背景:早期B细胞因子3(EBF3)是参与神经元分化和成熟的转录因子。致病变异与低张力有关,共济失调,和延迟发育综合征(HADDS)(MIM#617330)。泌尿系统表现很常见,可能对长期肾功能有影响。
目的:回顾所有已知的EBF3基因致病变异导致HADDS泌尿系统表现的患者。我们假设,由于EBF3变体对尿道括约肌松弛的影响,导致逼尿肌括约肌协同失调(DSD),膀胱功能障碍的发生率很高。
方法:在PubMed数据库中查询了2017年1月至2023年1月之间EBF3突变的出版物。搜索词为“EBF3突变或HADDS和泌尿外科或表型”。对在我们机构护理的HADDS患者进行了回顾性分析。收集人口统计学和临床信息。
结果:我们通过文献(28F:18M)和回顾性回顾(5F:1M)确定了52例患者(33F:19M)。泌尿生殖系统体检异常的患病率很高,尿路感染史,膀胱输尿管反流(VUR),和神经源性膀胱的诊断。在文献综述队列中,67%有泌尿外科诊断。女性受泌尿外科表现的影响不成比例。在我们的队列中,6名儿童中有4名被诊断为VUR和严重的排尿功能障碍,符合神经源性膀胱(67%).这些孩子接受了膀胱造口术。五名儿童肠功能障碍需要治疗。尿动力学表明外括约肌协同失调的患病率很高。根据非侵入性血流研究,认为不太严重的DSD形式与以后出现的儿童的异常排尿参数有关。
结论:HADDS患者的表型表现存在显著差异。虽然EBF3在神经发育中起着明确的作用,它还会影响肌肉发育,并可能影响肌肉放松。遗传变异的位置可能会影响DSD的程度,更严重的形式导致更早的演示。初始检查应包括肾超声(RUS)和后空隙残留(PVR)。可以考虑获得VCUG,DMSA扫描或尿动力学研究。考虑到出现的不同时机和严重程度,对于最初没有明显检查的患者,应使用RUS和PVR进行年度筛查。
结论:HADDS的泌尿系统表现包括DSD继发的膀胱功能障碍的发生率高,膀胱输尿管反流,尿路感染,和隐睾。如果未正确诊断和管理泌尿异常,这些患者有肾脏恶化的风险。
Early B-cell factor 3 (EBF3) is a transcription factor involved in neuronal differentiation and maturation. Pathogenic variants are associated with hypotonia, ataxia, and delayed development syndrome (HADDS) (MIM#617330). Urologic manifestations are common and may have implications regarding long term renal function.
To review all known patients with pathogenic variants of the EBF3 gene resulting in HADDS with urologic manifestations. We hypothesize a high rate of bladder dysfunction secondary to the EBF3 variant\'s impact on relaxation of the urinary sphincter leading to detrusor sphincter dyssynergia (DSD).
The PubMed database was queried for publications of the EBF3 mutation between January 2017 and January 2023. Search terms were \"EBF3 mutation OR HADDS AND urology OR phenotype\". Retrospective analysis of HADDS patients cared for in our institution was performed. Demographic and clinical information was collected.
We identified 52 patients (33F:19M) through literature (28F:18M) and retrospective review (5F:1M). There was a high prevalence of genitourinary physical exam abnormalities, history of urinary tract infection, vesicoureteral reflux (VUR), and diagnosis of neurogenic bladder. Within the literature review cohort, 67% had a urologic diagnosis. Females were disproportionately affected with urologic manifestations. In our cohort, four of six children were diagnosed with VUR and severe voiding dysfunction consistent with neurogenic bladder (67%). These children were managed with a vesicostomy. Five children had bowel dysfunction requiring therapy. Urodynamics suggested a high prevalence of external sphincter dyssynergia. Less severe forms of DSD were felt to be implicated in the abnormal voiding parameters in children who presented later in life based on non-invasive flow studies.
There is significant variability in the phenotypic presentation of patients with HADDS. While EBF3 plays a clear role in neurodevelopment, it also impacts muscle development and may impact muscle relaxation. The location of the genetic variant may impact the degree of DSD, with more severe forms leading to earlier presentations. Initial work-up should include a renal ultrasound (RUS) and post void residual (PVR). Consideration can be given to obtaining a VCUG, DMSA scan or urodynamic studies. Yearly screening should be pursued with an RUS and PVR in those with an initial unremarkable work-up given the variable timing and severity of presentation.
Urologic manifestations of HADDS include high rates of bladder dysfunction secondary to DSD, vesicoureteral reflux, urinary tract infection, and cryptorchidism. These patients are at risk of renal deterioration if urinary abnormalities are not properly diagnosed and managed.