Abstract
We report a newborn female from a consanguineous Sri Lankan family with clinical and biochemical features of neonatal severe hyperparathyroidism (NSHPT). Mutation screening of the calcium-sensing receptor (CASR) gene in genomic DNA revealed a homozygous truncating mutation (c.679C>T, predicting p.R227X), confirming the clinical diagnosis. Other mutations at the R227 position are reported to cause varying degrees of hypercalcemia and hyperparathyroidism, but this nonsense variant is novel and expected to induce unremitting hyperparathyroidism from birth onward. In our patient with NSHPT, early bisphosphonate therapy was crucial in counteracting the marked hypercalcemia and allowed for safe surgical intervention (“total” parathyroidectomy, “thymectomy and hemithyroidectomy”) at 3 months of age. Conclusion: This report highlights the continuing challenges in diagnosis and management of this life-threatening condition.
Similar content being viewed by others
Abbreviations
- NHPT:
-
neonatal hyperparathyroidism
- CaSR:
-
calcium-sensing receptor
- NSHPT:
-
neonatal severe primary hyperparathyroidism
- FHH:
-
familial hypocalciuric hypercalcemia
- PTH:
-
parathyroid hormone
References
Bai M, Pearce SH, Kifor O, Trivedi S, Stauffer UG, Thakker RV, Brown EM, Steinmann B (1997) 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. J Clin Invest 99(1):88–96
Bambach CP, Reeve TS (1978) Parathyroid identification by methylene blue infusion. Aust N Z J Surg 48(3):314–317
Brown EM (2010) Clinical utility of calcimimetics targeting the extracellular calcium-sensing receptor (CaSR). Biochem Pharmacol 80:297–307
Cole DE, Forsythe CR, Dooley JM, Grantmyre EB, Salisbury SR (1997) Primary neonatal hyperparathyroidism: a devastating neurodevelopmental disorder if left untreated. J Craniofac Genet Dev Biol 10:205–214
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 71:202–210
Cole DE, Yun FH, Wong BY, Shuen AY, Booth RA, Scillitani A, Pidasheva S, Zhou X, Canaff L, Hendy GN (2009) Calcium-sensing receptor mutations and denaturing high performance liquid chromatography. J Mol Endocrinol 42:331–339
Doria AS, Huang C, Makitie O, Thorner P, Kooh SW, Sochett E, Daneman A (2002) Neonatal, severe primary hyperparathyroidism: a 7-year clinical and radiological follow-up of one patient. Pediatr Radiol 32:684–689
D’Souza-Li L, Canaff L, Janicic N, Cole DE, Hendy GN (2001) An acceptor splice site mutation in the calcium-sensing receptor (CASR) gene in familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Hum Mutat 18:411–421
Eftekhari F, Yousefzadeh D (1982) Primary infantile hyperparathyroidism: clinical, laboratory, and radiographic features in 21 cases. Skeletal Radiol 8:201–208
Egbuna OI, Brown EM (2008) Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations. Best Pract Res Clin Rheumatol 22:129–148
Fox L, Sadowsky J, Pringle KP, Kidd A, Murdoch J, Cole DE, Wiltshire E (2007) Neonatal hyperparathyroidism and pamidronate therapy in an extremely premature infant. Pediatrics 120:e1350–e1354
Goldbloom RB, Gillis DA, Prasad M (1972) Hereditary parathyroid hyperplasia: a surgical emergency of early infancy. Pediatrics 49:514–523
Grantmyre E (1973) Roentgenographic features of ‘primary’ hyperparathyroidism in infancy. J Can Assoc Radiol 24:257–260
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 16:281–296
Hendy GN, Guarnieri V, Canaff L (2009) Calcium-sensing receptor and associated diseases. Progr Mol Biol Transl Sci 89C:31–95
Hendy GN, Guarnieri V, Canaff L (2009) Chapter 3: Calcium-sensing receptor and associated diseases. Prog Mol Biol Transl Sci 89:31–95
Ho C, Conner DA, Pollak MR, Ladd DJ, Kifor O, Warren HB, Brown EM, Seidman JG, Seidman CE (1995) A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Nat Genet 11:389–394
Mallet E, Working Group on Calcium Metabolism (2008) Primary hyperparathyroidism in neonates and childhood. The French experience (1984–2004). Horm Res 69:180–188
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 306:257–264
