quantitative immunoglobulin measurements alone. Comprehensive evaluation of vaccine responses and memory B-cell maturation may improve recognition and individualized management of immune dysfunction in patients with THES-II.