Linkage studies in a kindred from Oklahoma, with familial benign (hypocalciuric) hypercalcaemia (FBH) and developmental elevations in serum parathyroid hormone levels, indicate a third locus for FBH.

A five-generation kindred (19 affected, two obligate carriers and 20 unaffected) from Oklahoma USA, in which familial benign (hypocalciuric) hypercalcaemia (FBH) was associated with a developmental elevation in serum parathyroid hormone (PTH) levels, has been investigated for linkage to the candidate chromosomal regions 3q21-q24 and 19p13.3, 11q13, and 11p15, to which the genes for FBH, multiple endocrine neoplasia type 1 (MEN1) and PTH have been mapped respectively. By means of 17 polymorphic markers from these regions, linkage was excluded [LOD scores < -2.00 at (theta) = 0.05-0.25]. In addition, an analysis of multipoint crossovers and use of the LINKMAP program confirmed the exclusion from these regions. Thus, this form of FBH, designated the Oklahoma variant FBH(Ok), is not linked to markers that segregate with FBH, MEN1 and PTH; our results indicate further genetic heterogeneity and the presence of a third locus for FBH.

Significant developmental elevation in serum parathyroid hormone levels in a large kindred with familial benign (hypocalciuric) hypercalcemia.

PURPOSE: A large kindred with familial benign hypercalcemia (FBH) is described because of the new observation of developmental increases in serum immunoreactive parathyroid hormone (iPTH) levels in affected individuals that lead to significantly elevated values in adults. PATIENTS AND METHODS: After identification of the proposita, 46 kindred members spanning 5 generations, ages 1.5 to 91 years, were surveyed biochemically and/or studied by chart review. Two hypercalcemic adults underwent biopsy of the iliac crest following tetracycline labeling for histomorphometric study. RESULTS: Of the 46 individuals studied, 19 were found to be affected. Serum iPTH levels, determined in three separate immunoassays, became supranormal by about age 30 years in the group of 15 hypercalcemic subjects examined biochemically and appeared to increase further thereafter. Serum alkaline phosphatase activity and creatinine levels were normal in these individuals, but inorganic phosphate levels were lower than in unaffected kindred members. Three of five affected adults older than age 40 years who were studied radiographically had changes suggestive of osteomalacia. Biopsy of the iliac crest of one of the subjects, a 51-year-old woman, confirmed the presence of defective skeletal mineralization. CONCLUSIONS: In this kindred, FBH in adults can be especially difficult to distinguish from primary hyperparathyroidism because serum iPTH levels may be elevated. Furthermore, the disorder may not be totally benign. Osteomalacia, perhaps due to mild hypophosphatemia, can develop during adulthood. Review of data from other kindreds for evidence of developmental elevations in serum iPTH levels with careful search for skeletal disease in late adult life will help to clarify if we have observed an unusual variant of FBH.