Basics
Description
- Neurofibromatosis type 1 (NF-1) is an autosomal dominant tumor suppressor gene disorder.
- NF-1 is diagnosed based on the presence of any 2 of the following National Institutes of Health (NIH) Consensus Conference diagnostic criteria:
- 6 or more cafe au lait spots, at least 1.5 cm in diameter in postpubertal individuals or 0.5 cm in diameter in prepubertal individuals
- Inguinal or axillary freckling
- 2 or more cutaneous neurofibromas or 1 plexiform neurofibroma
- 2 or more iris Lisch nodules
- Optic nerve glioma
- Osseous lesions, including sphenoid wing dysplasia, dysplasia of a long bone (most commonly tibia)
- A 1st-degree relative (parent, sibling, or offspring) with NF-1
Alert
Note: Neurofibromatosis type 2 (NF-2) is a rare distinct autosomal dominant tumor suppressor gene disorder characterized by bilateral vestibular schwannomas as well as schwannomas of cranial and peripheral nerves, meningiomas, and ependymomas. It is caused by mutations in the NF2 gene, which codes for a protein known as merlin. This chapter focuses on NF-1.
Epidemiology
Incidence
- NF-1: 1 in 3,000 live births
- NF-2: 1 in 33,000 live births
Prevalence
- NF-1: 1 in 4,000 " 5,000
- NF-2: 1 in 60,000
Risk Factors
Genetics
- Autosomal dominant
- 50% of the cases are inherited; others occur as sporadic mutations.
- Penetrance is complete; however, expression is variable even between family members who have same mutation.
- NF1 gene, which codes for neurofibromin, is located on chromosome 17q11.2
- No known ethnic predisposition
- Course impossible to predict except in two circumstances
- Deletion of whole NF1 gene leads to early appearance and large numbers of cutaneous neurofibromas, severe cognitive impairment, and dysmorphic features.
- 3 base pair in-frame deletion of exon 17 leads to multiple cafe au lait spots and intertriginous freckling but no other NF-1 manifestations.
Diagnosis
History
- Growth
- Accelerated linear growth may be first sign of precocious puberty and presence of optic pathway tumor.
- Vision
- Optic pathway tumors (OPTs) generally occur before 7 years of age; young children rarely complain of visual loss.
- Development
- Speech delay, motor incoordination, learning problems, and attention-deficit/hyperactivity disorder (ADHD)
- Headache
- Common; hydrocephalus due to obstructing tumor may occur.
- Family history
- 1st-degree relative may have unrecognized NF-1.
Physical Exam
- Growth
- Assess growth chart with attention to accelerated linear growth as early sign of precocious puberty, rarely growth hormone excess.
- Assess head circumference for macrocephaly.
- Cafe au lait spots
- Collections of heavily pigmented melanocytes of neural crest origin in the epidermis
- 53% of children with NF-1 will have 6 or more by 3 years; 97% by 6 years
- Axillary and inguinal freckling
- Present in 80% of children by 6 years
- Discrete neurofibromas
- Benign nerve sheath tumors that appear as discrete masses arising from peripheral nerve
- Cutaneous neurofibromas protrude just above the skin surface or lie just under the skin often with an overlying violaceous hue.
- Subcutaneous neurofibromas are generally much harder.
- Plexiform neurofibromas
- Benign peripheral nerve sheath tumors which involve single or multiple nerve fascicles, often arising from branches of major nerves
- "Wormy " sensation on palpation often with overlying hyperpigmentation or hypertrichosis
- Most external plexiform neurofibromas are present at birth or become apparent during the first several years of life.
- May lead to disfigurement, blindness (secondary to amblyopia, glaucoma, or proptosis), or loss of limb function
- Thoracic or abdominal plexiform neurofibromas may have no external manifestations but may lead to invasion or compression of vital structures (e.g., ureters, bowel, spinal cord).
- Lisch nodules
- Best assessed with slit lamp
- Slightly raised, well-circumscribed melanocytic hamartomas of the iris thought to be virtually pathognomonic of NF-1
- Increase with age; present in only 30% of children <6 years but >95% of adults
- OPTs
- Are present in 15% of children with NF-1, although only half are symptomatic and 40% of those will require treatment
- Complete yearly eye exams mandatory for NF-1 patients <10 years
- Ophthalmologic signs include afferent papillary defect, optic nerve atrophy, papilledema, strabismus, or defects in color vision.
- 40% of children who have chiasmal tumors develop precocious puberty.
- Bony dysplasias
- Sphenoid wing dysplasia may lead to enophthalmos or pulsating exophthalmos.
- Tibial dysplasia, congenital thinning and bowing; failure of primary union following fracture results in pseudarthrosis.
- Hypertension
- In children, most commonly due to fibromuscular dysplasia of renal artery
- Pheochromocytoma rare in children
- Complete neurologic exam
- Assess for signs of intracranial or intraspinal tumors.
- Scoliosis
- Assess for idiopathic juvenile scoliosis, short-segment dystrophic scoliosis.
Diagnostic Tests & Interpretation
Lab
- NF1 gene mutation
- Can be identified in >98% of individuals with clinical diagnosis of NF-1
- However, gene testing is not necessary in vast majority of cases.
- Gene testing may be useful for:
- Very young children who don 't meet diagnostic criteria
- Prenatal testing in familial cases
- Children with unusual or very mild manifestations of NF-1
Imaging
- "Screening neuroimaging " of asymptomatic children not recommended
- MRI of brain recommended for signs of increased intracranial pressure or focal neurologic deficits, abnormal visual exam, or accelerated growth suggestive of precocious puberty
- Unidentified bright objects ( "UBOs " )
- Regions of increased signal intensity on T2-weighted images found in the internal capsule, basal ganglia, cortex, cerebellar hemispheres, optic tract, or brainstem
- Disappear with age
- UBOs don 't enhance or cause mass effect.
