Genetics of hereditary forms of primary hyperparathyroidism

Abstract

Primary hyperparathyroidism (PHPT), a relatively common disorder characterized by hypercalcemia with raised or inappropriately normal serum parathyroid hormone (PTH) concentrations, may occur as part of a hereditary syndromic disorder or as a non-syndromic disease. The associated syndromic disorders include multiple endocrine neoplasia types 1–5 (MEN1-5) and hyperparathyroidism with jaw tumor (HPT-JT) syndromes, and the non-syndromic forms include familial hypocalciuric hypercalcemia types 1–3 (FHH1-3), familial isolated hyperparathyroidism (FIHP), and neonatal severe hyperparathyroidism (NS-HPT). Such hereditary forms may occur in > 10% of patients with PHPT, and their recognition is important for implementation of gene-specific screening protocols and investigations for other associated tumors. Syndromic PHPT tends to be multifocal and multiglandular with most patients requiring parathyroidectomy with the aim of limiting end-organ damage associated with hypercalcemia, particularly osteoporosis, nephrolithiasis, and renal failure. Some patients with non-syndromic PHPT may have mutations of the MEN1 gene or the calcium-sensing receptor (CASR), whose loss of function mutations usually cause FHH1, a disorder associated with mild hypercalcemia and may follow a benign clinical course. Measurement of the urinary calcium-to-creatinine ratio clearance (UCCR) may help to distinguish patients with FHH from those with PHPT, as the majority of FHH patients have low urinary calcium excretion (UCCR < 0.01). Once genetic testing confirms a hereditary cause of PHPT, further genetic testing can be offered to the patients’ relatives and subsequent screening can be carried out in these affected family members, which prevents inappropriate testing in normal individuals.

Insights into Hyperparathyroidism–Jaw Tumour Syndrome: From Endocrine Acumen to the Spectrum of CDC73 Gene and Parafibromin-Deficient Tumours

“…Larger studies are needed for more accurate estimates. The post-operatory complications were similar to the usual ones [102], including recurrent nerve palsy and transient or permanent hyperparathyroidism. A higher risk of permanent hyperparathyroidism in patients with subtotal parathyroidectomy was found in one study [46].…”

“…The age at diagnosis varied between 19 and 60 years, with a mean of 31.9 ± 13 years. 71.43% of them (N = 15) were females [101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120]. Of note, the female predominance was not confirmed by the above mentioned studies on HJT [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] that, however, embrace a higher level of statistical evidence.…”

“…Thus, we additionally found twenty articles [101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120], a total of 21 individuals with HJT. The age at diagnosis varied between 19 and 60 years, with a mean of 31.9 ± 13 years.…”

“…Of note, the female predominance was not confirmed by the above mentioned studies on HJT [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] that, however, embrace a higher level of statistical evidence. The genetic configuration in these subjects was associated with an interesting CDC73 spectrum in terms of deletions, such as heterozygous deletion of exons 8-9 ("de novo" variant), heterozygous (large) deletion of exons 1-17, 4.1-Mb deletion on chromosome 1q31.2-31.3, heterozygous c.-16:8del, c.(136_144)del5 or c.18_48del31; insertions, for example, 99-bp insertion in exon 2, p.Asn65_Phe531delinsIleLysTyr, respectively, nonsense variant p.Arg9Stop (R9X) [101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120]. Moreover, a secondary genetic anomaly (c.179 T.A somatic mutation on the other allele) was found at the level of the jaw tumour in a 28-year-old woman [118].…”

“…Uterine lesions were reported in 33.33% of the HJT females (N = 5) and included leiomyomas (N = 2), endometrial polyps (N = 2), and an endocervical glandular polyp (N = 1). Kidney manifestations were found in 28.57% (N = 6) of the individuals, being represented by cysts (N = 3), a renal cell carcinoma (N = 1), nephroblastoma (N = 1), and mixed epithelial and stromal tumours (N = 1) [101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120]. One report included an incidentally detected small thyroid lesion underlying a differentiated type of carcinoma [111].…”