First case report of the ARMC5 (c.2692C>T, p.Arg898Trp) variant in a Chinese family with adrenocorticotropic hormone-independent macronodular adrenal hyperplasia

Introduction

Background

Adrenocorticotropic hormone (ACTH)-independent macronodular adrenal hyperplasia (AIMAH), also termed primary bilateral macronodular adrenal hyperplasia (PBMAH), is a rare cause of Cushing’s syndrome (CS) or subclinical CS, characterized by bilateral adrenal macronodules and variable cortisol secretion (1). First described in 1964, the disease manifests heterogeneously, ranging from classic CS features and hyperandrogenism to metabolic disturbances and atypical presentations such as depression, osteoporosis, or hypokalemia (2). Radiologically, the condition typically shows bilateral adrenal enlargement with nodules >1 cm, though imaging patterns can vary (3). Germline mutations in the ARMC5 gene on chromosome 16p constitute a major genetic etiology for familial PBMAH (4). ARMC5 encodes a tumor suppressor, and its biallelic inactivation conforms to the “two-hit” model of tumorigenesis (5). To date, over 110 pathogenic ARMC5 variants have been reported (6).

Rationale and knowledge gap

The annual incidence of CS is estimated at 1.8–3.2 cases per million (7,8). Adrenal etiologies account for 20–30% of endogenous CS cases, among which PBMAH represents less than 5% (9). ARMC5 inactivation is detected in approximately 20–25% of sporadic and 80% of familial PBMAH cases (6,8,10). Although inherited in an autosomal dominant pattern with incomplete penetrance (3), the mutational spectrum and genotype-phenotype correlations remain incompletely characterized. The broad clinical variability from asymptomatic carriage to overt CS complicates timely diagnosis and familial management (3,8). Consequently, detailed phenotypic documentation of novel variants, particularly in familial settings, is required. Furthermore, the postoperative course of the contralateral adrenal gland following unilateral adrenalectomy in ARMC5 mutation carriers is not well defined, underscoring the need for extended longitudinal data to guide management (9,11).

Objective

This case report describes a familial instance of AIMAH associated with a novel ARMC5 missense mutation (c.2692C>T, p.Arg898Trp). We systematically detail the proband’s clinical, biochemical, imaging, and histopathological features, demonstrate familial segregation with evidence of incomplete penetrance, and discuss the implications for genetic counseling, long-term surveillance, and clinical management. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0029/rc).

Case presentation

A 51-year-old man had a 5-year history of hypertension (on nifedipine and irbesartan) and diabetes mellitus (treated with metformin, repaglinide, and gliquidone, without regular glucose monitoring). He reported no smoking, alcohol use, or long-term use of other medications. He presented with a 2-week history of fatigue and abdominal distension. Following the progression of symptoms, he was evaluated at our urology clinic. Physical examination revealed prominent violaceous abdominal striae, cutaneous atrophy, and telangiectasias. Adrenal magnetic resonance imaging (MRI) demonstrated bilateral adrenal enlargement consistent with hyperplasia. Dexamethasone suppression tests (both low- and high-dose) were positive, indicating ACTH-independent hypercortisolism and supporting a provisional diagnosis of AIMAH.

The patient initially declined the recommended laparoscopic adrenalectomy and sought further evaluation at another tertiary hospital (Ruijin Hospital, Shanghai). There, diagnostic workup confirmed CS, with biochemical evidence of hypercortisolism (serum cortisol 429.92 nmol/L; ACTH <5.00 pg/mL; 24-hour urinary free cortisol 836 µg/24 hours) and concomitant hypokalemia (serum potassium 3.2 mmol/L). After 5 months of unsuccessful medical therapy, he was admitted to our Department of Endocrinology and Metabolism at the First Affiliated Hospital of Anhui Medical University.

A comprehensive inpatient diagnostic workup was performed, including assessment of cortisol and ACTH circadian rhythm, repeat dexamethasone suppression tests, evaluation of the renin-angiotensin-aldosterone system, 24-hour urinary biochemical profiling, and adrenal computed tomography (CT) (Table 1, Figure 1). These collective findings confirmed CS secondary to bilateral macronodular adrenal hyperplasia. The diagnosis of AIMAH is challenging due to its heterogeneous clinical manifestations and overlap with other causes of CS. In this case, persistently suppressed ACTH levels excluded ACTH-dependent (pituitary or ectopic) etiologies. Bilateral adrenal involvement argued against unilateral pathologies like adenoma or carcinoma, which typically present asymmetrically. While primary pigmented nodular adrenocortical disease (PPNAD) was considered, the presence of macronodules (>1 cm) and the patient’s later age at onset favored PBMAH/AIMAH. Definitive diagnosis typically requires histopathological confirmation and genetic testing.

