摘要：

目的 探讨结节性硬化症之皮质结节病理学和分子遗传学特征。 方法与结果 2 例女性患儿，2 岁9 个月和15 岁，临床表现为发作性双眼斜视和间断性惊恐发作伴四肢抽搐，头部MRI 仅表现为局灶性皮质信号异常或多灶性皮质信号可疑异常，临床考虑局灶性皮质发育不良（FCD）。遂采用脑深部电极植入术定位致灶，手术切除多脑叶致灶。大体标本观察可见灰质结节和白质内带状灰质异位。组织学形态，皮质薄厚不均且灰质异位，部分皮质全层可见胞核大、核仁明显、体积巨大的异形细胞，累及白质深部伴钙化，其内可见畸形核神经元和巨大细胞，胶质细胞增生明显。免疫组织化学染色，畸形核神经元胞质神经微丝蛋白呈阳性；巨大细胞胞质胶质纤维酸性蛋白（GFAP）和波形蛋白呈阳性，大畸形核神经元和巨大细胞增生的皮质区域GFAP 呈弥漫性阳性，提示胶质细胞增生明显。结合临床资料，例1 为多脑叶皮质发育不良和肾脏错构瘤、例2 为多脑叶皮质结节病变和灰质异位，诊断为疑似的结节性硬化症。进一步行基因检测，例1 存在TSC1 基因c.647_648del 杂合突变（无义突变）、例2 存在TSC2 基因c.4672G > A 杂合突变（错义突变），最终诊断为确诊的结节性硬化症。 结论 结节性硬化症临床表现多样，皮质结节组织学形态与FCDⅡb 型有众多重叠之处，仅关注组织学形态和免疫表型易误诊为FCDⅡb型，明确诊断应结合临床表现、影像学和基因检测结果综合判断。

关键词: 结节性硬化症, 免疫组织化学, 病理学

Abstract:

Objective To investigate the clinicopathological and molecular genetic features of cortical tubers in tuberous sclerosis complex (TSC).  Methods and Results  Two girls, one was 33 months old and the other was 15 years old, presented paroxysmal strabismus and intermittent panic with convulsion of limbs. Head MRI revealed focal cortical abnormal signal and multifocal cortical suspected abnormal signals indicating focal cortical dysplasia (FCD). The implantation of intracranial electrode indicated epileptogenic zones, and multi?lobectomy was conducted to remove the epileptogenic zones. From the gross specimen, gray matter nodule and banded heterotopic gray matter were observed. Histological examination showed uneven cortical thickness and heterotopic gray matter. Part of the cortex showed giant heterocyst proliferation with big nuclei and obvious nucleoli, and involved deep white matter with calcification. Neurons with deformed nuclei, giant cells and obvious proliferation of glial cells could be seen. Immunohistochemically, the dysmorphic neurons were positive for neurofilament protein (NF) in ytoplasm, giant cells were positive for glial fibrillary acidic protein (GFAP) and vimentin (Vim) in cytoplasm, and the diffuse positivity of GFAP in cortex indicated obvious proliferation of glial cells. Combined with clinical data, Case 1 was diagnosed as cortical dysplasia in multiple lobes and one renal hamartoma, and Case 2 was diagnosed as cortical tubers in multiple lobes and heterotopic gray matter. They were diagnosed as suspected TSC. Genet detection found TSC1 gene in Case 1 had c.647_648del heterozygous mutation (nonsense mutation) and TSC2 in Case 2 had c.4672G>A heterozygous mutation (missense mutation). The diagnosis of TSC was confirmed.  Conclusions  TSC presents variable clinical features. There are several overlapping features in the aspect of histological  orphology between cortical tubers and FCD Ⅱ b. The confirmed diagnosis of TSC should consider clinical manifestations, imaging and genetic testing, not only the histological and immunohistochemical features which easily led to misdiagnosis of FCD Ⅱb.

Key words: Tuberous sclerosis, Immunohistochemistry, Pathology