Centre de Référence Maladies Rares « malformations et maladies congénitales du cervelet », Hôpital Trousseau-Paris, CHU de Lyon, CHU de Lille, Paris, France.
Orphanet J Rare Dis. 2012 Mar 27;7:18. doi: 10.1186/1750-1172-7-18.
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of diseases characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. According to clinical features, seven subtypes of PCH have been described, PCH type 2 related to TSEN54 mutations being the most frequent. PCH is most often autosomal recessive though de novo anomalies in the X-linked gene CASK have recently been identified in patients, mostly females, presenting with intellectual disability, microcephaly and PCH (MICPCH).
Fourteen patients (12 females and two males; aged 16 months-14 years) presenting with PCH at neuroimaging and with clinical characteristics unsuggestive of PCH1 or PCH2 were included. The CASK gene screening was performed using Array-CGH and sequencing. Clinical and neuroradiological features were collected.
We observed a high frequency of patients with a CASK mutation (13/14). Ten patients (8 girls and 2 boys) had intragenic mutations and three female patients had a Xp11.4 submicroscopic deletion including the CASK gene. All were de novo mutations. Phenotype was variable in severity but highly similar among the 11 girls and was characterized by psychomotor retardation, severe intellectual disability, progressive microcephaly, dystonia, mild dysmorphism, and scoliosis. Other signs were frequently associated, such as growth retardation, ophthalmologic anomalies (glaucoma, megalocornea and optic atrophy), deafness and epilepsy. As expected in an X-linked disease manifesting mainly in females, the boy hemizygous for a splice mutation had a very severe phenotype with nearly no development and refractory epilepsy. We described a mild phenotype in a boy with a mosaic truncating mutation. We found some degree of correlation between severity of the vermis hypoplasia and clinical phenotype.
This study describes a new series of PCH female patients with CASK inactivating mutations and confirms that these patients have a recognizable although variable phenotype consisting of a specific form of pontocerebellar hypoplasia. In addition, we report the second male patient to present with a severe MICPCH phenotype and a de novo CASK mutation and describe for the first time a mildly affected male patient harboring a mosaic mutation. In our reference centre, CASK related PCH is the second most frequent cause of PCH. The identification of a de novo mutation in these patients enables accurate and reassuring genetic counselling.
桥小脑发育不良（PCH）是一组异质性疾病，其特征为小脑和脑干发育不良和/或早期神经退行性变。根据临床特征，已描述了 PCH 的七种亚型，与 TSEN54 突变相关的 PCH 型 2 最为常见。PCH 多为常染色体隐性遗传，但最近在主要为女性的智力残疾、小头畸形和 PCH（MICPCH）患者中发现了 X 连锁基因 CASK 的从头异常。
我们纳入了 14 名影像学表现为 PCH 且临床特征不提示 PCH1 或 PCH2 的患者（12 名女性和 2 名男性，年龄 16 个月至 14 岁）。使用微阵列比较基因组杂交和测序进行 CASK 基因筛查。收集临床和神经影像学特征。
我们观察到 CASK 突变患者的高频发生率（14/14）。10 名患者（8 名女孩和 2 名男孩）存在基因内突变，3 名女性患者存在包括 CASK 基因的 Xp11.4 亚微缺失。所有突变均为从头突变。表型严重程度不一，但 11 名女孩的表型高度相似，表现为精神运动发育迟缓、严重智力障碍、进行性小头畸形、肌张力障碍、轻度畸形和脊柱侧凸。其他体征常伴有，如生长迟缓、眼科异常（青光眼、巨角膜和视神经萎缩）、耳聋和癫痫。正如主要在女性中表现为 X 连锁疾病的预期那样，携带剪接突变的半合子男孩的表型非常严重，几乎没有发育且癫痫难以控制。我们描述了一名男孩存在镶嵌性截断突变，表现为轻度表型。我们发现小脑蚓部发育不全的严重程度与临床表型之间存在一定程度的相关性。
本研究描述了一组新的 CASK 失活突变的 PCH 女性患者，证实这些患者具有可识别的、但存在变异性的表型，包括一种特定形式的桥小脑发育不良。此外，我们报告了第二例严重 MICPCH 表型和新发 CASK 突变的男性患者，并首次描述了一名携带镶嵌性突变的轻度受影响的男性患者。在我们的参考中心，CASK 相关 PCH 是第二常见的 PCH 病因。这些患者中存在的新生突变可进行准确且令人安心的遗传咨询。
