CDC73 mutations in young patients with primary hyperparathyroidism: A description of two clinical cases

The article describes two clinical cases of severe primary hyperparathyroidism (PHPT) caused by parathyroid carcinoma in young female patients who underwent molecular genetic testing to rule out the hereditary forms of PHPT. In both patients, heterozygous germline nonsense mutations of tumor suppressor gene CDC73 encoding parafibromin (p.R91X and p.Q166X) were identified using next-generation sequencing with Ion Torrent Personal Genome Machine (Thermo Fisher Scientific — Life Technologies, USA). It is the first description of CDC73 mutations in Russia, one of the mutations is described for the first time in the world. Identification of germline mutations in the CDC73 gene in patients with PHPT necessitates regular lifelong screening for other manifestations of hyperparathyroidism-jaw tumor syndrome (HPT-JT), PHPT recurrence due to parathyroid carcinoma as well, and identification of mutation carriers among first-degree relatives.

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Molecular and genetic features of primary hyperparathyroidism in young patients

Problems of Endocrinology ◽

10.14341/probl20166224-11 ◽

2016 ◽

Vol 62 (2) ◽

pp. 4-11 ◽

Cited By ~ 1

Author(s):

Elizaveta O. Mamedova ◽

Natalya G. Mokrysheva ◽

Ekaterina A. Pigarova ◽

Iya A. Voronkova ◽

Sergey N. Kuznetsov ◽

...

Keyword(s):

Family History ◽

Primary Hyperparathyroidism ◽

Parathyroid Carcinoma ◽

Positive Family History ◽

Young Patients ◽

Clinical Manifestations ◽

Genetic Characteristics ◽

Men1 Gene ◽

Ion Torrent Pgm ◽

Genetic Features

When primary hyperparathyroidism (PHPT) is diagnosed in a young patient in the absence of other clinical manifestations differential diagnosis between a sporadic form of PHPT and PHPT as the first manifestation of one of hereditary syndromes may be challenging. Diagnosis of sporadic or hereditary PHPT determines the extent of surgical intervention, a strategy for further observation and treatment, and the need for examination and treatment of first-degree relatives. Aim of the study — to determine genetic characteristics of PHPT with manifestation at a young age (<40 years old) with clinically sporadic PHPT and familial isolated hyperparathyroidism (FIHP).Material and methods. 40 patients with manifestation of PHPT at the age younger than 40 years, 4 of which with FIHP, were included in the study. In 11 patients Sanger sequencing of MEN1 gene was performed (ABI 3130 Genetic Analyser, «Applied Biosystems», USA). 37 patients underwent next-generation sequencing (NGS) (Ion Torrent PGM, Thermo Fisher Scientific — Life Technologies, USA) using a panel of candidate genes (MEN1, CASR, CDC73, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2C, CDKN2D). Results. In 3 (7,5%) patients (1 of which with FIHP) we revealed germline heterozygous mutations in MEN1 gene: in exon 9 p.D418N, exon 3 p.R176Q, intron 3 с.654+1G>A. In 4 (4/40, 10%) patients we revealed germline heterozygous mutations in CDC73 gene: 3 nonsense mutations in patients with parathyroid carcinoma — in exon 3 p.R91X, exon 6 p.Q166X, exon 7 p.R229X, and 1 missense mutation in a patient with parathyroid hyperplasia in exon 8 p.R263C. Conclusions. In the majority of cases (75%) PHPT in young patients without positive family history is sporadic. Search for germline mutations in the genes, leading to development of hereditary forms of PHPT (first of all in MEN1 and CDC73), is appropriate in young patients with positive family history, or when positive family history may be suspected, and in patients with parathyroid carcinoma. In the majority (75%) of FIHP cases search for other, probably yet unknown, genes is necessary.

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Rhabdoid Tumor of the Kidney is a Component of the Rhabdoid Predisposition Syndrome

Pediatric and Developmental Pathology ◽

10.1007/s10024-001-0259-z ◽

2002 ◽

Vol 5 (4) ◽

pp. 395-399 ◽

Cited By ~ 27

Author(s):

Hwei-Yee Lee ◽

Chui-Shuen Yoon ◽

Nicolas Sevenet ◽

Vasanthi Rajalingam ◽

Olivier Delattre ◽

...

