MULTIPLE DURAL LESIONS MIMICKING MENINGIOMAS IN PATIENTS WITH CCM3/PDCD10 MUTATIONS

Abstract

MULTIPLE DURAL LESIONS MIMICKING MENINGIOMAS IN PATIENTS WITH CCM3/ PDCD10 MUTATIONSCerebral cavernous malformations (CCM) are in most cases located within the brain parenchyma. Familial forms of CCM (FCCM) are characterized by an autosomal dominant pattern of inheritance and the presence of multiple cerebral lesions. 1 Three CCM genes have been identified: CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. 1,2 They are involved in 53%, 15%, and 10% of patients with FCCM. 3 All mutations lead to premature stop codons. Herein, we identified, within a series of 197 index patients with CCM mutations, four patients with multiple dural-based lesions mimicking meningiomas. All four index patients carried a mutation in CCM3. Methods and results.A consecutive cohort of 267 CCM index patients with either multiple lesions or an affected relative who gave written informed consent were screened for mutations within the three CCM genes as previously reported. 3 This study was approved by our local ethics committee. Genetic screening identified a deleterious mutation in 197 of these index patients, which constituted our study group. Clinical manifestations and mutations of 128 of these index patients were previously reported. 2 A total of 129 out of the 197 index patients had a CCM1 mutation (65.4%), 39 had a CCM2 mutation (19.7%), and 29 had a CCM3 mutation (14.7%) (data not shown).Multiple intracranial dural-based lesions were detected in four index patients whose main imaging features are shown in the figure. Briefly, these four patients (three women/one man; mean age: 48 years, range: 42-64) show the following: 1) multiple parenchymal cavernous angiomas; and 2) multiple dural-based lesions with similar magnetic resonance patterns, i.e., hypointense on T1, hyperintense on T2 sequences, markedly enhanced by gadolinium injection, and a diffuse dural enhancement. Gradient echo MRI did not show hyposignals suggestive of hemosiderin deposits within those dural-based lesions. The number of dural lesions increased with age in two of them (cases C30 and C161). All four pa-tients carry a deleterious mutation in CCM3/ PDCD10. C030 index patient has an R196X stop codon mutation. C107 showed a c.475-1 G ϾA splice site mutation leading to an aberrant splicing of exon 9. C158 has a c.474 ϩ 5GϾA splice site mutation leading to several abnormal transcripts. C161 has a one bp deletion within exon 9 leading to a frameshift and a stop codon at codon 188.The proportion of patients with CCM3 mutations who had multiple dural lesions in this consecutive series is approximately 14% (4/29). Percentages of patients carrying dural-based lesions within the three CCM1/CCM2/CCM3 groups were clearly different (p Ͻ 0.0001/Fisher test). None of the patients with CCM without an identified mutation showed dural-based lesions.

<b><i>CCM3</i></b> Mutations Are Associated with Early-Onset Cerebral Hemorrhage and Multiple Meningiomas

“…In a previous study on 333 CCM mutation carriers including 28 CCM3 patients belonging to 17 families, we suggested that the proportion of CCM3 patients with a childhood onset was higher compared to CCM1 and CCM2 patients [Denier et al, 2006]. We also showed in 4 unrelated CCM3 patients the occurrence of multiple dural-based lesions; however, the pathological nature of these lesions was unknown since none of these patients had undergone neurosurgery [Labauge et al, 2009].…”

“…Our study group was composed of these 54 probands and 22 of their mutated relatives. Partial information on some of these patients have been previously reported [Denier et al, 2006;Ahdab et al, 2008;Labauge et al, 2009;Choe et al, 2010].…”

Highly variable intrafamilial manifestations of a CCM3 mutation ranging from acute childhood cerebral haemorrhage to late-onset meningiomas

“…Early onset fulminant cerebral haemorrhage has previously been reported in patients with CCM3 mutations and seems to be more prevalent in this subgroup than in CCM1 or CCM2 mutation carriers [2,3]. A subset of CCM3 mutation carriers has been identified which has both, parenchymal CCM and dural-based lesions which show typical MRI features of meningiomas [4][5][6]. Previous histological studies in patients with mainly solitary dural-based MRI lesions showed that these lesions are cavernous angiomas [7].…”

Genomic landscape of intracranial meningiomas

“…84 Multiple meningiomas have been observed in patients with mutations in CCM3/PDCD10, a gene associated with cerebral cavernous malformations that contributes to proliferation and resistance to apoptosis via activation of AKT signaling, 20,48,56,75 and the SUFU gene, which regulates hedgehog signaling.…”