Cartilage-hair hypoplasia: A ribosomopathy

Cartilage-hair hypoplasia (CHH) is caused by biallelic variants in RMRP, encoding the RNA component of a ribonucleoprotein complex called RNase MRP. Clinically, CHH is characterized by the combination of metaphyseal skeletal dysplasia and T-cell impairment that can lead to a combined immunodeficiency. The spectrum of recognized features includes anemia, autoimmune manifestations and gastrointestinal complications such as Hirschsprung disease. Patients with CHH also have a highly increased risk of developing malignancy, particularly non-Hodgkin lymphoma and basal cell carcinoma. The mechanism linking RNase MRP dysfunction with disease has been debated. Recent studies have clarified that disease-associated RMRP mutations impair pre-ribosomal RNA processing and cause a reduction in mature cytosolic ribosomes, establishing CHH as a ribosomopathy. CHH is also associated with cell cycle defects and shorter telomeres, but whether these features are secondary to the ribosome synthesis defect or driven by other mechanisms remains to be clarified. In this review, we summarize the clinical manifestations and current management of CHH, with a particular emphasis on its hematological and immunological manifestations. We then discuss the evidence linking RMRP mutations to defective ribosome synthesis and appraise possible alternative or complementary disease mechanisms. We also review recently described disorders caused by mutations in protein-coding components of the RNase MRP complex (POP1 and RMP64/NEPRO). Finally, we discuss unresolved questions, including why impaired ribosome synthesis in CHH causes a predominantly T-cell phenotype, in contrast to the erythroid and myeloid failures characteristic of other ribosomopathies such as Diamond-Blackfan anemia.