Neurofibromatosis: Draft Copy Of Book With Research Links

The chapters of the final book got renamed, but paging through this early rough draft should give a very good sense of the research for the final book. There are also sections on cancer,headaches, and other issues that got left out of the final book.

Helping Your NF1 Child

Dr. Christopher Maloney, N.D.

 

DEDICATION

To all children diagnosed with NF1 and all the parents who care for them. May you find daily happiness in small victories.

 

1

What Is NF1?

I must admit when I began researching Neurofibromatosis (NF1) I thought I would find a straightforward genetic disease. We’ve all encountered genetic diseases, mostly commonly Down Syndrome. Perhaps we know and love someone with a genetic disease, but we don’t consider it possible to “get better” from a genetic disease. You manage the symptoms of the illness for the life of the person.

        Neurofibromatosis seems like a relatively new genetic disease because the name has changed and more research is being done now than before. But before NF1 (there is NF2 and other sub-diagnoses, but I will focus on NF1) was called that, it was called  von Recklinghausen disease, based on Frederich von Recklinghausen’s 1882 German treatise. But in 1849, Irish physician R.W. Smith published a treatise on the neuroma. So there is some debate over whether it should have been called Smith’s disease. NF1 is now also a patented disease, the patent granted in 2002 to the University of Michigan.

        Whatever we may call it today, NF1 is not a single disease. It’s not a single genetic problem. For comparison, Down Syndrome patients have some variation in the genetic cause of their condition. But the vast majority share a similar genetic situation, 88% of them share the same Trisomy 21 (an extra copy of that gene).

        To quote NF1 researchers “Neurofibromatosis type I is an autosomal dominant disease with complete penetrance and variable age-dependent expressivity. It is caused by
heterozygous mutations in neurofibromin 1 (NF1). These occur throughout the
length of the gene, with no apparent hotspots. Even though some mutations have
been found repeatedly, most have been observed only once.
At this writing, NF1 patients have over two thousand different variations in the area of genetic abnormality on chromosome 17. These two thousand variations do not cause a single defect, they mottle the entire chromosome 17 area in new and different ways. So it is virtually impossible to tell from genetic testing what the outcomes of the diagnosis of NF1 will be for the patient.

        Possibly a better comparison for NF1 would be cystic fibrosis, which has a major genetic variation but also has 1500 known mutations that may cause symptoms. Cystic Fibrosis only occurs when both parents give the bad gene to the child, ‘ However, growing awareness of CFTR mutations that do not ever or do not always cause CFIn cystic fibrosis some of the mutations cause severe disease, while others cause almost no systemic illness. Like cystic fibrosis, an NF1 patient may live a relatively normal life or be severely impacted by the diagnosis. We have no idea from the genetic diagnosis what the outcome will be.

        As a parent, knowing that NF1 is genetic is fraught with guilt. the mean paternal age for non-familial NF1 cases was 4.34
years (95% CI 3.23-5.46, p ≤ 0.0001) and 3.39 years (95% CI 1.57-5.20, p ≤
0.0001) older
, respectively, after adjusting for birth year. A
similar pattern was observed for maternal age. But NF1 has “ a
mutation rate some 10-fold higher compared to most other disease genes. As a
consequence, a high number of cases (up to 50%) are sporadic
” It is also necessary to note that, while NF1 is considered autosomal dominant, “ None of the patients has so far not been detected mutations in both alleles of the NF1 gene, suggesting that at least one
normal copy of the gene is essential for the survival of the fetus and the subsequent functioning of the body

        On its surface, NF1 seems straightforwardly genetic from birth. Signs and symptoms apparent from birth (brown skin spots, head size, freckling, eye spots) give a clinical diagnosis that can be confirmed by genetic testing. So NF1 can be diagnosed genetically, but the diagnosis currently does not give us a clear picture of what to expect for the child going forward.

        When judging a patient clinically, researchers base their diagnosis on a range of symptoms. The diagnostic criteria for NF-1 are met in an individual if two or more of the following are found:

  •         Six or more caf�-au-lait macules over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals.
  •        
    Two or more
    neurofibromas of any type or one plexiform neurofibroma.
  •        
    Freckling in the
    axillary or inguinal region.
  •        
    Optic glioma.
  •        
    Two or more Lisch
    nodules (iris hamartomas).
  •        
    A distinctive osseous
    lesion such as sphenoid dysplasia or thinning of long bone cortex with or
    without pseudarthrosis.
  •        
    A first-degree
    relative (parent, sibling, or offspring) with NF-1 by the above criteria.

        But these criteria may not absolutely NF1. In studying a group of undiagnosed patients, doctors found that: “78
satisfied the NIH diagnostic criteria for NF1. Within this better defined
cohort of NF1 patients, NF1 mutations were identified in 61 individuals (78%)

        In fact, NF1 is not strictly a genetic disease. It is a problem that often  occurs when the initial fertilized egg is dividing. At the blastocyst stage of human embryo development, even before the fertilized egg has implanted itself in the uterine wall, the error in the long arm of Chromosome 17 can occur. Because it occurs after the initial fertilization, NF1 has a very wide range of variability as well as a very high individual mutation rate. Once the error occurs, it is classified as autosomal dominant (passed directly from parent to child. Once the parent has the abnormality, it is passed directly to all children. But many NF1 patients, about half, have no parent with the illness.

        The variability of that initial error can be seen in studies of identical twins. Despite sharing the same genes, twins show a 30-40% variability in the symptoms and progression of their NF1 diagnosis.

        How is it possible that two twins, sharing the same NF1 variation (one of two thousand documented) still have so much variability in their outcomes? Because every NF1 patient has one working chromosome 17. We receive two from our parents, one from each. In order to be born alive, all NF1 patients are heterozygous (one error), not homozygous (two errors). If both copies of chromosome 17 have errors, the result is a miscarriage, not an infant. So in every patient with NF1 each one of his or her cells also contains a working copy of chromosome 17.

