Neurofibromatosis: Type 1
Neurofibromatosis Type 1 (NF-1) is an autosomal dominant disorder that is characterized by hallmark clinical signs, particularly pigmentary skin lesions called café au lait macules, dermal tumors called neurofibromas, and skinfold freckling, among other clinical manifestations. NF-1 may result in a number of both physical and cognitive complications.
NF-1 is a genetic disorder resulting from a germline mutation of the NF-1 tumor-suppressor gene on chromosome 17 that normally encodes for a protein called neurofibromin, resulting in functional loss of the protein. Neurofibromin normally serves as a negative regulator of the RAS proto-oncogene, RAS being a key signaling molecule in promoting cell growth/division.
Epidemiology including risk factors and primary prevention
NF-1 (also known as von Recklinghausen disease) is a relatively common disorder, with a prevalence of approximately 1 in 2,500 to 3,500 individuals. Around half of the cases of NF-1 are familial (inherited), while the other half of cases occur from sporadic mutations of the NF-1 gene. Genetic testing has identified over 3,000 different germline NF-1 gene mutations, thus far.
Diagnosis of NF-1 is usually made clinically, although genetic testing may be required for diagnosis on rare occasion. National Institutes of Health (NIH) Consensus Development Conference criteria requires two or more of the following clinical features:
- 6 or more café-au-lait macules present (> 5mm in diameter in prepuberty or > 15 mm in diameter postpuberty).
- 2 or more neurofibromas (benign nerve sheath tumors), or 1 plexiform neurofibroma
- Skinfold freckling (axillary or inguinal)
- 2 or more Lisch nodules (iris hamartomas)
- A distinct bony lesion (such as long bone dysplasias and sphenoid wing dysplasia)
- Optic pathway glioma (OPG)
- First-degree relative with diagnosis of NF-1
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
Clinical features usually evident by early infancy include café au lait macules, a positive family history of NF-1, and characteristic bony abnormalities. Skinfold freckling is often first observed in early childhood, between ages 5 and 8. Optic pathway gliomas (OPGs) develop usually prior to age 7. Up to half of patients exhibit iris hamartomas by age 6; over 90%, by adulthood. Dermal neurofibromas usually begin to appear around puberty. Plexiform neurofibromas are considered congenital and may cause symptoms later in life, especially if they progress. Rate of progression is generally variable, but may be increased with puberty or pregnancy. Life expectancy of those with NF-1 is thought to be reduced by around 8 to 21 years, with one common cause of earlier mortality being malignant tumor.
Specific secondary or associated conditions and complications
In addition to peripheral nerve sheath tumors, NF-1 is associated with development of other tumors, both benign and malignant, scoliosis and other orthopedic manifestations, and vascular dysplasias and hypertension. In children, NF-1 is associated with learning disabilities, attention deficit, and other cognitive delay, precocious puberty, seizures, and pain.
2. Essentials of Assessment
Children with NF-1 may exhibit both physical and cognitive issues related to the disorder. A thorough history for symptoms experienced by the child may help to direct appropriate workup to identify tumor or disorder-related complications.
Pediatric NF-1 patients need regular ophthalmologic examination, through age 12, to screen for OPGs. Skin should be inspected for macules and neurofibromas. Patients should be monitored at every clinic visit for growth and developmental delays, precocious puberty, hypertension, scoliosis and other bony abnormalities, and cognitive/behavioral difficulties.
Children with NF-1 may exhibit reduced intellectual capacity, with a slight reduction seen in average Intelligence Quotient (IQ) scores. In addition, memory, literacy, executive functioning, attention, and visuospatial difficulties have been reported. Screening is therefore important to detect and to intervene for attention deficit, autism, and other potential cognitive-behavioral conditions. A proper functional mobility assessment should also be performed.
No specific routine laboratory studies for NF-1 are required, although monitoring for bone health, including through checking Vitamin D levels, may be considered.
Routine neuroimaging (brain) with magnetic-resonance imaging (MRI) to screen for OPG is not recommended, although some institutions employ this for patients up to the age of 15 months.
Some experts advocate whole body MRI between the ages of 16 and 18 to survey for size and extent of neurofibromas. Dedicated imaging of specific areas of the body, such as with plain films, are otherwise indicated based on history obtained during each clinic visit.
Supplemental assessment tools
Genetic testing is usually not necessary to diagnose the condition of NF-1; rather, it is a clinical diagnosis. Genetic and molecular testing, however, may identify the causative mutations in the NF-1 gene, and some genotypic-phenotypic correlations do exist.
