Expanding the Clinical and Molecular Spectrum of Cartilage-Hair Hypoplasia in the Mexican Population

Abstract

Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive skeletal dysplasia caused by variants in RMRP (RNA component of mitochondrial RNA processing endoribonuclease), which encodes a non-coding RNA. Despite its well-established clinical and molecular spectrum in some populations, data from Mexico remain limited. We report eight patients from seven unrelated families with CHH. Clinical and radiographic findings were assessed, and RMRP was analyzed by polymerase chain reaction and Sanger sequencing. All patients exhibited disproportionate short stature; prenatal long-bone shortening and short stature at birth occurred in 50%. Radiographs showed widened long bones and metaphyseal dysplasia in all patients. Extraskeletal manifestations were observed in four patients, each with a distinct feature: immunodeficiency, anemia, Hirschsprung disease, or lymphopenia. RMRP variants were identified in all patients, comprising two homozygous and six compound heterozygous genotypes. Eight variants were detected: three pathogenic (n.6C>T, n.147G>A, and n.72A>G), two likely pathogenic (n.127C>T and n.125C>T), two variants of uncertain significance (n.128G>C and n.215C>T), and a novel promoter deletion (n.-39_-19del) encompassing the RMRP TATA box, classified as likely pathogenic according to the ClinGen RMRP variant interpretation specifications (GN088, Version 1.3). This study expands the clinical and molecular spectrum of CHH in the Mexican population and provides additional evidence for RMRP variant interpretation.