        While the diagnosis of NF1 does not tell us everything we need to know about what to expect for a growing child, it does give us a warning to watch the child more closely. All of the subsequent issues of NF1 can and should be thought of not as the direct consequence of a genetic disease but as the result of the failure and recovery of the single working copy of chromosome 17.

        Reformulating the progression of NF1 to its various symptoms as being the result of an ongoing struggle rather than a foreordained conclusion gives an entirely different picture to caring parents. Rather than simply watchfully waiting for symptoms to occur, perhaps a caregiver can work to prevent that breakdown. The symptoms are no longer inevitable, they are highly variable, and some of them may be preventable.

 

2

What Does NF1 Do?

Given the isolation of NF1 to the long arm of Chromosome 17 was discovered in 1987, you’d think that we have a clear picture of what NF1 does in the body.  Yes, NF1 research is not a priority because it is relatively rare. But surely some laboratory would have given us a clear answer by now.

        We don’t know what NF1 does. We do know that it normally produces a protein, conveniently called Neurofibromin. That protein acts, we think, as a suppressor for an intracellular signaling system called the RAS system. For this reason, NF1 may soon be classified as one of the RAS-opathies because it isn’t the only protein that affects this system.

        If we’re right, then Neurofibromin acts to slow down the RAS system, slowing the signals. But we aren’t sure what that does in the cell, because there are multiple signaling systems, not just RAS. It’s a little like putting a muzzle on one barking dog. Do the others bark louder, softer, or stop altogether? Maybe some variation of all three.

        To give a sense of how little we know, there is another disease, called Legius Syndrome. If you are a parent with NF1 and you haven’t had genetic testing, your child may have Legius Syndrome (particularly if your child lacks the typical eye problem called Lisch Nodules.) A recent analysis showed that clinically you can’t tell Legius Syndrome from NF1 and that 2% of patients with NF1 had been misdiagnosed (Legius is much less common). Legius Syndrome involves a mutation on a different chromosome, Chromosome 15, so it shouldn’t look that similar to NF1. But it does because it affects the same pathway.

        While NF1’s Neurofibromin inhibits the RAS signaling system higher up the pathway, Legius’ mutation in the Spred1 gene affects the pathway slightly further down. As a result, NF1 tends to be much more severe, and Legius patients have far fewer problems later in life. But initially the two diseases look very similar.

        The other insight we have into NF1 is that mutations in NF1 are very common in cancer cells. Because the RAS signaling system helps regulate cellular growth, it makes some sense that cancer cells would require an error in NF1 to allow them to grow without any control. But clearly the RAS system does not simply lead to uncontrolled growth in NF1 patients. They are maintained by their healthy chromosome and there is good evidence to support the reality that NF1 patients only develop cancer if their second chromosome fails them.

        If we think of NF1’s Neurofibromin as the moderator of the cell, it balances out too little growth with too much (and keep in mind that this ignores several other cell pathways that can override the RAS one). Keeping this in mind, we can look at some of the common symptoms of NF1 and come to some understanding of why they can occur.

 

3

What does Neurofibromin Do?

“Neurofibromin is a cytoplasmic protein that is predominantly expressed in neurons, Schwann cells, oligodendrocytes, astrocytes and leukocytes.

        To be born, a child must have at least some neurofibromin. “Neurofibromin is necessary for
embryonic development and involved mainly in the
differentiation of neural crest derived cells, mesenchymal cells, neural cells,
melanocytes and bone cells.”

        Remember, we are guesstimating at best because Neurofibromin is defined as the protein missing from NF1 patients.  NF1 is defined as having one gene that lacks the ability to make Neurofibromin. It’s  a closed definition that offers no further complete explanation.

        While Neurofibromin is defined as a tumor suppressor gene, than definition is the result of seeing what a lack of both Neurofibromin genes does in a patient. When both genes fail, as in any of a number of cancers, uncontrolled growth is the result. But in NF1 patients puberty can bring on the production of many neurofibromas without any subsequent cancerous growth. So NF1 patients still have a functioning second gene, but can generate neurofibromas nonetheless.

        To understand the production of neurofibromas without other cancerous growth, we must understand that the body has multiple signaling pathways. During puberty, the RAS signaling system is placed in high gear, pushing the body to grow. The other signaling systems in the cell are all turning to maximum, and the hormones are overriding any suppression of growth. When researchers look at NF1 patients they see that their cells are particularly susceptible to hormonal signaling. A regular cell will have a mild response to any hormones. But a NF1 patient’s cells will have a strong response to that same hormone.

        Since Neurofibromin exists in many cells, the effects of unregulated behavior can be felt anywhere in the body. But NF1 is particularly known for creating neurofibromas along the nerves. These tumors are often harmless and only occasionally progress to cancerous tumors. According to pioneering NF1 neurologist Dr. Riccardi, the neurofibromas should not be thought of as tumors but rather scar tissue. But whether tumors or scar tissue, neurofibromas can impact patients when they block nerves, causing pain and other symptoms.

 

4

NF1 And Social Stigma

Neurofibromatosis is virtually unknown in medical circles. It is completely unknown to anyone nonmedical, with the possible exception of anyone who is familiar with the rumors regarding the Elephant Man, John Merrick. For those of you who have not seen the movie, or the play, John Merrick was a deformed man who died in 1890. He had toured as a freak, half-man and half-elephant earlier in his life before a doctor discovered that he was quite intelligent and brought Merrick under his care. Merrick died in his sleep at the age of 27.

