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Neurofibromatosis Type 1

Overview

Neurofibromatosis type 1 (NF1) is a common autosomal dominant neurocutaneous genetic disorder. It was 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." Pathogenic variants 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: 2021]).
In up to 95% of cases, the diagnosis can be made through straightforward clinical evaluation by the time a child is 11 years old. [Friedman: 1997] Hallmark findings of NF1 include:

Other Names & Coding

NF1 Von Recklinghausen's disease
ICD-10 coding

Q85.01, Neurofibromatosis, type 1

Coding for Neurofibromatosis, Type 1 (icd10data.com) provides further coding details.

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 sex.

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] NF1 is completely penetrant in adolescents and young adults with variable age-dependent onset of manifestations.
In adults, NF1 can be diagnosed with relative certainty on a clinical basis and thus rarely requires molecular confirmation. A trained clinical geneticist should evaluate all individuals, including adults, suspected of having NF1. However, older individuals with only pigmentary manifestations of NF1 may have a different condition (e.g., Legius syndrome). In such cases, SPRED1 and/or NF1 molecular analysis can help clarify the diagnosis. DNA testing is clinically available. [Friedman: 2019].

Prognosis

Manifestations of NF1 vary considerably; therefore, prognosis also varies. However, overall, the average life expectancy of individuals with NF1 is probably 10-15 years shorter than the general population. Malignancies, including brain tumors and malignant peripheral nerve sheath tumors, are rare but are likely the most common cause of increased mortality. [Rasmussen: 2000] [Tonsgard: 2006]

Practice Guidelines

The article by Miller et al. is from the American Academy of Pediatrics' Committee on Genetics; Stewart et al. is from the American College of Medical Genetics. The others are not endorsed by an official entity but offer excellent information that is widely accepted.

Miller DT, Freedenberg D, Schorry E, Ullrich NJ, Viskochil D, Korf BR.
Health Supervision for Children With Neurofibromatosis Type 1.
Pediatrics. 2019;143(5). PubMed abstract

Stewart DR, Korf BR, Nathanson KL, Stevenson DA, Yohay K.
Care of adults with neurofibromatosis type 1: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).
Genet Med. 2018;20(7):671-682. PubMed abstract

Viskochil DH.
Neurofibromatosis Type 1, 4th edition.
Management of Genetic Syndromes, 4th Edition. ISBN: 978-1-119-43267-8. 2021; 629. New York: Wiley-Blackwell
Excellent review of NF1 by an expert in the field. The book has chapters for 63 different medical conditions and is a great resource for medical home clinicians.

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

Roles of the Medical Home

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

Clinical Assessment

Overview

Neurofibromatosis type 1 (NF1) is typically diagnosed clinically during childhood. Because the clinical features are quite variable, the age at diagnosis may vary. Molecular 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.

Pearls & Alerts for Assessment

A clinical geneticist should evaluate all individuals who are suspected of having NF1

Older children, adolescents, and adults with only pigmentary findings may have Legius syndrome due to a variant in a different gene other than the NF1 gene (i.e., the SPRED1 gene) or may have germline mosaicism and an attenuated form of NF1. [Muram-Zborovski: 2010] These individuals may need genetic testing to determine their diagnosis.

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 nerve gliomas and should have yearly assessments by pediatric ophthalmology.

Intellectual development

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, to identify areas of concern and methods to maximize the child’s potential.

Screening

Of Family Members

Screening for NF1 in other family members should consist of physical examination for any of the diagnostic clinical findings of 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 nerve gliomas
  • Blood pressure measurements twice a year and at each physician visit looking for hypertension. Essential hypertension is most common, but hypertension may also be secondary to pheochromocytomas or renal artery stenosis
  • “Bend over” examination of the back at least yearly looking for scoliosis

