Roifman Revisited: Embracing the spectrum of RNU4ATAC-Opathies

RNU4ATAC-opathies are genetic conditions that include growth restriction, skeletal dysplasia, and cognitive impairment. Historically, these have been divided phenotypically into microcephalic osteodysplastic primordial dwarfism type I (MOPDI), Roifman syndrome, and Lowry-Wood syndrome. In this case series, we highlight the variety of presentations of three novel patients with RNU4ATAC-opathy associated most closely with Roifman syndrome. Patient 1 (female, 14y) had a history of skeletal dysplasia, short stature, and mild developmental delay. She developed hypothyroidism and had recurrent migraines. She had a history of recurrent otitis and pneumonia, along with recurrent HSV stomatitis and recurrent urinary tract infections (UTIs). Immune evaluation identified combined T and B cell immunodeficiency, and IgG replacement was initiated at age 3y. RMRP-targeted sequencing identified a variant of uncertain significance (VUS) for which she carried a diagnosis of presumed cartilage hair hypoplasia (CHH). More recent targeted gene panel found two heterozygous pathogenic variants in RNU4ATAC. Patient 2 (female, 12y) is the sister of patient 1, also with presumed CHH due to the same VUS. She had a history of skeletal dysplasia, short stature, and cognitive delay. She had intrauterine growth restriction at birth as well as congenital hip dysplasia. In addition to recurrent otitis and pneumonia, she also had eczema and hypergonadotropic hypogonadism. At 18 months of age, immune evaluation revealed specific antibody deficiency managed with monthly IgG replacement. Genetic testing revealed the same two mutations in RNU4ATAC found in her sister. Patient 3 (male, 36y) had a history of brachydactyly, partial syndactyly, short stature, and intellectual disability. Microcephaly and a flattened philtrum were noted at birth, though acetabular dysplasia and femoral head flattening were not identified until adulthood. After an episode of severe cardiomyopathy and subsequent renal failure, genetic testing revealed two mutations in RNU4ATAC as well. Subsequent immune evaluation revealed a profound combined immune deficiency with very low T cells and hypogammaglobulinemia, for which he is now on replacement IgG as well as prophylactic antimicrobials. These cases illustrate the variability and overlap in the spectrum of RNU4ATAC-opathies and broaden the phenotypic range of these disorders.