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      13-year-old tuberous sclerosis patient with renal cell carcinoma associated with multiple renal angiomyolipomas developing multifocal micronodular pneumocyte hyperplasia

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          Abstract

          Background

          The autosomal dominant tumor syndrome tuberous sclerosis complex is caused by the mutated TSC1 gene, hamartin, and the TSC2 gene, tuberin. Patients with this complex develop typical cutaneus symptoms such as peau chagrin or angiofibromas of the skin as well as other lesions such as astrocytomas in the brain and lymphangioleiomyomatosis in the lung. Only a few tuberous sclerosis patients have been described who showed a multifocal micronodular pneumocyte hyperplasia of the lung. Another benign tumor which often occurs together with tuberous sclerosis is the angiomyolipoma of the kidney. Furthermore, an increased incidence of renal cell carcinoma in connection with tuberous sclerosis has also been proven.

          Case presentation

          We report a 13-year-old white girl with epilepsy and hypopigmented skin lesions. Radiological studies demonstrated the typical cortical tubers leading to the diagnosis of tuberous sclerosis. In the following examinations a large number of angiomyolipomas were found in both kidneys. One lesion showed an increasing size and tumor like aspects in magnetic resonance imaging. The pathological examination of the following tumorectomy demonstrated an unclassified renal cell carcinoma. Four months postoperatively, a follow-up computer tomography revealed multiple bilateral pulmonary nodules. To exclude lung metastases of the renal cell carcinoma, multiple open-lung biopsies were performed.

          Conclusion

          Here we report a diagnostically challenging case of a 13-year-old patient with tuberous sclerosis and angiomyolipomas of the kidney who developed an unclassified renal cell carcinoma as well as multifocal micronodular pneumocyte hyperplasia.

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          Most cited references16

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          Malignant tumors of the kidney, brain, and soft tissues in children and young adults with the tuberous sclerosis complex.

          The tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by seizures, mental retardation, and benign tumors of the brain, heart, skin, and kidney. Malignant tumors also can occur in patients with tuberous sclerosis, particularly in the kidney, although they occur less frequently than benign tumors. The types of malignancy that occur in TSC have not been characterized fully. Clinical and pathologic features of 8 malignant tumors from 6 TSC patients ranging in age from 22 months to 21 years are reviewed. Six tumors were renal, one was from the inguinal region, and one was from the brain. The tumors were analyzed for loss of heterozygosity (LOH) in the chromosomal regions of the TSC1, TSC2, and VHL genes. Three patients (ages 7, 8, and 20 years) had renal cell carcinomas (RCCs). Two of these patients had multifocal RCCs. All three patients with RCC also had prominent multifocal dysplasia of renal cyst epithelium. Two patients (ages 20 and 21 years) had malignant angiomyolipomas (1 renal and 1 inguinal). One patient (age 22 months) had a Grade 4 giant cell astrocytoma (glioblastoma multiforme). LOH in the region of the TSC2 gene was found, either in the malignant tumor or in benign tumors, in all five patients whose DNA could be analyzed. Children with TSC, as well as adults with the disease, are at risk for developing malignant tumors. Two types of renal malignancy occur in TSC: RCC, which appears to arise from dysplastic renal cyst epithelial cells, and malignant angiomyolipoma. Tumors cytologically similar to malignant angiomyolipomas also may occur at extrarenal sites. LOH analyses suggest that the majority of patients with TSC who develop malignant tumors have germline TSC2, rather than TSC1, gene mutations.
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            Predisposition to renal carcinoma in the Eker rat is determined by germ-line mutation of the tuberous sclerosis 2 (TSC2) gene.

            Genetic predisposition to neoplasia often involves tumor suppressor genes. One such model of hereditary renal carcinoma was described in the rat by Eker. These tumors share morphologic similarities with human renal cancer. Linkage analysis localized the inherited mutation to rat chromosome band 10q12. This region is syntenic with human chromosome band 16p13.3, the site of the tuberous sclerosis 2 (TSC2) gene. A specific rearrangement of the rat homologue of TSC2 was found to cosegregate with carriers of the predisposing mutation. Tumors with or without loss of heterozygosity expressed only the mutant allele, consistent with the two-hit hypothesis. This mutation gave rise to an aberrant transcript that deletes the 3' end normally containing a region of homology with the catalytic domain of rap1GAP.
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              A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer.

              The Eker rat hereditary renal carcinoma (RC) is an excellent example of a mendelian dominant predisposition to a specific cancer in an experimental animal. We have previously established a new conserved linkage group on rat chromosome 10q and human chromosome 16p13.3, and shown that the Eker mutation is tightly linked to the tuberous sclerosis (Tsc2) gene. We now describe a germline mutation in the gene encoding Tsc2 caused by the insertion of an approximately 5 kilobase DNA fragment in the Eker rat, resulting in aberrant RNA expression from the mutant allele. The phenotype of tuberous sclerosis in humans differs from that of the Eker rat, except for the occurrence of renal tumours. The Eker rat may therefore provide insights into species-specific differences in tumourigenesis and/or phenotype-specific mutations.
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                Author and article information

                Journal
                BMC Clin Pathol
                BMC Clin Pathol
                BMC Clinical Pathology
                BioMed Central
                1472-6890
                2013
                5 February 2013
                : 13
                : 4
                Affiliations
                [1 ]Department of Pathology, University Medicine Göttingen, Robert-Koch-Str. 40, Göttingen, D-37075, Germany
                [2 ]Department of Neuroradiology, University Medicine Göttingen, Robert-Koch-Str. 40, Göttingen, D-37075, Germany
                [3 ]Department of Diagnostic Radiology, University Medicine Göttingen, Robert-Koch-Str. 40, Göttingen, D-37075, Germany
                Article
                1472-6890-13-4
                10.1186/1472-6890-13-4
                3568416
                23379654
                a9fb1352-2bdb-4746-b219-1162c574c263
                Copyright ©2013 Behnes et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 September 2012
                : 30 January 2013
                Categories
                Case Report

                Pathology
                angioleiomyolipoma,multifocal micronodular pneumocyte hyperplasia (mmph),renal cell carcinoma,tuberous sclerosis complex

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