Macronodular Adrenal Hyperplasia due to Mutations in an Armadillo Repeat Containing 5 (<i>ARMC5</i>) Gene: A Clinical and Genetic Investigation

Faucz, Fábio R.; Zilbermint, Mihail; Lodish, Maya; Szarek, Eva; Trivellin, Giampaolo; Sinaii, Ninet; Berthon, Annabel; Libé, Rossella; Assié, Guillaume; Espiard, Stéphanie; Drougat, Ludivine; Ragazzon, Bruno; Bertherat, Jérôme; Stratakis, Constantine A.

doi:10.1210/jc.2013-4280

Cited by 134 publications

(121 citation statements)

References 22 publications

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“…Similarly, pathogenic ARMC5 mutations were found in a second cohort of 34 apparently sporadic cases of BMAH with CS with a prevalence of 20.6% (19) and very recently ARMC5-damaging mutations were identified in 24/98 (26%) index cases of BMAH (20). Furthermore, we and others identified causal germline ARMC5 mutations in six families with BMAH (21,22,23).…”

Section: Introductionsupporting

confidence: 71%

“…Very recently, Ebelt et al (22) described a German family with a heterozygous c.323_324insC ARMC5 mutation which is the same mutation that we report here, although according to the recommendations by the Human Genome Variation Society, it should be preferentially named c.327_328insC. In contrast to studies on sporadic cases (18,19), we had access to only two BMAH tissues and found a second additional somatic ARMC5 mutation in the BMAH tissue as reported by Gagiardi et al (23). In addition to the causative germline mutation, we found a second germline heterozygous A705V ARMC5 alteration in the daughter who presented a very early onset of severe BMAH (even though a second somatic mutation was not found); although this latest genetic alteration reported as a gene polymorphism (rs11150624) does not affect the main ARMC5 transcript but instead the ARMC5 isoform b precursor, it is intriguing that an isolated non-damaging alteration of a potential ARMC5 transcript accelerates the clinical evolution of the disease.…”

Section: European Journal Of Endocrinologysupporting

confidence: 58%

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ARMC5 mutations in a large French-Canadian family with cortisol-secreting β-adrenergic/vasopressin responsive bilateral macronodular adrenal hyperplasia

Bourdeau

Oble²,

Magne³

et al. 2016

European Journal of Endocrinology

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Background: Bilateral macronodular adrenal hyperplasia (BMAH) is a rare cause of Cushing's syndrome (CS) and its familial clustering has been described previously. Recent studies identified that ARMC5 mutations occur frequently in BMAH, but the relation between ARMC5 mutation and the expression of aberrant G-protein-coupled receptor has not been examined in detail yet. Methods: We studied a large French-Canadian family with BMAH and sub-clinical or overt CS. Screening was performed using the 1-mg dexamethasone suppression test (DST) in 28 family members. Screening for aberrant regulation of cortisol by various hormone receptors were examined in vivo in nine individuals. Sequencing of the coding regions of ARMC5 gene was carried out. Results: Morning ambulating cortisol post 1 mg DST were O50 nmol/l in 5/8 members in generation II (57-68 years old), 9/22 in generation III (26-46 years old). Adrenal size was enlarged at different degrees. All affected patients increased cortisol following upright posture, insulin-induced hypoglycemia and/or isoproterenol infusion. b-blockers led to the reduction of cortisol secretion in all patients with the exception of two who had adrenalectomies because of b-blockers intolerance. We identified a heterozygous germline variant in the ARMC5 gene c.327_328insC, (p.Ala110Argfs*9) in nine individuals with clinical or subclinical CS, in four out of six individuals with abnormal suppression to dexamethasone at initial investigation and one out of six individuals with current normal clinical screening tests. Conclusions: Systematic screening of members of the same family with hereditary BMAH allows the diagnosis of unsuspected subclinical CS associated with early BMAH. The relation between the causative ARMC5 mutation and the reproducible pattern of aberrant b-adrenergic and V 1 -vasopressin receptors identified in this family remains to be elucidated.

