European Journal of Pediatrics

, Volume 163, Issue 10, pp 589–594 | Cite as

Neonatal severe hyperparathyroidism: genotype/phenotype correlation and the use of pamidronate as rescue therapy

  • Simon Waller
  • Tom Kurzawinski
  • Lewis Spitz
  • Rajesh Thakker
  • Treena Cranston
  • Simon Pearce
  • Tim Cheetham
  • William G. van’t HoffEmail author
Original Paper


Familial hypocalciuric hypercalcaemia (FHH) is an autosomal dominant condition due to heterozygous loss of function calcium sensing receptor (CaSR) mutations. However, individuals who are homozygous for CaSR mutations have neonatal severe hyperparathyroidism (NSHPT), which unlike the relatively benign and asymptomatic FHH can be fatal without parathyroidectomy. We report three patients with NSHPT associated with marked hypercalcaemia and severe hyperparathyroidism with related skeletal demineralisation. We describe the novel use of intravenous pamidronate in NSHPT, to control severe hypercalcaemia in these patients prior to parathyroidectomy and in one individual as a rescue therapy to stabilise life-threatening demineralisation. Furthermore, a marked phenotypic heterogeneity was observed amongst four members from a large kindred with the same homozygous CaSR mutations: one patient would have died without parathyroidectomy in infancy; a second patient survived infancy but underwent parathyroidectomy in early childhood following severe symptomatic hypercalcaemic episodes; whilst the other two patients have survived to adolescence without parathyroidectomy. Additionally, in contrast to the literature these two individuals suffered minimal morbidity. Conclusion:we commend the short-term use of pamidronate in neonatal severe hyperparathyroidism to treat extreme hypercalcaemia and halt hyperparathyroid-driven skeletal demineralisation in preparation for parathyroidectomy. The remarkable degree of phenotypic variation demonstrated remains unexplained without functional studies; this variability highlights the challenge of treating this rare condition.


Calcium sensing receptor Familial hypocalciuric hypercalcaemia Parathyroidectomy 



calcium sensing receptor


familial hypocalciuric hypercalcaemia


neonatal severe hyperparathyroidism





S Waller is partly funded by the special trustees of Great Ormond Street Hospital. We thank Dr Gerald McEnery for referring two of the patients for further management.


