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Bi-allelic missense ABCA3 mutations in a patient with childhood ILD who reached adulthood
Author(s): Manali ED, Legendre M, Nathan N et al
Digest Author(s): Manali Effrosyni, Papiris Spyridon / 18 August, 2019
Children’s interstitial lung diseases (chILD) are increasingly recognized and contain many genetic disorders mostly related to rare mutations in the surfactant protein genes and in the adenosine triphosphate (ATP)-binding cassette subfamily A member 3 (ABCA3) gene. ABCA3 is a transmembrane glycoprotein that uses energy of ATP hydrolysis to transport phospholipids into the lamellar bodies of type 2 alveolar epithelial cells and regulates lung surfactant homeostasis. Patients carrying ABCA3 mutations in a homozygous or compound heterozygous state present a great heterogeneity of phenotypes, from lethal neonatal respiratory distress syndrome (nRDS) to childhood and rarely adult interstitial lung disease (ILD).
This study reports a very rare case of a chILD patient with bi-allelic missense ABCA3 mutations who survived from childhood to adulthood. During childhood, the patient initially failed a trial with systemic corticosteroids and was treated alternatively with hydroxychloroquine with remarkable improvement attaining stabilization for 18 years. Withdrawal of hydroxychloroquine due to eye toxicity led to respiratory deterioration. Given the recent knowledge on chILD and adult ILD, the diagnosis was re-appraised histologically and the patient was further evaluated in order to look for a molecular cause of her disease. The diagnosis of ABCA3 mutation-related ILD reaching adulthood was then established. Non-progression to end-stage fibrosis was proven by a second biopsy 20 years later.
This is the first report of an ABCA3 mutation-related ILD patient with such a long-term follow-up and with two lung biopsies in a time-frame of 20 years. The study further analyses all patients reported in the literature with bi-allelic ABCA3 mutation-related ILD who survived from childhood into adulthood, comments on the available therapeutic options that so far differ significantly from those used in adult ILDs and provides further evidence that: a) children with ABCA3 mutations may survive beyond infancy and reach adulthood and b) that genetic mechanisms should always be examined in adult patients with childhood onset ILD and molecular analysis should be accordingly performed.
It highlights how important the interaction and international collaboration between pediatricians, pediatric and adult pneumonologists, radiologists, pathologists and geneticists in specialized referral centers are, for the ideal management of those patients Finally it heralds a new era where adult pneumonologists will have to undertake the care of young adults with childhood-onset ILD who survive into adulthood.