Early predictions of outcomes
Greater disease severity is associated with reduced quality of life (QOL). Pain is inversely proportional to QOL scores. Affective-emotional functioning, as reported through depressed mood, anxiety, and social stress impacts QOL scores.
Social role and social support system
Children with evidence of cognitive-behavioral impairments requires prompt neuropsychological evaluation and treatment. Management includes pharmacologic therapy, teacher engagement, and any possible, permissible educational adaptations.
3. Pain Management Approach
Available or current treatment guidelines
The American Academy of Pediatrics (AAP) Committee on Genetics provides guidelines for monitoring and for intervention to optimize the health, growth, and development of children with NF-1 (see Bibliography for the reference).
At different disease stages
Longitudinal care and anticipatory guidance for patients with NF-1 is important to detect and to treat problems or complications as they occur over time, which can improve outcomes when addressed in a timely fashion. Management begins at the prenatal visit, where the pediatrician may educate the parents about NF-1 and its expected course. From birth to 1 month of age, examination for cutaneous lesions and presence of plexiform neurofibromas should be taken. Some experts also suggest imaging (by MRI) to evaluate for OPGs or other intracranial tumors. During infancy, patients’ growth and development should be tracked, physical examination should look for cutaneous and skeletal abnormalities, particularly in the spine and the legs. Ophthalmologic evaluation continues during this time. In early childhood, the presence of skinfold freckling and dermal neurofibromas should be documented for reference. Routine visual examination should continue, and blood pressure and cognitive-behavioral assessment should commence. During late childhood, in addition to the above, sexual maturity should be evaluated, as precocity may indicate intracranial tumor. From adolescence to adulthood, in addition to the aforementioned, ophthalmologic examination is recommended every 2 years, until the age of 18. Progression of neurofibromas may result in severe pain and muscular weakness, resulting in functional mobility impairment and interference with self-care, daily activities, and extracurricular involvement. There is no standard protocol for rehabilitation in NF-1; however, rehab interventions should focus on gait, balance, and postural training, cervicoscapular and lumbar stabilization, stretching, strengthening, range of motion, coordination, fine motor skills, community re-integration, task-specific training, and a progressive home exercise program. Pain interventions should include myofascial release, hot/cold modalities, massage, and other modalities.
Coordination of care
Due to multiorgan involvement and associated complications seen in NF-1, a care team that includes pediatricians, oncologists, ophthalmologists, neurologists, psychologists, therapists, and surgical specialists can provide valuable multidisciplinary clinical management.
Patient & family education
Both the patient and family members need education about the genetics, clinical features, potential symptoms, and typical course of NF-1. It is appropriate to include discussion about expected evaluation steps and interventional considerations, including surgical, for complications of NF-1.
Measurement of Treatment Outcomes
The primary long term visual outcome measure for patients with sporadic OPGs is visual acuity in the more severely affected side, usually categorized in an ordinal scale of three categories: 20/30 or better; 20/40 to 20/80; and 20/100 or worse.
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
Clinical management of patients with NF-1 requires age-appropriate examination and anticipatory guidance, from infancy to adulthood. Involvement and education of family throughout the child’s development is essential, and a multidisciplinary team approach offers the best chance for improving clinical outcomes, not only from a standpoint of physical well-being, but also from a standpoint of psychosocial well-being.
4. Cutting edge/emerging and unique concepts and practice
Cutting edge concepts and practice
The signaling pathways controlled by neurofibromin protein are better understood, and preclinical studies involving genetically engineered NF-1 mice are leading to the identification of biological targets, for instance downstream to RAS, to treat tumors, such as plexiform neurofibromas, OPGs, and malignant peripheral nerve sheath tumors. These bench studies are being translated to clinical trials in part through the Neurofibromatosis Clinical Trials Consortium.
5. Gaps in the evidence-based knowledge
Gaps in the evidence-based knowledge
Gutmann DH, Ferner RE, Listernick RH, Korf BR, Wolters PL, Johnson KJ. Neurofibromatosis type 1. Nat Rev Dis Pri 2017; 3: 1-17.
Anderson JL, Gutmann DH. Neurofibromatosis type 1. Handbook of Clinical Neurology 2015; 132: 75-86.
Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary approach to care 2014; 13: 834-843.
Hersh JH, Committee on Genetics. Health Supervision for Children with Neurofibromatosis. Pediatrics 2008; 121: 633-648.
Girish S Shroff MD
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Sheetal Shroff MD
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Siddarth Thakur MD
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Carlos J Roldan MD
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