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Neurofibromatosis Type 1

Description

Other Names

NF1, von Recklinghausen's disease

ICD-9

237.7, Neurofibromatosis

For additional ICD-9 codes of related conditions, see NF1 ICD9(PDF Document 54 KB).

Description

Neurofibromatosis type 1 (NF1) is a common autosomal dominant neurocutaneous genetic disorder, first described in the medical literature in 1882 and previously known as von Recklinghausen disease. The NF1 gene product, neurofibromin is a Ras-GAP protein and acts as a "tumor suppressor." Mutations in this gene, located on the long arm of chromosome 17, typically inactivate neurofibromin and lead to the tumor phenotype seen in NF1 (reviewed in [Viskochil: 2010]).

In up to 95% of cases, the diagnosis can be made through straightforward clinical evaluation by the time a child is 11 years of age. [Friedman: 1997] Hallmark findings of NF1 include:
  • café au lait macules
  • neurofibromas (benign tumors that arise from the nerve sheath, and typically composed of Schwann cells, fibroblasts, mast cells, and pericytes)
  • axillary or groin freckling
  • optic pathway tumors
  • Lisch nodules (benign hamartomas of the iris)
  • dyplastic skeletal findings (long bone bowing/pseudoarthrosis and/or sphenoid wing dysplasia)
learning disabilities (in greater than 50% of individuals [Jett: 2010]) and behavioral abnormalities, including autistic features

Prevalence

The reported prevalence of NF1 varies from study to study, but a general estimate of the prevalence is approximately 1/3000. [Rasmussen: 2000] NF1 affects individuals without predilection to ethnicity or gender.

Genetics

NF1 is caused by mutations in the NF1 gene, which is located at 17q11.2. Many different mutations in the gene have been found, but the type of mutation typically doesn't correlate with a specific phenotype. For more information, see [Viskochil: 2002]. Within any one family, affected members may display significantly different clinical manifestations. Modifying factors have been suggested but are not well understood. [Szudek: 2002]

NF1 is an autosomal dominant condition. Although the spontaneous mutation rate for the NF1 gene may be as high as 50% [Kandt: 2003], parents and siblings of children with NF1 should be evaluated for signs of NF1. [Jones: 1997] The penetrant of NF1 in adults is full with variable age-dependent onset of manifestations.

In adults, NF1 can be diagnosed with relative certainty on a clinical basis and thus rarely requires mutation analysis. All individuals, including adults, suspected of having NF1 should be evaluated by a trained clinical geneticist. However, older individuals with only pigmentary manifestations of NF1 may have a different condition (e.g. Legius syndrome) and, in such cases, SPRED1 and/or NF1 mutation analysis can be helpful in clarifying the diagnosis. DNA testing is clinically available – for information on available gene testing, see [Friedman: 2002].

See also NF1: Genetics

Prognosis

As features vary considerably in individuals with NF1, prognosis will also vary. However, overall, the average life expectancy of individuals with NF1 is probably 10-15 years shorter than the general population. Malignancy is the most common cause of death, although still rare, including brain tumors and malignant peripheral nerve sheath tumors. [Rasmussen: 2000] [Tonsgard: 2006]

Roles Of The Medical Home

In addition to well child and acute care evaluations, the Medical Home provider may wish to schedule chronic care visits where problems associated with NF1 may be monitored if an NF1 specific clinic is not available. These include surveillance of neurofibromas, especially during puberty where accelerated tumor growth may occur, scoliosis, hypertension, and the management of learning disorders.

Practice Guidelines

The article by Hersh is from the American Academy of Pediatrics' Committee on Genetics. The others are not endorsed by an official entity but offer excellent information that is widely accepted.

Committee on Genetics.
Health supervision for children with neurofibromatosis. American Academy of Pediatrics.
Pediatrics. 1995;96(2 Pt 1):368-72. PubMed abstract

Viskochil DH.
Neurofibromatosis Type 1.
Management of Genetic Syndromes, 3rd Edition. 2010; 549-568. New York: Wiley-Blackwell; http://www.wiley.com/WileyCDA/WileyTitle/productCd-0470191414.html
Excellent review of NF1 by an expert in the field. Book is a great resource for Medical Home providers, with chapters on 25 different genetic conditions.

Friedman JM.
Neurofibromatosis 1.
Copyright, University of Washington, Seattle. 1997-2004; (2002) http://www.geneclinics.org/servlet/access?db=geneclinics&site=gt&id=88.... In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Available at http://www.genetests.org/. Accessed on 8/14/04.
A concise and well organized review of NF1 with a focus on gene testing.

Helpful Articles

PubMed search for articles on Neurofibromatosis Type 1 in children for the last 3 years

Payne JM, Moharir MD, Webster R, North KN.
Brain structure and function in neurofibromatosis type 1: current concepts and future directions.
J Neurol Neurosurg Psychiatry. 2010;81(3):304-9. PubMed abstract

Elefteriou F, Kolanczyk M, Schindeler A, Viskochil DH, Hock JM, Schorry EK, Crawford AH, Friedman JM, Little D, Peltonen J, Carey JC, Feldman D, Yu X, Armstrong L, Birch P, Kendler DL, Mundlos S, Yang FC, Agiostratidou G, Hunter-Schaedle K, Stevenson DA.
Skeletal abnormalities in neurofibromatosis type 1: approaches to therapeutic options.
Am J Med Genet A. 2009;149A(10):2327-38. PubMed abstract

Clinical Assessment

Overview

Neurofibromatosis type 1 (NF1) is typically diagnosed clinically during childhood. Mutation analysis of NF1 is available and can be helpful in rare cases to clarify the diagnosis in some individuals in which the diagnosis is in question. Because the clinical features are quite variable, the age at diagnosis may vary.

Screening

For The Condition

In individuals with a family history of NF1, ongoing screening for manifestions that are among the diagnostic criteria is appropriate.

Of Family Members

Screening for NF1 in other family members should consist of physical examination for any of the clinical diagnostic criteria for NF1. The disorder is fully penetrant and follows an autosomal dominant pattern and hence evaluation of other family members should start with first degree relatives based on symptoms.

