Salt Wasting, Hydro-sodium Balance and Fludrocortisone Requirement in Congenital Adrenal Hyperplasia
Condition: Congenital Adrenal Hyperplasia (CAH)
MeSH terms: Adrenal Hyperplasia, Congenital; Adrenogenital Syndrome; Wasting Syndrome; Adrenocortical Hyperfunction; Hyperplasia; Cachexia
Study type: Observational

Summary: 
      Congenital adrenal hyperplasia (CAH) in its classic neonatal form with severe salt-wasting
      represents a challenge for pediatric endocrinologists in order to maintain sodium balance,
      especially as the physiopathology and optimal therapeutic management of this urinary salt
      loss remain poorly studied, particularly during the neonatal period.

      The human kidney presents the characteristic of being immature at birth with a functional
      tubulopathy associating sodium wasting and difficulty to concentrate urine, in connection
      with a transient renal resistance to aldosterone action, which is exacerbated in case of CAH
      by insufficiency of aldosterone production.

      The objective of project is therefore to study the secretion profiles of plasma and urinary
      steroids in neonates with classical salt-wasting form of CAH before treatment and under
      treatment with Fludrocortisone and Hydrocortisone during the first months of life, using an
      advanced technology: LC-MSMS (Liquid chromatography coupled with tandem mass spectrometry).
      The study of the existence of a correlation between plasma and urinary steroid profiles will
      also make it possible to subsequently consider simplified medical follow-up for these
      patients.

      This project will lead to a better understanding of sodium handling and steroid secretion and
      excretion profiles in CAH neonates, in order to improve the therapeutic management of
      mineralocorticoid replacement in these patients.
    

Detailed description: 
      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.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Newborns (boys and girls) diagnosed with a neonatal form of CAH and followed up in one of
        the following 5 French reference centres: Robert Debré Hospital, Paris; Necker Hospital,
        Paris; Bicêtre Hospital, Le Kremlin-Bicêtre; Trousseau Hospital, Paris; Femme-Mère-Enfant
        Hospital, Lyon.
      
Biospecimen description: 
      For blood samples, the biochemistry laboratory of each investigating centre will centrifuge
      all blood samples, collect the plasma and transfer it into a new tube on which the
      corresponding labels will be affixed.

      The tubes will be frozen at -20° C in a freezer at a specific location where the tubes with
      the same identification number (blood and urine sample from the same child) will be grouped.

      The urinary samples (H0, H48, M1, M3 and M6) collected on a gauze compress will arrive at the
      laboratory of each centre in tubes already labelled (sterile urine jar) and will be frozen
      directly at -20° C with the tubes.
    
Keywords: CAH; Salt-wasting; LC-MSMS; plasma and urine steroid profile; Fludrocortisone