Neurofibromatosis

Author: Gerald Hagler, MD, MBA and Emily Mylhousen, MD

Definition

Neurofibromatosis (NF) is an autosomal-dominant, neurocutaneous disorder causing a tumor predisposition predominantly in the form of neurofibromas, optic gliomas, Lisch nodules, café au lait spots, axillary and inguinal freckling, and osseous lesions. Traditionally NF has been divided into three major subtypes: NF type 1 (NF1), NF type 2 (NF2), and schwannomatosis (SWN). However, nomenclature and diagnostic criteria for neurofibromatosis were recently updated (Box E1) to incorporate clinical and genetic discoveries made since the previous consensus conference in the late 1990s.

BOX E1 Revised Diagnostic Criteria for Neurofibromatosis Type 1 (NF1)

A: The diagnostic criteria for NF1 are met in an individual who does not have a parent diagnosed with NF1 if two or more of the following are present:

•Six or more café-au-lait macules over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals ^a
•Freckling in the axillary or inguinal region ^a
•Two or more neurofibromas of any type or one plexiform neurofibroma
•Optic pathway glioma
•Two or more iris Lisch nodules identified by slit lamp examination or two or more choroidal abnormalities (CAs)-defined as bright, patchy nodules imaged by optical coherence tomography (OCT)/near-infrared reflectance (NIR) imaging
•A distinctive osseous lesion such as sphenoid dysplasia,^b anterolateral bowing of the tibia, or pseudarthrosis of a long bone
•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 one or more of the criteria in A are present.

From Legius E et al: Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation, Genet Med 23,1506-1513, 2021.

Synonyms

NF1: NF, von Recklinghausen disease, peripheral NF
Schwannomatosis, as further subdivided:
- NF2-related schwannomatosis (previous known as NF2 or central NF)
- SMARCB1-related schwannomatosis
- LZTR1-related schwannomatosis
- 22q-related schwannomatosis
- Schwannomatosis-not otherwise specified (NOS)
- Schwannomatosis-not elsewhere classified (NEC)
- NF

ICD-10CM CODES
Q85.00		Neurofibromatosis, unspecified
Q85.01		Neurofibromatosis, type 1
Q85.02		Neurofibromatosis, type 2
Q85.03		Schwannomatosis

Epidemiology & Demographics

•NF1 and NF2-related SWN are autosomal dominant; however, approximately 50% of cases are de novo mutations with no family history.
•NF1 has an incidence of 1/3000 live births and prevalence of 1/5000 persons.
•NF2-related SWN has an incidence of 1/25,000 live births and prevalence of 1/60,000 persons.
•These two disorders affect approximately 100,000 people in the US.
•Affects males and females equally.¹
•NF1 may be associated with optic gliomas, astrocytomas, spinal neurofibromas, pheochromocytomas, and chronic myeloid leukemia.
•NF2-related SWN may be associated with acoustic neuromas, meningiomas, spinal schwannomas, and gliomas.²
•The incidence of non-NF2-related SWN is 1/40,000 live births. The disease is mostly sporadic in nature; however, approximately 20% of cases appear to be inherited.¹

Physical Findings & Clinical Presentation

•Common features of NF1 include:
1. 1.Café-au-lait macules (100% of children by age 2 yr)
  1. a.Hyperpigmented skin lesions (Fig. E1) occurring anywhere on the body except the face, palms, and soles
  2. b.Appear early in life and increase in size and number during puberty
  3. c.Are focal or diffuse
2. 2.Axillary and inguinal freckling (70%)
3. 3.Multiple neurofibromas (Fig. E2) can be soft or firm; three subtypes:
  1. a.Cutaneous: Circumscribed, not specific for NF1
  2. b.Subcutaneous: Circumscribed, not specific for NF1
  3. c.Plexiform: Noncircumscribed, thick and irregular; can cause derangement of supportive structures and is specific for NF1
4. 4.Lisch nodule (small hamartoma of the iris) found in >90% of adult cases
5. 5.Visual defects possibly related to optic gliomas (2% to 5%)
6. 6.Neurodevelopment problems, such as learning disability and mental retardation (30%-40%)
7. 7.Skeletal disorders including long bone dysplasia, pseudoarthrosis, scoliosis, short stature, and decreased bone mineral density ³
•Common features of NF2-related SWN include:
1. 1.Hearing loss and tinnitus related to bilateral acoustic neuromas (>90% of adults)
2. 2.Cataracts (81%), retinal hamartoma, and epiretinal membranes
3. 3.Headache, which may be due to intracranial meningiomas, present in 80% of patients
4. 4.Unsteady gait
5. 5.Cutaneous and subcutaneous neurofibromas but fewer than in NF1
6. 6.Café-au-lait macules (1%) (Fig. E3)³^,⁴
•Common features of SMARCB1-, LZTR1-, and 22q-related SWN include ⁵:
1. 1.Painful multiple schwannomas of the spinal (74%), peripheral (89%), or cranial nerves except the vestibular nerve (9%)

Figure E1 Systemic features of neurofibromatosis type 1.

