Cerebral cavernous malformations associated to meningioma: High penetrance in a novel family mutated in the PDCD10 gene

Introduction

Meningiomas are the most common benign intracranial neoplasm¹ accounting for up to 20% of all primary intracranial tumours^1,2 with annual incidence 5.5 per 100,000 individuals.³ They arise from the arachnoid cap cells of meningeal coverings of the spinal cord and the brain.¹ Meningiomas occur as multiple tumours in less than 10% of cases, either isolated or in combination with other features, e.g. neurofibromatosis type 2 (NF2).³

Cerebral cavernous malformations (CCMs; Online Mendelian Inheritance in Man (OMIM)#116860) represent approximately 15% of all cerebral vascular lesions affecting 0.1–0.8% of the general population, with a familial incidence of almost 20%.^5,6 CCMs are asymptomatic in up to 40% of cases or may clinically present with a variety of neurological manifestations.⁶ Loss-of-function mutations in one of three genes (CCM1/KRIT1, CCM2/MGC4607 or CCM3/PDCD10) predispose to CCM and are detected in up to 94% of familial CCM cases and 60% of sporadic CCM cases.^5,7 A phenotype consisting of CCM and dural lesions showing meningioma features at Magnetic Resonance Imaging (MRI) has been reported in a dozen patients.^8–10 Histopathological analyses defined the dural lesions as meningiomas in some of them. In a family study, the penetrance of this meningioma-phenotype was lower than CCM-phenotype alone and interestingly all genetically tested individuals with CCM and meningioma were mutated in the PDCD10 gene.⁸

Here, we describe an Italian family in which three symptomatic individuals mutated in the PDCD10 gene harboured parenchymal CCM lesions associated to multiple dural lesions with meningioma features at MRI.

Materials and methods

Three related individuals came to our observation in the course of the clinical-radiological assessment for seizure crises. The family pedigree is shown in Figure 1. The index case (II-6) presented with seizures at the age of 66 years. She had been suffering from recurrent headaches for 10 years previously. Her parents were non-consanguineous and her father (I-1), who suffered from recurrent headaches, died at the age of 84 years from femur fracture complications, while her mother (I-2) died at the age of 78 years from stroke. One of her sibling (II-3) presented at the age of 73 years with a first episode of seizure and had a daughter (III-3) affected by a severe form of epilepsy since she was 25 years old.

The three symptomatic subjects (II-3, II-6 and III-3) underwent MRI examination in the course of their clinical assessment. All of them, and an unaffected relative (II-7), agreed with informed consent for genetic testing of CCM genes. The molecular analysis of DNA extracted from blood lymphocytes was performed as previously described⁸ and included direct sequencing of KRIT1, MGC4607 and PDCD10 genes and the sequencing for the identified PDCD10 gene mutation.

Results

All subjects showed multiple dural masses with meningioma features, presenting as multiple masses or diffuse dural thickening, and multiple intra-axial lesions, some with central areas of mixed signal on T1-weighted images other with low signal on gradient echo (GRE), consistent with CCMs (Figures 2–4). According to Zabramski classification,¹¹ different types of CCM were observed in the same subjects. MR images were reviewed by three experienced neuroradiologists, who reached final interpretation (meningiomas and CCMs) by consensus.

A mutation in the PDCD10 gene was detected in all affected individuals (II-3, II-6 and III-3). This mutation consisted in a deletion of four base-pairs in exon 7 (c.334_337del) that results in a frame-shift leading to a premature stop codon (p.Gln112PhefsX13). The mutation was absent in the healthy relative (II-7).

Discussion

Multiple meningiomas occur in 1–10% of patients in different series.¹² NF2 is the most common genetic condition displaying multiple meningiomas, which have also been described in other genetic syndromes, including schwannomatosis, Werner and Proteus syndromes. At present, it is unclear whether these represent true or casual association. In addition, familial multiple meningiomas showing autosomal dominant inheritance not linked to the NF2 locus has been exceptionally described.³

This is the first report describing multiple individuals from the same family with both CCMs and dural lesions, following autosomal dominant inheritance. We reviewed all previously 12 reported sporadic patients with CCMs and meningiomas from the literature and, surprisingly, all genetically tested patients harboured mutations in the PDCD10 gene, as observed in our family.^8–10 Notably, the penetrance of this CCM ‘meningioma-phenotype’ in our family is higher than in previously reported families. The mutation we identified was previously described by Spiegler et al. in an individual presenting with familial CCMs but in whom the presence of dural lesions were not investigated.⁷ We cannot exclude that dural lesions may have been underdiagnosed in previously reported CCM families, hence the importance of a detailed neuroradiologic examination, especially in PDCD10-mutated individuals.

No histopathologic definition of the dural lesions of our patients is available as none of them underwent surgery or biopsy. However, all MRI findings were highly suggestive of meningiomas. Indeed, the dural masses of our patients presented homogenous enhancement and the typical ‘dural tails’ after gadolinium injection. Moreover, a thickened dura (isolated or close to the masses) was almost always observed, frequently featuring the ‘en plaque’ meningiomas. Importantly, among PDCD10-mutated patients presenting multiple parenchymal CCMs associated with dural enhancing lesions (multiples in all cases except one), some have been examined and confirmed as meningioma.^8–10 Although different type of lesions might be found within the dura mater, according to the neuroradiological pattern as well as to the evidence from the literature, we consider that the most likely diagnosis of the dural lesions herein reported is meningioma.

Our data support the association of CCMs and meningioma representing a distinct syndromic entity linked to CCM3/PDCD10. Although rare, this phenotype is clinically relevant because CCMs are high-risk lesions with clinical manifestations in approximately 60% of cases, namely recurrent headaches, seizures, progressive focal neurological deficits and haemorrhagic stroke, depending on the localisation, size and number of the lesions and the occurrence of bleeding.^11,13 Meningiomas are commonly encountered in neuroradiological practice, but they are routinely diagnosed through imaging techniques that are not highly sensitive for CCMs so that latter lesions may in some cases be under diagnosed in meningioma patients. In particular, GRE sequences have been shown to reveal up to three times the number of CCMs compared to routine T1 and T2-weighted imaging MRI sequences.¹⁴ Susceptibility-weighted imaging (SWI) sequences seem to have an even higher sensitivity for multiple/familial CCMs as compared to classical GRE imaging.¹⁵ Aside from the unsolved discussion on which technique is the best imaging tool, we suggest the investigation of CCM lesions, performing appropriate MRI sequences (either GRE or SWI), whenever multiple and/or familial meningioma-like lesions are observed. Conversely, when dural masses are suspected in CCMs, post gadolinium injection scans may help defining the meningioma-phenotype, especially in PDCD10-mutated patients.

Further work describing CCM patients with multiple meningiomas are needed to clarify the prevalence of this likely underestimated condition. More importantly, since CCMs are high-risk lesions early recognition of this phenotype is warranted to plan appropriate management and care.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest

The authors declare that there is no conflict of interest.