Familial spinal neurofibromatosis: three generations of identical level symptomatic tumours

Abstract

A 62-year-old man with neurofibromatosis type 1 presented with slowly progressive weakness in the right leg and impaired bladder function. Physical examination revealed bilateral brisk deep tendon reflexes and extensor plantar reflex. He had dozens of café au lait spots and cutaneous neurofibromas. His 12-year-old granddaughter presented with toe walking and weakness in the right hand. She showed several (>6) café au lait spots and axillary freckling, but no cutaneous neurofibromas or Lisch nodules. Physical examination of his asymptomatic 39-year-old son also revealed brisk deep tendon reflexes. He had six café au lait spots but no other cutaneous signs of neurofibromatosis. An ocular examination revealed Lisch nodules. All of them satisfied the NIH diagnostic criteria for neurofibromatosis type 1. In all three family members, spine MRI showed an intradural extramedullary tumour compressing the spinal cord at C1eC2 (figure 1), which necessitated neurosurgical removal. Upon histological evaluation, the tumours were found to be neurofibroma. In the proband, MRI of the cervical spine showed this single tumour alone, and other spinal regions were not examined. In his granddaughter and son, a spine MRI revealed multiple paraspinal tumours on both sides at almost all levels of the vertebral column from C1 to the sacrum. At follow-up visits, the proband's motor impairment persisted, his son remained asymptomatic, and his granddaughter had slight neurological sequelae.Familial spinal neurofibromatosis is a variant of neurofibromatosis type 1. 1 Multiple symmetrical tumours on the nerve roots with minimal cutaneous signs of neurofibromatosis type 1 are considered typical for this entity. 1 To our knowledge, the granddaughter represents the youngest person afflicted by familial spinal neurofibromatosis with symptomatic spinal tumour. 1 2 REFERENCES 1. Upadhyaya M, Spurlock G, Kluwe L, et al. The spectrum of somatic and germline NF1 mutations in NF1 patients with spinal neurofibromas. Neurogenetics 2009;10:251e63. 2. Kluwe L, Tatagiba M, Fünsterer C, et al. NF1 mutations and clinical spectrum in patients with spinal neurofibromas. J Med Genet 2003;40:368e71.Figure 1 T2-weighted sagittal MR images of the cervical spine show an intradural extramedullary tumour (arrowheads) compressing the spinal cord at C1eC2 in each of three family members across three generations.

The natural history of spinal neurofibromatosis: a critical review of clinical and genetic features

“…Three out of the original 98 patients, labelled as having SNF , were excluded from present analysis as they had involvement of only one spinal root (patients 406, 894 and 548) .…”

“…Relaxing the application of strict criteria requiring neurofibromas of all spinal nerves generated the second cohort, and we identified 32 patients with multiple neurofibromas in multiple (but not all) spinal roots, which we named MNFSR (Table S3). Three individuals, in this cohort had massive involvement of almost all spinal roots (Table S3) and six other individuals, with MNFSR, belonged to four single‐generation or multi‐generation families with SNF (Tables S1 and S2) : such phenotypic variability must be taken into consideration and is likely part of the phenotypic spectrum of SNF. Individuals with MNFSR, unless part of a family with affected members having SNF, should not be regarded as having SNF.…”

“…By critically reviewing the published reports labelled as (familial/hereditary) spinal neurofibromatosis (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), we realized that not all the reported cases presented with involvement of all the 38 spinal roots. In many individuals, the affected status of SNF was assigned to (familial or sporadic) patients with few or multiple neurofibromas involving multiple (but not all) segments of the spine (either unilaterally or bilaterally).…”

“…After these two reports (1,2), 17 further studies recorded 83 additional (both familiar sporadic) patients for a total of 98 patients labelled under the umbrella term of 'familial/hereditary spinal neurofibromatosis' or just 'spinal neurofibromatosis' (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). The condition has been regarded as a true NF1 variant or subtype, and either linkage to the NF1 locus (1,2) or mutations in the NF1 gene have been recorded in most reported cases (3, 5-11, 13, 16-20).…”

“…typical pigmentary manifestations, Lisch nodules and cutaneous and nodular neurofibromas) and other NF1-associated manifestations (e.g. scoliosis, long bone dysplasia, optic and non-optic pathway gliomas, plexiform neurofibromas (PNFs), pheochromocytoma and the typical T2 hyperintensities in the brain) (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Besides the classical families with multiple spinal neurofibromas, several sporadic cases have been recorded and, more recently, the phenotypic spectrum has included a set of concordant twins with SNF (16) and individuals with SNF belonging to families with classical NF1 (20).…”