Correspondence
A multidisciplinary approach in neurofibromatosis 1 We read the Review on neurofibromatosis type 1 (NF1) by Angela Hirbe and David Gutmann1 with great interest. Although Hirbe and Gutmann precisely described the genetic, phenotypic, and skin features, their focus is on the less frequent clinical manifestations including dysplastic abnormalities of the central and peripheral nervous system, changes to musculoskeletal and respiratory systems, and the occurrence of CNS and non-CNS tumours. Cardiac and peripheral vascular disorders are also possible clinical complications in NF1 that require specific discussion.2 Our experience shows that vascular complications in NF1 can occur in different sites and can evolve rapidly, with patients developing new aneurysms, even after endovascular treatment. Cardiovascular abnormalities are often underestimated because a diagnosis is usually made only in patients with specific clinical manifestations. Echocardiograph data suggest that up to 27% of patients with NF1 have cardiac involvement, with a half of patients having pulmonary artery stenosis.3 NF1-related vasculopathy includes renal and cerebral artery stenosis, aortic coarctation, and arteriovenous malformations. The pathogenesis, clinical features, and natural history of these anomalies remain poorly understood; however, impaired NF1 gene function in vascular endothelial cells has been shown to increase proliferation and growth.1–3 Vasculopathy usually affects the arterial system, leading to cerebrovascular disease (eg, narrowed or ectatic blood vessels, vascular stenosis, aneurysm, or moyamoya disease) or renal artery stenosis. Stenotic lesions are the most common and are caused mostly by intimal proliferation with resulting www.thelancet.com/neurology Vol 14 January 2015
luminal obstruction; the renal artery is the most frequent site involved, and renovascular hypertension is the most common clinical presentation.4 Investigators have noted intimal thickening, thinning of the media, and parietal dilatation in small vessels of patients with NF1.5,6 Many other vessels such as the aorta, and intercostal, subclavian, brachial, radial, and vertebral arteries can be affected by aneurysmal dilatations.4,6–8 Lumbar arteries are rarely involved, with only one case described.9 Patients with NF1 can have aneurysms, but the synchronous involvement of two different circulatory regions is not yet known.8 However, the real incidence of these abnormalities is indeed unknown because many lesions are undetected. Traditional surgery with arterial clipping and aneurysmal excision is the only available option for treatment; in patients with NF1, complications are of major concern because of the fragility of the dysplastic vessels. Endovascular treatments, such as coil transarterial embolisation or percutaneous stentgraft placement, are sometimes considered preferable when it is mandatory to maintain an efficient blood flow in the regions perfused by the treated vessel; these are less invasive and have low intra-operative and post-operative mortality.10 Clinicians must be aware of the diverse clinical features, particularly with vascular complication and recurrence, of NF1. Prompt diagnosis is needed to provide optimum care, and serial diagnostic procedures are needed to increase awareness, to avoid early and late adverse events, and to prevent deleterious outcomes. We declare no competing interests.
*Alberto Palazzuoli, Marco Pellegrini, Gaetano Ruocco, Ranuccio Nuti [email protected] Department of Medical, Surgical, and Neuro Sciences, Internal Medicine Unit, Cardiology Section, Le Scotte Hospital, Siena, Italy
1
2
3
4
5
6
7
8
9
10
Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol 2014; 13: 834–43. Brasfield RD, Das Gupta TK. Von Recklinghausen’s disease: a clinicopathological study. Ann Surg 1972; 175: 86–104. Lin AE, Birch P, Korf BR, et al. Cardiovascular malformations and other cardiovascular abnormalities in Neurofibromatosis type I. Am J Med Genet 2000; 95: 108–17. Greene JF Jr, Fitzwater JE, Burgess J. Arterial lesions associated with neurofibromatosis. Am J Clin Pathol 1974; 62: 481–87. Oderich GS, Sullivan TM, Bower TC, et al. Vascular abnormalities in patients with neurofibromatosis syndrome type I: clinical spectrum, management, and results. J Vasc Surg 2007; 46: 475–84. Tatebe S, Asami F, Shinohara H, Okamoto T, Kuraoka S. Ruptured aneurysm of the subclavian artery in a patient with von Recklinghausen’s disease. Circ J 2005; 69: 503–06. Matsumoto I, Ohta Y, Tsunezuka Y, Tamura M, Oda M, Watanabe G. Treatment for Intercostal Arterial Aneurysm in Neurofibromatosis Type 1. Asian Cardiovasc Thorac Ann 2007; 15: 16–19. Schievink WI, Piepgras DG. Cervical vertebral artery aneurysms and arteriovenous fistulae in neurofibromatosis type 1: case reports. Neurosurgery 1991; 29: 760–65. Shimizu Y, Tanaka T, Nakae A, et al. A case report of spontaneous rupture of bilateral lumbar artery in a patient with von Recklinghausen disease. Nihon Geka Gakkai Zasshi 1993; 94: 420–43. Kim SJ, Kim CW, Kim S, et al. Endovascular treatment of a ruptured internal thoracic artery pseudoaneurysm presenting as a massive hemothorax in a patient with type I neurofibromatosis. Cardiovasc Intervent Radiol 2005; 28: 818–21.
