A rare case of primary hyperparathyroidism associated with primary aldosteronism and breast cancer is reported. A 44-year-old woman was admitted to our hospital to undergo surgical removal of breast cancer. She had hypertension with low serum potassium, and slightly but significantly elevated serum calcium levels. Further studies demonstrated an enlarged left superior parathyroid gland and a left aldosterone-producing adrenocortical adenoma. Blood pressure was controlled with spironolactone and nifedipine, and left mastectomy was done for breast cancer. The pathological diagnosis was scirrhous breast carcinoma. Although the postoperative course was uneventful, her serum calcium gradually and progressively rose to higher levels. Left superior parathyroidectomy and left adrenalectomy were then performed simultaneously. The pathological diagnoses of the resected parathyroid gland and adrenal gland were parathyroid chief cell adenoma and adrenocortical adenoma with hyperplasia of zona glomerulosa, respectively. To clarify if the occurence of these tumors may be related to MEN1 gene mutations, we analyzed MEN1 gene in this patient, and found a loss of heterozygosity of the MEN1 locus in the parathyroid adenoma and breast cancer. Thus, we conclude that an alteration of the MEN1 gene and/or another tumor suppressor gene located at the MEN1 locus on chromosome 11q13 may be responsible for the development of parathyroid adenoma and breast cancer in our patient suggesting that the clinical spectrum of MEN1 might include breast cancer. In addition, serum calcium should be interpreted with caution in primary aldosteronism, because hypercalcemia may be masked in the presence of aldosterone excess. (Internal Medicine 43: 310-314, 2004)Key words: multiple endocrine neoplasia type 1 (MEN1), MEN1 gene, loss of heterozygosity, breast cancer, primary hyperparathyroidism, primary aldosteronism

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Objective: To determine whether familial isolated hyperparathyroidism (FIHP) is a variant of multiple endocrine neoplasia type 1 (MEN1) we analyzed the MEN1 gene in such a kindred. Design and methods:The study included the 70-year-old proband and nine relatives. Blood was drawn for biochemical evaluation and germline mutation analysis by direct sequencing of the MEN1 gene amplified by PCR. A hyperplastic parathyroid gland obtained from a family member served for a loss of heterozygosity (LOH) study. Results: Three members from two generations in this kindred were found to have primary hyperparathyroidism, while none had clinical or biochemical evidence of MEN1, MEN2 or hyperparathyroidismjaw tumor syndrome. Analysis of germline DNA in the proband showed a missense mutation (GGC → GAC) at codon 305 in exon 7 of the MEN1 gene that predicts an amino acid change from glycine to aspartic acid (G305D). This mutation segregated with primary hyperparathyroidism in the kindred, and, in addition, there were two asymptomatic mutant-gene carriers at relatively advanced ages. In contrast, the mutation was not detected in genomic DNA from five unaffected individuals and from 50 healthy subjects. The LOH study showed a loss of the wild-type allele, which confirmed that a functional defect of the MEN1 gene product, menin, is etiological for FIHP. Conclusions: FIHP is a genetically heterogeneous disease with a subset linked to MEN1, most likely representing a variant of MEN1. The late onset and the reduced penetrance of disease found in this kindred may be related to the site and the type of mutation, although the precise mechanism involved is unknown at present.

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We report a case of type 1 diabetes onset and recurrence of Graves' disease during pegylated interferon (PEG-IFN)-alpha plus ribavirin treatment for chronic hepatitis C. The patient was a 55-year-old woman diagnosed with chronic hepatitis at age 46 years. She was treated for Graves' disease at 50 years of age. Because Graves' disease remitted, PEG-IFN-alpha plus ribavirin treatment was started for chronic hepatitis C. She was examined because of complaints of general fatigue, weight loss, and palpitations after 24 weeks of the treatment. She was diagnosed with a recurrence of Graves' disease, and methimazole treatment was started. However, she complained of malaise, thirst, polyuria, and loss of body weight. Her fasting blood glucose level was 292 mg/dL and HbA1c was 9.3%. Serum anti-GAD (glutamic acid decarboxylase) antibodies were 2.2 U/mL. She was diagnosed with type 1 diabetes with ketosis, and insulin treatment was started. Serum anti-GAD antibodies gradually increased to 15.1 U/mL. Graves' disease and type 1 diabetes are often complicated, and the coincidental occurrence of these 2 diseases is known as autoimmune polyglandular syndrome type III. However, only a few cases have shown that these diseases occur after IFN treatment.

A malignant pheochromocytoma is described in a 71-year-old man. Osseous metastases became manifest 12 years after successful removal of the primary tumor which originated in paraganglionic tissue near the right adrenal gland. Although the patient had no symptomsof catecholamine excess initially, hypertension, tachycardia and excessive sweating appeared several months before his death, concomitantly with a sharp increase in noradrenaline secretion due to an accelerated growth of metastatic tumors. Since there is no histologic criterion of malignancy in this neoplasm, it would be prudent to consider every case of pheochromocytomaas potentially malignant and to followup carefully for a long time after removal of the primary tumor. (Internal Medicine 39: 820-825, 2000)

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