Journal of the Neurological Sciences 350 (2015) 98–100
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Occurrence of multiple Cerebral Cavernous Malformations in a patient with Neurofibromatosis type 1 K. Rerat a,b, F. Parker b, G. Nasser c, D. Vidaud d, F. Riant e,f, E. Tournier-Lasserve e,f, C. Denier a,⁎ a
Department of Neurology, Université Paris Sud, Faculté de Médecine Paris Sud, Hôpital de Bicêtre, Assistance Publique, Hôpitaux de Paris (AP-HP), France Department of Neurosurgery, Université Paris Sud, Faculté de Médecine Paris Sud, Hôpital de Bicêtre, Assistance Publique, Hôpitaux de Paris (AP-HP), France Department of NeuroRadiology, Université Paris Sud, Faculté de Médecine Paris Sud, Hôpital de Bicêtre, Assistance Publique, Hôpitaux de Paris (AP-HP), France d INSERM UMR745, Paris Descartes University, France e AP-HP, Service de Génétique, Hôpital Lariboisière, France f INSERM UMR 1161, Paris Diderot University, France b c
a r t i c l e
i n f o
Article history: Received 27 November 2014 Received in revised form 8 February 2015 Accepted 10 February 2015 Available online 18 February 2015 Keywords: Neurofibromatosis type 1 Cerebral Cavernous Malformations Cavernous angiomas Neurocutaneous syndromes Phakomatoses Cavernoma
a b s t r a c t Background: Neurofibromatosis 1 (NF1) belongs to the autosomal dominant neurocutaneous disorders' group, which mainly includes NF1 and NF2, tuberous sclerosis, von Hippel-Lindau disease and Cerebral Cavernous Malformations (CCMs). NF1 has a major impact on the nervous system, eye, skin, bone or cardiovascular system. Cerebrovascular lesions have been reported in NF1 including aneurysm, pseudoaneurysm, arteriovenous malformations, vascular stenosis or occlusion and Moya moya syndrome. Objective: To report a case of an NF1 patient with multiple CCMs. Observation: A 47-year-old man with café-au-lait skin lesions, countless cutaneous neurofibromas, short stature and scoliosis was admitted for progressive spinal cord compression due to histologically proven neurofibroma. Systematic cerebral MRI screening including gradient echo sequences showed multiple asymptomatic CCMs. Screening of CCM1, CCM2 and CCM3 genes was negative while a deleterious frameshift mutation was identified in NF1 gene. Conclusion: While single CCM can occur in NF1 patients following radiation exposure, they are only rarely reported in non-irradiated NF1 brain. Even if it could be a fortuitous association, plausible links and explanations exist. If cerebral MRI can be systematic in NF1 to detect asymptomatic gliomas, used protocols in neuroradiology do not usually include gradient echo sequences, the most sensitive test for CCM detection, leading possibly to failure to detect these vascular lesions. More reports having this combination and further investigations of NF1 families will certainly provide a better understanding of links between these 2 phakomatoses, as recently reported with “multiple meningiomas” phenotype associated with multiple CCMs in patients with CCM3 gene mutations or café-au-lait skin lesions in CCM1 mutation carriers. © 2015 Published by Elsevier B.V.
1. Introduction Neurofibromatosis type 1 (NF1), also called von Recklinghausen's disease, is an autosomal dominant multisystem genetic disorder affecting 1 in 3500 people and predisposing to tumour formation [1]. NF1 belongs to the neurocutaneous syndromes or phakomatoses, which also include Neurofibromatosis type 2, tuberous sclerosis complex, von Hippel–Lindau disease, and Cerebral Cavernous Malformations (CCMs). The NF1 diagnosis may be established on clinical data. Cardinal
⁎ Corresponding author at: Department of Neurology, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, France. Tel.: +33 1 4521 2618; fax: +33 1 4521 2853. E-mail address: [email protected] (C. Denier).
http://dx.doi.org/10.1016/j.jns.2015.02.023 0022-510X/© 2015 Published by Elsevier B.V.
