Immunodeficiency in cartilage-hair hypoplasia : correlation with pulmonary disease, infections and malignancy

Research output: ThesisDoctoral ThesisCollection of Articles


Cartilage-hair hypoplasia (CHH) is a rare chondrodysplasia with short stature, hair hypoplasia, variable degree of immunodeficiency and increased risk of malignancy. The non-coding RNA gene RMRP is mutated in CHH. The gene has multiple functions, including cell cycle regualtion. Several aspects of CHH remain inadequately explored, including the pathogenesis, detailed characteristics of immunologic phenotype, correlations of clinical and laboratory features, as well as disease course and prognosis. To address these questions, we recruited and carefully examined a large cohort of Finnish children and adults with CHH. We performed detailed immunologic evaluation, explored the prevalence of bronchiectasis and compared the diagnostic performance of lung high-resolution computed tomography (HRCT) and magnetic resonance imaging (MRI). We also conducted a prospective 30-year follow-up study to identify factors associated with adverse outcomes. In addition, we investigated the role of telomere machinery in the pathogenesis of CHH by measuring relative telomere length (RTL). Study patients (n=56) demonstrated specific abnormalities in B and T cell compartments: 1) decreased thymic naive, naive CD4+ and CD8+ T cells; 2) increased activated CD4+, central memory CD4+ and effector memory CD8+ T cells; 3) normal regulatory T cells; 4) decreased naive, transitional and memory B cells; and 5) increased activated B cells. Specific antibody deficiency was demonstrated in the majority of patients immunized with unconjugated pneumococcal vaccine. No significant correlations were observed between clinical and laboratory features. Children with CHH demonstrated significantly shorter median RTL compared with healthy controls. HRCT showed bronchiectasis in 10/34 patients (29%), justifying lung evaluation also in those without apparent immunodeficiency. Lung MRI was comparable to HRCT in the assessment of bronchiectasis and could be implemented in the follow-up of lung changes. In the prospective study of 80 subjects with CHH, in a significant proportion of patients (17/79, 22%) clinical features of immunodeficiency progressed over time, including six cases of adult-onset immunodeficiency. Of the 15 subjects with non-skin malignancy, eight demonstrated no preceding symptoms of immunodeficiency. These findings call for careful follow-up and screening for cancer even in asymptomatic patients. Altogether 20/80 patients had died during the follow-up, and causes of death included pneumonia (n = 4), malignancy (n = 7) and pulmonary disease (n = 4). Increased mortality was associated with severe short stature at birth, Hirschsprung disease, pneumonia, autoimmunity and symptoms of combined immunodeficiency. In addition, warts in adulthood and actinic keratosis were associated with the development of skin cancer. The study findings should be considered when establishing management guidelines for patients with CHH.
Original languageEnglish
  • Mäkitie, Outi, Supervisor
  • Klemetti, Paula, Supervisor
Place of PublicationHelsinki
Print ISBNs978-951-51-5227-5
Electronic ISBNs978-951-51-5228-2
Publication statusPublished - 2019
MoE publication typeG5 Doctoral dissertation (article)

Bibliographical note

M1 - 79 s. + liitteet

Fields of Science

  • Immunologic Deficiency Syndromes
  • +diagnosis
  • +immunology
  • +mortality
  • Osteochondrodysplasias
  • +congenital
  • Hair
  • +abnormalities
  • Hirschsprung Disease
  • Bronchiectasis
  • +epidemiology
  • Lung
  • +diagnostic imaging
  • +pathology
  • Lung Diseases
  • Neoplasms
  • Warts
  • Keratosis, Actinic
  • Communicable Diseases
  • Telomere Shortening
  • Risk Factors
  • Tomography, X-Ray Computed
  • Magnetic Resonance Imaging
  • 3123 Gynaecology and paediatrics

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