Spinal Neurofibromatosis with Central Nervous System Involvement in a Set of Twin Girls and a Boy: Further Expansion of the Phenotype
12 December 2011
18 February 2013
18 June 2013 (online)
Background Familial spinal neurofibromatosis is a form of neurofibromatosis 1 (NF1), consisting of extensive, symmetrical, histologically proven, multiple neurofibromas of the spinal roots at every level and of all major peripheral nerves sometimes associated with typical NF1 stigmata; most cases underlie NF1 gene mutations.
Objectives The objectives of this study are (1) to report the findings in a set of 16-year-old monozygotic twin girls and a 14-year-old boy and (2) to review the existing literature.
Methods and Results In this article, we report the cases of three children who (1) had manifested mildly different symptomatic neuropathy (twins, aged 4 years; and a boy, aged 9 years) associated with massive, symmetrical neurofibromas; (2) had few café-au-lait spots with irregular margins and pale brown pigmentation; (3) were presented with, at brain magnetic resonance imaging (MRI), bilateral, NF1–like high-signal abnormalities in the basal ganglia; (4) yielded missense NF1 gene mutations in exon 39; and (5) had unaffected parents with negative NF1 genetic testing as well as discuss 12 families and 20 sporadic and 5 additional cases that presented spinal neurofibromatosis within classical NF1 families (53 cases) that were reported in the literature.
Conclusions This article presents the first report on (1) spinal neurofibromatosis in a set of affected monozygotic twins; (2) the earliest onset of the disease; and (3) the occurrence of high signal lesions in the brain at MRI.
- 1 Pulst SM, Riccardi VM, Fain P, Korenberg JR. Familial spinal neurofibromatosis: clinical and DNA linkage analysis. Neurology 1991; 41 (12) 1923-1927
- 2 Poyhonen M, Leisti EL, Kytölä S, Leisti J. Hereditary spinal neurofibromatosis: a rare form of NF1?. J Med Genet 1997; 34 (3) 184-187
- 3 Ars E, Kruyer H, Gaona A , et al. A clinical variant of neurofibromatosis type 1: familial spinal neurofibromatosis with a frameshift mutation in the NF1 gene. Am J Hum Genet 1998; 62 (4) 834-841
- 4 Kaufmann D, Müller R, Bartelt B , et al. Spinal neurofibromatosis without café-au-lait macules in two families with null mutations of the NF1 gene. Am J Hum Genet 2001; 69 (6) 1395-1400
- 5 Wimmer K, Mühlbauer M, Eckart M , et al. A patient severely affected by spinal neurofibromas carries a recurrent splice site mutation in the NF1 gene. Eur J Hum Genet 2002; 10 (5) 334-338
- 6 Messiaen L, Riccardi V, Peltonen J , et al. Independent NF1 mutations in two large families with spinal neurofibromatosis. J Med Genet 2003; 40 (2) 122-126
- 7 Pascual-Castroviejo I, Pascual-Pascual SI, Velazquez-Fragua R, Botella P, Viaño J. Familial spinal neurofibromatosis. Neuropediatrics 2007; 38 (2) 105-108
- 8 Upadhyaya M, Spurlock G, Kluwe L , et al. The spectrum of somatic and germline NF1 mutations in NF1 patients with spinal neurofibromas. Neurogenetics 2009; 10 (3) 251-263
- 9 Tsuji M, Harada S, Ueno Y, Osaka N. Neurological pictures. Familial spinal neurofibromatosis: three generations of identical level symptomatic tumours. J Neurol Neurosurg Psychiatry 2010; 81 (12) 1382
- 10 Pascual-Castroviejo I, Pascual-Pascual SI, Viaño J, Velazquez-Fragua R, López-Gutierrez JC. Bilateral spinal neurofibromas in patients with neurofibromatosis 1. Brain Dev 2012; 34 (7) 563-569
- 11 Pizzuti A, Bottillo I, Inzana F , et al. Familial spinal neurofibromatosis due to a multiexonic NF1 gene deletion. Neurogenetics 2011; 12 (3) 233-240
- 12 Núñez-Farías AC, Borzutzky A, Morales PS, Zunino R, del Villar S. Severe spinal neurofibromatosis in a child. J Pediatr 2012; 161 (2) 368 , e1
- 13 Ruggieri M, Upadhyaya M, Di Rocco C, Gabriele A, Pascual-Castroviejo I. Neurofibromatosis type 1 and related disorders. In: Ruggieri M, Pascual-Castroviejo I, Di Rocco C, , eds. Neurocutaneous Disorders: Phakomatosis and Hamartoneoplastic Syndromes. Wien/New York: Springer-Verlag; 2008: 51-151
- 14 Gabriele AL, Ruggieri M, Patitucci A , et al. A novel NF1 gene mutation in an Italian family with neurofibromatosis type 1. Childs Nerv Syst 2011; 27 (4) 635-638
- 15 Blakley P, Louis DN, Short MP, MacCollin M. A clinical study of patients with multiple isolated neurofibromas. J Med Genet 2001; 38 (7) 485-488
- 16 Ruggieri M, Huson SM. The clinical and diagnostic implications of mosaicism in the neurofibromatoses. Neurology 2001; 56 (11) 1433-1443
- 17 Sestini R, Bacci C, Provenzano A, Genuardi M, Papi L. Evidence of a four-hit mechanism involving SMARCB1 and NF2 in schwannomatosis-associated schwannomas. Hum Mutat 2008; 29 (2) 227-231
- 18 Ruggieri M, Iannetti P, Polizzi A , et al. Earliest clinical manifestations and natural history of neurofibromatosis type 2 (NF2) in childhood: a study of 24 patients. Neuropediatrics 2005; 36 (1) 21-34
- 19 Plotkin SR, Bredella MA, Cai W , et al. Quantitative assessment of whole-body tumor burden in adult patients with neurofibromatosis. PLoS ONE 2012; 7 (4) e35711
- 20 Sbidian E, Wolkenstein P, Valeyrie-Allanore L , et al; Members of NF France Network. NF-1Score: a prediction score for internal neurofibromas in neurofibromatosis-1. J Invest Dermatol 2010; 130 (9) 2173-2178
- 21 Vezina G, Barkovich AJ. The phakomatoses. In: Barkovich AJ, Raybaud C, , eds. Pediatric Neuroimaging. 5th ed. Philadelphia, PA: Wolters Kluwer/Lippincott Williams and Wilkins; 2012: 569-636
- 22 Smith MJ, Wallace AJ, Bowers NL , et al. Frequency of SMARCB1 mutations in familial and sporadic schwannomatosis. Neurogenetics 2012; 13 (2) 141-145
- 23 Richetta A, Giustini S, Recupero SM , et al. Lisch nodules of the iris in neurofibromatosis type 1. J Eur Acad Dermatol Venereol 2004; 18 (3) 342-344