title: Neonatal severe hyperparathyroidism: genotype/phenotype correlation and the use of pamidronate as rescue therapy.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Nephro-Urology Unit, Institute of Child Health, University College of London Medical Schools and Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, WC1N 3JH London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Waller
authors.forename: Tom
authors.initials: T
authors.lastname: Kurzawinski
authors.forename: Lewis
authors.initials: L
authors.lastname: Spitz
authors.forename: Rajesh
authors.initials: R
authors.lastname: Thakker
authors.forename: Treena
authors.initials: T
authors.lastname: Cranston
authors.forename: Simon
authors.initials: S
authors.lastname: Pearce
authors.forename: Tim
authors.initials: T
authors.lastname: Cheetham
authors.forename: William G
authors.initials: WG
authors.lastname: van't Hoff
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D003681:Dehydration / Q000209:etiology; D004164:Diphosphonates / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D006801:Humans; D006934:Hypercalcemia / Q000150:complications* / Q000188:drug therapy / Q000235:genetics; D006961:Hyperparathyroidism / Q000150:complications* / Q000235:genetics / Q000601:surgery; D007231:Infant, Newborn; D008297:Male; D000077268:Pamidronate; D010280:Parathyroid Glands / Q000601:surgery; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D044169:Receptors, Calcium-Sensing / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D044169:Receptors, Calcium-Sensing; D000077268:Pamidronate