        We do not know what caused John Merrick’s deformities, but several doctors speculated that Merrick could have had NF1. Currently the medical consensus is that Merrick suffered from Proteus Syndrome, an extremely rare disease that causes the uncontrolled growth of body parts. But people familiar with Merrick’s deformities may still associate NF1 with his condition. Until genetic testing can be done on Merrick’s bones (testing which has been invalidated because his bones were bleached multiple times) he remains the most “famous” person who might have had NF1.

Beyond that particular reference, overwhelmingly parents will need to educate teachers, school boards, and caregivers about NF1. Since other diagnoses overlap NF1 behaviors including attention deficient and the autistic spectrum, pupils may be lumped in with others who have a different set of symptoms. NF1 patients are not inattentive because they are misbehaving, they are inattentive because neuropeptides that are available to other children are not as available in their brains.

Another aspect of the virtual anonymity of NF1 is that other parents and children may not understand the nature of the illness. Children may ask your child what is wrong with them, and parents may be afraid what your child has might be infectious. At this point the genetic nature of NF1 is very helpful for assuaging concerns and allows your child to feel that it is nothing that they did wrong.

The process of opposing stigma for the NF1 community comes from within the lay parents, not from their doctors. Western medicine has many talents, but rarely does an M.D. engage in community-wide re-education about social prejudices. Fortunately for NF1 patients, many active lay organizations are pushing both research and acceptance.

 

5

MANAGING NF1: CANCER

At the most recent international conference of NF1, the experts concluded: “we remain ignorant of the mechanisms underlying the transformations of benign neurofibromas to malignancy.” (Summary, 2012)  We don’t know how it happens, and we’d really like to because NF1 mutations don’t just occur in NF1 patients. The same mutation can be found in a variety of cancer cells. Understanding NF1 would help with the understanding of cancer as a whole.

        A number of experts call the neurofibromas themselves tumors, but almost all of them remain benign, causing pain and other issues only by compression of other body processes. Very rarely do they mutate into MPNSTs (malignant peripheral nerve sheath tumors). Dr. Vincent Riccardi states that neurofibromas should be considered like scar tissue rather than tumors themselves. Another researcher  describes the situation as: “ cutaneous
neurofibromas invariably retain their benign phenotype. Their neoplastic cells
never undergo malignant transformation and the tumor diameter usually varies
from millimeters to 2 cm, rarely exceeding 3 cm
.

But for now NF1 remains a tumor suppression gene, and the mutation of NF1 allows tumors to grow more rapidly.

        In NF1 patients, there is no assurance that cancer will occur. From identical twin studies of NF1, the second, functioning NF1 gene must also be “knocked out ” for cancer to occur. So even in twins, the rate of cancer is widely variable. But the overall risk, estimated by a Finnish study of NF1 patients, is 59% over an NF1 patient’s lifetime. Included in that risk is a higher risk of breast cancer and cancer at a younger age in addition to cancers of the peripheral nervous system (MPNSTs) and central nervous system. Mean lifespan for NF1 is 62, about 15 years less
than a control group.
The majority of these deaths are due to  malignant peripheral nerve sheath tumors
[MPNST]. Although our preclinical model and single-institution patient cohort show gender dimorphism in MPNST onset, no significant gender disparity was detected in the larger MPNST patient
meta-dataset. NF-1 patients develop MPNST 13 years earlier than patients with
spontaneous MPNST, with little geographical variance.

        The increased breast cancer risk is particularly interesting because NF1 mutated cells show a robust response to any female hormones. Normal cells have a mild response. So NF1 tissues are much more reactive to hormones than normal tissues. Puberty for an NF1 patient coincides with the growth of any neurofibromas, so we must assume an overactive hormonal response within those nerve tissues as well. In assessing the tissue, researcher note that: “ 75% of neurofibromas carry progesterone receptors. However, there is no evidence that progesterone and combined oral contraceptive pill stimulate growth of neurofibromas. For pregnant NF1 patient, obstetrician and clinicians should be aware that spinal and pelvic neurofibromas may progress rapidly and thus need to be monitored closely.” Progesterone increases with stress.

        In some way NF1 is related to the skin and melatonin, because “ NF1
somatic mutations also occur in 15% of sporadic melanoma, a cancer originating
from melanocytes
 After adjusting for birth year, we observed a significantly reduced odds of brain tumor diagnoses in individuals self-identified or clinically reported as Black (OR = 0.13, 95% CI 0.05-0.31), Asian (OR = 0.15, 95% CI 0.04-0.64), and other/unknown (OR = 0.61, 95% CI 0.41-0.93) race compared with those with reported as White race. There was no significant difference in the odds of pediatric brain tumor diagnosis by Hispanic ethnicity.

mononuclear cells from asymptomatic NF1 patients
have increased oxidative DNA damage, an indicator of chronic exposure to
oxidative stress.

human NF1 tumour cell lines either went through apoptosis or ceased growth in the presence of 2-methoxyoestradiol (2ME2), a naturally occurring anticancer metabolite of 17-β estradiol…We found that STX3451-induced apoptosis in human malignant peripheral nerve sheath tumour (MPNST) cell lines, even in the presence of elevated oestrogen and progesterone. It inhibits both PI3 kinase and mTOR signalling pathways. It disrupts actin- and microtubule-based cytoskeletal structures in cell lines derived from human MPNSTs and in cells derived from benign plexiform neurofibromas. STX3451 selectively kills MPNST-derived cells, but also halts growth of other tumour-derived NF1 cell lines.

Tamoxifen was also effective in vivo, demonstrating potent antitumor activity in mice orthotopically xenografted with human MPNST cells. We conclude that 4-hydroxy-tamoxifen inhibits MPNST cell proliferation and survival via an ER-independent mechanism. The in vivo effectiveness of tamoxifen provides a rationale for clinical trials in cases of MPNSTs.