Figure 1 Preoperative adrenal CT imaging findings. (A) Non-contrast image; (B) contrast-enhanced image. Imaging demonstrates diffusely enlarged bilateral adrenal glands with effacement of the normal Y-shaped configuration. Multiple round, hypodense lesions are present within the adrenal parenchyma and exhibit mild post-contrast enhancement. Additionally, a punctate calcification is seen in the right adrenal gland. The imaging features are diagnostic of BMAH and represent a characteristic etiology of ACTH-independent CS. ACTH, adrenocorticotropic hormone; BMAH, bilateral macronodular adrenal hyperplasia; CS, Cushing’s syndrome; CT, computed tomography.

Genetic analysis identified a heterozygous pathogenic variant in ARMC5 (c.2692C>T, p.Arg898Trp) (Figure 2). Family history revealed no adrenal, CS, or other endocrine disorders in relatives. The father, an asymptomatic carrier of the same ARMC5 variant, remained clinically and biochemically unaffected, with normal cortisol levels and no adrenal abnormalities on imaging. No other family members reported metabolic conditions suggestive of subclinical hypercortisolism. Following multidisciplinary consultation, the patient underwent an uncomplicated laparoscopic right adrenalectomy. Histopathological examination of the resected specimen confirmed the diagnosis (Figure 3). Postoperative recovery was uneventful, and he was discharged 1 week after surgery.

Figure 2 Identification of a heterozygous ARMC5 mutation in the proband. A missense variant (c.2692C>T, p.Arg898Trp) was detected and confirmed by Sanger sequencing (electropherogram shown). As indicated in the pedigree (Figure 5), the chr16:31478094 c.2692C>T (p.Arg898Trp) variant was shown to be paternally inherited. This alteration resides in exon 6 of the ARMC5 gene (OMIM: 615549) at chromosomal locus 16p11.2 and is classified as pathogenic. The variant is predicted to result in a loss-of-function change. The father was identified as an asymptomatic carrier, supporting the role of ARMC5 mutations in disease with incomplete penetrance. Clinical surveillance and further follow-up are therefore warranted.

Figure 3 Pathological examination of the right adrenal tumor (H&E, ×200). Histological analysis reveals that the tumor is composed of cells with clear, lipid-rich cytoplasm arranged in nested patterns. The cells exhibit minimal cytological atypia. No definitive vascular invasion or tumor necrosis is identified, and mitotic figures are exceptionally rare. A key histological finding is the observation of focal tumor extension beyond the capsule into the adjacent adipose tissue. These morphological features, particularly the predominance of clear cells with a nested architecture, are consistent with subtype 1 of the recently established histopathological classification for BMAD (Violon et al., 2024) (12). This subtype has been strongly associated with germline ARMC5 pathogenic variants (Bouys et al., 2025) (6). BMAD, bilateral macronodular adrenocortical disease; H&E, hematoxylin and eosin.

Serial follow-up evaluations were performed. At the 4-week assessment, serum cortisol levels had decreased by approximately 48% from preoperative values, with ACTH remaining suppressed (Table 1). By the 6-month follow-up, morning serum cortisol was 210.69 nmol/L, indicating a further decline; however, levels persisted above the normal range without restoration of circadian rhythmicity, and ACTH suppression continued (Table 1). Surveillance adrenal CT at 6 months confirmed expected postoperative changes on the right side (Figure 4). In contrast, left adrenal lesions persisted and exhibited progression toward a cystic morphology. No intraoperative, immediate postoperative, or surgery-related adverse events were documented during the hospitalization or the 6-month follow-up period. The timeline of the patient’s clinical course from initial presentation to surgery is summarized in Table 2. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient and his parents for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 4 Adrenal CT imaging at 6-month postoperative follow-up. (A) Non-contrast image; (B) contrast-enhanced image. Comparative analysis with preoperative studies reveals expected post-surgical changes in the right adrenal bed, with no identifiable residual glandular tissue or nodular recurrence. Of note, the left adrenal gland demonstrates multiple cystic, hypodense lesions that exhibit mild contrast enhancement. These imaging features are consistent with status post right adrenalectomy and indicate persistent disease in the contralateral gland, suggesting a pattern of cystic evolution. CT, computed tomography.

