Variability of clinical and laboratory features among patients with ribonuclease mitochondrial RNA processing endoribonuclease gene mutations

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Cartilage hair hypoplasia is an autosomal recessive type of metaphyseal chondrodysplasia, caused by mutations in the ribonuclease mitochondrial RNA processing (RMRP) gene. Typical features of cartilage hair hypoplasia include short stature, a predisposition to malignancy, and a variable degree of impairment of cellular immunity.


We sought to describe the heterogeneity of clinical and immunologic phenotype in 12 consecutive patients withRMRPmutations who were referred to 2 different institutions for immunologic evaluation.


We have retrospectively analyzed the clinical and laboratory features in 12 patients with molecular defects in theRMRPgene. T-cell repertoire was investigated by quantitating Vβ families' expression and analyzing their diversity. T-cell receptor excision circle analysis was used to study thymic output.


All 12 patients had significant immune abnormalities, leading to severe immune deficiency in 9. CD8 lymphocytopenia was identified as a novel phenotype associated withRMRPmutations. Significant, even intrafamilial, phenotypic heterogeneity was observed. In 3 cases, severe immunodeficiency was the only phenotypic manifestation associated withRMRPmutations, a novel finding. Mutations leading to significant immune defects were most often located in the promoter, and the first case of a compound heterozygote for 2 such mutations is reported.


This report broadens the spectrum of phenotypes associated withRMRPmutations and suggests that mutations in this gene should be considered when evaluating patients with combined immune deficiency, regardless of the presence of other manifestations.

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