Presentations

Though NF1 is fully penetrant, its clinical expressivity is highly variable, even among family members. A severely affected child may have a mildly affected parent who may not even know that they have NF1. Despite the variable expressivity, there are some generalities in age-specific presentations:
  • Café-au-lait macules, light brown with relatively well-defined borders, are typically the first manifestation of NF1 noted by the primary care clinician. They may be present at birth but usually appear in the first year (80% of NF1 individuals will have >5 café-au-lait macules by 1 year of age). [Viskochil: 2021]
  • Intertriginous freckling usually develops after the presence of café-au-lait macules.
  • Optic nerve 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: 2021]
  • Plexiform neurofibromas can be seen early in childhood and are quite specific for NF1. Neurofibromas may increase in size and number during puberty and pregnancy [Friedman: 2002]
Approximately 90% of individuals with NF1 will have 2 or more of the clinical diagnostic criteria by 6 years of age [Friedman: 2002]

Diagnostic Criteria

Criteria for diagnosis of NF1 were initially developed by the NIH at a Consensus Development Conference. The updated 2021 version (adapted and modified from [National: 1988], [Gutmann: 1997], [Stevenson: 2007] and [Legius: 2021]) is shown below:
A: The diagnostic criteria for NF1 are met in an individual who does not have a parent diagnosed with NF1 if 2 or more of the following are present:
  • Six or more café au lait macules(over 5mm in prepubertal individuals - over 15mm in postpubertal individuals). If only café-au-lait macules and freckling are present, the diagnosis is most likely NF1; exceptionally, the person might have another diagnosis such as Legius syndrome. At least 1 of the 2 pigmentary findings (café-au-lait macules or freckling) should be bilateral.
  • Two or more neurofibromas of any type or 1 or more plexiform neurofibroma(s)
  • Freckling in the axillary or inguinal region. If only café-au-lait macules and freckling are present, the diagnosis is most likely NF1; exceptionally, the person might have another diagnosis such as Legius syndrome. At least 1 of the 2 pigmentary findings (café-au-lait macules or freckling) should be bilateral.
  • Optic pathway glioma
  • Two or more iris Lisch nodules or 2 or more choroidal abnormalities
  • A distinctive osseous lesion such as sphenoid wing dysplasia, anterolateral bowing of the tibia, or pseudarthrosis of a long bone. Sphenoid wing dysplasia is not a separate criterion in case of an ipsilateral orbital plexiform neurofibroma.
  • A heterozygous pathogenic NF1 variant with a variant allele fraction of 50% in apparently normal tissue such as white blood cells
B: A child of a parent who meets the diagnostic criteria specified in “A” merits a diagnosis of NF1 if 1 or more of the criteria in A are present.
Other features of NF1 include (modified from [Viskochil: 2021] and [Young: 2002]):
  • Educational difficulty (40-60%)
  • Macrocephaly (38-45%)
  • Short stature (18-34%)
  • Scoliosis (10-30%)
  • Headache (22%)
  • Seizures (5-7%)
  • Precocious puberty (4-5%)
  • Hypertension (4%)
  • Hydrocephalus (3-4%)
  • Congenital heart disease (2-4%)

Differential Diagnosis

Neurofibromas typically appear after the development of café-au-lait macules, beginning in late childhood and adolescence, and the presence of other NF1 findings aids in their diagnosis as benign tumors.
Legius syndrome, delineated in 2007, is due to pathogenic variants in SPRED1, a gene that encodes a protein that acts as a docking protein for neurofibromin in the Ras-MAPK signal transduction pathway. [Brems: 2007] Individuals with Legius syndrome often have café-au-lait spots and variable intertriginous freckling pattern 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 (e.g., neurofibromas, Lisch nodules, optic nerve pathway tumors). [Legius: 2010] 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 typically are not confused with NF1 given the presence and lack of other manifestations: [Viskochil: 2021] [Jones: 1997]
  • Noonan syndrome – webbing of the neck, pectus abnormality, cryptorchidism, pulmonic stenosis
  • McCune-Albright syndrome – polyostotic fibrous dysplasia, irregular skin pigmentation, sexual precocity
  • Noonan syndrome with multiple lentigines – 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
  • Fanconi anemia – bone marrow failure, thumb anomalies, organ malformations, microcephaly
  • Sotos syndrome – large size, large hands and feet, hypotonia
  • Dubowitz syndrome – unusual facies, infantile eczema, small stature, mild microcephaly
  • Klippel-Trenaunay syndrome – asymmetric limb hypertrophy, cutaneous vascular malformations
  • Proteus syndrome – hemihypertrophy, subcutaneous tumors, macrodactyly
Neurofibromas in NF1 can be confused, albeit rarely, with other tumor syndromes, including: [Viskochil: 2021] [Jones: 1997]
  • Bannayan-Riley-Ruvalcaba syndrome/Cowden 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
  • Maffucci 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

History & Examination

See Comorbid Conditions above for findings that occur commonly in NF1.

