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Context Primary macronodular adrenal hyperplasia (PMAH) is a rare type of Cushing or subclinical Cushing syndrome and is associated with bilateral multinodular formation. ARMC5 is one of the responsible genes for PMAH. Objectives This study was performed to identify the genotype-phenotype correlation of ARMC5 in a cohort of Japanese patients. Patients and Methods Fourteen patients with clinically diagnosed PMAH and family members of selected patients were studied for ARMC5 gene alteration and clinical phenotype. The associated nonadrenal tumor tissues were also studied. Results Of fourteen patients with PMAH, 10 had pathogenic or likely pathogenic variants of ARMC5. We found two variants. Five unrelated patients had identical variants (p.R619*). In two patients, the variant was found in offspring with the asymptomatic or presymptomatic state. Six of ten patients who tested positive for the ARMC5 pathogenic or likely pathogenic variant carried nonadrenal tumors; however, no loss of heterozygosity (LOH) or second hit of the ARMC5 gene was evident. The ARMC5 variant–positive group showed a significantly higher basal cortisol level. Furthermore, age-dependent cortisol hypersecretion was seen in the ARMC5 variant–positive group. Conclusions ARMC5 pathogenic variants are common (71%) in Japanese patients with PMAH. p.R619* might be a hot spot in Japanese patients with PMAH. Asymptomatic or presymptomatic pathogenic variant carriers were found among the family members of the patients. Although 50% of ARMC5 variant carriers had nonadrenal neoplastic lesions, no LOH or second hit of ARMC5 in the tumor tissues was evident. The ARMC5 variant–positive mutant group showed a higher basal cortisol level than the negative group.

BACKGROUND: Thyroid storm (TS) is a life-threatening condition requiring emergency treatment. The reported mortality of TS is 10-20%, but there have not been many large clinical studies regarding the severity and prognosis of TS. The 2017 Guidelines for the Management of Thyroid Storm (The Japan Thyroid Association (JTA) and The Japan Endocrine Society) indicate that there is a significant correlation between TS mortality and the Acute Physiology and Chronic Health Evaluation (APACHE II) score (Odds ratio: 1.15), as well as between TS mortality and the Sequential Organ Failure Assessment (SOFA) score (Odds ratio: 1.33). In this report, we examined which severity score is a prognostic predictor of TS severity, in a comparison between the JTA score and the Burch-Wartofsky point scale (BWPS). CLINICAL CASES: In a retrospective chart review of patients diagnosed and treated at the Kurashiki Central Hospital (Kurashiki City, Japan) from 2005 to 2017, 3361 patients were diagnosed with Graves' disease, but only 5 developed TS (0.14%). TS was defined using the JTA and BWPS criteria; based on the use of either diagnostic criteria, the diagnosis of TS did not differ. Its severity was defined using the SOFA and APACHE II scores. The median age was 56 years [49-77 years]; females comprised 3 of the 5 patients (60%). Only 1 patient experienced a fatal case of TS. All 5 cases met the JTA criteria for definite diagnosis of TS; the median BWPS score was 80 points [55-85 points]. The median SOFA score was 3 points [0-5 points] and the media APACHE II score was 16 points [10-20 points]. The APACHE II score of the fatal case was 20 points, which was the highest among all 5 cases. Among the surviving cases, the periods of treatment in the Intensive Care Unit was less than 3 days. All survival cases were treated with antithyroid drugs, β-blockers, glucocorticoids, and acetaminophen. None of the patients in our report underwent hemodialysis. The APACHE II score is an accurate measure of severity of illness that correlates strongly with patient outcome. In our analysis, there was no difference between the survival cases and the fatal case, with respect to the JTA and BWPS criteria, or the SOFA score. However, the APACHE II score of the fatal case was higher than that of the survival cases. Notably, Aa-DO2/PaO2, arterial blood pH/venous blood HCO3-, and Glasgow Coma Scale were the major factors associated with mortality. CONCLUSION: Our data suggested that there was no difference in the diagnosis of TS, based on the diagnostic criteria of JTA and BWPS. The APACHE II score was helped to estimate the severity of multiple organ dysfunction of TS.

Adrenal cortex and medulla are derived from mesoderm and ectoderm, respectively. Mixed corticomedullary tumors (MCMTs), comprising an intimately admixed population of both adrenal cortical cells and pheochromocytes in a single adrenal tumor, are extremely rare and its pathogenesis has remained unknown. Here, we report a case of MCMT whose cells co-expressed cortical and medullary antigens in the same tumor cells.[Case description]A 40-year-old woman was referred to our hospital for investigating Takotsubo cardiomyopathy following resection of uterine fibroids. An abdominal CT scan depicted a 24 mm tumor on her left adrenal gland. Her basal serum ACTH, cortisol levels and urinary cortisol were 13.8 pg/mL, 9.5 μg/dL, and 26.5 μg/day respectively. The cortisol level was normally suppressed by an administration of 1 mg dexamethasone (1.4 μg/dL). Plasma renin activity, aldosterone levels and urinary aldosterone were 15.0 ng/mL/h, 122 pg/mL, and 5.0 μg/day, respectively (with administration history of azosemide). On the other hand, her plasma adrenaline and noradrenaline levels were elevated as high as 177 pg/mL and 536 pg/mL, and urinary metanephrine and normetanephrine were 2.12 mg/day and 1.10 mg/day. A 123I-metaiodobenzylguanidine scan revealed high uptake in the tumor. After adequate adrenergic α-receptor blockage, left adrenalectomy was performed. Her postoperative endocrine and clinical findings were normalized without any further complications.[Pathology] Immunohistochemistry (IHC) revealed the presence of MCMT. Cells morphologically consistent with pheochromocytoma and adrenocortical cells were confirmed by immunostaining of chromogranin A and SF-1, respectively. Chromogranin A-positive medullary-derived and SF-1-positive cortical-derived tumor cells were intermixed in the chimeric fashion. In addition, some tumor cells were positive for both proteins, indicating hybrid nature of the cells. Tumor cells of cortical origin expressed CYP11β1, 3β-HSD, p450c21, and p450c17, but not CYP11β2. Non neoplastic adrenal cortex were atrophic, whereas the glomerulosa was hyperplastic positive for CYP11β2, consistent with diffuse hyperplasia and adrenal medullar unremarkable. [Conclusions:]The adrenal tumor was clinically diagnosed as pheochromocytoma, but the pathological findings did reveal cortisol production in the tumor and aldosterone overproduction in the accompanying cortex. This is the first case of MCMT co-expressing adrenal medullary and cortical antigens in the same tumor cells as hybrid cells.