features include pigmentation abnormalities — multiple café au lait patches, benign neurofibromas and iris hamartomas. Other common manifestations are learning disabilities, epilepsy and skeletal abnormalities (hypostature, scoliosis, osteoporosis, pseudoarthrosis and sphenoid wing dysplasia). The involved NF1 gene encodes neurofibromin, an inactivator of the proto-oncogene Ras. It acts as a tumour suppressor and participates in signalling pathways that regulate cell viability, proliferation and differentiation, which explains why NF1 patients are prone to develop benign and malignant tumours [1]. Indeed, in addition to multiple peripheral neurofibromas, NF1 predisposes to CNS tumours (mainly pilocytic astrocytomas located in the optic pathways), but also meningioma, anaplastic astrocytomas, glioblastomas or dysplastic neuroepithelial tumour [1]. Vascular abnormalities have been reported in association with NF1 and are increasingly recognized as an own feature of this disorder.
K. Rerat et al. / Journal of the Neurological Sciences 350 (2015) 98–100
We herein report a patient with clinically defined and genetically confirmed NF1 who presented multiple CCMs. 2. Case report A 47-year-old man presented with slowly progressive weakness in the legs and impaired bladder function. Physical examination revealed short stature, scoliosis, bilateral brisk deep tendon reflexes and extensor plantar reflex. He had numerous cutaneous neurofibromas and café au lait skin lesions satisfying the NIH diagnostic criteria for NF1 [1]. He did not have any cardiovascular risk factor. Spine MRI showed an intradural extramedullary tumour compressing the spinal cord which required neurosurgery. Following complete removal of the symptomatic tumour, histological study concluded that it was a neurofibroma. At follow-up visits, systematic cerebral MRI screening identified multiple asymptomatic CCM lesions (Fig. 1). One typical CCM lesion was located in the right temporal lobe associating MR mixed hyper- and hypointense signals surrounded by a rim of hypointense signal on T2 sequence (type II-CCM lesion according to the Zabramski classification [2]). Seven type IV-CCM lesions were observed throughout the remaining brain (hypointense signals only detected on gradient echo sequences). NF1 gene screening identified the c.902delA frameshift deleterious mutation in exon 7, while CCM gene screening was negative for CCM1, CCM2 and CCM3 mutations both in direct sequencing and QMPSF. There was no particular familial history. 3. Discussion CCMs (OMIM 116860) are vascular malformations histologically characterized by abnormally enlarged capillary cavities without affecting
99
brain parenchyma [2]. Their prevalence has been estimated to be close to 0.5%. Both sporadic and familial autosomal dominant forms have been identified; the latter form being characterized by the presence of multiple lesions whereas sporadic cases only present a single lesion. Three genes are involved in familial cases, namely CCM1/KRIT1, CCM2/ MGC4607, and CCM3/PDCD10, which encode intracellular adaptor proteins. The latter interacts with a range of signalling, cytoskeletal proteins, presumably accounting for their roles in a range of basic cellular processes including cell adhesion, polarity, apoptosis, and migration. Loss of function mutations in any one of these 3 genes lead to hereditary CCM. In “sporadic” cases with multiple CCM lesions, the genetic nature of the disease is most likely since CCM gene screening identifies a mutation in N 75% of the cases [2]. In our patient, CCM1, CCM2 and CCM3 gene screening was negative while a typical deleterious NF1 mutation was identified. The first question raised by the present report regards the pathological nature of these cerebral lesions. Indeed, we do not have histological data for these lesions. However, their typical MRI aspects and the association of one type II and multiple type IV lesions strongly suggest the CCM nature of these lesions [2]. Even if a fortuitous association between multiple CCMs and NF1 cannot be excluded, plausible links between CCM and NF1 pathogenesis exist. Multisystem vasculopathy is a significant complication of NF1 including aneurysm, pseudoaneurysm, arteriovenous malformations, vascular stenosis or occlusion [3,4]. They mostly involve aortic, renal, mesenteric and carotid–vertebral arteries. More recently, intracranial angiopathy is increasingly recognized as an own feature of NF1 [3,4]. NF1 cerebral vasculopathy includes Moya moya syndrome, cerebral aneurysm, internal carotid and cerebral artery stenosis or occlusion, clearly visible on routine MRI of the brain. These cerebrovascular
Fig. 1. Cervical and cerebral MRI: conventional and gradient echo sequences. Left panel: a./b. Cervical MRI showed multiple neurofibromas of the peripheral nerves and brachial plexus (arrows), numerous cutaneous neurofibromas (arrowheads) and scoliosis. Right panel: Upper 1., 2. and 3. Conventional T1-, T2-weighted and gradient echo sequences (T2*) imaging disclosed right temporal most usual and typical CCM type II-lesion, defined with mixed hyper- and hypointense signals surrounded by a rim of hypointense signal on T2 sequences, reflecting association of acute and chronic haemorrhage. Downer I., II., and III. Seven different asymptomatic hypointense signals were detected only on gradient echo sequences. They fulfilled criteria for type IV-CCM lesions. In this case, the association of type II and multiple type IV lesions strongly suggests the CCM nature of these lesions.