We read with great interest the Review about neurofibromatosis type 1 (NF1) by Angela Hirbe and David Gutmann.1 Although the Review has much neurooncological detail, we would like to make some comments about the outlined diagnostic approach, on the basis of our clinical experience. The diagnostic criteria for NF1 were drawn up in 1988 at the National Institute of Health Consensus Conference.2 Since then, understanding of the disease has improved. Over the past 26 years, the gene for NF1 has been discovered, observations have been made of further clinical features such as choroidal hamartomas, unidentified bright objects, anaemic nevi, glomus tumours, and juvenile xanthogranulomas,3–5 and histological and molecular assessments of freckles have revealed that they do not differ 29
Correspondence
from café-au-lait macules and, therefore, should not be considered as a separate criterion. We have recently highlighted the need to revise the classic clinical criteria to help clinicians to make an early diagnosis and benefit patient care, especially during childhood when clinical signs might only be partially seen.2 Unlike some of the classic criteria, which occur during late childhood (eg, Lisch nodules) or adolescence (eg, neurofibromas), all of the recently reported signs (other than glomus tumours) can be measured early, although the inclusion of genetic testing might be a matter for future discussion. Furthermore, several studies have shown that the established diagnostic criteria are not sensitive enough; some features are not present in infancy, thus leading to a delayed diagnosis with clinical and psychological implications for the patients and their families.2 Given the need for improved knowledge and a multidisciplinary approach to NF1 shown by Hirbe and Gutmann,1 we believe that it is time for a new consensus conference where clinicians and molecular biologists with experience in NF1 can draw up a new list of age-related criteria that would allow for earlier diagnosis, better patient care, and the development of new targeted treatments. We declare no competing interests.
Donatella Milani, Lidia Pezzani, Gianluca Tadini, Francesca Menni, *Susanna Esposito [email protected] Pediatric Highly Intensive Care Unit (DM, LP, GT, FM, SE) and Unit of Dermatology (GT), Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan 20122, Italy 1
2
3
30
Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol 2014; 13: 834–43. Tadini G, Milani D, Menni F, Pezzani L, Sabatini C, Esposito S. Is it time to change the neurofibromatosis 1 diagnostic criteria? Eur J Intern Med 2014; 25: 506–10. Viola F, Villani E, Natacci F, et al. Choroidal abnormalities detected by near-infrared reflectance imaging as a new diagnostic criterion for neurofibromatosis 1. Ophthalmology 2012; 119: 369–75.
4
5
DeBella K, Poskitt K, Szudek J, Friedman JM. Use of “unidentified bright objects” on MRI for diagnosis of neurofibromatosis 1 in children. Neurology 2000; 54: 1646–50. Tadini G, Brena M, Pezzani L, et al. Anemic nevus in neurofibromatosis type 1. Dermatology 2013; 226: 115–18.
