Combined adrenal failure and testicular adrenal rest tumor in a patient with nicotinamide nucleotide transhydrogenase deficiency

Hershkovitz, Eli; Arafat, Maram; Loewenthal, Neta; Haim, Alon; Parvari, Ruti

doi:10.1515/jpem-2015-0075

Cited by 14 publications

(16 citation statements)

References 5 publications

(8 reference statements)

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“…4A). This is in accordance with the literature, where the minimum NNT, adrenal and extra-adrenal defects age at diagnosis is 3 days (12) and the median age at onset is 12 months for the 29 patients for whom data are available (9,11,12,13,15,16). Unlike the data by Jazayeri et al (2015), our data suggest earlier onset in patients with global adrenal deficiency compared with those with isolated glucocorticoid deficiency ( Fig.…”

Section: Discussionsupporting

confidence: 93%

“…Two of our patients had cryptorchidism (patients 11a and b) and two others (7 and 9) presented similar histories involving, both at about 5 years of age, the development of palpable nodules on the testicular surface or testicular enlargement followed by the onset of puberty with high testosterone levels. These last two cases are comparable to that reported by Hershkovitz et al (13). For our patients 7 and 9, gonadotropins were in the normal pre-pubertal range and the increase in testosterone seemed to be due to secretion by autonomous nodules responsible for the onset of puberty.…”

Section: Discussionsupporting

confidence: 91%

“…It is clear that NNT mutations can result in global adrenal deficiency. In the literature and comparably to 14 of our patients, 5 families were recently described with mineralocorticoid deficiency present at onset and 3 others with elevated renin or electrolyte imbalance (11,12,13,16). Our patient 3 had salt wasting at age 15, although aldosterone requirements normally decrease throughout life (30).…”

Section: Discussionsupporting

confidence: 67%

“…Since the regression of puberty for patient 9 was due to either the removal of the adenoma or the short GNRH analog treatment, we cannot pronounce as to the central, peripheral or mixed origin of the precocious puberty. Reporting on a boy with a mutation in DAX-1/ NR0B1, Domenice et al (32) concluded that chronic excessive ACTH levels may stimulate Leydig cells and lead to gonadotropin-independent precocious puberty, a view shared by Hershkovitz et al (13) as well. In contrast, the testicular inclusions of our patient 12, associated with azoospermia but normal testosterone values at age 18, although not reduced by glucocorticoid therapy, should be TART, often found in congenital adrenal hyperplasia (33).…”

Section: Discussionmentioning

confidence: 98%

“…Twelve more families have been reported (12 additional mutations), some with mineralocorticoid defects (11,12,13,14,15,16).…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 98%

“…Twelve more families have been reported (12 additional mutations), some with mineralocorticoid defects (11,12,13,14,15,16).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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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Three‐Dimensional Model of Human Nicotinamide Nucleotide Transhydrogenase (NNT) and Sequence‐Structure Analysis of its Disease‐Causing Variations

et al. 2016

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Defective mitochondrial proteins are emerging as major contributors to human disease. Nicotinamide nucleotide transhydrogenase (NNT), a widely expressed mitochondrial protein, has a crucial role in the defence against oxidative stress. NNT variations have recently been reported in patients with familial glucocorticoid deficiency (FGD) and in patients with heart failure. Moreover, knockout animal models suggest that NNT has a major role in diabetes mellitus and obesity. In this study, we used experimental structures of bacterial transhydrogenases to generate a structural model of human NNT (H‐NNT). Structure‐based analysis allowed the identification of H‐NNT residues forming the NAD binding site, the proton canal and the large interaction site on the H‐NNT dimer. In addition, we were able to identify key motifs that allow conformational changes adopted by domain III in relation to its functional status, such as the flexible linker between domains II and III and the salt bridge formed by H‐NNT Arg882 and Asp830. Moreover, integration of sequence and structure data allowed us to study the structural and functional effect of deleterious amino acid substitutions causing FGD and left ventricular non‐compaction cardiomyopathy. In conclusion, interpretation of the function–structure relationship of H‐NNT contributes to our understanding of mitochondrial disorders.

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Disorders of Niacin, NAD, and Pantothenate Metabolism

Ardissone

Diodato

Meo

et al. 2022

Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases

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Combined adrenal failure and testicular adrenal rest tumor in a patient with nicotinamide nucleotide transhydrogenase deficiency

Abstract: We demonstrated for the first time that the clinical spectrum of NNT deficiency may consist of mineralocorticoid deficiency and testicular involvement as well.

Cited by 14 publications

References 5 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

Three‐Dimensional Model of Human Nicotinamide Nucleotide Transhydrogenase (NNT) and Sequence‐Structure Analysis of its Disease‐Causing Variations

Disorders of Niacin, NAD, and Pantothenate Metabolism

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