Nonclassic Lipoid Congenital Adrenal Hyperplasia Masquerading as Familial Glucocorticoid Deficiency

Metherell, Louise A.; Naville, Danielle; Halaby, G.; Bégeot, Martine; Huebner, Angela; Nürnberg, Gudrun; Nürnberg, Peter; Green, Jane; Tomlinson, Jeremy W.; Krone, Nils; Lin, Lin; Racine, Michael S.; Berney, Daniel M.; Achermann, John C.; Arlt, Wiebke; Clark, Adrian

doi:10.1210/jc.2009-0467

Cited by 143 publications

(121 citation statements)

References 19 publications

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“…Patients present episodes of hypoglycemia in the neonatal period or early childhood with low or unquantifiable cortisol, elevated ACTH levels, and normal aldosterone and plasma renin measurements. Until 2012, only a half of FGD cases could be explained by homozygous or compound heterozygous mutations in genes involved in the steroidogenic pathway: MC2R (25%), MRAP (20%), STAR (5%), and more rarely CYP11A1 (3,4,5,6,7). Over the last 3 years, thanks to whole exome sequencing, three more causative genes have been discovered: mini chromosome maintenance deficient 4 homolog (MCM4), nicotinamide nucleotide transhydrogenase (NNT) and thioredoxin reductase 2 (TXNRD2) (8,9,10).…”

Section: Introductionmentioning

confidence: 99%

NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects

Roucher‐Boulez

Mallet-Motak

Samara-Boustani³

et al. 2016

European Journal of Endocrinology

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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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Section: Introductionmentioning

confidence: 99%

NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects

Roucher‐Boulez

Mallet-Motak

Samara-Boustani³

et al. 2016

European Journal of Endocrinology

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“…This observation indicates that although germ cells follow a different lineage than steroidogenic cells of the testis, endogenous testosterone production is required for normal germ cell evolution and maintenance. It must be mentioned that testicular biopsy in a 36-year-old male with mild STAR gene mutation, investigated for infertility, showed partial atrophy with interstitial fibrosis, many Reincke crystalloids (confirming the presence of Leydig cells), and reduced spermatogenesis (12). In a 15-year-old patient (23), a carcinoma in situ was detected in the excised testis.…”

Section: Discussionmentioning

confidence: 94%

“…There have been cases, however, characterized by late onset of adrenal failure and normal male genitalia (10,11) or by a phenotype that could be misinterpreted as familial glucocorticoid deficiency (12,13).…”

Section: Introductionmentioning

confidence: 99%

Long-term clinical data and molecular defects in the STAR gene in five Greek patients

Sertedaki

Dracopoulou²,

Voutetakis³

et al. 2013

European Journal of Endocrinology

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Context: Steroidogenic acute regulatory (STAR) gene mutations lead to adrenal and gonadal failure. Interesting, though as yet unexplained, features are the formation of ovarian cysts and the potential presence of CNS findings. Objective: To report biochemical, genetic, and long-term clinical data in five Greek patients from four different families with STAR gene defects (three 46,XX and two 46,XY). Methods and results: All patients presented in early infancy with adrenal insufficiency. The STAR gene mutation c.834del11bp, detected in three of our patients, completely alters the carboxyl end of the STAR protein and has not thus far been described in other population groups. These three patients belong to three separate families, possibly genetically related, as they live in different villages located in a small region of a Greek island. However, their interrelationship has not been proven. A second mutation, p.W250X, detected in our fourth family, was previously described only in two Serbian patients. Ovarian cysts were detected ultrasonographically in our 46,XX patients and seemed to respond to a low dose of a contraceptive. The histology of an excised ovarian cyst was diagnosed as a corpus luteum (CL) cyst. In two out of the four patients who had undergone brain magnetic resonance imaging, asymptomatic Chiari-1 malformation was observed. Conclusions: The occurrence of STAR gene mutation c.834del11bp in three families living in a restricted geographic region could indicate either a founder effect or simply reflect a spread of this defect in a highly related population. The ovarian histological findings suggest that ovarian cysts detected ultrasonographically in 46,XX individuals with STAR gene defects may be CL cysts. The Chiari-1 malformation in two of our patients may be part of the STAR gene mutation phenotype. Nevertheless, more data are needed to confirm or disprove the existence of specific CNS pathology in patients with STAR gene mutations.

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“…This is a rare, lifethreatening autosomal recessive disorder of adrenal resistance to ACTH wherein affected individuals have low serum levels of cortisol despite the presence of extremely high circulating levels of plasma ACTH. Patients typically present within a few months www.frontiersin.org (Metherell et al, 2009;Hughes et al, 2010;Meimaridou et al, 2012). The classical presentation of FGD comprises isolated perturbation of the glucocorticoid axis; however, a small number of cases have been described where this is accompanied by a disorder of mineralocorticoid secretion (Lin et al, 2007;Chan et al, 2009a (Metherell et al, 2005).…”

Section: Mc2rmentioning

confidence: 99%

“…The classical presentation of FGD comprises isolated perturbation of the glucocorticoid axis; however, a small number of cases have been described where this is accompanied by a disorder of mineralocorticoid secretion (Lin et al, 2007;Chan et al, 2009a (Metherell et al, 2005). Mutations in steroidogenic acute regulatory (STAR) protein are known to give rise to lipoid congenital adrenal hyperplasia, a severe form of adrenal insufficiency characterized by both glucocorticoid and mineralocorticoid deficiency together with gonadal deficiency; however, STAR mutations have also been identified in a number of patients with FGD suggesting that mutations in this gene can give rise to a spectrum of clinical phenotypes encompassing FGD (Metherell et al, 2009). Recently, mutations in nicotinamide nucleotide transhydrogenase (NNT) a mitochondrial membrane constituent which is involved in detoxification of reactive oxygen species were also associated with FGD .…”

Section: Mc2rmentioning

confidence: 99%

Melanocortin receptors and their accessory proteins

Cooray

Clark

2011

Molecular and Cellular Endocrinology

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Nonclassic Lipoid Congenital Adrenal Hyperplasia Masquerading as Familial Glucocorticoid Deficiency

Cited by 143 publications

References 19 publications

NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects

NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects

Long-term clinical data and molecular defects in the STAR gene in five Greek patients

Melanocortin receptors and their accessory proteins

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