A Familial Case of a Whole Germline CDC73 Deletion Discordant for Primary Hyperparathyroidism

Naomi Hatabu, Naho Katori, Takeshi Sato, Naonori Maeda, Eri Suzuki, Osamu Komiyama, Hidemitsu Tsutsui, Toshitaka Nagao, Hana Nakauchi-Takahashi, Tatsuo Matsunaga, Tomohiro Ishii, Tomonobu Hasegawa, Kazuki Yamazawa

Research output: Contribution to journalArticle

Abstract

Introduction: Primary hyperparathyroidism (PHPT) occurs as part of familial syndromes, including CDC73-related disorders caused by germline pathogenic variants of the CDC73 gene, particularly in early adulthood. Herein, we report a familial case of a whole germline CDC73 deletion discordant for PHPT. Case Description: A 15-year-old boy was admitted to our hospital because of persistent nausea and vomiting. Laboratory tests showed hypercalcemia (13.6 mg/dL), hypophosphatemia (2.4 mg/dL), and elevated intact PTH level (149 pg/mL). Imaging studies showed an enlarged single parathyroid gland. Thus, the diagnosis of PHPT was made. Microarray analysis of peripheral blood DNA showed a 3.4-Mb heterozygous deletion of 1q31 encompassing 11 genes, including CDC73. Total thyroidectomy/parathyroidectomy was performed; histology was compatible with parathyroid adenoma without any evidence of malignancy. DNA sequencing of the removed adenoma confirmed a hemizygous nonsense variant in the CDC73 gene in a mosaic manner, which was potentially involved in parathyroid tumorigenesis as the "second hit." Importantly, the same deletion was identified in his 52-year-old father who had an unremarkable medical history. Conclusions: These data clearly demonstrate the Knudson two-hit theory from a molecular viewpoint. Phenotypic variability and incomplete penetrance of CDC73-related disorders, even if caused by a gross deletion, should be noted in a clinical setting.

Original languageEnglish
JournalHormone Research in Paediatrics
DOIs
Publication statusPublished - 2019 Jan 1

Fingerprint

Primary Hyperparathyroidism
Genes
Hypophosphatemia
Parathyroid Neoplasms
Parathyroidectomy
Parathyroid Glands
Penetrance
Thyroidectomy
Hypercalcemia
Microarray Analysis
DNA Sequence Analysis
Fathers
Adenoma
Nausea
Vomiting
Histology
Carcinogenesis
DNA
Neoplasms

Keywords

  • CDC73 gene
  • Knudson two-hit theory
  • Parafibromin
  • Primary hyperparathyroidism
  • Whole deletion

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

A Familial Case of a Whole Germline CDC73 Deletion Discordant for Primary Hyperparathyroidism. / Hatabu, Naomi; Katori, Naho; Sato, Takeshi; Maeda, Naonori; Suzuki, Eri; Komiyama, Osamu; Tsutsui, Hidemitsu; Nagao, Toshitaka; Nakauchi-Takahashi, Hana; Matsunaga, Tatsuo; Ishii, Tomohiro; Hasegawa, Tomonobu; Yamazawa, Kazuki.

In: Hormone Research in Paediatrics, 01.01.2019.

Research output: Contribution to journalArticle

Hatabu, Naomi ; Katori, Naho ; Sato, Takeshi ; Maeda, Naonori ; Suzuki, Eri ; Komiyama, Osamu ; Tsutsui, Hidemitsu ; Nagao, Toshitaka ; Nakauchi-Takahashi, Hana ; Matsunaga, Tatsuo ; Ishii, Tomohiro ; Hasegawa, Tomonobu ; Yamazawa, Kazuki. / A Familial Case of a Whole Germline CDC73 Deletion Discordant for Primary Hyperparathyroidism. In: Hormone Research in Paediatrics. 2019.
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AU - Katori, Naho

AU - Sato, Takeshi

AU - Maeda, Naonori

AU - Suzuki, Eri

AU - Komiyama, Osamu

AU - Tsutsui, Hidemitsu

AU - Nagao, Toshitaka

AU - Nakauchi-Takahashi, Hana

AU - Matsunaga, Tatsuo

AU - Ishii, Tomohiro

AU - Hasegawa, Tomonobu

AU - Yamazawa, Kazuki

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N2 - Introduction: Primary hyperparathyroidism (PHPT) occurs as part of familial syndromes, including CDC73-related disorders caused by germline pathogenic variants of the CDC73 gene, particularly in early adulthood. Herein, we report a familial case of a whole germline CDC73 deletion discordant for PHPT. Case Description: A 15-year-old boy was admitted to our hospital because of persistent nausea and vomiting. Laboratory tests showed hypercalcemia (13.6 mg/dL), hypophosphatemia (2.4 mg/dL), and elevated intact PTH level (149 pg/mL). Imaging studies showed an enlarged single parathyroid gland. Thus, the diagnosis of PHPT was made. Microarray analysis of peripheral blood DNA showed a 3.4-Mb heterozygous deletion of 1q31 encompassing 11 genes, including CDC73. Total thyroidectomy/parathyroidectomy was performed; histology was compatible with parathyroid adenoma without any evidence of malignancy. DNA sequencing of the removed adenoma confirmed a hemizygous nonsense variant in the CDC73 gene in a mosaic manner, which was potentially involved in parathyroid tumorigenesis as the "second hit." Importantly, the same deletion was identified in his 52-year-old father who had an unremarkable medical history. Conclusions: These data clearly demonstrate the Knudson two-hit theory from a molecular viewpoint. Phenotypic variability and incomplete penetrance of CDC73-related disorders, even if caused by a gross deletion, should be noted in a clinical setting.

AB - Introduction: Primary hyperparathyroidism (PHPT) occurs as part of familial syndromes, including CDC73-related disorders caused by germline pathogenic variants of the CDC73 gene, particularly in early adulthood. Herein, we report a familial case of a whole germline CDC73 deletion discordant for PHPT. Case Description: A 15-year-old boy was admitted to our hospital because of persistent nausea and vomiting. Laboratory tests showed hypercalcemia (13.6 mg/dL), hypophosphatemia (2.4 mg/dL), and elevated intact PTH level (149 pg/mL). Imaging studies showed an enlarged single parathyroid gland. Thus, the diagnosis of PHPT was made. Microarray analysis of peripheral blood DNA showed a 3.4-Mb heterozygous deletion of 1q31 encompassing 11 genes, including CDC73. Total thyroidectomy/parathyroidectomy was performed; histology was compatible with parathyroid adenoma without any evidence of malignancy. DNA sequencing of the removed adenoma confirmed a hemizygous nonsense variant in the CDC73 gene in a mosaic manner, which was potentially involved in parathyroid tumorigenesis as the "second hit." Importantly, the same deletion was identified in his 52-year-old father who had an unremarkable medical history. Conclusions: These data clearly demonstrate the Knudson two-hit theory from a molecular viewpoint. Phenotypic variability and incomplete penetrance of CDC73-related disorders, even if caused by a gross deletion, should be noted in a clinical setting.

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