Update on Genetic and Clinical Aspects of Primary Hyperparathyroidism: Update on Genetic and Clinical Aspects of Primary Hyperparathyroidism

S. Miedlich, K. Krohn, R. Paschke


Clin Endocrinol. 2003;59(5) 

In This Article

Which Pathophysiological Mechanisms Underlie Parathyroid Neoplasia?

pHPT is a common endocrine disorder. As shown by a population-based study at the Mayo Clinic, the estimated incidence of pHPT had been increasing from 15 person-years (1965-1974) to 112/100 000 person-years (1975) after the introduction of autoanalysers to measure serum electrolytes. Thereafter, a decline to 4/100 000 person-years (1992) has been reported (Wermers et al., 1997). The authors suggest a systematic dietary change in the population as regards calcium intake and a less frequent use of head and neck irradiation as possible reasons. The precise causes for this phenomenon remain unclear.In Sweden, the prevalence of pHPT has been estimated at 0·17% for men, and 0·45% for women (1994-1995; Jorde et al., 2000). A similar prevalence of the disease, reported 30 years ago in two large Swedish studies, argues against major changes in the epidemiology of pHPT in Scandinavia (Christensson et al., 1976; Palmer et al., 1988).

In more than 80% of the patients with pHPT, a single parathyroid adenoma can be found; in 15-20% of the cases, parathyroid hyperplasia or multiple adenomas can be found (Silverberg & Bilezikian, 1997). Parathyroid carcinomas are only a rare cause of pHPT (Silverberg & Bilezikian, 1997).

Inherited syndromes, which are the cause of pHPT in a minority of the patients (< 5%), include multiple endocrine neoplasia type 1 and type 2a (MEN-1, MEN-2a), familial hypocalciuric hypercalcaemia (FHH) and neonatal severe pHPT, as well as hyperparathyroidism-jaw tumour syndrome (reviewed in Marx, 2000). However, the prevalence of pHPT and the clinical features of the patients with inherited syndromes differ. In patients with MEN-1, parathyroid hyperplasia or multiple adenomas occur in approximately 90%. In fact, some families may present with pHPT as the only manifestation of the disease (for review see Miedlich et al., 2001b). Anterior pituitary, enteropancreatic and other tumours are found less frequently in MEN-1 patients (Trump et al., 1996). MEN-1 is inherited as an autosomal dominant trait. It is caused by inactivating mutations of the MEN1 gene, which is thought to be a tumour suppressor gene (discussed below).

In MEN-2a, parathyroid tumours are found in approximately 35% of affected family members (Howe et al., 1993). More frequently, these patients present with medullary thyroid carcinoma and phaeochromocytoma. MEN-2 is an autosomal dominant disorder, caused by activating mutations of the RET proto-oncogene.

In families with hyperparathyroidism-jaw tumour syndrome, the genetic defect has been mapped to chromosome 1q21-q32 (Teh et al., 1998). Very recently, inactivating mutations of a currently unknown gene called parafibromin could be identified in 14 of 26 index cases (Carpten et al., 2002). Like MEN, hyperparathyroidism-jaw tumour syndrome is also inherited as an autosomal dominant trait, and apart from pHPT, patients in these families may present with jaw tumours consisting of fibro-osseous lesions found in the mandible or maxilla (Jackson et al., 1990). Furthermore, patients with hyperparathyroidism-jaw tumour syndrome often show atypical parathyroid adenomas at surgery, are at risk forparathyroid carcinoma (Frayha et al., 1972; Leborgne et al., 1975; Dinnen et al., 1977; Streeten et al., 1992) or may develop Wilm's tumours, polycystic kidney disease or renal hamartomas (Kakinuma et al., 1994; Teh et al., 1996).

FHH and neonatal severe pHPT are caused by heterozygous and homozygous inactivating mutations of CaR, respectively. Inactivation of this G protein-coupled receptor results in half-maximal inhibition of PTH secretion only at increased concentrations of serum calcium (calcium set-point), although the magnitude of PTH suppression by increased serum calcium concentrations is normal in patients with FHH (Khosla et al., 1993). At surgery, hyperplasia of the parathyroid glands can be found. In contrast to other forms of pHPT, hypercalcaemia is highly penetrant at all ages (Marx et al., 1981). In general, these patients show relative hypocalciuria (urinary calcium/creatinine ratio typically < 0·01) in the presence of hypercalcaemia and hyperparathyroidism due to inactivation of CaR in renal tubules. Furthermore, mild hypermagnesemia can be found (Marx et al., 1981; Kristiansen et al., 1985). Whereas neonatal severe pHPT is a potentially lethal disorder and requires immediate total parathyroidectomy, patients with FHH are mostly asymptomatic and surgery is almost always contraindicated. In one kindred with a highly atypical phenotype (hypercalciuria, nephrolithiasis, nodular hyperplasia and adenoma), long-term benefit from subtotal parathyroid surgery has been reported (Carling et al., 2000). However, additional pathophysiological abnormalities cannot completely be ruled out in the patients with this atypical phenotype.

In summary, an inherited syndrome should be suspected in younger patients with pHPT (< 40 years old), in patients with multiple parathyroid adenomas or hyperplasia at surgery (indicative of MEN-1 or FHH), atypical parathyroid adenomas or parathyroid carcinoma (indicative of hyperparathyroidism-jaw tumour syndrome), and a family or past medical history pointing to one of the described syndromes. Sporadic pHPT is only rarely diagnosed before the age of 50 and is mostly caused by solitary parathyroid adenomas (Wermers et al., 1997; Jorde et al., 2000). If suspected, MEN-1 (MEN1 gene), and MEN-2 (RET proto-oncogene) should be confirmed by mutational analysis of leucocyte DNA. In patients with suspected FHH or neonatal severe pHPT, evaluation of serum calcium and PTH concentrations, as well as urinary calcium/creatinine clearances of family members (autosomal dominant inheritance) may be sufficient to obtain the diagnosis, and mutational analysis of CaR should be reserved for cases with an atypical clinical presentation (Carling et al., 2000; Simonds et al., 2002).

The majority of patients with pHPT suffers from the sporadic form of the disease that is caused by solitary parathyroid adenomas. It is assumed that these neoplasms originate from single cells with a mutation conferring a growth advantage upon them and their progeny (Knudson, 1977). Such mutations could lead to activation of a proto-oncogene or inactivation of a tumour suppressor gene with increased cellular proliferation. The subsequent monoclonal cell expansion ultimately results in the clinically apparent tumour. For most parathyroid tumours within the setting of sporadic pHPT it could be confirmed by X-chromosome inactivation analysis that they indeed are monoclonal lesions (Arnold et al., 1988; Shan et al., 1997; Miedlich et al., 2000).

In addition to monoclonal growth initiated by a mutation, other factors, e.g. aberrant patterns of DNA methylation, hormonal and environmental influences on gene expression or secretion of growth factors could allow proliferation to proceed more readily (Arnold, 1994). The spectrum of possible mutations could include point mutations (e.g. CaR, discussed below), short deletions/insertions (e.g. MEN1 gene) and chromosomal aberrations (chromosomal re-arrangements, e.g. PRAD 1 gene, gains and losses of chromosomal parts).