Abstract. Drug-induced hypersensitivity syndrome (DIHS) is a severe systemic adverse drug reaction. Previous studies showed that DIHS is associated with the onset of fulminant type 1 diabetes mellitus (FT1D). Although genetic background and abnormalities in immune response or viral infection are considered to be associated with pathogenesis of FT1D, it remains unclear whether virus infection and specific human leukocyte antigen (HLA) typing are involved in DIHS-associated FT1D. Here, we report a case of a 78-year-old female patient with FT1D after DIHS treatment. She was diagnosed as DIHS caused by carbamazepine, and treatment with predonisolone was initiated. After 46 days from the occurrence of DIHS, she was admitted to our hospital because of type 1 diabetes mellitus and diabetic ketoacidosis. Although her Hemoglobin A1c (HbA1c) was elevated by predonisolone treatment (HbA1c: 9.2%), we diagnosed her as fulminant type 1 diabetes mellitus considering the abrupt onset of the ketoacidosis. Her general condition was improved by treatment with fluid infusion and insulin administration. During her clinical course, the infection of coxsackie B4 virus was observed. In addition, the examination of HLA typing showed HLA-A24 haplotype. These findings suggest that the coxsackie B4 virus infection may be involved in the pathogenesis of DIHS-induced FT1D, and that HLA-A24 haplotype might relate to DIHS-associated FT1D.Key words: Fulminant type 1 diabetes mellitus, Drug-induced hypersensitivity syndrome, Coxsackie virus B4FULMINANT TYPE 1 DIABETES MELLITUS (FT1D) is a subtype of type 1 diabetes mellitus characterized by extremely rapid progression of hyperglycemia and diabetic ketoacidosis (DKA) due to almost complete pancreatic beta-cell destruction [1,2]. Because FT1D often causes poor prognosis, we have to pay special attention to the development of FT1D in clinical settings. Drug-induced hypersensitivity syndrome (DIHS) is a severe systemic adverse drug reaction characterized by rash, fever, leukocytosis, eosinophilia and liver injury [3,4]. Reactivation of human herpes virus 6 (HHV-6) is one Submitted Jun. 8, 2017; Accepted Sep. 4, 2017 as EJ17-0249 Released online in J-STAGE as advance publication Sep. 29, 2017 Correspondence to: Ippei Kanazawa, Internal Medicine 1, Shimane University Faculty of Medicine, 89-1, Enya-cho, Izumo, Shimane, 693-8501, Japan E-mail: ippei.k@med.shimane-u.ac.jp of specific characteristics of DIHS [3]. Recently, it is reported that FT1D sometimes occurs after DIHS treatment [4,5]. Indeed, Onuma et al. previously reported that the clinical characteristics of FT1D with DIHS were similar to those without DIHS, but the frequency was much higher than that in the general population (0.54% vs. 0.01%) [4]. Because the mechanism of DIHSassociated FT1D still remains unclear, the investigation of clinical characteristics including genetic background and serological testing for viral infection are necessary to clarify this issue. Case ReportA 78-year-old female patient visited a clinic for her blepharo...

Background and ObjectiveThyrotoxicosis is associated with accelerated bone turnover and increases the risk of fractures and osteoporosis. Graves' disease is the most common cause of hyperthyroidism. However, studies that examined risk factors associated with fragility fractures only in patients with Graves' disease are limited. Here, we investigated whether the risk of vertebral fracture (VF) of postmenopausal Graves' disease patients is high and tried to identify the risk factors for VF in that population.Design and MethodsForty‐three postmenopausal women with Graves' disease were enrolled. Physical and biochemical indices, thyroid indices and bone mineral density (BMD) were measured, and lateral X‐rays were obtained to evaluate VFs. Age‐ and sex‐matched healthy individuals were enrolled as the control group (n = 86).ResultsThe prevalence of VFs (35% vs 17%, P < .05), osteoporosis (63% vs 33%, P < .01) and severe osteoporosis (40% vs 17%, P < .01) was significantly higher in the Graves' disease group. Although there was no significant difference in either thyroid hormone levels or the positive ratio of thyroid antibodies, the prevalence of thyroid‐stimulating antibody (TSAb) was significantly higher in Graves' disease patients with VF compared to without (100% vs 68%, P < .05). Multivariate logistic regression analyses adjusted for age identified Graves' disease as being associated with the presence of VFs (OR 2.72, 95% CI: 1.13‐6.54, P < .05) in postmenopausal women.ConclusionsPostmenopausal Graves' disease patients had high risks of VF and severe osteoporosis. TSAb could be involved as a risk factor for VF in postmenopausal Graves' disease.

