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. 1997 Jan 1;99(1):88–96. doi: 10.1172/JCI119137

In vivo and in vitro characterization of neonatal hyperparathyroidism resulting from a de novo, heterozygous mutation in the Ca2+-sensing receptor gene: normal maternal calcium homeostasis as a cause of secondary hyperparathyroidism in familial benign hypocalciuric hypercalcemia.

M Bai 1, S H Pearce 1, O Kifor 1, S Trivedi 1, U G Stauffer 1, R V Thakker 1, E M Brown 1, B Steinmann 1
PMCID: PMC507771  PMID: 9011580

Abstract

We characterized the in vivo, cellular and molecular pathophysiology of a case of neonatal hyperparathyroidism (NHPT) resulting from a de novo, heterozygous missense mutation in the gene for the extracellular Ca2+ (Ca2+(o))-sensing receptor (CaR). The female neonate presented with moderately severe hypercalcemia, markedly undermineralized bones, and multiple metaphyseal fractures. Subtotal parathyroidectomy was performed at 6 wk; hypercalcemia recurred rapidly but the bone disease improved gradually with reversion to an asymptomatic state resembling familial benign hypocalciuric hypercalcemia (FBHH). Dispersed parathyroid cells from the resected tissue showed a set-point (the level of Ca2+(o) half maximally inhibiting PTH secretion) substantially higher than for normal human parathyroid cells (approximately 1.8 vs. approximately 1.0 mM, respectively); a similar increase in set-point was observed in vivo. The proband's CaR gene showed a missense mutation (R185Q) at codon 185, while her normocalcemic parents were homozygous for wild type (WT) CaR sequence. Transient expression of the mutant R185Q CaR in human embryonic kidney (HEK293) cells revealed a substantially attenuated Ca2+(o)-evoked accumulation of total inositol phosphates (IP), while cotransfection of normal and mutant receptors showed an EC50 (the level of Ca2+(o) eliciting a half-maximal increase in IPs) 37% higher than for WT CaR alone (6.3+/-0.4 vs. 4.6+/-0.3 mM Ca2+(o), respectively). Thus this de novo, heterozygous CaR mutation may exert a dominant negative action on the normal CaR, producing NHPT and more severe hypercalcemia than typically seen with FBHH. Moreover, normal maternal calcium homeostasis promoted additional secondary hyperparathyroidism in the fetus, contributing to the severity of the NHPT in this case with FBHH.

