RNU4atac-opathy

Clinical characteristics: RNU4atac-opathy encompasses the phenotypic spectrum of biallelic RNU4ATAC pathogenic variants, including the three historically designated clinical phenotypes microcephalic osteodysplastic primordial dwarfism type I/III (MOPDI), Roifman syndrome, and Lowry-Wood syndrome, as well as varying combinations of the disease features / system involvement that do not match specific defined phenotypes. Findings present in all affected individuals include growth restriction, microcephaly, skeletal dysplasia, and cognitive impairment. Less common but variable findings include brain anomalies, seizures, strokes, immunodeficiency, and cardiac anomalies, as well as ophthalmologic, skin, renal, gastrointestinal, hearing, and endocrine involvement.

Diagnosis/testing: The diagnosis of RNU4atac-opathy is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in RNU4ATAC identified by molecular genetic testing.

Management: Treatment of manifestations: Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields, including orthopedists to monitor the associated skeletal dysplasia and immunologists to manage antibiotic treatment of infections and use of immunoglobulin replacement therapy as indicated to avoid life-threatening infections.

Surveillance: To monitor existing manifestations and response to supportive care (such as growth, developmental progress, and educational needs), and to detect new manifestations (particularly brain MRI for detection of stroke in children with MOPDI with neurologic deterioration).

Agents/circumstances to avoid: Perform immunologic evaluation prior to administration of live vaccines. For those with MOPDI, minimize medically stressful situations as much as possible, including stress during anesthesia, due to energy-related strokes.

Genetic counseling: RNU4atac-opathy is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an RNU4ATAC pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Intrafamilial clinical variability has been reported between sibs who inherit the same biallelic RNU4ATAC pathogenic variants. Once the RNU4ATAC pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.