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Section: Introductionsupporting

confidence: 71%

Section: European Journal Of Endocrinologysupporting

confidence: 58%

ARMC5 mutations in a large French-Canadian family with cortisol-secreting β-adrenergic/vasopressin responsive bilateral macronodular adrenal hyperplasia

Bourdeau

Oble²,

Magne³

et al. 2016

European Journal of Endocrinology

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“…Subsequently, two studies have confirmed that ARMC5 mutations are frequent in PBMAH. ARMC5 mutations were reported in almost 25% of PBMAH index cases in theses series, which include operated as well as non-operated patients (9,40).…”

Section: Armadillo Repeat Containing 5 the Main Genetic Cause Of Pbmahmentioning

confidence: 90%

“…CS in PBMAH is often mild and insidious, even if serious forms can be encountered. PBMAH seems to be predominant in females as observed with other causes of CS (9,10,11). Finally, the exact prevalence of PBMAH in the general population is unknown and dependent of the diagnosis criteria.…”

Section: Introductionmentioning

confidence: 87%

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Genetics of primary bilateral macronodular adrenal hyperplasia: a model for early diagnosis of Cushing's syndrome?

Drougat

Espiard

Bertherat

2015

European Journal of Endocrinology

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Long-term consequences of cortisol excess are frequent despite appropriate treatment after cure of Cushing's syndrome. This might be due to diagnostic delay, often difficult to reduce in rare diseases. The identification of a genetic predisposing factor might help to improve early diagnosis by familial screening. Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Hypercortisolism in PBMAH is most often diagnosed between the fifth and sixth decades of life. The bilateral nature of the adrenocortical tumors and the occurrence of rare clear familial forms suggest a genetic origin. Indeed, a limited subset of PBMAH can be observed as part of multiple tumors syndromes due to alterations of the APC, Menin or Fumarate Hydratase genes. Rare variants of the phosphodiesterases PDE11A have been associated with PBMAH. The recent identification of ARMC5 germline alterations in 25-50% of PBMAH patients without obvious familial history or associated tumors opens new perspectives. ARMC5 alterations follow the model of a tumor suppressor gene: a first germline inactivating mutation of this 16p located gene is followed by a somatic secondary hit on the other allele (inactivating mutation or allelic loss). Functional studies demonstrate that ARMC5 controls apoptosis and steroid synthesis. The phenotype of index cases patients with the mutation seems more severe than the one of WT index cases. However, phenotype variability within a family is often observed. This review summarizes the genetics of PBMAH, focusing on ARMC5, which offer new perspectives for early diagnosis of Cushing's syndrome.

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New pathogenic variants in ARMC5 gene in a series of Italian patients affected by primary bilateral macronodular adrenocortical hyperplasia (PBMAH)

Giacchè

Panarotto

Mori

et al. 2023

Molec Gen & Gen Med

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Background To perform genetic screening for ARMC5 gene germline pathogenic variants in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH). Subjects and Methods In a group of 10 PBMAH patients, we performed complete sequencing of the coding region of the ARMC5 gene and MLPA analysis for large deletion detection. In subjects with the ARMC5 variant, we searched ARMC5 gene somatic variants on tumor samples. Results Among 10 PBMAH patients, we identified four ARMC5 germline variants (40%). One variant, c:174dupC p.Glu59Argfs*44, was already known; one variant p.Gly323Asp, was already reported and classified as likely disease‐causing VUS (class 3–4); two variants p.Leu596Arg and p.Arg811Pro, were never reported before. For p.Gly323Asp and p.Arg811Pro, we identified second deleterious variants at the somatic level, enforcing the possible pathogenic effect of germline variants. Conclusions Our results underscore the importance of performing genetic testing also in sporadic PBMAH patients and broaden the spectrum of molecular variants involved in PBMAH syndrome.

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Macronodular Adrenal Hyperplasia due to Mutations in an Armadillo Repeat Containing 5 (ARMC5) Gene: A Clinical and Genetic Investigation

Abstract: ARMC5 mutations are implicated in clinically severe Cushing's syndrome associated with MAH. Knowledge of a patient's ARMC5 status has important clinical implications for the diagnosis of Cushing's syndrome and genetic counseling of patients and their families.

Cited by 134 publications

References 22 publications

ARMC5 mutations in a large French-Canadian family with cortisol-secreting β-adrenergic/vasopressin responsive bilateral macronodular adrenal hyperplasia

ARMC5 mutations in a large French-Canadian family with cortisol-secreting β-adrenergic/vasopressin responsive bilateral macronodular adrenal hyperplasia

Genetics of primary bilateral macronodular adrenal hyperplasia: a model for early diagnosis of Cushing's syndrome?

New pathogenic variants in ARMC5 gene in a series of Italian patients affected by primary bilateral macronodular adrenocortical hyperplasia (PBMAH)

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