A, Discrete neurofibromas. B, Nodular plexiform neurofibroma of the eyelid. C, Elephantiasis nervosa. D, Café-au-lait spots.

(Courtesy S. Kumar Puri. Kanski JJ, Bowling B: Clinical ophthalmology: a systemic approach, ed 7, Philadelphia, 2010, Elsevier.)

Figure E2 Multiple neurofibromas are present in this individual.

(From Callen JP et al: Dermatological signs of systemic disease, ed 5, Philadelphia, 2017, Elsevier, pp. 345-358.)

Figure E3 A Café-Au-Lait Spot and Multiple Freckles (Crowe Sign) in the Axillary Vault are Seen in This Patient with Neurofibromatosis

(From Callen JP et al: Dermatological signs of systemic disease, ed 5, Philadelphia, 2017, Elsevier, pp. 345-358.)

Etiology

•NF1 is caused by DNA mutations located at 17q11.2 on chromosome 17, which is responsible for encoding the protein neurofibromin, a guanosine triphosphatase protein modulating signaling through the Ras/MAPK and PI3K/mTOR pathways.
•NF2-related SWN is caused by DNA mutations located at 22q12.2 on chromosome 22 and is responsible for encoding the protein merlin, a potent inhibitor of glioma growth that modulates signaling through the PI3K/AKT, Raf/MEK/ERK, and mTOR pathways.
•Both proteins are speculated to act as tumor suppressors.¹
•Over 50% de novo NF2-related SWN have mosaicism.⁴
•Germline mutations in tumor suppressor genes SMARCB1 and LZTR1 on chromosome 22 account for 70% to 80% of non-NF2-related familial SWN. However, additional somatic mutations are required to trigger this condition. A four-hit hypothesis has been proposed for tumorigenesis in SMARCB1- and LZTR1-related SWN.

a If only café-au-lait macules and freckling are present, the diagnosis is most likely NF1 but, exceptionally, the person might have another diagnosis such as Legius syndrome. At least one of the two pigmentary findings (café-au-lait macules or freckling) should be bilateral.

b Sphenoid wing dysplasia is not a separate criterion in the case of an ipsilateral orbital plexiform neurofibroma.

•The major clinical features of NF1 are summarized in Table E1.⁶ Diagnostic criteria, as proposed by an international consensus released by the Children’s Tumor Foundation in 2021, are listed below. NF1 is diagnosed if the person has two or more of the seven following features:
1. 1.Six or more café-au-lait macules >5 mm in prepubertal patients and >15 mm in post-pubertal patients
2. 2.Two or more neurofibromas of any type or one plexiform neurofibroma
3. 3.Axillary or inguinal freckling
4. 4.Optic glioma
5. 5.Two or more Lisch nodules (iris hamartomas)
6. 6.A distinctive osseous lesion such as sphenoid wing dysplasia, anterolateral bowing of the tibia, or pseudarthrosis of a long bone
7. 7.A heterozygous pathogenic NF1 variant with a variant allele fraction of 50% in apparently normal tissue such as white blood cells
•Additionally, a child of a parent who meets the diagnostic criteria specified above merits a diagnosis of NF1 if one or more criteria listed above are present.⁷
•Diagnostic criteria for both NF2 and SWN were restructured by an international consensus released by the Children’s Tumor Foundation in June 2022 in Genetics in Medicine after it was revealed that a significant number of patients who were clinically diagnosed with one (NF2 or SWN) actually have the other on genetic analysis. Instead of being a separate entity, NF2 has been found to be part of the spectrum of schwannomatosis and is now termed NF2-related schwannomatosis, which can be diagnosed by any of the following criteria:
1. 1.Bilateral vestibular schwannomas
2. 2.An identical NF2 pathogenic variant in at least two anatomically distinct NF2-related tumors (schwannoma, meningioma, and/or ependymoma)
3. 3.Either two major or one major and two minor criteria as described below:
  1. a.Major criteria
    - (1)Unilateral vestibular schwannoma
    - (2)First-degree relative other than sibling with NF2-related schwannomatosis
    - (3)Two or more meningiomas (single meningioma qualifies as minor criteria)
    - (4)NF2 pathogenic variant in an unaffected tissue such as blood
  2. b.Minor criteria
    - (1)Can count >one of a type (e.g., two distinct schwannomas would count as two minor criteria): Ependymoma, schwannoma, meningioma (multiple meningiomas qualify as a major criteria)
    - (2)Can count only once (e.g., bilateral cortical cataracts count as a single minor criterion): Meningioma, juvenile subcapsular or cortical cataract, retinal hamartoma, epiretinal membrane in a person <40 yr ⁴
•As stated previously, diagnostic criteria for SWN were updated in 2022. SWN is now subdivided into NF2-related schwannomatosis (see diagnostic criteria above), SMARCB1-related schwannomatosis, LZTR1-related schwannomatosis, 22q-related schwannomatosis, schwannomatosis NOS (not otherwise specified), and schwannomatosis NEC (not elsewhere classified).
•SMARCB1- and LZTR1-related schwannomatosis are diagnosed if the person has any of the following criteria:
1. 1.At least one pathologically confirmed schwannoma or hybrid nerve sheath tumor and a SMARCB1 (or LZTR1) pathogenic variant in an unaffected tissue such as blood
2. 2.A shared SMARCB1 (or LZTR1) pathogenic variant in two schwannomas or hybrid nerve sheath tumors.
•22q-related schwannomatosis diagnosis can be made if the person does not meet criteria for NF2-, SMARCB1-, or LZTR1-related schwannomatosis, does not have a germline DGCR8 pathogenic variant, and has both LOH of the same chromosome 22q markers in two anatomically distinct schwannomas or hybrid nerve sheath tumors and a different NF2 pathogenic variant in each tumor which cannot be detected in unaffected tissue.
•Schwannomatosis-NOS is reserved for patients who have clinical features of NF2/SWN but have not had molecular analysis.
•Schwannomatosis-NEC is reserved for patients in whom molecular analysis of blood and tumors has failed to detect a pathogenic variant (PV).⁴