For Complications

  • Annual ophthalmology evaluations through adolescence looking for evidence of optic gliomas
  • Blood pressure measurements twice a year and at each physician visit looking for hypertension that may be secondary to pheochromocytomas or renal artery stenosis
  • “Bend over” examination of the back at least yearly looking for scoliosis

Presentations

The expressivity of NF1 is highly variable, even among family members. A child who is severely affected may have a parent who is mildly affected and may not even know that he/she has NF1. NF1, however, is fully penetrant. Despite the variable expressivity, there are some generalities in age-specific presentation:
  • Typically, the first sign observed is café au lait macules, which are usually present in the first year (80% of NF1 individuals will have >5 café au lait macules by 1 year of age) [Viskochil: 2010]
  • Intertriginous freckling usually develops after the presence of cafe au lait macules
  • Optic gliomas are usually seen within the first 4 years of life [Friedman: 2002]
  • Sphenoid wing and long bone dysplasia (anterolateral bowing with or without fracture and nonunion) are often apparent in infancy and early childhood and are fairly specific for NF1
  • Cutaneous neurofibromas and Lisch nodules are usually detected a little later, in the teenage years [Viskochil: 2010]
  • Plexiform neurofibromas can be seen early in childhood and are quite specific for NF1. They may increase in size and number during puberty and pregnancy [Friedman: 2002]
Approximately 90% of individuals with NF1 will have two or more of the clinical diagnostic criteria by 6 years of age [Friedman: 2002]

Diagnostic Criteria

The criteria for the diagnosis of NF1, developed by the NIH at a Consensus Development Conference, require the presence of two or more of the following (adapted and modified from [National: 1988], [Gutmann: 1997] and [Stevenson: 2007]):
  • six or more café au lait macules,
    • 1.5 cm or larger in postpubertal patient, or
    • 0.5 cm or larger in prepubertal patients
  • two or more neurofibromas (see café au lait with plexiform) or one or more plexiform neurofibroma(s);
  • freckling in the axillary or groin region (Crowe's sign)
  • optic pathway tumor
  • two or more Lisch nodules (benign hamartomas of the iris)
  • a distinctive osseous lesion (anterolateral bowing of the leg/pseudoarthrosis or sphenoid wing dysplasia)
  • a first-degree relative with NF1

Other features of NF1 include (modified from [Viskochil: 2010]and [Young: 2002]):
  • educational difficulty (40-60%)
  • macrocephaly (38-45%)
  • short stature (18-34%)
  • scoliosis (10-30%)
  • headache (22%)
  • seizures (5-7%)
  • neoplasms (5%)
  • sensorineural hearing loss (5%)
  • precocious puberty (4-5%)
  • hypertension (4%)
  • hydrocephalus (3-4%)
  • congenital heart disease (2-4%)

Differential Diagnosis

Typically café au lait macules will be the first manifestation of NF1 seen by a primary care provider. These spots are light brown with relatively well-defined borders. Although they may be present at birth, they usually appear over the first few years of life – the first is usually present before 2 years of age. Macules tend to increase in number and size as the child gets older. However, the presentation, number, size, and location of the café au lait macules have a high degree of clinical variability. Although many individuals in the general population will have one or two café au lait macules, it is important to watch for increasing numbers of them. Neurofibromas typically appear after the development of the café au lait macules, beginning in late childhood and adolescence, and the presence of other NF1 findings aids in their diagnosis as benign hamartomas.

Legius syndrome, delineated in 2007, is due to mutations in SPRED1, a gene that interacts in the same signal transduction pathway as NF1. [Brems: 2007] Individuals with Legius syndrome often have café au lait spots and intertriginous freckling and can fulfill the clinical diagnostic criteria for NF1 based on pigmentary findings, which may lead to an incorrect diagnosis. Individuals with Legius syndrome may also present with macrocephaly and learning disorders, further adding to diagnostic confusion with NF1. However, individuals with Legius syndrome have not been reported to have the same tumorigenic potential of NF1 (eg. neurofibromas, Lisch nodules, optic pathway tumors). Caution must be taken in diagnosing individuals with NF1 based solely on pigmentary findings. [Stevenson: 2009] [Muram-Zborovski: 2010]

Other syndromes that involve café au lait spots or similar pigmentary findings or tumors are listed below, but are typically not confused with NF1 given the presence and lack of other manifestations: [Viskochil: 2010] [Jones: 1997]
  • Noonan syndrome – webbing of the neck, pectus abnormality, cryptorchidism, pulmonic stenosis
  • McCune-Albright syndrome – polyostotic fibrous dysplasia, irregular skin pigmentation, sexual precocity
  • LEOPARD syndrome – multiple lentigines, ocular hypertelorism, pulmonic stenosis, abnormalities of the genitalia, growth retardation, deafness, pectus deformity
  • Silver-Russel syndrome – short stature of prenatal onset, skeletal asymmetry, small incurved fifth finger
  • Bloom syndrome – short stature, malar hypoplasia, telangiectatic erythema of the face
  • Sotos syndrome – large size, large hands and feet, hypotonia
  • Dubowitz syndrome – unusual facies, infantile eczema, small stature, mild microcephaly
  • Klippel-Trenaunay-Weber syndrome – asymmetric limb hypertrophy, cutaneous vascular malformations
  • Proteus syndrome – hemihypertrophy, subcutaneous tumors, macrodactyly
Neurofibromas in NF1 can be confused with other tumor syndromes, including ([Viskochil: 2010] [Jones: 1997]):
  • Bannayan-Riley-Ruvalcaba syndrome – macrocephaly, polyposis of colon, lipomas, pigmentary changes of the penis
  • Carney syndrome – nevi, atrial myxoma, neurofibromas, endocrine overactivity
  • Proteus syndrome – hemihypertrophy, subcutaneous tumors, macrodactyly
  • Maffuci syndrome – enchondromatosis, hemangiomata
  • Multiple endocrine neoplasia 2B – multiple neuromata of tongue, lips with or without medullary thyroid carcinoma, with or without pheochromocytoma
  • von Hippel-Lindau syndrome – retinal angiomata, cerebellar hemangioblastoma
  • Gardner syndrome – intestinal polyposis
  • Schwannomatosis
See also NF1: Differential Diagnosis

Pearls & Alerts

Older individuals with only pigmentary findings

Older children, adolescents and adults with only pigmentary findings may have Legius syndrome, due to a mutation in a different gene from NF1 (i.e. the SPRED1 gene) or may have germline mosaicism and an attentuated form of NF1. [Muram-Zborovski: 2010] These individuals may need genetic testing to determine their diagnosis. All individuals who are suspected of having NF1 should be evaluated by a clinical geneticist.

