Constitutive activation of the PI3K-AKT pathway and cardiovascular abnormalities in an individual with Kosaki overgrowth syndrome

Am J Med Genet A. 2019 Jun;179(6):1047-1052. doi: 10.1002/ajmg.a.61145. Epub 2019 Apr 2.


Kosaki overgrowth syndrome is a recently described syndrome characterized by distinctive facial features, brain white matter lesions, and developmental delay. Germline activating heterozygous PDGFRB mutations have been reported in this condition. Systemic connective tissue-type findings have been described in some individuals. We describe a 19-year-old Caucasian female with a history of hydrocephalus, Dandy-Walker malformation, cervical spine arachnoid cyst, progressive scoliosis, and overgrowth. Her physical exam included distinctive craniofacial dysmorphism, as well as soft and hyperextensible skin. Cardiovascular imaging during adolescence revealed saccular aneurysms in both coronary artery systems and subtle tortuosity of the cervical vertebral arteries. Exome sequencing trio analysis identified a de novo previously reported pathogenic variant in PDGFRB, c.1696T>C (p.[Trp566Arg]). Further functional studies included platelet-derived growth factor cellular metabolic pathway activity that confirmed the variant causes a constitutive activation of the PI3K-AKT pathway. This is the first report to characterize the activating nature of this PDGFRB variant. We also highlight the connective tissue findings seen in Kosaki overgrowth syndrome and recommend baseline echocardiographic evaluation in all individuals with this condition with particular emphasis on coronary arteries.

Keywords: AKT; Kosaki overgrowth; PDGFRB; aneurysm; connective tissue.

Publication types

  • Case Reports
  • Review

MeSH terms

  • Cardiovascular Abnormalities / diagnosis
  • Cardiovascular Abnormalities / etiology*
  • Cardiovascular Abnormalities / metabolism*
  • Energy Metabolism
  • Exome Sequencing
  • Facies
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Growth Disorders / complications*
  • Growth Disorders / diagnosis
  • Growth Disorders / genetics
  • Humans
  • Magnetic Resonance Imaging
  • Phenotype
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Receptor, Platelet-Derived Growth Factor beta / genetics
  • Signal Transduction*
  • Young Adult


  • PDGFRB protein, human
  • Receptor, Platelet-Derived Growth Factor beta
  • Proto-Oncogene Proteins c-akt