characteristic of NF1 The following is a list of conditions and complications associated with NF-1, and, where available, age range of onset and progressive development, occurrence percentage of NF-1 population, method of earliest diagnosis, and treatments and related medical specialties. The progression of the condition is roughly as follows: • Congenital musculoskeletal disorders may or may not be present. • Cutaneous conditions may be observed in early infancy. • Small tumors may arise in the retina which can eventually lead to blindness. Also, Lisch nodules may grow on the iris, but these are harmless. • Learning disabilities may arise in preschool children. • Neurofibromas may occur and can sometimes cause many dependent neurological conditions and cutaneous and skeletal disfigurement. • Depression and social anxiety may occur as a result of disabilities caused by the condition. • Neurofibromas may, in 8-13% of cases, transition into cancer, which can be fatal.
Musculoskeletal disorder Musculoskeletal abnormalities affecting the
skull include
sphenoid bone dysplasia, congenital
hydrocephalus and associated neurologic impairment. Disorders affecting the
spine include: • In NF-1, there can be a generalized abnormality of the soft tissues in the
fetus, which is referred to as
mesodermal
dysplasia, resulting in maldevelopment of skeletal structures. •
Meningoceles and formation of cystic diverticula of the dura of the spine, unrelated to
Spina bifida • Radiographically,
dural ectasia can lead to scalloping of the posterior vertebral bodies and to the formation of cystic
diverticula of the dura of the spine. This may result in temporary or permanent loss of lower extremity sensorimotor function. • Focal
scoliosis and/or
kyphosis are the most common skeletal manifestation of NF-1, occurring in 20% of affected patients. Approximately 25% of patients will require corrective surgery.
Skeletal muscle weakness and motor control deficits Deficits in motor function in NF-1 have been long recognised and have been historically attributed to nerve dysfunction. In recent years however, studies suggest NF-1 is associated with a primary problem in muscle function (myopathy). Clinical findings in people with NF-1 include: • Reduced skeletal muscle size • Reduced exercise capacity • Muscle weakness (the most recent study reports between 30–50% reduced upper and lower limb muscle strength in NF-1 children compare with matched controls). Studies in genetically modified mice have thus far confirmed that the NF1 gene is vital for normal muscle development and metabolism. Knockout of the NF1 gene in muscle results in deregulated lipid metabolism and muscle weakness. NF-1 is a disease in the
RASopathy family of diseases, which include
Costello syndrome,
Noonan syndrome, and
cardiofaciocutaneous syndrome. The RASopathies also present with skeletal muscle weakness. It is likely that impaired muscle function in these disorders is linked to altered Ras/MAPK signalling, however, the precise molecular mechanisms remain unknown. •
Freckling of the
axillae or
inguinal regions. •
Dermal neurofibroma, manifested as single or multiple firm, rubbery bumps of varying sizes on a person's skin. Age of onset is puberty. Progressive in number and size. Not malignant. Can be treated with
CO2 lasers or by removal by a plastic surgeon specialized in NF1.
Eye disease •
Lisch nodules in the
iris. •
Optic nerve gliomas along one or both
optic nerves or the
optic chiasm can cause bulging of the eyes, involuntary eye movement, squinting, and / or vision loss. Treatment may include surgery, radiation ± steroids, or chemotherapy (in children).
Neurobehavioral developmental disorder The most common complication in patients with NF-1 is cognitive and learning disability. These cognitive problems have been shown to be present in approximately 90% of children and adults with NF-1 and have significant effects on their schooling and everyday life. These cognitive problems have been shown to be stable into adulthood mainly in the mid 20s to early 30s and do not get worse unlike some of the other physical symptoms of NF-1. The most common cognitive problems are with perception, executive functioning and attention. Disorders include: • Approximately 42% of children with NF-1 have symptoms of
autism, with 36.78% of them being severe cases, 33.33% being mild to moderate cases, and 29.89% of them having both symptoms of autism and ADHD. •
Attention deficit hyperactivity disorder has been shown to be present in approximately 40% of children with NF-1. • Motor deficits are common. Motor deficits due to NF-1 are probably not
cerebellar. •
Spatial deficit.
Nervous system disease The primary neurologic involvement in NF-1 is of the peripheral nervous system, and secondarily of the central nervous system.
Schwannomatosis is a rare condition defined by the presence of multiple benign tumors of nerves that are frequently very painful. In addition to pain, weakness is a common problem. Symptoms usually begin in young or mid-adult years.
