背景:Wolf-Hirschhorn综合征(WHS)是一种明确定义的疾病,其核心表型包括生长限制,面部完形,智力残疾和癫痫发作。然而,由于负责的4p缺失的程度不同,因此存在很大的表型变异性。此外,外显子组测序分析,最近发现了两个基因,即NSD2和NELFA,其功能丧失变异导致与非典型或部分WHS一致的临床谱。对表现出类似WHS的临床特征的患者的观察,只有轻度发育迟缓,没有典型的畸形特征,携带保留NSD2的微缺失导致了以下假设:NSD2负责WHS的智力残疾和面部完形。在介绍WHS(智力障碍,面部完形,小头畸形,生长受限和先天性心脏缺陷),删除NSD2的儿童倾向于表现出更温和的骨骼异常,通常由斜体组成,并且不表现出癫痫发作。我们描述了由于NSD2的从头突变而患有WHS的儿童的临床表现,并讨论了临床和诊断意义。
方法:对一个6岁男孩进行宫内生长受限史评估,低出生体重,新生儿低张力,和精神运动延迟。没有报告癫痫发作。在体检时,他展示了马phanoid习性,肌肉肥大和面部畸形,包括高额叶发际线,上倾斜的睑裂和丰满的嘴唇,两裂的丑陋。隐睾,披肩阴囊,还注意到右侧小指轻度倾斜,II和III脚趾双侧并指,有凉口。影像学文章显示骨龄延迟,超声心动图显示轻度二尖瓣脱垂。全基因组测序分析揭示了NSD2的杂合从头变体(c.2523delG)。
结论:完整的WHS表型可能来自4p16.3区域内几个致病基因组合单倍体不足的累积效应,作为一种连续的基因综合征,根据参与缺失的特定基因,表型略有不同。用类似WHS的图片评估儿童时,在没有癫痫发作的情况下,临床医生应该考虑这种鉴别诊断.
BACKGROUND: Wolf-Hirschhorn syndrome (WHS) is a well-defined disorder, whose core phenotype encompasses growth restriction, facial gestalt, intellectual disability and seizures. Nevertheless, great phenotypic variability exists due to the variable extent of the responsible 4p deletion. In addition, exome sequencing analyses, recently identified two genes, namely NSD2 and NELFA, whose loss-of-function variants contribute to a clinical spectrum consistent with atypical or partial WHS. The observation of patients exhibiting clinical features resembling WHS, with only mild developmental delay and without the typical dysmorphic features, carrying microdeletions sparing NSD2, has lead to the hypothesis that NSD2 is responsible for the intellectual disability and the facial gestalt of WHS. While presenting some of the typical findings of WHS (intellectual disability, facial gestalt, microcephaly, growth restriction and congenital heart defects), NSD2-deleted children tend to display a milder spectrum of skeletal abnormalities, usually consisting of clinodactyly, and do not exhibit seizures. We describe the clinical picture of a child with WHS due to a de novo mutation of NSD2 and discuss the clinical and diagnostic implications.
METHODS: A 6-year-old boy was evaluated for a history of intrauterine growth restriction, low birth weight, neonatal hypotonia, and psychomotor delay. No episodes of seizure were reported. At physical examination, he displayed marphanoid habitus, muscle hypotrophy and facial dysmorphisms consisting in high frontal hairline, upslanting palpebral fissures and full lips with bifid ugula. Cryptorchidism, shawl scrotum, mild clinodactyly of the right little finger and bilateral syndactyly of the II and III toes with sandal gap were also noted. The radiographic essay demonstrated delayed bone age and echocardiography showed mild mitral prolapse. Whole genome sequencing analysis revealed a heterozygous de novo variant of NSD2 (c.2523delG).
CONCLUSIONS: Full WHS phenotype likely arises from the cumulative effect of the combined
haploinsufficiency of several causative genes mapping within the 4p16.3 region, as a contiguous genes syndrome, with slightly different phenotypes depending on the specific genes involved in the deletion. When evaluating children with pictures resembling WHS, in absence of seizures, clinicians should consider this differential diagnosis.