Introduction: Primary hyperparathyroidism in a young adult is rare and should prompt testing for possible causative germline mutations in the menin, RET and CDC73 genes. Germline mutations in CDC73 can cause atypical parathyroid adenoma or parathyroid carcinoma, ossifying fibromas of the jaw, and tumours of the kidney and uterus. We report a patient where a whole gene deletion of CDC73 was not detected by next generation sequencing (NGS) but was identified by multiplex ligation probe amplification (MLPA).
Case: A 19 year-old women with mild intellectual impairment presented with oligoamenorhoea. Investigations revealed severe hypercalcaemia due to primary hyperparathyroidism (Corrected Calcium = 3.3 mmol/L, PTH = 39.9 pmol/L). History elicited a three month history of polydipsia, polyuria, abdominal pain, mood and memory disturbance. There was no known family history of hypercalcaemia. A large mass was identified inferior to the left thyroid gland on ultrasound and low dose CT, however the lesion did not demonstrate increased SESTAMIBI activity. A 4.1g cystic and encapsulated left upper parathyroid was excised by focal parathyroid exploration. Histologic features were of an atypical parathyroid adenoma; the lesion did not meet criteria for parathyroid carcinoma. Immunohistochemistry staining was positive for PGP9.5 and negative for parafibromin. No pathologic sequence variants were detected in the menin, RET and CDC73 genes by NGS. However, a heterozygous whole gene deletion of the CDC73 gene was detected by MLPA. Postoperatively serum calcium has normalized and further investigation including gynaecologic review, pelvic and renal ultrasound and panoramic jaw x-ray is being arranged.
Conclusion: Germline mutations of CDC73 may not be detected using NGS techniques alone. When a mutation in CDC73 is suspected, absence of a pathogenic sequence variant on NGS should prompt MLPA to assess for large gene deletions.