Pediatric Research Center, Children's Hospital, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland.
Folkhälsan Research Center, Institute of Genetics, Helsinki, Finland.
Front Immunol. 2019 Jul 16;10:1581. doi: 10.3389/fimmu.2019.01581. eCollection 2019.
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%, = 46) manifested no symptoms of immunodeficiency during follow-up while 19% ( = 15) and 24% ( = 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 ( = 7, SMR = 10, 95%CI = 4.1-21) and lung disease ( = 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.
软骨毛发发育不全（CHH）是一种骨骼发育不良，伴有联合免疫缺陷，临床表现多样，且恶性肿瘤风险增加。由于缺乏长期随访数据以及预后因素的相关知识，CHH 的管理较为复杂。我们对 1985 年至 1991 年间招募并随访至 2016 年的 80 例 CHH 患者进行了前瞻性队列研究，评估了他们的临床病程和死亡风险因素。我们从健康记录和国家医疗数据库和死因登记处收集了所有患者的额外健康信息。主要结局是免疫缺陷相关死亡，包括感染、肺部疾病和恶性肿瘤导致的死亡。使用国家死亡率作为参考计算标准化死亡率比（SMR）。半数患者（57%，46 例）在随访期间无免疫缺陷症状，19%（15 例）和 24%（19 例）表现出体液或联合免疫缺陷症状，包括 6 例成人发病免疫缺陷。在相当一部分患者（17/79，22%）中，免疫缺陷的临床表现随时间进展。在 15 例非皮肤癌患者中，有 8 例无先前的免疫缺陷临床症状。共有 20 例患者死亡（SMR=7.0，95%CI=4.3-11）；最常见的死因是恶性肿瘤（7 例，SMR=10，95%CI=4.1-21）和肺部疾病（4 例，SMR=46，95%CI=9.5-130）。与出生长度低于-4 个标准差（与正常相比，SMR/SMR 比值=5.4，95%CI=1.5-20）、联合免疫缺陷症状（与无症状相比，SMR/SMR 比值=3.9，95%CI=1.3-11）、先天性巨结肠（OR=7.2，95%CI=1.04-55）、出生后第一年或成人后反复肺炎（OR=7.6/19，95%CI=1.3-43/2.6-140）和成人自身免疫（OR=39，95%CI=3.5-430）相关的患者，与出生长度正常（与正常相比，SMR/SMR 比值=3.0，95%CI=2.1-4.2）相比，死亡风险增加。总之，CHH 患者可能在无先前免疫缺陷临床症状的情况下发展为成人发病免疫缺陷或恶性肿瘤，需要密切随访。应认识到疾病的多变病程和死亡风险因素。
