title: Variability of clinical and laboratory features among patients with ribonuclease mitochondrial RNA processing endoribonuclease gene mutations.
abstract: 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 Vbeta 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Immunology and Allergy, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Fotini D
authors.initials: FD
authors.lastname: Kavadas
authors.forename: Silvia
authors.initials: S
authors.lastname: Giliani
authors.forename: Yiping
authors.initials: Y
authors.lastname: Gu
authors.forename: Evelina
authors.initials: E
authors.lastname: Mazzolari
authors.forename: Andrea
authors.initials: A
authors.lastname: Bates
authors.forename: Eleonora
authors.initials: E
authors.lastname: Pegoiani
authors.forename: Chaim M
authors.initials: CM
authors.lastname: Roifman
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002357:Cartilage Diseases / Q000201:enzymology / Q000235:genetics* / Q000276:immunology*; D004722:Endoribonucleases / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D005260:Female; D030342:Genetic Diseases, Inborn / Q000201:enzymology / Q000235:genetics* / Q000276:immunology*; D006579:Heterozygote; D006801:Humans; D008231:Lymphopenia / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000276:immunology*; D010009:Osteochondrodysplasias / Q000201:enzymology / Q000235:genetics* / Q000276:immunology*; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012189:Retrospective Studies
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta; D004722:Endoribonucleases; C058330:mitochondrial RNA-processing endoribonuclease