Peripheral neuropathy Neurofibroma A
neurofibroma is a lesion of the peripheral nervous system. Its cellular lineage is uncertain, and may derive from
Schwann cells, other perineural cell lines, or
fibroblasts. Neurofibromas may arise sporadically, or in association with NF-1. Neurofibroma conditions are progressive and include: •
Plexiform neurofibroma: Often congenital. Lesions are composed of sheets of neurofibromatous tissue that may infiltrate and encase major nerves, blood vessels, and other vital structures. These lesions are difficult and sometimes impossible to routinely resect without causing any significant damage to surrounding nerves and tissue. •
Cutaneous neurofibroma, affecting 8–12% of patients with NF-1. This occurs in a deep nerve trunk. Diagnosis by cross-sectional imaging (e.g.,
computed tomography or
magnetic resonance) as a
fusiform enlargement of a nerve. •
Schwannomas, peripheral nerve-sheath tumors which are seen with increased frequency in NF-1. The major distinction between a schwannoma and a solitary neurofibroma is that a schwannoma can be
resected while sparing the underlying nerve, whereas resection of a neurofibroma requires the sacrifice of the underlying nerve. • Nerve root neurofibroma. • Bones, especially the ribs, can develop chronic erosions (pits) from the constant pressure of adjacent neurofibroma or schwannoma. Similarly, the neural foramen of the
spine can be widened due to the presence of a nerve root neurofibroma or schwannoma. Surgery may be needed when NF-1 related tumors compress organs or other structures.
Nerve sheath tumor • Chronic pain, numbness, and/or paralysis due to peripheral
nerve sheath tumor.
Other complications • Renal artery anomalies or
pheochromocytoma and associated chronic
hypertension •
Schwannoma • Plexiform fibromas • Optic nerve glioma • Epilepsy
Central nervous system disease Epilepsy •
Occurrence. Epileptic seizures have been reported in up to 7% of patients. •
Diagnosis. Electroencephalograph, magnetic resonance imaging, computed tomographic scan, single-photon emission CT and positron emission tomographic scan. •
Etiology. Due to cerebral tumors, cortical malformation, mesial temporal sclerosis. •
Therapy. Drug therapy (57% amenable) where not resistant (29%).
Glial tumors Intracranially, NF-1 patients have a predisposition to develop glial tumors of the central nervous system, primarily
optic nerve gliomas and associated blindness.
Focally degenerative myelin Another CNS manifestation of NF-1 is the so-called "unidentified bright object" or UBO, which is a lesion which has increased signal on a T2 weighted sequence of a
magnetic resonance imaging examination of the brain. These UBOs are typically found in the
Cerebral peduncle, pons, midbrain, globus pallidus, thalamus, and optic radiations. Their exact identity remains a bit of a mystery since they disappear over time (usually, by age 16), and they are not typically biopsied or resected. They may represent a focally degenerative bit of
myelin.
Dural ectasia Within the CNS, NF-1 manifests as a weakness of the
dura, which is the tough covering of the brain and spine. Weakness of the dura leads to focal enlargement due to chronic exposure to the pressures of
CSF pulsation, and typically presents as paraesthesia or loss of motor or sensory function.
Acetazolamide has shown promise as a treatment for this condition, and in very few cases do dural ectasia require surgery. People with NF1 are much more likely to experience suicidal thoughts than the general population. One study found that 45% of people with NF had suicidal thoughts compared to 10% of a healthy control group. Another study found that 46.5% were of people with NF1 were found to have at least one psychiatric comorbid diagnosis.
Neurodivergence Children and adults with NF-1 often have
Autism and/or
ADHD. • 30 - 50% of people with NF1 also meet the diagnostic criteria for ADHD • 11-26% of people with NF1 also have
Autism Spectrum Disorder Puberty and height Children diagnosed with NF-1 may experience delayed or precocious puberty. Recent studies have correlated precocious puberty in individuals with NF-1 with the presence of optic pathway tumours. Furthermore, the heights of children affected by NF-1 have been shown to increase normally until puberty, after which increases in height lessen when compared to healthy counterparts. •
Frequency. A plexiform neurofibroma has a lifetime risk of 8–12% of transformation into a malignant tumor. •
Diagnosis.
MRI. •
Treatment. Surgery (primary), radiation therapy. •
Mortality. Malignant nerve sheath tumor was the main cause of death (60%) in a study of 1895 patients with NF-1 from France in the time period 1980–2006 indicated excess mortality in NF-1 patients compared to the general population. The cause of death was available for 58 (86.6%) patients. The study found excess mortality occurred among patients aged 10 to 40 years. Significant excess mortality was found in both males and females.
Breast cancer Biological females with NF also have a five-fold increased risk of
breast cancer and may have an increased breast cancer related mortality. The median survival for breast cancer in people with NF was 5 years vs. the reported median survival of over 20 years in the general population using the SEER database. ==Cause==