Keyword(s):

Molecular Genetic ◽

Germline Mutations ◽

Suppressor Gene ◽

Molecular Genetic Analysis ◽

Rhabdoid Tumor ◽

Cerebellar Tumor ◽

Nonsense Mutations ◽

Pleural Tumor ◽

Chromosome 22Q11.2 ◽

Atypical Teratoid

The rhabdoid predisposition syndrome (RPS) is characterized by pedigrees in which two or more individuals carry germline mutations of the hSNF5/INI1 tumor suppressor gene. The tumors associated with the syndrome include atypical teratoid/rhabdoid tumor (AT/RT), choroid plexus carcinoma, medulloblastoma, and extrarenal rhabdoid tumor. Rhabdoid tumor of the kidney (RTK) has not been described as part of the RPS. We report a case of a 7-month-old boy with RTK whose sister had a malignant cerebellar tumor followed by a malignant lung and pleural tumor of childhood with typical rhabdoid histology. Molecular genetic analysis of the RTK and tissue from the pleural tumor revealed in both cases identical nonsense mutations of the hSNF5/INI1 gene on chromosome 22q11.2, where thymidine was substituted for cytosine in base 472. The proband had an identical germline mutation. This is the fifth genetically analyzed RPS pedigree and the first to include an RTK.

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Parathyroid Pathology: Hyperparathyroidism and Parathyroid Tumors

Archives of Pathology & Laboratory Medicine ◽

10.5858/2009-0578-ccr.1 ◽

2010 ◽

Vol 134 (11) ◽

pp. 1639-1644 ◽

Cited By ~ 6

Author(s):

Diane Carlson

Keyword(s):

Primary Hyperparathyroidism ◽

Parathyroid Carcinoma ◽

Gene Mutations ◽

Suppressor Gene ◽

Outpatient Setting ◽

Cancer Center ◽

Parathyroid Tumors ◽

Parathyroid Adenomas ◽

Parathyroid Lesions ◽

Hrpt2 Gene

Abstract Context.—Primary hyperparathyroidism is the most common cause of hypercalcemia in the outpatient setting. Parathyroid adenomas are common, unlike other parathyroid tumors. This review presents a brief summary of current updates in parathyroid pathology. Objective.—To review parathyroid development and discuss issues in hyperparathyroidism and diagnosis of parathyroid lesions, including the application of immunohistochemistry and molecular biology. Data Sources.—Current texts, PubMed (National Library of Medicine) articles, and Memorial Sloan-Kettering Cancer Center archives. Conclusions.—Primary hyperparathyroidism is most commonly seen with sporadic adenomas, followed by hyperplasia, multiple adenomas, and carcinoma. Autosomal dominant familial hyperparathyroidism syndromes should be considered in the evaluation of patients with parathyroid lesions, particularly in association with parathyroid carcinoma. While the incidence of parathyroid carcinoma is quite low, it is seen with a greater frequency in those patients with hyperparathyroidism-jaw tumor syndrome. Inactivation of the tumor suppressor gene HRPT2 can be identified in a large number of parathyroid carcinomas. Hence, germline HRPT2 gene mutations may reflect unrecognized syndromic patients.

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Molecular genetic insights into sporadic primary hyperparathyroidism

Endocrine Related Cancer ◽

10.1530/erc-18-0304 ◽

2019 ◽

Vol 26 (2) ◽

pp. R53-R72 ◽

Cited By ~ 10

Author(s):

Kelly Brewer ◽

Jessica Costa-Guda ◽

Andrew Arnold

Keyword(s):