Marx SJ, Lasker RD, Brown EM, Fitzpatrick LA, Sweezey NB, Goldbloom RB, Gillis DA, Cole DE (1986) Secretory dysfunction in parathyroid cells from a neonate with severe primary hyperparathyroidism. J Clin Endocrinol Metab 62:445–449
Meeran K, Husain M, Puccini M, Scott H, Dionisi-Vici C, Harvey DR, Lynn J, Thakker RV (1994) Neonatal primary hyperparathyroidism masked by vitamin D deficiency. Clin Endocrinol (Oxf) 41:531–534
Obermannova B, Banghova K, Sumník Z, Dvorakova HM, Betka J, Fencl F, Kolouskova S, Cinek O, Lebl J (2009) Unusually severe phenotype of neonatal primary hyperparathyroidism due to a heterozygous inactivating mutation in the CASR gene. Eur J Pediatr 168(5):569–573
Pearce SH, Trump D, Wooding C, Besser GM, Chew SL, Grant DB, Heath DA, Hughes IA, Paterson CR, Whyte MP, Thakker RV (1995) Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism. J Clin Invest 96:2683–2692
Pearce SH, Wooding C, Davies M, Tollefsen SE, Whyte MP, Thakker RV (1996) Calcium-sensing receptor mutations in familial hypocalciuric hypercalcaemia with recurrent pancreatitis. Clin Endocrinol (Oxf) 45:675–680
Pidasheva S, D’Souza-Li L, Canaff L, Cole DEC, Hendy GN (2004) CASRdb: calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Hum Mutation 24:107–111
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 93:1108–1112
Southern Reh CM, Hendy GN, Cole DE, Jeandron DD (2010) Neonatal hyperparathyroidism with a de novo heterozygous R185Q calcium-sensing receptor (CASR) mutation: novel use of cinacalcet. J Clin Endocrinol Metab (in press)
Specker B (2004) Vitamin D requirements during pregnancy. Am J Clin Nutr 80:1740S–1747S
Steinmann B, Gnehm HE, Rao VH, Kind HP, Prader A (1984) Neonatal severe primary hyperparathyroidism and alkaptonuria in a boy born to related parents with familial hypocalciuric hypercalcemia. Helv Paediatr Acta 39(2):171–186
Tfelt-Hansen J, Brown EM (2005) The calcium-sensing receptor in normal physiology and pathophysiology: a review. Crit Rev Clin Lab Sci 42:35–70
Waller S, Kurzawinski T, Spitz L, Thakker R, Cranston T, Pearce S, Cheetham T, van’t Hoff WG (2004) Neonatal severe hyperparathyroidism: genotype/phenotype correlation and the use of pamidronate as rescue therapy. Eur J Pediatr 163:589–594
Ward BK, Magno AL, Davis EA, Hanyaloglu AC, Stuckey BG, Burrows M, Eidne KA, Charles AK, Ratajczak T (2004) Functional deletion of the calcium-sensing receptor in a case of neonatal severe hyperparathyroidism. J Clin Endocrinol Metab 89:3721–3730
Ward BK, Cameron FJ, Magno AL, McDonnell CM, Stuckey BG, Ratajczak T (2006) A novel homozygous deletion in the calcium-sensing receptor ligand-binding domain associated with neonatal severe hyperparathyroidism. J Pediatr Endocrinol Metab 19:93–100
Wilkinson H, James J (1993) Self limiting neonatal primary hyperparathyroidism associated with familial hypocalciuric hypercalcaemia. Arch Dis Child 69:319–321
Wystrychowski A, Pidasheva S, Canaff L, Chudek J, Kokot F, Wiecek A, Hendy GN (2005) Functional characterization of calcium-sensing receptor codon 227 mutations presenting as either familial (benign) hypocalciuric hypercalcemia or neonatal hyperparathyroidism. J Clin Endocrinol Metab 90:864–870
Zajickova K, Vrbikova J, Canaff L, Pawelek PD, Goltzman D, Hendy GN (2007) Identification and functional characterization of a novel mutation in the calcium-sensing receptor gene in familial hypocalciuric hypercalcemia: modulation of clinical severity by vitamin D status. J Clin Endocrinol Metab 92:2616–2623
Acknowledgments
The authors would like to thank the patient and her family for their excellent collaboration.
Author information
Authors and Affiliations
Corresponding author
Additional information
Declaration of interest
There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
Rights and permissions
About this article
Cite this article
Al-Khalaf, F.A., Ismail, A., Soliman, A.T. et al. Neonatal severe hyperparathyroidism: further clinical and molecular delineation. Eur J Pediatr 170, 625–631 (2011). https://doi.org/10.1007/s00431-010-1335-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00431-010-1335-z