100
K. Rerat et al. / Journal of the Neurological Sciences 350 (2015) 98–100
abnormalities, mainly asymptomatic, have been estimated to be occurring in 2–5% of NF1 patients [3,4]. Their origin remains unclear. Histopathology analysis revealed intimal proliferation, thinning and fibrosis of media, and previous studies showed that reduced neurofibromin expression was associated with smooth muscle cell proliferation in blood vessels. Histologically confirmed acquired CCM de novo formation is known to occur following radiotherapy, in NF1 or not [5]. On the contrary and exceptionally, single intracranial cavernous angiomas have been reported in the absence of radiation exposure in patients with NF1 phenotype [6,7]. This rarity can be due to the absence of systematic gradient echo sequences in MRI screening protocol searching for asymptomatic gliomas in the optic pathway of NF1 individuals. Another well-known causative alteration shown to be closely related to NF-1 phenotype and the development of malignancies is the so called constitutional mismatch repair deficiency (CMMR-D) [7,11]. Genes such as the MLH1, MSH2, MSH6 and PMS2 play a crucial role in the machinery that contributes to genome integrity. Germline mutations in these genes lead to the early onset of haematological malignancies and Lynch syndrome-associated tumours such as colorectal cancer, endometrial carcinoma, and brain tumours/malformations and a phenotype that resembles NF-1. It has been speculated that the NF1-like clinical features in CMMR-D result from germline mosaicism arising early during embryonic development [11]. Extensive and systematic mutation analysis in other CMMR-D patients will be useful to better define the entire phenotype of these affections. 4. Conclusion In conclusion, we report a DNA-confirmed NF1 patient presenting multiple CCMs. Both neurocutaneous disorders occurring in this patient can be hazardous but CCM gene screening was negative, knowing that all NF1 and CCM genes play a role in cell proliferation. To explain the possible underestimation of CCM lesions in NF1, most MRI protocols in NF1 patients focused on T1- and T2-weighted sequences and Gadolinium-enhanced sequences, screening in particular on the optic pathways for tumours such as gliomas [8]. If MR neuroimaging modalities are valuable in the diagnosis and management of NF1, gradient echo sequences, the most sensitive test for CCM detection, do not belong to
these protocols, leading possibly to failure to detect CCM, especially type IV-CCM lesions. More reports and additional investigations of NF1 families, including gradient echo sequences in MRI protocols, will certainly provide better understanding of the link between these 2 phakomatoses, namely NF1 and CCM, as recently reported with “multiple meningiomas” phenotype associated with multiple CCMs in patients with mutations in the CCM3 gene [9] or associated café-au-lait skin lesions in patients with multiple CCM lesions due to a truncating CCM1/KRIT1 mutation [10]. Conflict of interest statement The authors have nothing to disclose. References [1] Ferner RE. Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective. Lancet Neurol 2007;6:340–51. [2] Labauge P, Denier C, Bergametti F, Tournier-Lasserve E. Genetics of cavernous angiomas. Lancet Neurol 2007;6:237–44. [3] Ghosh PS, Rothner AD, Emch TM, Friedman NR, Moodley M. Cerebral vasculopathy in children with neurofibromatosis type 1. J Child Neurol 2013;28:95–101. [4] Kaas B, Huisman TA, Tekes A, Bergner A, Blakeley JO, Jordan LC, et al. Spectrum and prevalence of vasculopathy in pediatric neurofibromatosis type 1. J Child Neurol 2013;28:561–9. [5] Van Calenbergh F, Demaerel P, Sciot R, van Loon J. Acquired cerebellar cavernous angioma following childhood radiotherapy in a patient with neurofibromatosis type 1. Acta Neurol Belg 2003;103:103–6. [6] Mitsuhashi T, Hashimoto R, Nagahama S, Nagata Y. Intrasellar cavernous angioma in neurofibromatosis. Hum Pathol 1991;22:623–4. [7] Furlanetti