Clinical and molecular landscape of paediatric cerebral and spinal cavernous malformations

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Abstract We aimed to decipher the natural history of paediatric cerebral and intraspinal medullary cavernous malformations and their genetic background, with an emphasis on the effect of mutational burden on their radiological features and haemorrhagic risk. We retrospectively collected clinical and radiological data and the natural history of the disease during the follow-up of all consecutive patients with cavernous malformations over the last 2 decades at a unique paediatric centre. We created an MRI atlas after lesion segmentation and normalization to perform voxel-based lesion symptom mapping. Targeted germline DNA sequencing of CCM1-3 genes and somatic lesions and targeted sequencing of RAS and PI3 K pathway genes were performed. In total, 257 patients carrying 786 brain and 14 spinal cavernous malformations were analysed. Age at diagnosis was 9.5 ± 5 years. Follow-up data were available for 718 lesions with a mean follow-up of 5.59 ± 3.28 years. Then, 134 brain (80 with focal onset seizures) and 10 spinal cavernous malformations were surgically excised. Furthermore, 95 of the/144 DNA extracted from lesions were successfully sequenced for somatic variants (PIK3CA, MAP3K3, KRIT1 and KRAS). We found an annual haemorrhagic risk of 1.9%, which was increased by type (sporadic or postradiation), location (brainstem or spinal), and radiological parameters (extracapsular haemorrhage, volume, signal, or presence of developmental venous anomaly). Cavernous malformations symptoms and radiological features were highly dependent on brain location. Surgical risk for cortical brain lesions was 0.9%, with 85% international league against epilepsy score grade of 1–2. Furthermore, 62% of operated lesions carried a pathogenic PIK3CA variant. The MAP3K3 somatic variant alone or in association with a PIK3CA variant decreased the annual haemorrhagic risk by 4.8 ± 1.5 (P < 0.05). We confirmed that 96% of cavernous malformations that are satellites of a developmental venous anomaly carried a PIK3CA variant and increased the relative haemorrhagic risk by 3 ± 0.31 (P = 3.8.10−3). We report an annual haemorrhagic risk of 1.9%, which is modulated by radiological features (i.e. extracapsular haemorrhage, volume, signal, and location) and lesion type. Here, we describe the first MRI atlas. Surgery yields excellent general outcomes in supratentorial superficial lesions, unlike deep-seated cavernous malformations, which is associated with high morbidity. Molecular diagnosis of operated lesions highlighted PIK3CA as a factor associated with aggressiveness in both sporadic and familial cavernous malformations. MAP3K3 decreased the risk. Finally, we confirmed that developmental venous anomaly is a radiological landmark of PIK3CA.

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