Discussions

Key findings

This report describes a familial case of AIMAH associated with an ARMC5 missense mutation (c.2692C>T, p.Arg898Trp). Comprehensive clinical, biochemical, and imaging evaluation confirmed the diagnosis of ACTH-independent hypercortisolism secondary to bilateral adrenal macronodular hyperplasia. Genetic testing identified the pathogenic ARMC5 variant, and segregation analysis demonstrated paternal inheritance with an asymptomatic carrier father, offering direct evidence of the incomplete penetrance characteristic of ARMC5-related disease (3,4) (see Figure 5). Notably, follow-up imaging after unilateral right adrenalectomy revealed cystic transformation of the contralateral adrenal gland, indicating persistent autonomous activity and reinforcing the bilateral nature of the disease process (3,9).

Figure 5 Pedigree analysis of the ARMC5 variant segregation. The proband (II-1) carries a heterozygous ARMC5 c.2692C>T (p.Arg898Trp) mutation and presents with corresponding clinical features. The identical heterozygous variant was identified in the father (I-1), who remains asymptomatic, whereas the mother (I-2) carries the wild-type allele. This segregation pattern is consistent with an autosomal dominant mode of inheritance with incomplete penetrance, and the mutation in the proband was confirmed to be de novo. The asymptomatic carrier status of the father illustrates the incomplete penetrance characteristic of ARMC5-related disease, which has important implications for genetic counseling and clinical surveillance in at‑risk family members.

Strengths and limitations

Strengths

This study is strengthened by its integrative methodology, which synthesized detailed clinical, biochemical, radiological, histopathological, and genetic data to construct a comprehensive phenotypic profile of the case. The familial segregation analysis clearly demonstrates autosomal dominant inheritance with incomplete penetrance, thereby expanding the phenotypic spectrum documented for ARMC5-related disease (4,6). Moreover, the documentation of contralateral adrenal cystic transformation following surgery offers new insights into the postoperative disease course in mutation carriers.

Limitations

Several limitations are inherent to this single-center familial case report. The detailed phenotypic characterization provided notwithstanding, our observations regarding genotype-phenotype correlations and postoperative progression require validation in larger, multicenter cohorts (3,8). Although computational predictions and clinical database annotations support the pathogenicity of the ARMC5 variant c.2692C>T (p.Arg898Trp), definitive confirmation of its loss-of-function mechanism and precise impact on adrenal signaling pathways awaits experimental functional validation (4,6). While unilateral adrenalectomy preserved adrenal function in this case, the procedure carries a substantial risk of incomplete biochemical remission (~40%). In the present case, a key limitation is that adrenal venous sampling (AVS) was not performed to identify the dominant cortisol-secreting side. Guidelines recommend unilateral adrenalectomy of the radiologically dominant side for PBMAH patients with markedly asymmetric involvement (11). In our case, imaging (Figure 1) revealed more extensive right-sided involvement, guiding right adrenalectomy. However, the lack of biochemical remission suggests imaging alone may be insufficient to determine the functional dominant side, and that the left adrenal was likely a major cortisol source (3,9). Therefore, we recommend preoperative AVS for PBMAH patients considered for unilateral adrenalectomy to improve remission rates (3). Postoperative surveillance in this patient revealed contralateral cystic transformation on contrast-enhanced CT at 6 months. Although this follow-up duration was sufficient to document the initial response, it is too short to assess long-term outcomes, including disease recurrence, the natural history of the cystic transformation, or de novo nodule formation (9,11). All attempts to schedule further follow-up failed, resulting in the patient being lost to contact and precluding the acquisition of long-term progression data. Finally, while ARMC5 is the principal gene associated with familial AIMAH, our targeted genetic analysis cannot rule out the contribution of other genetic modifiers or rare variants in unrelated genes to the disease expressivity (3). Future studies utilizing multi-gene panels or whole-exome sequencing in similar familial contexts are warranted to investigate this possibility.