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Selected References

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  1. Aida K., Koishi S., Inoue M., Nakazato M., Tawata M., Onaya T. Familial hypocalciuric hypercalcemia associated with mutation in the human Ca(2+)-sensing receptor gene. J Clin Endocrinol Metab. 1995 Sep;80(9):2594–2598. doi: 10.1210/jcem.80.9.7673400. [DOI] [PubMed] [Google Scholar]
  2. Attie M. F., Gill J. R., Jr, Stock J. L., Spiegel A. M., Downs R. W., Jr, Levine M. A., Marx S. J. Urinary calcium excretion in familial hypocalciuric hypercalcemia. Persistence of relative hypocalciuria after induction of hypoparathyroidism. J Clin Invest. 1983 Aug;72(2):667–676. doi: 10.1172/JCI111016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Auwerx J., Demedts M., Bouillon R. Altered parathyroid set point to calcium in familial hypocalciuric hypercalcaemia. Acta Endocrinol (Copenh) 1984 Jun;106(2):215–218. doi: 10.1530/acta.0.1060215. [DOI] [PubMed] [Google Scholar]
  4. Bai M., Quinn S., Trivedi S., Kifor O., Pearce S. H., Pollak M. R., Krapcho K., Hebert S. C., Brown E. M. Expression and characterization of inactivating and activating mutations in the human Ca2+o-sensing receptor. J Biol Chem. 1996 Aug 9;271(32):19537–19545. doi: 10.1074/jbc.271.32.19537. [DOI] [PubMed] [Google Scholar]
  5. Baron J., Winer K. K., Yanovski J. A., Cunningham A. W., Laue L., Zimmerman D., Cutler G. B., Jr Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism. Hum Mol Genet. 1996 May;5(5):601–606. doi: 10.1093/hmg/5.5.601. [DOI] [PubMed] [Google Scholar]
  6. Bradford W. D., Wilson J. W., Gaede J. T. Primary neonatal hyperparathyroidism--an unusual cause of failure to thrive. Am J Clin Pathol. 1973 Feb;59(2):265–275. [PubMed] [Google Scholar]
  7. Brown E. M., Gamba G., Riccardi D., Lombardi M., Butters R., Kifor O., Sun A., Hediger M. A., Lytton J., Hebert S. C. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature. 1993 Dec 9;366(6455):575–580. doi: 10.1038/366575a0. [DOI] [PubMed] [Google Scholar]
  8. Brown E. M., Hebert S. C. A cloned Ca(2+)-sensing receptor: a mediator of direct effects of extracellular Ca2+ on renal function? J Am Soc Nephrol. 1995 Dec;6(6):1530–1540. doi: 10.1681/ASN.V661530. [DOI] [PubMed] [Google Scholar]
  9. Brown E. M., Pollak M., Seidman C. E., Seidman J. G., Chou Y. H., Riccardi D., Hebert S. C. Calcium-ion-sensing cell-surface receptors. N Engl J Med. 1995 Jul 27;333(4):234–240. doi: 10.1056/NEJM199507273330407. [DOI] [PubMed] [Google Scholar]
  10. Brown E. M., Wilson R. E., Eastman R. C., Pallotta J., Marynick S. P. Abnormal regulation of parathyroid hormone release by calcium in secondary hyperparathyroidism due to chronic renal failure. J Clin Endocrinol Metab. 1982 Jan;54(1):172–179. doi: 10.1210/jcem-54-1-172. [DOI] [PubMed] [Google Scholar]
  11. Brown E. M., Wilson R. E., Thatcher J. G., Marynick S. P. Abnormal calcium-regulated PTH release in normal parathyroid tissue from patients with adenoma. Am J Med. 1981 Oct;71(4):565–570. doi: 10.1016/0002-9343(81)90207-2. [DOI] [PubMed] [Google Scholar]
  12. Ch'ng J. L., Kaiser A., Lynn J., Joplin G. F. Post-parathyroidectomy restoration of normal calcium homeostasis in neonatal primary hyperparathyroidism. Acta Endocrinol (Copenh) 1984 Mar;105(3):350–353. doi: 10.1530/acta.0.1050350. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Chou Y. H., Pollak M. R., Brandi M. L., Toss G., Arnqvist H., Atkinson A. B., Papapoulos S. E., Marx S., Brown E. M., Seidman J. G. Mutations in the human Ca(2+)-sensing-receptor gene that cause familial hypocalciuric hypercalcemia. Am J Hum Genet. 1995 May;56(5):1075–1079. [PMC free article] [PubMed] [Google Scholar]
  15. Davies M., Adams P. H., Lumb G. A., Berry J. L., Loveridge N. Familial hypocalciuric hypercalcaemia: evidence for continued enhanced renal tubular reabsorption of calcium following total parathyroidectomy. Acta Endocrinol (Copenh) 1984 Aug;106(4):499–504. doi: 10.1530/acta.0.1060499. [DOI] [PubMed] [Google Scholar]
  16. Dezateux C. A., Hyde J. C., Hoey H. M., O'Riordan J. L., Spitz L., Taylor G. W., Grant D. B. Neonatal hyperparathyroidism. Eur J Pediatr. 1984 Jun;142(2):135–136. doi: 10.1007/BF00445595. [DOI] [PubMed] [Google Scholar]
  17. FRETHEIM B., GARDBORG O. PRIMARY HYPERPARATHYROIDISM IN AN INFANT; REPORT OF A CASE. Acta Chir Scand. 1965 May;129:557–566. [PubMed] [Google Scholar]
