Neurofibromatosis – Causes, Symptoms, Diagnosis, Treatment and Ongoing care
- Neurofibromatosis type 1 (NF1) and 2 (NF2) are neurocutaneous syndromes (phakomatoses). Although they share a name and are both autosomal dominant disorders, they are distinct and unrelated conditions with genes on different chromosomes. NF2 causes bilateral vestibular schwannomas. NF2 is rare and not further discussed in this post.
- 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; Neuro-ophthalmologic
- Synonym(s): von Recklinghausen disease, formerly “peripheral NF”
- Predominant sex for NF1: Male = Female
- Birth incidence NF1: 1/2,500–3,000
- Having an affected 1st-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; 1/12 will be severely affected.
- Individuals with segmental NF1 may have gonadal mosaicism and may be at risk for transmission of the mutated gene.
- NF1: OMIM #162200
- Caused by a mutation in the NF1 gene on chromosome 17q11.2; autosomal dominant inheritance; protein product is called neurofibromin
- 1/2 of cases are attributed to new mutations. Prenatal diagnosis is possible.
- Penetrance is high; expressivity is highly variable.
- NF1 is a large gene with a variety of mutations causing neurofibromatosis. Molecular technology can detect 95% of clinically important NF1 mutations, but it is usually not indicated because clinical diagnosis can frequently be established in childhood.
- About 5% of individuals with NF1 have a large deletion of the entire NF1 gene (or nearly so). These individuals usually have a more severe phenotype.
- A variant of NF1, known as segmental NF, is limited to a single body region and may be explained by mosaicism for the NF1 mutation.
- Neurofibromin belongs to a family of GTPase-activating proteins and acts as a tumor suppressor by downregulating a cellular proto-oncogene, p21-ras, that enhances cell growth and proliferation.
- Neurofibromata are benign tumors composed of Schwann cells, fibroblasts, mast cells, and vascular components that develop along nerves.
- The 2-hit hypothesis has been invoked to explain malignant transformation in NF1.
Commonly Associated Conditions
Cardiovascular disease: Congenital heart disease, pulmonary stenosis, hypertension
Diagnostic criteria for NF1 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
- 1st-degree relative with NF1 according to above criteria
- NF1 can be diagnosed by routine exam by ages 6–8, with attention to skin stigmata (1). Prenatal diagnosis is possible, although not predictive of the clinical course.
- Family history of a 1st-degree relative with NF1
- Manifestations generally not visible at birth, although plexiform neurofibromata usually are congenital, and tibial bowing is congenital.
- In addition to cutaneous lesions, NF1 may present with painful neurofibromata, pathologic fractures, or headaches secondary to hypertension caused by pheochromocytomas.
- Café-au-lait macules develop during the 1st 3 years of childhood and are usually the presenting feature of NF1. Evenly pigmented, irregularly shaped (coast-of-California borders), light brown macules present in 97% with NF1; although many unaffected individuals have 1 or 2 such macules, <1% of unaffected children have >2.
- Neurofibromata: Can be cutaneous, subcutaneous, or plexiform, and may be soft or firm; buttonhole invagination is pathognomonic, generally are not present until late adolescence.
- Plexiform neurofibromata are present in up to 50% of individuals with NF1:
- Freckling or hypertrichosis may be present over plexiform neurofibromata; may affect underlying structures, or cause focal hyperplasia.
- Many are internal, and not obvious on physical exam.
- 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: (30% have Lisch nodules)
- 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 blood pressure yearly. Hypertension is more common in NF1 and could be secondary to renal artery stenosis, aortic stenosis, or pheochromocytoma.
- Evaluate neurodevelopmental progress in children.
In NF1, cutaneous lesions and tumors increase in size and number with age.
Children who have inherited the NF1 gene of an affected parent usually are identified by age 1, but external stigmata may be subtle. If no stigmata by age 2, NF unlikely, but child should be reexamined at age 5. Definite diagnosis can be made by age 8 using NIH criteria (1).
Diagnostic Tests & Interpretation
Clinical diagnosis. DNA sequence and deletion/duplication analysis of the NF1 gene can identify mutations in ∼96% of those with a clinical diagnosis. Genetic testing challenging due to large number of mutations. Diagnostic laboratory information is available at www.genetests.org.
- Characteristic radiographic findings in NF1 include sphenoid dysplasia, long-bone cortical thinning, ribbon ribs, and angular scoliosis. Screening radiographs of the knees in adolescents is controversial. CT scan can demonstrate bony changes.
- MRI may demonstrate findings of the orbits, brain, or spine (86%). The value of performing routine head MRI scanning in asymptomatic individuals with NF1 is controversial. Optic glioma by MRI (11–15%), may lead to blindness. Although areas of increased T2 signal intensity are commonly identified on brain MRI, they are not diagnostic of NF1 and are of no clinical significance. Therefore, the NIH Consensus Development Conference does not recommend routine neuroimaging of the brain as a means of establishing a diagnosis of NF1 (1,2).
- Ophthalmologic evaluation including slit-lamp examination of the irides
- Neuropsychological testing: Intelligence is usually normal, although significant deficits in language, visuospatial skills, and neuromotor skills may be present.