Current & Past Medical History

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

Family History

NF1 is an autosomal dominant genetic disorder; about 50% of individuals with NF1 inherit the gene mutation from 1 parent. 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/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.

Developmental & Educational Progress

Ask about developmental milestones, especially speech and language issues, and school performance in both the child and family members.

Maturationalprogress

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

Social & Family Functioning

An understanding of family functioning and existing problems, especially in those families with NF1, may help guide the medical home's approach. Knowledge of other family members with NF1, their health, and course may help the clinician to better understand the family’s 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

Individuals with NF1 tend to have relatively short stature and relative macrocephaly. Growth parameters should be monitored and plotted on specific NF1 growth charts (found under Clinical Tools in Neurofibromatosis Type 1). [Friedman: 1999] [Clementi: 1999] Children who are not following percentile lines may need further evaluation, including brain MRI for those with accelerated growth in childhood and growth hormone stimulation testing for individuals who are short with flat growth velocity.

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.

HEENT/Oral

A routine eye exam should include looking for proptosis, strabismus, and ptosis. The typical findings of NF1, such as Lisch nodules, can often only be seen by an experienced ophthalmologist performing a slit lamp exam and, more importantly, a dilated exam to identify abnormalities of the optic disc for evidence of optic nerve gliomas.

Heart

Congenital heart defects are sometimes seen in NF1 patients. The most common is pulmonary valve stenosis, which can be readily identified on auscultation. Routine echocardiograms and a cardiology referral are not recommended unless clinically indicated.

Genitalia

Although uncommon (~4-5%), observe for signs of precocious puberty.

Extremities/Musculoskeletal

Carefully examine 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 in the absence of symptoms is not generally indicated. Vitamin D deficiency has been reported, and one could consider periodic screening. See Calcium and Vitamin D.

Imaging

MRI – Controversy exists over the routine use of imaging studies in individuals with NF1. Some groups perform an initial MRI of the brain upon diagnosis. Hyperintense T2-weighted signals, called focal areas of signal intensity (FASI), 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. Many radiologists unfamiliar with NF1 raise an alarm that leads to additional unnecessary screening in asymptomatic patients. Some experts obtain MRI studies only when clinical symptoms suggest a need.
However, one must seriously consider imaging relevant body regions to look for plexiform neurofibromas, malignancies, hydrocephalus, and vascular anomalies if there is a new-onset or increasing pain, rapidly growing masses, or neurologic and/or behavior changes. It has been suggested that magnetic resonance angiography (MRA) be included with MRI in individuals with NF1 since cerebral angiopathy is found in up to 6% of individuals and perhaps more frequently in those with optic nerve glioma. [Payne: 2010]
X-rays – 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 testing of the NF1 gene is available clinically. It is usually unnecessary for a clinical diagnosis; although, testing can be considered in individuals with only pigmentary findings because of the phenotypic overlap with Legius syndrome. Issues regarding insurance coverage for genetic testing are often complicated. Prior approval is suggested unless individuals are willing to pay the entire cost.

Specialty Collaborations & Other Services

Medical Genetics (see NW providers [1])

It is appropriate for anyone suspected of having NF1 to be evaluated by a clinical geneticist to consider differential diagnoses and discuss the inheritance pattern and recurrence risks. Up-to-date information on research and new developments in 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.

Pediatric Ophthalmology (see NW providers [1])

Initial evaluation for Lisch nodules is helpful to aid in diagnosis. Since these are often visible only with slit lamp examination, all children suspected of having NF1 should be evaluated by an ophthalmologist (even though Lisch nodules tend to emerge in older individuals). Yearly evaluations are needed to monitor for findings seen in optic pathway tumors. Children with optic nerve gliomas will most likely require more frequent follow-up along with periodic imaging. If a patient reports eye pain, vision loss, or visual changes, the patient should be seen urgently by an ophthalmologist.

