Autosomal dominant primary hyperparathyroidism and jaw tumor syndrome associated with renal hamartomas and cystic kidney disease: linkage to 1q21-q32 and loss of the wild type allele in renal hamartomas.

Abstract

Hereditary hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant disease (OMIM 145001) that has recently been mapped to chromosomal region 1q21-q32 (HRPT2). Here we report two families with HPT-JT syndrome in which adult renal hamartomas or cystic kidney disease were prominent associated features, possibly representing a new phenotypic variant of the HPT-JT syndrome. In the first family, renal lesions were present in five out of six affected individuals, whereas HPT and JT were seen in four and two cases, respectively. In the second family, JT was found in three of the five affected individuals and two affected members also exhibited polycystic kidney disease. The possibility of the latter cosegregating as a separate autosomal dominant gene can not be ruled out. A sex-dependent penetrance of primary HPT, resulting in predominantly male-affected cases was evident in the two families. Twenty microsatellite markers in the HRPT2 region were typed, in addition to markers in the multiple endocrine neoplasia (MEN) types 1 and 2 regions at 11q13 and 10q11. The disease in these two kindreds was linked to five markers in the 1q21-q32 region (logarithm-of-odds scores: 3.2-4.2), whereas linkage to the MEN1 and MEN2 regions was excluded. Meiotic recombinations detected in affected individuals placed the locus telomeric of D1S215, thus narrowing the HRPT2 region from > 60 to approximately 34 centimorgans. Loss of heterozygosity was studied in seven renal hamartomas from two affected individuals in the first family, as well as in a jaw tumor and a parathyroid tumor from the second family. All renal hamartomas showed loss of heterozygosity at the 1q21-q32 region. The losses invariably involved the wild type allele derived from the unaffected parent, suggesting the inactivation of a tumor suppressor gene in this region.

Parafibromin, product of the hyperparathyroidism-jaw tumor syndrome gene HRPT2, regulates cyclin D1/PRAD1 expression

“…The major features are primary hyperparathyroidism (90%) including 15% of all affected by HPT-JT with parathyroid cancer, jaw tumors (30%), bilateral renal cysts (10%), and less commonly solid renal tumors (Jackson, 1958;Firat and Stutzman, 1968;Kennett and Pollick, 1971;Dinnen et al, 1977;Rosen and Palmer, 1981;Warnakulasuriya et al, 1985;Mallette et al, 1987;Jackson et al, 1990;Streeten et al, 1992;Visset et al, 1992;Wassif et al, 1993;Kakinuma et al, 1994;Inoue et al, 1995;Szabo et al, 1995;Teh et al, 1996Teh et al, , 1998Fujikawa et al, 1998;Yoshimoto et al, 1998;Cavaco et al, 2001;Simonds et al, 2002). Nearly 10% of mutation carriers appear to remain clinically silent in adulthood (Teh et al, 1996;Simonds et al, 2002). Germline inactivating HRPT2 mutation has also been reported in a minority of kindreds with familial isolated hyperparathyroidism (FIHP) (Carpten et al, 2002;Howell et al, 2003;Simonds et al, 2004;Villablanca et al, 2004).…”

Familial and Hereditary Forms of Primary Hyperparathyroidism

“…2,[126][127][128][129] In addition, some patients may also develop Wilms' tumors, renal cysts, renal hematomas, renal cortical adenomas, papillary renal cell carcinomas, pancreatic adenocarcinomas, uterine tumors, testicular mixed germ cell tumors with a major seminoma component, and Hurthle cell thyroid adenomas. 2,126,130,131 It is important to note that the parathyroid tumors may occur in isolation and without any evidence of jaw tumors, and this may cause confusion with other hereditary hypercalcemic disorders such as MEN1, FHH, and FIHP.…”

Hereditary Hyperparathyroidism Syndromes

“…This syndrome is characterized by the occurrence of fibrous-osseous tumors of mandible and/or maxilla (ossifying fibroma), Wilms' tumor, papillary renal carcinoma, polycystic kidney disease, renal cysts, and PHPT (51). PHPT is the first manifestation of the disease in more than 95% of patient, exhibiting an aggressive behavior and being sustained with unusually high frequency by parathyroid carcinoma (10e15%).…”

“…Patients tend to have a severe hypercalcemia, with hypercalcemic crisis, often representing the first clinical evidence. The HPT-JTeassociated jaw lesions have been reported to be histologically distinct from the bone disease classically associated to PHPT (51,55). HRPT2 gene, responsible for this syndrome, has been mapped on chromosome 1 in 2002.…”