Multiple Endocrine Tumors Associated with Germline MAX Mutations: Multiple Endocrine Neoplasia Type 5?

Amanda J. Seabrook; Jessica E. Harris; Sofia B. Velosa; Edward Kim; Aideen M. McInerney-Leo; Trisha Dwight; Jason I. Hockings; Nicholas G. Hockings; Judy Kirk; Paul J. Leo; Amanda J. Love; Catherine Luxford; Mhairi Marshall; Ozgur Mete; David J. Pennisi; Matthew A. Brown; Anthony J. Gill; Gregory I. Hockings; Roderick J. Clifton-Bligh; Emma L. Duncan

doi:10.1210/clinem/dgaa957

Multiple Endocrine Tumors Associated with Germline MAX Mutations: Multiple Endocrine Neoplasia Type 5?

Amanda J. Seabrook, Jessica E. Harris, Sofia B. Velosa, Edward Kim, Aideen M. McInerney-Leo, Trisha Dwight, Jason I. Hockings, Nicholas G. Hockings, Judy Kirk, Paul J. Leo, Amanda J. Love, Catherine Luxford, Mhairi Marshall, Ozgur Mete, David J. Pennisi, Matthew A. Brown, Anthony J. Gill, Gregory I. Hockings, Roderick J. Clifton-Bligh, Emma L. Duncan

Twin Research & Genetic Epidemiology

Research output: Contribution to journal › Article › peer-review

51 Citations (Scopus)

Abstract

CONTEXT: Pathogenic germline MAX variants are associated with pheochromocytoma and paraganglioma (PPGL), pituitary neuroendocrine tumors and, possibly, other endocrine and nonendocrine tumors. OBJECTIVE: To report 2 families with germline MAX variants, pheochromocytomas (PCs) and multiple other tumors. METHODS: Clinical, genetic, immunohistochemical, and functional studies at University hospitals in Australia on 2 families with germline MAX variants undergoing usual clinical care. The main outcome measures were 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 2 children (to date, without PC) with neuroendocrine tumors (paravertebral ganglioneuroma and abdominal neuroblastoma, respectively). One individual has acromegaly; immunohistochemistry of PC tissue showed positive growth hormone-releasing hormone staining. Another individual with previously resected PCs has pituitary enlargement and elevated insulin-like growth factor (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, multigland parathyroid adenomas, chondrosarcoma, and multifocal pulmonary adenocarcinomas. A truncating germline MAX variant (c.22G>T, p.Glu8*) was identified. CONCLUSION: Germline MAX mutations are associated with PCs, ganglioneuromas, neuroblastomas, pituitary neuroendocrine tumors, and, possibly, parathyroid adenomas, as well as nonendocrine tumors of chondrosarcoma and lung adenocarcinoma, suggesting MAX is a novel multiple endocrine neoplasia gene.

Original language	English
Pages (from-to)	1163-1182
Number of pages	20
Journal	The Journal of clinical endocrinology and metabolism
Volume	106
Issue number	4
DOIs	https://doi.org/10.1210/clinem/dgaa957
Publication status	Published - 1 Apr 2021

Keywords

MAX germline mutation
neuroendocrine tumor
paraganglioma
pheochromocytoma
pituitary adenoma

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1210/clinem/dgaa957

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Seabrook, A. J., Harris, J. E., Velosa, S. B., Kim, E., McInerney-Leo, A. M., Dwight, T., Hockings, J. I., Hockings, N. G., Kirk, J., Leo, P. J., Love, A. J., Luxford, C., Marshall, M., Mete, O., Pennisi, D. J., Brown, M. A., Gill, A. J., Hockings, G. I., Clifton-Bligh, R. J., & Duncan, E. L. (2021). Multiple Endocrine Tumors Associated with Germline MAX Mutations: Multiple Endocrine Neoplasia Type 5? The Journal of clinical endocrinology and metabolism, 106(4), 1163-1182. https://doi.org/10.1210/clinem/dgaa957

