Naomi Hatabu1, Naho Katori1, Takeshi Sato2, Naonori Maeda1, Eri Suzuki1, Osamu Komiyama1, Hidemitsu Tsutsui3, Toshitaka Nagao4, Hana Nakauchi-Takahashi5, Tatsuo Matsunaga5,6, Tomohiro Ishii2, Tomonobu Hasegawa2, Kazuki Yamazawa7,8. 1. Department of Pediatrics, National Hospital Organization Tokyo Medical Center, Tokyo, Japan. 2. Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan. 3. Department of Thoracic and Thyroid Surgery, Tokyo Medical University, Tokyo, Japan. 4. Department of Pathology, Tokyo Medical University, Tokyo, Japan. 5. Medical Genetics Center, National Hospital Organization Tokyo Medical Center, Tokyo, Japan. 6. Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan. 7. Department of Pediatrics, National Hospital Organization Tokyo Medical Center, Tokyo, Japan, kyamazawa@ntmc-hosp.jp. 8. Medical Genetics Center, National Hospital Organization Tokyo Medical Center, Tokyo, Japan, kyamazawa@ntmc-hosp.jp.
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.
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.
Authors: Lauriane Le Collen; Sara Barraud; Antoine Braconnier; Lucie Coppin; Dominique Zachar; Camille Boulagnon; Sophie Deguelte; Pierre François Souchon; Marta Spodenkiewicz; Céline Poirsier; Sébastien Aubert; Marie Françoise Odou; Brigitte Delemer Journal: Endocrine Date: 2021-05-17 Impact factor: 3.633