当前位置: X-MOL 学术Am. J. Med. Genet. Semin. Med. Genet. Part C › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Kosaki overgrowth syndrome: A newly identified entity caused by pathogenic variants in platelet-derived growth factor receptor-beta.
American Journal of Medical Genetics Seminars in Medical Genetics, Part C ( IF 3.1 ) Pub Date : 2019-11-11 , DOI: 10.1002/ajmg.c.31755
Toshiki Takenouchi 1 , Hironobu Okuno 2 , Kenjiro Kosaki 3
Affiliation  

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.

中文翻译:

小崎过度生长综合征:一种新发现的实体,由血小板衍生的生长因子受体-β中的致病变异引起。

PDGFRB(血小板衍生的生长因子受体-β)的从头杂合功能获得性病原体变体的特定类别会引起独特的过度生长综合症,称为Kosaki过度生长综合症(KOGS)(OMIM#616592)。迄今为止,已有文献报道了六例这种情况的患者。除骨骼过度生长外,这些患者还表现出超弹性,半透明和脆弱的皮肤,脊柱侧弯,皮下脂肪组织进行性丧失,颅骨畸形,小儿肌纤维瘤,神经精神症状以及蛛网膜下腔窝蛛网膜囊肿和脑室白质信号异常。这种表型构象清楚地将KOGS与其他PDGFRB相关疾病(包括特发性基底节神经钙化,婴儿肌纤维瘤,和Penttinen型早衰综合症。从分子角度看,PDGFRB是一种二聚体酪氨酸激酶,在细胞生长和肿瘤发生中起关键作用。导致KOGS的PDGFRB的两种已知类型的致病变体(p。(Pro584Arg)和p。(Trp566Arg))仅位于调节PDGFRB自激活/抑制作用的近肾小球结构域中。体外证据表明,p。(Pro584Arg)代表功能获得性病原体变体。使用多激酶抑制剂抑制PDGFRB活性似乎是一种潜在的有前途的治疗方法。目前正在使用诱导的多能干细胞研究这种疾病的发病机理的分子机制。存在骨骼过度生长,独特的面部特征,典型的超弹性和脆弱的皮肤,
更新日期:2019-11-01
down
wechat
bug