The tubulinopathies refer to a wide range of brain malformations caused by mutations in one of the seven genes encoding different tubulin's isotypes. The β‐tubulin isotype III (TUBB3 ) gene has a primary function in nervous system development and axon generation and maintenance, due to its neuron‐specific expression pattern. A recurrent heterozygous mutation, c.1228G > A; p.E410K, in TUBB3 gene is responsible of a rare disorder clinically characterized by congenital fibrosis of the extraocular muscle type 3 (CFEOM3), intellectual disability and a wide range of neurological and endocrine abnormalities. Other mutations have been described spanning the entire gene and genotype–phenotype correlations have been proposed. We report on a 3‐year‐old boy in whom clinical exome sequencing allowed to identify a de novo TUBB3 E410K mutation as the molecular cause underlying a complex phenotype characterized by a severe bilateral palpebral ptosis refractory to eye surgery, psychomotor delay, absent speech, hypogonadism, celiac disease, and cyclic vomiting. Brain MRI revealed thinning of the corpus callosum with no evidence of malformation cortical dysplasia. We reviewed available records of patients with TUBB3 E410K mutation and compared their phenotype with the clinical outcome of patients with other mutations in TUBB3 gene. The present study confirms that TUBB3 E410K results in a clinically recognizable phenotype, unassociated to the distinct cortical dysplasia caused by other mutations in the same gene. Early molecular characterization of TUBB3 E410K syndrome is critical for targeted genetic counseling and prompt prospective care in term of neurological, ophthalmological, endocrine, and gastrointestinal follow‐up.

中文翻译：

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TUBB3 E410K综合征：病例报告和TUBB3突变临床谱的回顾。

微管病变是指由编码不同微管蛋白同种型的七个基因之一的突变引起的广泛的脑畸形。由于其神经元特异性表达方式，β-微管蛋白同型III（TUBB3）基因在神经系统发育以及轴突的产生和维持中起主要作用。复发性杂合突变，c.1228G> A；p.E410K，在TUBB3中该基因是一种罕见疾病，其临床特征是3型先天性眼外肌纤维化（CFEOM3），智力残疾以及广泛的神经和内分泌异常。已经描述了跨越整个基因的其他突变，并提出了基因型与表型的相关性。我们报道了一个3岁男孩，在该男孩中，临床外显子组测序可以确定从头进行的TUBB3 E410K突变，这是复杂表型的分子原因，该表型的特征是严重的双侧睑板下垂症对眼外科手术具有难治性，精神运动迟缓，言语缺失，性腺功能低下，腹腔疾病和周期性呕吐。脑部MRI显示revealed体变薄，没有皮质畸形发育不良的证据。我们审查了患者的可用记录TUBB3 E410K突变并将其表型与TUBB3基因其他突变患者的临床结果进行比较。本研究证实，TUBB3 E410K导致临床上可识别的表型，该表型与同一基因中其他突变引起的明显皮层发育不良无关。在神经，眼科，内分泌和胃肠道随访方面，TUBB3 E410K综合征的早期分子特征对于有针对性的遗传咨询和及时的前瞻性护理至关重要。