A Novel Entity of Clinically Isolated Adrenal Insufficiency Caused by a Partially Inactivating Mutation of the Gene Encoding for P450 Side Chain Cleavage Enzyme (CYP11A1)

Parajes, Silvia; Kamrath, Clemens; Röse, I; Taylor, Angela E.; Mooij, Christiaan F.; Dhir, Vivek; Grötzinger, Joachim; Arlt, Wiebke; Krone, Nils

doi:10.1210/jc.2011-1277

Cited by 53 publications

(48 citation statements)

References 32 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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“…Nonclassic CYP11A1 deficiency has been described in nearly a dozen cases where residual enzymatic activity was maintained in in vitro assays [64-67]. Good correlation between clinical phenotype and residual enzyme activity has been reported [67].…”

Section: Monogenic Disorders Of Adrenal Steroidogenesismentioning

confidence: 99%

“…Good correlation between clinical phenotype and residual enzyme activity has been reported [67]. Similar to nonclassic StAR deficiency, patients can present with late-onset adrenal insufficiency manifesting in early to mid-childhood with variable degrees of sex steroid deficiency [66].…”

Section: Monogenic Disorders Of Adrenal Steroidogenesismentioning

confidence: 99%

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Monogenic Disorders of Adrenal Steroidogenesis

2018

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Disorders of adrenal steroidogenesis comprise autosomal recessive conditions affecting steroidogenic enzymes of the adrenal cortex. Those are located within the 3 major branches of the steroidogenic machinery involved in the production of mineralocorticoids, glucocorticoids, and androgens. This mini review describes the principles of adrenal steroidogenesis, including the newly appreciated 11-oxygenated androgen pathway. This is followed by a description of pathophysiology, biochemistry, and clinical implications of steroidogenic disorders, including mutations affecting cholesterol import and steroid synthesis, the latter comprising both mutations affecting steroidogenic enzymes and co-factors required for efficient catalysis. A good understanding of adrenal steroidogenic pathways and their regulation is crucial as the basis for sound management of these disorders, which in the majority present in early childhood.

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“…Affected children typically present with life-threatening adrenal insufficiency in early infancy, and males appear phenotypically female due to impaired testicular androgen synthesis in utero. Nonclassic forms of both lipoid CAH and P450scc deficiency have been described, presenting with late-onset isolated glucocorticoid insufficiency and normal external genitalia 23–26 .…”

Section: Congenital Adrenal Hyperplasia-brief Overviewmentioning

confidence: 99%

The next 150 years of congenital adrenal hyperplasia

Turcu

Auchus

2015

The Journal of Steroid Biochemistry and Molecular Biology

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Congenital adrenal hyperplasias (CAH) are a group of autosomal recessive defects in cortisol biosynthesis. Substantial progress has been made since the description of the first report, 150 years ago. This article reviews some of the recent advances in the genetics, diagnosis and treatment of CAH. In addition, we underline the aspects where further progress is required, including, among others, better diagnostic modalities for the mild phenotype and for some of the rare forms of disease, elucidation of epigenetic factors that lead to different phenotypes in patients with identical genotype and expending on treatment options for controlling the adrenal androgen excess.

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A Novel Entity of Clinically Isolated Adrenal Insufficiency Caused by a Partially Inactivating Mutation of the Gene Encoding for P450 Side Chain Cleavage Enzyme (CYP11A1)

Abstract: We provide the first evidence that partial CYP11A1 deficiency has to be considered as a differential diagnosis in clinically isolated adrenal insufficiency. Our assays demonstrate a tighter genotype-phenotype correlation in CYP11A1 deficiency than previous in vitro studies.

Cited by 53 publications

References 32 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

Monogenic Disorders of Adrenal Steroidogenesis

The next 150 years of congenital adrenal hyperplasia

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