Fundus photograph of the left eye of proband C052 showing a cluster of peripheral saccular aneurysms of various sizes.
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Labauge P, Krivosic V, Denier C, Tournier-Lasserve E, Gaudric A. Frequency of Retinal Cavernomas in 60 Patients With Familial Cerebral Cavernomas: A Clinical and Genetic Study. Arch Ophthalmol. 2006;124(6):885–886. doi:10.1001/archopht.124.6.885
JANEY L.WIGGSMD, PhDAuthor Affiliations: Department of Neurology, Centre Hospitalo-Universitaire de Montpellier-Nîmes, Montpellier, France (Dr Labauge); Institut National de la Santé et de la Recherche Médicale Unit 740, Faculté de Médecine Lariboisière, Paris, France (Drs Labauge, Denier, and Tournier-Lasserve); and Department of Ophthalmology (Drs Krivosic and Gaudric) and Laboratoire de génétique (Dr Tournier-Lasserve), Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris.
To define the frequency of retinal lesions in a large panel of patients with familial cerebral cavernomas and to screen the cerebral cavernous malformation genes in patients with cerebral and retinal lesions.
Fundus examination was proposed to each of the index patients of 70 families with cerebral cavernous malformation who have been included in a prospective clinical and neuroradiological follow-up. All of the coding exons of the KRIT1, MGC4607, and PDCD10 genes were screened as previously described.
Of the 70 index patients, 60 were consecutively examined. The 10 remaining patients refused the fundus examination. Three of the 60 examined patients had a retinal cavernoma diagnosis. Three mutations were found: a point mutation within exon 5 of the KRIT1 gene, a large deletion that encompassed exons 1 and 2 of the MGC4607 gene, and a large genomic de novo deletion encompassing the whole PDCD10 gene.
Retinal cavernoma frequency can be estimated to be about 5% of the patients with familial cerebral cavernomas. Retinal cavernomas are not restricted to KRIT1 mutation carriers but can be observed in patients carrying a mutation in any of the 3 cerebral cavernous malformation genes.
Five percent of patients with familial cerebral cavernomas have retinal cavernomas. These lesions are clinically asymptomatic. They can be associated with any of the 3 cerebral cavernous malformation genes.
Cerebral cavernomas are histologically defined by abnormally enlarged capillary cavities without any intervening brain parenchyma. The most common symptoms include seizures and focal neurological deficits due to cerebral hemorrhages. Their prevalence is close to 0.5% of the general population. Familial autosomal dominant forms are increasingly being recognized. Three cerebral cavernous malformation (CCM) genes have been mapped and identified.1-5 Cavernomas can be observed in other organs such as the skin and eye.6,7 Eye lesions associated with CCM are usually retinal cavernomas and are rarely choroidal hemangiomas.8 Retinal cavernomas generally appear as an isolated cluster of retinal saccular aneurysms. To our knowledge, the frequency of eye cavernomas in patients with familial cerebral cavernomas is unknown so far, and only 1 patient with familial cerebral and retinal cavernomas has been molecularly screened and shown to harbor a KRIT1 mutation.9
The objectives of this study were to define the frequency of retinal lesions in a large panel of patients with familial cerebral cavernomas and to screen the CCM genes in patients with cerebral and retinal lesions.
Fundus examination was proposed to each of the index patients of 70 families with CCM who have been included in a prospective clinical and neuroradiological follow-up.10 The CCM diagnosis was based on magnetic resonance imaging investigation in each patient. Each patient has at least 1 relative with CCM and/or has multiple cerebral lesions.10 Each patient showing an abnormal fundus underwent a second examination by an independent ophthalmologist (V.K. or A.G.). The refraction was not checked in the examination protocol. Fluorescein angiography was not performed in this study, as it was judged to be too invasive for a screening. In addition, fluorescein angiography is not necessary to diagnose retinal cavernomas. All of the coding exons of the KRIT1, MGC4607, and PDCD10 genes were screened as previously described.4,5,11,12
Of the 70 index patients, 60 were consecutively examined. The 10 remaining patients refused the fundus examination. Three of the 60 examined patients had a retinal cavernoma diagnosis (probands C167, C127, and C052). Neurological symptoms of these patients (1 male and 2 female) were brainstem symptoms (proband C167) and cerebral hemorrhage (probands C127 and C052). The age of patients with and without retinal cavernomas was not different (mean age, 40.3 years [range, 20.2-55.3 years] vs 42.6 years [range 9.6-67.8 years], respectively). Fundus examination patterns consisted of peripheral retinal vascular lesions seen as clusters of saccular whitish to dark red aneurysms (proband C052) (Figure). Retinal cavernomas were clinically asymptomatic, unilateral, and single in each case. They were located in the inferotemporal periphery. The lesions were 3 to 4 disc diameters in the 3 patients. There was no other eye abnormality. No other lesion was observed, and notably, no cutaneous angioma was seen. Molecular genotyping of proband C167 revealed a point mutation within exon 5 of the KRIT1 gene (c.112delC).11 Genotyping of proband C127 and her family revealed a large deletion that encompassed exons 1 and 2 of the MGC4607 gene.5 Proband C052 was shown to harbor a large genomic de novo deletion encompassing the whole PDCD10 gene.4
Retinal cavernomas are rare and usually asymptomatic.13 The largest series reported so far comprised 9 cases and used neither cerebral magnetic resonance imaging investigation nor DNA molecular analysis.14,15 Co-occurrence of cerebral and retinal cavernomas was rarely reported.9 To our knowledge, retinal cavernoma diagnosis did not reveal brain cavernomas. However, retinal cavernomas are most likely underdiagnosed since they are usually asymptomatic.
In this study, the occurrence of retinal lesions in patients with CCM was estimated to be close to 5% (3/60 patients). The estimated incidence of retinal cavernomas could be 1 per 40 000 persons in the general population since the incidence of familial cerebral cavernomas is 10% of sporadic cerebral cavernomas (the sporadic cerebral cavernoma incidence is 0.5% of the general population). The exact incidence of retinal cavernomas in the general population is not known. The observed retinal lesions were unilateral and single in all of the 3 cases. We did not observe choroidal hemangiomas. Evolution of these lesions is unknown since the fundus was only examined once.
Furthermore, this study shows that retinal and cerebral cavernomas can be associated with mutations in all of the 3 CCM genes.
To our knowledge, we show for the first time that the frequency of retinal cavernomas can be estimated to be about 5% of the patients with familial cerebral cavernomas. We also show that retinal cavernomas are not restricted to KRIT1 mutation carriers but can be observed in patients carrying a mutation in any of the 3 CCM genes.
Correspondence: Pierre Labauge, MD, PhD, Service de Neurologie, Centre Hospitalo-Universitaire de Montpellier-Nîmes, Hôpital Caremeau, 2 Avenue du Pr Debré, 30029 Nîmes, CEDEX 4, France (firstname.lastname@example.org).
Submitted for Publication: October 12, 2004; final revision received February 21, 2005; accepted March 14, 2005.
Financial Disclosure: None.
Funding/Support: This work was supported by the Institut National de la Santé et de la Recherche Médicale and by grants AO2002-2004 from GIS Maladies Rares and AOR030312003 from the Programme Hospitalier de Recherche Clinique.