Probability of Positive Genetic Testing Results in Patients with Family History of Primary Hyperparathyroidism

Lakis, Mustapha El; Nockel, Pavel; Gaitanidis, Apostolos; Guan, Bin; Agarwal, Sunita K.; Welch, James; Simonds, William F.; Weinstein, Lee S.; Marx, Stephen J.; Nilubol, Naris; Patel, Daxesh P.; Merkel, Roxanne; Tirosh, Amit; Kebebew, Electron

doi:10.1016/j.jamcollsurg.2018.01.007

Cited by 23 publications

(23 citation statements)

References 16 publications

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“…When considering young patients (< 40), one in four patients had clinical genetic testing that led to altered clinical management. The results of our clinical experience are in accordance with other studies that systematically studied archived clinical samples or patients with a family history of pHPT [19,20]. Changes in clinical care occurred in four patients with rare variants in CASR, two patients with rare variants in CDC73, and one patient with a pathogenic variant in MEN1.…”

Section: Discussionsupporting

confidence: 88%

Outcome of Clinical Genetic Testing in Patients with Features Suggestive for Hereditary Predisposition to PTH-Mediated Hypercalcemia

et al. 2020

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Primary hyperparathyroidism (pHPT) is associated with familial syndromes such as multiple endocrine neoplasia type 1 (MEN1), 2A (MEN2A), MEN-like syndromes (CDKN1B), and CDC73-related disorder (hyperparathyroidismjaw tumor syndrome (HPJT)). Familial hypocalciuric hypercalcemia (FHH) caused by CASR variants is an important differential diagnosis for pHPT. In order to evaluate the contribution of hereditary causes to pHPT in patients encountered in a specialized clinic, we conducted a retrospective study on patients with pHPT that underwent germline genetic testing. We evaluated 46 patients referred to a Cancer Genetics Clinic. Reasons for referral were young age (age < 40) for 29 patients (63%), multi-gland disease for 23 patients (50%), and a positive family history of pHPT for 11 patients (24%). All 46 patients underwent genetic evaluation. A total of 11 rare variants were found (CASR (4), CDC73 (2), MEN1 (2) CDKN1B (1), and RET (2)). One MEN1 variant was classified as pathogenic, and all others were variants of uncertain significance (VUS). All patients with CASR variants had clinical features of FHH and were counselled against parathyroidectomy. Both patients with CDC73 variants were counselled about recurrence of pHPT and parathyroid cancer. Neither of the RET variants were MEN2-associated. The CDKN1B variant was regarded as a true VUS and no action was taken. In this study, genetic testing impacted clinical care in 7 (15%) patients. We suggest that all patients < 40 years of age, with multi-gland disease, single gland disease refractory to treatment, and a positive family history for pHPT or associated tumors should be considered for genetic evaluation.

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Section: Discussionsupporting

confidence: 88%

Outcome of Clinical Genetic Testing in Patients with Features Suggestive for Hereditary Predisposition to PTH-Mediated Hypercalcemia

et al. 2020

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“…El Lakis et al (1) also demonstrated that activating mutations of GCM2 were associated with a greater rate of multi-glandular diseases. In our study, some patients with class 3 or 4 variants harbored parathyroid hyperplasia or multiple glandular adenomas but the lack of anatomopathological information available for many patients did not allow us to confirm this point.…”

Section: Discussionmentioning

confidence: 96%

“…It can result from a single or multiglandular lesion, adenoma, hyperplasia or much less frequently carcinoma. The prevalence of this disease is estimated around 1-7 cases per 1000 persons (1). PHPT can be either sporadic or inherited.…”

Section: Introductionmentioning

confidence: 99%

Should the GCM2 gene be tested when screening for familial primary hyperparathyroidism?

Coppin

Dufosse

Romanet

et al. 2020

European Journal of Endocrinology

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Objective Primary hyperparathyroism (PHPT) is a disease with either sporadic or inherited presentation. Germline mutations responsible for this disease can be found in different genes, the most frequently involved being MEN1, CDC73 = HRPT2 and CASR. During the last few years, new genes have been described as responsible for the development of PHPT such as GCM2. These genes are not systematically included in PHPT genetic screening yet. The aim of this work was to assess the importance of GCM2 genetic analysis in PHPT to determine if this gene should be included in gene panel investigated for this disease. Design and methods The TENGEN network (French Oncogenetic Network of Neuroendocrine Tumors) collected and interpreted allelic variants according to the clinical characteristics of the GCM2-positive patients identified through genetic testing performed in French laboratories (713 patients with PHPT). Results From 713 patients with PHPT included in this study, 85 (6.6%) carried at least one GCM2 variant. A total of 12 variants classified as uncertain significance or likely pathogenic were reported in 47 patients. Their mean age at PHPT diagnosis was 49 years. Additionally, the investigation of a large family showed that GCM2 variants could be associated with low penetrance. Conclusion We provide a description and interpretation for GCM2 variants identified in a French population. We suggest that this gene should be included in genetic screening of patients with PHPT and propose the follow-up of asymptomatic patients carrying such variants for calcemia.

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“…2 The characteristics of this patient should prompt an evaluation for genetic causes of PHPT because the factors associated with hereditary PHPT are young age at diagnosis (<40 years), the presence of syndromic features/tumors, contributory family history, and multigland disease. [1][2][3][4][5] Male sex is also a factor to consider because there is a female predominance in sporadic PHPT. 3 We support consideration of genetic testing for any patient with PHPT presenting at a young age (with the cutoff varying from <30 to 45 years or from <40 to 45 years with multigland disease), harboring syndromic features, or having a positive family history of PHPT and/or other syndromic tumors.…”

Section: Men1 Diagnosismentioning

confidence: 99%

“…This is important to recognize because hereditary disease influences prognosis, surgical strategy, and the risk of other syndromic manifestations and has important implications for family members 2 . The characteristics of this patient should prompt an evaluation for genetic causes of PHPT because the factors associated with hereditary PHPT are young age at diagnosis (<40 years), the presence of syndromic features/tumors, contributory family history, and multigland disease 1‐5 . Male sex is also a factor to consider because there is a female predominance in sporadic PHPT 3 .…”

Section: Men1 Diagnosismentioning

confidence: 99%

It's not a mystery, it's in the history: Multidisciplinary management of multiple endocrine neoplasia type 1

Shirali

Pieterman

Lewis

et al. 2021

CA A Cancer J Clinicians

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Probability of Positive Genetic Testing Results in Patients with Family History of Primary Hyperparathyroidism

Abstract: In addition to a family history of PHPT, male sex, age 45 years and younger, and presence of multigland disease, should prompt physicians to offer the opportunity for genetic counseling and testing, as it could influence the management of patients with PHPT.

Cited by 23 publications

References 16 publications

Outcome of Clinical Genetic Testing in Patients with Features Suggestive for Hereditary Predisposition to PTH-Mediated Hypercalcemia

Outcome of Clinical Genetic Testing in Patients with Features Suggestive for Hereditary Predisposition to PTH-Mediated Hypercalcemia

Should the GCM2 gene be tested when screening for familial primary hyperparathyroidism?

It's not a mystery, it's in the history: Multidisciplinary management of multiple endocrine neoplasia type 1

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