Authors’ reply We thank Alberto Palazzouli and colleagues for their comments on our Review on the management of patients with neurofibromatosis type 1 (NF1).1 Although our paper mainly focused on nervous system manifestations, people with NF1 are also prone to the development of renovascular, cardiovascular, and cerebrovascular abnormalities.2–4 As mentioned by Palazzuoli and colleagues and as outlined in the 2000 National Neurofibromatosis Foundation (now Children’s Tumor Foundation) NF1 Cardiovascular Task Force summary,5 renal and cerebral artery stenosis, pulmonary hypertension, aortic coarctation, and arteriovenous malformations sometimes occur in NF1. Although NF1-specific treatments have not yet emerged for these clinical problems, there has been intense laboratory research specifically designed to gain crucial insights into the molecular and cellular processes that underlie these vascular abnormalities. The NF1 protein, neurofibromin, is robustly expressed in endothelial cells that line both intracranial and extracranial vessels, cardiac myocytes, and smooth muscle cells,6,7 where it functions as a negative regulator of cell growth. Neurofibromin is also expressed in marrow-derived monocytes and circulating monocytes, which are important cells in the regulation of vascular homeostasis.8 Neurofibromin controls endothelial, cardiac muscle, vascular smooth muscle cell, and myeloid cell growth through inhibition of ras protein activity.9–11 Based on these observations, increased neointima formation following vascular injury can be
corrected in mouse models with either ras inhibitors or the multiple kinase inhibitor imatinib.12 These preclinical molecular data on the mechanisms for neurofibromin function in the cardiovascular system, combined with robust small-animal models of NF1-associated congenital heart defects and vasculopathy, firmly establish the foundations for targeted drug discovery, preclinical validation, and future translation to clinical trials in children and adults with NF1. We also appreciate the comments from Donatella Milani and colleagues about the use of the diagnostic criteria for neurofibromatosis type 1 (NF1), originally formulated by the National Institutes of Health (NIH) at their Neurofibromatosis Consensus Development Conference.13 Although the main objective of the conference was to create a set of standards to diagnose NF1, it also aimed to identify families affected by NF1 so that investigators could positionally clone the NF1 gene. In the past 25 years since the identification of NF1, great progress has been made in our understanding of the molecular and cellular outcomes of disrupted NF1 in the distinct cell types relevant to the many clinical features of NF1. Likewise, investigators have begun to critically examine and expand the range of clinical abnormalities associated with NF1, and have selectively started to incorporate accurate NF1 genetic testing into clinical practice. However, despite these advances, we argue that it is premature to discard the established diagnostic criteria in the absence of clinically-validated evidence. Since the diagnosis of NF1 in a young child without an affected first-degree relative needs caféau-lait macules to be coupled with another feature,14 most children with only café-au-lait macules will not be given a formal diagnosis of NF1 for several years, until skinfold freckling, Lisch nodules, or neurofibromas are noted. As such, although 30% of www.thelancet.com/neurology Vol 14 January 2015
A multidisciplinary approach in neurofibromatosis 1 We read the Review on neurofibromatosis type 1 (NF1) by Angela Hirbe and David Gutmann1 with great interest. Although Hirbe and Gutmann precisely described the genetic, phenotypic, and skin features, their focus is on the less frequent clinical manifestations including dysplastic abnormalities of the central and peripheral nervous system, changes to musculoskeletal and respiratory systems, and the occurrence of CNS and non-CNS tumours. Cardiac and peripheral vascular disorders are also possible clinical complications in NF1 that require specific discussion.2 Our experience shows that vascular complications in NF1 can occur in different sites and can evolve rapidly, with patients developing new aneurysms, even after endovascular treatment. Cardiovascular abnormalities are often underestimated because a diagnosis is usually made only in patients with specific clinical manifestations. Echocardiograph data suggest that up to 27% of patients with NF1 have cardiac involvement, with a half of patients having pulmonary artery stenosis.3 NF1-related vasculopathy includes renal and cerebral artery stenosis, aortic coarctation, and arteriovenous malformations. The pathogenesis, clinical features, and natural history of these anomalies remain poorly understood; however, impaired NF1 gene function in vascular endothelial cells has been shown to increase proliferation and growth.1–3 Vasculopathy usually affects the arterial system, leading to cerebrovascular disease (eg, narrowed or ectatic blood vessels, vascular stenosis, aneurysm, or moyamoya disease) or renal artery stenosis. Stenotic lesions are the most common and are caused mostly by intimal proliferation with resulting www.thelancet.com/neurology Vol 14 January 2015
luminal obstruction; the renal artery is the most frequent site involved, and renovascular hypertension is the most common clinical presentation.4 Investigators have noted intimal thickening, thinning of the media, and parietal dilatation in small vessels of patients with NF1.5,6 Many other vessels such as the aorta, and intercostal, subclavian, brachial, radial, and vertebral arteries can be affected by aneurysmal dilatations.4,6–8 Lumbar arteries are rarely involved, with only one case described.9 Patients with NF1 can have aneurysms, but the synchronous involvement of two different circulatory regions is not yet known.8 However, the real incidence of these abnormalities is indeed unknown because many lesions are undetected. Traditional surgery with arterial clipping and aneurysmal excision is the only available option for treatment; in patients with NF1, complications are of major concern because of the fragility of the dysplastic vessels. Endovascular treatments, such as coil transarterial embolisation or percutaneous stentgraft placement, are sometimes considered preferable when it is mandatory to maintain an efficient blood flow in the regions perfused by the treated vessel; these are less invasive and have low intra-operative and post-operative mortality.10 Clinicians must be aware of the diverse clinical features, particularly with vascular complication and recurrence, of NF1. Prompt diagnosis is needed to provide optimum care, and serial diagnostic procedures are needed to increase awareness, to avoid early and late adverse events, and to prevent deleterious outcomes. We declare no competing interests.