- Significance unknown; may be associated with cognitive impairment or learning disabilities
Diagnostic Procedures/Other
A biopsy of plexiform neurofibroma looking for malignancy (malignant peripheral nerve sheath tumor) is necessary if there are signs of rapid growth, new onset pain, or neurologic dysfunction.
Differential Diagnosis
McCune-Albright syndrome has large cafe au lait spots with irregular margins, polyostotic fibrous dysplasia, and autonomous endocrine hyperfunction (Cushing syndrome, hyperthyroidism, precocious puberty).
Treatment
General Measures
- Treatment of neurofibromatosis (NF) is multidisciplinary and should be performed in a multidisciplinary setting.
- All 1st-degree relatives should be examined for the cutaneous manifestations of NF-1 and should undergo slit-lamp examination to ascertain presence of Lisch nodules.
- Available consultants should include experts in orthopedics, oncology, ophthalmology, genetics, endocrinology, surgery, neurosurgery, plastic surgery, and psychiatry.
Ongoing Care
Follow-up Recommendations
- Yearly visits allow the physician to identify early NF-1 complications while providing counseling and dissemination of information regarding NF-1.
- All children with NF-1 who are 10 years old and younger should have complete yearly ophthalmologic examinations looking for signs of an optic pathway tumor.
- Blood pressure taken at each visit
- Vigilance/anticipatory care regarding common psychological and developmental issues, such as speech delay, incoordination, ADHD, and learning disabilities
- Early educational assessment and interventions may improve developmental outcome.
Complications
- Cognitive impairment
- Mean IQ ~95
- 60% incidence of learning disabilities/ADHD; visual/perceptual disabilities common
- Malignancies
- Malignant peripheral nerve sheath tumor (5 " 10% lifetime incidence)
- Acute myelogenous leukemia
- Juvenile myelomonocytic leukemia
- Rhabdomyosarcoma
- Gastrointestinal stromal tumors
- Pheochromocytoma
- Skeletal
- Pseudarthrosis
- Scoliosis
- Osteoporosis
- Vasculopathy
- May involve any arterial vessel
- Renal artery stenosis, hypertension
- Moyamoya disease, poststenotic capillary proliferation in cerebral vasculature may lead to cerebral infarct; treatment by encephaloduroarteriomyosynangiosis (EDAMS) procedure.
- Intermittent claudication of an extremity
- Endocrine
- Precocious puberty due to chiasmal glioma
- Pheochromocytoma (rare in children)
- Growth hormone excess (also rare)
Additional Reading
- American Academy of Pediatrics Committee on Genetics. Health supervision for children with neurofibromatosis. Pediatrics. 1995;96(2, Pt 1):368 " 372. [View Abstract]
- Avery RA, Fisher MJ, Liu GT. Optic pathway gliomas. J Neuroophthalmol. 2011;31(3):269 " 278. [View Abstract]
- Feldman DS, Jordan C, Fonseca L. Orthopaedic manifestations of neurofibromatosis type 1. J Am Acad Orthop Surg. 2010;18(6):346 " 357. [View Abstract]
- Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA. 1997;278(1):51 " 57. [View Abstract]
- Hoa M, Slattery WH III. Neurofibromatosis 2. Otolaryngol Clin N Am. 2012;45(2):315 " 332. [View Abstract]
- Lehtonen A, Howie E, Trump D, et al. Behaviour in children with neurofibromatosis type 1: cognition, executive function, attention, emotion, and social competence. Develop Med Child Neurol. 2013;55(2):111 " 125. [View Abstract]
- Listernick R, Ferner RE, Liu GT, et al. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol. 2007;61(3):189 " 198. [View Abstract]
- Messiaen L, Yao S, Brems H, et al. Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome. JAMA. 2009;302(19):2111 " 2118. [View Abstract]
- North KN, Riccardi V, Samango-Sprouse C, et al. Cognitive function and academic performance in neurofibromatosis 1: consensus statement from the NF1 Cognitive Disorders Task Force. Neurology. 1997;48(4):1121 " 1127. [View Abstract]
- Rosser T, Packer RJ. Intracranial neoplasms in children with neurofibromatosis 1. J Child Neurol. 2002;17(8):630 " 637, discussion 646 " 651. [View Abstract]
- Zenker M. Clinical manifestations of mutations in RAS and related intracellular signal transduction factors. Curr Opin Pediatr. 2011;23(4):443 " 451. [View Abstract]
Codes
ICD09
- 237.71 Neurofibromatosis, type 1 [von recklinghausen 's disease]
- 709.09 Other dyschromia
ICD10
- Q85.01 Neurofibromatosis, type 1
- L81.3 Cafe au lait spots
SNOMED
- 92824003 neurofibromatosis, type 1 (disorder)
- 403816002 multiple cafe-au-lait macules due to neurofibromatosis (disorder)
- 403815003 Axillary freckling due to neurofibromatosis (disorder)
FAQ
- Q: My child has NF-1. What specialists must he see?
- A: Your child should have yearly check-ups with a physician familiar with the issues of NF, ideally in a NF-1 multidisciplinary clinic.
- Q: Does my child with NF-1 need any x-rays?
- A: X-rays or MRI scans need only be done if your child has signs or symptoms suggestive of a particular complication of NF-1.
- Q: Is my child going to die because of NF-1?
- A: Although a very small minority of children with NF-1 has life-threatening complications, almost all individuals with NF-1 live long, productive lives.