Kosaki overgrowth syndrome: A newly identified entity caused by pathogenic variants in platelet-derived growth factor receptor-beta

Research output: Contribution to journalArticle

Abstract

Specific classes of de novo heterozygous gain-of-function pathogenic variants of the PDGFRB (platelet-derived growth factor receptor-beta) cause a distinctive overgrowth syndrome, named the Kosaki overgrowth syndrome (KOGS) (OMIM #616592). Until now, six patients with this condition have been reported in the literature. In addition to skeletal overgrowth, these patients exhibit hyperelastic, translucent, and fragile skin, scoliosis, progressive loss of subcutaneous adipose tissue, skull deformity, infantile myofibromas, neuropsychiatric symptoms, and arachnoid cysts in the posterior fossa and periventricular white matter signal abnormalities on neuroimaging. This constellation of phenotypes clearly distinguishes KOGS from other PDGFRB-related disorders, including idiopathic basal ganglia calcification, infantile myofibroma, and Penttinen-type premature aging syndrome. From a molecular standpoint, PDGFRB is a dimeric receptor tyrosine kinase that plays critical roles in cell growth and tumorigenesis. The two known types of pathogenic variants (p.(Pro584Arg) and p.(Trp566Arg)) of the PDGFRB that cause KOGS are exclusively located in the juxtaglomerular domain that regulates autoactivation/inhibition of PDGFRB. In-vitro evidence suggests that p.(Pro584Arg) represents a gain-of-function pathogenic variant. Inhibition of PDGFRB activity using multi-kinase inhibitors appears to be a potentially promising therapeutic approach. Investigation of the molecular mechanisms underlying the pathogenesis of this disease using induced pluripotent stem cells is under way. Presence of skeletal overgrowth, distinctive facial features, characteristic hyperelastic and fragile skin, and cerebral white matter lesions with neuropsychiatric symptoms should prompt genetic analysis of the PDGFRB.

Original languageEnglish
JournalAmerican Journal of Medical Genetics, Part C: Seminars in Medical Genetics
DOIs
Publication statusAccepted/In press - 2019 Jan 1

Fingerprint

Platelet-Derived Growth Factor beta Receptor
Myofibroma
Genetic Databases
Arachnoid Cysts
Induced Pluripotent Stem Cells
Skin
Subcutaneous Fat
Receptor Protein-Tyrosine Kinases
Scoliosis
Basal Ganglia
Skull
Neuroimaging
Carcinogenesis
Phosphotransferases
Phenotype
Growth

Keywords

  • imatinib mesylate
  • induced pluripotent stem cells
  • Kosaki overgrowth syndrome
  • myofibroma
  • platelet-derived growth factor receptor-beta

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

@article{eb0218eac2ba4479804b568979ef215d,
title = "Kosaki overgrowth syndrome: A newly identified entity caused by pathogenic variants in platelet-derived growth factor receptor-beta",
abstract = "Specific classes of de novo heterozygous gain-of-function pathogenic variants of the PDGFRB (platelet-derived growth factor receptor-beta) cause a distinctive overgrowth syndrome, named the Kosaki overgrowth syndrome (KOGS) (OMIM #616592). Until now, six patients with this condition have been reported in the literature. In addition to skeletal overgrowth, these patients exhibit hyperelastic, translucent, and fragile skin, scoliosis, progressive loss of subcutaneous adipose tissue, skull deformity, infantile myofibromas, neuropsychiatric symptoms, and arachnoid cysts in the posterior fossa and periventricular white matter signal abnormalities on neuroimaging. This constellation of phenotypes clearly distinguishes KOGS from other PDGFRB-related disorders, including idiopathic basal ganglia calcification, infantile myofibroma, and Penttinen-type premature aging syndrome. From a molecular standpoint, PDGFRB is a dimeric receptor tyrosine kinase that plays critical roles in cell growth and tumorigenesis. The two known types of pathogenic variants (p.(Pro584Arg) and p.(Trp566Arg)) of the PDGFRB that cause KOGS are exclusively located in the juxtaglomerular domain that regulates autoactivation/inhibition of PDGFRB. In-vitro evidence suggests that p.(Pro584Arg) represents a gain-of-function pathogenic variant. Inhibition of PDGFRB activity using multi-kinase inhibitors appears to be a potentially promising therapeutic approach. Investigation of the molecular mechanisms underlying the pathogenesis of this disease using induced pluripotent stem cells is under way. Presence of skeletal overgrowth, distinctive facial features, characteristic hyperelastic and fragile skin, and cerebral white matter lesions with neuropsychiatric symptoms should prompt genetic analysis of the PDGFRB.",
keywords = "imatinib mesylate, induced pluripotent stem cells, Kosaki overgrowth syndrome, myofibroma, platelet-derived growth factor receptor-beta",
author = "Toshiki Takenouchi and Hironobu Okuno and Kenjiro Kosaki",
year = "2019",
month = "1",
day = "1",
doi = "10.1002/ajmg.c.31755",
language = "English",
journal = "American Journal of Medical Genetics, Part C: Seminars in Medical Genetics",
issn = "1552-4868",