 

6

MANAGING NF1: LEARNING DISABILITIES

We don’t know why NF1 causes learning disabilities. But we have several guesses. Dr. Vincent Riccardi describes NF1: “acknowledging that compromised attentiveness is the most consistent cognitive element of the disorder, one can characterize the NF1 gene as an “attentiveness suppressor gene” and
appropriately rename Nfn as Attentin. If
the clinical approach has any merit at all, it is most likely to be fruitful in
this regard: The wild-type NF1
alleles contribute to human performance, with specific regard to functions of
the central, peripheral and autonomic nervous systems, particularly when time
is of the essence, when response “on the instant” is required for organism and
species survival. This conclusion is reinforced by acknowledging the NF1
person’s lean habitus and absence of diabetes.”

In one paragraph Dr. Riccardi gives us the cause, a lack of focus, and a reason: focus may be necessary elsewhere. NF1 patients may not be the best at focusing in the classroom, but they are more likely to keep their heads in a time of crisis? So far we don’t have any studies to confirm this hypothesis. NF1 research is so new there aren’t any retrospective studies on NF1 in soldiers, firefighters, or other emergency personnel.

While we aren’t clear on the connection, ” genetic links between NF1 and genes involved in melanocyte biology have been described,” which could mean that NF1 children are genetically programmed to have difficulty with sleep.

        There was 2.68:1 male:female ratio in children meeting ASD
criteria on the deep phenotyping measures. On symptom profile, males with
neurofibromatosis type 1 (NF1) + ASD were more impaired on reciprocal social
interaction and communication domains
of the ADI-R but we found no differences on
the restricted, repetitive behaviours (RRBs) domain of the ADI-R and no
differences on the social on the ADOS. NF1 ASD males and females were
comparable on verbal IQ, and the inattention/hyperactivity domains of the
Conners questionnaire.

Of the ADHD sample, 21 % met ASD cut-offs on the ADOS and 30
% met ASD cut-offs on all domains of the ADI-R. Four social communication ADOS
items (Quality of Social Overtures, Unusual Eye Contact, Facial Expressions
Directed to Examiner, and Amount of Reciprocal Social Communication) adequately
differentiated the groups while none of the items on the ADI-R met the criteria
for adequate discrimination
.

Twenty-two (1-in-558) children with ASD had diagnosed NF1,
exceeding NF1 general population estimates by four to five fold. Children with ASD/NF1 versus ASD without NF1 were
significantly less likely to receive a community-based ASD diagnosis
(p = 0.04) and understand non-verbal
communication (p = 0.001).

Our results indicated that although EF is highly influenced
by IQ and severity of ASD symptoms, EF deficits seem to be a core feature ofNF1 and not merely a secondary effect of a lower
IQ and/or increased ASD symptoms.

We demonstrated a selective social learning
deficit in mice with deletion of a single Nf1 allele (Nf1(+/-)), along with
greater activation of the mitogen-activated protein kinase pathway in neurons
from the amygdala and frontal cortex, structures that are relevant to social
behaviors.
The Nf1(+/-) mice showed aberrant amygdala glutamate and
GABA neurotransmission, deficits in long-term potentiation and specific
disruptions in the expression of two proteins that are associated with
glutamate and GABA neurotransmission: a disintegrin and metalloprotease domain
22 (Adam22) and heat shock protein 70 (Hsp70), respectively. All of these
amygdala disruptions were normalized by the additional deletion of the p21
protein-activated kinase (Pak1) gene. We also rescued the social behavior
deficits in Nf1(+/-) mice with pharmacological blockade of Pak1 directly in the
amygdala. T

Academic difficulties and school failure are the
most common reported complication of NF1 in childhood and are present in 40% to
60% of the cases.

A common complication is neuropsychological problems,
including developmental delays and learning difficulties that affect as many as
60% of patients. For children with NF1, significant difficulties were
demonstrated on lab-based mid-level and complex fine motor tasks, even after controlling
for nonverbal reasoning abilities, but not on simple fine motor tasks. Parental
report also indicated difficulties in everyday adaptive fine motor functioning. No significant correlations were found between
complex fine motor ability and attention difficulties.

The dental age of children with NF1 was similar to
that of a Finnish control population.

men with NF1 had more speech deviations than women
with NF1.

Children with neurofibromatosis type 1 were
significantly more likely to have disturbances in initiating and maintaining
sleep
, arousal, sleep-wake transition, and hyperhidrosis, but not
problems with abnormal sleep breathing, or excessive somnolence. Although the
overall sleep scores were higher in children with neurofibromatosis type 1,
this was not related to a coexisting attention deficit disorder, cognitive
impairment, or stimulant medication use.

Psychiatric disorders are more frequent in NF1
than in the general population, especially in children. They include dysthymia,
depressive mood, anxiety, and personality disorders.
Bipolar mood disorders or schizophrenia are
rather rare. The majority of studies have focused on physical health and
neurocognitive function in NF1, whereas psychiatric disorders associated with
this disease remain unclear and poorly documented.

