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Front Immunol. 2019 Jul 16;10:1581. doi: 10.3389/fimmu.2019.01581. eCollection 2019.

A 30-Year Prospective Follow-Up Study Reveals Risk Factors for Early Death in Cartilage-Hair Hypoplasia.

Author information

1
Pediatric Research Center, Children's Hospital, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland.
2
Folkhälsan Research Center, Institute of Genetics, Helsinki, Finland.
3
Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
4
Faculty of Social Sciences, Tampere University, Tampere, Finland.
5
Department of Molecular Medicine and Surgery, Karolinska Institutet, Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
6
Department of Clinical Genetics, HUSLAB, Helsinki University Hospital, Helsinki, Finland.

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.

KEYWORDS:

RMRP; adult-onset immunodeficiency; cancer; combined immunodeficiency; lung disease; lymphoma; mortality; skeletal dysplasia

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