> Table of Contents > Neurofibromatosis Type 1
Neurofibromatosis Type 1
Rayna Goldstein, MD
Michele Roberts, MD, PhD
image BASICS
DESCRIPTION
  • Neurofibromatosis types 1 (NF1) and 2 (NF2) are neurocutaneous syndromes (phakomatoses). Although they share a name, they are distinct and unrelated conditions with genes on different chromosomes.
    • NF2 is a rare condition that causes bilateral vestibular schwannomas.
    • NF1 is a multisystem disorder that may affect any organ. It is the most common of the phakomatoses.
  • System(s) affected: musculoskeletal, nervous, skin/exocrine, cardiovascular, neuroophthalmologic
  • Synonym(s): von Recklinghausen disease, formerly peripheral NF
EPIDEMIOLOGY
Incidence
  • Predominant sex for NF1: male = female
  • Birth incidence NF1: 1:2,500 to 3,000
Prevalence
1:3,000 to 1:4,000
ETIOLOGY AND PATHOPHYSIOLOGY
  • Neurofibromin is a guanosine triphosphatase-activating protein that acts as a tumor suppressor by downregulating a cellular protooncogene, p21-ras, which enhances cell growth and proliferation.
  • Neurofibromata are benign tumors composed of Schwann cells, fibroblasts, mast cells, and vascular components that develop along nerves.
  • The two-hit hypothesis has been invoked to explain malignant transformation in NF1.
Genetics
  • Online Mendelian Inheritance in Man 162200
  • Caused by a mutation in the NF1 gene on chromosome 17q11.2; autosomal dominant inheritance; protein product is called neurofibromin.
  • 50% of cases are due to de novo mutations, mostly paternal; likelihood increases with paternal age
  • Prenatal diagnosis is possible if mutation is known.
  • Penetrance is nearly 100%; expressivity is highly variable, even within a family.
  • Gene is large, with a variety of mutations causing NF1. Molecular technology can detect 95% of clinically important NF1 mutations, but clinical diagnosis frequently can be made in childhood.
  • ˜5% of individuals with NF1 have a large deletion of the entire NF1 gene (or nearly so); they usually have a more severe phenotype.
  • Segmental NF is limited to a single body region and is caused by mosaicism for the NF1 mutation.
RISK FACTORS
  • Having an affected first-degree relative is a diagnostic criterion for NF1, although relatives may be unaware of their condition.
  • Affected individuals with a positive family history, as well as those with a new mutation, have a 50% risk of transmitting NF1 to each of their offspring; 1 in 12 will be severely affected.
  • Individuals with segmental NF1 may have gonadal mosaicism and may be at risk for transmission of the mutated gene.
COMMONLY ASSOCIATED CONDITIONS
Congenital heart disease, pulmonary stenosis, hypertension, renal artery stenosis
image DIAGNOSIS
  • NF1 can be diagnosed by routine exam by age 4 years, with attention to skin stigmata; diagnostic criteria include ≥2 of the following (1):
    • ≥6 café au lait (light brown) macules, ≥5 mm in prepubertal individuals or ≥15 mm in adults
    • ≥2 neurofibromata of any type or 1 plexiform (noncircumscribed) neurofibroma
    • Axillary or inguinal freckling
    • ≥2 Lisch nodules (benign iris hamartomas, asymptomatic)
    • Optic glioma by MRI
    • Characteristic osseous lesions: sphenoid dysplasia, long-bone cortical thinning, ribbon ribs, angular scoliosis
    • First-degree relative with NF1 by above criteria
  • Prenatal diagnosis is possible with known mutation or by linkage testing (with positive family history), although not predictive of clinical course.
PHYSICAL EXAM
  • Skin
    • Café au lait macules develop during the first 3 years of childhood and are usually the presenting feature of NF1. Evenly pigmented, irregularly shaped (coast-of-California), light brown macules present in 97% of patients with NF1; many unaffected individuals have one to three such macules.
    • Neurofibromata can be cutaneous, subcutaneous, or plexiform and may be soft or firm; buttonhole invagination is pathognomonic. Cutaneous neurofibromata usually begin to appear during late childhood or adolescence.
    • Plexiform neurofibromata are present in up to 50% of individuals with NF1
      • Usually congenital; may be subtle in infancy
      • Freckling or hypertrichosis may be present over plexiform neurofibromata; may affect underlying structures or cause focal hyperplasia
      • Many are internal, not obvious on exam.
      • Most grow slowly over many years but can have rapid growth, especially in early childhood.
    • Evaluate for new lesions and progression of preexisting ones. Rapidly growing cutaneous lesions should be evaluated thoroughly.