}

TY - JOUR

T1 - Kosaki overgrowth syndrome

T2 - A newly identified entity caused by pathogenic variants in platelet-derived growth factor receptor-beta

AU - Takenouchi, Toshiki

AU - Okuno, Hironobu

AU - Kosaki, Kenjiro

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Specific classes of de novo heterozygous gain-of-function pathogenic variants of the PDGFRB (platelet-derived growth factor receptor-beta) cause a distinctive overgrowth syndrome, named the Kosaki overgrowth syndrome (KOGS) (OMIM #616592). Until now, six patients with this condition have been reported in the literature. In addition to skeletal overgrowth, these patients exhibit hyperelastic, translucent, and fragile skin, scoliosis, progressive loss of subcutaneous adipose tissue, skull deformity, infantile myofibromas, neuropsychiatric symptoms, and arachnoid cysts in the posterior fossa and periventricular white matter signal abnormalities on neuroimaging. This constellation of phenotypes clearly distinguishes KOGS from other PDGFRB-related disorders, including idiopathic basal ganglia calcification, infantile myofibroma, and Penttinen-type premature aging syndrome. From a molecular standpoint, PDGFRB is a dimeric receptor tyrosine kinase that plays critical roles in cell growth and tumorigenesis. The two known types of pathogenic variants (p.(Pro584Arg) and p.(Trp566Arg)) of the PDGFRB that cause KOGS are exclusively located in the juxtaglomerular domain that regulates autoactivation/inhibition of PDGFRB. In-vitro evidence suggests that p.(Pro584Arg) represents a gain-of-function pathogenic variant. Inhibition of PDGFRB activity using multi-kinase inhibitors appears to be a potentially promising therapeutic approach. Investigation of the molecular mechanisms underlying the pathogenesis of this disease using induced pluripotent stem cells is under way. Presence of skeletal overgrowth, distinctive facial features, characteristic hyperelastic and fragile skin, and cerebral white matter lesions with neuropsychiatric symptoms should prompt genetic analysis of the PDGFRB.

AB - Specific classes of de novo heterozygous gain-of-function pathogenic variants of the PDGFRB (platelet-derived growth factor receptor-beta) cause a distinctive overgrowth syndrome, named the Kosaki overgrowth syndrome (KOGS) (OMIM #616592). Until now, six patients with this condition have been reported in the literature. In addition to skeletal overgrowth, these patients exhibit hyperelastic, translucent, and fragile skin, scoliosis, progressive loss of subcutaneous adipose tissue, skull deformity, infantile myofibromas, neuropsychiatric symptoms, and arachnoid cysts in the posterior fossa and periventricular white matter signal abnormalities on neuroimaging. This constellation of phenotypes clearly distinguishes KOGS from other PDGFRB-related disorders, including idiopathic basal ganglia calcification, infantile myofibroma, and Penttinen-type premature aging syndrome. From a molecular standpoint, PDGFRB is a dimeric receptor tyrosine kinase that plays critical roles in cell growth and tumorigenesis. The two known types of pathogenic variants (p.(Pro584Arg) and p.(Trp566Arg)) of the PDGFRB that cause KOGS are exclusively located in the juxtaglomerular domain that regulates autoactivation/inhibition of PDGFRB. In-vitro evidence suggests that p.(Pro584Arg) represents a gain-of-function pathogenic variant. Inhibition of PDGFRB activity using multi-kinase inhibitors appears to be a potentially promising therapeutic approach. Investigation of the molecular mechanisms underlying the pathogenesis of this disease using induced pluripotent stem cells is under way. Presence of skeletal overgrowth, distinctive facial features, characteristic hyperelastic and fragile skin, and cerebral white matter lesions with neuropsychiatric symptoms should prompt genetic analysis of the PDGFRB.

KW - imatinib mesylate

KW - induced pluripotent stem cells

KW - Kosaki overgrowth syndrome

KW - myofibroma

KW - platelet-derived growth factor receptor-beta

UR - http://www.scopus.com/inward/record.url?scp=85075219377&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85075219377&partnerID=8YFLogxK

U2 - 10.1002/ajmg.c.31755

DO - 10.1002/ajmg.c.31755

M3 - Article

C2 - 31710779

AN - SCOPUS:85075219377

JO - American Journal of Medical Genetics, Part C: Seminars in Medical Genetics

JF - American Journal of Medical Genetics, Part C: Seminars in Medical Genetics

SN - 1552-4868

ER -