Unilateral nodular adrenocortical hyperplasia presenting as Cushing’s syndrome: a case report

Cushing syndrome results from chronic exposure to excess cortisol. Nodular adrenal hyperplasia is usually bilateral and has only a few case reports of unilateral presentation. Biochemically it is presented as hyperaldosteronism or as Cushing’s syndrome. Here, we are reporting a 17-year-old female presenting with weight gain over 5 months and uncontrolled hypertension. Biochemically she was found to have diabetes mellitus, secondary hypothyroidism and hypogonadotrophic hypogonadism due to Cushing’s syndrome of adrenal origin. Unilateral adrenal adenoma/hyperplasia in right adrenal gland was evident by radiology. Histopathological examination was done after laparoscopic adrenalectomy showed nodular adrenocortical hyperplasia in right adrenal mass. Following surgery, clinical features of the patient improved notably. Cushing syndrome due to unilateral nodular adrenocortical hyperplasia is a rare entity. Biochemical evaluation of hypothalamo-pituitary-adrenal axis, radiological evidence and histopathology are the important armaments can guide to final diagnosis. BIRDEM Med J 2022; 12(1): 78-82

Synergistic cortisol suppression by ketoconazole–osilodrostat combination therapy

Summary Here, we describe a case of a patient presenting with adrenocorticotrophic hormone-independent Cushing’s syndrome in a context of primary bilateral macronodular adrenocortical hyperplasia. While initial levels of cortisol were not very high, we could not manage to control hypercortisolism with ketoconazole monotherapy, and could not increase the dose due to side effects. The same result was observed with another steroidogenesis inhibitor, osilodrostat. The patient was finally successfully treated with a well-tolerated synergitic combination of ketoconazole and osilodrostat. We believe this case provides timely and original insights to physicians, who should be aware that this strategy could be considered for any patients with uncontrolled hypercortisolism and delayed or unsuccessful surgery, especially in the context of the COVID-19 pandemic. Learning points Ketoconazole–osilodrostat combination therapy appears to be a safe, efficient and well-tolerated strategy to supress cortisol levels in Cushing syndrome. Ketoconazole and osilodrostat appear to act in a synergistic manner. This strategy could be considered for any patient with uncontrolled hypercortisolism and delayed or unsuccessful surgery, especially in the context of the COVID-19 pandemic. Considering the current cost of newly-released drugs, such a strategy could lower the financial costs for patients and/or society.

ARMC5-associated Bilateral Macronodular Adrenocortical Hyperplasia: A Novel Germline Variant Associated with Concomitant Papillary Thyroid Carcinoma and Meningioma

Introduction/Objective Germline mutations in the tumor suppressor gene Armadillo-containing repeat protein 5 gene (ARMC5) have been very recently recognized as a cause for a familial form of bilateral macronodular adrenocortical hyperplasia (BMAH), itself a rare cause of Cushing syndrome. In patients with ARMC5 mutations, scattered case reports have also shown an association with meningiomas and cancers of the pancreas, breast, colon, and thyroid. Methods/Case Report We present the case of BMAH, arising in a 61-year-old female with a history of metastatic papillary thyroid carcinoma and meningioma. The patient presented with bilateral but asymmetric adrenal enlargement (right greater than left) and Cushing syndrome. Given history of thyroid cancer and meningioma, genetics referral was ordered. Counseling revealed a pedigree without a strongly evident familial pattern of hereditary endocrine neoplasia characteristic of any of the more common inherited dispositions to endocrine neoplasia. Additionally, a targeted capture-based NGS germline genetic sequencing study for variants in 12 genes associated with associated with hereditary thyroid cancer was performed and negative. However, based on recent scholarship regarding ARMC5, follow-up germline NGS and Sanger sequencing studies encompassing the entire coding sequences of ARMC5 were ordered. These identified a germline, heterozygous, novel (not in ClinVar) but likely pathogenic variant in (c.802C>T, p.Arg268*), providing a likely explanation for the patient’s BMAH. In attempt to control the patient’s Cushing symptoms, right-sided adrenalectomy was performed, revealing a 220g adrenal gland with marked multinodular hyperplasia with solid, nested, and tubular architecture. Results (if a Case Study enter NA) NA Conclusion While case reports exist describing an association between other ARMC5 mutations and BMAH with concomitant meningiomas and/or malignancies, greater study is needed in order to better characterize the phenotypic spectrum of this disease. Our experience with this case not only reports a novel, apparently pathogenic mutation, but it documents its association with BMAH and, additionally, papillary thyroid carcinoma and meningioma.

A novel nonsense mutation in ARMC5 causes primary bilateral macronodular adrenocortical hyperplasia

Background Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) is a rare form of adrenal Cushing’s syndrome. The slowly progressing expansion of bilateral adrenal tissues usually persists for dozens of years, leading to delayed onset with severe conditions due to chronic mild hypercortisolism. About 20–50% cases were found to be caused by inactivating mutation of armadillo repeat-containing protein 5 (ARMC5) gene. Case presentation A 51-year-old man was admitted for severe diabetes mellitus, resistant hypertension, centripedal obesity and edema. PBMAH was diagnosed after determination of adrenocorticotropic hormone and cortisol levels, dexamethasone suppression tests and abdominal contrast-enhanced CT scanning. The metabolic disorders of the patient remarkably improved after sequentially bilateral laparoscopic adrenalectomy combined with hormone replacement. Sanger sequencing showed germline nonsense mutation of ARMC5 c.967C>T (p.Gln323Ter). The second somatic missense mutation of ARMC5 was detected in one out of two resected nodules, reflecting the second-hit model of tumorigenesis. Routine genetic testing in his apparently healthy offspring showed one of two daughters and one son harbored the germline mutation. Conclusions In conclusion, our case report highlight the importance of genetic testing in the molecular diagnosis of PBMAH. Genetic screening in related family members will find out asymptomatic variant carriers to guide life-long follow-up.