Pediatric Orthopedics (see NW providers [4])

A baseline evaluation for scoliosis, long bone dysplasia, or bone pain (possibly secondary to bone cysts) is recommended by primary care clinicians. Concurrent care by an orthopedic surgeon may be helpful for some children.

Pediatric Neurology (see NW providers [0])

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

Pediatric Endocrinology (see NW providers [1])

Referral may be helpful in the management of endocrinologic complications of intracranial tumors, extreme short stature with proven growth hormone deficiency, or pheochromocytomas.

Pediatric Hematology/Oncology (see NW providers [1])

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

Pediatric Nephrology (see NW providers [0])

Children should be evaluated by nephrology if hypertension is persistent or renal artery stenosis is detected on imaging.

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 the complications due to them.

Pearls & Alerts for Treatment & Management

Short stature

Individuals with NF1 are generally shorter than the general population and have 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]

Plexiform neurofibromas

Individuals with NF1 are at risk for the development of plexiform neurofibromas. Pharmacologic treatments have been limited for plexiform neurofibromas, but recent clinical trials showed some effect of a MEK inhibitor (i.e., selumetinib), which is now an approved drug for NF1-related inoperable plexiform neurofibromas. [Mukhopadhyay: 2021] [Gross: 2020] [Dombi: 2016]

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.

Common Complaints

Headaches and pain should be taken seriously in individuals with NF1. Have a low threshold for obtaining imaging studies (particularly for pain that wakes a patient up at night or is increasing in intensity). Abdominal migraine and constipation are common in NF1 but rarely have an identified underlying etiology.

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 nerve pathway tumors, low-grade intracranial gliomas, 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 cutaneous 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 and electrodessication. [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 and electrodessication have been adopted at different centers, but presently there is no accepted protocol for medical management or prevention of cutaneous neurofibromas.

Specialty Collaborations & Other Services

Pediatric Dermatology (see NW providers [1])

May be helpful in the management of neurofibromas.

Pediatric General Surgery (see NW providers [0])

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 yearly ophthalmologic evaluations by an experienced ophthalmologist until late adolescence. The primary care physician should perform a routine eye exam looking for findings such as proptosis, strabismus, peripheral vision, color vision, and ptosis, though the typical findings of NF1 usually only can 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 tumor growth as measured by sequential MRI, then medical management is sometimes initiated with low-level chemotherapy, using carboplatin/vincristine. 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 nerve glioma is identified.

Specialty Collaborations & Other Services

Pediatric Ophthalmology (see NW providers [1])

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 nonunion 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; 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 1 of the following dystrophic osseous findings: 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 high index of suspicion for facial plexiform neurofibromas in individuals with sphenoid wing dysplasia, and they may benefit from earlier imaging by MRI. Exophthalmos is a rare complication that may require intervention, but the sphenoid wing dysplasia usually does not cause significant clinical complications or require therapeutic management. Plastic surgery and neurosurgery are needed for repair of sphenoid wing dysplasia.

Specialty Collaborations & Other Services

Pediatric Orthopedics (see NW providers [4])

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); educational difficulties are 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. See Attention-Deficit/Hyperactivity Disorder (ADHD) for treatment.
Individuals with a large NF1 gene deletion have been noted to have an increased chance for cognitive/developmental delay. [Viskochil: 2021]. A karyotype and FISH study (fluorescence in situ hybridization) looking for an NF1 gene deletion could be considered when cognitive impairment is a prominent feature.

Ears/Hearing

Sensorineural hearing loss is relatively infrequent in 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.

Specialty Collaborations & Other Services

Audiology (see NW providers [3])

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 nerve 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 are no data to support this recommendation. While some investigators recommend that children with NF1 should receive an MRI yearly, other investigators have found that routine brain MRIs do not change clinical outcomes. [Mentzel: 2005] [Blanchard: 2009] Children and adolescents should receive headache medication as appropriate if no underlying cause is 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.
Cerebral arteriopathy and subsequent risk of stroke are found in approximately 6% of children with NF1, possibly more in those with optic nerve glioma. [Rea: 2009] It has therefore been suggested that MRA be included with MRI when performed for other reasons, such as screening for optic nerve glioma. [Payne: 2010] If cerebral arteriopathy is found, pediatric neurology or neurosurgery should be consulted for the possibility of medical and/or neurosurgical treatment.

