Florence Roucher-Boulez1, Delphine Mallet-Motak2, Dinane Samara-Boustani3, Houweyda Jilani2, Asmahane Ladjouze4, Pierre-François Souchon5, Dominique Simon6, Sylvie Nivot7, Claudine Heinrichs8, Maryline Ronze9, Xavier Bertagna10, Laure Groisne11, Bruno Leheup12, Catherine Naud-Saudreau13, Gilles Blondin13, Christine Lefevre14, Laetitia Lemarchand15, Yves Morel16. 1. Molecular Endocrinology and Rare DiseasesLyon University Hospital, Bron, France Claude Bernard Lyon 1 UniversityLyon, France florence.roucher@chu-lyon.fr. 2. Molecular Endocrinology and Rare DiseasesLyon University Hospital, Bron, France. 3. Pediatric Endocrinology, Gynecology and DiabetologyNecker University Hospital, Paris, France. 4. Pediatric DepartmentBab El Oued University Hospital, Alger, Algeria. 5. Pediatric Endocrinology and DiabetologyAmerican Memorial Hospital, Reims, France. 6. Pediatric EndocrinologyRobert Debré Hospital, Paris, France. 7. Department of PediatricsRennes Teaching Hospital, Rennes, France. 8. Pediatric EndocrinologyQueen Fabiola Children's University Hospital, Brussels, Belgium. 9. Endocrinology DepartmentL.-Hussel Hospital, Vienne, France. 10. Endocrinology DepartmentCochin University Hospital, Paris, France. 11. Endocrinology DepartmentLyon University Hospital, Bron-Lyon, France. 12. Paediatric and Clinical Genetic DepartmentNancy University Hospital, Vandoeuvre les Nancy, France. 13. Pediatric Endocrinology and DiabetologyBretagne Sud Hospital Center, Lorient, France. 14. Pediatric EndocrinologyJeanne de Flandre Hospital, Lille, France. 15. Pediatric DepartmentLa Rochelle-Ré-Aunis Hospital Group, La Rochelle, France. 16. Molecular Endocrinology and Rare DiseasesLyon University Hospital, Bron, France Claude Bernard Lyon 1 UniversityLyon, France.
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.
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.
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