A novel homozygous insertion and review of published mutations in the NNT gene causing familial glucocorticoid deficiency (FGD)

Jazayeri, Omid; Liu, Xuanzhu; Diemen, Cleo C. van; Waarde, Willie M. Bakker-van; Sikkema‐Raddatz, Birgit; Sinke, Richard J.; Zhang, Jianguo; Ravenswaaij-Arts, Conny M. A. van

doi:10.1016/j.ejmg.2015.11.001

Cited by 31 publications

(25 citation statements)

References 27 publications

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“…FGD is a rare autosomal recessive condition with no racial predilection. Cases of the condition have been reported in white [4] , [12] , black, Indian [5] , and Middle Eastern [13] populations. To our knowledge, our patient is the first reported Chinese Han patient with FGD type 2, with a known MRAP mutation.…”

Section: Discussionmentioning

confidence: 99%

“…Affected individuals typically present with hyperpigmentation, hypoglycemic seizures, failure to thrive, failure to thrive and recurrent infections [1] . Causal mutations of FGD have been identified in MC2R [2] , MRAP [3] , MCM4 [1] , TXNRD2 [4] , STAR [5] and NNT [4] . MC2R accessory protein (MRAP), a 19-kDa single-transmembrane domain protein, is essential for trafficking of MC2R from the endoplasmic reticulum (ER) to the cell surface and subsequent signaling in response to ACTH [6] .…”

Section: Introductionmentioning

confidence: 99%

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Neonatal presentation of familial glucocorticoid deficiency with a MRAP mutation: A case report

Chen

Zhou

Fang

et al. 2016

Molecular Genetics and Metabolism Reports

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Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder in which the adrenal cortex fails to respond appropriately to stimulation by adrenocorticotropic hormone (ACTH) to produce cortisol. The disease is characterized in laboratory testing by glucocorticoid deficiency and markedly elevated ACTH levels. FGD may present in infancy or early childhood with symptoms related to low cortisol and high ACTH, such as hyperpigmentation, severe hypoglycemia, failure to thrive and recurrent infections. Mutations in the MC2R accessory protein (MRAP) cause FGD types 2, which accounts for approximately 15–20% of FGD cases. Here, we report a female neonate of Chinese Han origin, who presented with noted hyperpigmentation at birth. Laboratory investigations revealed hypocortisolaemia (cortisol < 1.0 μg/dl) and elevated plasma ACTH (1051 pg/ml). She responded to hydrocortisone treatment. Genetic studies confirmed the diagnosis showing homozygous deletion (c. 106 + 1delG) in intron 3 of MRAP gene, a mutation already reported as responsible for FDG type 2. This mutation can cause complete lack of ACTH response thus explaining the early presentation in this case. Her parents and maternal grandmother were heterozygous for the same mutation. To our knowledge, this is the first Chinese Han patient reported with FGD type 2 due to a known MRAP mutation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neonatal presentation of familial glucocorticoid deficiency with a MRAP mutation: A case report

Chen

Zhou

Fang

et al. 2016

Molecular Genetics and Metabolism Reports

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

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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“…We also found a novel pathogenic variant in the NNT gene (c.2274delT, p.I758Mfs*10). Researchers reported that 53% of patients with NNT gene variants presented with hyperpigmentation, while 17% had mineralocorticoid de ciency [27]. Cardiac and thyroid involvement may also exist [28]; therefore, a close long-term follow-up is still needed as our patient presented with only hyperpigmentation.…”

Section: Discussionmentioning

confidence: 88%

Genetic Aetiology of Primary Adrenal Insufficiency in Chinese Children

Chang

Lü

Zhao

et al. 2020

Preprint

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Background Primary adrenal insufficiency (PAI) is a life-threatening condition, and a definitive aetiological diagnosis is essential for management and prognostication. We conducted this study to investigate the genetic aetiologies of PAI in South China and explore their clinical features. Results Among the 70 children, 84.29% (59/70) were diagnosed with congenital adrenal hyperplasia (CAH), and a diagnosis of 21-hydroxylase deficiency (21-OHD) was subsequently genetically confirmed in 91.53% of the cases. Salt wasting (SW), simple virilization (SV), and non-classic (NC) CAH accounted for 66.10% (39/59), 30.51% (18/59), and 3.39% (2/59) of the cases, respectively. Interestingly, 17-hydroxyprogesterone (17-OHP) and testosterone levels in females were significantly higher than those in males among both SW and SV CAH patients. Additionally, 15.71% (11/70) of the patients were diagnosed with PAI, 72.73% (8/11) of whom had positive genetic findings. Among all the cases, two novel variants in CYP21A2, c.833dupT (p. 279GfsX17) and c.651 + 2T > G, were harboured by CAH patients. A microdeletion (Xp21.2-21.3) and five novel variants, including 2 in the NR0B1 gene (p. 108S > X, p.L411Vfs*6, c.1231_1234delCTCA, p.L411Vfs*6), 2 in the AAAS gene (c.399 + 1G > A, p.V103Afs*8, c.250delT, p.W84Gfs*10) and 1 in the NNT gene (p.I758Mfs*10), were detected. The novel variant c.399 + 1G > A in the AAAS gene was further confirmed to lead to exon 4 deletion in mRNA transcription and produce a truncated ALADIN protein. Conclusions We found ethnic differences in the CYP21A2 gene variant spectrum among different study populations. Female 21-OHD patients tended to have higher 17-OHP and testosterone levels, which warrants caution in relation to the virilization effect both physically and psychologically. Novel gene variants detected in the CYP21A2, NR0B1, AAAS and NNT genes expanded the genetic spectrum of paediatric PAI; however, further improvement of genetic testing tools beyond our protocol is still needed to uncover the complete aetiology of PAI in children.

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A novel homozygous insertion and review of published mutations in the NNT gene causing familial glucocorticoid deficiency (FGD)

Cited by 31 publications

References 27 publications

Neonatal presentation of familial glucocorticoid deficiency with a MRAP mutation: A case report

Neonatal presentation of familial glucocorticoid deficiency with a MRAP mutation: A case report

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

Genetic Aetiology of Primary Adrenal Insufficiency in Chinese Children

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