WDR45B中的纯合致病变异首先在来自三个不相关家族的六名受试者中发现,难治性癫痫发作,痉挛性四肢瘫痪,大脑畸形.自2018年首次报告以来,没有描述进一步的病例。在这份报告中,我们提供了来自七个不相关家庭的另外12个人和他们的临床,放射学,和分子发现。确定了WDR45B中的六种不同变体,其中五个是小说。在所有受试者中观察到小头畸形和整体发育迟缓,大多数癫痫发作和痉挛性四肢瘫痪。脑成像的常见发现包括脑萎缩,除了真空心室扩张,脑干容量减少,和对称欠操作性。El-Hattab-Alkuraya综合征与一种一致的表型相关,其特征是早发性脑萎缩导致小头畸形,发育迟缓,痉挛性四肢瘫痪,和癫痫发作。在具有功能丧失变体的个体中,表型似乎更为严重,而具有错义变体的个体受到的影响较小,表明该疾病中潜在的基因型-表型相关性。大脑成像模式的出现在功能丧失变异的个体之间是一致的,并且可能提醒神经放射科医生或临床医生考虑与WDR45B相关的El-Hattab-Alkuraya综合征。
Homozygous pathogenic variants in
WDR45B were first identified in six subjects from three unrelated families with global development delay, refractory seizures, spastic quadriplegia, and brain malformations. Since the initial report in 2018, no further cases have been described. In this report, we present 12 additional individuals from seven unrelated families and their clinical, radiological, and molecular findings. Six different variants in
WDR45B were identified, five of which are novel. Microcephaly and global developmental delay were observed in all subjects, and seizures and spastic quadriplegia in most. Common findings on brain imaging include cerebral atrophy, ex vacuo ventricular dilatation, brainstem volume loss, and symmetric under-opercularization. El-Hattab-Alkuraya syndrome is associated with a consistent phenotype characterized by early onset cerebral atrophy resulting in microcephaly, developmental delay, spastic quadriplegia, and seizures. The phenotype appears to be more severe among individuals with loss-of-function variants whereas those with missense variants were less severely affected suggesting a potential genotype-phenotype correlation in this disorder. A brain imaging pattern emerges which is consistent among individuals with loss-of-function variants and could potentially alert the neuroradiologists or clinician to consider
WDR45B-related El-Hattab-Alkuraya syndrome.