  18. 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]
  19. Fujimoto Y., Hazama H., Oku K. Severe primary hyperparathyroidism in a neonate having a parent with hypercalcemia: treatment by total parathyroidectomy and simultaneous heterotopic autotransplantation. Surgery. 1990 Nov;108(5):933–938. [PubMed] [Google Scholar]
  20. Fujita T., Watanabe N., Fukase M., Tsutsumi M., Fukami T., Imai Y., Sakaguchi K., Okada S., Matsuo M., Takemine H. Familial hypocalciuric hypercalcemia involving four members of a kindred including a girl with severe neonatal primary hyperparathyroidism. Miner Electrolyte Metab. 1983 Jan-Feb;9(1):51–54. [PubMed] [Google Scholar]
  21. Goldbloom R. B., Gillis D. A., Prasad M. Hereditary parathyroid hyperplasia: a surgical emergency of early infancy. Pediatrics. 1972 Apr;49(4):514–523. [PubMed] [Google Scholar]
  22. Gyapay G., Morissette J., Vignal A., Dib C., Fizames C., Millasseau P., Marc S., Bernardi G., Lathrop M., Weissenbach J. The 1993-94 Généthon human genetic linkage map. Nat Genet. 1994 Jun;7(2 Spec No):246–339. doi: 10.1038/ng0694supp-246. [DOI] [PubMed] [Google Scholar]
  23. HILLMAN D. A., SCRIVER C. R., PEDVIS S., SHRAGOVITCH I. NEONATAL FAMILIAL PRIMARY HYPERPARATHYROIDISM. N Engl J Med. 1964 Mar 5;270:483–490. doi: 10.1056/NEJM196403052701001. [DOI] [PubMed] [Google Scholar]
  24. Harris S. S., D'Ercole A. J. Neonatal hyperparathyroidism: the natural course in the absence of surgical intervention. Pediatrics. 1989 Jan;83(1):53–56. [PubMed] [Google Scholar]
  25. Heath H., 3rd, Jackson C. E., Otterud B., Leppert M. F. Genetic linkage analysis in familial benign (hypocalciuric) hypercalcemia: evidence for locus heterogeneity. Am J Hum Genet. 1993 Jul;53(1):193–200. [PMC free article] [PubMed] [Google Scholar]
  26. Heath H., 3rd, Odelberg S., Jackson C. E., Teh B. T., Hayward N., Larsson C., Buist N. R., Krapcho K. J., Hung B. C., Capuano I. V. Clustered inactivating mutations and benign polymorphisms of the calcium receptor gene in familial benign hypocalciuric hypercalcemia suggest receptor functional domains. J Clin Endocrinol Metab. 1996 Apr;81(4):1312–1317. doi: 10.1210/jcem.81.4.8636323. [DOI] [PubMed] [Google Scholar]
  27. Ho C., Conner D. A., Pollak M. R., Ladd D. J., Kifor O., Warren H. B., Brown E. M., Seidman J. G., Seidman C. E. A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Nat Genet. 1995 Dec;11(4):389–394. doi: 10.1038/ng1295-389. [DOI] [PubMed] [Google Scholar]
  28. Janicic N., Pausova Z., Cole D. E., Hendy G. N. Insertion of an Alu sequence in the Ca(2+)-sensing receptor gene in familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Am J Hum Genet. 1995 Apr;56(4):880–886. [PMC free article] [PubMed] [Google Scholar]
  29. Khosla S., Ebeling P. R., Firek A. F., Burritt M. M., Kao P. C., Heath H., 3rd Calcium infusion suggests a "set-point" abnormality of parathyroid gland function in familial benign hypercalcemia and more complex disturbances in primary hyperparathyroidism. J Clin Endocrinol Metab. 1993 Mar;76(3):715–720. doi: 10.1210/jcem.76.3.8445032. [DOI] [PubMed] [Google Scholar]
  30. Kifor O., Kifor I., Brown E. M. Effects of high extracellular calcium concentrations on phosphoinositide turnover and inositol phosphate metabolism in dispersed bovine parathyroid cells. J Bone Miner Res. 1992 Nov;7(11):1327–1336. doi: 10.1002/jbmr.5650071113. [DOI] [PubMed] [Google Scholar]
  31. Kunkel T. A. Rapid and efficient site-specific mutagenesis without phenotypic selection. Proc Natl Acad Sci U S A. 1985 Jan;82(2):488–492. doi: 10.1073/pnas.82.2.488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. 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]
  33. LeBoff M. S., Shoback D., Brown E. M., Thatcher J., Leombruno R., Beaudoin D., Henry M., Wilson R., Pallotta J., Marynick S. Regulation of parathyroid hormone release and cytosolic calcium by extracellular calcium in dispersed and cultured bovine and pathological human parathyroid cells. J Clin Invest. 1985 Jan;75(1):49–57. doi: 10.1172/JCI111696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. 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]
  35. 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]
  36. Marx S. J., Fraser D., Rapoport A. Familial hypocalciuric hypercalcemia. Mild expression of the gene in heterozygotes and severe expression in homozygotes. Am J Med. 1985 Jan;78(1):15–22. doi: 10.1016/0002-9343(85)90455-3. [DOI] [PubMed] [Google Scholar]
