Continuing Medical Education

CONTINUING MEDICAL EDUCATION Medicina (Kaunas) 2011;47(11):635-9 Carcinoma of Two Parathyroid Glands Caused by a Novel MEN1 Gene Mutation – a Rare Feature of the MEN 1 Syndrome Linas Juodelė1, Danielius Serapinas2, Gintaras Sabaliauskas3, Aurelija Krasauskienė4, Virgilijus Krasauskas5, Rasa Verkauskienė6, Diana Barkauskienė2, Elona Juozaitytė1 1Department of Oncology, Medical Academy, Lithuanian University of Health Sciences, 2Department of Pulmonology and Immunology, Medical Academy, Lithuanian University of Health Sciences, 3Department of Pathological Anatomy, Medical Academy, Lithuanian University of Health Sciences, 4Institute of Endocrinology, Medical Academy, Lithuanian University of Health Sciences, 5Department of Surgery, Medical Academy, Lithuanian University of Health Sciences, 6Department of Endocrinology, Medical Academy, Lithuanian University of Health Sciences, Lithuania Key words: multiple endocrine neoplasia type 1; parathyroid carcinoma; insulinoma; MEN1 gene. Summary. Multiple endocrine neoplasia type 1 (MEN 1) is a rare syndrome inherited in an autosomal dominant pattern, characterized by combinations of tumors of the parathyroid glands, pituitary gland, and pancreatic islet cells and more rare tumors of endocrine organs and nonen- docrine tissues. Germline mutations in the MEN1 gene are responsible for the MEN 1 syndrome, leading to an inactive form of menin protein. Benign lesions of the parathyroid glands are characteristic in patients with the MEN 1 syndrome; however, patients can develop parathyroid carcinomas very rarely. This report presents a clinical case of the MEN 1 syndrome: a 39-year-old woman underwent surgery for carcinoma of two parathyroid glands as well as was treated for pituitary prolactinoma, which caused infertility, and malignant insulinoma; the patient had multiple subcutaneous lipomas as well. Genetic analysis revealed a novel germline mutation in the MEN1 gene – a nucleotide insertion at codon 43 in exon 2 (c.129insA), which caused the occurrence of the MEN1 syndrome. The clinical case of the MEN 1 syndrome presented here is relevant in gathering the data on etiopathogenesis of not only MEN 1 syndrome, but an extremely rare pathology – parathyroid carcinoma – as well. Introduction MEN 1 syndrome (4). In the literature, the associa- Multiple endocrine neoplasia type 1 (MEN 1) is tion of the MEN 1 syndrome with parathyroid car- a rare syndrome inherited in an autosomal dominant cinoma has been reported very rare (5, 6), and not pattern, characterized by combinations of tumors of always mutations in the MEN1 gene are identifi ed the parathyroid glands, pituitary gland, and pancre- in patients (7). atic islet cells (1). Some patients may also develop benign adrenocortical, thyroid tumors; gastric, Case Report bronchial, and thymic carcinoid tumors; subcuta- Written informed consent was obtained from neous and visceral lipomas, cutaneous leiomyomas, all the participants, and the study was approved by angiofi bromas and collagenomas, ependymomas of the Bioethics Committee of Lithuanian University the spinal cord (1). The parathyroid lesions associ- of Health Sciences (former Kaunas University of ated with the MEN 1 syndrome – hyperplasia and Medicine). A 39-year-old woman was examined adenomas causing primary hyperparathyroidism – and treated for two enlarging masses palpable in the are usually benign, and carcinoma of the parathy- left and right lobes of the thyroid gland at the Clinic roid glands is very rarely diagnosed in patients with of Endocrinology, Hospital of Lithuanian Univer- the MEN 1 syndrome and it is not included in di- sity of Health Sciences. The patient complained agnostic clinical criteria of the MEN 1 syndrome. of general weakness, fatigue, weight loss, and bi- The MEN 1 syndrome is caused by germline muta- lateral galactorrhea as well. Lesions in the thyroid tions in the MEN1 tumor suppressor gene located were followed-up for 4 years (from the age of 35 in 11q13, which inactivate a protein, menin (2, 3). years). Repeat aspiration biopsy of the node in the Mutations in this gene are determined in approxi- left lobe of the thyroid gland showed atypical cells mately 90% of patients with clinically diagnosed suspicious for malignancy, which was not seen during previous cytologic examination. The patient Correspondence to L. Juodelė, Department of Oncology, Medical was found to have an increased plasma parathor- Academy, Lithuanian University of Health Sciences, Eivenių 2, 50028 Kaunas, Lithuania. E-mail: [email protected] mone level (34.3 pmol/L; normal range, 1.18–8.43 Medicina (Kaunas) 2011;47(11) 636 Linas Juodelė, Danielius Serapinas, Gintaras Sabaliauskas, et al. pmol/L) as well as calcium (3.34 mmol/L; normal mor, malignant cells were found. Pancreatoduode- range, 2.15–2.5 mmol/L; Ca2+ 1.5 mmol/L; nor- nal resection as well as resection of the left adrenal mal range, 0.98–1.13 mmol/L) and phosphorus gland was