Segmental NF1

Occasionally, NF1 may appear in only a segment of the body, including the face or limbs. [Oguzkan: 2004]

Gliomas

Children with NF1 are prone to developing optic gliomas and should have yearly assessments by pediatric ophthalmology.

History & Examination

See Comorbid conditions above for findings that occur more commonly in NF1.

Family History

NF1 is an autosomal dominant genetic disorder and about 50% of individuals with NF1 inherit the gene mutation from one of their parents. Obtain a detailed family history and, when possible, examine both parents to look for cutaneous and ocular signs of NF1 (café au lait macules, intertriginous freckling, neurofibromas, and Lisch nodules).

Pregnancy Or Perinatal History

Few prenatal findings suggest a diagnosis of NF1. Rare reports have documented tibial bowing/pseudarthrosis on prenatal ultrasound [Stevenson: 1999], but in general the pregnancy/perinatal history is unremarkable.

Current & Past Medical History

Appropriate questions regarding the associated features listed above will help the primary care physician identify areas of concern. Ask about visual problems, headaches, painful lumps, back pain, gait abnormalities, and seizures.

Developmental & Educational Progress

Ask about developmental milestones and school performance in both the child and family members.

Maturational Progress

Ask about signs of puberty (precocious puberty may be observed in children with NF1).

Social & Family Functioning

An understanding of family functioning and existing problems, especially in those families with NF1, may be helpful in guiding the Medical Home's approach to the child and family. Knowing of other family members with NF1 and their health and course may enable the clinician to better understand the family and child's perspectives on the condition.

Physical Exam

Vital Signs

Blood pressure measurements should be performed at every visit. Hypertension may be the result of renal artery stenosis, coarctation of the aorta, or, less commonly, pheochromocytomas. [Xu: 1992]

Growth Parameters

NF1 individuals tend to have relatively short stature and relative macrocephaly. Growth parameters should be monitored and can be plotted on specific NF1 growth charts, which can be found under Clinical Tools in Neurofibromatosis Type 1, Services & Other Resources. [Friedman: 1999] [Clementi: 1999] Children who are not following percentile lines may need further evaluation. See also NF1: Growth.

Skin

Documentation of the size, number, and location of café au lait macules will help in diagnosis. Careful examination for freckling in the axillae and groin regions (areas not typically exposed to sun and hence devoid of freckling in the general population) will also help. Cutaneous neurofibromas may be difficult to appreciate when they first begin to develop. Some are raised and soft, others are firm and well beneath the skin. Particular attention should be made to neurofibromas that are painful upon palpation or larger plexiform neurofibromas. See also NF1: Tumors.

HEENT

Routine eye exam should include looking for proptosis, strabismus, etc. The typical findings of NF1, such as Lisch nodules, can often only be seen by an experienced ophthalmologist. See also NF1: Ophthalmic Issues.

Heart

Congenital heart defects are sometimes seen in NF1 patients. Routine echocardiograms and cardiology referral are not recommended unless clinically indicated. See also NF1: Cardiac Problems.

Genitalia

Observe for signs of precocious puberty, although this is uncommon (~4-5%).

Extremities/Musculoskeletal

Careful examination of the spine for scoliosis and the long bones for bowing/pseudarthrosis.

Testing

Sensory Testing

Periodic assessment of vision and hearing may detect changes that reflect disease progression.

Laboratory Testing

Routine laboratory testing is not indicated.

Imaging

RI – Controversy exists over the routine use of imaging studies in individuals with NF1. Some groups perform an initial MRI upon diagnosis. Hyperintense T2-weighted signals are commonly seen, but have unknown clinical significance. These and other incidental findings can cause anxiety, particularly when there is no known associated clinical problem or resultant management. Our group at the University of Utah obtains MRI studies only when there are clinical symptoms suggesting their need. However, one must seriously consider imaging of relevant body regions for new onset or increasing pain, rapidly growing masses, or neurologic changes to look for plexiform neurofibromas, malignancies, hydrocephalus, etc. It has been suggested that magnetic resonance angiography (MRA) be included with MRI in individuals with NF since cerebral angiopathy is found in up to 6% of individuals, and perhaps more frequently in those with optic glioma. [Payne: 2010]

Xrays – If a child has clinical evidence of scoliosis or long bone bowing, x-rays are indicated with subsequent referral to orthopedics.

Genetic Testing

Genomic DNA and cDNA-based testing of the NF1 gene is available clinically but is usually not necessary for a clinical diagnosis, although testing can be considered in older individuals with only pigmentary findings because of the phenotypic overlap with Legius syndrome. For information on available gene testing, see the review by Dr. Jan Friedman. [Friedman: 2002] Issues regarding insurance coverage for genetic testing are often complicated. Prior approval is suggested unless individuals are willing to pay the entire cost.

Subspecialist Collaborations & Other Resources

Pediatric Genetics (see Services below for relevant providers)

It is appropriate for anyone suspected of having NF1 to be evaluated by a clinical geneticist to consider the broader differential diagnosis and for a discussion of the inheritance pattern and recurrence risks. Up-to-date information on research and new developments in the field of genetics pertaining to NF1 are usually provided to the family and, by letter, to the primary care physician. Genetic counseling is also available. Parents and siblings are sometimes found to also have NF1. See also NF1: Genetics.

Pediatric Ophthalmology (see Services below for relevant providers)

Initial evaluation for Lisch nodules is helpful to aid in diagnosis. As these are often visible only with slit lamp examination, all children suspected of having NF1 should be evaluated by an ophthalmologist. Yearly evaluations are needed to monitor for findings seen in optic pathway tumors. Children with optic gliomas will most likely require more frequent follow-up.

If a patient reports eye pain, vision loss, or visual changes, the patient should be seen urgently by an ophthalmologist. See also NF1: Ophthalmic Issues.

