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Figure.
Fundus photograph of the left eye of proband C052 showing a cluster of peripheral saccular aneurysms of various sizes.

Fundus photograph of the left eye of proband C052 showing a cluster of peripheral saccular aneurysms of various sizes.

1.
Craig  HDGünel  MCepeda  O  et al.  Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27. Hum Mol Genet 1998;71851- 1858
PubMedArticle
2.
Laberge-le Couteulx  SJung  HHLabauge  P  et al.  Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet 1999;23189- 193
PubMedArticle
3.
Sahoo  TJohnson  EWThomas  JW  et al.  Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1). Hum Mol Genet 1999;82325- 2333
PubMedArticle
4.
Bergametti  FDenier  CLabauge  P  et al.  Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet 2005;7642- 51
PubMedArticle
5.
Denier  CGoutagny  SLabauge  P  et al.  Mutations within the MGC4607 gene cause cerebral cavernous malformations. Am J Hum Genet 2004;74326- 337
PubMedArticle
6.
Wood  MWWhite  RJKernohan  JW Cavernous hemangiomatosis involving the brain, spinal cord, heart, skin and kidney. Mayo Clin Proc 1957;32249- 254
PubMed
7.
Labauge  PEnjolras  OBonerandi  JJ  et al.  An association between autosomal dominant cerebral cavernomas and a distinctive hyperkeratotic cutaneous vascular malformation in 4 families. Ann Neurol 1999;45250- 254
PubMedArticle
8.
Sarraf  DPayne  AMKitchen  NDSehmi  KSDownes  SMBird  AC Familial cavernous hemangioma. Arch Ophthalmol 2000;118969- 973
PubMedArticle
9.
Couteulx  SLBrezin  AFontaine  BTournier-Lasserve  ELabauge  P A novel KRIT1/CCM1 truncating mutation in a patient with cerebral and retinal cavernous angiomas. Arch Ophthalmol 2002;120217- 218
PubMed
10.
Labauge  PLaberge  SBrunereau  SLévy  CTournier-Lasserve  ESociété française de Neurochirurgie, Hereditary cerebral cavernous angiomas. Lancet 1998;3521892- 1897
PubMedArticle
11.
Cave-Riant  FDenier  FLabauge  P  et al.  Spectrum and expression analysis of KRIT1 mutations in 121 consecutive and unrelated patients with cerebral cavernous malformations. Eur J Hum Genet 2002;10733- 740
PubMedArticle
12.
Denier  CLabauge  PBrunereau  L  et al.  Clinical features of cerebral cavernous malformations patients with KRIT1 mutations. Ann Neurol 2004;55213- 220
PubMedArticle
13.
Pancurak  JGoldberg  MFFrenkel  MCrowell  RM Cavernous hemangioma of the retina. Retina 1985;5215- 220
PubMedArticle
14.
Messmer  ELaqua  HWessing  A  et al.  Nine cases of cavernous hemangioma of the retina. Am J Ophthalmol 1983;95383- 390
PubMed
15.
Messmer  EFont  RLLaqua  HHöpping  WNaumann  GOH Cavernous hemangioma of the retina. Arch Ophthalmol 1984;102413- 418
PubMedArticle
Ophthalmic Molecular Genetics
June 2006

Frequency of Retinal Cavernomas in 60 Patients With Familial Cerebral CavernomasA Clinical and Genetic Study

Author Affiliations
 

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.

Arch Ophthalmol. 2006;124(6):885-886. doi:10.1001/archopht.124.6.885
Abstract

Objectives  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.

Methods  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.

Results  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.

Conclusions  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.

Clinical Relevance  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.15 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.

METHODS

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

RESULTS

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

COMMENT

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.

CONCLUSIONS

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.

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Article Information

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 (labauge@hotmail.com).

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.

References
1.
Craig  HDGünel  MCepeda  O  et al.  Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27. Hum Mol Genet 1998;71851- 1858
PubMedArticle
2.
Laberge-le Couteulx  SJung  HHLabauge  P  et al.  Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet 1999;23189- 193
PubMedArticle
3.
Sahoo  TJohnson  EWThomas  JW  et al.  Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1). Hum Mol Genet 1999;82325- 2333
PubMedArticle
4.
Bergametti  FDenier  CLabauge  P  et al.  Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet 2005;7642- 51
PubMedArticle
5.
Denier  CGoutagny  SLabauge  P  et al.  Mutations within the MGC4607 gene cause cerebral cavernous malformations. Am J Hum Genet 2004;74326- 337
PubMedArticle
6.
Wood  MWWhite  RJKernohan  JW Cavernous hemangiomatosis involving the brain, spinal cord, heart, skin and kidney. Mayo Clin Proc 1957;32249- 254
PubMed
7.
Labauge  PEnjolras  OBonerandi  JJ  et al.  An association between autosomal dominant cerebral cavernomas and a distinctive hyperkeratotic cutaneous vascular malformation in 4 families. Ann Neurol 1999;45250- 254
PubMedArticle
8.
Sarraf  DPayne  AMKitchen  NDSehmi  KSDownes  SMBird  AC Familial cavernous hemangioma. Arch Ophthalmol 2000;118969- 973
PubMedArticle
9.
Couteulx  SLBrezin  AFontaine  BTournier-Lasserve  ELabauge  P A novel KRIT1/CCM1 truncating mutation in a patient with cerebral and retinal cavernous angiomas. Arch Ophthalmol 2002;120217- 218
PubMed
10.
Labauge  PLaberge  SBrunereau  SLévy  CTournier-Lasserve  ESociété française de Neurochirurgie, Hereditary cerebral cavernous angiomas. Lancet 1998;3521892- 1897
PubMedArticle
11.
Cave-Riant  FDenier  FLabauge  P  et al.  Spectrum and expression analysis of KRIT1 mutations in 121 consecutive and unrelated patients with cerebral cavernous malformations. Eur J Hum Genet 2002;10733- 740
PubMedArticle
12.
Denier  CLabauge  PBrunereau  L  et al.  Clinical features of cerebral cavernous malformations patients with KRIT1 mutations. Ann Neurol 2004;55213- 220
PubMedArticle
13.
Pancurak  JGoldberg  MFFrenkel  MCrowell  RM Cavernous hemangioma of the retina. Retina 1985;5215- 220
PubMedArticle
14.
Messmer  ELaqua  HWessing  A  et al.  Nine cases of cavernous hemangioma of the retina. Am J Ophthalmol 1983;95383- 390
PubMed
15.
Messmer  EFont  RLLaqua  HHöpping  WNaumann  GOH Cavernous hemangioma of the retina. Arch Ophthalmol 1984;102413- 418
PubMedArticle
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