2
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      A Novel, Likely Pathogenic MAX Germline Variant in a Patient With Unilateral Pheochromocytoma

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Context

          Inherited MYC-associated factor X ( MAX) gene pathogenic variants (PVs) increase risk for pheochromocytomas (PCCs) and/or paragangliomas (PGLs) in adults and children. There is little clinical experience with such mutations.

          Objective

          This report highlights an important approach.

          Methods

          Clinical assessment, including blood chemistry, imaging studies, and genetic testing were performed.

          Results

          A 38-year-old Hispanic woman was diagnosed with PCC in 2015, treated with adrenalectomy, and referred to endocrinology clinic. Notably, she presented to her primary care physician 3 years earlier complaining of left flank pain, intermittent diaphoresis, and holocranial severe headache. We confirmed severe hypertension (180/100 mm Hg) over multiple antihypertensive regimens. Biochemical and radiological studies workup revealed high plasma metanephrine of 255 pg/mL (normal range, < 65 pg/mL) and plasma normetanephrine of 240 pg/mL (normal range, < 196 pg/mL). A noncontrast computed tomography scan of the abdomen revealed a 4.2 × 4.3 × 4.9-cm, round-shaped and heterogenous contrast enhancement of the left adrenal gland, and a 2-mm nonobstructive left kidney stone. A presumptive diagnosis of secondary hypertension was made. After pharmacological therapy, laparoscopic left adrenalectomy was performed and confirmed the diagnosis of pheochromocytoma. Based on her age, family history, and a high suspicion for genetic etiology, genetic testing was performed that revealed the presence of a novel likely pathogenic variant involving a splice consensus sequence in the MAX gene, designated c0.64-2A > G.

          Conclusion

          The phenotype of MAX PV-related disease and paraganglioma are highlighted. The novel c0.64-2A > G mutation is reported here and should be considered in the diagnostic workup of similar cases.

          Related collections

          Most cited references26

          • Record: found
          • Abstract: not found
          • Article: not found

          Pheochromocytoma and Paraganglioma

            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            Splicing mutations in human genetic disorders: examples, detection, and confirmation

            Precise pre-mRNA splicing, essential for appropriate protein translation, depends on the presence of consensus “cis” sequences that define exon-intron boundaries and regulatory sequences recognized by splicing machinery. Point mutations at these consensus sequences can cause improper exon and intron recognition and may result in the formation of an aberrant transcript of the mutated gene. The splicing mutation may occur in both introns and exons and disrupt existing splice sites or splicing regulatory sequences (intronic and exonic splicing silencers and enhancers), create new ones, or activate the cryptic ones. Usually such mutations result in errors during the splicing process and may lead to improper intron removal and thus cause alterations of the open reading frame. Recent research has underlined the abundance and importance of splicing mutations in the etiology of inherited diseases. The application of modern techniques allowed to identify synonymous and nonsynonymous variants as well as deep intronic mutations that affected pre-mRNA splicing. The bioinformatic algorithms can be applied as a tool to assess the possible effect of the identified changes. However, it should be underlined that the results of such tests are only predictive, and the exact effect of the specific mutation should be verified in functional studies. This article summarizes the current knowledge about the “splicing mutations” and methods that help to identify such changes in clinical diagnosis.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma.

              Hereditary pheochromocytoma (PCC) is often caused by germline mutations in one of nine susceptibility genes described to date, but there are familial cases without mutations in these known genes. We sequenced the exomes of three unrelated individuals with hereditary PCC (cases) and identified mutations in MAX, the MYC associated factor X gene. Absence of MAX protein in the tumors and loss of heterozygosity caused by uniparental disomy supported the involvement of MAX alterations in the disease. A follow-up study of a selected series of 59 cases with PCC identified five additional MAX mutations and suggested an association with malignant outcome and preferential paternal transmission of MAX mutations. The involvement of the MYC-MAX-MXD1 network in the development and progression of neural crest cell tumors is further supported by the lack of functional MAX in rat PCC (PC12) cells and by the amplification of MYCN in neuroblastoma and suggests that loss of MAX function is correlated with metastatic potential.
                Bookmark

                Author and article information

                Contributors
                Journal
                J Endocr Soc
                J Endocr Soc
                jes
                Journal of the Endocrine Society
                Oxford University Press (US )
                2472-1972
                01 August 2021
                03 June 2021
                03 June 2021
                : 5
                : 8
                : bvab085
                Affiliations
                [1 ] Neuroendocrinology Clinic, Department of Endocrinology and Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán , Tlalpan 14000, Mexico City, Mexico
                [2 ] Department of Genetics, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán , Tlalpan 14000, Mexico City, Mexico
                [3 ] Department of Hemato-Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán , Tlalpan 14000, Mexico City, Mexico
                [4 ] Department of Pathology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán , Tlalpan 14000, Mexico City, Mexico
                [5 ] Department of Radiology and Imaging, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán , Tlalpan 14000, Mexico City, Mexico
                [6 ] City of Hope Cancer Center , Duarte, California 91010, USA
                Author notes
                Correspondence: Daniel Cuevas-Ramos, MD, PhD, Neuroendocrinology Clinic, Department of Endocrinology and Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Sección XVI, Tlalpan 14000, Mexico City, Mexico. Email: daniel.cuevasr@ 123456incmnsz.mx .
                Author information
                https://orcid.org/0000-0003-2156-3753
                https://orcid.org/0000-0001-6330-670X
                Article
                bvab085
                10.1210/jendso/bvab085
                8218934
                0a286539-1f35-4fa5-a258-3dbad7dc0433
                © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 04 May 2021
                : 22 June 2021
                Page count
                Pages: 6
                Funding
                Funded by: Breast Cancer Research Foundation, DOI 10.13039/100001006;
                Award ID: BCRF-19-172
                Funded by: Conquer Cancer Research Professorship in Breast Cancer Disparities;
                Funded by: National Cancer Institute, DOI 10.13039/100000054;
                Funded by: National Institutes of Health, DOI 10.13039/100000002;
                Award ID: RC4CA153828
                Categories
                Clinical Research Articles
                AcademicSubjects/MED00250

                max gene,pheochromocytoma,paraganglioma,adrenal,hypertension

                Comments

                Comment on this article