recommended for the patient; however, (0.73 mmol/L; normal range, 0.9–1.53 mmol/L) she refused further treatment. After 6 months, the concentrations. The patient had a 4-year history of patient experienced severe, recurrent hypoglycemic galactorrhea and amenorrhea (from the age of 35 episodes; she developed multiple liver and pulmo- years), which were detected some months earlier nary metastases and ascites. She died after 1.5 years than thyroid nodules; she was unable to conceive. following the fi rst surgery (at the age of 41 years). Elevated plasma prolactin level (>3600 mIU/L) and nuclear magnetic resonance imagining of the pitui- Family History tary gland led to the diagnosis of pituitary micropro- Fig. 2 shows the scheme of possible inheritance lactinoma (0.9×0.8×0.7 cm in size). Treatment with of the MEN 1 syndrome. A family history revealed bromocriptine (2.5–12.5 mg per day) resulted in a that the patient’s father (I-1) died due to compli- decrease in prolactin concentration to 76 mIU/L; cations of refractory gastric ulcer (possibly undiag- the return of menses was documented. After one nosed gastrinoma) at the age of 44 years. The pa- year of treatment with bromocriptine, the patient tient’s mother (I-2) was long-lived, and the cause became pregnant (at the age of 36 years) and gave of her death was not related to oncological disease. birth to a 2800-g full-term male infant. After birth, The patient’s sister (II-2) was healthy and had no the infant was breastfed for 14 months. clinical signs characteristic of the MEN 1 syndrome. Given that tumors in the thyroid were enlarg- No clinical signs typical of MEN 1 syndrome were ing, atypical cells were found at biopsy, and elevated noted in a 4-year-old patient’s son (III-1) as well. PTH level and symptoms of hyperparathyroidism were documented, the patient was suspected of har- Genetic Testing boring carcinoma of the left parathyroid gland as For genetic testing, patient’s DNA was extracted well as tumor of the right parathyroid gland (ad- from blood leukocytes using the SORPO® DNA enoma). The patient at the age of 39 years under- purifi cation kit (“Thermo Fisher Scientifi c” UAB, went thyroidectomy with parathyroidectomies and Lithuania) according to the standard protocol pre- neck lymphadenectomy as well. After the surgery, sented together with the kit. From 2 to 10 exons of developed hypocalcemia was corrected with cal- the MEN1 gene were amplifi ed (primers sequences cium supplements, and thyroid hormone replace- can be found at http://www.sciencemag.org and ment therapy for hypothyroidism was administered. http://www.nhgri.nih.gov). Their sequencing was Histological examination revealed carcinomas of the performed using a capillary sequencer, 3130xI Ge- two parathyroid glands: the right inferior parathy- netic Analyzer (Applied Biosystems, Foster City, roid carcinoma was 2.5 cm in diameter and the left CA, USA). Analysis of DNA sequencing results superior parathyroid carcinoma was 2.0 cm in diam- showed a nucleotide insertion at codon 43 in exon eter. Both the tumors grew penetrating the capsule 2 (c.129insA). Fig. 3 depicts DNA sequencing. of the parathyroid glands, invaded into the thyroid Due to this nucleotide insertion, codon 115 of the gland, and metastases of parathyroid carcinoma to MEN1 gene becomes a premature stop codon, lead- the right lobe of the thyroid gland were observed. ing to inactivation by producing a truncated form of Fig. 1 shows photomicrographs of both parathyroid menin, composed of only 114 amino acids. A search carcinomas. for this mutation in the Human Gene Mutation Da- Taking into account the combination of para- tabase performed on July 9, 2010, showed no analo- thyroid carcinoma and pituitary prolactinoma in gous mutation in the MEN1 gene. Therefore, we the patient, the MEN 1 syndrome was suspected. think that this is a novel mutation of the MEN1 During the examination of the patient, multiple gene, causing the MEN 1 syndrome. The patient’s subcutaneous lipomas (n=15) measuring between son (III-1) and sister (II-1) underwent genetic test- 1.5 and 4 cm in diameter were documented. Aim- ing as well: the son inherited an analogous mutation ing to detect other tumors typical of the MEN 1 in the MEN1 gene, and no mutation was found in syndrome, computed tomography of the abdomen the sister. was performed. A computed tomography scan con- fi rmed the presence of multiple tumors in the head Discussion and tail of the pancreas (between 1.1 and 3.2 cm in Parathyroid carcinoma is a very rare malignant diameter) as well as a metastatic focus about 1.1 cm tumor with an estimated incidence of 0.5%–1% in diameter in the hepatic segment S7. A sonogram among primary hyperparathyroidism cases except of the kidneys revealed calculi in the right kidney. A for Japan where this tumor is reported more fre- lesion measuring 1.2×1.5 cm in size was seen in the quently, in 5% of cases (8).

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