Expansion of the phenotype of Kosaki overgrowth syndrome

Mari Minatogawa, Toshiki Takenouchi, Yu Tsuyusaki, Fuminori Iwasaki, Tomoko Uehara, Kenji Kurosawa, Kenjiro Kosaki, Cynthia J. Curry

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)


Skeletal overgrowth is a characteristic of several genetic disorders that are linked to specific molecular signaling cascades. Recently, we established a novel overgrowth syndrome (Kosaki overgrowth syndrome, OMIM #616592) arising from a de novo mutation in PDGFRB, that is, c.1751C>G p.(Pro584Arg). Subsequently, other investigators provided in vitro molecular evidence that this specific mutation in the juxtamembrane domain of PDGFRB causes an overgrowth phenotype and is the first gain-of-function point mutation of PDGFRB to be reported in humans. Here, we report the identification of a mutation in PDGFRB, c.1696T>C p.(Trp566Arg), in two unrelated patients with skeletal overgrowth, further confirming the existence of PDGFRB-related overgrowth syndrome arising from mutations in the juxtamembrane domain of PDGFRB. A review of all four of these patients with an overgrowth phenotype and PDGFRB mutations revealed postnatal skeletal overgrowth, premature aging, cognitive impairment, neurodegeneration, and a prominent connective tissue component to this complex phenotype. From a functional standpoint, hypermorphic mutations in PDGFRB lead to Kosaki overgrowth syndrome, infantile myofibromatosis (OMIM #228550), and Penttinen syndrome (OMIM #601812), whereas hypomorphic mutations lead to idiopathic basal ganglia calcification (OMIM #615007). In conclusion, a specific class of mutations in PDGFRB causes a clinically recognizable syndromic form of skeletal overgrowth.

Original languageEnglish
Pages (from-to)2422-2427
Number of pages6
JournalAmerican Journal of Medical Genetics, Part A
Issue number9
Publication statusPublished - 2017 Sept


  • Kosaki overgrowth syndrome
  • premature aging
  • skeletal overgrowth

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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