Elsevier

The Lancet

Volume 352, Issue 9144, 12 December 1998, Pages 1892-1897
The Lancet

Articles
Hereditary cerebral cavernous angiomas: clinical and genetic features in 57 French families

https://doi.org/10.1016/S0140-6736(98)03011-6Get rights and content

Summary

Background

Cavernous angiomas, which are vascular malformations mostly located in the central nervous system, may be inherited as an autosomal dominant disorder known as familial cerebral cavernoma (FCC). FCC has been studied in Hispanoamerican families, in which a strong founder effect was shown. We studied the families of 57 non-Hispanic patients with cavernous angiomas.

Methods

All 28 neurosurgery centres in France collaborated in the study. Inclusion criteria were: families of index patients known to have at least one clinically affected relative, and families of index patients with multiple cavernous angiomas who initially presented as sporadic cases. Clinical and cerebral magnetic resonance imaging (MRI) investigations were done in all patients and in other at-risk individuals who consented to take part.

Findings

On MRI, 16 of 22 sporadic index patients had relatives with cavernous angiomas. 51 multiple-case families, including 100 patients with symptoms and 164 symptom-free individuals had MRI lesions. Most FCC patients had multiple lesions and there was a strong correlation betwen number of lesions and age (p<0·01). The sensitivity of gradient-echo sequences was higher than that of standard MRI for detection of small cavernous angiomas. Pattern of inheritance was autosomal dominant, with incomplete clinical penetrance. The occurence of denovo mutations was strongly suggested in some families.

Interpretation

Neuroimaging penetrance of FCC is much higher than clinical penetrance. 75% of sporadic cases with multiple lesions are in fact familial cases. The proportion of patients developing clinical symptoms is higher in the hereditary form than in the sporadic form of the disorder.

Introduction

Cavernous angiomas are vascular malformations, mostly located in the central nervous system, characterised by abnormally enlarged capillary cavities without intervening brain parenchyma.1 The most common symptoms in affected patients are seizures (38-51% of cases), haemorrhage (11-32%), and focal neurological deficits (12-45%).2 From large series based on necropsy or magnetic resonance imaging, the frequency of cavernomas in the general population was calculated as 0·5%.3, 4, 5 Cavernous angiomas can occur in a familial form but the frequency of this is unknown other than for a series of non-consecutive Hispanoamerican patients, in which the frequency was estimated at close to 50%.6 In 1995, in a detailed clinical investigation of the first-degree and second-degree relatives of 50 consecutive French patients who underwent neurosurgery for cavernous angiomas, we showed that five patients had a clinically affected relative, suggesting that the frequency of familial cerebral cavernoma (FCC) is lower in that population (ETL, unpublished results).

Around 50 families with FCC have been studied. In most studies, only one or two families were included. MRI was available in only the latest studies, and symptom-free individuals were generally not investigated. Two independent studies, of 13 and six Hispanoamerican families, helped to define the main features of FCC-the autosomal dominant pattern of inheritance, the incomplete clinical penetrance, and the high frequency of multiple lesions in FCC patients.6, 7 In 1995, Dubovsky and colleagues8 studied a large Hispanoamerican family and mapped a gene (CCM1) associated with FCC to chromosome 7q11-q22. Analysis of other families showed that all Hispanoamerican families were linked to chromosome 7 and they shared a common haplotype, which suggested that they had a common ancestor.9, 10, 11, 12 Only seven non-Hispanoamerican families (six North American,10, 13, 14, 15 one European16) have been analysed: two of these families were not linked to chromosome 7, which established genetic heterogeneity.14

These data suggest that Hispanoamerican families with FCC are a distinct group in which reported clinical and neuroimaging features might differ from other populations. In the absence of data on non-Hispanic families, we studied more than 50 French families with FCC.

Section snippets

Patients

28 French university neurosurgery centres, all members of the Société Francaise de Neurochirurgie, participated in the study. The study was approved by the local ethics committees.

An index patient was the first individual in a given family in whom cavernous angiomas were diagnosed. 57 index patients and their families were studied. Because there is a high frequency of multiple lesions in FCC patients we had two eligibility criteria: families of any index patient previously known to have at

Results

The 57 index patients included 35 patients previously known to have at least one clinically affected relative, and 22 who were not known to have any affected relative but who had multiple cavernous angiomas (figure 1). All index patients and their families were French, except the families of patient 33, from Belgium, and patient 42, from Italy. No patient was known to have Spanish or Hispanoamerican ancestors. A diagnosis of cavernous angioma was histologically proven in at least one member of

MRI findings

MRI data for patients with symptoms and symptom-free individuals-MRI (T2-weighted) data were available for 83 patients with symptoms (mean age at MRI 35·1 years). 69 (83%) had multiple lesions, with a mean number of 7·3 lesions per patient (range 1-51). Total lesion count was 628 lesions, of which 122 were infratentorial. There were 44 lesions of type I, 147 of type II, and 437 of type III. Of the 278 at-risk symptom-free relatives, 164 had an MRI assessment (81 male, 83 female; mean age 44

Discussion

We have characterised several features of FCC that may be of importance for clinical care. Around 75% of patients who have multiple cavernous lesions and who present as sporadic cases in fact have a hereditary form of the disorder. The pattern of inheritance observed in these families, and in families that include several individuals with symptoms, is consistent with an autosomal dominant mode with incomplete clinical penetrance and possible de-novo mutations.

The penetrance observed in

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