Primary Hyperparathyroidism ◽

Molecular Genetic ◽

Suppressor Gene ◽

Tumor Formation ◽

Driver Genes ◽

Genetic Abnormalities ◽

Sporadic Primary Hyperparathyroidism ◽

Parathyroid Hormone Release ◽

Pathogenic Process

Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by dysregulation of parathyroid hormone release. The large majority of PHPT cases are attributable to sporadic, single-gland parathyroid adenoma, in which MEN1 and CCND1/cyclin D1 are the most well-established drivers of tumorigenesis. Sporadic parathyroid carcinoma, which appears to mostly arise through molecular pathways distinct from those causing benign parathyroid tumors, is rare and is most frequently driven by mutational inactivation of the CDC73 (HRPT2) tumor suppressor gene. Targeted investigation of suspected tumor driver genes, as well as unbiased whole-genome or exome sequencing of small cohorts, have revealed additional novel candidate tumor genes in sporadic parathyroid neoplasia, generally at modest or low mutational frequencies consistent with marked molecular genetic heterogeneity from tumor to tumor. The ability of these additional candidates to participate in the pathogenic process of driving parathyroid tumorigenesis in vivo largely remains to be demonstrated experimentally. This review will summarize the molecular genetic abnormalities identified to date in sporadic PHPT and discuss the strength of evidence for their proposed roles in parathyroid tumor formation.

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SAT-334 A Genetic Cause of Primary Hyperparathyroidism

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.225 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Travis Weaver ◽

Thanh Hoang

Keyword(s):

Family History ◽

Primary Hyperparathyroidism ◽

Parathyroid Adenoma ◽

Serum Calcium ◽

Parathyroid Carcinoma ◽

Age Of Onset ◽

Young Patients ◽

Renal Tumors ◽

Caucasian Woman ◽

Uterine Neoplasms

Abstract Background: Primary hyperparathyroidism is a relatively common endocrine condition, affecting up to 7 out of every 1000 adults. Median age of onset is during the sixth decade of life. When present in younger patients primary hyperparathyroidism may indicate an underlying genetic cause. Case: A 23-year-old woman is referred for evaluation of hypercalcemia that was found on labs drawn after surgery for bilateral ovarian cyst removal. At the time of presentation she felt well and was without complaint. Her medical history is otherwise unremarkable. Her family history includes multiple family members with nephrolithiasis. Physical exam revealed a well appearing Caucasian woman without a palpable neck mass. Laboratory results showed: serum calcium 11.7 mg/dL (ref 8.4–10.2), ionized calcium 1.44 mmol/L (ref 1.12–1.32) and serum PTH 192 pg/mL (ref 11–65). Technetium-99 sestamibi scan revealed a low attenuating mass with focal and persistent uptake just inferior to the left thyroid lobe. She subsequently underwent left inferior parathyroidectomy, which confirmed parathyroid adenoma, with resultant normalization of serum calcium and PTH. Due to her young age of diagnosis genetic testing was performed which revealed a mutation if CDC 73. Discussion: CDC 73 mutation is known cause of inheritable neoplasia’s with a high prevalence of parathyroid dysfunction. Although penetrance and expression is variable, the mutation is associated primarily with Hyperparathyroidism Jaw Tumor Syndrome (HPT-JT), Familial Isolated Hyperparathyroidism and sporadic parathyroid carcinoma. Our patient had an allele mutation associated with HPT-JT. This syndrome classically presents with parathyroid adenoma, ossifying tumors of the mandible and renal or uterine neoplasms. The mutation is inherited in an autosomal dominant pattern and family history plays a key role in diagnosis of this rare condition. This patient had an early age of onset for hyperparathyroidism and a family history suggestive of an inherited calcium metabolism disorder. A single parathyroid adenoma is the most common presentation and surgical resection is often curative of hyperparathyroidism. In Hyperparathyroidism Jaw Tumor Syndrome patients classically develop ossifying tumors of the mandible and renal or uterine neoplasms in addition to parathyroid lesions. Rarely patients with CDC 73 mutation can develop parathyroid carcinoma. For this reason it is recommended that all first degree relatives undergo testing for CDC 73 mutation. This patient currently has no evidence of jaw, uterine or renal tumors on screening imaging. Ovarian tumors have been described separately to be associated with CDC 73 mutation, this patient may actually have an unrecognized phenotype of CDC 73 mutation. Given the potential impact of inheritable neoplasia, all young patients with unexplained hyperparathyroidism should be considered for genetic screening.

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