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American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1993 Jul;53(1):193–200.

Genetic linkage analysis in familial benign (hypocalciuric) hypercalcemia: evidence for locus heterogeneity.

H Heath 3rd 1, C E Jackson 1, B Otterud 1, M F Leppert 1
PMCID: PMC1682230  PMID: 8317484

Abstract

Familial benign hypercalcemia (FBH, or hypocalciuric hypercalcemia) is characterized by inheritance, in an autosomal dominant pattern, of lifelong hypercalcemia without hypercalciuria, which is often mistaken for classical primary hyperparathyroidism. Recently, the FBH trait was linked, in four families, to chromosome 3q. We report genetic linkage analysis in 140 persons from five additional families having FBH (65 affected, 67 unaffected, and 8 unclassifiable). In four families, FBH mapped to chromosome 3q, between D3S1215 and D3S20, maximum multipoint lod score 12.9. By contrast, in the fifth kindred FBH mapped to chromosome 19p13.3, tightly linked to the marker loci D19S20 and D19S266 (two-point lod score at recombination fraction = .001 is 3.44 and 3.70, respectively). Thus, the FBH phenotype results from mutations at two separate loci on chromosomes 3q and 19p.

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Selected References

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  1. Almahroos G. M., Docherty K., Fletcher J. A., Webb T., Heath D. A. Studies of the parathyroid hormone gene in normal subjects, and in subjects with primary hyperparathyroidism and familial benign hypercalcaemia. J Endocrinol. 1987 Oct;115(1):183–186. doi: 10.1677/joe.0.1150183. [DOI] [PubMed] [Google Scholar]
  2. Burritt M. F., Slockbower J. M., Forsman R. W., Offord K. P., Bergstralh E. J., Smithson W. A. Pediatric reference intervals for 19 biologic variables in healthy children. Mayo Clin Proc. 1990 Mar;65(3):329–336. doi: 10.1016/s0025-6196(12)62533-6. [DOI] [PubMed] [Google Scholar]
  3. Chou Y. H., Brown E. M., Levi T., Crowe G., Atkinson A. B., Arnqvist H. J., Toss G., Fuleihan G. E., Seidman J. G., Seidman C. E. The gene responsible for familial hypocalciuric hypercalcemia maps to chromosome 3q in four unrelated families. Nat Genet. 1992 Jul;1(4):295–300. doi: 10.1038/ng0792-295. [DOI] [PubMed] [Google Scholar]
  4. Cooper L., Wertheimer J., Levey R., Brown E., Leboff M., Wilkinson R., Anast C. S. Severe primary hyperparathyroidism in a neonate with two hypercalcemic parents: management with parathyroidectomy and heterotopic autotransplantation. Pediatrics. 1986 Aug;78(2):263–268. [PubMed] [Google Scholar]
  5. Foley T. P., Jr, Harrison H. C., Arnaud C. D., Harrison H. E. Familial benign hypercalcemia. J Pediatr. 1972 Dec;81(6):1060–1067. doi: 10.1016/s0022-3476(72)80232-4. [DOI] [PubMed] [Google Scholar]
  6. Heath H., 3rd Familial benign (hypocalciuric) hypercalcemia. A troublesome mimic of mild primary hyperparathyroidism. Endocrinol Metab Clin North Am. 1989 Sep;18(3):723–740. [PubMed] [Google Scholar]
  7. Heath H., 3rd, Leppert M. F., Lifton R. P., Penniston J. T. Genetic linkage analysis in familial benign hypercalcemia using a candidate gene strategy. I. Studies in four families. J Clin Endocrinol Metab. 1992 Sep;75(3):846–851. doi: 10.1210/jcem.75.3.1517376. [DOI] [PubMed] [Google Scholar]
  8. Kao P. C., van Heerden J. A., Grant C. S., Klee G. G., Khosla S. Clinical performance of parathyroid hormone immunometric assays. Mayo Clin Proc. 1992 Jul;67(7):637–645. doi: 10.1016/s0025-6196(12)60717-4. [DOI] [PubMed] [Google Scholar]
  9. Keating F. R., Jr, Jones J. D., Elveback L. R., Randall R. V. The relation of age and sex to distribution of values in healthy adults of serum calcium, inorganic phosphorus, magnesium, alkaline phosphatase, total proteins, albumin, and blood urea. J Lab Clin Med. 1969 May;73(5):825–834. [PubMed] [Google Scholar]