… the relaxation response resiliency program
(3RP).
..The intervention was highly acceptable, as evidenced by an
80% completion rate (16/20). Paired t tests showed significant improvement in
resiliency, satisfaction with life, depression, stress, anxiety, mindfulness
and post traumatic growth

Eighty-one percent of the children with NF1 had
moderate to severe impairment in one or more areas of cognitive functioning.
Although 51% of children with NF1 performed
poorly on tasks of reading, spelling, and mathematics, specific learning disabilities
(as defined by IQ-achievement discrepancies) were present in only 20% of the
children. Sustained attention difficulties were present in 63% of children with
NF1, with 38% of children with NF1 fulfilling the diagnostic criteria for
attention deficit-hyperactivity disorder. The NF1 neuropsychological profile is
characterized by deficits in perceptual skills (visuospatial and
visuoperceptual), executive functioning (planning and abstract concept
formation), and attention (sustained and switching). Interestingly, both verbal
and visual memory was unaffected in NF1 children, and their memory skills were
in general stronger than their level of general intellectual function.

implicated neurofibromin in regulation of the release of the
inhibitory neurotransmitter γ-amino butyric acid (GABA)
in the hippocampus and frontal lobe, which can
regulate memory. Mutations in neurofibromin thus lead to perturbed ERK
signaling, which alters GABA release, LTP, and subsequently leads to learning
deficits. In addition to these cognitive deficits, Nf1 patients also have
defects in fine and gross motor coordination as well as decreased muscle
strength. Although the mechanisms underlying these motor deficits are unknown,
deficits in GABAergic neurotransmission in both the motor cortex and cerebellum

Individuals with NF1 showed impaired impulse
control and reduced EEG correlates of early visual processing
(parieto-occipital P1) and inhibitory control (frontal P3).
MRS data revealed a reduction in medial
frontal GABA+/tCr (total Creatine) levels in the NF1 group, in parallel with
the already reported reduced occipital GABA levels.. the relationship between inhibitory
control and medial frontal GABA was reversed in NF1: higher GABA was associated
with a faster response style whereas in controls it was related to a cautious
strategy. Abnormal GABAergic physiology appears, thus, as an important factor
underlying impaired cognition in NF1, in a level and region dependent manner..

In a mouse model of NF1, a loss of function
mutation of the neurofibromin gene resulted in increased gamma aminobutyric
acid (GABA)-mediated inhibition
which led to decreased synaptic plasticity and deficits in
attentional performance. Most importantly, these deficits were normalized by
lovastatin. This placebo-controlled, double blind, randomized study aimed to
investigate synaptic plasticity and cognition in humans with NF1…lovastatin revealed significant decrease of intracortical inhibition,
significant increase of synaptic plasticity as well as significant increase of
phasic alertness

Twenty-four children with neurofibromatosis type 1 underwent
a dose-escalation protocol for 3 months to identify the maximum tolerated dose
and potential toxicity. Minimal side effects were evident, and no child
experienced dose-limiting toxicity. Cognitive evaluations were completed before and
after treatment, and the results suggested improvement in areas of verbal and
nonverbal memory.
Additional analyses, using reliable change indices,
indicated improvements exceeding those of test-retest or practice effects in
some participants. These observations may be analogous to the improvements
observed in a neurofibromatosis type 1murine model treated with lovastatin,

Simvastatin for 12 months had no effect on full-scale intelligence (treatment effect
compared with placebo -1·3 IQ points [95% CI -3·8 to 1·3]; p=0·33), attention
problems (-1·6 T-score points [-4·3 to 1·0]; p=0·23), and internalising
behavioural problems (-0·1 T-score points [-3·3 to 3·1]; p=0·96). 38 (88%) of
43 patients on simvastatin and 39 (95%) of 41 patients on placebo reported
adverse events, which were serious in two and four patients, respectively.

INTERPRETATION:

12 month simvastatin treatment did not
ameliorate cognitive deficits or behavioural problems in children
withneurofibromatosis type 1. The use of 20-40 mg simvastatin per day for
cognitive enhancement in children with neurofibromatosis type 1 is not recommended.

Lovastatin was well-tolerated, with no serious adverse events. Differential improvement favoring lovastatin
treatment was observed for one primary (working memory; effect size f (2) = 0.70,
P < 0.01) and two secondary outcome measures (verbal memory, f (2) = 0.19, P
= 0.02, and adult self-reported internalizing problems, f (2) = 0.26, P = 0.03).
Exploratory moderator analyses revealed that
higher baseline neural activity in frontal regions was associated with larger
treatment effects.

 

7 MANAGING NF1: OTHER PHYSICAL COMPLAINTS

Complications are severe in one third of patients,
and the clinical variability is pronounced, even within families.

HEADACHES

http://www.ncbi.nlm.nih.gov/pubmed/10805189

Of 132 patients with neurofibromatosis-1, 81 were identified
with any headache by screening history. Recurrent headaches were present in 77%
of patients and in 47% of our neurofibromatosis-1 clinic population.
Fifty-three of 81 patients were accessible for and agreeable to telephone
interview. There were 23 male patients and 30 female patients aged 5 6/12 to 49
6/12 years, with a mean age of 20.9 years. Eighty-one percent reported having
experienced recurrent headaches within the year. The majority reported onset of
headache prior to the age of 10 years. Headache characteristics included the
following: frequency of monthly or less, frontotemporal location, pulsating or
pressing quality, and moderate severity (pain scale 4 to 5 out of 10).
Headaches interfered with daily activities, had weekend occurrence, and had a
duration less than 2 hours. Common headache triggers included stress,
“change in weather,” menstruation, fatigue, and certain foods. A high
percentage of patients reported associated symptoms of nausea with or without
vomiting (37%), phonophobia, photophobia, pallor, and visual scotoma. We
classified 34% of the patients as having migraine (25% with aura, 9% without
aura), 45% with nonmigrainous headache only, and 15% with mixed headache types
(either intermittently), and 7.5% with other head pains. We conclude that
patients with neurofibromatosis-1 are at greater risk for headaches than the
general population. While the prevalence of both migraine and nonnigraine
headache is somewhat greater than in the general population, the proportion of
tension-type headache, especially in young children, is greater than expected.

http://www.ncbi.nlm.nih.gov/pubmed/23532548

Aim of this study is to verify the efficacy and safety of a
nutraceutical complex containing Ginkgolide B/Coenzyme Q10/Riboflavin/Magnesium
for prophylaxis in a sample of children affected by NF1 presenting migraine
without aura. Ginkgolide
B/Coenzyme Q10/Riboflavin/Magnesium
complex was orally administered twice a day for 6 months, to 18 school-aged
patients with NF1 and presenting symptoms of migraine without aura (10 M, mean
age 8.4 ± 1.65)…After treatment,
a reduction was reported (p < 0.001) in all migraine outcomes (frequency, duration, intensity, and grade of
disability).

