Neurofibromatosis: Physical Issues

Here are my notes on the physical issues from chapter eight. 

What Can You Do About The Physical Symptoms of NF1?

As a parent, some of the most difficult times are those when our child is struggling. For NF1 children, these struggles can be harder than most.

If you are a NF1-deficient parent, you may be expecting that your own children will follow your life’s path. It can be both worrying and alarming to think that you know what to expect. But you don’t.

Researchers following families with NF1-deficiency have found a widely varied connection between the symptoms of children compared to their parents. It seems that the NF1-deficiency’s presentation in the body is not dependent on that gene alone but on other genes. For every characteristic, researchers found that it was independent of other characteristics (more spots do not equal more fibromas) and determined by other genes besides the original NF1.

Yes, twins share many of the same symptoms. And families can share similarities, though researchers note that close family members often share environments and that the environmental factors might be a greater cause of the similarities than what comes from the genes.

analysis of 43 subjects for whom longitudinal assessments were available revealed that children often migrated between delayed and nondelayed groups in all areas except gross motor development. Based on these findings, we advocate early developmental screening and intervention for this at-risk pediatric population, especially in the area of gross motor function.

Reduced muscle size

3 to 43% weaker

What are all the common physical issues of NF1ers?

A rare de novo microdeletion at 17q11.2 not involving NF1 gene is associated with developmental delay and dysmorphic features.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder which displays considerable inter- and intra-familial variability in phenotypic expression. To evaluate the genetic component of variable expressivity in NF1, we examined the phenotypic correlations between affected relatives in 750 NF1 patients from 275 multiplex families collected through the NF-France Network. Twelve NF1-related clinical features, including five quantitative traits (number of café-au-lait spots of small size and of large size, and number of cutaneous, subcutaneous and plexiform neurofibromas) and seven binary ones, were scored. All clinical features studied, with the exception of neoplasms, showed significant familial aggregation after adjusting for age and sex. For most of them, patterns of familial correlations indicated a strong genetic component with no apparent influence of the constitutional NF1 mutation. Heritability estimates of the five quantitative traits ranged from 0.26 to 0.62. Moreover, we investigated for the first time the role of the normal NF1 allele in the variable expression of NF1 through a family-based association study. Nine tag SNPs in NF1 were genotyped in 1132 individuals from 313 NF1 families. No significant deviations of transmission of any of the NF1 variants to affected offspring was found for any of the 12 clinical features examined, based on single marker or haplotype analysis. Taken together, our results provided evidence that genetic modifiers, unlinked to the NF1 locus, contribute to the variable expressivity of the disease.

the variance component attributable to NF1 germ-line effects was low for CAL of small and large size (0.14 and 0.12, respectively) and it was null for the three types of neurofibromas. It was not significant in all cases (P > 0.05).

Lower phenotypic correlations between distant relatives than between close relatives are expected in a model with strong modifying genetic effects, but could also result from environmental factors that are more likely to be shared among first-degree relatives than among more distant relatives.

the six pairs of MZ twins were almost completely concordant for numbers of neurofibromas…Correlations were found to be weaker but still highly significant among siblings (r = 0.39, P < 0.001) and parent–offspring pairs (r = 0.27, P < 0.001)

For CAL spots of large size, skin-fold freckling, Lisch nodules and facial dysmorphism, greater correlations among siblings than among parent–offspring pairs were observed.

No significant deviations of transmission of any of the NF1 variants to affected offspring was found for any of the clinical features examined, based on single marker or haplotype analysis. These results suggest that genetic variants in NF1, where either located in cis or in trans position to the primary mutation, are unlikely to contribute to the variable expressivity of the disease. We can therefore exclude the possibility of an influence of the normal NF1 allele….a strong genetic component in most NF1 clinical features with no apparent influence of the NF1 gene on disease variation since neither the constitutional NF1 mutation nor the normal NF1 allele seem to contribute significantly to the overall phenotypic variation for each trait. The remainder of this phenotypic variation could be due to unlinked genetic modifiers, environmental factors or some combination of these.

Maria Acosta (Children’s National Medical Center) summarized a recently completed Phase I trial of Lovastatin for children with NF1 and cognitive deficits. Twenty-four patients were treated for three months. Lovastatin was extremely well tolerated and no safety concerns arose during study period. A subgroup of patients underwent 12-hr pharmacokinetic analysis and it was found that the concentration of drug in plasma was extremely variable between participants, as were drug-related changes in cholesterol levels. Although a Phase I toxicity trial, intellectual testing of participants indicated specific areas of cognitive improvement, including memory, recall, and recognition. Interestingly, a reduction in cholesterol level was positively correlated with improved cognitive function. This information provides valuable support for the now ongoing multisite Phase II study ongoing by the NF Phase II Clinical Trials Consortium.

