title: NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects.
abstract: OBJECTIVE
  Nicotinamide nucleotide transhydrogenase (NNT), one of the several genes recently discovered in familial glucocorticoid deficiencies (FGD), is involved in reactive oxygen species detoxification, suggesting that extra-adrenal manifestations may occur, due to the sensitivity to oxidative stress of other organs rich in mitochondria. Here, we sought to identify NNT mutations in a large cohort of patients with primary congenital adrenal insufficiency without molecular etiology and evaluate the degree of adrenal insufficiency and onset of extra-adrenal damages.
  
  
  METHODS
  Sanger or massive parallel sequencing of NNT and patient monitoring.
  
  
  RESULTS
  Homozygous or compound heterozygous NNT mutations occurred frequently (26%, 13 unrelated families, 18 patients) in our cohort. Seven new mutations were identified: p.Met337Val, p.Ala863Glu, c.3G>A (p.Met1?), p.Arg129*, p.Arg379*, p.Val665Profs*29 and p.Ala704Serfs*19. The most frequent mutation, p.Arg129*, was found recurrently in patients from Algeria. Most patients were diagnosed belatedly (8-18 months) after presenting severe hypoglycemia; others experiencing stress conditions were diagnosed earlier. Five patients also had mineralocorticoid deficiency at onset. One patient had congenital hypothyroidism and two cryptorchidism. In follow-up, we noticed gonadotropic and genitalia impairments (precocious puberty, testicular inclusions, interstitial Leydig cell adenoma, azoospermia), hypothyroidism and hypertrophic cardiomyopathy. Intrafamilial phenotype heterogeneity was also observed.
  
  
  CONCLUSIONS
  NNT should be sequenced, not only in FGD, but also in all primary adrenal insufficiencies for which the most frequent etiologies have been ruled out. As NNT is involved in oxidative stress, careful follow-up is needed to evaluate mineralocorticoid biosynthesis extent, and gonadal, heart and thyroid function.
authors.affiliation: Molecular Endocrinology and Rare DiseasesLyon University Hospital, Bron, France Claude Bernard Lyon 1 UniversityLyon, France florence.roucher@chu-lyon.fr.
authors.forename: Florence
authors.initials: F
authors.lastname: Roucher-Boulez
authors.affiliation: Molecular Endocrinology and Rare DiseasesLyon University Hospital, Bron, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Mallet-Motak
authors.affiliation: Pediatric Endocrinology, Gynecology and DiabetologyNecker University Hospital, Paris, France.
authors.forename: Dinane
authors.initials: D
authors.lastname: Samara-Boustani
authors.affiliation: Molecular Endocrinology and Rare DiseasesLyon University Hospital, Bron, France.
authors.forename: Houweyda
authors.initials: H
authors.lastname: Jilani
authors.affiliation: Pediatric DepartmentBab El Oued University Hospital, Alger, Algeria.
authors.forename: Asmahane
authors.initials: A
authors.lastname: Ladjouze
authors.affiliation: Pediatric Endocrinology and DiabetologyAmerican Memorial Hospital, Reims, France.
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Souchon
authors.affiliation: Pediatric EndocrinologyRobert Debré Hospital, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Simon
authors.affiliation: Department of PediatricsRennes Teaching Hospital, Rennes, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Nivot
authors.affiliation: Pediatric EndocrinologyQueen Fabiola Children's University Hospital, Brussels, Belgium.
authors.forename: Claudine
authors.initials: C
authors.lastname: Heinrichs
authors.affiliation: Endocrinology DepartmentL.-Hussel Hospital, Vienne, France.
authors.forename: Maryline
authors.initials: M
authors.lastname: Ronze
authors.affiliation: Endocrinology DepartmentCochin University Hospital, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Bertagna
authors.affiliation: Endocrinology DepartmentLyon University Hospital, Bron-Lyon, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Groisne
authors.affiliation: Paediatric and Clinical Genetic DepartmentNancy University Hospital, Vandoeuvre les Nancy, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Leheup
authors.affiliation: Pediatric Endocrinology and DiabetologyBretagne Sud Hospital Center, Lorient, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Naud-Saudreau
authors.affiliation: Pediatric Endocrinology and DiabetologyBretagne Sud Hospital Center, Lorient, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Blondin
authors.affiliation: Pediatric EndocrinologyJeanne de Flandre Hospital, Lille, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Lefevre
authors.affiliation: Pediatric DepartmentLa Rochelle-Ré-Aunis Hospital Group, La Rochelle, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Lemarchand
authors.affiliation: Molecular Endocrinology and Rare DiseasesLyon University Hospital, Bron, France Claude Bernard Lyon 1 UniversityLyon, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Morel
mesh_terms: D000293:Adolescent; D000309:Adrenal Insufficiency / Q000151:congenital* / Q000235:genetics; D000328:Adult; D053713:Azoospermia / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D006720:Homozygote; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009250:NADP Transhydrogenases / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics*; D011629:Puberty, Precocious / Q000235:genetics; D055815:Young Adult
chemical_list: D009250:NADP Transhydrogenases