Does the presence of dystrophic features in patients with type 1 neurofibromatosis and spinal deformities increase the risk of surgery?

STUDY DESIGN: Retrospective chart and radiographical review. OBJECTIVE: To present the demographics of patients with scoliosis and neurofibromatosis type 1 (NF-1), to record the incidence of dystrophic features, and to determine whether the presence of dystrophic features increase the risk of surgery in patients with NF-1 and associated spinal pathology. SUMMARY OF BACKGROUND DATA: The most common of the osseous complications of NF-1 is spinal deformity, occurring in 10% to 30% of individuals with NF-1. Many of these patients will eventually require surgery for curve progression, which makes study of demographics and identification of features predicting the need for surgery essential in this patient population. METHODS: A retrospective review was performed in patients with NF-1 and spinal deformities, followed in a multidisciplinary neurofibromatosis center. A subset of 56 patients with complete radiographical evaluation was reviewed for identification of risk factors for spine surgery. RESULTS: One hundred thirty-one patients from a population of 694 patients with NF-1 (19%) had scoliosis. Mean age at diagnosis of scoliosis was 9 years (range; 1-17 yr). Scoliosis and need for surgery were equally distributed between males and females. In the group of 56 patients, 63% had 3 or more dystrophic features. The presence of 3 or more dystrophic features was the strongest predictor of the need for surgery (odds ratio = 14.34; P < 0.001). Individual features most predictive of need for surgery were the presence of vertebral scalloping (odds ratio = 13.19; P < 0.001) followed by the presence of dural ectasia (odds ratio = 6.38; P = 0.005). Patients with no dystrophic features were unlikely to progress to need for surgery. CONCLUSION: Scoliosis and need for surgery were equally distributed between males and females. The presence of 3 or more dystrophic features was highly predictive of the need for surgery, with the most significant individual predictors being vertebral scalloping and dural ectasia. A combination of radiographical and MRI features can be used to predict need for spinal surgery. LEVEL OF EVIDENCE: 3.

Fractures in children with neurofibromatosis type 1 from two NF clinics.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder with osseous abnormalities occurring in up to one-third of patients. Several studies have documented osteopenia in both children and adults with NF1; however, the significance of lower bone mineral density (BMD) in relationship to fracture incidence is not well elucidated in NF1, particularly in children. We undertook a retrospective study to determine prevalence and location of fractures in children and adolescents with NF1, ages 5-20 years, using a standardized questionnaire. We surveyed 256 individuals with NF1 from two multidisciplinary NF centers and 178 controls without NF1 of similar ages and sex. Participants with known long bone dysplasia (LBD) were analyzed separately. Data collected included numbers and location of fractures, dietary calcium intake, and physical activity levels. There was no difference in prevalence of ever having a fracture between the NF1 group without LBD (22%) and the control group (25%); median number of fractures also did not differ. There were significant differences in fracture location with a higher frequency of fractures of the lower extremities in NF1 individuals without LBD compared to controls. Both NF1 cohorts had lower rates of physical activity than controls (P < 0.0001). Our data demonstrate that the likelihood of having had a fracture is not higher in young NF1 individuals without LBD in comparison to healthy controls. The lower physical activity level may have a "protective effect" for those with NF1, thus keeping their fracture incidence lower than expected for their relative degree of osteopenia.

Variable expression of neurofibromatosis 1 in monozygotic twins.

Neurofibromatosis 1 (NF1) is a common autosomal dominant disorder with high penetrance but extreme variability of expression. Monozygotic (MZ) twins with NF1 who have phenotypic discordances are a useful tool in evaluating which traits are influenced by non-hereditary influences such as second hit somatic events, environmental agents, epigenetic modification, or post-zygotic mutations. We evaluated nine sets of MZ twins and one set of MZ triplets, ages 4-18 years, for NF1 features and calculated probandwise concordance (P(C)) for each feature. MZ twins were highly concordant in numbers of café-au-lait spots (P(C) = 0.89) and cutaneous neurofibromas. IQ scores were within 10 points for all twin pairs tested, and similar patterns of learning disabilities and speech disorders were observed. Twin pairs showed significant discordance for tumors, particularly plexiform neurofibromas (P(C) = 0.40) and malignant peripheral nerves sheath tumors (MPNST), as expected if post-natal second-hit events were contributing to these features. One set of twins was concordant for multiple, large paraspinal neurofibromas, suggesting that there may be more hereditary factors involved in production of paraspinal neurofibromas. Four sets were concordant for pectus deformities of the chest (P(C) = 0.80). Three sets of twins were discordant for scoliosis (P(C) = 0.40); an additional set was concordant for scoliosis but differed in presence of dystrophic features and need for surgery. Our data suggest there are additional non-hereditary factors modifying the NF1 phenotype and causing discordancies between MZ twins. Future studies may focus on differences in epigenetic changes or somatic mosaicism which have been documented for other disease genes in MZ twins.