Pediatric Orthopedics (see Services below for relevant providers)

A baseline evaluation for scoliosis, long bone dysplasia, or bone pain (possibly secondary to bone cysts) is recommended. Concurrent care by an orthopedic surgeon may be helpful for some children. See also NF1: Associated Bony Abnormalities.

Pediatric Neurology (see Services below for relevant providers)

If seizures or intracranial tumors are suspected, an evaluation and management by a pediatric neurologist may be helpful.

Pediatric Endocrinology (see Services below for relevant providers)

Endocrinologists may be helpful in the management of endocrinologic complications of intracranial tumors or pheochromocytomas.

Pediatric Hematology/Oncology (see Services below for relevant providers)

An evaluation by oncology is recommended for symptoms suggestive of malignant tumor development or optic gliomas. A sarcoma team may be optimal for management of malignant peripheral nerve sheath tumors and/or plexiform neurofibromas.

Pediatric Nephrology (see Services below for relevant providers)

Children should be evaluated by nephrology if hypertension is persistent.

Treatment & Management

Overview

There is no treatment for the underlying genetic defect that causes neurofibromatosis type 1 (NF1). The treatment of patients with NF1 is based on identifying manifestations of NF1 and treating complications due to these manifestations accordingly.

How should common problems be managed differently in children with Neurofibromatosis Type 1?

Growth Or Weight Gain

Individuals with NF1 often have short stature for family background and relative macrocephaly. Extensive workup for short stature if growth velocity is normal is likely not required without other symptoms. Specific growth charts for NF1 can be found under Clinical Tools in Neurofibromatosis Type 1, Services & Other Resources. See also NF1: Growth.

Development (cognitive, motor, language, social-emotional)

Individuals with NF1 are at increased risk for ADHD, cognitive impairment, problems with social skills, and learning problems. However, most individuals with NF1 will have normal cognition. There should be a low threshold for a neuropsychology evaluation particularly upon entry into the school system in order to identify areas of concern and methods to maximize the child’s potential. See also NF1: Learning Problems.

Common Complaints

Headaches and pain should be taken seriously in individuals with NF1 with a low threshold for obtaining imaging studies (particularly for pain that wakes a patient up at night or is increasing in intensity).

Pearls & Alerts

Height

Individuals with NF1 are generally shorter than the general population with a larger head (relative macrocephaly). Specific growth charts for individuals with NF1 are available and can prove useful in differentiating NF1-related issues from general pediatric causes of short stature. [Friedman: 1999] [Clementi: 1999]

Systems

Hematology/Oncology

The cutaneous neurofibromas in neurofibromatosis type 1 (NF1) are benign. Other tumors, however, occur and include but are not limited to optic pathway tumors, leukemia, malignant peripheral nerve sheath tumors, rhabdomyosarcomas, pheochromocytomas, and various brain tumors. The brain tumors sometimes can be managed more conservatively than similar presentations in the general population (they usually have a more indolent course), but malignant peripheral nerve sheath tumors tend to be more aggressive. [Korf: 2000] Treatment of the various tumors in NF1 is an area of ongoing research. If a patient develops unexplained pain and/or rapid tumor growth, one should be suspicious for a neoplasm. Referral to a tertiary care center familiar with NF1 and sarcoma management is recommended for concerns of tumors other than the benign neurofibromas.

The benign dermal neurofibromas generally do not cause significant morbidity. They can be removed for cosmetic reasons, pain, or if they are in an area where the tumor catches onto clothing etc. The mainstay of treatment is surgical excision. [Packer: 2002] Excision does not mean the neurofibroma will not return, as it is difficult to excise the entire tumor. The neurofibromas usually present after the pigmentary lesions and increase with age with a more rapid increase during puberty and pregnancy. Various modalities of surgical excision have been adopted at different centers, but presently there is not an accepted protocol for medical management or prevention. See also NF1: Tumors.

Subspecialist Collaborations & Other Resources

Pediatric Dermatology (see Services below for relevant providers)

Pediatric dermatologists may be helpful in the management of neurofibromas.

General Pediatric Surgery (see Services below for relevant providers)

Pediatric surgeons may need to be involved in the excision of large neurofibromas, depending on size and location.

Eyes/Vision

Individuals with NF1 should have an ophthalmologic evaluation by an experienced ophthalmologist yearly until late adolesence. The primary care physician should perform a routine eye exam looking for proptosis, strabismus, etc., but the typical findings of NF1 usually can only be seen by an experienced ophthalmologist. Lisch nodules are benign iris growths that aid in the diagnosis of NF1, but have no clinical consequences. Optic pathway tumors often can be picked up by clinical exam by an experienced ophthalmologist (pale optic nerve) and then confirmed by MRI scan. Asymptomatic patients are often followed closely with dedicated sequential brain MRI studies and frequent ophthalmological evaluations. If there is vision loss or increased growth of the tumor as measured by sequential MRI, then medical management is sometimes initiated with low-level chemotherapy. These treatment options are considered, but the tumors may regress or remain stable in NF1 patients. [Listernick: 1999] This is an ongoing area of research, therefore referral to neuro-oncology is indicated when an optic glioma is identified. See also NF1: Ophthalmic Issues.

Subspecialist Collaborations & Other Resources

Pediatric Ophthalmology (see Services below for relevant providers)

Pediatric ophthalmologists should follow children with NF1 on at least a yearly basis.

Nutrition/Growth/Bone

The osseous abnormalities classically associated with NF1 include long bone dysplasia, scoliosis, and sphenoid wing dysplasia. Other osseous findings include short stature (compared to familial background), bone cysts, and relative macrocephaly. Of NF1 individuals, approximately 1/3 have one or more orthopedic findings. [Crawford: 1999]

Long bone dysplasia is seen in 5% of NF1 individuals and classically involves the tibia (though involvement of other long bones has been reported), with fibular involvement seen in 43% of those with long bone dysplasia. Tibial pseudarthrosis is strongly associated with NF1; greater than or equal to 50% of individuals with tibial pseudarthrosis have NF1. The bowing usually presents before 4 years of age. The typical presentation is anterior lateral bowing leading to fracture and non-union or pseudarthrosis. Before 2 years of age, 53% of NF1 individuals with long bone bowing will experience a fracture, and fractures have been seen in utero. [Stevenson: 1999]

The extremities (particularly the lower leg) of children with NF1 should be carefully examined for any anterior-lateral bowing. If anterior-lateral bowing is evident, an x-ray and referral to orthopedics should be made. Bracing should then be initiated if fractures have not yet occurred. Treatment of pseudarthrosis is controversial and studies are underway to determine the clinical outcome and long-term treatment results of this complication.