LL, Santos MV, Valera ET, Brassesco MS, de Oliveira RS. Metachronous occurrence of nonradiation-induced brain cavernous hemangioma and medulloblastoma in a child with neurofibromatosis type I phenotype. Pediatr Neurosci 2012;7:43–6. [8] Truhan AP, Filipek PA. Magnetic resonance imaging. Its role in the neuroradiologic evaluation of neurofibromatosis, tuberous sclerosis, and Sturge–Weber syndrome. Arch Dermatol 1993;129:219–26. [9] Riant F, Bergametti F, Fournier HD, Chapon F, Michalak-Provost S, Cecillon M, et al. CCM3 mutations are associated with early-onset cerebral hemorrhage and multiple meningiomas. Mol Syndromol 2013;4:165–72. [10] Musunuru K, Hillard VH, Murali R. Widespread central nervous system cavernous malformations associated with café-au-lait skin lesions. Case report. J Neurosurg 2003;99:412–5. [11] Wimmer K, Kratz C. Constitutional mismatch repair-deficiency syndrome. Haematologica 2010;95:699–701.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Occurrence of multiple Cerebral Cavernous Malformations in a patient with Neurofibromatosis type 1 K. Rerat a,b, F. Parker b, G. Nasser c, D. Vidaud d, F. Riant e,f, E. Tournier-Lasserve e,f, C. Denier a,⁎ a
Department of Neurology, Université Paris Sud, Faculté de Médecine Paris Sud, Hôpital de Bicêtre, Assistance Publique, Hôpitaux de Paris (AP-HP), France Department of Neurosurgery, Université Paris Sud, Faculté de Médecine Paris Sud, Hôpital de Bicêtre, Assistance Publique, Hôpitaux de Paris (AP-HP), France Department of NeuroRadiology, Université Paris Sud, Faculté de Médecine Paris Sud, Hôpital de Bicêtre, Assistance Publique, Hôpitaux de Paris (AP-HP), France d INSERM UMR745, Paris Descartes University, France e AP-HP, Service de Génétique, Hôpital Lariboisière, France f INSERM UMR 1161, Paris Diderot University, France b c
a r t i c l e
i n f o
Article history: Received 27 November 2014 Received in revised form 8 February 2015 Accepted 10 February 2015 Available online 18 February 2015 Keywords: Neurofibromatosis type 1 Cerebral Cavernous Malformations Cavernous angiomas Neurocutaneous syndromes Phakomatoses Cavernoma
a b s t r a c t Background: Neurofibromatosis 1 (NF1) belongs to the autosomal dominant neurocutaneous disorders' group, which mainly includes NF1 and NF2, tuberous sclerosis, von Hippel-Lindau disease and Cerebral Cavernous Malformations (CCMs). NF1 has a major impact on the nervous system, eye, skin, bone or cardiovascular system. Cerebrovascular lesions have been reported in NF1 including aneurysm, pseudoaneurysm, arteriovenous malformations, vascular stenosis or occlusion and Moya moya syndrome. Objective: To report a case of an NF1 patient with multiple CCMs. Observation: A 47-year-old man with café-au-lait skin lesions, countless cutaneous neurofibromas, short stature and scoliosis was admitted for progressive spinal cord compression due to histologically proven neurofibroma. Systematic cerebral MRI screening including gradient echo sequences showed multiple asymptomatic CCMs. Screening of CCM1, CCM2 and CCM3 genes was negative while a deleterious frameshift mutation was identified in NF1 gene. Conclusion: While single CCM can occur in NF1 patients following radiation exposure, they are only rarely reported in non-irradiated NF1 brain. Even if it could be a fortuitous association, plausible links and explanations exist. If cerebral MRI can be systematic in NF1 to detect asymptomatic gliomas, used protocols in neuroradiology do not usually include gradient echo sequences, the most sensitive test for CCM detection, leading possibly to failure to detect these vascular lesions. More reports having this combination and further investigations of NF1 families will certainly provide a better understanding of links between these 2 phakomatoses, as recently reported with “multiple meningiomas” phenotype associated with multiple CCMs in patients with CCM3 gene mutations or café-au-lait skin lesions in CCM1 mutation carriers. © 2015 Published by Elsevier B.V.
