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      A patient with novel mutations causing MEN1 and hereditary multiple osteochondroma

      , 1 , 2 , 3
      Endocrinology, Diabetes & Metabolism Case Reports
      Bioscientifica Ltd
      Adult, Male, White, Germany, Bone, Parathyroid, Pituitary, Pituitary, MEN1, Hyperparathyroidism (primary), Pituitary adenoma, Non-functioning pituitary adenoma, Hereditary multiple osteochondroma, Osteoporosis, Visual field defect, Skeletal deformity, Bone pain, Genetic analysis, Testosterone, IGF1, FT4, Prolactin, Visual field assessment, Immunohistochemistry, PTH, Calcium (serum), phosphate (serum), Sestamibi scan, CT, X-ray, Octreotide scan, Ultrasound, Endosonography, Transsphenoidal surgery, Levothyroxine, Testosterone, Hydrocortisone, Glucocorticoids, Calcitriol, Gastroenterology, Unique/unexpected symptoms or presentations of a disease , March, 2015

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          We report of a male patient aged 32 years who presented with primary hyperparathyroidism. Three parathyroid glands were resected. At the age of 46 years, nervus facialis irritation was noted, and an MRI scan incidentally revealed a non-functioning pituitary adenoma with affection of the chiasma opticum. The patient underwent transsphenoidal operation resulting in pituitary insufficiency postoperatively. At the same time, primary hyperparathyroidism reoccurred and a parathyroid adenoma located at the thymus was resected. The mother of the patient died early due to multiple tumors. The patient was suspected to have multiple endocrine neoplasia type 1 (MEN1) and genetic analysis was performed. In addition, on clinical examination, multiple exostoses were noticed and an additional genetic analysis was performed. His father was reported to have multiple osteochondromas too. MEN1 was diagnosed in the patient showing a novel heterozygote mutation c.2T>A in exon 2, codon 1 (start codon ATG>AAG;p.Met1?) of the MEN1 gene. In genetic mutational analysis of the EXT1 gene, another not yet known mutation c.1418-2A>C was found in intron 5 of the EXT1 gene (heterozygotic). In conclusion, we report novel mutations of the EXT1 and the MEN1 genes causing hereditary multiple osteochondromas and MEN1 in one patient.

          Learning points

          • It is important to ask for the patient's family history in detail.

          • Patients with MEN1 are characterized by the occurrence of tumors in multiple endocrine tissues and nonendocrine tissues, most frequently parathyroid (95%), enteropancreatic neuroendocrine (50%), and anterior pituitary (40%) tissues.

          • Familiar MEN1 has a high degree of penetrance (80–95%) by the age over 50; however, combinations of the tumors may be different in members of the same family.

          • Patients with EXT1 gene mutations should be monitored for possible transformation of bone lesions into osteochondrosarcoma.

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          Most cited references8

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          Positional cloning of the gene for multiple endocrine neoplasia-type 1.

          Multiple endocrine neoplasia-type 1 (MEN1) is an autosomal dominant familial cancer syndrome characterized by tumors in parathyroids, enteropancreatic endocrine tissues, and the anterior pituitary. DNA sequencing from a previously identified minimal interval on chromosome 11q13 identified several candidate genes, one of which contained 12 different frameshift, nonsense, missense, and in-frame deletion mutations in 14 probands from 15 families. The MEN1 gene contains 10 exons and encodes a ubiquitously expressed 2.8-kilobase transcript. The predicted 610-amino acid protein product, termed menin, exhibits no apparent similarities to any previously known proteins. The identification of MEN1 will enable improved understanding of the mechanism of endocrine tumorigenesis and should facilitate early diagnosis.
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            Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses.

            Hereditary multiple exostoses (EXT; MIM 133700) is an autosomal dominant bone disorder characterized by the presence of multiple benign cartilage-capped tumors (exostoses). Besides suffering complications caused by the pressure of these exostoses on the surrounding tissues, EXT patients are at an increased risk for malignant chondrosarcoma, which may develop from an exostosis. EXT is genetically heterogeneous, and three loci have been identified so far: EXT1, on chromosome 8q23-q24; EXT2, on 11p11-p12; and EXT3, on the short arm of chromosome 19. The EXT1 and EXT2 genes were cloned recently, and they were shown to be homologous. We have now analyzed the EXT1 and EXT2 genes, in 26 EXT families originating from nine countries, to identify the underlying disease-causing mutation. Of the 26 families, 10 families had an EXT1 mutation, and 10 had an EXT2 mutation. Twelve of these mutations have never been described before. In addition, we have reviewed all EXT1 and EXT2 mutations reported so far, to determine the nature, frequency, and distribution of mutations that cause EXT. From this analysis, we conclude that mutations in either the EXT1 or the EXT2 gene are responsible for the majority of EXT cases. Most of the mutations in EXT1 and EXT2 cause premature termination of the EXT proteins, whereas missense mutations are rare. The development is thus mainly due to loss of function of the EXT genes, consistent with the hypothesis that the EXT genes have a tumor- suppressor function.
              • Record: found
              • Abstract: found
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              Is Open Access

              Mutations in the EXT1 and EXT2 genes in Spanish patients with multiple osteochondromas

              Multiple osteochondromas is an autosomal dominant skeletal disorder characterized by the formation of multiple cartilage-capped tumours. Two causal genes have been identified, EXT1 and EXT2, which account for 65% and 30% of cases, respectively. We have undertaken a mutation analysis of the EXT1 and EXT2 genes in 39 unrelated Spanish patients, most of them with moderate phenotype, and looked for genotype-phenotype correlations. We found the mutant allele in 37 patients, 29 in EXT1 and 8 in EXT2. Five of the EXT1 mutations were deletions identified by MLPA. Two cases of mosaicism were documented. We detected a lower number of exostoses in patients with missense mutation versus other kinds of mutations. In conclusion, we found a mutation in EXT1 or in EXT2 in 95% of the Spanish patients. Eighteen of the mutations were novel.

                Author and article information

                Endocrinol Diabetes Metab Case Rep
                Endocrinol Diabetes Metab Case Rep
                Endocrinology, Diabetes & Metabolism Case Reports
                Bioscientifica Ltd (Bristol )
                25 February 2015
                : 2015
                : 14-0120
                [1]Charité University Medicine , Berlin, Germany
                [2]Laboratory for Molecular Genetics , Hamburg, Germany
                [3]Institute of Pathology , HELIOS Klinikum Emil von Behring, Stiftung Oskar-Helene-Heim, Berlin, Germany
                [4]Endocrinology in Charlottenburg , Stuttgarter Platz 1, Berlin, D 10627, Germany
                This is an Open Access article distributed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License .

                : 30 January 2015
                : 25 February 2015
                Unique/Unexpected Symptoms or Presentations of a Disease

                adult,male,white,germany,bone,parathyroid,pituitary,men1,hyperparathyroidism (primary),pituitary adenoma,non-functioning pituitary adenoma,hereditary multiple osteochondroma,osteoporosis,visual field defect,skeletal deformity,bone pain,genetic analysis,testosterone,igf1,ft4,prolactin,visual field assessment,immunohistochemistry,pth,calcium (serum),phosphate (serum),sestamibi scan,ct,x-ray,octreotide scan,ultrasound,endosonography,transsphenoidal surgery,levothyroxine,hydrocortisone,glucocorticoids,calcitriol,gastroenterology,unique/unexpected symptoms or presentations of a disease,march,2015


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