Both idiopathic and dystrophic forms of scoliosis are seen in individuals with NF1 (combined 10-33%), with a typical onset between 7-16 years. [Vitale: 2002] The dystrophic form is defined by one of the following dystrophic osseous finding: spinal canal widening, vertebral body narrowing, rib-penciling, vertebral wedging, defective pedicles, and vertebral scalloping. The non-dystrophic form of scoliosis is more common in children with NF1 [Vitale: 2002], but dystrophic scoliosis (typical presenting with a sharply angulated curve) is progressively debilitating and requires a more aggressive approach, with surgical intervention sooner. Every child with NF1 should be screened for scoliosis and any suspicion should prompt a PA and lateral erect thoracolumbar spine image. Referral to orthopedics is indicated if scoliosis is evident.

Sphenoid wing dysplasia is a congenital abnormality seen in approximately 7-11% of NF1 patients. [Friedman: 1997] [Young: 2002] It is unilateral, and approximately 50% will have a clinically apparent plexiform neurofibroma of the temporal-orbital region. One should have a lower index of suspicion for facial plexiforms in individuals with sphenoid wing dysplasia, and they may benefit from earlier imaging by MRI. Exophthalmosis is a rare complication that may require intervention, but the sphenoid wing dysplasia usually does not cause significant clinical complications or require therapeutic management.

See also NF1: Associated Bony Abnormalities.

Subspecialist Collaborations & Other Resources

Pediatric Orthopedics (see Services below for relevant providers)

Children with NF1 should be evaluated and, if needed, managed by pediatric orthopedics if not available as part of a multi-disciplinary NF1 specific clinic.

Learning/Education/Schools

Learning disabilities are common in neurofibromatosis (NF1) with educational difficulties being seen in approximately 40-60% of individuals. Additional educational resources will be needed by many individuals with NF1 to help them reach their potential. The school system should be informed of the association of learning disabilities in NF1 with a recommendation for a full evaluation and an individualized program to optimize educational outcomes. Reports have also shown an association between attention deficit hyperactivity disorder (ADHD) and NF1 [Koth: 2000]. Patients should be evaluated for ADHD if concerns arise and appropriately managed. Although clinical trials are currently underway testing targeted pharmacologic agents for ADHD, treatment at this time should be the same as for individuals without NF1. Individuals with a large NF1 gene deletion have been noted to have an increased chance for cognitive/developmental delay [Viskochil: 2010]. A karyotype and FISH study (flourescence in situ hybridization) looking for an NF1 gene deletion could be considered when cognitive impairment is a prominent feature. See also NF1: Learning Problems.

Ears/Hearing

Sensorineural hearing loss (5%) is relatively infrequent in neurofibromatosis type 1 (NF1), but primary care physicians should be sensitized to any hearing deficits and refer to audiology when indicated. The exact etiology is not well delineated. [Pensak: 1989]. Every child should have a newborn hearing screen. See also NF1: Hearing Loss.

Subspecialist Collaborations & Other Resources

Audiology (see Services below for relevant providers)

Hearing evaluations are available through these providers.

Neurology

Recurrent headaches are more common in children with NF1 than in the general population, with approximately 1/3 of those migrainous in nature. [DiMario: 2000] Hypertension should be ruled out in all children with headaches. Because individuals with NF1 are predisposed to brain tumors, including optic gliomas, astrocytomas, and plexiform neurofibromas, it is difficult to decide when it is appropriate to order imaging studies. Children and adolescents with NF1 who present with new headaches or changes in their headaches should probably be imaged, although there is no data to support this. Some investigators recommend that children with NF should be imaged with MRI on a yearly basis, [Mentzel: 2005] although other investigators have found that routine brain MRIs don't change clinical outcome. [Blanchard: 2009] Children and adolescents should receive headache medication as appropriate if there is no underlying cause found. These should include rescue medications and preventative medications if headaches are occurring often and interfering with school/employment function.

Seizures have been reported to potentially be slightly increased in frequency in individuals with NF1 (5-7%) as compared to the general population. [Young: 2002] The natural history and types of seizures in NF1, however, are similar to that in the general population [Korf: 1993]. The seizures are usually not the result of an anatomic abnormality, but any NF1 individual with seizure activity should have an MRI of the brain to look for structural abnormalities and tumors, and be evaluated by a neurologist. See also NF1: Seizures.

Cerebral arteriopathy and subsequent risk of stroke [Rea: 2009] are found in approximately 6% of children with NF1, possibly more in those with optic glioma. It has therefore been suggested that MRA be included with MRI when performed for other reasons, such as screening for optic glioma. [Payne: 2010] If cerebral arteriopathy is found, pediatric neurology or neurosurgery should be consulted for the possibility of medical and/or neurosurgical treatment.

Subspecialist Collaborations & Other Resources

Pediatric Neurology (see Services below for relevant providers)

If recurrent headaches and/or seizures occur, pediatric neurology may be helpful.

Cardiology

In NF1, congenital heart disease (2-4%) and hypertension (4%) are infrequent but can be serious complications. The most common associated lesion is valvar pulmonic stenosis. [Lin: 2000] A referral to cardiology and routine echocardiography are not indicated unless the patient has clinical findings.

Vasculopathies
have been documented in NF1 and can involve the heart, renal arteries, and brain. [Friedman: 2002] Hypertension should be taken seriously in any individual with NF1 and blood pressure measurements performed at every visit, including four-extremity blood pressures at least once to help rule out coarctation if hypertension is present. Hypertension may be the result of renal artery stenosis, coarctation of the aorta or, less commonly, pheochromocytomas [Xu: 1992]. Most NF1 individuals with hypertension, however, have typical essential hypertension. Given the possibility of other causes, individuals with hypertension should receive imaging studies to rule out renal artery stenosis and be referred to nephrology. If the above evaluation is normal, a work-up for pheochromocytoma should be considered in individuals with hypertension and/or signs of excess catecholamine release. See also NF1: Cardiac Problems.

