ESPE Abstracts (2016) 86 FC10.1

CYP11B1 Deficiency in Very Preterms: Evidence for an Adrenal Cortex Zone-Specific and Developmental-Dependent Maturation

Simon Traversa,c, Laetitia Martineriea,d, Pascal Boileaue,f, Marc Lombèsa,b & Eric Pussarda,c

aInserm, U1185, Le Kremlin-Bicêtre, France; bFac Med Paris-Sud, Univ Paris-Sud, Université Paris Saclay, UMR-S 1185, Le Kremlin-Bicêtre, France; cService de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Hôpital de Bicêtre, Hôpitaux Universitaires Paris Sud, Assisatance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France; dService d’Endocrinologie Pédiatrique, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, Paris, France; eService de Réanimation Néonatale, CH Poissy St-Germain en-Laye, Poissy, France; fEA 7285, UFRE des Sciences de la Santé, Simone Veil, Université Versailles St-Quentin en Yveline, Montigny le Bretonneux, France

Background: Unlike term neonates, known to exhibit a physiological pseudohypoaldosteronism, very preterms (VPT) display a high sodium waste at birth with partial aldosterone deficiency. This context, combined with a low aldosterone/renin ratio is highly suggestive of a defect in mineralocorticoid biosynthesis.

Objectives and hypotheses: To investigate mineralocorticoid and glucocorticoid pathways in newborns, and to clarify the impact of prematurity upon steroid biosynthesis at birth and during early post-natal development.

Methods: Steroidomic profiles were assessed in umbilical cord blood samples originating from 152 neonates divided into three groups: < 33 gestational weeks (GW), group 1 (46 patients), 33–37 GW, group 2 (67 patients) and ≥ 37 GW, group 3 (39 patients). Fifteen circulating corticosteroids (hormones, precursors and metabolites) were measured on <250 μl samples using a LC-MS/MS method.

Results: An aldosterone secretion deficiency at birth was demonstrated in VPT (376±137 vs 721±404 pg/ml (mean±S.D.) in group 1 and 3, respectively, P<0.0001). Likewise, aldosterone precursor levels were also decreased in VPT. A global defect in glucocorticoid secretion was also detected in VPT: cortisol (F, 16.3±21.2 vs 46.9±28.8 ng/ml, P<0.0001), as well as its precursors 11-deoxycortisol (S) and 17-hydroxyprogesterone. The activity of each biosynthesis step was evaluated by a product/substrate ratio as an index of enzymatic activity. Low corticosterone/11-deoxycorticosterone (B/DOC) and F/S ratios were consistent with a partial CYP11B1 deficiency while other product/substrate ratios were normal. Surprisingly, analyses of blood samples at 3 days of life revealed that partial CYP11B1 deficiency as estimated from B/DOC ratio was fully restored in VPT whereas F/S ratio remains altered suggesting a distinct and developmental enzymatic maturation in zona glomerulosa vs fasciculata.

Conclusion: We identify a transient global steroid deficiency at birth in VPT, related to an unrecognized partial CYP11B1 deficiency. We also provide evidence for a zone-dependent CYP11B1 maturation during the first days of life, opening new therapeutic interventions.

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