Russo Alexandra, Neu Marie Astrid, Theruvath Johanna, Kron Bettina, Wingerter Arthur, Hey-Koch Silla, Tanyildizi Yasemin, Faber Joerg
Department of Pediatric Hematology/Oncology/Hemostaseology, University Medical Center Mainz, Langenbeckstraße 1, 55131, Mainz, Germany.
Department of Radiation Oncology and Radiation Therapy, University Medical Center Mainz, Mainz, Germany.
Childs Nerv Syst. 2017 Aug;33(8):1275-1283. doi: 10.1007/s00381-017-3434-x. Epub 2017 May 9.
Cerebrospinal cavernous malformations (CCMs) are vascular lesions characterized by dilated and leaky capillary caverns. CCMs can cause seizures, focal neurological deficits or acute intracranial hemorrhage; however, most patients are asymptomatic. CCMs occur either sporadically or as a familial autosomal-dominant disorder. We present a clinical and molecular study of a patient with distinctive cerebral and spinal cavernous malformations following radiochemotherapy for a malignant brain tumor.
The patient had multiple magnet resonance imaging (MRI) examinations of his brain and spine following radiochemotherapy for a primary intracranial germ cell tumor (GCT), as part of his oncologic follow-up. The MRI sequences included susceptibility-weighted imaging (SWI). The coding exons and their flanking intronic regions of KRIT1/CCM1 gene were analyzed for mutations by polymerase chain reaction (PCR) and direct sequencing.
MRI revealed numerous cerebral and spinal microhemorrhages and pronounced cavernous malformations that progressed with subsequent follow-up imaging. Genetic analysis demonstrated a novel heterozygous KRIT1/CCM1 two base pair deletion (c.1535_1536delTG) in exon 14. This deletion leads to a frameshift with a premature stop codon at nucleotide position 1553 and a highly likely loss of function of the KRIT1 protein.
We describe a patient with a novel heterozygous germ line loss of function mutation in KRIT1, which is associated with rapid-onset and highly progressive CCMs after radiochemotherapy for a malignant brain tumor.
脑脊髓海绵状畸形（CCMs）是一种血管病变，其特征为扩张且有渗漏的毛细血管海绵体。CCMs可导致癫痫发作、局灶性神经功能缺损或急性颅内出血；然而，大多数患者无症状。CCMs可散发出现，也可作为一种常染色体显性遗传病发生。我们报告了一例恶性脑肿瘤放化疗后出现独特的脑和脊髓海绵状畸形患者的临床及分子研究。
作为肿瘤学随访的一部分，该患者在接受原发性颅内生殖细胞瘤（GCT）放化疗后，对其脑和脊柱进行了多次磁共振成像（MRI）检查。MRI序列包括磁敏感加权成像（SWI）。通过聚合酶链反应（PCR）和直接测序分析KRIT1/CCM1基因的编码外显子及其侧翼内含子区域是否存在突变。
MRI显示大量脑和脊髓微出血以及明显的海绵状畸形，在后续的随访成像中病变进展。基因分析显示外显子14中存在一种新的杂合KRIT1/CCM1两个碱基对缺失（c.1535_1536delTG）。这种缺失导致移码，在核苷酸位置1553处出现过早的终止密码子，很可能导致KRIT1蛋白功能丧失。
我们描述了一例患者，其KRIT1基因存在新的杂合种系功能丧失突变，该突变与恶性脑肿瘤放化疗后快速发生且高度进展的CCMs相关。
