Studies of Inherited Diseases of Metabolism

Familial multiple endocrine neoplasia type 1 (MEN1), familial hypocalciuric (or familial benign) hypercalcemia (FHH), hyperparathyroidism - jaw tumor syndrome (HPT-JT), other causes of familial isolated hyperparathyroidism FIH, familial carcinoid tumor, and pseudohypoparathyroidism (PHP) are disorders of metabolism that are generally inherited in an autosomal dominant fashion. MEN1 is characterized by overgrowth and hyperfunction of the parathyroids, anterior pituitary and gastrointestinal endocrine tissue. The gene for MEN1 on chromosome 11q13 was cloned in 1997. P15, p18, p 21 are other genes for MEN1-like states. Familial carcinoid tumor can be a component of MEN1 or isolated without other endocrine tumors (FIC). FHH is characterized by a usually benign syndrome sometimes mistaken for typical primary hyperparathyroidism, which may result in unnecessary and unsuccessful parathyroid surgery. The CASR gene for the calcium-sensing receptor of the parathyroid cell was cloned, and members of most FHH kindreds have been noted to have mutations in this gene. HPT-JT is a distinctive subtype of familial isolated hyperparathyroidism (FIH) that has combinations of parathyroid adenoma, parathyroid cancer, jaw tumor, kidney tumor and kidney cysts. It is caused by mutation of the HRPT2 gene. PHP is characterized by parathyroid hormone resistance, and one form is associated with mutations in the gene encoding the stimulatory G protein located on chromosome 20q13. We are continuing to collect blood and tissue samples from affected and unaffected members of known and suspected MEN1, FIC, FHH, HPT-JT, FIH, PHP, and related kindreds for the purpose of genetic analysis and gene identification. In most cases, the procurement of specimens will be at an off-site location. Samples will be processed for extraction of DNA, RNA, and/or the creation of transformed cell lines. This will provide a ready source of DNA and other molecules for genetic analysis to delineate the genetic and molecular basis of these disorders. As genetic analyses often reveal conclusive information about these disorders, genetic counseling is being offered to the individual family members who have provided the specimens.