Dr. Susan Lindquist (The Whitehead Institute for Biomedical Research) gave a keynote presentation on her work relating to the role of Heat Shock Factor 1 (HSF1) in cancer. Dr. Lindquist’s work has shown that inhibition of HSF1 inhibits the growth of cancer cells in vitro and in mouse models. HSF1 is known to be the major regulator of the heat-shock response in all animals. This response is one of the most ancient and highly conserved homeostatic mechanisms known. It acts to enhance survival under stressful conditions, regulates a multitude of growth responses and modulates the degenerative changes associated with aging. As a result, HSF1 is ideally situated to shape and modify the cellular landscape in which NF1 mutation operates, thereby modulating its impact on tumor formation. Immunostaining of NF1-associated MPNST specimens demonstrates HSF1 over-expression and nuclear localization consistent with its activation.

studies in children with NF1 showing significant reductions in total motor composite scores and strength. In addition, preliminary data from 16 individuals with NF1 suggest that energy expenditure/metabolism may also be abnormal in NF1 muscles. He theorized that impaired muscle function may be a feature common to RASopathies, suggesting an underlying importance of RAS signaling in muscle function [Stevenson et al., 2012]. These clinical findings were supported by hand-held dynamometry results from the lab of Joshua Burns (Children’s Hospital, Westmead, Sydney, Australia) showing mean reductions of 30-45% in strength in a range of muscle movements. Juliana de Souza (Federal University of Minas Gerais, Belo Horizonte, Brazil) presented data showing that a range of muscle outcomes in NF1 patients were affected (aerobic capacity [de Souza et al., 2013], handgrip strength, 6 minute walk, respiratory muscle force) and were not affected (cardiac function, myocardial mass and pulmonary function).

NF1 can manifest very differently from patient to patient, and no one person will have all of the possible symptoms of NF1. The severity of NF1 ranges from extremely mild cases to more severe cases, in which one or more serious manifestations may develop. There is no way to predict who will have a mild case and who will develop more serious symptoms, but the majority of those with NF1 will have minor cases (60%).

Neurofibromatosis (NF) type 1 (NF1) is notable for its variable expression. To determine whether variation in expression has an inherited component, we examined 175 individuals in 48 NF families, including six MZ twin pairs. Three quantitative traits were scored–number of café-au-lait patches, number of cutaneous neurofibromas, and head circumference; and five binary traits were scored–the presence or absence of plexiform neurofibromas, optic gliomas, scoliosis, epilepsy, and referral for remedial education. For café-au-lait patches and neurofibromas, correlation was highest between MZ twins, less high between first-degree relatives, and lower still between more distant relatives. The high correlation between MZ twins suggests a strong genetic component in variation of expression, but the low correlation between distant relatives suggests that the type of mutation at the NF1 locus itself plays only a minor role. All of the five binary traits, with the exception of plexiform neurofibromas, also showed significant familial clustering. The familial effects for these traits were consistent with polygenic effects, but there were insufficient data to rule out other models, including a significant effect of different NF1 mutations. There was no evidence of any association between the different traits in affected individuals. We conclude that the phenotypic expression of NF1 is to a large extent determined by the genotype at other “modifying” loci and that these modifying genes are trait specific.

  1. ¾ of families show significant differences between affected members.
  2. Decreasing effects from twins to siblings to cousins blocks autosomal dominant idea. Variation
  3. A lack of correlation between any of the eight traits among any of the individuals studied suggests a different set of unlinked genes is likely to be involved in each trait.
  4. By 1993, 14 pairs of twins were known with NF1. These form the basis for the best genetic comparison.
  5. Our results suggest polygenic rather than a single gene mechanism, making further genetic clarification very difficult.
  6. Disease tends to be similar among close relatives, but not enough to be predictable.

Café-Au-Lait Spots



Cognitive Differences

Head Size

Delayed or Early Puberty

Small Stature

Optic Gliomas

Bone Issues

Cosmetic Concerns

High Blood Pressure (Hypertension)

What causes the big head?

facial anomalies, large hands, feet, and head, and developmental impairment.

a potential neuroimaging cognitive function biomarker, abnormal signal in the frontal cingulate white matter. In a study of 62 children with NF1 compared with 62 age-matched non-NF1 affected controls, Dr. Kadom found that bright T2/FLAIR signal in the frontal subcortical cingulate white matter had greatest sensitivity for cognitive dysfunction in children 2–5 years of age and the greatest specificity in children >5 years of age Comparison of 46 children with NF1 to 30 controls demonstrated a significantly enlarged corpus callosum in the NF1 patients and correlation of corpus callosum size with lowered IQ and several measures of cognitive dysfunction. They note that some cognitive deficits may have a structural basis and may not be reversible with pharmacological treatments, in contrast with other NF1-associated learning problems.

Dr. André Bernards (Harvard Medical School/Massachusetts General Hospital) moderated a special discussion panel reviewing the latest progress in research on NF1 modifier genes.

Dr. Mark Daly (Massachusetts General Hospital Center for Human Genetic Research and the Broad Institute) gave a general introduction and reviewed how genome-wide association studies (GWAS) often implicate multiple loci in complex genetic disorders, such as inflammatory bowel disease. Interestingly, disease -associated genes may encode functionally related proteins, providing important clues to underlying pathways.