Subspecialist Collaborations & Other Resources

Pediatric Nephrology (see Services below for relevant providers)

Consider management by pediatric nephrology if hypertension is present.

Pediatric Cardiology (see Services below for relevant providers)

Pediatric cardiology may be helpful if cardiac problems are suspected.

Recreation & Leisure

Some individuals with NF1 have difficulty with coordination, which may impact their involvement in sporting activities. We recommend that they be encouraged to continue with various activities to keep a healthy lifestyle. See Resources below for recreational therapy and camping programs. See also NF1: Recreation Needs.

Subspecialist Collaborations & Other Resources

Recreation Programs/Activities (see Services below for relevant providers)

Programs focused on children with special needs

Social & Recreational Opportunities (see Services below for relevant providers)

A variety of options for recreation and social interaction

Adaptive Recreation (see Services below for relevant providers)

For those children with a variety of disabilities

Frequently Asked Questions

Can neurofibromatosis type 1 progress to neurofibromatosis type 2?

No. These two conditions are very different genetic disorders. Both have tumors as part of the clinical findings, but have a variety of divergent features. The NF1 gene is located on the long arm of chromosome 7 while the NF2 gene is located on the long arm of chromosome 22. Neurofibromatosis type 2 (NF2) is a rare condition and usually has a later onset. Some features of NF2 include vestibular schwannomas, meningiomas, juvenile posterior subcapsular lenticular opacities, and gliomas. The hallmark feature of NF2 is the vestibular schwannomas.

Issues Related to Neurofibromatosis Type 1

Clinical Assessment

NF1: Differential Diagnosis

Ears/Hearing

NF1: Hearing Loss

Funding & Access to Care

Supplemental Security Income (SSI)

Genetics

NF1: Genetics

Learning/Education/Schools

NF1: Learning Problems

Mental Health/Behavior

NF1: Seizures

Nutrition/Growth/Bone

NF1: Growth

Recreation & Leisure

NF1: Recreation Needs

Resources

Information for Clinicians

Neurofibromatosis 1 (GeneReviews)
Comprehensive article by JM Friedman on NF1 addressing clinical, genetic, and treatment issues; from the National Center for Biotechnology Information and University of Washington

Neurofibromatosis type 1 (OMIM)
Comprehensive article about NF1 focused on its genetics; from Online Mendelian Inheritance in Man.

Genetics in Primary Care Institute (GPCI)
Increases collaboration in the care of children with known or suspected genetic disorders. Includes health supervision and management guidelines, and other useful resources; a collaboration among the Health Resources & Services Administration, the Maternal & Child Health Bureau, and the American Academy of Pediatrics.

Helpful Articles

PubMed search for articles on Neurofibromatosis Type 1 in children for the last 3 years

Elefteriou F, Kolanczyk M, Schindeler A, Viskochil DH, Hock JM, Schorry EK, Crawford AH, Friedman JM, Little D, Peltonen J, Carey JC, Feldman D, Yu X, Armstrong L, Birch P, Kendler DL, Mundlos S, Yang FC, Agiostratidou G, Hunter-Schaedle K, Stevenson DA.
Skeletal abnormalities in neurofibromatosis type 1: approaches to therapeutic options.
Am J Med Genet A. 2009;149A(10):2327-38. PubMed abstract

Payne JM, Moharir MD, Webster R, North KN.
Brain structure and function in neurofibromatosis type 1: current concepts and future directions.
J Neurol Neurosurg Psychiatry. 2010;81(3):304-9. PubMed abstract

Clinical Tools

Information & Support for Families

Family Diagnosis Page

Information on the Web

Neurofibromatosis type 1 (Genetic Science Learning Center)
From a science and health education program at the University of Utah that provides educational materials and programs; this page focuses on the genetics of NF1.

Children's Tumor Foundation
The Children’s Tumor Foundation (CTF) is a non-profit medical foundation dedicated to improving the health and well being of individuals and families affected by the neurofibromatoses. Look under "How You Can Help" to find a local chapter. The CTF sponsors an annual summer camp for children with NF.

Neurofibromatosis (MedlinePlus)
From the National Library of Medicine and National Institutes of Health.

Neurofibromatosis type 1 (Genetics Home Reference)
This site, sponsored by the National Library of Medicine, offers a wealth of information and links to more information about neurofibromatosis type 1. The information is aimed at consumers/patients/families.

Understanding NF1 (Harvard University)
A medical resource about NF1 for parents, patients, and providers from the Harvard Medical School Center for Neurofibromatosis and Allied Disorders; offers several frequently asked questions and their answers.

Support National & Local

Neurofibromatosis, Inc.
NF, Inc. is a national organization whose mission is to create a community of support for those affected by NF through education, advocacy, coalitions, raising public awareness, and supporting research for treatments and a cure; sponsor a limited number of local groups.

Children's Tumor Foundation
The Children’s Tumor Foundation (CTF) is a non-profit medical foundation dedicated to improving the health and well being of individuals and families affected by the neurofibromatoses. Look under "How You Can Help" to find a local chapter. The CTF sponsors an annual summer camp for children with NF.

Studies/Registries

Clinical trials in NF1 (clinicaltrials.gov)
From the National Institutes of Health, a compilation of clinical trials in NF1 and related conditions.

Services for Patients & Families

Adaptive Recreation

See all Adaptive Recreation services providers (53) in our database.

Audiology

See all Audiology services providers (64) in our database.

General Pediatric Surgery

See all General Pediatric Surgery services providers (2) in our database.

Local Support Groups, Disability/Diag

See all Local Support Groups, Disability/Diag services providers (139) in our database.

Pediatric Cardiology

See all Pediatric Cardiology services providers (1) in our database.

Pediatric Dermatology

See all Pediatric Dermatology services providers (1) in our database.

Pediatric Endocrinology

See all Pediatric Endocrinology services providers (5) in our database.

Pediatric Genetics

See all Pediatric Genetics services providers (3) in our database.