Comparison with similar researches

According to Bouys et al. [2025], exon 6 is a critical region for ARMC5 pathogenic variants, with reported alterations including p.Arg811Pro, p.Leu754Pro, p.Arg879Trp, and the p.Arg898Trp variant identified here. Notably, p.Arg898Trp has been identified in nine unrelated probands, making it one of the most recurrent ARMC5 variants (6). Its gnomAD allele frequency is exceptionally low (0.000006316), consistent with a rare pathogenic variant. Although the c.2692C>T (p.Arg898Trp) variant is annotated as pathogenic in databases including ClinVar, to our knowledge, this study offers the first comprehensive report within a Chinese pedigree to demonstrate clinical-genetic cosegregation and to delineate the associated phenotypic spectrum systematically.

The surgical strategy aligns with recently reported familial PBMAH cases. Wang et al. described a Chinese family with an ARMC5 p.Arg315Trp mutation undergoing left adrenalectomy for a larger left nodule (9), while Vena et al. reported a patient with an ARMC5 exon 6 frameshift mutation (p.Cys813Vfs*104) who underwent left adrenalectomy due to marked left adrenal enlargement (13). In our case, preoperative imaging (Figure 1) revealed more extensive right-sided involvement, guiding right adrenalectomy to prioritize resection of the side with greater nodular burden. Across all three cases, postoperative cortisol improved but failed to normalize, reinforcing the cytoreductive intent of unilateral adrenalectomy in ARMC5-related PBMAH. Importantly, the contralateral cystic transformation observed in our patient represents a novel finding not previously reported, suggesting a distinct imaging phenotype in ARMC5 mutation carriers.

Explanations of findings

The ARMC5 gene encodes a tumor suppressor characterized by a central Armadillo repeat domain and a C-terminal BTB domain (9,14). In PBMAH, biallelic inactivation of ARMC5 abolishes its tumor-suppressive function—a pathogenic process that embodies Knudson’s classic “two-hit” model (5). According to this model, an inherited germline mutation (first hit) is followed by a somatic alteration in the contralateral allele (second hit) within adrenal cortical cells, culminating in a complete loss of function (5).

Loss of ARMC5 triggers interconnected pathogenic cascades. As a substrate-specific adaptor for the CRL3, ARMC5 inactivation impedes ubiquitin-mediated proteolysis. This leads to marked stabilization of the cell-cycle regulator MNAT1, which in turn drives constitutive hyperactivation of CDK7 and CDK2. The resulting kinase cascade inactivates the retinoblastoma (Rb) protein, thereby releasing the G1/S checkpoint restraint and promoting clonal expansion of adrenal cortical cells (15,16). Concurrently, ARMC5 deficiency induces aberrant expression of various non-ACTH G-protein-coupled receptors (GPCRs). Persistent stimulation of these ectopic receptors by circulating ligands mimics tonic ACTH signaling, sustaining cAMP/PKA pathway activity and potently upregulating cortisol-synthesizing enzymes (3,14). Moreover, nuclear β-catenin accumulation observed in a subset of PBMAH nodules suggests concomitant Wnt pathway activation, which may synergize with ARMC5 loss to further drive proliferation and dedifferentiation (9).

We identified a c.2692C>T (p.Arg898Trp) missense mutation in exon 6 of ARMC5 in this pedigree. This substitution replaces a positively charged, hydrophilic arginine with a bulky, hydrophobic tryptophan at codon 898—a change predicted to disrupt local protein conformation and critical interaction interfaces, culminating in a loss-of-function effect. The variant’s pathogenicity is corroborated by clinical database annotations. While our findings provide clear evidence for germline ARMC5 mutations, poor DNA quality from archived material precluded definitive validation of the somatic “second hit” required for biallelic loss. Future research should prioritize prospectively collected fresh tissue to elucidate this second somatic event. This pedigree includes an asymptomatic carrier, illustrating the incomplete penetrance of ARMC5 mutations. The presence of the identical variant in the unaffected father indicates that the germline defect alone is insufficient for disease expression; additional somatic hits or environmental factors are likely required. Similar incomplete penetrance patterns have been documented in other ARMC5-mutated families (6,9). This clinical variability underscores the importance of periodic biochemical and imaging surveillance in all carriers, regardless of initial presentation.

