Tumor predisposition in an individual with chromosomal rearrangements of 1q31.2‐q41 encompassing cell division cycle protein 73

Abstract

Hyperparathyroidism-jaw tumor (HPT-JT) is caused by a loss-offunction mutation or haploinsufficiency of cell division cycle protein 73 (CDC73), a tumor-suppressor gene in chromosome 1q31.2. CDC73 mutation leads to parathyroid tumor development, parathyroid carcinoma, and mandible/maxilla ossifying fibroma in 90%, 15%, and 25% cases, respectively; approximately 75% female patients develop benign or malignant uterine tumors. HPT-JT is less frequently caused by 1q31.2 deletion; however, little is known about the genotypephenotype correlations with respect to 1q31.2 deletion relative to CDC73 mutation. Here, we report a patient with HPT-JT, intellectual disability, and multiple congenital anomalies with chromosomal rearrangements of 1q31.2-q41 encompassing CDC73. The proposita visited our hospital complaining of intellectual disability and facial dysmorphisms at 3 years old (Figure 1A); detailed clinical information is provided in Data S1 (Supporting Information). Chromosome testing showed 46,XX,dup(1)(q32.1q32.3). At 29, she had an irregular menstrual cycle and experienced left femoral pain. Magnetic resonance imaging confirmed uterine tumors and left femoral bone cysts (Figure S1). Preoperative blood test revealed hypercalcemia (serum calcium, 13.1 mg/dL) and high intact parathyroid hormone levels (309 pg/mL), suggestive of hyperparathyroidism (HPT). Enhanced computed tomography and 99 m Tc-Sestamibi detected a mass lesion in the parathyroid gland (Figure S2). Pathological analysis of surgically resected tumors in the uterus and parathyroid gland revealed an endometrial polyp and parathyroid adenoma, respectively. Informed consent was obtained from the parents in accordance with the Kanagawa Children s Medical Center Review Board and Ethics Committee. Array comparative genomic hybridization (Agilent SurePrint G3 Human comparative genomic hybridization Microarray Kit 60K) showed a 6.8 Mb deletion in 1q31.2-q32.1 encompassing CDC73 and an 18.1 Mb duplication in 1q32.1-q41 (arr[GRCh37] 1q31.2q32.1 (192985283_199779466)×1, 1q32.1q41(202128778_220262846)×3) (Figure 1B). Fluorescence in situ hybridization confirmed these findings (Figure 1C); both parents had normal karyotypes. Three patients with 1q31.2 deletion-induced HPT-JT were reported to date (Figure 1D and Table S1). The clinical phenotypes of the patients, including our patient, vary depending on the sizes of the deleted intervals. However, for all the patients, tumor-suppressor genes, excluding CDC73, were not present in the deleted intervals. All the patients with CDC73 gross deletion had HPT, and only one had mandibular ossifying fibromas. The femoral bone cysts found in our patient has never been reported in patients with missense or truncating mutations, suggesting that CDC73 haploinsufficiency potentially has tumor predisposition in other organs. The 1q31.2-q32.1 deletion in our patient encompassed CDC73, KCNT2, CFH, CFHR1, CFHR3, CFHR5, ASPM, CRB1, and PTPRC. The 1q32.1-q41 duplication in our patient encompassed UBE2T, SYT2, KDM5B, CHI3L1, CHIT1, SNRPE, REN, KISS1, PPP1R15B, NFASC, CNTN2, DSTYK, IL10, CD55, CR1, CR2, CD46, LAMB3, HSD11B1, IRF6, SYT14, KCNH1, RD3, NEK2, FLVCR1, PTPN14, CENPF, USH2A, TGFB2, SLC30A10, and EPRS1; however, only CDC73 could explain tumor predisposition due to haploinsufficiency or triplosensitivity. 1q32.1-q41 partial trisomy has been shown to be associated with intellectual disability and multiple congenital anomalies, but not with tumor predisposition (Figure S3). Received: 14 August 2019 Revised: 11 September 2019 Accepted: 18 September 2019 DOI: 10.1111/cga.12356