Novel ARMC5 mutations in primary bilateral macronodular adrenal hyperplasia: a family report

doi:10.21203/rs.3.rs-4320615/v1

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Case Report

Novel ARMC5 mutations in primary bilateral macronodular adrenal hyperplasia: a family report

https://doi.org/10.21203/rs.3.rs-4320615/v1

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Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of overt Cushing's syndrome (CS), which usually manifests as bilateral macronodular adrenal nodules and varying levels of cortisol secretion. Previous studies have shown that ARMC5 gene belongs to tumor suppressor gene, and its germline variants play a huge role in the occurrence of PBMAH, which may be inherited to family members and lead to more severe clinical symptoms. ARMC5 variants may be associated with meningiomas, which is also illustrated by our report. In addition, our discovery of a new mutation site in a family can also provide new targets and new directions for the study of PBMAH patients with ARMC5 mutations, and can also deepen clinicians' understanding of this disease.

Primary bilateral macronodular adrenal hyperplasia

Cushing's syndrome

ARMC5 gene

meningiomas

Patients with PBMAH have different levels of cortisol secretion, which can lead to asymptomatic, subclinical and overt CS. Patients with overt CS only account for about 2%-6.2% of all CS patients^{[1, 2]}. Therefore, the clinical manifestations of patients with PBMAH are not typical, and accurate diagnosis is difficult. Patients are often diagnosed because of the discovery of bilateral adrenal incidental tumors or the clinical manifestations of cortisol excess.

The pathogenesis of PBMAH has not been well studied. Abnormal expression of membrane G protein-coupled receptors, abnormal activation of cAMP/PKA and wnt/ b-catenin signaling pathways, and inappropriat autonomous or paracrine secretion of ACTH are all possible mechanisms of nodule development and hormone dysregulation^[3]. Pathogenic variants in ARMC5 are responsible for 20–25% of PBMAH^[4]. ARMC5 (armadillo repeatcontaining 5) is a protein that contains an armadillo (ARM) domain that contains multiple ARM repeats at its middle end and a BTB domain at its c terminus. Studies have shown that ARMC5 is a part of RPB1-specific ubiquitin ligase, which is related to adrenal hyperplasia. Gene mutation of ARMC5 can lead to changes in degradation of ARMC5 by proteasome, thereby affecting the above mechanisms and causing PBMAH^{[3, 5]}. In addition to ARMC5 germline mutations, somatic mutations are frequently detected in patients with PBMAH, which supports ARMC5 as a "double-hit" model of tumor suppressor gene. A second somatic mutation or second hit may induce tumorigenesis or promote greater nodule progression^[6].

PBMAH with ARMC5 mutation may have an autosomal dominant mode of inheritance, but the penetrance is incomplete^[7]. Here, we report a PBMAH family with ARMC5 mutation, in which two family members had meningioma, and the inheritance pattern was also an autosomal dominant inheritance pattern.

A 41-year-old male patient was admitted to the hospital due to multiple bilateral adrenal nodules. He had a history of hypertension for more than 10 years, and was currently treated with irbesartan and hydrochlorothiazide tablets. Physical examination showed thin dry skin, central obesity, multiple ecchymosis, and facial redness and swelling. After admission, enhanced CT examination of the adrenal gland showed that the shape of bilateral adrenal glands was irregular, and multiple cyst-like low- density shadows with bed-like changes were seen locally, which was considered as multiple nodular hyperplasia. Laboratory tests showed that the patient had abnormal cortisol rhythm, increased cortisol secretion, and decreased adrenocorticotropic hormone secretion(Fig. 1). The patient's father had been diagnosed with adrenal hyperplasia and pituitary tumor, which was treated surgically, and his mother died of an accident. Based on the results of various examinations and clinical manifestations, we diagnosed the patient as PBMAH.

Further examination was performed. Pituitary magnetic resonance imaging (MRI) showed a possible microadenoma and meningioma. Laboratory tests showed increased secretion of parathyroid hormone, progesterone and prolactin. After consideration, total adrenalectomy on the larger left side was performed. Pathology reported a left adrenal cortical adenoma, multifocal, 2cm to 3cm in diameter. Immunohistochemical results: CK (-), CgA (-), Syn (-), Vim (+), Melan-A (+), Ki67 (+ 1%), Inhibinα (+).

Molecular analysis of DNA extracted from the patient's peripheral blood revealed a heterozygous mutation, NM_0011052472:c.943C > T (p.Arg315Trp), at chr16: 31473811, in the ARMC5 gene, which was classified as likely pathogenic. To our knowledge, this variant site has not been reported previously. Subsequently, we performed genetic testing on his father, brother and two daughters, and found that the father and one of the daughters had the same gene mutation(Fig. 2). The daughter was doing well, with no manifestations of disease, but required active monitoring(Fig. 3).

PBMAH is a heterogeneous disease with a variety of clinical, hormonal, and imaging manifestations. Although sporadic cases are relatively common, it has also been linked to genetic syndromes such as multiple endocrine neoplasia type 1 (MEN1), familial adenomatous polyposis (FAP), or hereditary leiomyomatosis and renal cell carcinoma (HLRCC)^[8]. Interestingly, the most common clinical manifestation of MEN1 is parathyroid hyperplasia/adenoma with an estimated penetrance of 90%, and the penetrance of pituitary adenoma is 30–40%. Patients can also present with meningioma, similar to the clinical presentation of the case reported here. Therefore, some scholars have found that 76 (68.4%) of 111 patients with sporadic neuroendocrine tumors (spNETs) or multiple endocrine tumors type 1 (MEN1) carry ARMC5 germline variants, and concluded that ARMC5 variants may play a role in the phenotype of spNETs or MEN1 patients^[9]. The relationship between them needs to be further studied.

ARMC5 germline mutations are responsible for the majority of familial cases of PBMAH, while the ARMC5 mutation rate is approximately 20%-25% in sporadic cases of PBMAH. ARMC5 variants are present in 55% of PBMAH patients with severe CS^[10]. Through comparison and research, scholars have confirmed that the condition of most patients with ARMC5 mutations is more obvious than that of PBMAH patients without mutations, including cortisol secretion, adrenal morphology and metabolic complications^[4].

Cavalcante et al. cultured ARMC5-silenced PBMAH cells and found that their steroidogenic enzyme gene expression was reduced and their proliferation ability was enhanced^[11]. This suggests that ARMC5 inactivation leads to hyperplasia of adrenal tissue with a large increase in the total number of cells. Although the ability of the cells to produce steroids is reduced, the increase in the number of cells results in steroid overproduction. This may also explain why patients show no clinical signs in the early stages and are not detected until they are between the ages of 40 and 70^[12].

In conclusion, screening of family members of PBMAH patients with ARMC5 germline mutations and active monitoring of family members carrying ARMC5 variants are recommended, and relevant examinations should include brain imaging for early detection and early treatment. The pattern of autosomal dominant inheritance is also supported by our report.

Acknowledgements

The authors thank doctors, nurses, and clinical staff who provided care for the patient.

Authors’ contributions

Conceptualization, WS; methodology, YK; investigation, YK; data curation, YK; writing—original draft preparation, WS and YK; writing—review and editing, YK; supervision, WS. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable. Written informed consent has been obtained from the patient to publish this paper.

Consent for publication

Written informed consent has been obtained from the patient to publish this paper.

Competing interests

The authors declare no competing interests.

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No competing interests reported.

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Novel ARMC5 mutations in primary bilateral macronodular adrenal hyperplasia: a family report

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