Complementing these genetic findings, the histopathological observations align with the emerging genotype-phenotype correlation in bilateral macronodular adrenocortical disease. Violon et al. [2024] proposed a four-tiered classification demonstrating that subtype 1 (predominantly clear cells with fibrous septa) is highly specific for ARMC5-mutated cases (12). Our observation of a predominantly clear cell tumor in a patient with the ARMC5 p.Arg898Trp variant provides further validation of this classification, highlighting the value of histopathology in raising suspicion of the underlying genetic defect and directing genetic testing.

Beyond the histopathological correlations, bilateral, multifocal involvement—evident at initial presentation and in postoperative contralateral evolution—constitutes a hallmark of ARMC5 dysfunction. Following resection of the dominant right adrenal, the left gland—harboring the same germline ARMC5 mutation—remained susceptible to unidentified ‘second hits’ driving progression. The observed cystic transformation may represent degeneration from chronic overstimulation of genetically predisposed tissue. This aligns with the understanding that ARMC5 inactivation creates a permissive environment for adrenal proliferation, with the specific morphological outcome likely depending on local factors or the nature of the second somatic event. Further studies are needed to determine the prognostic implications of cystic transformation in ARMC5 mutation carriers.

Implications and actions needed

This case yields significant clinical insights. It substantiates the integration of ARMC5 genetic testing into the standard diagnostic evaluation of bilateral adrenal hyperplasia, particularly for patients with a positive family history. Identifying a pathogenic mutation both confirms the diagnosis and obligates cascade genetic screening of at-risk first-degree relatives. As exemplified by the asymptomatic father, identified carriers require comprehensive genetic counseling coupled with adherence to a structured, long-term surveillance protocol—encompassing periodic adrenal imaging and biochemical assessments—to facilitate early disease detection.

With respect to surgical intervention, the case elucidates that unilateral adrenalectomy for ARMC5-related AIMAH typically represents a cytoreductive, not curative, procedure. Consequently, patients and clinicians must be counseled unequivocally that this approach necessitates lifelong surveillance of the contralateral adrenal gland for disease progression or hypercortisolism recurrence. Optimal management, therefore, hinges on coordinated, multidisciplinary collaboration among endocrinologists, endocrine surgeons, radiologists, pathologists, and genetic counselors to individualize care plans.

Looking forward, key priorities should encompass enhancing awareness of ARMC5-related AIMAH to reduce diagnostic delays, developing evidence-based surveillance guidelines for mutation carriers, and fostering research into the functional characterization of genetic variants. Elucidating postoperative disease dynamics, particularly the clinical relevance of distinctive imaging features such as the cystic transformation documented herein, warrants dedicated investigation.

Conclusions

This case report describes an ARMC5 missense mutation (p.Arg898Trp) in a familial context of AIMAH, integrating clinical, genetic, and pathological observations. The study underscores ARMC5 dysfunction as a key pathogenic driver in both familial and sporadic AIMAH and highlights the critical role of genetic testing in diagnosis and familial risk stratification. Management of AIMAH requires balancing effective cortisol suppression against the preservation of adrenal function, with unilateral adrenalectomy often representing a palliative strategy necessitating lifelong surveillance. Importantly, establishing a comprehensive, genetics-guided familial screening and long-term monitoring protocol is paramount for optimizing outcomes in patients and at-risk carriers. This report aims to enhance recognition of this rare disorder and to provide a foundation for future research on genotype-phenotype correlations and evidence-based therapeutic strategies.

Patient perspective

I wish to express my profound gratitude to the multidisciplinary team for their exceptional care. Their thorough counseling—clarifying the anticipated cytoreductive outcome of surgery versus the limited efficacy of medical therapy—was pivotal in my decision to proceed with laparoscopic right adrenalectomy. The procedure and recovery were uneventful. While I am mindful of the need for lifelong surveillance, the substantial alleviation of my debilitating symptoms has markedly enhanced my quality of life. I am sincerely thankful for their expertise and support.

Acknowledgments

The authors would like to thank the patient and his family for their participation and cooperation. We also acknowledge the clinical and technical staff at the Department of Endocrinology and Urology for their support in patient management and data collection.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0029/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0029/prf

Funding: This work was supported by the Anhui Provincial Department of Education University Research Projects 2025 (No. 2025AHGXZK20229 to D.D.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0029/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient and his parents for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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