title: Long-term response to growth hormone therapy in a patient with short stature caused by a novel heterozygous mutation in NPR2.
abstract: BACKGROUND
  Heterozygous loss-of-function mutations in the natriuretic peptide receptor B gene (NPR2) are responsible for short stature in patients without a distinct phenotype. Some of these patients have been treated with recombinant human growth hormone (rhGH) therapy with a variable response.
  
  
  METHODS
  The proband was a healthy boy who presented at the age of 5.1 years with familial short stature (height SDS of -3.1). He had a prominent forehead, a depressed nasal bridge, centripetal fat distribution and a high-pitched voice resembling that of children with GH deficiency. His hormonal evaluation showed low insulin-like growth factor-1 (IGF-1) but a normal GH peak at a stimulation test. During the first year of rhGH treatment, his growth velocity increased from 3.4 to 10.4 cm/year (height SDS change of +1.1). At the last visit, he was 8.8 years old and still on treatment, his growth velocity was 6.4 cm/year and height SDS was -1.8.
  
  
  RESULTS
  We identified through exome sequencing a novel heterozygous loss-of-function NPR2 mutation (c.2905G>C; p.Val969Leu). Cells cotransfected with the p.Val969Leu mutant showed a significant decrease in cyclic guanosine monophosphate (cGMP) production compared to the wild type (WT), suggesting a dominant negative effect.
  
  
  CONCLUSIONS
  This case reveals a novel heterozygous loss-of-function NPR2 mutation responsible for familial short stature and the good response of rhGH therapy in this patient.
authors.forename: Gabriela A
authors.initials: GA
authors.lastname: Vasques
authors.forename: Alfonso
authors.initials: A
authors.lastname: Hisado-Oliva
authors.forename: Mariana F A
authors.initials: MF
authors.lastname: Funari
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Lerario
authors.forename: Elisangela P S
authors.initials: EP
authors.lastname: Quedas
authors.forename: Paulo
authors.initials: P
authors.lastname: Solberg
authors.forename: Karen E
authors.initials: KE
authors.lastname: Heath
authors.forename: Alexander A L
authors.initials: AA
authors.lastname: Jorge
mesh_terms: D001827:Body Height / Q000235:genetics*; D002675:Child, Preschool; D004392:Dwarfism / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005838:Genotype; D006130:Growth Disorders / Q000188:drug therapy* / Q000209:etiology; D006579:Heterozygote; D019382:Human Growth Hormone / Q000627:therapeutic use*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011379:Prognosis; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics*; D000099242:Atrial Natriuretic Factor Receptor B
chemical_list: D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D017461:Receptors, Atrial Natriuretic Factor; D000099242:Atrial Natriuretic Factor Receptor B