Kosaki overgrowth syndrome: A newly identified entity caused by pathogenic variants in platelet‐derived growth factor receptor‐beta
Kosaki overgrowth syndrome: A newly identified entity caused by pathogenic variants in platelet‐derived growth factor receptor‐beta
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DOI：
10.1002/ajmg.c.31755
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发表时间：
2019-11
期刊：
影响因子：
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通讯作者：
T. Takenouchi;Hironobu Okuno;K. Kosaki
中科院分区：
文献类型：
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作者：
T. Takenouchi;Hironobu Okuno;K. Kosaki
特定类别的PDGFRB（血小板衍生生长因子受体- β）的新杂合功能增益致病性变异引起一种独特的过度生长综合征，称为Kosaki过度生长综合征（KOGS） （OMIM #616592）。到目前为止，文献中已经报道了6例患有这种疾病的患者。除了骨骼过度生长外，这些患者还表现为皮肤超弹性、半透明和脆弱、脊柱侧凸、皮下脂肪组织进行性丢失、颅骨畸形、婴儿肌纤维瘤、神经精神症状、后窝蛛网膜囊肿和脑室周围白质信号异常。这些表型明显地将KOGS与其他PDGFRB相关疾病（包括特发性基底神经节钙化、婴儿肌纤维瘤和Penttinen型早衰综合征）区分开来。从分子的角度来看，PDGFRB是一种二聚体受体酪氨酸激酶，在细胞生长和肿瘤发生中起关键作用。导致KOGS的PDGFRB的两种已知致病性变异（p.（Pro584Arg）和p.(Trp566Arg)）仅位于调节PDGFRB自激活/抑制的小球旁结构域。体外证据表明，p.（Pro584Arg）代表了一种功能增益致病变异。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。利用诱导多能干细胞研究这种疾病发病机制的分子机制正在进行中。骨骼过度生长、独特的面部特征、特征性的超弹性和脆弱的皮肤，以及伴有神经精神症状的脑白质病变，应提示PDGFRB的遗传分析。
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.