Decreased Telomere Length and Complex Immunologic Phenotype in Patients with Cartilage-Hair Hypoplasia

Prof. Outi Mäkitie’s Research Group has in two recent studies on cartilage-hair hypoplasia (CHH), a pleiotropic chondrodysplasia of the Finnish disease heritage, been able to show that the patients’ immune deficiency is much more complex than previously thought and that the patients have decreased telomere length.

CHH is an autosomal recessive chondrodysplasia caused by mutations in the untranslated RMRP gene, encoding the RNA component of mitochondrial RNA processing endoribonuclease. Manifestations include short stature, variable immunodeficiency, anemia and increased risk for malignancies. All these manifestations have been described also in telomere biology disorders. Heterogeneity of clinical and immunologic phenotype and lack of robust assessment of immune function complicate management. These two studies sought to gain further knowledge of the immunologic characteristics in a large cohort of patients, and to elucidate the suggested role of RMPR in telomere biology.

The Mäkitie Group studied infectious manifestations, laboratory characteristics and their correlation in a cohort of 56 Finnish CHH patients. Symptoms of humoral and combined immunodeficiency (CID) were detected in 46% and 27% of patients respectively, others demonstrated no clinical signs of immunodeficiency despite laboratory abnormalities. Many patients showed clinical signs of humoral immunodeficiency only. Clinical signs of CID associated with lower CD3+, CD8+ and thymic naive cell counts; severe varicella associated with lower IgG2 levels. Specific abnormalities in B and T cell compartments were detected. Antibody responses in most tested patients were normal to protein, but impaired topolysaccharide antigens.

The second study was based on the observation that RMRP interacts with the telomerase RT (TERT) subunit, but the influence of RMRP mutations on telomere length has remained unknown. The relative telomere length (RTL) was measured in patients with CHH, their first-degree relatives and healthy controls and correlated RTL with clinical and laboratory features. Compared with age-matched and sex-matched healthy controls, median RTL was significantly shorter in patients with CHH, but not in mutation carriers. Further, RTL correlated significantly with age only in RMRP mutation carriers, but not in CHH patients. In particular children with CHH had shorter telomeres than controls (Figure). There was no correlation between RTL and clinical or laboratory parameters in patients with CHH.

Figure: Comparison of relative telomere length in 40 patients with cartilage-hair hypoplasia (CHH) and matched healthy controls.


Original Studies:
Kostjukovits S, Klemetti P, Valta H, Martelius T, Notarangelo LD, Seppänen M, Taskinen M, Mäkitie O. Analysis of clinical and immunologic phenotype in a large cohort of children and adults with cartilage-hair hypoplasia. J Allergy Clin Immunol 140: 612-614, 2017

Kostjukovits S, Degerman S, Pekkinen M, Klemetti P, Landfors M, Roos G, Taskinen M, Mäkitie O. Decreased telomere length in children with cartilage-hair hypoplasia. J Med Genet 54: 365-370, 2017