BOWEL PROBLEMS

Gastrointestinal manifestations occur in up to 25%
of patients with neurofibromatosis type 1.

About one third of patients affected by von Recklinghausen’s
disease present involvement of the bowel, but only 5% of them are symptomatic.
The intestinal tumours are usually neurofibromas and are mainly localized in
the jejunum. However, there have also been reports of stromal, nervous and
endocrine tumours and even other tumours not belonging to these categories,
including adenocarcinoma. The overall incidence of intestinal malignancy in
patients with von Reckilnghausen’s disease is about 10%.

Six children with NF1 and intermittent, episodic, severe abdominal
pain
are reported. Investigations for obstructive or inflammatory
causes of abdominal pain were negative. All patients had previously been
diagnosed with migraine headaches by a neurologist. In five of the six
patients, propranolol (10-15 mg three times daily) resulted in relief of their
abdominal pain within days of starting therapy.

Bowel symptoms have been reported, but gastrointestinal
function in NF1 remains to be described in detail. In this first systematic
study of bowel function in children with NF1, we aimed to investigate symptoms
of constipation and test the hypotheses that children with NF1 have abnormally large rectum and
prolonged colonic transit time (CTT)
…A total of 6 children with NF1 (30%) were
constipated according to Rome III criteria. Average rectal diameter was
significantly larger than for healthy children (32.9 ± 7.2 mm vs 21.4 ± 5.9 mm,
P < 0.0001). Median CTT in NF1 children was 53 hours (range 26-101).
Compared with existing normative data, CTT was prolonged (>84 hours) in 3
(19%).

Mast cells have been implicated in the pathogenesis of both
neurofibromatosis type 1 and ulcerative colitis (He, 2004; Yoshida et al.,
2010). Mast cells are typically
present in neurofibromas microenvironment where they appear to contribute to
tumor initiation, progression and angiogenesis
(Staser et al., 2010, 2013). Moreover,
interaction of mast cells with nerves throughout the gastrointestinal tract has
been correlated with progression and maintenance of ulcerative colitis
(Stoyanova and Gulubova, 2002).

Intestinal ganglioneuromatosis is a rare disorder of the enteric nervous
system. It is often associated with neurofibromatosis type 1 and multiple endocrine
neoplasia type 2b but, more rarely, it can present in a sporadic and isolated
form. A 66-year-old man presented with a 14-year history of iron deficiency
anaemia,..Histological analysis demonstrated the presence of diffuse intestinal
ganglioneuromatosis.

There has been a growing number of literature reporting an
association between NF1 and
gastrointestinal stromal tumors (GIST)
.NF1-associated GIST has been described to
comprise a minority of cases, in which there is an alternative molecular
pathogenesis. This difference between NF1-related GISTs and that of the general
population has important therapeutic implications. The presence of kinase
mutations has been shown to be predictive of clinical response to imatinib, a
tyrosine kinase inhibitor.

Consecutive exploratory laparotomy confirmed the diagnosis
and 70 cm of the small intestine was resected due to an affection of the mesentery by multiple
neurofibromas.
The gastrointestinal tract is affected in approximately 10%
of patients with NF-1, however the mesentery is almost always spared.

BONE LOSS

Osteoporosis
is found in ~20-40% of adult patients with NF1 affecting both genders. A recent
register-based study has shown that patients with NF1 have an increased
fracture risk, especially, and in men and women aged ~40 or more, and in
children with NF1. The increased fracture risk in adults with NF1 is associated
with low BMD.

We showed bone alterations in 35% of patients and
the increase of bone formation markers
, such as bone isoenzyme of alkaline phosphatase
(41.2 ± 15.5 vs. 25.6 ± 8.7 UI; P < 0.05, respectively) and osteocalcin
(18.1 ± 5.6 vs. 7.6 ± 1.9 ng/ml; P < 0.05) and reduction of circulating
levels of (25OH)-vitamin D (21.8 ± 12.3 ng/ml) with an high percentage of hypovitaminosys D (>60%). Moreover, we revealed a significant reduction of
bone mass density at spine (L1-L4) (0.935 ± 0.13 vs. 1.110 ± 0.17 g/cm(2); P
< 0.001) and femoral neck side (0.765 ± 0.09 vs. 0.839 ± 0.12 g/cm(2); P
< 0.02), with high prevalence of osteopenia (44%) and osteoporosis (18%). After 12 months of calcium (1,200 mg/die) and cholecalciferol (800 UI/die)
supplementation, we found a significant increase of (25) OH-vitamin D level
(21.8 ± 12.3 vs. 35 ± 13 ng/ml; P < 0.01), without changes in bone mass density.

1952 case of vitamin D
resistance with 250,000 units
given, use the term “phosphate diabetes” as the phosphate is
dumped.

we performed the treatment of pigmented lesions
with NF1 by intense pulsed-radio frequency (IPL-RF) in combination with topical
application of vitamin D(3) ointment
. Eight patients were treated in this study and
the improvement was moderate to good in six cases (75%) although the response
was relatively mild

Bowing and/or pseudarthrosis of the tibia is a
known severe complication of neurofibromatosis type 1
(NF1). Mice with conditionally inactivated neurofibromin
(Nf1) in the developing limbs and cranium (Nf1Prx1) show bowing of the tibia
caused by decreased bone mineralisation and increased bone vascularisation

25(OH)D deficiency or insufficiency was not more frequent in NF1 patients than in controls (p = 0.074).

