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Kosaki overgrowth syndrome: A newly identified entity caused by pathogenic variants in platelet-derived growth factor receptor-beta.
Am J Med Genet C Semin Med Genet 2019; 181(4):650-657AJ

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.

Authors+Show Affiliations

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.Department of Physiology, Keio University School of Medicine, Tokyo, Japan.Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31710779

Citation

Takenouchi, Toshiki, et al. "Kosaki Overgrowth Syndrome: a Newly Identified Entity Caused By Pathogenic Variants in Platelet-derived Growth Factor Receptor-beta." American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, vol. 181, no. 4, 2019, pp. 650-657.
Takenouchi T, Okuno H, Kosaki K. Kosaki overgrowth syndrome: A newly identified entity caused by pathogenic variants in platelet-derived growth factor receptor-beta. Am J Med Genet C Semin Med Genet. 2019;181(4):650-657.
Takenouchi, T., Okuno, H., & Kosaki, K. (2019). Kosaki overgrowth syndrome: A newly identified entity caused by pathogenic variants in platelet-derived growth factor receptor-beta. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 181(4), pp. 650-657. doi:10.1002/ajmg.c.31755.
Takenouchi T, Okuno H, Kosaki K. Kosaki Overgrowth Syndrome: a Newly Identified Entity Caused By Pathogenic Variants in Platelet-derived Growth Factor Receptor-beta. Am J Med Genet C Semin Med Genet. 2019;181(4):650-657. PubMed PMID: 31710779.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Kosaki overgrowth syndrome: A newly identified entity caused by pathogenic variants in platelet-derived growth factor receptor-beta. AU - Takenouchi,Toshiki, AU - Okuno,Hironobu, AU - Kosaki,Kenjiro, Y1 - 2019/11/11/ PY - 2019/04/10/received PY - 2019/10/23/revised PY - 2019/10/23/accepted PY - 2019/11/12/pubmed PY - 2019/11/12/medline PY - 2019/11/12/entrez KW - Kosaki overgrowth syndrome KW - imatinib mesylate KW - induced pluripotent stem cells KW - myofibroma KW - platelet-derived growth factor receptor-beta SP - 650 EP - 657 JF - American journal of medical genetics. Part C, Seminars in medical genetics JO - Am J Med Genet C Semin Med Genet VL - 181 IS - 4 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. SN - 1552-4876 UR - https://www.unboundmedicine.com/medline/citation/31710779/Kosaki_overgrowth_syndrome:_A_newly_identified_entity_caused_by_pathogenic_variants_in_platelet-derived_growth_factor_receptor-beta L2 - https://doi.org/10.1002/ajmg.c.31755 DB - PRIME DP - Unbound Medicine ER -