1. Introduction Neurofibromatosis type 1 (NF1), also called von Recklinghausen's disease, is an autosomal dominant multisystem genetic disorder affecting 1 in 3500 people and predisposing to tumour formation [1]. NF1 belongs to the neurocutaneous syndromes or phakomatoses, which also include Neurofibromatosis type 2, tuberous sclerosis complex, von Hippel–Lindau disease, and Cerebral Cavernous Malformations (CCMs). The NF1 diagnosis may be established on clinical data. Cardinal
⁎ Corresponding author at: Department of Neurology, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, France. Tel.: +33 1 4521 2618; fax: +33 1 4521 2853. E-mail address: [email protected] (C. Denier).
http://dx.doi.org/10.1016/j.jns.2015.02.023 0022-510X/© 2015 Published by Elsevier B.V.
features include pigmentation abnormalities — multiple café au lait patches, benign neurofibromas and iris hamartomas. Other common manifestations are learning disabilities, epilepsy and skeletal abnormalities (hypostature, scoliosis, osteoporosis, pseudoarthrosis and sphenoid wing dysplasia). The involved NF1 gene encodes neurofibromin, an inactivator of the proto-oncogene Ras. It acts as a tumour suppressor and participates in signalling pathways that regulate cell viability, proliferation and differentiation, which explains why NF1 patients are prone to develop benign and malignant tumours [1]. Indeed, in addition to multiple peripheral neurofibromas, NF1 predisposes to CNS tumours (mainly pilocytic astrocytomas located in the optic pathways), but also meningioma, anaplastic astrocytomas, glioblastomas or dysplastic neuroepithelial tumour [1]. Vascular abnormalities have been reported in association with NF1 and are increasingly recognized as an own feature of this disorder.
