PDF(Pubmed)
Abstract：
BACKGROUND: Periventricular nodular heterotopia-7 (PVNH7) is a neurodevelopmental disorder associated with improper neuronal migration during neurogenesis in cortex development caused by pathogenic variants in the NEDD4L gene.
UNASSIGNED: We report the case of a polystigmatized 2-year-old boy having significant symptomatologic overlap with PVNH7, such as delayed psychomotor and mental development, seizures and infantile spasms, periventricular nodular heterotopia, polymicrogyria, cleft palate, 2 to 3 toe syndactyly, hypotonia, microretrognathia, strabismus, and absent speech and walking. The patient showed also distinct symptoms falling outside PVNH7 symptomatology, also present in the proband\'s older brother, such as blue sclerae, hydronephrosis, transversal palmar crease (found also in their father), and bilateral talipes equinovarus. In addition, the patient suffered from many other symptoms.
UNASSIGNED: The boy, his brother and their parents were subjected to whole-exome sequencing. Because of uncertainties in symptomatology and inheritance pattern, the top-down approach was hard to apply. Using the bottom-up approach, we identified a known pathogenic variant, NM_001144967.2(NEDD4L):c.2677G>A:p.Glu893Lys, in the proband\'s genome that absented in any other analyzed family member, suggesting its de novo origin.
RESULTS: The patient was treated with Convulex 300 mg/mL for the successful seizure control and Euthyrox 25mg for the treatment of thyroid malfunction. He also took various supplements for the metabolism support and digestion regulation. Moreover, the patient underwent the corrective surgeries of cleft palate and talipes equinovarus.
CONCLUSIONS: We successfully identified the causative mutation NM_001144967.2(NEDD4L):c.2677G>A:p.Glu893Lys explaining symptoms overlapping those reported for PVNH7. Symptoms shared with the brother were not explained by this variant, since he was not a carrier of the pathogenic NEDD4L variant. These are most likely not extended phenotypes of PVNH7, rather an independent clinical entity caused by a yet unidentified genetic factor in the family, highlighting thus the importance of thorough evaluation of symptomatology and genomic findings in affected and unaffected family members, when such data are available.
UNASSIGNED: We report the case of a polystigmatized 2-year-old boy having significant symptomatologic overlap with PVNH7, such as delayed psychomotor and mental development, seizures and infantile spasms, periventricular nodular heterotopia, polymicrogyria, cleft palate, 2 to 3 toe syndactyly, hypotonia, microretrognathia, strabismus, and absent speech and walking. The patient showed also distinct symptoms falling outside PVNH7 symptomatology, also present in the proband\'s older brother, such as blue sclerae, hydronephrosis, transversal palmar crease (found also in their father), and bilateral talipes equinovarus. In addition, the patient suffered from many other symptoms.
UNASSIGNED: The boy, his brother and their parents were subjected to whole-exome sequencing. Because of uncertainties in symptomatology and inheritance pattern, the top-down approach was hard to apply. Using the bottom-up approach, we identified a known pathogenic variant, NM_001144967.2(NEDD4L):c.2677G>A:p.Glu893Lys, in the proband\'s genome that absented in any other analyzed family member, suggesting its de novo origin.
RESULTS: The patient was treated with Convulex 300 mg/mL for the successful seizure control and Euthyrox 25mg for the treatment of thyroid malfunction. He also took various supplements for the metabolism support and digestion regulation. Moreover, the patient underwent the corrective surgeries of cleft palate and talipes equinovarus.
CONCLUSIONS: We successfully identified the causative mutation NM_001144967.2(NEDD4L):c.2677G>A:p.Glu893Lys explaining symptoms overlapping those reported for PVNH7. Symptoms shared with the brother were not explained by this variant, since he was not a carrier of the pathogenic NEDD4L variant. These are most likely not extended phenotypes of PVNH7, rather an independent clinical entity caused by a yet unidentified genetic factor in the family, highlighting thus the importance of thorough evaluation of symptomatology and genomic findings in affected and unaffected family members, when such data are available.
摘要：
背景：脑室周围结节性异位症-7（PVNH7）是一种神经发育障碍，与NEDD4L基因致病变异引起的皮质发育过程中神经元迁移不当有关。
■我们报告了一个多面手化的2岁男孩的案例，该男孩与PVNH7有明显的症状重叠，例如精神运动和智力发育延迟，癫痫发作和婴儿痉挛,脑室周围结节性异位症，polymicrogyria,腭裂,2到3个脚趾并指，低张力,微回颌,斜视,没有说话和走路。患者还表现出明显的症状，超出PVNH7症状，也出现在先证者的哥哥中，如蓝色巩膜，肾积水,横向手掌折痕（也发现在他们的父亲），和双侧马蹄内翻足.此外,病人还有许多其他症状。
■那个男孩,他的兄弟和他们的父母接受了全外显子组测序。由于症状学和遗传模式的不确定性，自上而下的方法很难应用。使用自下而上的方法，我们发现了一个已知的致病变种,NM_001144967.2（NEDD4L）：c.2677G>A：p。Glu893Lys,在先证者的基因组中，在任何其他分析的家庭成员中都不存在，暗示它的从头起源。
结果：患者成功控制癫痫发作，使用Convulex300mg/mL治疗甲状腺功能不全，使用Euthrx25mg治疗。他还服用了各种补充剂用于代谢支持和消化调节。此外，患者接受了腭裂和马蹄内翻足的矫正手术。
结论：我们成功鉴定了致病突变NM_001144967.2（NEDD4L）：c.2677G>A：p。Glu893Lys解释与PVNH7报告的症状重叠。与兄弟共有的症状没有用这个变体解释，因为他不是致病性NEDD4L变体的携带者。这些很可能不是PVNH7的扩展表型，而是由家族中尚未识别的遗传因素引起的独立临床实体。因此强调彻底评估受影响和未受影响的家庭成员的症状学和基因组发现的重要性，当这些数据可用时。
■我们报告了一个多面手化的2岁男孩的案例，该男孩与PVNH7有明显的症状重叠，例如精神运动和智力发育延迟，癫痫发作和婴儿痉挛,脑室周围结节性异位症，polymicrogyria,腭裂,2到3个脚趾并指，低张力,微回颌,斜视,没有说话和走路。患者还表现出明显的症状，超出PVNH7症状，也出现在先证者的哥哥中，如蓝色巩膜，肾积水,横向手掌折痕（也发现在他们的父亲），和双侧马蹄内翻足.此外,病人还有许多其他症状。
■那个男孩,他的兄弟和他们的父母接受了全外显子组测序。由于症状学和遗传模式的不确定性，自上而下的方法很难应用。使用自下而上的方法，我们发现了一个已知的致病变种,NM_001144967.2（NEDD4L）：c.2677G>A：p。Glu893Lys,在先证者的基因组中，在任何其他分析的家庭成员中都不存在，暗示它的从头起源。
结果：患者成功控制癫痫发作，使用Convulex300mg/mL治疗甲状腺功能不全，使用Euthrx25mg治疗。他还服用了各种补充剂用于代谢支持和消化调节。此外，患者接受了腭裂和马蹄内翻足的矫正手术。
结论：我们成功鉴定了致病突变NM_001144967.2（NEDD4L）：c.2677G>A：p。Glu893Lys解释与PVNH7报告的症状重叠。与兄弟共有的症状没有用这个变体解释，因为他不是致病性NEDD4L变体的携带者。这些很可能不是PVNH7的扩展表型，而是由家族中尚未识别的遗传因素引起的独立临床实体。因此强调彻底评估受影响和未受影响的家庭成员的症状学和基因组发现的重要性，当这些数据可用时。