Background Thyroid crisis is a life-threatening condition in thyrotoxic patients. Although differentiated thyroid cancer is one of the causes of hyperthyroidism, reports on thyroid crisis caused by thyroid cancer are quite limited. Here, we describe a case of thyroid crisis caused by metastatic thyroid cancer. Case presentation A 91-year-old woman was admitted to our hospital because of loss of appetite. Two years prior to this hospitalization, she presented with subclinical thyrotoxicosis and was diagnosed with histologically unidentified thyroid cancer with multiple metastases, and she refused aggressive medical interventions. On admission, she exhibited extreme thyrotoxicosis, and the presence of fever, severe tachycardia, impaired consciousness, and heart failure revealed the presence of thyroid crisis. All thyroid autoantibodies were negative. Multidisciplinary conservative treatment was initiated; however, she died on the fifth day after admission. Autopsy revealed the presence of primary anaplastic thyroid carcinoma and multiple metastatic foci arising from follicular thyroid carcinoma. Both primary and metastatic follicular thyroid carcinoma likely induced thyrotoxicosis, which could have been exacerbated by anaplastic thyroid carcinoma. Conclusions Even though the trigger of thyroid crisis in this patient is not clear, the aggravated progression of her clinical course suggests that careful monitoring of thyroid hormones and appropriate intervention are essential for patients with thyroid cancer.

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In a small number of cases, the development of ectopic residual adrenal lesions during embryogenesis causing Cushing’s syndrome due to the production of excess cortisol has been reported. A 29-year-old woman was admitted to our hospital for fatigue and recent amenorrhea. Her plasma ACTH was &lt;1.5 pg/mL, and her serum cortisol was 21.4 pg/mL after the 8 mg dexamethasone suppression test, revealing the presence of ACTH-independent Cushing’s syndrome; however, her bilateral adrenal glands were atrophied. Abdominal CT revealed a 40-mm round tumor on the right renal hilum and remarkably accumulated 131I-labelled adosterol. CT and bone scintigraphy showed that 99mTc-methylene diphosphonate had accumulated in her dissymmetric skull at the right-frontoparietal region. The tumor on the right renal hilum was laparoscopically removed. Her cortisol levels rapidly decreased to below the normal range, and glucocorticoids were administered to rescue adrenal insufficiency. The resected tumor was yellowish in appearance and 4.5×3.0×2.8 cm in size. Immunohistochemical staining for SF-1, P450scc, CYP17A, CYP21A, and CYP11B1 indicated that this tumor produced cortisol. Exome sequencing analysis revealed that the GNAS heterozygous mutation (c.601C&gt;T, p. Arg201Cys; accession number, NM_000516.5) was found in approximately 20% of the adrenal tumor sample. A mutation of GNAS, encoding the Gsα subunit that mediates GPCR signaling, causes the constitutive activation of adenylyl cyclase, resulting in hypersecretion of hormones regulated by the GPCR. GNAS mutation is one of the major genetic causes of cortisol-producing adrenal tumors independent of ACTH secretion. Considering the combination of GNAS mutation with one of the typical clinical triad characteristics, fibrous dysplasia of bone, we diagnosed this patient with McCune–Albright syndrome accompanied by ACTH-independent Cushing’s syndrome caused by an ectopic residual adrenal tumor due to GNAS mutation. This case highlights that GNAS involves a previously unknown pathological mechanism in which inhibition of the natural elimination of remnant tissue leads to ectopic endocrine hypersecretion.