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Background <p>Multiple endocrine neoplasia type 5 (MEN5) is an emerging syndrome caused by germline pathogenic variants involving the <i>MYC Associated Factor X (MAX)</i> gene. Affected individuals typically have pheochromocytomas, often bilateral, at a relatively early age. In <i>MAX</i> pheochromocytoma cohorts, pituitary adenomas are rarely reported. The role of <i>MAX</i> as a tumor suppressor gene in the pituitary gland has not been directly proven to date.</p> Methods <p>The propositus came from a pheochromocytoma kindred with a germline pathogenic <i>MAX</i> variant c.97 C&gt;T (p.R33*). In his late thirties he developed asynchronous bilateral pheochromocytomas and underwent bilateral adrenalectomy. At age 46, he developed hyperprolactinemia (45.1 μg/L; 3x ULN) and increased IGF-1 (460 ng/mL; 1.9x ULN). Total testosterone was low (1.5 ng/mL) as was LH (1.2 IU/L). Pituitary MRI showed a microadenoma (6 mm), which was resected and his prolactin, IGF-1, and testosterone levels normalized. A&#xa0;Pituitary adenoma was confirmed on pathology, which showed positivity for prolactin only and a Ki67 of 2%. </p> Results <p><i>MAX</i> immunohistochemical staining was lost in the pituitary adenoma cells. Tumoral DNA analysis (120X read depth) showed that at the <i>MAX</i> locus the pathogenic variant c.97 C&gt;T constituted &gt; 90% of the sequencing reads supporting tumoral loss of heterozygosity (LOH).</p> Conclusions <p>Loss of MAX staining and the identification of tumor LOH at the <i>MAX</i> locus confirms pituitary adenomas as a component tumor in the emerging MEN5 syndrome due to germline pathogenic <i>MAX</i> variants.</p>

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Loss of heterozygosity and absence of MAX immunostaining in a prolactinoma associated with multiple endocrine neoplasia type 5 (MEN5)

  • 期刊论文

  • 发表日期：

    2025年11月12日

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  • Brigitte Delemer,
  • Simona M. Florea,
  • Benedicte Decoudier,
  • Camille Boulagnon-Rombi,
  • Bhargavi Karna,
  • Natalia S. Pellegata,
  • Alexandre Buffet,
  • Albert Beckers,
  • Patrick Pétrossians,
  • Adrian F. Daly

摘要

Background

Multiple endocrine neoplasia type 5 (MEN5) is an emerging syndrome caused by germline pathogenic variants involving the MYC Associated Factor X (MAX) gene. Affected individuals typically have pheochromocytomas, often bilateral, at a relatively early age. In MAX pheochromocytoma cohorts, pituitary adenomas are rarely reported. The role of MAX as a tumor suppressor gene in the pituitary gland has not been directly proven to date.

Methods

The propositus came from a pheochromocytoma kindred with a germline pathogenic MAX variant c.97 C>T (p.R33*). In his late thirties he developed asynchronous bilateral pheochromocytomas and underwent bilateral adrenalectomy. At age 46, he developed hyperprolactinemia (45.1 μg/L; 3x ULN) and increased IGF-1 (460 ng/mL; 1.9x ULN). Total testosterone was low (1.5 ng/mL) as was LH (1.2 IU/L). Pituitary MRI showed a microadenoma (6 mm), which was resected and his prolactin, IGF-1, and testosterone levels normalized. A Pituitary adenoma was confirmed on pathology, which showed positivity for prolactin only and a Ki67 of 2%.

Results

MAX immunohistochemical staining was lost in the pituitary adenoma cells. Tumoral DNA analysis (120X read depth) showed that at the MAX locus the pathogenic variant c.97 C>T constituted > 90% of the sequencing reads supporting tumoral loss of heterozygosity (LOH).

Conclusions

Loss of MAX staining and the identification of tumor LOH at the MAX locus confirms pituitary adenomas as a component tumor in the emerging MEN5 syndrome due to germline pathogenic MAX variants.