*Alberto Palazzuoli, Marco Pellegrini, Gaetano Ruocco, Ranuccio Nuti [email protected] Department of Medical, Surgical, and Neuro Sciences, Internal Medicine Unit, Cardiology Section, Le Scotte Hospital, Siena, Italy
1
2
3
4
5
6
7
8
9
10
Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol 2014; 13: 834–43. Brasfield RD, Das Gupta TK. Von Recklinghausen’s disease: a clinicopathological study. Ann Surg 1972; 175: 86–104. Lin AE, Birch P, Korf BR, et al. Cardiovascular malformations and other cardiovascular abnormalities in Neurofibromatosis type I. Am J Med Genet 2000; 95: 108–17. Greene JF Jr, Fitzwater JE, Burgess J. Arterial lesions associated with neurofibromatosis. Am J Clin Pathol 1974; 62: 481–87. Oderich GS, Sullivan TM, Bower TC, et al. Vascular abnormalities in patients with neurofibromatosis syndrome type I: clinical spectrum, management, and results. J Vasc Surg 2007; 46: 475–84. Tatebe S, Asami F, Shinohara H, Okamoto T, Kuraoka S. Ruptured aneurysm of the subclavian artery in a patient with von Recklinghausen’s disease. Circ J 2005; 69: 503–06. Matsumoto I, Ohta Y, Tsunezuka Y, Tamura M, Oda M, Watanabe G. Treatment for Intercostal Arterial Aneurysm in Neurofibromatosis Type 1. Asian Cardiovasc Thorac Ann 2007; 15: 16–19. Schievink WI, Piepgras DG. Cervical vertebral artery aneurysms and arteriovenous fistulae in neurofibromatosis type 1: case reports. Neurosurgery 1991; 29: 760–65. Shimizu Y, Tanaka T, Nakae A, et al. A case report of spontaneous rupture of bilateral lumbar artery in a patient with von Recklinghausen disease. Nihon Geka Gakkai Zasshi 1993; 94: 420–43. Kim SJ, Kim CW, Kim S, et al. Endovascular treatment of a ruptured internal thoracic artery pseudoaneurysm presenting as a massive hemothorax in a patient with type I neurofibromatosis. Cardiovasc Intervent Radiol 2005; 28: 818–21.
We read with great interest the Review about neurofibromatosis type 1 (NF1) by Angela Hirbe and David Gutmann.1 Although the Review has much neurooncological detail, we would like to make some comments about the outlined diagnostic approach, on the basis of our clinical experience. The diagnostic criteria for NF1 were drawn up in 1988 at the National Institute of Health Consensus Conference.2 Since then, understanding of the disease has improved. Over the past 26 years, the gene for NF1 has been discovered, observations have been made of further clinical features such as choroidal hamartomas, unidentified bright objects, anaemic nevi, glomus tumours, and juvenile xanthogranulomas,3–5 and histological and molecular assessments of freckles have revealed that they do not differ 29
Correspondence
from café-au-lait macules and, therefore, should not be considered as a separate criterion. We have recently highlighted the need to revise the classic clinical criteria to help clinicians to make an early diagnosis and benefit patient care, especially during childhood when clinical signs might only be partially seen.2 Unlike some of the classic criteria, which occur during late childhood (eg, Lisch nodules) or adolescence (eg, neurofibromas), all of the recently reported signs (other than glomus tumours) can be measured early, although the inclusion of genetic testing might be a matter for future discussion. Furthermore, several studies have shown that the established diagnostic criteria are not sensitive enough; some features are not present in infancy, thus leading to a delayed diagnosis with clinical and psychological implications for the patients and their families.2 Given the need for improved knowledge and a multidisciplinary approach to NF1 shown by Hirbe and Gutmann,1 we believe that it is time for a new consensus conference where clinicians and molecular biologists with experience in NF1 can draw up a new list of age-related criteria that would allow for earlier diagnosis, better patient care, and the development of new targeted treatments. We declare no competing interests.