What causes the spots?

the MSH6 mismatch repair gene was one of three genes whose expression level significantly correlated with the number of café-au-lait spots, a phenotype that, like NF1 tumors, requires bi-allelic NF1 inactivation. This is especially interesting in light of previous observations that children homozygous or compound heterozygous for MSH6 mutations develop an NF1-like phenotype [Menko et al., 2004; Ostergaard et al., 2005].

an array of other conditions associated with multiple cafe-au-lait macules (CALM) were reviewed, including NF2, McCune-Albright syndrome, ring chromosomes (ch. 7, 11, 12, 15, 17, 22), LEOPARD syndrome, constitutive mismatch repair deficiency, Cowden, Fanconi anemia, tuberous sclerosis complex, Silver-Russell, and piebaldism. She noted that the NIH diagnostic criteria for NF1 are not specific, as some patients with pigmentary signs only (CALM and skinfold freckling) have Legius syndrome, due to mutations in SPRED1, instead of NF1.

What causes the short stature?

NF1 have a variety of malignant and non-malignant manifestations, including skeletal manifestations, such as osteoporosis, scoliosis and short statures. However, the mechanism(s) underlying the osseous manifestations in NF1 are poorly understood. In the present study, utilizing Nf1 haploinsufficient (+/-) mice, we demonstrate that Nf1+/- mesenchymal stem/progenitor cells (MSPC) have increased proliferation and colony forming unit-fibroblast (CFU-F) capacity compared with wild-type (WT) MSPC. Nf1+/- MSPC also have fewer senescent cells and have a significantly higher telomerase activity compared with WT MSPC. Nf1+/- MSPC have impaired osteoblast differentiation as determined by alkaline phosphatase staining, and confirmed by single CFU-F replating assays. The impaired osteoblast differentiation in Nf1+/- MSPC is consistent with the reduced expression of osteoblast markers at the mRNA level, including osteocalcin and osteonectin. Importantly, re-expression of the full-length NF1 GTPase activating related domain (NF1 GAP-related domain) is sufficient to restore the impaired osteoblast differentiation in Nf1+/- MSPC. Taken together, our results suggest that neurofibromin plays a crucial role in modulating MSPC differentiation into osteoblasts, and the defect in osteoblast differentiation may contribute at least in part to the osseous abnormalities seen in individuals with NF1.

Dr. Lodish found osteopenia at any one-bone site in 48% of patients, most commonly at the lumbar spine. Two-thirds were severely or mild-moderately vitamin D deficient, but deficiency did not correlate with BMAD.

What causes the high blood pressure?

When compared with the general population, the odds of any type of stroke are significantly increased for patients with NF1, both adult and pediatric

Hypertension is one of the major complications in neurofibromatosis type 1 (NF1). It is known to be caused by renal artery stenosis or pheochromocytoma. However, more than half of hypertensive patients with NF1 do not have either disorder. We report here on a 13-year-old male with NF1 who had hypertension and a stenosis of the right renal artery associated with elevated renal vein renin on the diseased side. He underwent percutaneous transluminal renal angioplasty. In spite of successful dilation of the artery and normalized renin level, high blood pressure persisted beyond 6 months requiring antihypertensive medication. His wide pulse pressure suggested arterial stiffness due to NF1 vasculopathy. We posit that the cause of hypertension in this patient was considered to be arterial stiffness ascribed to NF1 vasculopathy rather than renal artery stenosis. Increased pulse pressure supports the hypothesis.

Neurofibromin, the protein product of NF1, functions as a negative regulator of Ras activity in circulating hematopoietic and vascular wall cells, which are critical for maintaining vessel wall homeostasis. NF1 patients have evidence of chronic inflammation resulting in the development of premature cardiovascular disease, including arterial aneurysms, which may manifest as sudden death. However, the molecular pathogenesis of NF1 aneurysm formation is unknown.


With the use of an angiotensin II-induced aneurysm model, we demonstrate that heterozygous inactivation of Nf1 (Nf1(+/-)) enhanced aneurysm formation with myeloid cell infiltration and increased oxidative stress in the vessel wall. Using lineage-restricted transgenic mice, we show that loss of a single Nf1 allele in myeloid cells is sufficient to recapitulate the Nf1(+/-) aneurysm phenotype in vivo. Finally, oral administration of simvastatin or the antioxidant apocynin reduced aneurysm formation in Nf1(+/-) mice.


These data provide genetic and pharmacological evidence that Nf1(+/-) myeloid cells are the cellular triggers for aneurysm formation in a novel model of NF1 vasculopathy and provide a potential therapeutic target.

What Causes Uncoordination?

These results indicate that young children with NF1 have poor postural control. However, postural control appears to improve with maturation.

Because of complex bio-feedback loops, multiple escape mechanisms exist which may render growth relatively resistant to a single drug. As a result there is significant interest in utilizing combined or multiple biologic agents in synergy to attack different parts of the pathway to overcome this means of resistance.

They found internal plexiform neurofibromas in 48% of patients and observed that more rapid tumor growth occurred in younger patients. No new plexiform tumors were found in patients followed over time, confirming that these tumors are likely to be either congenital or to have onset in early childhood.