Abstract
Cartilage-hair hypoplasia (CHH) is a skeletal dysplasia with combined immunodeficiency, variable clinical course and increased risk of malignancy. Management of CHH is complicated by a paucity of long-term follow-up data, as well as knowledge on prognostic factors. We assessed clinical course and risk factors for mortality in a prospective cohort study of 80 patients with CHH recruited in 1985–1991 and followed up until 2016. For all patients we collected additional health information from health records and from the national Medical Databases and Cause-of-death Registry. The primary outcome was immunodeficiency-related death, including death from infections, lung disease and malignancy. Standardized mortality ratios (SMRs) were calculated using national mortality rates as reference. Half of the patients (57%, n = 46) manifested no symptoms of immunodeficiency during follow-up while 19% (n = 15) and 24% (n = 19) demonstrated symptoms of humoral or combined immunodeficiency, including six cases of adult-onset immunodeficiency. In a significant proportion of patients (17/79, 22%), clinical features of immunodeficiency progressed over time. Of the 15 patients with non-skin cancer, eight had no preceding clinical symptoms of immunodeficiency. Altogether 20 patients had deceased (SMR = 7.0, 95%CI = 4.3–11); most commonly from malignancy (n = 7, SMR = 10, 95%CI = 4.1–21) and lung disease (n = 4, SMR = 46, 95%CI = 9.5–130). Mortality associated with birth length below −4 standard deviation (compared to normal, SMR/SMR ratio = 5.4, 95%CI = 1.5–20), symptoms of combined immunodeficiency (compared to asymptomatic, SMR/SMR ratio = 3.9, 95%CI = 1.3–11), Hirschsprung disease (odds ratio (OR) 7.2, 95%CI = 1.04–55), pneumonia in the first year of life or recurrently in adulthood (OR = 7.6/19, 95%CI = 1.3–43/2.6–140) and autoimmunity in adulthood (OR = 39, 95%CI = 3.5–430). In conclusion, patients with CHH may develop adult-onset immunodeficiency or malignancy without preceding clinical symptoms of immune defect, warranting careful follow-up. Variable disease course and risk factors for mortality should be acknowledged.
Highlights
Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive chondrodysplasia, with combined immunodeficiency (CID), short stature, hair hypoplasia, anemia, increased risk of malignancies, and Hirschsprung disease
The expected numbers of deaths for each stratum were calculated by multiplying person-years by the corresponding sex, age and period specific mortality rates in the general population produced by the Statistics Finland
Exact 95% confidence intervals (95%CI) for the standardized mortality ratio (SMR) were defined with the assumption that the number of observed deaths followed a Poisson distribution
Summary
Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive chondrodysplasia, with combined immunodeficiency (CID), short stature, hair hypoplasia, anemia, increased risk of malignancies, and Hirschsprung disease. CHH is caused by mutations in RMRP, the gene encoding the RNA component of mitochondrial RNA-processing endoribonuclease [1]. Disease prevalence is exceptionally high among the Amish and Finnish populations [2]. The pathogenesis involves defective cell proliferation, impaired telomere machinery and abnormal gene regulation [3,4,5]. Increased mortality in CHH relates to infections in childhood and malignancies in young adulthood [6]. NonHodgkin lymphoma and basal cell carcinoma (BCC) are the most common associated cancer types [7]. Lung disease related to bronchiectasis is an important contributor to morbidity [8]
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