25-Hydroxyvitamin D3 increased from winter to
summer (mean: 21.0 to 46.5nmol/l) in NF1 adults. This increase was even larger
(p=0.0001) than in healthy controls (mean: 50.5 to 60.5nmol/l). However, there
were no differences of 25-hydroxyvitamin D3 concentrations in NF1 children and
healthy controls both in winter and in summer.

CONCLUSIONS:

Only adults with NF1 showed lower
25-hydroxyvitamin D3 levels in winter and summer, which are unlikely due to
impaired UV-dependent dermal synthesis, but rather might be caused by an
accelerated catabolism.

Eight of the 18 clinical biochemical measures
of bone health had at least 10% of NF1 patients outside the standard reference
range. Serum 25-hydroxy-vitamin D
concentrations were low in 56% of the NF1 patients, serum parathyroid hormone
(PTH) concentrations were high in 34%, and urine deoxypyridinoline cross-link
concentrations were high in 50%. Mean serum 25-hydroxy-vitamin D concentrations
were significantly lower in people with NF1 than in season matched controls in
both summer (p = 0.008) and winter (p<0.001). 36 (50%) of the 72 people with
NF1studied had BMD consistent with osteopenia
, and 14 (19%) had BMD consistent with
osteoporosis. High serum PTH concentration, high serum bone tartrate resistant
acid phosphatase concentration, and high serum calcium concentration were
associated with lower BMD among the NF1patients. Males were more likely than
females to have low BMD. The reported frequency of fractures in individuals
with NF1 was much higher than in their unaffected siblings and spouses (p<0.001),
and pathological fractures were reported only in NF1 patients.

injury
results in the occurrence of unmineralised bone
,
which is present not only in the vicinity of the drill site, but also at sites
distant to it. The aetiology remains obscure but the phenomenon seems to be
important for understanding the nature of NF1 pseudarthrosis. We hypothesise
that the injury-induced demineralisation process is driven by locally and systemically
secreted factors. NF1 is associated with decreased bone mineral content and in
acute cases osteomalacia/rickets of unknown aetiology has been observed [2628]. A
tumour inductive role has also been suggested [29].
Our results indicate that in Nf1 deficient limbs, the injury itself triggers a
partial demineralisation of the neighbouring bone. The mechanism behind this
process as well as the nature of the involved signalling pathways awaits future
investigation.

Statins have been shown to promote fracture healing in wild-type mice
and rats [1214].
Inhibition of the mevanolate pathway and the BMP2-dependent bone anabolic
action of lovastatin are likely to be involved [30]. In
the context of Nf1 deficiency lovastatin’s activity as a posttranslational
inhibitor of Ras seems to be of central importance

We might hypothesize that putative melatonin deficiency in cases of
neurofibromatosis 1might play a role in the pathogenesis of hyperphosphaturea
by decreasing sodium-phosphate cotransport,
increasing the level of cAMP, the un-antagonized effect of dopamine on
phosphate reabsorption and increasing glucocorticoid levels.

Puberty

The proband is
a 6-year-old boy with signs of precocious puberty. His penis was 10 cm,
testicles 8 ml, pubic hair P2-3, and the genital skin was hyperpigmented.
Multiple cafe au lait spots well above 5 mm were noticeable on his skin, as
well as hard subcutaneous nodules, mostly on his trunk….The MRI of the brain
showed a tumor of the
suprasellar region with compression of the pituitary stal
k.

In this translational investigation, we found that Nf1 activity regulates excessive drinking and
basal and ethanol-stimulated GABA release in the mouse central amygdala. We
also found that genetic variation in NF1 may confer an inherent susceptibility
to the transition from nondependent to
dependent drinking in humans.

In conclusion, there is evidence of increased
perfusion and increased density of microglia in juvenile NF1 mice specifically
in the amygdala
, both of which might be associated with
altered synaptic plasticity and, therefore, with cognitive deficits in NF1.

Finally, after showing the patient a picture of Datura
flowers, which she recognized immediately, we made the unusual diagnosis of
angle closure glaucoma by Datura
, a well-known toxic plant with mydriatic
properties

The expression of transforming growth factor beta
1 (TGF-beta 1), TGF-beta receptor type II, hepatocyte growth factor alpha
(HGF-alpha), c-met, p53, and N-CAM was higher in the areas of MPNST than in the
neurofibromatous
areas in four, five, five, eight, five, and three of the
eight cases, respectively. CD34 expression was lower in the areas of MPNST than
in the neurofibroma areas in three of the eight cases.

Feb 2016 We offer a suggestion for an alternative drug
discovery approach. In the new approach, selective and tolerable targeted
therapies would be developed for NF and later expanded to patients
with more complex diseases such as malignant
cancer in which the NF downstream pathways are deregulated.

The neurofibroma, a common feature of neurofibromatosis type
1 (NF1), is a benign peripheral nerve sheath tumor that contains predominantly
Schwann cells (SC). There are reports that neurofibroma growth may be affected
by hormonal changes, particularly in puberty and pregnancy, suggesting an
influence by steroid hormones. This study examined the effects of estrogen and
progesterone on proliferation and apoptosis in a panel of NF1 tumor xenografts.
SC-enriched cultures derived from three human NF1 tumor types (dermal
neurofibroma, plexiform neurofibroma, and malignant peripheral nerve sheath
tumor (MPNST)) were xenografted in sciatic nerves of ovariectomized scid
/Nf1-/+ mice. At the same time, mice were implanted with time-release pellets
for systemic delivery of progesterone, estrogen or placebo. Proliferation and
apoptosis by the xenografted SC were examined two months after implantation, by
Ki67 immunolabeling and TUNEL. Estrogen was found to increase the growth of all
three MPNST xenografts. Progesterone was associated with increased growth in
two of the three MPNSTs, yet decreased growth of the other.
Of the four dermal neurofibroma xenografts
tested, estrogen caused a statistically significant growth increase in one, and
progesterone did in another. Of the four plexiform neurofibroma SC xenografts,
estrogen and progesterone significantly decreased growth in one of the
xenografts, but not the other three. No relationship of patient age or gender
to steroid response was observed.

