Treatment experience and long-term follow-up data in two severe neonatal hyperparathyroidism cases
-
Senay Savas-Erdeve
,
Corinne Magdelaine
Abstract
The calcium sensing receptor (CASR) is expressed most abundantly in the parathyroid glands and the kidney. CASR regulates calcium homeostasis through its ability to modulate parathormone secretion and renal calcium reabsorption. Inactivating mutations in the CASR gene may result in disorders of calcium homeostasis manifesting as familial benign hypocalciuric hypercalcemia (FBHH) and neonatal severe hyperparathyroidsm (NSHPT). Two cases were referred with severe hypercalcemia in the neonatal period. Laboratory evaluation revealed severe hypercalcemia and elevated PTH. The parents also had mild hypercalcemia. The serum calcium level did not normalize with conventional hypercalcemia treatment and there was also no response to cinacalcet in case 1. Total parathyroidectomy was performed when the patient was 70 days old. Genetic analysis revealed a novel homozygous p.Arg544* mutation in the CASR gene. Case 2 underwent total parathyroidectomy and autoimplantation when she was 97 days old, but the parathyroid gland implanted into the forearm was removed 27 days later because the hypercalcemia continued. Genetic evaluation revealed a novel homozygous p.Pro682Leu mutation with normal anthropometric measurements. The neurological development is consistent with age in both cases while case 2 has mild mental retardation. No bone deformity or fracture is present in either case and normocalcemia is ensured with calcitriol in both cases.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Jack MM, Stone ML, Clifton-Bligh R. Neonatal hypercalcemia due to polymorphisms of the calcium sensing receptor. J Pediatr Endocrinol Metab 2009;22:561–3.10.1515/JPEM.2009.22.6.561Search in Google Scholar
2. Hannan FM, Thakker RV. Calcium-sensing receptor (CASR) mutations and disorders of calcium, electrolyte and water metabolism. Best Pract Res Clin Endocrinol Metab 2013;27:359–71.10.1016/j.beem.2013.04.007Search in Google Scholar
3. Brown EM, MacLeod RJ. Extracellular calcium sensing and extracellular calcium signaling. Physiol Rev 2001;81:239–97.10.1152/physrev.2001.81.1.239Search in Google Scholar
4. Taki K, Kogai T, Sakumoto J, Namatame T, Hishinuma A. Familial hypocalciuric hypercalcemia with a de novo heterozygous mutation of calcium-sensing receptor. Endocrinol Diabetes Metab Case Rep 2015;2015:150016.10.1530/EDM-15-0016Search in Google Scholar
5. Atay Z, Bereket A, Haliloglu B, Abali S, Ozdogan T, et al. Novel homozygous inactivating mutation of the calcium-sensing receptor gene (CASR) in neonatal severe hyperparathyroidism – lack of effect of cinacalcet. Bone 2014;64:102–7.10.1016/j.bone.2014.04.010Search in Google Scholar
6. Wilhelm-Bals A, Parvex P, Magdelaine C, Girardin E. Successful use of bisphosphonate and calcimimetic in neonatal severe primary hyperparathyroidism. Pediatrics 2012;129:e812–6.10.1542/peds.2011-0128Search in Google Scholar
7. Kahvecioglu D, Atasay B, Berberoglu M, Yildiz D, Cakir U, et al. A novel mutation in the calcium sensing receptor gene in a neonate with severe hyperparathyroidism. Genet Couns 2014;25:331–5.Search in Google Scholar
8. Waller S, Kurzawinski T, Spitz L, Thakker R, Cranston T, et al. Neonatal severe hyperparathyroidism: genotype/phenotype correlation and the use of pamidronate as rescue therapy. Eur J Pediatr 2004;163:589–94.10.1007/s00431-004-1491-0Search in Google Scholar
9. Fox L, Sadowsky J, Pringle KP, Kidd A, Murdoch J, et al. Neonatal hyperparathyroidism and pamidronate therapy in an extremely premature infant. Pediatrics 2007;120:e1350–4.10.1542/peds.2006-3209Search in Google Scholar
10. Gurevich Y, Poretsky L. Possible prevention of hungry bone syndrome following parathyroidectomy by preoperative use of pamidronate. Otolaryngol Head Neck Surg 2008;138:403–4.10.1016/j.otohns.2007.11.014Search in Google Scholar