  1. 1.
    Aida K, Koishi S, Inoue M, Nakazato M, Tawata M, Onaya T (1995) Familial hypocalciuric hypercalcemia associated with mutation in the human Ca(2+)-sensing receptor gene. J Clin Endocrinol Metab 80: 2594–2598CrossRefPubMedGoogle Scholar
  2. 2.
    Allgrove J (2002) Use of bisphosphonates in children and adolescents. J Pediatr Endocrinol Metab 15[Suppl 3]: 921–928Google Scholar
  3. 3.
    Brown EM (1999) Physiology and pathophysiology of the extracellular calcium-sensing receptor. Am J Med 106: 238–253CrossRefPubMedGoogle Scholar
  4. 4.
    Brumsen C, Hamdy NA, Papapoulos SE (1997) Long-term effects of bisphosphonates on the growing skeleton. Studies of young patients with severe osteoporosis. Medicine (Baltimore) 76: 266–283Google Scholar
  5. 5.
    Chikatsu N, Fukumoto S, Suzawa M, Tanaka Y, Takeuchi Y, Takeda S, Tamura Y, Matsumoto T, Fujita T (1999) An adult patient with severe hypercalcaemia and hypocalciuria due to a novel homozygous inactivating mutation of calcium-sensing receptor. Clin Endocrinol (Oxf) 50: 537–543Google Scholar
  6. 6.
    Cole DE, Janicic N, Salisbury SR, Hendy GN (1997) Neonatal severe hyperparathyroidism, secondary hyperparathyroidism, and familial hypocalciuric hypercalcemia: multiple different phenotypes associated with an inactivating Alu insertion mutation of the calcium-sensing receptor gene. Am J Med Genet 71: 202–210CrossRefPubMedGoogle Scholar
  7. 7.
    Glorieux FH, Bishop NJ, Plotkin H, Chabot G, Lanoue G, Travers R (1998) Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 339: 947–952CrossRefPubMedGoogle Scholar
  8. 8.
    Heath D (1994) Familial hypocalciuric hypercalcaemia. In: Bilezikian J, Levine M, Marcus R (eds) The parathyroids. Raven Press, New York, pp 699–710Google Scholar
  9. 9.
    Hendy GN, D’Souza-Li L, Yang B, Canaff L, Cole DE (2000) Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Hum Mutat 16: 281–296CrossRefPubMedGoogle Scholar
  10. 10.
    Isaia GC, Lala R, Defilippi C, Matarazzo P, Andreo M, Roggia C, Priolo G, de Sanctis C (2002) Bone turnover in children and adolescents with McCune-Albright syndrome treated with pamidronate for bone fibrous dysplasia. Calcif Tissue Int 71: 121–128CrossRefPubMedGoogle Scholar
  11. 11.
    Kanis JA, Hamdy NA (1998) Hypo-hypercalcaemia. In: Davidson A, Cameron J, Grunfeld J, Kerr D, Ritz E, Winearls C (eds) Oxford textbook of clinical nephrology, vol 1, 2nd edn. , OUP, Oxford, pp 225–247Google Scholar
  12. 12.
    Kos CH, Karaplis AC, Peng JB, Hediger MA, Goltzman D, Mohammad KS, Guise TA, Pollak MR (2003) The calcium-sensing receptor is required for normal calcium homeostasis independent of parathyroid hormone. J Clin Invest 111: 1021–1028CrossRefPubMedGoogle Scholar
  13. 13.
    Kovacs CS, Ho-Pao CL, Hunzelman JL, Lanske B, Fox J, Seidman JG, Seidman CE, Kronenberg HM (1998) Regulation of murine fetal-placental calcium metabolism by the calcium-sensing receptor. J Clin Invest 101: 2812–2820PubMedGoogle Scholar
  14. 14.
    Marini JC (2003) Do bisphosphonates make children’s bones better or brittle? N Engl J Med 349: 423–426CrossRefPubMedGoogle Scholar
  15. 15.
    Marx SJ, Attie MF, Spiegel AM, Levine MA, Lasker RD, Fox M (1982) An association between neonatal severe primary hyperparathyroidism and familial hypocalciuric hypercalcemia in three kindreds. N Engl J Med 306: 257–264PubMedGoogle Scholar
  16. 16.
    Pearce S, Steinmann B (1999) Casting new light on the clinical spectrum of neonatal severe hyperparathyroidism. Clin Endocrinol (Oxf) 50: 691–693Google Scholar
  17. 17.
    Pearce SH, Trump D, Wooding C, Besser GM, Chew SL, Grant DB, Heath DA, Hughes IA, Paterson CR, Whyte MP (1995) Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism. J Clin Invest 96: 2683–2692PubMedGoogle Scholar
  18. 18.
    Pearce SH, Bai M, Quinn SJ, Kifor O, Brown EM, Thakker RV (1996) Functional characterization of calcium-sensing receptor mutations expressed in human embryonic kidney cells. J Clin Invest 98: 1860–1866PubMedGoogle Scholar
  19. 19.
    Pollak MR, Chou YH, Marx SJ, Steinmann B, Cole DE, Brandi ML, Papapoulos SE, Menko FH, Hendy GN, Brown EM (1994) Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype. J Clin Invest 93: 1108–1112PubMedGoogle Scholar
  20. 20.
    Profumo RJ, Reese JC, Foy TM, Garibaldi LR, Kane RE (1994) Severe immobilization-induced hypercalcemia in a child after liver transplantation successfully treated with pamidronate. Transplantation 57: 301–303PubMedGoogle Scholar
  21. 21.
    Russell RG, Rogers MJ (1999) Bisphosphonates: from the laboratory to the clinic and back again. Bone 25: 97–106CrossRefPubMedGoogle Scholar
  22. 22.
    Shoemaker LR (1999) Expanding role of bisphosphonate therapy in children. J Pediatr 134: 264–267PubMedGoogle Scholar
  23. 23.
    So NP, Osorio AV, Simon SD, Alon US (2001) Normal urinary calcium/creatinine ratios in African-American and Caucasian children. Pediatr Nephrol 16: 133–139CrossRefPubMedGoogle Scholar
  24. 24.
    Srivastava T, Alon US (2003) The role of bisphosphonates in diseases of childhood. Eur J Pediatr 162: 735–751CrossRefPubMedGoogle Scholar
  25. 25.
    Tezer Kutluk M (1999) Use of bisphosphonates in hypercalcemia associated with childhood cancer. J Clin Oncol 17: 1960Google Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Simon Waller
    • 1
  • Tom Kurzawinski
    • 2
  • Lewis Spitz
    • 3
  • Rajesh Thakker
    • 4
  • Treena Cranston
    • 5
  • Simon Pearce
    • 6
  • Tim Cheetham
    • 6
  • William G. van’t Hoff
    • 1
    Email author
  1. 1.Nephro-Urology UnitInstitute of Child Health, University College of London Medical Schools and Great Ormond Street Hospital for Children NHS TrustLondon UK
  2. 2.Pancreatic and Endocrine Surgical UnitThe Middlesex Hospital, University College London Hospitals NHS TrustLondon UK
  3. 3.Department of SurgeryGreat Ormond Street Hospital for Children NHS TrustLondonUK
  4. 4.Nuffield Department of Clinical MedicineUniversity of OxfordOxford UK
  5. 5.Genetics LaboratoriesOxford Radcliffe Hospitals NHS TrustOxford UK
  6. 6.Royal Victoria InfirmaryThe Newcastle Upon Tyne Hospitals NHS TrustNewcastle Upon Tyne UK

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