BACKGROUND Walker-Warburg syndrome (WWS), an autosomal recessive disease, is the most severe phenotype of congenital muscular dystrophies. Its diagnosis remains primarily clinical and radiological. Identification of its causative variants will assist genetic counseling. We aim to describe genetic and neuroimaging findings of WWS and investigate the correlation between them. METHODS We retrospectively reviewed the clinical, genetic and neuroimaging findings of eleven Saudi neonates diagnosed with WWS between April 2012 and December 2018 in a single tertiary care center. Correlation between neuroimaging and genetic findings was investigated. RESULTS All patients had macrocephaly except one who had intrauterine growth restriction. Dysmorphic features were identified in nearly half of the patients. Creatine kinase levels were available in nine patients and were always elevated. Homozygous pathogenic variants were identified in all patients spanning POMT1 (n = 5), TMEM5 (n = 3), ISPD (n = 2) and POMT2 (n = 1) including one patient who had a dual molecular diagnosis of ISPD and PGAP2. On neuroimaging, all patients showed cobblestone cortex, classical infratentorial findings, and hydrocephalus. Other cerebral cortical malformations included subependymal heterotopia, polymicrogyria and open-lip schizencephaly in four, two and one patients, respectively. Buphthalmos and microphthalmia were the most prevalent orbital findings and found in all patients either unilaterally or bilaterally. CONCLUSION WWS is a genetically heterogeneous disorder among Saudis. The case with an additional PGAP2-related phenotype exemplifies the increased risk of dual autosomal recessive disorders in consanguineous populations. MRI is excellent in demonstrating spectrum of WWS brain and orbital malformations; however, no definite correlation could be found between the MRI findings and the genetic variant.

中文翻译：

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沙特患者 Walker-Warburg 综合征的神经影像学表现和遗传异质性

背景 Walker-Warburg 综合征 (WWS) 是一种常染色体隐性疾病，是先天性肌营养不良症最严重的表型。其诊断仍主要是临床和放射学。鉴定其致病变异将有助于遗传咨询。我们旨在描述 WWS 的遗传和神经影像学发现，并研究它们之间的相关性。方法 我们回顾性审查了 2012 年 4 月至 2018 年 12 月在一个三级医疗中心诊断为 WWS 的 11 名沙特新生儿的临床、遗传和神经影像学结果。研究了神经影像学和遗传学发现之间的相关性。结果 除一名宫内生长受限的患者外，所有患者均患有巨头畸形。在近一半的患者中发现了畸形特征。九名患者可获得肌酸激酶水平，并且总是升高。在跨越 POMT1 (n = 5)、TMEM5 (n = 3)、ISPD (n = 2) 和 POMT2 (n = 1) 的所有患者中都发现了纯合致病变异，其中包括一名具有 ISPD 和 PGAP2 双重分子诊断的患者。在神经影像学检查中，所有患者均表现出鹅卵石皮质、经典的幕下表现和脑积水。其他大脑皮质畸形包括室管膜下异位、多小脑回和开唇裂脑畸形，分别出现在 4 名、2 名和 1 名患者中。眼球突出和小眼球是最常见的眼眶表现，在所有患者中发现，无论是单侧还是双侧。结论 WWS 在沙特人中是一种遗传异质性疾病。具有额外 PGAP2 相关表型的病例证明了近亲人群中双重常染色体隐性遗传疾病的风险增加。MRI 在显示 WWS 脑和眼眶畸形的频谱方面表现出色；然而，在 MRI 结果和遗传变异之间没有发现明确的相关性。