Background Knowledge about the clinical spectrum of lung disease caused by variations in the ATP binding cassette subfamily A member 3 (ABCA3) gene is limited. Here we describe genotype-phenotype correlations in a European cohort.
Methods We retrospectively analysed baseline and outcome characteristics of 40 patients with two disease-causing ABCA3 mutations collected between 2001 and 2015.
Results Of 22 homozygous (15 male) and 18 compound heterozygous patients (3 male), 37 presented with neonatal respiratory distress syndrome as term babies. At follow-up, two major phenotypes are documented: patients with (1) early lethal mutations subdivided into (1a) dying within the first 6 months or (1b) before the age of 5 years, and (2) patients with prolonged survival into childhood, adolescence or adulthood. Patients with null/null mutations predicting complete ABCA3 deficiency died within the 1st weeks to months of life, while those with null/other or other/other mutations had a more variable presentation and outcome. Treatment with exogenous surfactant, systemic steroids, hydroxychloroquine and whole lung lavages had apparent but many times transient effects in individual subjects.
Conclusions Overall long-term (>5 years) survival of subjects with two disease-causing ABCA3 mutations was <20%. Response to therapies needs to be ascertained in randomised controlled trials.
- Paediatric interstitial lung disease
- Surfactant protein
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Contributors MG designed the study, collected the cases, analysed the data and drafted and revised the manuscript. He is the guarantor of the entire manuscript. CK organised and analysed the data and drafted the manuscript. MKl, MH, MKa, NC, TS, ATA, IC, MP, TS, ST-L, NR, EE, JS, NS, CA, CK and MG contributed and evaluated patients and performed chart review. RZ, DR and TW performed laboratory and immunohistochemical analyses, FB and SR performed the histological investigations, VT the radiological investigations. CA and PL performed genetic analysis and contributed to the long-term collection of subjects. All contributors read and critically revised the manuscript and agreed to the final version of the manuscript.
Funding The work of MG was supported by the Deutsche Forschungsgemeinschaft Gr970/8-1, chILD-EU (FP7, No. 305653) and the “Else Kröner-Fresenius-Stiftung” grant 2013_A72.
Competing interests None declared.
Ethics approval Institutional Review Board (EK 026-06), chILD-EU (EK 111-13).
Provenance and peer review Not commissioned; externally peer reviewed.