Pediatric Hematology/Oncology

See all Pediatric Hematology/Oncology services providers (1) in our database.

Pediatric Nephrology

See all Pediatric Nephrology services providers (1) in our database.

Pediatric Neurology

See all Pediatric Neurology services providers (5) in our database.

Pediatric Ophthalmology

See all Pediatric Ophthalmology services providers (5) in our database.

Pediatric Orthopedics

See all Pediatric Orthopedics services providers (3) in our database.

Recreation Programs/Activities

See all Recreation Programs/Activities services providers (240) in our database.

Social & Recreational Opportunities

See all Social & Recreational Opportunities services providers (31) in our database.

For other services related to this condition, browse our Services categories or search our database.

Authors

Author: David A. Stevenson, MD - 10/2010
Content Last Updated: 6/2013

Bibliography

Blanchard G, Pinson S, Rousselle C, Lorthois S, Combemale P, Bernard M, Lion Francois L.
[Usefulness of systematic brain magnetic resonance imaging in children with neurofibromatosis type 1].
(Article in French) Arch Pediatr. 2009;16(12):1527-32. PubMed abstract

Brems H, Chmara M, Sahbatou M, Denayer E, Taniguchi K, Kato R, Somers R, Messiaen L, De Schepper S, Fryns JP, Cools J, Marynen P, Thomas G, Yoshimura A, Legius E.
Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype.
Nat Genet. 2007;39(9):1120-6. PubMed abstract

Clementi M, Milani S, Mammi I, Boni S, Monciotti C, Tenconi R.
Neurofibromatosis type 1 growth charts.
Am J Med Genet. 1999;87(4):317-323. PubMed abstract
Article reports growth differences in NF1.

Committee on Genetics.
Health supervision for children with neurofibromatosis. American Academy of Pediatrics.
Pediatrics. 1995;96(2 Pt 1):368-72. PubMed abstract

Crawford AH, Schorry EK.
Neurofibromatosis in children: the role of the orthopaedist.
J Am Acad Orthop Surg. 1999;7(4):217-230. PubMed abstract
Excellent review of the orthopedic manifestations of NF1 particularly for orthopedic physicians managing NF1 patients.

DiMario FJ Jr, Langshur S.
Headaches in patients with neurofibromatosis-1.
J Child Neurol. 2000;15(4):235-8. PubMed abstract

Elefteriou F, Kolanczyk M, Schindeler A, Viskochil DH, Hock JM, Schorry EK, Crawford AH, Friedman JM, Little D, Peltonen J, Carey JC, Feldman D, Yu X, Armstrong L, Birch P, Kendler DL, Mundlos S, Yang FC, Agiostratidou G, Hunter-Schaedle K, Stevenson DA.
Skeletal abnormalities in neurofibromatosis type 1: approaches to therapeutic options.
Am J Med Genet A. 2009;149A(10):2327-38. PubMed abstract

Friedman JM.
Neurofibromatosis 1.
Copyright, University of Washington, Seattle. 1997-2004; (2002) http://www.geneclinics.org/servlet/access?db=geneclinics&site=gt&id=88.... In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Available at http://www.genetests.org/. Accessed on 8/14/04.
A concise and well organized review of NF1 with a focus on gene testing.

Friedman JM.
Neurofibromatosis 1: clinical manifestations and diagnostic criteria.
J Child Neurol. 2002;17(8):548-54; discussion 571-2,. PubMed abstract

Friedman JM, Arbiser J, Epstein JA, Gutmann DH, Huot SJ, Lin AE, McManus B, Korf BR.
Cardiovascular disease in neurofibromatosis 1: report of the NF1 Cardiovascular Task Force.
Genet Med. 2002;4(3):105-11. PubMed abstract
Summary of experts on NF1 from a task force meeting on cardiovascular disease in NF1, with recommendations on surveillance and diagnostic evaluation.

Friedman JM, Birch PH.
Type 1 neurofibromatosis: a descriptive analysis of the disorder in 1,728 patients.
Am J Med Genet. 1997;70(2):138-143. PubMed abstract
A large case series utilizing an international database; authors are international authorities on clinical aspects of NF1. Excellent review, focused on clinical characteristics and natural history.

Friedman JM, Gutmann DH, MacCollin M, Riccardi VM.
Neurofibromatosis: Phenotype, Natural History, and Pathogenesis.
3rd ed. Baltimore, MD: Johns Hopkins University Press; 1999. 080186285X
Excellent overview of NF1 by some of the world experts on NF1.

Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A, Viskochil D.
The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2.
JAMA. 1997;278(1):51-7. PubMed abstract
Another resource on the diagnostic evaluation of NF1 to supplement the NIH consensus statement.

Jett K, Friedman JM.
Clinical and genetic aspects of neurofibromatosis 1.
Genet Med. 2010;12(1):1-11. PubMed abstract

Jones KL.
Smith's Recognizable Patterns of Human Malformation.
5th ed. Philadelphia: W. B. Saunders Company; 1997. 0721661157
Concise reviews of syndromes with an emphasis on dysmorphology. Syndromes described in sections broken down into abnormalities, natural history, and etiology.

Kandt RS.
Tuberous sclerosis complex and neurofibromatosis type 1: the two most common neurocutaneous diseases.
Neurol Clin. 2003;21(4):983-1004. PubMed abstract

Korf BR.
Malignancy in neurofibromatosis type 1.
Oncologist. 2000;5(6):477-85. PubMed abstract
Excellent review of the malignancies in NF1 with particular focus on malignant peripheral nerve sheath tumors.

Korf BR, Carrazana E, Holmes GL.
Patterns of seizures observed in association with neurofibromatosis 1.
Epilepsia. 1993;34(4):616-20. PubMed abstract
Retrospective review of 359 NF1 individuals looking at seizure frequency.

Koth CW, Cutting LE, Denckla MB.
The association of neurofibromatosis type 1 and attention deficit hyperactivity disorder.
Neuropsychol Dev Cogn Sect C Child Neuropsychol. 2000;6(3):185-94. PubMed abstract
Study compared the ADHD status of children affected with NF-1 to that of their unaffected-NF-1 siblings and to that of their biological parents suggesting ADHD may occur as a component of NF1.

