A Novel Phenotype of Germline Pathogenic Variants in MAX: Concurrence of Pheochromocytoma and Ganglioneuroma in a Chinese Family and Literature Review.

Xiaoyan Chang,Yunying Cui,Xiaosen Ma,Shuchun Chen,Zelin Li,Anli Tong

doi:10.3389/fendo.2020.00558

Abstract

Background: MYC associated factor X (MAX) is a tumor suppressor gene and has been identified as one of the pathogenic genes of hereditary pheochromocytoma (PCC). To date, there have been no reports of ganglioneuroma (GN) with MAX variants.Case Presentation: The proband was a 45-years-old Chinese female with paroxysmal hypertension and palpitations who had undergone adrenalectomy for PCC 14 years ago. Her plasma free normetanephrine and 24-h urinary norepinephrine excretion were significantly increased, and abdominal computed tomography (CT) revealed an irregular mass in the left adrenal region, suggesting a recurrence of PCC. The mass was surgically removed and pathologically diagnosed as PCC with lymph node metastasis. The proband's son suffered from paroxysmal hypertension and palpitations. His plasma free metanephrine levels were normal. CT revealed a mass in the right adrenal. The tumor was surgically removed, and the pathological diagnosis was GN. Genetic testing of peripheral blood DNA revealed that the proband and her son had germline pathogenic MAX variant c.C97T, p.Arg33Ter, while proband's parents did not have MAX variants. Tumor DNA sequencing showed the same MAX variant (c.C97T, p.Arg33Ter) in PCC of the proband and GN of her son, both with retention of heterozygosity. Immunohistochemistry demonstrated loss of MAX protein expression in most tumor cells in PCC of the proband and some Schwannian cells in GN of the proband's son.Conclusion: We report a family with a new clinical phenotype of germline pathogenic variants in MAX who developed both PCC and GN. Germline pathogenic variants in MAX may contribute to the development of GN. Our findings suggest that it is not just paternally inherited MAX variants that can cause tumors.

Highlights

MYC associated factor X (MAX), a tumor suppressor gene encoding MAX protein, locates on chromosome 14q23.3
Germline MAX variants have been associated with PCC/PGL and renal oncocytoma, while somatic MAX mutations have been linked to the formation of other tumors such as endometrioid carcinoma and colon cancer [4]
This case is the first report of GN in a patient with germline MAX variants, suggesting the possibility of germline pathogenic MAX variants contributing to the development of GN

Summary

A Novel Phenotype of Germline Pathogenic Variants in MAX

Concurrence of Pheochromocytoma and Ganglioneuroma in a Chinese Family and Literature Review. Reviewed by: Letizia Canu, University of Florence, Italy Fady Hannah-Shmouni, National Institutes of Health (NIH), United States. Specialty section: This article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology. Xiaoyan Chang 1†, Zelin Li 2,3†, Xiaosen Ma 2, Yunying Cui 2, Shuchun Chen 3 and Anli Tong 2*

Background

Conclusion

INTRODUCTION

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ETHICS STATEMENT