Salt Wasting, Hydro-sodium Balance and Fludrocortisone Requirement in Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia in its severe salt-wasting form is a challenge in order to maintain sodium balance. The pathophysiology of this impaired sodium balance is still poorly investigated as well as its therapeutic management, notably in the neonatal period. Consensus practice guidelines have been established for hydrocortisone replacement therapy, in order to maintain negative feedback on the pituitary-adrenal axis to prevent from virilization and excessive growth velocity. However, mineralocorticoid substitution and sodium supplementation is currently empirically adapted based on weight gain and renin levels. There is significant need for improvement of this essential part of CAH treatment. Particularly, CAH patients have higher risk of adverse cardio-vascular outcomes, which could relate to an excessive glucocorticoid and/or mineralocorticoid exposure in early infancy rather than to the genotype of the patient.

A clinical human study in classical CAH neonates, using Liquid Chromatography coupled to tandem Mass Spectrometry LC-MS/MS technology will assess prospectively plasma and urinary steroid profiling (precursors and substitute hormones, notably Fludrocortisone dosages) during the first six months of life, before and under treatment; and in correlation with genotype.

Thirty neonates (boys and girls) diagnosed with a severe form of CAH and followed in one of the 5 following French reference tertiary centers: Robert Debré Hospital, Paris; Necker Hospital, Paris; Bicetre Hospital, Le Kremlin-Bicetre; Trousseau Hospital, Paris; Lyon Hospital, , will be included in the study and will be followed for a period of six months. The duration of inclusion will be 24 months.

Genotyping will be processed for all children in Lyon.This project will lead to a better understanding of sodium handling and steroid secretion and excretion profiles in CAH neonates, in order to improve management of mineralocorticoid replacement.

Inclusion criteria

• Newborns with confirmation or strong suspicion of diagnosis of congenital adrenal hyperplasia:
• Newborns with abnormal differentiation of the external genitalia, without palpable gonad at birth and high 17 OHP plasma level
• Newborns diagnosed with antenatal CAH,
• Newborns diagnosed at birth with CAH (due to parents at risk of transmission of the disease),
• Newborns diagnosed by systematic screening for 17 OHP on the 3rd day of life (thus having a high dosage of 17 OHP), confirmed by a second sample.

For all these patients the diagnosis of CAH will have to be confirmed secondarily by molecular biology.

Exclusion criteria

• Newborn with an anomaly of sexual differentiation from another origin,
• Newborn already under treatment with Fludrocortisone and/or Hydrocortisone.