Specialty Collaborations & Other Services

Pediatric Neurology (see NW providers [0])

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. Blood pressure measurements should be 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 workup for pheochromocytoma should be considered in individuals with hypertension and/or signs of excess catecholamine release.

Specialty Collaborations & Other Services

Pediatric Nephrology (see NW providers [0])

Consider management by pediatric nephrology if hypertension is present.

Pediatric Cardiology (see NW providers [0])

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 and maintain bone density. See Resources below for recreational therapy and camping programs.

Specialty Collaborations & Other Services

Rec Centers, Parks, Zoos & Museums (see NW providers [2])

These programs focus on children with special needs.

Adaptive Sports (see NW providers [8])

For those children with a variety of disabilities

No Related Issues were found for this diagnosis.

Ask the Specialist

Can neurofibromatosis type 1 progress to neurofibromatosis type 2?

No. These 2 conditions are different genetic disorders. Both have tumors as part of the clinical findings, but they have a variety of divergent features. The NF1 gene is located on the long arm of chromosome 17, while the NF2 gene is located on the long arm of chromosome 22. Neurofibromatosis type 2 (NF2) is rare (1:30,000) and usually has a later age of symptom onset. Some features of NF2 include vestibular schwannomas, meningiomas, juvenile posterior subcapsular lenticular opacities, and gliomas. The hallmark feature of NF2 is bilateral vestibular schwannomas.

My patient does not have any neurofibromas now. Does that mean they will not get any in the future?

No. Many of the findings of NF1 are age-related and this includes the cutaneous neurofibromas. Cutaneous neurofibromas develop over time; there is limited information to determine when or how many neurofibromas an individual will develop.

Resources for Clinicians

On the Web

Neurofibromatosis 1 (GeneReviews)
A 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)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

Helpful Articles

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

Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC.
Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas.
N Engl J Med. 2016;375(26):2550-2560. PubMed abstract / Full Text

Miller DT, Freedenberg D, Schorry E, Ullrich NJ, Viskochil D, Korf BR.
Health Supervision for Children With Neurofibromatosis Type 1.
Pediatrics. 2019;143(5). 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

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 Tools

Growth/BMI Charts

The growth charts below are for children with neurofibromatosis type 1 and are adapted from [Szudek: 2000].

Boys with NF1 - Length Growth 1-36 months (PDF Document 97 KB)

Girls with NF1 - Length Growth 1-36 months (PDF Document 94 KB)

Boys with NF1 - Weight Growth 1-36 months (PDF Document 97 KB)

Girls with NF1 - Weight Growth 1-36 months (PDF Document 95 KB)

Boys with NF1 - Head Growth 1-36 months (PDF Document 95 KB)

Girls with NF1 - Head Growth 1-36 months (PDF Document 95 KB)

Boys with NF1 - Height Growth 2-18 years (PDF Document 113 KB)

Girls with NF1 - Height Growth 2-18 years (PDF Document 106 KB)

Boys with NF1 - Weight Growth 2-18 years (PDF Document 104 KB)

Girls with NF1 - Weight Growth 2-18 years (PDF Document 101 KB)

Boys with NF1 - Head Growth 2-18 years (PDF Document 117 KB)

Girls with NF1 - Head Growth 2-18 years (PDF Document 108 KB)

Males with NF1 - BMI 2-40 years (PDF Document 109 KB)

Females with NF1 - BMI 2-40 years (PDF Document 117 KB)

Boys with NF1 - OFC/Ht 2-18 years (PDF Document 113 KB)

Girls with NF1 - OFC/Ht 2-18 years (PDF Document 110 KB)

Full Set of Growth Charts for Boys and Girls with NF1 (PDF Document 1.5 MB)

Patient Education & Instructions

About NF1 (Children's Tumor Foundation)
Useful information for families about NF1, its manifestations, diagnosis, treatments, and other resources.

Resources for Patients & Families

Information on the Web

The Portal's pages about Financing Your Child's Healthcare and Health Insurance/Financial Aids may be helpful for families.

