CONTEXT: Familial pheochromocytoma (PCC) has been associated with germline mutations in 16 genes. Here we investigated three siblings presenting with bilateral pheochromocytomas. In addition, the index patient also exhibited renal oncocytoma and erythrocytosis, whereas the second sibling presented with a lymph node metastasis. DESIGN: First, single-nucleotide polymorphism array and exome sequencing were performed on germline and PCC-derived DNA to identify genomic alterations in the index patient. Second, alterations were confirmed and validated by Sanger sequencing, analyzed by (multiplexed) PCR to determine the loss of the wild-type allele, and investigated by immunohistochemistry in the tumors of the three siblings. RESULTS: The index patient's germline DNA revealed a large complex genomic alteration encompassing the intragenic and promoter regions of Myc-associated factor X (MAX) and alpha-(1,6)-fucosyltransferase (FUT8). In all three siblings the MAX alteration was confirmed, and the loss of the wild-type MAX and FUT8 alleles was demonstrated in all tumors. Uniparental disomy of chromosome 14q, previously demonstrated as a hallmark for MAX-related PCC, was shown in the index patient's PCC by single-nucleotide polymorphism array. Loss of MAX and FUT8 protein expression was demonstrated by immunohistochemistry in the tumors from the three siblings. CONCLUSIONS: Our results indicate that large genomic deletions of MAX should be considered in familial and bilateral PCC with prior negative testing for gene mutations. In addition, our results confirm that MAX is a tumor suppressor gene for renal oncocytomas.
CONTEXT: Familial pheochromocytoma (PCC) has been associated with germline mutations in 16 genes. Here we investigated three siblings presenting with bilateral pheochromocytomas. In addition, the index patient also exhibited renal oncocytoma and erythrocytosis, whereas the second sibling presented with a lymph node metastasis. DESIGN: First, single-nucleotide polymorphism array and exome sequencing were performed on germline and PCC-derived DNA to identify genomic alterations in the index patient. Second, alterations were confirmed and validated by Sanger sequencing, analyzed by (multiplexed) PCR to determine the loss of the wild-type allele, and investigated by immunohistochemistry in the tumors of the three siblings. RESULTS: The index patient's germline DNA revealed a large complex genomic alteration encompassing the intragenic and promoter regions of Myc-associated factor X (MAX) and alpha-(1,6)-fucosyltransferase (FUT8). In all three siblings the MAX alteration was confirmed, and the loss of the wild-type MAX and FUT8 alleles was demonstrated in all tumors. Uniparental disomy of chromosome 14q, previously demonstrated as a hallmark for MAX-related PCC, was shown in the index patient's PCC by single-nucleotide polymorphism array. Loss of MAX and FUT8 protein expression was demonstrated by immunohistochemistry in the tumors from the three siblings. CONCLUSIONS: Our results indicate that large genomic deletions of MAX should be considered in familial and bilateral PCC with prior negative testing for gene mutations. In addition, our results confirm that MAX is a tumor suppressor gene for renal oncocytomas.
Authors: Thomas G Papathomas; Diederik P D Suurd; Alfred K Lam; Ronald R de Krijger; Karel Pacak; Arthur S Tischler; Menno R Vriens Journal: Endocr Pathol Date: 2021-01-12 Impact factor: 3.943
Authors: Maria Currás-Freixes; Elena Piñeiro-Yañez; Cristina Montero-Conde; María Apellániz-Ruiz; Bruna Calsina; Veronika Mancikova; Laura Remacha; Susan Richter; Tonino Ercolino; Natalie Rogowski-Lehmann; Timo Deutschbein; María Calatayud; Sonsoles Guadalix; Cristina Álvarez-Escolá; Cristina Lamas; Javier Aller; Julia Sastre-Marcos; Conxi Lázaro; Juan C Galofré; Ana Patiño-García; Amparo Meoro-Avilés; Judith Balmaña-Gelpi; Paz De Miguel-Novoa; Milagros Balbín; Xavier Matías-Guiu; Rocío Letón; Lucía Inglada-Pérez; Rafael Torres-Pérez; Juan M Roldán-Romero; Cristina Rodríguez-Antona; Stephanie M J Fliedner; Giuseppe Opocher; Karel Pacak; Esther Korpershoek; Ronald R de Krijger; Laurent Vroonen; Massimo Mannelli; Martin Fassnacht; Felix Beuschlein; Graeme Eisenhofer; Alberto Cascón; Fátima Al-Shahrour; Mercedes Robledo Journal: J Mol Diagn Date: 2017-05-25 Impact factor: 5.568
Authors: Ozgur Mete; Sylvia L Asa; Anthony J Gill; Noriko Kimura; Ronald R de Krijger; Arthur Tischler Journal: Endocr Pathol Date: 2022-03-13 Impact factor: 3.943