Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Giacche M

PROVIDER: S-EPMC10094083 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Giacché Mara M Panarotto Alessandra A Mori Luigi L Poliani Pietro Luigi PL Lanzi Roberto R Lena Marco Schiavo MS Castellano Maurizio M

Molecular genetics & genomic medicine 20230202 4

<h4>Background</h4>To perform genetic screening for ARMC5 gene germline pathogenic variants in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH).<h4>Subjects and methods</h4>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.<h4>Results</h4>Among 10 PBMAH patients, we identified fo ...[more]

PMID: 36727580

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Project description:ContextRadiological characterization of adrenal size in primary bilateral macronodular adrenocortical hyperplasia (PBMAH) has not been previously investigated.ObjectiveWe hypothesized that volumetric modeling of adrenal gland size may correlate with biochemical disease severity in patients with PBMAH. Secondary analysis of patients with concurrent primary aldosteronism (PA) was performed.DesignA retrospective cross-sectional analysis of 44 patients with PBMAH was conducted from 2000 to 2019.SettingTertiary care clinical research center.PatientsPatients were diagnosed with PBMAH based upon clinical, genetic, radiographic and biochemical characteristics.InterventionClinical, biochemical, and genetic data were obtained. Computed tomography scans were used to create volumetric models by manually contouring both adrenal glands in each slice using Vitrea Core Fx v6.3 software (Vital Images, Minnetonka, Minnesota).Main outcome and measures17-hydroxycorticosteroids (17-OHS), ARMC5 genetics, and aldosterone-to-renin ratio (ARR) were retrospectively obtained. Pearson test was used for correlation analysis of biochemical data with adrenal volume.ResultsA cohort of 44 patients with PBMAH was evaluated, with a mean age (±SD) of 53 ± 11.53. Eight patients met the diagnostic criteria for PA, of whom 6 (75%) were Black. In the Black cohort, total adrenal volumes positively correlated with midnight cortisol (R = 0.76, P = 0.028), urinary free cortisol (R = 0.70, P = 0.035), and 17-OHS (R = 0.87, P = 0.0045), with a more pronounced correlation with left adrenal volume alone. 17-OHS concentration positively correlated with total, left, and right adrenal volume in patients harboring pathogenic variants in ARMC5 (R = 0.72, P = 0.018; R = 0.65, P = 0.042; and R = 0.73, P = 0.016, respectively).ConclusionsVolumetric modeling of adrenal gland size may associate with biochemical severity in patients with PBMAH, with particular utility in Black patients.

Project description:BackgroundPrimary bilateral macronodular adrenal hyperplasia is a rare cause of Cushing's syndrome characterized by the presence of bilateral secretory adrenal nodules. Recent studies have shown that primary bilateral macronodular adrenal hyperplasia is caused by combined germline and somatic mutations of the ARMC5 gene. Exophthalmos is an underappreciated sign of Cushing's syndrome.Case presentationA 52-year-old Chinese woman with progressively worsening bilateral proptosis presented to our hospital. Subsequently she was diagnosed as having primary bilateral macronodular adrenal hyperplasia and underwent bilateral laparoscopic adrenalectomy. Genomic deoxyribonucleic acid was isolated from lymphocytes as well as seven different adrenal nodules and the ARMC5 sequence was determined by Sanger sequencing. We identified one heterozygous ARMC5 germline mutation c.682C>T (p. Gln228*) and five heterozygous somatic mutations (c.310delG, c.347_357del11, c.267delC, c.283_289del7, and c.205-322del118) in five different adrenal nodules. All mutations are novel and were not found in any of the available online databases. To test whether the ARMC5 mutation induced messenger ribonucleic acid decay, real-time reverse transcriptase polymerase chain reaction was performed on patient and control adrenal tissue. We found that the adrenal cortex of our patient showed a low ARMC5 messenger ribonucleic acid expression compared with normal adrenal cortex, possibly as a result of nonsense-mediated messenger ribonucleic acid decay CONCLUSIONS: We demonstrated extensive genetic diversity of ARMC5 in a patient with primary bilateral macronodular adrenal hyperplasia that started with exophthalmos, which contributes to further understanding of the pathogenesis of this disease. Early recognition of atypical symptoms and screening for ARMC5 mutation in patients with primary bilateral macronodular adrenal hyperplasia has important clinical implications for the diagnosis and genetic counseling.

Dataset Information

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

Background

Subjects and methods

Results

Conclusions

Publications

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

Similar Datasets

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