Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene

Am J Med Genet A. 2014 Jan;164A(1):156-63. doi: 10.1002/ajmg.a.36218. Epub 2013 Nov 20.


The signal pathway of the C-type natriuretic (CNP) and its receptor, natriuretic peptide receptor 2 (NPR2) is involved in the longitudinal growth of long bones. Loss of function mutations at NPR2 cause acromesomelic dysplasia, type Maroteaux, while overproduction of CNP by chromosomal translocation and a gain-of-function mutation at NPR2 have been reported to be responsible for an overgrowth syndrome in three cases and one family, respectively. We identified a four-generation family with an overgrowth syndrome characterized by tall stature, macrodactyly of the great toes, scoliosis, coxa valga and slipped capital femoral epiphysis, similar to those previously reported in association with CNP/NPR2 overactivity. The serum level of amino-terminal proCNP was normal in the proband. A novel missense mutation of NPR2, c.1462G>C (p.Ala488Pro) was found to co-segregate with the phenotype in this family. In vitro transfection assay of the mutant NPR2 revealed overactivity of the mutant receptor at baseline as well as with the ligand. This overgrowth syndrome caused by a gain-of-function mutation at NPR2 should be differentiated from Marfan or related syndromes, and may be categorized along with the overgrowth syndrome caused by overproduction of CNP due to its phenotypical similarity as overgrowth CNP/NPR2 signalopathy.

Keywords: CNP signal; macrodactyly of the big toe; scoliosis; slipped capital femoral epiphysis; tall stature.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Base Sequence
  • Bone and Bones / diagnostic imaging
  • Bone and Bones / pathology
  • Child
  • DNA Mutational Analysis
  • Fingers / abnormalities
  • Genetic Association Studies
  • Growth Disorders / diagnosis
  • Growth Disorders / genetics*
  • Humans
  • Limb Deformities, Congenital
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Mutation, Missense
  • Pedigree
  • Phenotype
  • Radiography
  • Receptors, Atrial Natriuretic Factor / genetics*
  • Receptors, Atrial Natriuretic Factor / metabolism


  • Receptors, Atrial Natriuretic Factor
  • atrial natriuretic factor receptor B

Supplementary concepts

  • Megalodactyly