Children's Tumor Foundation
A non-profit medical foundation dedicated to improving the health and well-being of individuals and families affected by the neurofibromatoses. The "Find a Doctor" tab links to information about NF clinics and specialists across the country.

Neurofibromatosis (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

Neurofibromatosis Type 1 (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

National & Local Support

Neurofibromatosis Network
A national organization with some local chapters whose mission is to create a community of support through education, advocacy, coalitions, raising public awareness, and supporting research for treatments and a cure.

Studies/Registries

Clinical Trials in NF1 (clinicaltrials.gov)
Studies looking at better understanding, diagnosing, and treating this condition; from the National Library of Medicine.

NF Registry (Children's Tumor Foundation)
The NF Registry is for all types of NF (including NF1, NF2, and schwannomatosis). It is open to all populations, including any age, race, ethnicity, or gender. Information in the NF Registry is used only for communicating with you about updates and clinical trials that match your needs and providing qualified researchers a summary of anonymous patient data about NF symptoms.

Services for Patients & Families Nationwide (NW)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: February 2004; last update/revision: July 2021
Current Authors and Reviewers:
Author: David A. Stevenson, MD
Reviewer: David Viskochil, MD, PhD
Authoring history
2018: update: David A. Stevenson, MDA; David Viskochil, MD, PhDR
2010: update: David A. Stevenson, MDA
2004: first version: David A. Stevenson, MDA; Karin Dent, MS, CGCR; David Viskochil, MD, PhDR
AAuthor; CAContributing Author; SASenior Author; RReviewer

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.

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

Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC.
Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas.
N Engl J Med. 2016;375(26):2550-2560. PubMed abstract / Full Text

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; (2019) https://www.ncbi.nlm.nih.gov/books/NBK1109/. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Available at http://www.genetests.org/. Accessed on June 2021.
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.

Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, Weiss B, Kim A, Bornhorst M, Shah AC, Martin S, Roderick MC, Pichard DC, Carbonell A, Paul SM, Therrien J, Kapustina O, Heisey K, Clapp DW, Zhang C, Peer CJ, Figg WD, Smith M, Glod J, Blakeley JO, Steinberg SM, Venzon DJ, Doyle LA, Widemann BC.
Selumetinib in Children with Inoperable Plexiform Neurofibromas.
N Engl J Med. 2020;382(15):1430-1442. PubMed abstract / Full Text

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.

Legius E, Messiaen L, Wolkenstein P, Pancza P, Avery RA, Berman Y, Blakeley J, Babovic-Vuksanovic D, Cunha KS, Ferner R, Fisher MJ, Friedman JM, Gutmann DH, Kehrer-Sawatzki H, Korf BR, Mautner VF, Peltonen S, Rauen KA, Riccardi V, Schorry E, Stemmer-Rachamimov A, Stevenson DA, Tadini G, Ullrich NJ, Viskochil D, Wimmer K, Yohay K, Huson SM, Evans DG, Plotkin SR.
Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation.
Genet Med. 2021. PubMed abstract

Legius E, Stevenson D.
Legius Syndrome.
GeneReviews® [Internet]. 2010. PubMed abstract

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

Miller DT, Freedenberg D, Schorry E, Ullrich NJ, Viskochil D, Korf BR.
Health Supervision for Children With Neurofibromatosis Type 1.
Pediatrics. 2019;143(5). PubMed abstract

Mukhopadhyay S, Maitra A, Choudhury S.
Selumetinib: the first ever approved drug for neurofibromatosis-1 related inoperable plexiform neurofibroma.
Curr Med Res Opin. 2021;37(5):789-794. 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

Stewart DR, Korf BR, Nathanson KL, Stevenson DA, Yohay K.
Care of adults with neurofibromatosis type 1: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).
Genet Med. 2018;20(7):671-682. 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, 4th edition.
Management of Genetic Syndromes, 4th Edition. ISBN: 978-1-119-43267-8. 2021; 629. New York: Wiley-Blackwell
Excellent review of NF1 by an expert in the field. The book has chapters for 63 different medical conditions and is a great resource for medical home clinicians.

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 review of clinical aspects of NF1 with focus on unusual manifestations.