Amanda J Seabrook1,2, Jessica E Harris3, Sofia B Velosa4, Edward Kim1,2, Aideen M McInerney-Leo5, Trisha Dwight1,2, Jason I Hockings6, Nicholas G Hockings7, Judy Kirk8, Paul J Leo9, Amanda J Love10, Catherine Luxford1,2, Mhairi Marshall9, Ozgur Mete11,12, David J Pennisi9, Matthew A Brown13, Anthony J Gill2,14,15, Gregory I Hockings16,17, Roderick J Clifton-Bligh1,2,18, Emma L Duncan9,17,19,20. 1. Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, Sydney, NSW, Australia, 2065. 2. The University of Sydney, Sydney, NSW, Australia, 2006. 3. The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia, 4102. 4. Noosa Hospital, Noosaville, QLD, Australia, 4566. 5. Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, 4102. 6. Dandenong Hospital, Dandenong, VIC, Australia, 3175. 7. Science Department, Carey Baptist Grammar School, Kew, VIC, Australia, 3101. 8. Familial Cancer Service, Westmead Hospital, Sydney, NSW, Australia, 2145. 9. Australian Translational Genomics Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT), Translational Research Institute, Woolloongabba, QLD, Australia, 4102. 10. Department of Endocrinology, Royal Brisbane and Women's Hospital, Herston, QLD, Australia. 11. Department of Pathology, University Health Network, Toronto, Ontario, Canada, 416. 12. Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Toronto, Canada. 13. Guy's and St Thomas' NHS Foundation Trust and King's College London NIHR Biomedical Research Centre, King's College London, London, United Kingdom, LS. 14. NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW, Australia. 15. Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, NSW, Australia, 2064. 16. Endocrinology Unit, Greenslopes Private Hospital, Brisbane, QLD, Australia. 17. University of Queensland Faculty of Medicine, The University of Queensland, Brisbane, QLD. 18. Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia. 19. Department of Twin Research & Genetic Epidemiology, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London; St Thomas' Campus, London, United Kingdom, EH. 20. Department of Endocrinology, Guy's and St Thomas' NHS Foundation Trust, United Kingdom, SE1 9RT.
Abstract
CONTEXT: Pathogenic germline MAX variants are associated with pheochromocytoma and paraganglioma (PPGL), pituitary neuroendocrine tumors and, possibly, other endocrine and non-endocrine tumors. OBJECTIVE: To report two families with germline MAX variants, pheochromocytomas (PC) and multiple other tumors. DESIGN: Clinical, genetic, immunohistochemical, and functional studies. SETTING: University Hospitals in Australia. PARTICIPANTS: Two families with germline MAX variants. INTERVENTIONS: Usual clinical care. MAIN OUTCOME MEASURES: Phenotyping; germline and tumor sequencing; immunohistochemistry of PC and other tumors; functional studies of MAX variants. RESULTS: Family A has multiple individuals with PC (including bilateral and metastatic disease) and two children (to date, without PC) with neuroendocrine tumors (paravertebral ganglioneuroma and abdominal neuroblastoma, respectively). One individual has acromegaly; immunohistochemistry of PC tissue showed positive GHRH staining. Another individual with previously resected PCs has pituitary enlargement and elevated IGF-1. A germline MAX variant (c.200C>A, p.Ala67Asp) was identified in all individuals with PC and both children, with loss-of-heterozygosity in PC tissue. Immunohistochemistry showed loss of MAX staining in PCs and other neural crest tumors. In vitro studies confirmed the variant as loss-of-function. In Family B, the proband has bilateral and metastatic PC, prolactin-producing pituitary tumor, multi-gland parathyroid adenomas, chondrosarcoma, and multifocal pulmonary adenocarcinomas. A truncating germline MAX variant (c.22G>T, p.Glu8*) was identified. CONCLUSIONS: Germline MAX mutations are associated with PCs, ganglioneuromas, neuroblastomas, pituitary neuroendocrine tumors, and, possibly, parathyroid adenomas, as well as non-endocrine tumors of chondrosarcoma and lung adenocarcinoma, suggesting MAX is a novel multiple endocrine neoplasia gene.
CONTEXT: Pathogenic germline MAX variants are associated with pheochromocytoma and paraganglioma (PPGL), pituitary neuroendocrine tumors and, possibly, other endocrine and non-endocrine tumors. OBJECTIVE: To report two families with germline MAX variants, pheochromocytomas (PC) and multiple other tumors. DESIGN: Clinical, genetic, immunohistochemical, and functional studies. SETTING: University Hospitals in Australia. PARTICIPANTS: Two families with germline MAX variants. INTERVENTIONS: Usual clinical care. MAIN OUTCOME MEASURES: Phenotyping; germline and tumor sequencing; immunohistochemistry of PC and other tumors; functional studies of MAX variants. RESULTS: Family A has multiple individuals with PC (including bilateral and metastatic disease) and two children (to date, without PC) with neuroendocrine tumors (paravertebral ganglioneuroma and abdominal neuroblastoma, respectively). One individual has acromegaly; immunohistochemistry of PC tissue showed positive GHRH staining. Another individual with previously resected PCs has pituitary enlargement and elevated IGF-1. A germline MAX variant (c.200C>A, p.Ala67Asp) was identified in all individuals with PC and both children, with loss-of-heterozygosity in PC tissue. Immunohistochemistry showed loss of MAX staining in PCs and other neural crest tumors. In vitro studies confirmed the variant as loss-of-function. In Family B, the proband has bilateral and metastatic PC, prolactin-producing pituitary tumor, multi-gland parathyroid adenomas, chondrosarcoma, and multifocal pulmonary adenocarcinomas. A truncating germline MAX variant (c.22G>T, p.Glu8*) was identified. CONCLUSIONS: Germline MAX mutations are associated with PCs, ganglioneuromas, neuroblastomas, pituitary neuroendocrine tumors, and, possibly, parathyroid adenomas, as well as non-endocrine tumors of chondrosarcoma and lung adenocarcinoma, suggesting MAX is a novel multiple endocrine neoplasia gene.
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
Authors: Beata Rak-Makowska; Bernard Khoo; Piya Sen Gupta; P Nicholas Plowman; Ashley B Grossman; Márta Korbonits Journal: J Endocr Soc Date: 2022-06-03