Neurofibromatosis, Familial Spinal

A number sign (#) is used with this entry because familial spinal neurofibromatosis is caused by heterozygous mutation in the neurofibromin gene (NF1; 613113) on chromosome 17q11.

Spinal neurofibromatosis is an autosomal dominant disorder characterized by a high load of spinal tumors. These tumors may be asymptomatic or result in neurologic symptoms, including back pain, difficulty walking, and paresthesias. Spinal NF is considered to be a subtype of neurofibromatosis type I (NF1; 162200), which is an allelic disorder. Patients with spinal NF may or may not have the classic cutaneous cafe-au-lait pigmentary macules or ocular Lisch nodules typically observed in patients with classic NF1. Patients with spinal NF should be followed closely for spinal sequelae (summary by Burkitt Wright et al., 2013).

Pulst et al. (1991) reported 2 families with spinal neurofibromatosis. The first family also had cafe-au-lait spots, whereas the second family had no cafe-au-lait spots. Other signs of neurofibromatosis I (NF1; 162200) or neurofibromatosis type II (NF2; 101000), such as cutaneous tumors, Lisch nodules, or acoustic tumors, were absent in both families.

Poyhonen et al. (1997) described a family in which 7 members in 3 generations had spinal neurofibromatosis. The affected adults showed, at the ages of 32, 37, 38, and 61 years, respectively, multiple spinal neurofibromas symmetrically affecting all spinal roots. Two patients were operated on for histopathologically proven cervical spinal neurofibromas. All patients had cafe-au-lait spots, 1 had several freckles in the axillary area, and 2 had possible dermal neurofibromas, but iris Lisch nodules were not present. Other signs of neurofibromatosis type I and type II were absent. Several patients had lower extremity weakness.

Ars et al. (1998) reported a 3-generation family in which 5 members, all female, had spinal neurofibromatosis. All presented with multiple spinal neurofibromas and cafe-au-lait spots. The oldest affected patient was a 58-year-old woman who had developed progressive paraparesis of her legs and right arm at age 45 years. She had multiple cafe-au-lait spots, but no cutaneous neurofibromas. Her affected daughter was a 34-year-old woman who had surgery at 16 years of age to remove a mediastinal neurofibroma. She had multiple cafe-au-lait spots and 3 cutaneous neurofibromas. At age 23 years, she developed signs of progressive spastic paraparesis. Another 24-year-old daughter had multiple cafe-au-lait spots and a history of surgical resection of a plexiform neurofibroma on the right arm. Multiple intra- and extraspinal neurofibromas were demonstrated. A third woman in the second generation, aged 21 years, had multiple cafe-au-lait spots and Lisch nodules, as well as spinal tumors. An affected member of the third generation, a 12-year-old girl, had multiple cafe-au-lait spots and Lisch nodules. Spinal MRI showed multiple bilateral tumors from C2 to D4 and 2 paravertebral masses.

Kaufmann et al. (2001) reported 2 unrelated families with spinal neurofibromatosis but without cafe-au-lait macules. The 32-year-old proposita in the first family had an intrathoracic upper mediastinal tumor detected at age 17 years. Subsequent MRI examinations detected multiple tumors of the psoas muscle and cervical and lumbar spine. Two of the spinal tumors were surgically excised and identified as a schwannoma and neurofibroma. In addition, a subcutaneous neurofibroma and a subcutaneous schwannoma were excised. Tumors in the CNS typical of NF2 were not found. She had no cafe-au-lait macules, intertriginous freckling, or Lisch nodules. There were no signs of mental retardation or scoliosis. The 31-year-old proposita from the second family observed multiple painful intradermal tumors of the extremities and trunk at the age of 17 years, 1 of which was identified as a neurofibroma. Another tumor, identified histologically as a schwannoma, was excised from the thoracic spine at age 29 years. Multiple spinal tumors were identified by MRI scans in all segments of the spine, especially in C5/C6. Other symptoms typical of NF1, such as cafe-au-lait macules, freckles, Lisch nodules, scoliosis, or tumors of the CNS, were not found. The patient's mother had 2 lumbar hyperpigmentations and presented with acute lumbago. MRI scan showed enlarged spinal nerves in all segments of the spine.

Burkitt Wright et al. (2013) reported 5 families with spinal neurofibromatosis. Most of the probands presented with neurologic symptoms in adulthood and were found to have spinal tumors on imaging; they usually had no pigmentary features or subcutaneous neurofibromas. Affected family members were subsequently identified when screened by imaging and/or molecular studies. A range of mutations was found in the NF1 gene in these families, with no specific mutation type associated with the presentation.

The transmission pattern of spinal neurofibromatosis in the families reported by Pulst et al. (1991) was consistent with autosomal dominant inheritance, with at least 1 instance of male-to-male transmission in each family.

Using genetic linkage analysis with DNA markers tightly linked to the NF1 and NF2 loci, Pulst et al. (1991) determined that the likely location for the mutation in a family with spinal neurofibromatosis and cafe-au-lait spots was in the NF1 gene with odds of 97:1, whereas the mutation in a second family, with spinal neurofibromatosis but without cafe-au-lait spots, was excluded from the NF1 locus with odds of more than 100,000:1. However, markers for the NF2 locus were uninformative in the unlinked family.

Linkage study of the affected family reported by Poyhonen et al. (1997) suggested close linkage to the NF1 locus and excluded linkage with the NF2 locus. DNA analysis of histopathologically verified spinal neurofibromas in 2 patients showed no evidence of loss of heterozygosity (LOH) at 17q11.2. Poyhonen et al. (1997) suggested that the disorder was a clinically distinct form of neurofibromatosis with extensive spinal involvement and cafe-au-lait macules which may be allelic to classic NF1.

In affected members of a family with spinal neurofibromatosis, Ars et al. (1998) identified a frameshift mutation in the NF1 gene (613113.0018).

In affected members of 2 families with spinal neurofibromas but no cafe-au-lait macules, Kaufmann et al. (2001) identified 2 different mutations in the NF1 gene (613113.0028 and 613113.0029, respectively). Both NF1 mutations caused a reduction in neurofibromin of approximately 50%, with no truncated protein present in the cells. The findings demonstrated that typical NF1 null mutations can result in a phenotype that is distinct from classical NF1, showing only a small spectrum of the NF1 symptoms, such as multiple spinal tumors, but not completely fitting the current clinical criteria for spinal NF. Kaufmann et al. (2001) suggested that the spinal NF phenotype may be caused by a modifying gene that partially compensates for the effects of neurofibromin deficiency.

In 4 affected members of the family with spinal NF and cafe-au-lait spots reported by Pulst et al. (1991), Messiaen et al. (2003) identified a mutation in the NF1 gene (613113.0039). In affected members of the family with spinal NF reported by Poyhonen et al. (1997), Messiaen et al. (2003) identified a mutation in the NF1 gene (613113.0038).