Département de Génétique, APHP, Hopital Robert Debré, 75019 Paris, France.
Service des Explorations Fonctionnelles, APHP, Hopital Robert Debré, 75019 Paris, France.
J Med Genet. 2020 Jun;57(6):389-399. doi: 10.1136/jmedgenet-2019-106474. Epub 2020 Feb 3.
Primary hereditary microcephaly (MCPH) comprises a large group of autosomal recessive disorders mainly affecting cortical development and resulting in a congenital impairment of brain growth. Despite the identification of >25 causal genes so far, it remains a challenge to distinguish between different MCPH forms at the clinical level.
7 patients with newly identified mutations in (MCPH3) were investigated by performing prospective, extensive and systematic clinical, MRI, psychomotor, neurosensory and cognitive examinations under similar conditions.
All patients displayed neurosensory defects in addition to microcephaly. Small cochlea with incomplete partition type II was found in all cases and was associated with progressive deafness in 4 of them. Furthermore, the CDK5RAP2 protein was specifically identified in the developing cochlea from human fetal tissues. Microphthalmia was also present in all patients along with retinal pigmentation changes and lipofuscin deposits. Finally, hypothalamic anomalies consisting of interhypothalamic adhesions, a congenital midline defect usually associated with holoprosencephaly, was detected in 5 cases.
This is the first report indicating that not only governs brain size but also plays a role in ocular and cochlear development and is necessary for hypothalamic nuclear separation at the midline. Our data indicate that CDK5RAP2 should be considered as a potential gene associated with deafness and forme fruste of holoprosencephaly. These children should be given neurosensory follow-up to prevent additional comorbidities and allow them reaching their full educational potential.
NCT01565005.
原发性小头畸形（MCPH）是一组主要影响皮质发育并导致脑生长先天性受损的常染色体隐性疾病。尽管迄今为止已经确定了 >25 个致病基因，但在临床水平上区分不同的 MCPH 形式仍然是一个挑战。
对 7 名新发现 MCPH3 基因突变的患者进行前瞻性、广泛和系统的临床、MRI、精神运动、神经感觉和认知检查，检查条件相似。
所有患者均表现出小头畸形以外的神经感觉缺陷。所有病例均发现小耳蜗伴不完全分隔 II 型，其中 4 例伴有进行性耳聋。此外，CDK5RAP2 蛋白在人类胎儿组织发育中的耳蜗中特异性鉴定。所有患者均存在小眼球，伴有视网膜色素变化和脂褐素沉积。最后，5 例患者检测到下丘脑异常，包括下丘脑粘连，一种通常与前脑无裂畸形相关的先天性中线缺陷。
这是第一个表明 CDK5RAP2 不仅控制大脑大小，而且在眼部和耳蜗发育中发挥作用，并且是下丘脑核在中线分离所必需的报告。我们的数据表明，CDK5RAP2 应被视为与耳聋和前脑无裂畸形轻症相关的潜在基因。这些儿童应进行神经感觉随访，以预防其他并发症，并使他们充分发挥教育潜力。
NCT01565005。