K. Rerat et al. / Journal of the Neurological Sciences 350 (2015) 98–100
We herein report a patient with clinically defined and genetically confirmed NF1 who presented multiple CCMs. 2. Case report A 47-year-old man presented with slowly progressive weakness in the legs and impaired bladder function. Physical examination revealed short stature, scoliosis, bilateral brisk deep tendon reflexes and extensor plantar reflex. He had numerous cutaneous neurofibromas and café au lait skin lesions satisfying the NIH diagnostic criteria for NF1 [1]. He did not have any cardiovascular risk factor. Spine MRI showed an intradural extramedullary tumour compressing the spinal cord which required neurosurgery. Following complete removal of the symptomatic tumour, histological study concluded that it was a neurofibroma. At follow-up visits, systematic cerebral MRI screening identified multiple asymptomatic CCM lesions (Fig. 1). One typical CCM lesion was located in the right temporal lobe associating MR mixed hyper- and hypointense signals surrounded by a rim of hypointense signal on T2 sequence (type II-CCM lesion according to the Zabramski classification [2]). Seven type IV-CCM lesions were observed throughout the remaining brain (hypointense signals only detected on gradient echo sequences). NF1 gene screening identified the c.902delA frameshift deleterious mutation in exon 7, while CCM gene screening was negative for CCM1, CCM2 and CCM3 mutations both in direct sequencing and QMPSF. There was no particular familial history. 3. Discussion CCMs (OMIM 116860) are vascular malformations histologically characterized by abnormally enlarged capillary cavities without affecting
99
brain parenchyma [2]. Their prevalence has been estimated to be close to 0.5%. Both sporadic and familial autosomal dominant forms have been identified; the latter form being characterized by the presence of multiple lesions whereas sporadic cases only present a single lesion. Three genes are involved in familial cases, namely CCM1/KRIT1, CCM2/ MGC4607, and CCM3/PDCD10, which encode intracellular adaptor proteins. The latter interacts with a range of signalling, cytoskeletal proteins, presumably accounting for their roles in a range of basic cellular processes including cell adhesion, polarity, apoptosis, and migration. Loss of function mutations in any one of these 3 genes lead to hereditary CCM. In “sporadic” cases with multiple CCM lesions, the genetic nature of the disease is most likely since CCM gene screening identifies a mutation in N 75% of the cases [2]. In our patient, CCM1, CCM2 and CCM3 gene screening was negative while a typical deleterious NF1 mutation was identified. The first question raised by the present report regards the pathological nature of these cerebral lesions. Indeed, we do not have histological data for these lesions. However, their typical MRI aspects and the association of one type II and multiple type IV lesions strongly suggest the CCM nature of these lesions [2]. Even if a fortuitous association between multiple CCMs and NF1 cannot be excluded, plausible links between CCM and NF1 pathogenesis exist. Multisystem vasculopathy is a significant complication of NF1 including aneurysm, pseudoaneurysm, arteriovenous malformations, vascular stenosis or occlusion [3,4]. They mostly involve aortic, renal, mesenteric and carotid–vertebral arteries. More recently, intracranial angiopathy is increasingly recognized as an own feature of NF1 [3,4]. NF1 cerebral vasculopathy includes Moya moya syndrome, cerebral aneurysm, internal carotid and cerebral artery stenosis or occlusion, clearly visible on routine MRI of the brain. These cerebrovascular
Fig. 1. Cervical and cerebral MRI: conventional and gradient echo sequences. Left panel: a./b. Cervical MRI showed multiple neurofibromas of the peripheral nerves and brachial plexus (arrows), numerous cutaneous neurofibromas (arrowheads) and scoliosis. Right panel: Upper 1., 2. and 3. Conventional T1-, T2-weighted and gradient echo sequences (T2*) imaging disclosed right temporal most usual and typical CCM type II-lesion, defined with mixed hyper- and hypointense signals surrounded by a rim of hypointense signal on T2 sequences, reflecting association of acute and chronic haemorrhage. Downer I., II., and III. Seven different asymptomatic hypointense signals were detected only on gradient echo sequences. They fulfilled criteria for type IV-CCM lesions. In this case, the association of type II and multiple type IV lesions strongly suggests the CCM nature of these lesions.
