Neurofibromatosis Resource Center

Basics

Description

• Neurofibromatosis types 1 (NF1) and 2 (NF2) are neurocutaneous syndromes (phakomatoses). Although they share a name, they are unrelated.
  • NF1, the most common of the phakomatoses, is a multisystem disorder that may affect any organ: the defining feature of NF1 is the neurofibroma, a nerve sheath tumor that forms in intimate association with spinal, peripheral or cranial nerves (1). It is also characterized by café au lait macules (CALM), axillary and inguinal freckling, Lisch nodules, choroidal freckling.
  • NF2 is a rare condition that causes bilateral vestibular schwannomas.
• System(s) affected: musculoskeletal; nervous; skin/ exocrine; cardiovascular; neuro-ophthalmologic
• Synonym(s): von Recklinghausen disease, formerly peripheral NF

Epidemiology

Incidence

• Predominant sex for NF1: male 5 female
• Birth incidence NF1: 1:2,500 to 3,000

Prevalence

1:3,000 to 1:4,000

Etiology and Pathophysiology

• Neurofibromin is a GTPase–activating protein that acts as a tumor suppressor by down regulating p21-ras, a cellular proto-oncogene that enhances cell growth and proliferation.
• Some clinical manifestations of NF1, such as CALMs, require biallelic inactivation of NF1. Others, such as malignant peripheral nerve sheath tumors (MPNSTs), result from haploinsufficiency in combination with mutations in other genes, such as TP53.
• Neurofibromas are benign tumors composed of Schwann cells, fibroblasts, mast cells, and vascular components that develop along nerves.

Genetics

• 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.
• Gene is large (,60 exons), with .3,000 different germline mutations causing NF1. Molecular technology can detect 95% of clinically important NF1 mutations, but clinical diagnosis frequently can be made in childhood.
• Although expressivity is extremely variable, even within a family, the p.Arg1038Gly missense substitution correlates with a mild phenotype without neurofibromas or other complications.

Risk Factors

• Having an affected first-degree relative is a diagnostic criterion for NF1, although relatives may be unaware that they have NF1.
• Affected individuals with a positive family history (or a new mutation) have a 50% risk of transmitting NF1 to each offspring; 1 in 12 will be severely affected.

Commonly Associated Conditions

• Congenital heart disease, pulmonary stenosis, hypertension, renal artery stenosis
• Learning disabilities (50–75%)

Diagnosis

• NF1 is diagnosed based on the presence of clinical features. A diagnosis can be made through routine exam usually by age 4 with special attention to skin stigmata. At least two of the following clinical features must be present to make a diagnosis of NF1:
  • 6 café au lait (light brown) macules (CALMs), 5 mm in prepubertal individuals or 15 mm in adults
  • 2 neurofibromas of any type or 1 plexiform (uncircumscribed) neurofibroma
  • Axillary or inguinal freckling
  • 2 Lisch nodules (benign iris hamartomas)
  • 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.

History

• Family history of a first-degree relative with NF1
• Manifestations generally are not visible at birth, although plexiform neurofibromas are usually congenital, and tibial bowing is congenital.
• In addition to cutaneous lesions, NF1 may present with painful neurofibromas, pathologic fractures, or headaches secondary to hypertension caused by pheochromocytomas.
• Optic gliomas may present as involuntary eye movement, squinting, loss of vision, or as diencephalic syndrome.