Primary Macronodular Adrenal Hyperplasia Associated With Autosomal Dominant ARMC5 Mutation

Background: Primary macronodular adrenal hyperplasia (PMAH) is an uncommon cause of Cushing’s syndrome. In some cases, this is an inherited disorder due to a mutation in the armadillo repeat-containing 5 (ARMC5) gene. Clinical Case: A 43-year-old African American woman presented to clinic with weight gain, worsening type 2 diabetes mellitus, and symptomatic hypertensive cardiomyopathy. Physical exam was significant for central obesity, bilateral supraclavicular fat pads, acanthosis nigricans and wide striae over the abdomen. Her serum cortisol was 13.8 mcg/dL after 1 mg of dexamethasone (n<1.8 mcg/dL), urinary cortisol was 180 mcg in 24 hours (n=3.5–45 mcg/24h) and two midnight salivary cortisol tests were 227 and 118 ng/dL (n<100 ng/dL). Her ACTH was 2.4 pg/mL (n=7.2–63.3 pg/mL). Computed tomography (CT) of the abdomen showed nodularity, diffuse thickening and low-density (<10 Hounsfield units) of the bilateral adrenal glands. She underwent bilateral adrenalectomy for a diagnosis of PMAH. Pathology showed nodular adrenocortical hyperplasia; the right and left adrenal glands measured 75 grams and 68 grams, respectively. She was started on hydrocortisone and fludrocortisone postoperatively. Over the following two years, she had a 68-pound weight loss, an 86% reduction in her daily insulin requirement and a 10% improvement in her left ventricular ejection fraction. Approximately two years later, the patient’s brother was referred for bilateral macronodular hyperplasia incidentally discovered on a CT of the abdomen. He had a history of hypertension and type 2 diabetes mellitus with cushingoid features on exam. His serum cortisol was 20.7 mcg/dL after 1 mg of dexamethasone, urinary cortisol was 65.1 mcg in 24 hours, two midnight salivary cortisol tests were 232 and 404 ng/dL and ACTH was 2.0 pg/mL. Upon obtaining further family history, the patients reported clinical features of Cushing’s syndrome in their paternal grandmother but denied features in either parent. The second patient had genetic testing which showed a mutation in the ARMC5 gene, c.1777C>T, p.R593W, a mutation previously described. Due to clinical signs of Cushing’s syndrome, he underwent bilateral adrenalectomy in which pathology showed right and left nodular adrenocortical hyperplasia measuring 110 and 73 grams, respectively. He is doing well postoperatively. The patients recently reported their aunt was diagnosed with PMAH and mild Cushing’s syndrome. She had a unilateral adrenalectomy of the larger adrenal gland and is doing well postoperatively. Conclusion: In some cases, Cushing’s syndrome is an inherited disorder. Autosomal dominant mutations in the ARMC5 gene are occasionally seen in PMAH, which causes less than 2% of endogenous Cushing’s syndrome. For all patients diagnosed with PMAH, clinicians should consider screening their family members with a dexamethasone suppression test.

PRKACB variants in skeletal disease or adrenocortical hyperplasia: effects on protein kinase A

Genetic variants in components of the protein kinase A (PKA) enzyme have been associated with various defects and neoplasms in the context of Carney complex (CNC) and in isolated cases, such as in primary pigmented nodular adrenocortical disease (PPNAD), cortisol-producing adrenal adenomas (CPAs), and various cancers. PRKAR1A mutations have been found in subjects with impaired cAMP-dependent signaling and skeletal defects; bone tumors also develop in both humans and mice with PKA abnormalities. We studied the PRKACB gene in 148 subjects with PPNAD and related disorders, who did not have other PKA-related defects and identified two subjects with possibly pathogenic PRKACB gene variants and unusual bone and endocrine phenotypes. The first presented with bone and other abnormalities and carried a de novo c.858_860GAA (p.K286del) variant. The second subject carried the c.899C>T (p.T300M or p.T347M in another isoform) variant and had a PPNAD-like phenotype. Both variants are highly conserved in the PRKACB gene. In functional studies, the p.K286del variant affected PRKACB protein stability and led to increased PKA signaling. The p.T300M variant did not affect protein stability or response to cAMP and its pathogenicity remains uncertain. We conclude that PRKACB germline variants are uncommon but may be associated with phenotypes that resemble those of other PKA-related defects. However, detailed investigation of each variant is needed as PRKACB appears to be only rarely affected in these conditions, and variants such as p.T300M maybe proven to be clinically insignificant, whereas others (such as p.K286del) are clearly pathogenic and may be responsible for a novel syndrome, associated with endocrine and skeletal abnormalities.

Volumetric Modeling of Adrenal Gland Size in Primary Bilateral Macronodular Adrenocortical Hyperplasia

Context Radiological characterization of adrenal size in primary bilateral macronodular adrenocortical hyperplasia (PBMAH) has not been previously investigated. Objective We 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. Design A retrospective cross-sectional analysis of 44 patients with PBMAH was conducted from 2000 to 2019. Setting Tertiary care clinical research center. Patients Patients were diagnosed with PBMAH based upon clinical, genetic, radiographic and biochemical characteristics. Intervention Clinical, 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 Measures 17-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. Results A 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). Conclusions Volumetric modeling of adrenal gland size may associate with biochemical severity in patients with PBMAH, with particular utility in Black patients.