11. Nemeth EF, Fox J. Calcimimetic compounds: a direct approach to controlling plasma levels of parathyroid hormone in hyperparathyroidism. Trends Endocrinol Metab 1999;10:66–71.10.1016/S1043-2760(98)00119-2Search in Google Scholar
12. Garcia Soblechero E, Ferrer Castillo MT, Jimenez Crespo B, Dominquez Quintero ML, Gonzalez Fuentes C. Neonatal hypercalcemia due to a homozygous mutation in the calcium-sensing receptor: failure of cinacalcet. Neonatology 2013;104:104–8.10.1159/000350540Search in Google Scholar PubMed
13. Zhang Z, Qiu W, Quinn SJ, Conigrave AD, Brown EM, et al. Three adjacent serines in the extracellular domains of the CASR are required for L-amino acid-mediated potentiation of receptor function. J Biol Chem 2002;277:33727–35.10.1074/jbc.M200976200Search in Google Scholar PubMed
14. Health DA. Famillial hypocalciuric hypercalcemia. Rev Endocr Metab Disord 2000;1:2916.Search in Google Scholar
15. Rodrigues LS, Cáu AC, Bussmann LZ, Bastida G, Brunetto OH, et al. New mutation in the CASR gene in a family with familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT). Arq Bras Endocrinol Metabol 2011;55:67–71.10.1590/S0004-27302011000100009Search in Google Scholar PubMed
16. Diaz-Thomas A, Cannon J, Iyer P, Al-Maawali A, Fazalullah M, et al. A novel CASR mutation associated with neonatal severehyperparathyroidism transmitted as an autosomal recessive disorder. J Pediatr Endocrinol Metab 2014;27: 851–6.10.1515/jpem-2013-0343Search in Google Scholar PubMed
17. Wells Jr SA, Farndon JR, Dale JK, Leight GS, Dilley WG. Long-term evaluation of patients with primary parathyroid hyperplasia managed by total parathyroidectomy and heterotopic autotransplantation. Ann Surg 1980;192:451–8.10.1097/00000658-198010000-00003Search in Google Scholar PubMed PubMed Central
18. Al-Shanafey S, Al-Hosaini R, Al-Ashwal A, Al-Rabeeah A. Surgical management of severe neonatal hyperparathyroidism: one center’s experience. J Pediatr Surg 2010;45:714–7.10.1016/j.jpedsurg.2009.08.005Search in Google Scholar PubMed
19. Garcia-Garcia E, Dominguez-Pascual I, Requena-Diaz M, Cabello-Laureano R, Fernandez-Pineda I, et al. Intraoperative parathyroid hormone monitoring in neonatal severe primary hyperparathyroidism. Pediatrics 2014;134:e1203–5.10.1542/peds.2013-3668Search in Google Scholar PubMed
20. Mitchell DM, Regan S, Cooley MR, Lauter KB, Vrla MC, et al. Long-term follow-up of patients with hypoparathyroidism. J Clin Endocrinol Metab 2012;97:4507–14.10.1210/jc.2012-1808Search in Google Scholar PubMed PubMed Central
21. Cole D, Forsythe CR, Dooley JM, Grantmyre EB, Salisbury SR. Primary neonatal hyperparathyroidism: a devastating neurodevelopmental disorder if left untreated. J Craniofac Genet Dev Biol 1990;10:205–14.Search in Google Scholar
22. Chikatsu N, Fukumoto S, Suzawa M, Tanaka Y, Takeuchi Y, et al. An adult patient with severe hypercalcemia and hypocalciuria due to a novel homozygous inactivating mutation of calcium-sensing receptor. Clin Endocrinol (Oxf) 1999;50:537–43.10.1046/j.1365-2265.1999.00729.xSearch in Google Scholar PubMed
23. Sfar S, Bzeouich AA, Kerkeni E, Bouaziz S, Najjar MF, et al. A novel CASR mutation in a Tunisian FHH/NSHPT family associated with a mental retardation. Mol Biol Rep 2012;39:2395–400.10.1007/s11033-011-0990-0Search in Google Scholar PubMed
24. Yano S, Brown EM, Chattopadhyay N. Calcium-sensing receptor in the brain. Cell Calcium 2004;35:257–64.10.1016/j.ceca.2003.10.008Search in Google Scholar PubMed
25. Vizard TN, O’Keeffe GW, Gutierrez H, Kos CH, Riccardi D, et al. Regulation of axonal and dendritic growth by the extracellular calcium-sensing receptor. Nat Neurosci 2008;11:285–91.10.1038/nn2044Search in Google Scholar PubMed PubMed Central
26. Liu XL, Lu YS, Gao JY, Marshall C, Xiao M, et al. Calcium sensing receptor absence delays postnatal brain development via direct and indirect mechanisms. Mol Neurobiol 2013;48:590–600.10.1007/s12035-013-8448-0Search in Google Scholar PubMed
27. Hannan FM, Howles SA, Rogers A, Cranston T, Gorvin CM, et al. Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects. Hum Mol Genet 2015;24:5079–92.10.1093/hmg/ddv226Search in Google Scholar PubMed PubMed Central