@article{1d76a6dbc5a244bc89210f0b7be07f9f,

title = "Multiple Endocrine Tumors Associated with Germline MAX Mutations: Multiple Endocrine Neoplasia Type 5?",

abstract = "CONTEXT: Pathogenic germline MAX variants are associated with pheochromocytoma and paraganglioma (PPGL), pituitary neuroendocrine tumors and, possibly, other endocrine and nonendocrine tumors. OBJECTIVE: To report 2 families with germline MAX variants, pheochromocytomas (PCs) and multiple other tumors. METHODS: Clinical, genetic, immunohistochemical, and functional studies at University hospitals in Australia on 2 families with germline MAX variants undergoing usual clinical care. The main outcome measures were 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 2 children (to date, without PC) with neuroendocrine tumors (paravertebral ganglioneuroma and abdominal neuroblastoma, respectively). One individual has acromegaly; immunohistochemistry of PC tissue showed positive growth hormone-releasing hormone staining. Another individual with previously resected PCs has pituitary enlargement and elevated insulin-like growth factor (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, multigland parathyroid adenomas, chondrosarcoma, and multifocal pulmonary adenocarcinomas. A truncating germline MAX variant (c.22G>T, p.Glu8*) was identified. CONCLUSION: Germline MAX mutations are associated with PCs, ganglioneuromas, neuroblastomas, pituitary neuroendocrine tumors, and, possibly, parathyroid adenomas, as well as nonendocrine tumors of chondrosarcoma and lung adenocarcinoma, suggesting MAX is a novel multiple endocrine neoplasia gene.",

keywords = "MAX germline mutation, neuroendocrine tumor, paraganglioma, pheochromocytoma, pituitary adenoma",

author = "Seabrook, {Amanda J.} and Harris, {Jessica E.} and Velosa, {Sofia B.} and Edward Kim and McInerney-Leo, {Aideen M.} and Trisha Dwight and Hockings, {Jason I.} and Hockings, {Nicholas G.} and Judy Kirk and Leo, {Paul J.} and Love, {Amanda J.} and Catherine Luxford and Mhairi Marshall and Ozgur Mete and Pennisi, {David J.} and Brown, {Matthew A.} and Gill, {Anthony J.} and Hockings, {Gregory I.} and Clifton-Bligh, {Roderick J.} and Duncan, {Emma L.}",

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: [email protected]. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = apr,

day = "1",

doi = "10.1210/clinem/dgaa957",

language = "English",

volume = "106",

pages = "1163--1182",

journal = "The Journal of clinical endocrinology and metabolism",

issn = "0021-972X",

publisher = "Endocrine Society",

number = "4",

}

Seabrook, AJ, Harris, JE, Velosa, SB, Kim, E, McInerney-Leo, AM, Dwight, T, Hockings, JI, Hockings, NG, Kirk, J, Leo, PJ, Love, AJ, Luxford, C, Marshall, M, Mete, O, Pennisi, DJ, Brown, MA, Gill, AJ, Hockings, GI, Clifton-Bligh, RJ & Duncan, EL 2021, 'Multiple Endocrine Tumors Associated with Germline MAX Mutations: Multiple Endocrine Neoplasia Type 5?', The Journal of clinical endocrinology and metabolism, vol. 106, no. 4, pp. 1163-1182. https://doi.org/10.1210/clinem/dgaa957

TY - JOUR

T1 - Multiple Endocrine Tumors Associated with Germline MAX Mutations

T2 - Multiple Endocrine Neoplasia Type 5?

AU - Seabrook, Amanda J.

AU - Harris, Jessica E.

AU - Velosa, Sofia B.

AU - Kim, Edward

AU - McInerney-Leo, Aideen M.

AU - Dwight, Trisha

AU - Hockings, Jason I.

AU - Hockings, Nicholas G.

AU - Kirk, Judy

AU - Leo, Paul J.