100
K. Rerat et al. / Journal of the Neurological Sciences 350 (2015) 98–100
abnormalities, mainly asymptomatic, have been estimated to be occurring in 2–5% of NF1 patients [3,4]. Their origin remains unclear. Histopathology analysis revealed intimal proliferation, thinning and fibrosis of media, and previous studies showed that reduced neurofibromin expression was associated with smooth muscle cell proliferation in blood vessels. Histologically confirmed acquired CCM de novo formation is known to occur following radiotherapy, in NF1 or not [5]. On the contrary and exceptionally, single intracranial cavernous angiomas have been reported in the absence of radiation exposure in patients with NF1 phenotype [6,7]. This rarity can be due to the absence of systematic gradient echo sequences in MRI screening protocol searching for asymptomatic gliomas in the optic pathway of NF1 individuals. Another well-known causative alteration shown to be closely related to NF-1 phenotype and the development of malignancies is the so called constitutional mismatch repair deficiency (CMMR-D) [7,11]. Genes such as the MLH1, MSH2, MSH6 and PMS2 play a crucial role in the machinery that contributes to genome integrity. Germline mutations in these genes lead to the early onset of haematological malignancies and Lynch syndrome-associated tumours such as colorectal cancer, endometrial carcinoma, and brain tumours/malformations and a phenotype that resembles NF-1. It has been speculated that the NF1-like clinical features in CMMR-D result from germline mosaicism arising early during embryonic development [11]. Extensive and systematic mutation analysis in other CMMR-D patients will be useful to better define the entire phenotype of these affections. 4. Conclusion In conclusion, we report a DNA-confirmed NF1 patient presenting multiple CCMs. Both neurocutaneous disorders occurring in this patient can be hazardous but CCM gene screening was negative, knowing that all NF1 and CCM genes play a role in cell proliferation. To explain the possible underestimation of CCM lesions in NF1, most MRI protocols in NF1 patients focused on T1- and T2-weighted sequences and Gadolinium-enhanced sequences, screening in particular on the optic pathways for tumours such as gliomas [8]. If MR neuroimaging modalities are valuable in the diagnosis and management of NF1, gradient echo sequences, the most sensitive test for CCM detection, do not belong to
these protocols, leading possibly to failure to detect CCM, especially type IV-CCM lesions. More reports and additional investigations of NF1 families, including gradient echo sequences in MRI protocols, will certainly provide better understanding of the link between these 2 phakomatoses, namely NF1 and CCM, as recently reported with “multiple meningiomas” phenotype associated with multiple CCMs in patients with mutations in the CCM3 gene [9] or associated café-au-lait skin lesions in patients with multiple CCM lesions due to a truncating CCM1/KRIT1 mutation [10]. Conflict of interest statement The authors have nothing to disclose. References [1] Ferner RE. Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective. Lancet Neurol 2007;6:340–51. [2] Labauge P, Denier C, Bergametti F, Tournier-Lasserve E. Genetics of cavernous angiomas. Lancet Neurol 2007;6:237–44. [3] Ghosh PS, Rothner AD, Emch TM, Friedman NR, Moodley M. Cerebral vasculopathy in children with neurofibromatosis type 1. J Child Neurol 2013;28:95–101. [4] Kaas B, Huisman TA, Tekes A, Bergner A, Blakeley JO, Jordan LC, et al. Spectrum and prevalence of vasculopathy in pediatric neurofibromatosis type 1. J Child Neurol 2013;28:561–9. [5] Van Calenbergh F, Demaerel P, Sciot R, van Loon J. Acquired cerebellar cavernous angioma following childhood radiotherapy in a patient with neurofibromatosis type 1. Acta Neurol Belg 2003;103:103–6. [6] Mitsuhashi T, Hashimoto R, Nagahama S, Nagata Y. Intrasellar cavernous angioma in neurofibromatosis. Hum Pathol 1991;22:623–4. [7] Furlanetti LL, Santos MV, Valera ET, Brassesco MS, de Oliveira RS. Metachronous occurrence of nonradiation-induced brain cavernous hemangioma and medulloblastoma in a child with neurofibromatosis type I phenotype. Pediatr Neurosci 2012;7:43–6. [8] Truhan AP, Filipek PA. Magnetic resonance imaging. Its role in the neuroradiologic evaluation of neurofibromatosis, tuberous sclerosis, and Sturge–Weber syndrome. Arch Dermatol 1993;129:219–26. [9] Riant F, Bergametti F, Fournier HD, Chapon F, Michalak-Provost S, Cecillon M, et al. CCM3 mutations are associated with early-onset cerebral hemorrhage and multiple meningiomas. Mol Syndromol 2013;4:165–72. [10] Musunuru K, Hillard VH, Murali R. Widespread central nervous system cavernous malformations associated with café-au-lait skin lesions. Case report. J Neurosurg 2003;99:412–5. [11] Wimmer K, Kratz C. Constitutional mismatch repair-deficiency syndrome. Haematologica 2010;95:699–701.
