GCM2 variant - A rare genetic cause of Familial Isolated Hyperparathyroidism

Susan Mathew, Akheel Syed

Research output: Contribution to journalConference articlepeer-review


Section 1: Case history: A 46-year-old woman was referred to the Endocrinology clinic for evaluation of persistently elevated parathyroid hormone levels despite correction of previous vitamin D deficiency. She had a history of calcific tendinitis of the left shoulder and iris pigment dispersion syndrome. Notably, her mother had undergone two parathyroid surgeries for primary hyperparathyroidism with removal of three parathyroid glands, revealing multiple parathyroid adenomas and an incidentally detected papillary thyroid carcinoma. The mother had three sisters, one of whom had also been diagnosed with primary hyperparathyroidism; another (deceased) sister had had osteoporosis. Genetic screening in the mother had identified a heterozygous single nucleotide polymorphism of GCM2 gene at c. 1181A>C p. (Tyr394Ser). In view of the strong family history, the patient went on to have further investigations as follows: Section 2: Investigations: Corrected serum calcium: 2.32 (reference range, 2.20–2.60) mmol/l Parathyroid hormone: 11.2 (2.0–9.3) pmol/l Vitamin D: 53.6 (50.0–125.0) nmol/l Kidney and thyroid function: normal DEXA bone densitometry scan: normal Renal ultrasound scan: normal; no calculi. Ultrasound scan of neck: 5 mm paratracheal nodule inferior to the left thyroid gland which may represent a parathyroid adenoma. SESTAMIBI scan: no focus to suggest parathyroid adenoma. Section 3: Results and treatment: Genetic analysis in our patient confirmed heterozygous single nucleotide polymorphism of GCM2 gene at c. 1181A>C p. (Tyr394Ser) identical to her mother. In light of the familial GCM2 variant, she was advised that she runs the risk of developing symptomatic hyperparathyroidism in the future. Since there was no target end organ damage, she opted for wait and watch monitoring. Vitamin D replacement was increased to target a serum level >75 nmol/l. Section 4: Conclusions and points for discussion: GCM2 single nucleotide variant is a less well-known genetic cause of Familial Isolated Hyperparathyroidism (FIHP). GCM2 stands for Glial Cell Missing Transcription Factor-2. It is a gene that encodes a transcription factor required for parathyroid development, located on chromosome 6p24.2. Inactivating mutations of GCM2 result in hypoparathyroidism whereas gain-of-function mutations are associated with hyperparathyroidism. Persons with FIHP and GCM2 variants present as adults with mild hypercalcemia and multiple parathyroid tumours, as in this patient’s mother. The long-term prognosis and best practice clinical management remains unknown.
Original languageEnglish
JournalEndocrine Abstracts
Publication statusPublished - Mar 2020
EventSociety for Endocrinology National Clinical Cases 2020 - London, United Kingdom
Duration: 12 Mar 2020 → …


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