AU - Love, Amanda J.

AU - Luxford, Catherine

AU - Marshall, Mhairi

AU - Mete, Ozgur

AU - Pennisi, David J.

AU - Brown, Matthew A.

AU - Gill, Anthony J.

AU - Hockings, Gregory I.

AU - Clifton-Bligh, Roderick J.

AU - Duncan, Emma L.

N1 - Publisher Copyright: © 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: [email protected]. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/4/1

Y1 - 2021/4/1

N2 - CONTEXT: Pathogenic germline MAX variants are associated with pheochromocytoma and paraganglioma (PPGL), pituitary neuroendocrine tumors and, possibly, other endocrine and nonendocrine tumors. OBJECTIVE: To report 2 families with germline MAX variants, pheochromocytomas (PCs) and multiple other tumors. METHODS: Clinical, genetic, immunohistochemical, and functional studies at University hospitals in Australia on 2 families with germline MAX variants undergoing usual clinical care. The main outcome measures were 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 2 children (to date, without PC) with neuroendocrine tumors (paravertebral ganglioneuroma and abdominal neuroblastoma, respectively). One individual has acromegaly; immunohistochemistry of PC tissue showed positive growth hormone-releasing hormone staining. Another individual with previously resected PCs has pituitary enlargement and elevated insulin-like growth factor (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, multigland parathyroid adenomas, chondrosarcoma, and multifocal pulmonary adenocarcinomas. A truncating germline MAX variant (c.22G>T, p.Glu8*) was identified. CONCLUSION: Germline MAX mutations are associated with PCs, ganglioneuromas, neuroblastomas, pituitary neuroendocrine tumors, and, possibly, parathyroid adenomas, as well as nonendocrine tumors of chondrosarcoma and lung adenocarcinoma, suggesting MAX is a novel multiple endocrine neoplasia gene.

AB - CONTEXT: Pathogenic germline MAX variants are associated with pheochromocytoma and paraganglioma (PPGL), pituitary neuroendocrine tumors and, possibly, other endocrine and nonendocrine tumors. OBJECTIVE: To report 2 families with germline MAX variants, pheochromocytomas (PCs) and multiple other tumors. METHODS: Clinical, genetic, immunohistochemical, and functional studies at University hospitals in Australia on 2 families with germline MAX variants undergoing usual clinical care. The main outcome measures were 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 2 children (to date, without PC) with neuroendocrine tumors (paravertebral ganglioneuroma and abdominal neuroblastoma, respectively). One individual has acromegaly; immunohistochemistry of PC tissue showed positive growth hormone-releasing hormone staining. Another individual with previously resected PCs has pituitary enlargement and elevated insulin-like growth factor (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, multigland parathyroid adenomas, chondrosarcoma, and multifocal pulmonary adenocarcinomas. A truncating germline MAX variant (c.22G>T, p.Glu8*) was identified. CONCLUSION: Germline MAX mutations are associated with PCs, ganglioneuromas, neuroblastomas, pituitary neuroendocrine tumors, and, possibly, parathyroid adenomas, as well as nonendocrine tumors of chondrosarcoma and lung adenocarcinoma, suggesting MAX is a novel multiple endocrine neoplasia gene.

KW - MAX germline mutation

KW - neuroendocrine tumor

KW - paraganglioma

KW - pheochromocytoma

KW - pituitary adenoma

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U2 - 10.1210/clinem/dgaa957

DO - 10.1210/clinem/dgaa957

M3 - Article

C2 - 33367756

AN - SCOPUS:85100468477

SN - 0021-972X

VL - 106

SP - 1163

EP - 1182

JO - The Journal of clinical endocrinology and metabolism

JF - The Journal of clinical endocrinology and metabolism

IS - 4

ER -

Multiple Endocrine Tumors Associated with Germline MAX Mutations: Multiple Endocrine Neoplasia Type 5?

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Keywords

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