Neurofibromas develop in these patients when an
unknown cell type in the Schwann cell lineage loses its remaining functional
NF1 gene
and initiates a complex series of interactions with other
cell types; these interactions may be influenced by aberrant expression of
growth factors and growth factor receptors and the action of modifier genes.
Cells within certain neurofibroma subtypes subsequently accumulate additional
mutations affecting the p19(ARF)-MDM2-TP53 and p16INK4A-Rb signaling cascades,
mutations of other as yet unidentified genes, and amplification of growth
factor receptor genes, resulting in their transformation into MPNSTs.

It is well known that new neurofibromas frequently appear at
puberty and that existing neurofibromas increase in size during this period.
Neurofibromas also increase in size and frequency in pregnant women and regress
after parturition. These observations suggest that puberty- and
pregnancy-associated changes such as alterations in blood levels of sex
steroids promote neurofibroma growth. Despite these well-known
clinical observations, information supporting this hypothesis is surprisingly
sparse. In a series of 59 human neurofibromas, 75% of these neoplasms were
found to express progesterone receptors
(69), with expression of this steroid receptor
being more common in dermal neurofibromas (which occur with increased frequency
after puberty) than in plexiform neurofibromas (which are thought to be
congenital). Interestingly, the neurofibroma cells expressing progesterone
receptors were S-100 negative, indicating that they are not NF1−/− Schwann cells.

Majority (53 out of 58) of patients who received oral
estrogen-progestogen or pure progestogen preparations reported no associated tumor growth. In contrast,
significant tumor growth was reported by two patients who received depot
contraceptive containing high dose of synthetic progesteron
e.

Diverse regulatory mechanisms leading to either activation or
repression of particular genes frequently involve interactions between steroid
hormone receptors and other ubiquitous and/or cell-specific transcription
factors that act on the complex promoter of the regulated gene. Interplay
between steroid receptor-mediated and other signal transduction pathways may
also be involved. In addition, recent novel results indicate that moderate variations in the intracellular
concentration of pyridoxal 5′-phosphate (PLP), the biologically active form of
vitamin B6, can have pronounced modulatory effects on steroid-induced gene
expression. Specifically, elevation of intracellular PLP levels leads to
decreased transcriptional responses to glucocorticoid, progesterone, androgen,
or estrogen hormones. Conversely, cells in a vitamin B6-deficient state exhibit
enhanced responsiveness to steroid hormones
.

 

8

THE NF1 DIET

We know nothing about NF1 patients and diet. “ “A recent search of the MEDLINE, SCOPUS, Lilacs, and SciELO databases did
not identify any clinical studies regarding the eating habits, dietary patterns, or nutrient intake of NF1 patients.”

Forty-three patients (72%) recorded energy consumption lower than the estimated daily energy requirement (EER). Men (25/29, 86.2%) were more likely to fail to meet their target EER, compared to women (18/31, 58.1%) (P = 0.016). Inadequate intake of vitamin D, magnesium, calcium, and pyridoxine was noted between men and women, and all patients consumed excess sodium. NF1 patients did not consume adequate amounts of fiber or vitamins A and C. Excessive consumption of saturated fatty acids and lipids was also observed in both male and female patients.

 

All patients less than BMI of 25 (chart).

Lower blood sugars: adults with NF1 showed a
lower FBG level and a lower prevalence of high FBG level compared with non-NF1
controls.

 

9

NF1 EXERCISE AND RELAXATION

Brain magnetic resonance imaging (MRI) was available for 19 of these children. Chi-square analysis demonstrated a statistically significant correlation between
hypotonia and glioma in children with neurofibromatosis type 1 (90% sensitivity
and 78% specificity
). These results suggest that hypotonia might be a clinically useful
indicator of brain tumor in this at-risk population.

 

10

THE FUTURE OF NF1.

Several decades ago, Dr. Vincent Riccardi came up with the hypothesis that the progression of NF1 to neurofibromas was due to inflammation in the mast cells contained in high quantity within the tissue. His idea did not lead to a great deal more research, but Dr. Riccardi announced recently that a single NF1 patient placed on a mast cell suppressing drug (ketotifen) since infancy had, by the age of thirty, never developed any neurofibromas. While this is not a study, simply an anecdotal report, Dr. Riccardi’s assertions that inflammation in the body, exhibited by mast cell degranulation,  may well be the cause of much of the adult symptoms exhibited by NF1 patients.

        Other researchers including Dr. Cory Johannessen, have isolated NF1 to an opening mechanism within the cell, mTOR. Giving a cell with NF1 rapamycin, which blocks the opening of mTOR, also blocks the NF1 cell from becoming cancer. So another drug, rapamycin, may be useful for NF1 patients.  

        Zanthoxylum plants
are referred to as ‘toothache trees’ because their anesthetic or
counter-irritant properties render them useful in the treatment of pain.
9 The
characteristic biting or numbing taste of the pericarp of the dry seeds makes
it an indispensable spice among the people of South and South East Asia…Most
of the compounds inhibited growth of an Nf1– and p53-deficient
mouse glioma cell line at non-cytotoxic concentrations. https://en.wikipedia.org/wiki/Sichuan_pepper

One of the ingredients in
five spice. The Chinese pepper extract
selectively inhibits the growth of NF1-deficient malignant peripheral nerve
sheath tumor (MPNST) cells, without affecting the growth of normal fibroblasts,
and suppresses the growth of NF1-deficient human breast cancer (MDA-MB-231)
xenograft in mice