Donatella Milani, Lidia Pezzani, Gianluca Tadini, Francesca Menni, *Susanna Esposito [email protected] Pediatric Highly Intensive Care Unit (DM, LP, GT, FM, SE) and Unit of Dermatology (GT), Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan 20122, Italy 1
2
3
30
Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol 2014; 13: 834–43. Tadini G, Milani D, Menni F, Pezzani L, Sabatini C, Esposito S. Is it time to change the neurofibromatosis 1 diagnostic criteria? Eur J Intern Med 2014; 25: 506–10. Viola F, Villani E, Natacci F, et al. Choroidal abnormalities detected by near-infrared reflectance imaging as a new diagnostic criterion for neurofibromatosis 1. Ophthalmology 2012; 119: 369–75.
4
5
DeBella K, Poskitt K, Szudek J, Friedman JM. Use of “unidentified bright objects” on MRI for diagnosis of neurofibromatosis 1 in children. Neurology 2000; 54: 1646–50. Tadini G, Brena M, Pezzani L, et al. Anemic nevus in neurofibromatosis type 1. Dermatology 2013; 226: 115–18.
Authors’ reply We thank Alberto Palazzouli and colleagues for their comments on our Review on the management of patients with neurofibromatosis type 1 (NF1).1 Although our paper mainly focused on nervous system manifestations, people with NF1 are also prone to the development of renovascular, cardiovascular, and cerebrovascular abnormalities.2–4 As mentioned by Palazzuoli and colleagues and as outlined in the 2000 National Neurofibromatosis Foundation (now Children’s Tumor Foundation) NF1 Cardiovascular Task Force summary,5 renal and cerebral artery stenosis, pulmonary hypertension, aortic coarctation, and arteriovenous malformations sometimes occur in NF1. Although NF1-specific treatments have not yet emerged for these clinical problems, there has been intense laboratory research specifically designed to gain crucial insights into the molecular and cellular processes that underlie these vascular abnormalities. The NF1 protein, neurofibromin, is robustly expressed in endothelial cells that line both intracranial and extracranial vessels, cardiac myocytes, and smooth muscle cells,6,7 where it functions as a negative regulator of cell growth. Neurofibromin is also expressed in marrow-derived monocytes and circulating monocytes, which are important cells in the regulation of vascular homeostasis.8 Neurofibromin controls endothelial, cardiac muscle, vascular smooth muscle cell, and myeloid cell growth through inhibition of ras protein activity.9–11 Based on these observations, increased neointima formation following vascular injury can be
corrected in mouse models with either ras inhibitors or the multiple kinase inhibitor imatinib.12 These preclinical molecular data on the mechanisms for neurofibromin function in the cardiovascular system, combined with robust small-animal models of NF1-associated congenital heart defects and vasculopathy, firmly establish the foundations for targeted drug discovery, preclinical validation, and future translation to clinical trials in children and adults with NF1. We also appreciate the comments from Donatella Milani and colleagues about the use of the diagnostic criteria for neurofibromatosis type 1 (NF1), originally formulated by the National Institutes of Health (NIH) at their Neurofibromatosis Consensus Development Conference.13 Although the main objective of the conference was to create a set of standards to diagnose NF1, it also aimed to identify families affected by NF1 so that investigators could positionally clone the NF1 gene. In the past 25 years since the identification of NF1, great progress has been made in our understanding of the molecular and cellular outcomes of disrupted NF1 in the distinct cell types relevant to the many clinical features of NF1. Likewise, investigators have begun to critically examine and expand the range of clinical abnormalities associated with NF1, and have selectively started to incorporate accurate NF1 genetic testing into clinical practice. However, despite these advances, we argue that it is premature to discard the established diagnostic criteria in the absence of clinically-validated evidence. Since the diagnosis of NF1 in a young child without an affected first-degree relative needs caféau-lait macules to be coupled with another feature,14 most children with only café-au-lait macules will not be given a formal diagnosis of NF1 for several years, until skinfold freckling, Lisch nodules, or neurofibromas are noted. As such, although 30% of www.thelancet.com/neurology Vol 14 January 2015
