胰岛素生长因子2(IGF2)的量控制胚胎和出生后的生长速率。IGF2和相邻的H19是由差异甲基化区域(DMRs)或印迹中心(IC)调节的11p15染色体区域中端粒簇的印迹基因:H19/IGF2:IG-DMR(IC1)。由于IC1甲基化缺失(LoM)或甲基化增益(GoM)引起的调节异常导致与生长迟缓或过度生长相关的Silver-Russell综合征(SRS)或Beckwith-Wiedemann综合征(BWS)疾病。分别。特定的特征定义了两个综合症中的每一个,但是孤立的不对称是一个常见的基本特征,这被认为足以在BWS频谱中进行诊断。这里,我们报道了一个女孩身体不对称的案例,这表明BWS光谱。稍后,BWS/SRS分子分析确定IC1_LoM揭示了SRS的差异诊断。临床重新评估确定了出生时正常下限的相对大头畸形和先前未识别的生长速率,喂养困难,和不对称。有趣的是,以前从未在IC1_LoMSRS患者中描述过,从16岁起,她就患上了手写手的抽筋,抑郁症,和双相情感障碍。Trio-WES鉴定了VPS16杂合变体[NM_022575.4:c.2185C>G:p.Leu729Val]继承自她健康的母亲。VPS16参与内溶酶体系统,其失调与具有不完全外显率和可变表达的常染色体显性肌张力障碍有关。IGF2参与溶酶体途径使我们推测先证者的神经表型可能是由同时发生的IGF2缺陷和VPS16改变触发的。
The amount of Insulin Growth Factor 2 (
IGF2) controls the rate of embryonal and postnatal growth. The
IGF2 and adjacent H19 are the imprinted genes of the telomeric cluster in the 11p15 chromosomal region regulated by differentially methylated regions (DMRs) or imprinting centers (ICs): H19/
IGF2:IG-DMR (IC1). Dysregulation due to IC1 Loss-of-Methylation (LoM) or Gain-of-Methyaltion (GoM) causes Silver-Russell syndrome (SRS) or Beckwith-Wiedemann syndrome (BWS) disorders associated with growth retardation or overgrowth, respectively. Specific features define each of the two syndromes, but isolated asymmetry is a common cardinal feature, which is considered sufficient for a diagnosis in the BWS spectrum. Here, we report the case of a girl with right body asymmetry, which suggested BWS spectrum. Later, BWS/SRS molecular analysis identified IC1_LoM revealing the discrepant diagnosis of SRS. A clinical re-evaluation identified a relative macrocephaly and previously unidentified growth rate at lower limits of normal at birth, feeding difficulties, and asymmetry. Interestingly, and never previously described in IC1_LoM SRS patients, since the age of 16, she has developed hand-writer\'s cramps, depression, and bipolar disorder. Trio-WES identified a VPS16 heterozygous variant [NM_022575.4:c.2185C>G:p.Leu729Val] inherited from her healthy mother. VPS16 is involved in the endolysosomal system, and its dysregulation is linked to autosomal dominant dystonia with incomplete penetrance and variable expressivity.
IGF2 involvement in the lysosomal pathway led us to speculate that the neurological phenotype of the proband might be triggered by the concurrent
IGF2 deficit and VPS16 alteration.