  10. Kowalska G., Peacock C., Davies M., Dyer P. Absence of linkage between familial hypocalciuric hypercalcaemia and the major histocompatibility system. Tissue Antigens. 1987 Aug;30(2):91–95. doi: 10.1111/j.1399-0039.1987.tb01603.x. [DOI] [PubMed] [Google Scholar]
  11. Lange K., Weeks D. E. Efficient computation of lod scores: genotype elimination, genotype redefinition, and hybrid maximum likelihood algorithms. Ann Hum Genet. 1989 Jan;53(Pt 1):67–83. doi: 10.1111/j.1469-1809.1989.tb01122.x. [DOI] [PubMed] [Google Scholar]
  12. Law W. M., Jr, Heath H., 3rd Familial benign hypercalcemia (hypocalciuric hypercalcemia). Clinical and pathogenetic studies in 21 families. Ann Intern Med. 1985 Apr;102(4):511–519. doi: 10.7326/0003-4819-102-4-511. [DOI] [PubMed] [Google Scholar]
  13. Marx S. J., Attie M. F., Levine M. A., Spiegel A. M., Downs R. W., Jr, Lasker R. D. The hypocalciuric or benign variant of familial hypercalcemia: clinical and biochemical features in fifteen kindreds. Medicine (Baltimore) 1981 Nov;60(6):397–412. doi: 10.1097/00005792-198111000-00002. [DOI] [PubMed] [Google Scholar]
  14. Marx S. J., Attie M. F., Spiegel A. M., Levine M. A., Lasker R. D., Fox M. An association between neonatal severe primary hyperparathyroidism and familial hypocalciuric hypercalcemia in three kindreds. N Engl J Med. 1982 Feb 4;306(5):257–264. doi: 10.1056/NEJM198202043060502. [DOI] [PubMed] [Google Scholar]
  15. Marx S. J., Spiegel A. M., Brown E. M., Aurbach G. D. Family studies in patients with primary parathyroid hyperplasia. Am J Med. 1977 May;62(5):698–706. doi: 10.1016/0002-9343(77)90873-7. [DOI] [PubMed] [Google Scholar]
  16. Menko F. H., Bijvoet O. L., Meera Khan P., Nijenhuis L. E., von Loghem E., Schreuder I., Bernini L. F., Pronk J. C., Madan K., Went L. N. Familial benign hypercalcaemia (FBH; McK. No. 14598, 1983): linkage studies in a large Dutch family. Hum Genet. 1984;67(4):452–454. doi: 10.1007/BF00291409. [DOI] [PubMed] [Google Scholar]
  17. Nakamura Y., Lathrop M., O'Connell P., Leppert M., Lalouel J. M., White R. A primary map of ten DNA markers and two serological markers for human chromosome 19. Genomics. 1988 Jul;3(1):67–71. doi: 10.1016/0888-7543(88)90161-9. [DOI] [PubMed] [Google Scholar]
  18. Paterson C. R., Leheny W., O'Sullivan A. F. HLA antigens and familial benign hypercalcaemia. Clin Endocrinol (Oxf) 1985 Aug;23(2):111–113. doi: 10.1111/j.1365-2265.1985.tb00204.x. [DOI] [PubMed] [Google Scholar]
  19. Rajala M. M., Heath H., 3rd Distribution of serum calcium values in patients with familial benign hypercalcemia (hypocalciuric hypercalcemia): evidence for a discrete genetic defect. J Clin Endocrinol Metab. 1987 Nov;65(5):1039–1041. doi: 10.1210/jcem-65-5-1039. [DOI] [PubMed] [Google Scholar]
  20. Sopwith A. M., Burns C., Grant D. B., Taylor G. W., Wolf E., Besser G. M. Familial hypocalciuric hypercalcaemia: association with neonatal primary hyperparathyroidism, and possible linkage with HLA haplotype. Clin Endocrinol (Oxf) 1984 Jul;21(1):57–64. doi: 10.1111/j.1365-2265.1984.tb00136.x. [DOI] [PubMed] [Google Scholar]
  21. Steinmann B., Gnehm H. E., Rao V. H., Kind H. P., Prader A. Neonatal severe primary hyperparathyroidism and alkaptonuria in a boy born to related parents with familial hypocalciuric hypercalcemia. Helv Paediatr Acta. 1984 May;39(2):171–186. [PubMed] [Google Scholar]
  22. Weber J. L., May P. E. Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am J Hum Genet. 1989 Mar;44(3):388–396. [PMC free article] [PubMed] [Google Scholar]

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