Physical Exam

• Skin
  • CALMs, usually the presenting feature of NF1, develop before age 3 years. Evenly pigmented, irregularly shaped (coast of California), light-brown macules seen in 97% of patients with NF1; many unaffected individuals have 1 to 3 such macules.
  • Neurofibromas: can be soft or firm, cutaneous, subcutaneous, or plexiform; buttonhole invagination is pathognomonic. Cutaneous neurofibromas usually appear during late childhood or adolescence.
  • Plexiform neurofibromas present in up to 50%.
    • Usually congenital; may be subtle in infancy.
    • Freckling or hypertrichosis may be present over plexiform neurofibromas; may affect underlying structures or focal hyperplasia.
    • Many are internal, not obvious on exam.
    • Most grow slowly but can have rapid growth, especially in early childhood.
  • Evaluate for new or progressive lesions. Rapidly growing cutaneous lesions should be evaluated.
  • Axillary freckling (Crowe sign) or inguinal freckling (91%)
• Ophthalmologic
  • Lisch nodules in 30%: well-defined, dome-shaped, gelatinous hamartomatous lesions projecting from the iris, varying from clear yellow to browns
  • 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.
  • Choroidal freckling
• 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)
    • Nonossifying fibromas of the long bones in adolescents and adults are uncommon but can increase risk of fracture.
• Pay particular attention to neurologic examination (asymmetry) 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, 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, McCuneAlbright 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 no stigmata noted by age 2 years, NF is unlikely, but the child should be reexamined. Diagnosis usually can be made by age 4 years using NIH criteria, although young children may have multiple CALMs but no other stigmata.
• Periodic ophthalmologic evaluations at increasing intervals after 10 years of age (1)[C].
• Molecular confirmation may be appropriate, especially with atypical presentation.
• There may be some association between NF1 and lower urinary tract dysfunction in pediatric populations. Therefor children exhibiting symptoms of lower urinary tract dysfunction (urgency, daytime frequency, nocturia, weak or slow stream, incomplete bladder emptying) should be considered for a thorough urologic evaluation.
• Cerebrovascular diseases (migraine, aneurysm, stroke, cognitive deficits) have been observed in children with NF1. There may be some prognostic value to screen for cerebrovascular abnormalities early in the diagnostic evaluation.

Diagnostic Tests & Interpretation

• Molecular genetic testing often not necessary for diagnosis
• Confirmatory genetic testing is appropriate in those suspected of having NF1 but do not fulfill diagnostic criteria or for prenatal diagnosis or preimplantation genetic diagnosis (PGD).
• Molecular genetic testing of the NF1 gene can identify mutations in ,95% of those with a diagnosis.
• Multistep pathogenic variant detection with cDNA and gDNA sequence analysis recommended if molecular genetic testing is indicated. NF1 is caused by a wide variety of mutations in the NF1 gene.

Initial Tests (lab, imaging)

• Characteristic radiographic findings: sphenoid dysplasia, long bone cortical thinning, ribbon ribs, 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 is controversial. Optic gliomas (on MRI, 11–15%) may lead to blindness. Although areas of increased T 2 signal intensity (unidentified bright objects) are common on brain MRI, they are not diagnostic of NF1 and likely of no clinical significance.
• The NIH Consensus Development Conference does not recommend routine neuroimaging as a means of establishing a diagnosis, although modification of diagnostic criteria is discussed.

Diagnostic Procedures/Other

• Ophthalmologic evaluation, including slit-lamp exam of the irides; visual field testing to evaluate optic gliomas
• Neuropsychological testing: intelligence usually normal but may have significant deficits in language, visuospatial skills, and neuromotor skills
• Annual screening mammography and surveillance of breast lesions

Treatment

Medication

First Line

No specific therapeutic agents; symptoms are treated as they arise (e.g., anticonvulsants for seizures, medications for ADHD, management of blood pressure, vitamin D supplementation for osteopenia in those with low vitamin D levels).

Second Line

• Several biologically targeted therapies (e.g., mTOR inhibitors, imatinib, selective MEK inhibitors) that inhibit pathways responsible for tumor growth have been evaluated in clinical trials (1).
• Clinical trials with farnesyltransferase inhibitors, multikinase inhibitors, and antifibrotic agents have not been successful (1).
• A phase II trial of selumetinib is underway in adults and children with NF1 and symptomatic plexiform neurofibromas (1).
• Multiple clinical trials for NF1 are recruiting patients.

Issues for Referral

• Patients with more than minimal manifestations of NF1: Refer to a multidisciplinary NF clinic.
• Referral for psychosocial issues
• 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
• Laser therapy not recommended for CALMs
• The Children’s Tumor Foundation (CTF) has established the NF Clinical Trials Consortium and the CTF NF Clinic Network to facilitate clinical trials.