Familial café-au-lait spots (autosomal dominant; no other NF1 features); Watson syndrome; LEOPARD syndrome; McCune-Albright syndrome; neurocutaneous melanosis; proteus syndrome; lipomatosis
See Health Supervision of Children guidelines for NF1 (3) listed in “Ongoing Care” section.
Anticonvulsants for seizure control, medications for attention deficit hyperactivity disorder (ADHD), hypertension, etc.
Multiple clinical trials for NF1 are recruiting patients (see http://www.clinicaltrials.gov).
Issues for Referral
- Patients with more than minimal manifestations of NF1 should be referred to a multidisciplinary NF clinic.
- Referral for psychosocial issues of family and affected individuals
- Educational intervention for children with learning disabilities or ADHD (40%)
- 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 has established the NF Clinical Trials Consortium and the CTF NF Clinic Network to facilitate future clinical trials and help identify best practices (4).
Surgical treatment for severe scoliosis, plexiform neurofibromata, or malignancy
NF1 health supervision 2008 guidelines (3):
- Infancy–1 year:
- Growth and development, mild short stature, macrocephaly due to increased brain volume; also aqueductal stenosis/obstructive hydrocephalus, hydrocephalus
- Check for focal neurologic signs or asymmetric neurologic exam.
- Skeletal abnormalities, especially of spine and legs
- Neurodevelopmental progress
- 1–5 years:
- Café-au-lait spots and axillary freckling have no clinical significance.
- Annual ophthalmologic exam
- Order 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 preschool services, speech/language and/or motor therapy, and special education
- Monitor blood pressure annually.
- 5–13 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; complete eye examination every 2 years.
- Monitor blood pressure annually.
- Refer patient to a clinical psychologist or child psychiatrist for problems with self-esteem if indicated.
- Discuss growth of neurofibromata during adolescence and pregnancy.
- Counsel parents about discussing diagnosis with child.
- 13–21 years:
- Examine the adolescent for abnormal pubertal development.
- Perform a thorough skin examination for plexiform neurofibromata and a complete neurologic examination for findings suggestive of deep plexiform neurofibromata. Obtain surgical consultation if there are signs of pressure on deep structures.
- Continue monitoring blood pressure yearly.
- Continue ophthalmologic examination every 2 years until age 18.
- 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.
Annual evaluation and periodic assessment for at-risk individuals
- Genetic counseling and patient education regarding future complications about family planning.
- The National Neurofibromatosis Foundation has been incorporated in the Childrens Tumor Foundation, but many state chapters remain independent. The Children’s Tumor Foundation http://www.CTF.org. Support groups are important.
Variable; most patients have a mild expression of NF1 and lead normal lives.
- Disfigurement: Skin neurofibromata develop primarily on exposed areas. The number tends to increase with puberty or pregnancy.
- Scoliosis: 10–30%, but most cases are mild; bowing of long bones, 2%
- A large head is common but rarely associated with hydrocephalus.
- Increased risk of malignancy: Malignant peripheral nerve sheath tumor (MPNST), a highly aggressive spindle cell sarcoma, is the most common malignant neoplasm, occurring in 5–10% of individuals with NF1, usually in adults (1). Typically, MPNST arises from a plexiform neurofibroma. Slightly increased risk for other malignancies, e.g., pheochromocytoma, rhabdomyosarcoma, leukemia, Wilms tumor. Optic glioma or other central nervous system tumors arise, usually during childhood (5–15%).
- Learning disability: ∼50%; may be associated with ADHD; mental retardation 4–8%
- Gastrointestinal (GI) neurofibromata may cause a range of GI disturbances.
- Seizures 6–7%
- Hypertension is a frequent finding in adults, and may occur in childhood.
- Disorders of puberty
Increased risk of perinatal complications, stillbirth, IUGR; risk of cord compression and outlet obstruction by pelvic neurofibromata.
1. DeBella K, Szudek J, Friedman JM. Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics. 2000;105:608–14.
2. National Institutes of Health Consensus Development Conference Statement: neurofibromatosis. Bethesda, Md., USA, July 13–15, 1987. Neurofibromatosis. 1988;1:172–8.
3. Hersh JH. and Committee on Genetics. Health supervision for children with neurofibromatosis. Pediatrics. 2008;121:3:633–642.
4. Williams VC, Lucas J, Babcock MA, Gutmann DH, Korf B, Maria BL et al. Neurofibromatosis type 1 revisited. Pediatrics. 2009;123:124–33.
See Also (Topic, Algorithm, Electronic Media Element)
Ataxia-telangiectasia; Tuberous Sclerosis Complex; von Hippel–Lindau Disease
- 237.70 Neurofibromatosis, unspecified
- 237.71 Neurofibromatosis, type 1, von Recklinghausen’s disease
- 237.72 Neurofibromatosis, type 2, acoustic neurofibromatosis
- 92824003 Neurofibromatosis, type 1 (disorder)
- 92503002 Neurofibromatosis, type 2 (disorder)
- 19133005 neurofibromatosis syndrome (disorder)
- NF1 and NF2 are 2 distinct genetic disorders.
- NF1 has marked clinical variability. Even minimal findings necessitate monitoring. 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 1 of the diagnostic criteria for NF1.