  37. Meeran K., Husain M., Puccini M., Scott H., Dionisi-Vici C., Harvey D. R., Lynn J., Thakker R. V. Neonatal primary hyperparathyroidism masked by vitamin D deficiency. Clin Endocrinol (Oxf) 1994 Oct;41(4):531–534. doi: 10.1111/j.1365-2265.1994.tb02586.x. [DOI] [PubMed] [Google Scholar]
  38. Page L. A., Haddow J. E. Self-limited neonatal hyperparathyroidism in familial hypocalciuric hypercalcemia. J Pediatr. 1987 Aug;111(2):261–264. doi: 10.1016/s0022-3476(87)80083-5. [DOI] [PubMed] [Google Scholar]
  39. Pearce S. H., Bai M., Quinn S. J., Kifor O., Brown E. M., Thakker R. V. Functional characterization of calcium-sensing receptor mutations expressed in human embryonic kidney cells. J Clin Invest. 1996 Oct 15;98(8):1860–1866. doi: 10.1172/JCI118987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Pearce S. H., Trump D., Wooding C., Besser G. M., Chew S. L., Grant D. B., Heath D. A., Hughes I. A., Paterson C. R., Whyte M. P. Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism. J Clin Invest. 1995 Dec;96(6):2683–2692. doi: 10.1172/JCI118335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Pollak M. R., Brown E. M., Chou Y. H., Hebert S. C., Marx S. J., Steinmann B., Levi T., Seidman C. E., Seidman J. G. Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell. 1993 Dec 31;75(7):1297–1303. doi: 10.1016/0092-8674(93)90617-y. [DOI] [PubMed] [Google Scholar]
  42. Pollak M. R., Brown E. M., Estep H. L., McLaine P. N., Kifor O., Park J., Hebert S. C., Seidman C. E., Seidman J. G. Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation. Nat Genet. 1994 Nov;8(3):303–307. doi: 10.1038/ng1194-303. [DOI] [PubMed] [Google Scholar]
  43. Pollak M. R., Chou Y. H., Marx S. J., Steinmann B., Cole D. E., Brandi M. L., Papapoulos S. E., Menko F. H., Hendy G. N., Brown E. M. Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype. J Clin Invest. 1994 Mar;93(3):1108–1112. doi: 10.1172/JCI117062. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. RANDALL C., LAUCHLAN S. C. Parathyroid hyperplasia in an infant. Am J Dis Child. 1963 Apr;105:364–367. doi: 10.1001/archpedi.1963.02080040366007. [DOI] [PubMed] [Google Scholar]
  45. Rhone D. P. Primary neonatal hyperparathyroidism. Report of a case and review of the literature. Am J Clin Pathol. 1975 Oct;64(4):488–499. doi: 10.1093/ajcp/64.4.488. [DOI] [PubMed] [Google Scholar]
  46. 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]
  47. Spiegel A. M., Harrison H. E., Marx S. J., Brown E. M., Aurbach G. D. Neonatal primary hyperparathyroidism with autosomal dominant inheritance. J Pediatr. 1977 Feb;90(2):269–272. doi: 10.1016/s0022-3476(77)80649-5. [DOI] [PubMed] [Google Scholar]
  48. 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]
  49. Thakker R. V., Pook M. A., Wooding C., Boscaro M., Scanarini M., Clayton R. N. Association of somatotrophinomas with loss of alleles on chromosome 11 and with gsp mutations. J Clin Invest. 1993 Jun;91(6):2815–2821. doi: 10.1172/JCI116524. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Thompson N. W., Carpenter L. C., Kessler D. L., Nishiyama R. H. Hereditary neonatal hyperparathyroidism. Arch Surg. 1978 Jan;113(1):100–103. doi: 10.1001/archsurg.1978.01370130102020. [DOI] [PubMed] [Google Scholar]
  51. Trump D., Whyte M. P., Wooding C., Pang J. T., Pearce S. H., Kocher D. B., Thakker R. V. 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. Hum Genet. 1995 Aug;96(2):183–187. doi: 10.1007/BF00207376. [DOI] [PubMed] [Google Scholar]
  52. Wilkinson H., James J. Self limiting neonatal primary hyperparathyroidism associated with familial hypocalciuric hypercalcaemia. Arch Dis Child. 1993 Sep;69(3 Spec No):319–321. doi: 10.1136/adc.69.3_spec_no.319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Yandell D. W., Dryja T. P. Detection of DNA sequence polymorphisms by enzymatic amplification and direct genomic sequencing. Am J Hum Genet. 1989 Oct;45(4):547–555. [PMC free article] [PubMed] [Google Scholar]
  54. el-Hajj Fuleihan G., Chen C. J., Rivkees S. A., Marynick S. P., Stock J., Pallotta J. A., Brown E. M. Calcium-dependent release of N-terminal fragments and intact immunoreactive parathyroid hormone by human pathological parathyroid tissue in vitro. J Clin Endocrinol Metab. 1989 Oct;69(4):860–867. doi: 10.1210/jcem-69-4-860. [DOI] [PubMed] [Google Scholar]

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