Surgery/Other Procedures

• Dermal neurofibromas can cause itching, stinging, pain, tenderness, bleeding, and cosmetic problems. Management may involve surgical removal, laser ablation of small lesions, electrodessication, emollients, camouflage make-up, psychological support (1).
• Plexiform neurofibromas, usually benign, can cause pain, disfigurement, neurologic deficit, difficulty swallowing and breathing, and severe hemorrhage, and are at risk for malignant transformation. Treatment is surgical (1)[C].
• Surgical treatment for dystrophic scoliosis (although nondystrophic scoliosis frequently can be managed conservatively, with bracing) or malignancy (especially MPNST).

Ongoing Care

Follow-Up Recommendations

NF1 health supervision 2008 guidelines:

• Infancy to 1 year
  • Growth and development: mild short stature, macrocephaly (increased brain volume); aqueductal stenosis/obstructive hydrocephalus
  • Check for focal neurologic signs or asymmetric neurologic exam.
  • Skeletal abnormalities, especially spine and legs
  • Neurodevelopmental progress
• 1 to 5 years
  • CALMs 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
  • 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 neurofibromas during adolescence and pregnancy.
  • Counsel parents about discussing diagnosis with child.
• 13 to 21 years
  • Examine the adolescent for abnormal pubertal development.
  • Skin examination for plexiform neurofibromas and neurologic exam for findings suggestive of deep plexiform neurofibromas; surgical consultation for signs of pressure on deep structures
  • Continue to monitor BP yearly.
  • Ophthalmologic exam 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. Neurofibromas may enlarge, and new tumors may develop during pregnancy.
  • Review prenatal diagnosis or refer to a geneticist.

Patient Education

• Genetic counseling and patient education regarding future complications and family planning. Support groups are important.
• Children’s Tumour Foundation, Washington University NF Center, Neuro Foundation

Prognosis

Variable; most patients have a mild expression of NF1 and lead normal lives. Life expectancy may be reduced by ~8 to 21 years, with an excess of deaths in individuals <40 years of age (1).

Complications

• Disfigurement: Skin neurofibromas develop primarily on exposed areas. The number tends to increase with puberty or pregnancy.
• Scoliosis: 10–30% (most cases mild); bowing of long bones, 2%; osteopenia and osteoporosis
• A large head is common but rarely associated with hydrocephalus.
• Increased risk of malignancy: MPNST (5–10%) usually in adults, especially within the field of previous radiotherapy for plexiform neurofibroma
• CNS tumors (5–15%), optic pathway glioma most common, most often asymptomatic but usually presents before age 6 years if symptomatic; symptomatic lesions usually stable or slowly progressive
• High relative risk (RR) for uncommon malignancies
• Increased risk for pheochromocytoma, rhabdomyosarcoma, leukemia, Wilms tumor
• RR for cancer of the esophagus (3.3), stomach (2.8), colon (2.0), liver (3.8), lung (3.0), bone (19.6), thyroid (4.9), malignant melanoma (3.6), non-Hodgkin lymphoma (3.3), chronic myeloid leukemia (6.7), female breast (2.3), and ovary (3.7)
• Learning disability: ,50%; reduction in average IQ (,85) may be associated with ADHD; cognitive impairment in 4–8%.
• Neuropsychological phenotype: behavioral problems, executive dysfunction, reduced working memory; literacy, numeracy, and visual spatial difficulties
• GI neurofibromas may cause GI disturbances.
• Seizures: 6–7%. Focal, tonic-clonic are the most common type of seizure observed (60.9%).
• Hypertension frequent in adults, may occur in childhood
• Disorders of puberty

Pregnancy Considerations

Increased risk of perinatal complications, stillbirth, intrauterine growth constriction; risk of cord compression and outlet obstruction by pelvic neurofibromas

Reference

1. Gutmann DH, Ferner RE, Listernick RH, et al. Neurofibromatosis type 1. Nat Rev Dis Primers . 2017;3:17004.

See Also

Tuberous Sclerosis Complex; Von Hippel-Lindau Syndrome

Codes

ICD10
Q85.01 Neurofibromatosis, type 1

Clinical Pearls

• NF1 manifests marked clinical variability. External stigmata may be subtle or absent in young children. Minimally affected children may become severely affected adults.
• A single CALM is of no concern in a child, but having ?6 is a diagnostic criterion for NF1.

From 5-Minute Clinical Consult, Shannon L McCown, MD Reviewed 05/2023