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

Background

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.

Objective

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

Methods

We have retrospectively analyzed the clinical and laboratory features in 12 patients with molecular defects in the RMRP gene. 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.

Results

All 12 patients had significant immune abnormalities, leading to severe immune deficiency in 9. CD8 lymphocytopenia was identified as a novel phenotype associated with RMRP mutations. Significant, even intrafamilial, phenotypic heterogeneity was observed. In 3 cases, severe immunodeficiency was the only phenotypic manifestation associated with RMRP mutations, 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.

Conclusion

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

Key words: Cartilage hair hypoplasia, RNase mitochondrial RNA processing endoribonuclease, severe combined immunodeficiency, Omenn syndrome, CD8 lymphopenia

Abbreviations used: CHH, Cartilage hair hypoplasia, HCT, Hematopoietic cell transplantation, OS, Omenn syndrome, RMRP, Ribonuclease mitochondrial RNA processing endoribonuclease, SCID, Severe combined immunodeficiency, sj, Signal joint, TREC, T-cell receptor excision circle