©2016 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Review
- A germline mutation of HRPT2/CDC73 (70 G>T) in an adolescent female with parathyroid carcinoma: first case report and a review of the literature
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- Prevalence and awareness of functional and structural foot abnormalities in children and adolescents with type 1 diabetes
- WHO European Childhood Obesity Surveillance Initiative in Serbia: a prevalence of overweight and obesity among 6–9-year-old school children
- Pilot study of newborn screening of inborn error of metabolism using tandem mass spectrometry in Malaysia: outcome and challenges
- In children with autoimmune thyroid diseases the association with Down syndrome can modify the clustering of extra-thyroidal autoimmune disorders
- Identification of monogenic gene mutations in Japanese subjects diagnosed with type 1B diabetes between >5 and 15.1 years of age
- Referral pattern of children with short stature to a pediatric endocrine clinic in Kuwait
- Factors associated with post-menarcheal growth: results of a longitudinal study in Chilean girls from different socioeconomic statuses
- Percentiles for anthropometric measures in Iranian children and adolescents: the CASPIAN-IV study
- Hormone disorder and vitamin deficiency in attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASDs)
- Case Reports
- Hyperinsulinism-hyperammonemia syndrome: a de novo mutation of the GLUD1 gene in twins and a review of the literature
- Novel homozygous likely-pathogenic intronic variant in INS causing permanent neonatal diabetes in siblings
- A girl with permanent neonatal diabetes due to KCNJ11 mutation presented with Mauriac syndrome after improper adjustment in sulfonylurea dosage over 6 years
- Treatment experience and long-term follow-up data in two severe neonatal hyperparathyroidism cases
- A novel splice site mutation of FGD1 gene in an Aarskog-Scott syndrome patient with a large anterior fontanel
Articles in the same Issue
- Frontmatter
- Review
- A germline mutation of HRPT2/CDC73 (70 G>T) in an adolescent female with parathyroid carcinoma: first case report and a review of the literature
- Original Articles
- Seroprotection status of hepatitis B and measles vaccines in children with type 1 diabetes mellitus
- Prevalence and awareness of functional and structural foot abnormalities in children and adolescents with type 1 diabetes
- WHO European Childhood Obesity Surveillance Initiative in Serbia: a prevalence of overweight and obesity among 6–9-year-old school children
- Pilot study of newborn screening of inborn error of metabolism using tandem mass spectrometry in Malaysia: outcome and challenges
- In children with autoimmune thyroid diseases the association with Down syndrome can modify the clustering of extra-thyroidal autoimmune disorders
- Identification of monogenic gene mutations in Japanese subjects diagnosed with type 1B diabetes between >5 and 15.1 years of age
- Referral pattern of children with short stature to a pediatric endocrine clinic in Kuwait
- Factors associated with post-menarcheal growth: results of a longitudinal study in Chilean girls from different socioeconomic statuses
- Percentiles for anthropometric measures in Iranian children and adolescents: the CASPIAN-IV study
- Hormone disorder and vitamin deficiency in attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASDs)
- Case Reports
- Hyperinsulinism-hyperammonemia syndrome: a de novo mutation of the GLUD1 gene in twins and a review of the literature
- Novel homozygous likely-pathogenic intronic variant in INS causing permanent neonatal diabetes in siblings
- A girl with permanent neonatal diabetes due to KCNJ11 mutation presented with Mauriac syndrome after improper adjustment in sulfonylurea dosage over 6 years
- Treatment experience and long-term follow-up data in two severe neonatal hyperparathyroidism cases
- A novel splice site mutation of FGD1 gene in an Aarskog-Scott syndrome patient with a large anterior fontanel