    • Axillary freckling (Crowe sign) or inguinal freckling (91%)
  • Ophthalmologic
    • Lisch nodules (benign iris hamartomas) in 30%: well-defined, dome-shaped, gelatinous hamartomatous lesions projecting from the iris, varying from clear yellow to brown
    • Essentially unique to NF, Lisch nodules are asymptomatic; significant only for diagnosis.
    • Pallor or atrophy of optic disc, bulging of orbit, loss of vision may be signs of optic glioma.
  • Skeletal
    • Scoliosis and vertebral angulation
    • Localized bone hypertrophy, especially of the face
    • Limb abnormalities:
      • Pseudoarthrosis of the tibia
      • Tibial dysplasia (anterolateral bowing of the tibia) is congenital, if present.
      • Nonossifying fibromas of the long bones in adolescents and adults are uncommon but can increase risk of fracture.
  • Pay particular attention to neurologic examination or new focal pain.
  • Measure BP yearly. Hypertension is more common in patients with NF1 and could be secondary to renal artery stenosis, aortic stenosis, and pheochromocytoma.
  • Evaluate neurodevelopmental progress in children. Learning disabilities occur in 50-75%.
DIFFERENTIAL DIAGNOSIS
Familial café au lait spots (autosomal dominant, no other NF1 features), Legius syndrome, constitutional mismatch repair deficiency syndrome (CMMRD), NF2, Watson syndrome, LEOPARD syndrome, McCune-Albright syndrome, neurocutaneous melanosis, proteus syndrome, lipomatosis, Jaffe-Campanacci syndrome
Geriatric Considerations
In NF1, cutaneous lesions and tumors increase in size and number with age.
Pediatric Considerations
  • Children who have inherited the NF1 gene of an affected parent usually are identified by age 1 year, but external stigmata may be subtle. If there are no stigmata by age 2 years, NF is unlikely, but the child should be reexamined within the next few years. Definite diagnosis can be made by age 4 years using National Institute of Health (NIH) criteria (1).
  • Young children with multiple café au lait spots, but no other stigmata after careful physical and ophthalmologic evaluation, should be followed clinically as if they have NF1 (2).
  • Molecular confirmation may be appropriate, especially with atypical presentation (3).
DIAGNOSTIC TESTS & INTERPRETATION
  • DNA sequence and deletion/duplication analysis of the NF1 gene can identify mutations in ˜96% of those with a clinical diagnosis.
  • Molecular genetic testing is available, although often not necessary for diagnosis. Diagnostic laboratory information: https://www.genetests.org/
  • Confirmatory genetic testing is appropriate in those who are suspected of having NF1 but do not fulfill diagnostic criteria or for prenatal diagnosis or preimplantation genetic diagnosis (PGD) (4).
Initial Tests (lab, imaging)
  • Characteristic radiographic findings: sphenoid dysplasia, long bone cortical thinning, ribbon ribs, and angular scoliosis. Screening radiographs of the knees in adolescents is controversial. CT can demonstrate bony changes.
  • MRI findings of the orbits, brain, or spine (86%). Routine head MRI scanning in asymptomatic individuals with NF1 is controversial. Optic gliomata (seen on MRI, 11-15%) may lead to blindness. Although areas of increased T2 signal intensity (unidentified bright objects) are common on brain MRI, they are not diagnostic of NF1 and likely are of no clinical significance.
  • P.711

  • The NIH Consensus Development Conference does not recommend routine neuroimaging as a means of establishing a diagnosis, although modification of diagnostic criteria is discussed (1)[C].
Diagnostic Procedures/Other
  • Ophthalmologic evaluation, including slit-lamp exam of the irides; visual field testing to evaluate optic gliomata
  • Neuropsychological testing: Intelligence usually normal but may have significant deficits in language, visuospatial skills, and neuromotor skills.
image TREATMENT
MEDICATION
First Line
There are no specific therapeutic agents approved; individual aspects are treated as they arise (e.g., anticonvulsants for seizures, medications for ADHD, management of blood pressure).
Second Line
  • In case studies, Sirolimus, a mammalian target of rapamycin [mTOR] inhibitor, did not shrink nonprogressive plexiform neurofibromas, but did relieve pain and retard progression of inoperable plexiform neurofibromas (5)[C].
  • Multiple clinical trials for NF1 are recruiting patients (see https://www.clinicaltrials.gov/).
ISSUES FOR REFERRAL
  • Patients with more than minimal manifestations of NF1: Refer to a multidisciplinary NF clinic.
  • Referral for psychosocial issues of family and affected individuals
  • Educational intervention for children with learning disabilities or ADHD (40%)
  • Early referral to orthopedics for congenital tibial bowing
ADDITIONAL THERAPIES
  • Occupational therapy for children with NF1 who present with fine motor difficulties
  • There is no evidence supporting laser therapy for café au lait spots.
