A Patient With Hypogammaglobulinemia and Bi-allelic Variants in the RNU4ATAC Gene

Abstract

IntroductionThe RNU4ATAC gene codes for a small nuclear RNA involved in U12 minor intron splicing. Bi-allelic compound heterozygous pathogenic variants in the RNU4ATAC gene have been associated with Roifman Syndrome, which is an autosomal recessive disease manifesting with immunodeficiency, retinal dystrophy, developmental delay, poor growth, spondyloepiphyseal dysplasia and dysmorphic facial features. We present a case of a patient with similar characteristics seen in Roifman syndrome including impaired humoral immunity, short stature, developmental delay, osseous abnormalities and characteristic facial features found to have one likely pathogenic variant and one variant of uncertain significance (VUS) on the RNU4ATAC gene, raising the suspicion for Roifman syndrome. Case PresentationA 9-year-old male patient with a history of congenital hydrocephalus, seizure disorder, developmental delay, skeletal dysplasia, short stature and alopecia presented with headaches in the setting of EBV-meningitis requiring craniotomy and external ventricular drain placement. Prior infectious history was remarkable for four bacterial pneumonias, one sinusitis and recurrent otitis media infections in childhood. Initial evaluation of his immune system revealed decreased levels of IgG at 453 mg/dL (698–1560 mg/dL), IgM at 19 mg/dL (31–179 mg/dL), IgA at 36 mg/dL (63–236 mg/dL), and decreased CD19+ B-cells at 59/uL (200–600/uL), with suboptimal response to tetanus, pneumococcal-13, haemophilus influenzae and diphtheria vaccines. Although after receiving booster vaccinations, specific antibodies rose to protective levels, they began to drop within one year and IgG levels remained low, so he was started on immunoglobulin replacement, and has remained free of infections. Genetic evaluation revealed one de novo VUS and one maternally inherited likely pathogenic variant on the RNU4ATAC gene. Further VUS were detected in various genes with mode of inheritance and disease associations not consistent with our patient’s phenotype. DiscussionDisease-causing variants in compound heterozygosity have been associated with Roifman syndrome. The clinical similarities shared between this condition and our patient, including epiphyseal dysplasia, unique facial features, developmental delay and immunodeficiency characterized by hypogammaglobulinemia and impaired specific antibody response, raise the suspicion for Roifman syndrome. As broad testing failed to reveal any other possible etiologies, confirmation of clinical diagnosis may lead to future reclassification of the VUS into presumably pathogenic.