Lin AE, Birch PH, Korf BR, Tenconi R, Niimura M, Poyhonen M, Armfield Uhas K, Sigorini M, Virdis R, Romano C, Bonioli E, Wolkenstein P, Pivnick EK, Lawrence M, Friedman JM.
Cardiovascular malformations and other cardiovascular abnormalities in neurofibromatosis 1.
Am J Med Genet. 2000;95(2):108-17. PubMed abstract
Review of 2322 NF1 individuals from NF1 database documenting cardiovascular abnormalities seen in NF1.

Listernick R, Gutmann DH.
Tumors of the optic pathway.
Neurofibromatosis: Phenotype, Natural History, and Pathogenesis. 1999; 203-230. Baltimore, MD: Johns Hopkins University Press
Section, in book on NF1, reviewing optic pathway tumors by some of the world experts on NF1.

Mentzel HJ, Seidel J, Fitzek C, Eichhorn A, Vogt S, Reichenbach JR, Zintl F, Kaiser WA.
Pediatric brain MRI in neurofibromatosis type I.
Eur Radiol. 2005;15(4):814-22. PubMed abstract

Muram-Zborovski TM, Stevenson DA, Viskochil DH, Dries DC, Wilson AR, Mao R.
SPRED1 Mutations in a Neurofibromatosis Clinic.
J Child Neurol. 2010;. PubMed abstract

National Institutes of Health Consensus Development Conference.
Neurofibromatosis. Conference statement.
Arch Neurol. 1988;45(5):575-578. PubMed abstract
The consensus statement on the diagnostic criteria for the clinical diagnosis of NF1.

Oguzkan S, Cinbis M, Ayter S, Anlar B, Aysun S.
Familial segmental neurofibromatosis.
J Child Neurol. 2004;19(5):392-4. PubMed abstract

Packer RJ, Rosser T.
Therapy for plexiform neurofibromas in children with neurofibromatosis 1: an overview.
J Child Neurol. 2002;17(8):638-41; discussion 646-51. PubMed abstract

Payne JM, Moharir MD, Webster R, North KN.
Brain structure and function in neurofibromatosis type 1: current concepts and future directions.
J Neurol Neurosurg Psychiatry. 2010;81(3):304-9. PubMed abstract

Pensak ML, Keith RW, Dignan PS, Stowens DW, Towbin RB, Katbamna B.
Neuroaudiologic abnormalities in patients with type 1 neurofibromatosis.
Laryngoscope. 1989;99(7 Pt 1):702-6. PubMed abstract
Study of 44 NF1 indiviudals using ABR.

Rasmussen SA, Friedman JM.
NF1 gene and neurofibromatosis 1.
Am J Epidemiol. 2000;151(1):33-40. PubMed abstract

Rea D, Brandsema JF, Armstrong D, Parkin PC, Deveber G, Macgregor D, Logan WJ, Askalan R.
Cerebral Arteriopathy in Children With Neurofibromatosis Type 1.
Pediatrics. 2009;. PubMed abstract

Stevenson D, Viskochil D.
Pigmentary findings in neurofibromatosis type 1-like syndrome (Legius syndrome): potential diagnostic dilemmas.
JAMA. 2009;302(19):2150-1. PubMed abstract

Stevenson DA, Birch PH, Friedman JM, Viskochil DH, Balestrazzi P, Boni S, Buske A, Korf BR, Niimura M, Pivnick EK, Schorry EK, Short MP, Tenconi R, Tonsgard JH, Carey JC.
Descriptive analysis of tibial pseudarthrosis in patients with neurofibromatosis 1.
Am J Med Genet. 1999;84(5):413-419. PubMed abstract
One of the largest case series, through a multi-center, international collaboration, of tibial pseudarthrosis in NF1 describing the natural history and presentation of this hard to treat complication of NF1.

Stevenson DA, Viskochil DH, Schorry EK, Crawford AH, D'Astous J, Murray KA, Friedman JM, Armstrong L, Carey JC.
The use of anterolateral bowing of the lower leg in the diagnostic criteria for neurofibromatosis type 1.
Genet Med. 2007;9(7):409-12. PubMed abstract

Szudek J, Birch P, Friedman JM.
Growth charts for young children with neurofibromatosis 1 (NF1).
Am J Med Genet. 2000;92(3):224-8. PubMed abstract
Contains growth charts specific for NF1.

Szudek J, Joe H, Friedman JM.
Analysis of intrafamilial phenotypic variation in neurofibromatosis 1 (NF1).
Genet Epidemiol. 2002;23(2):150-64. PubMed abstract

Tonsgard JH.
Clinical manifestations and management of neurofibromatosis type 1.
Semin Pediatr Neurol. 2006;13(1):2-7. PubMed abstract

Viskochil D.
Genetics of neurofibromatosis 1 and the NF1 gene.
J Child Neurol. 2002;17(8):562-70; 571-2, 646-51. PubMed abstract

Viskochil DH.
Neurofibromatosis Type 1.
Management of Genetic Syndromes, 3rd Edition. 2010; 549-568. New York: Wiley-Blackwell; http://www.wiley.com/WileyCDA/WileyTitle/productCd-0470191414.html
Excellent review of NF1 by an expert in the field. Book is a great resource for Medical Home providers, with chapters on 25 different genetic conditions.

Vitale MG, Guha A, Skaggs DL.
Orthopaedic manifestations of neurofibromatosis in children: an update.
Clin Orthop. 2002;(401):107-118. PubMed abstract
A recent review of the orthopedic manifestations of NF1. Very well organized and informative.

Xu W, Mulligan LM, Ponder MA, Liu L, Smith BA, Mathew CG, Ponder BA.
Loss of NF1 alleles in phaeochromocytomas from patients with type I neurofibromatosis.
Genes Chromosomes Cancer. 1992;4(4):337-42. PubMed abstract
Study reports the association of pheochromocytomas with NF1.

Young H, Hyman S, North K.
Neurofibromatosis 1: clinical review and exceptions to the rules.
J Child Neurol. 2002;17(8):613-621. PubMed abstract
Concise, up to date, review of clinical aspects of NF1 with focus on unusual manifestations.