  • The Children's Tumor Foundation (CTF) has established the NF Clinical Trials Consortium and the CTF NF Clinic Network to facilitate future clinical trials and help identify best practices (6).
SURGERY/OTHER PROCEDURES
Surgical treatment for severe scoliosis, plexiform neurofibromata, or malignancy
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
NF1 health supervision 2008 guidelines:
  • Infancy to 1 year (7)[C]
    • Growth and development: mild short stature, macrocephaly (increased brain volume); aqueductal stenosis/obstructive hydrocephalus, hydrocephalus
    • Check for focal neurologic signs or asymmetric neurologic exam.
    • Skeletal abnormalities, especially spine and legs
    • Neurodevelopmental progress
  • 1 to 5 years (7)[C]
    • Café au lait spots and axillary freckling have no clinical significance.
    • Annual ophthalmologic exam
    • Brain MRI for visual changes, persistent headaches, seizures, marked increase in head size, plexiform neurofibroma of the head
    • Assess speech and language: hypernasal speech due to velopharyngeal insufficiency and delayed expressive language development.
    • Developmental evaluation of learning and motor abilities; may benefit from speech/language and/or motor therapy, and special education
    • Monitor BP annually.
  • 5 to 13 years (7)[C]
    • Evaluate for skin tumors causing disfigurement and obtain consultation if surgery is desired to improve appearance or function.
    • Evaluate for premature or delayed puberty. If sexual precocity is noted, evaluate for an optic glioma or hypothalamic lesion. Review the effects of puberty on NF.
    • Evaluate for learning disabilities and ADHD.
    • Evaluate social adjustment, development, and school placement.
    • Monitor ophthalmologic status yearly until age 8 years; complete eye exam every 2 years.
    • Monitor BP annually.
    • Refer patient to a clinical psychologist or child psychiatrist for problems with self-esteem.
    • Discuss growth of neurofibromata during adolescence and pregnancy.
    • Counsel parents about discussing diagnosis with child.
  • 13 to 21 years (7)[C]
    • Examine the adolescent for abnormal pubertal development.
    • Thorough skin examination for plexiform neurofibromata and a complete neurologic exam for findings suggestive of deep plexiform neurofibromata; seek surgical consultation for signs of pressure on deep structures.
    • Continue to monitor BP yearly.
    • Continue ophthalmologic examination every 2 years until age 18 years.
    • Discuss genetics of NF1 or refer for genetic counseling.
    • Discuss sexuality, contraception, and reproductive options.
    • Discuss effects of pregnancy on NF1, if appropriate. Neurofibromata may enlarge and new tumors may develop during pregnancy.
    • Review prenatal diagnosis or refer the patient to a geneticist.
PATIENT EDUCATION
  • Genetic counseling and patient education regarding future complications about family planning
  • Support groups are important: http://www.ctf.org/.
PROGNOSIS
Variable; most patients have a mild expression of NF1 and lead normal lives.
REFERENCES
1. DeBella K, Szudek J, Friedman JM. Use of the National Institutes of Health Criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics. 2000;105(3 Pt 1):608-614.
2. Nunley KS, Gao F, Albers AC, et al. Predictive value of café au lait macules at initial consultation in the diagnosis of neurofibromatosis type 1. Arch Dermatol. 2009;145(8):883-887.
3. Burkitt Wright EM, Sach E, Sharif S, et al. Can the diagnosis of NF1 be excluded clinically? A lack of pigmentary findings in families with spinal neurofibromatosis demonstrates a limitation of clinical diagnosis. J Med Genet. 2013;50(9):606-613.
4. National Institutes of Health Consensus Development Conference statement: neurofibromatosis. Bethesda, Md., USA, July 13-15, 1987. Neurofibromatosis. 1988;1(3):172-178.
5. Hua C, Zehou O, Decassou S, et al. Sirolimus improves pain in NF1 patients with severe plexiform neurofibromas. Pediatrics. 2014:133(6): e1792-e1797.
6. Williams VC, Lucas J, Babcock MA, et al. Neurofibromatosis type 1 revisited. Pediatrics. 2009;123(1):124-133.
7. Hersh JH. Health supervision for children with neurofibromatosis. Pediatrics. 2008;121(3):633-642.
See Also
&NA;
Tuberous Sclerosis Complex; Von Hippel-Lindau Syndrome
Codes
&NA;
ICD10
Q85.01 Neurofibromatosis, type 1
Clinical Pearls
&NA;
  • Marked clinical variability. External stigmata may be subtle or absent in young children. Minimally affected children may become severely affected adults.
  • A single café au lait spot is of no concern in a child, but having ≥6 is a diagnostic criterion for NF1.