Germinal defects of SDHx genes in patients with isolated pituitary adenoma

in European Journal of Endocrinology
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  • 1 Aix Marseille Univ, APHM, INSERM, MMG, Hospital La Conception, Laboratory of Molecular Biology, Marseille, France
  • 2 Department of Endocrinology, Hospital La Conception, APHM, Marseille, France
  • 3 Department of Pathology, Hospital La Timone, APHM, Marseille, France
  • 4 Department of Endocrinology, Hospital Lapeyronie, CHU Montpellier, Montpellier, France
  • 5 Department of Endocrinology, Hospital Larrey, CHU Toulouse, Toulouse, France
  • 6 Aix Marseille University, APHM, INSERM, MMG, Hospital La Conception, Department of Endocrinology, Marseille, France

Correspondence should be addressed to P Romanet; Email: pauline.romanet@ap-hm.fr
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Background:

The ‘3PAs’ syndrome, associating pituitary adenoma (PA) and pheochromocytoma/paraganglioma (PPGL), is sometimes associated with mutations in PPGL-predisposing genes, such as SDHx or MAX. In ’3PAs’ syndrome, PAs can occur before PPGL, suggesting a new gateway into SDHx/MAX-related diseases.

Objective:

To determine the SDHx/MAX mutation prevalence in patients with isolated PAs and characterize PAs of patients with SDHx/MAX mutations.

Design:

Genes involved in PAs (AIP/MEN1/CDKN1B) or PPGLs (SDHx/MAX) were sequenced in patients with isolated PAs. We then conducted a review of cases of PA in the setting of ’3PAs’ syndrome.

Results:

A total of 263 patients were recruited. Seven (likely) pathogenic variants were found in AIP, two in MEN1, two in SDHA, and one in SDHC. The prevalence of SDHx mutations reached 1.1% (3/263). Of 31 reported patients with PAs harboring SDHx/MAX mutations (28 published cases and 3 cases reported here), 6/31 (19%) developed PA before PPGL and 8/31 (26%) had isolated PA. The age of onset was later than in patients with AIP/MEN1 mutations. PAs were mainly macroprolactinomas and showed intracytoplasmic vacuoles seen on histopathology.

Conclusions:

We discovered SDHx mutations in patients bearing PA who had no familial or personal history of PPGL. However, the question of incidental association remains unresolved and data to determine the benefit of SDHx/MAX screening in these patients are lacking. We recommend that patients with isolated PA should be carefully examined for a family history of PPGLs. A family history of PPGL, as well as the presence of intracytoplasmic vacuoles in PA, requires SDHx/MAX genetic testing of patients.

Supplementary Materials

    • Supplemental Table 1. Clinical characteristics of the patients included in this study F: female, M: male, NA: not available, PA: pituitary adenoma, PRL: prolactinoma, ACTH: corticotropinoma, GH: somatotropinoma, NFPA: non-functional pituitary adenoma
    • Supplemental Table 2. Clinical and genetic characteristics of the patients harbouring MEN1 or AIP pathogenic or likely pathogenic variants in this study. F: female, M: male, Yrs: years, PRL: prolactin, GH: growth hormone, ACTH: adrenocorticotropic hormone, NFPA: non-functional pituitary adenoma, PA: pituitary adenoma, PV: pathologic variant, LPV: likely pathogenic variant; macroadenoma is defined by a diameter >10 mm, microadenoma is defined by a diameter <10 mm.*Classification using ACMG guidelines for classification of sequence variants (12).
    • Supplemental Table 3. Clinical and genetic characteristics of the patients with variants of uncertain significance* in this study F: female, M: male, NFPA: non-functional pituitary adenoma, yrs: years
    • Supplemental table 4. Patients with “3PA” syndrome with personal PPGL bearing SDHx/MAX mutations, from published cases F: female, M: male, PRL: prolactin, GH: growth hormone, PPGL: pheochromocytoma/paraganglioma, P: pheochromocytoma, PGL: paraganglioma, HNPGL: head and neck paraganglioma, LOH: loss of heterozygosity, IHC: immunohistochemical analysis, MEN1: multiple endocrine neoplasia type 1, pNET: pancreatic neuroendocrine tumor, MTC: medullary thyroid carcinoma, NFPA: non-functional pituitary adenoma, PTC: papillary thyroid carcinoma, GIST: gastro-intestinal stromal tumor, HPTH: hyperparathyroidism, NA: not available, NP: not performed, LPV: likely pathogenic variant, PV: pathologic variant, VUS: variant of uncertain significance.*Classification using ACMG guidelines for classification of sequence variants (12).
    • Supplemental table 5. Patients with “3PA” syndrome with isolated PA and familial PPGL bearing SDHx mutations from published cases. F: female, M: male, yrs: years, PA: pituitary adenoma, PRL: prolactin, P: pheochromocytoma, PGL: paraganglioma, NFPA: non-functional pituitary adenoma, LOH: loss of heterozygosity, IHC: immune histochemical analysis, PV: pathologic variant, NA: not available, *Classification using ACMG guidelines for classification of sequence variants (12).
    • Supplemental table 6. Characteristics of patients with pituitary adenoma in genetic and sporadic conditions NA: not available; M: male; F: female, PA: pituitary adenoma, PRL: prolactinome, macroPRL: macroprolactinoma, GH: somatotropinoma, NFPA: non-functional pituitary adenoma, ACTH: adrenocorticotropic hormone, LH: luteinising hormone, FSH: follicle stimulating hormone, TSH: thyroid-stimulating hormone. *percentages are calculated from available data, patients whose data were unavailable were excluded. AIP, MEN1, PRKAR1A, CDKN1B cases and control cases are from published cases with an individual description of the cases. Non-genetically determined PAs selected as reference are from the patients described by Daly et al. from a Belgian population (1). The AIP cases were 57 published cases (a list of references is available upon request). The MEN1 cases were extracted from the UMD-MEN1 Database (14), the Carney complex cases were from a literature review published by Cuny et al. (15), and the MEN4 (CDKN1B) cases were from reviews conducted by Alrezk et al. and Fredericksen et al. (16, 17).

 

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