TABLE E1 Major Clinical Features of Neurofibromatosis Type 1

Cutaneous
•Neurofibromas (60%-90%) •Café-au-lait macules (>90%) •Axillary and/or inguinal freckling (~80%) •Plexiform neurofibroma (25%) •Nevus anemicus (30%-50%) •Juvenile xanthogranuloma (15%-35% in first 3 yr of life)
Ocular
•Lisch nodules (~90% by age 20) •Choroidal nodules (>80% of adults) •Neovascular glaucoma, retinal vasoproliferative tumors
Skeletal
*Cranial*
•Macrocephaly (20%-50%) •Hypertelorism (25%) •Sphenoid wing dysplasia (<5%)
*Spinal*
•Scoliosis (5%-10%) •Spina bifida
*Limbs*
•Dysplasia of long bone cortex (5%), pseudarthrosis (2%)
*Other*
•Generalized osteopenia (~50%), osteoporosis (~20%) •Short stature (~30% <3rd percentile) •Pectus deformity (30%-50%)
*Tumors*
•Optic glioma (10%-15%) (with or without precocious puberty) •Malignant peripheral nerve sheath tumors (3%-15%) •Pheochromocytoma (~1%) •Juvenile myelomonocytic leukemia •CNS tumors other than optic gliomas (~5%) •Rhabdomyosarcoma, especially of the genitourinary tract •Duodenal carcinoid •Somatostatinoma •Parathyroid adenoma •Gastrointestinal stromal tumors (GIST) •Breast cancer (~5-fold increased risk in women <50 yr of age)
Neurologic
•Unidentified bright objects (UBO) on MRI (50%-75%) •Learning difficulties (30-50%) •Seizures (~5%) •Intellectual impairment (severe in <5%) •Aqueductal stenosis and hydrocephalus (~2%)
Cardiovascular
•Hypertension (~30%): Essential > renal artery stenosis or pheochromocytoma •Pulmonic stenosis (~1%) •Renal artery stenosis (~2%) •Cerebrovascular anomalies (2%-5%), including vascular stenoses and aneurysms

JXGs, Juvenile xanthogranulomas; MRI, magnetic resonance imaging.

From Bolognia JL: Dermatology, ed 4, Philadelphia, 2018, Elsevier.

Differential Diagnosis

•Abdominal NF
•Myxoid lipoma
•Nodular fasciitis
•Fibrous histiocytoma
•Segmental NF
•Metastasis of other tumors
•Genetic syndromes associated with nervous system tumors (Table E2)

TABLE E2 Genetic Syndromes Associated With Nervous System Tumors

Syndrome	Chromosome or Gene	Inheritance	CNS Tumors
Neurofibromatosis type 1 (NF1)	17q1	Autosomal dominant	Pilocytic astrocytomas of the optic nerve, other gliomas, meningiomas, nerve sheath tumors
NF2	22q	Autosomal dominant	Nerve sheath tumors, glioma, meningioma
Li-Fraumeni syndrome	TP53 germline mutations	Autosomal dominant	Glioma, medulloblastoma, choroid plexus tumors, nerve sheath tumors, meningioma
Turcot syndrome	APC and hMLH1/hPSM2 germline mutations	Autosomal dominant	Medulloblastoma
Gorlin syndrome	9q22.3 microdeletions PTCH1 gene	Autosomal dominant	Medulloblastoma
Tuberous sclerosis	9q32-34	Autosomal dominant	Subependymal giant cell astrocytoma (SEGA)
Von Hippel-Lindau disease	3p13-14 3p25-26	Autosomal dominant	Hemangioblastoma

APC, Adenomatous polyposis coli; CNS, central nervous system.

From Jankovic J et al: Bradley and Daroff’s neurology in clinical practice, ed 8, Philadelphia, 2022, Elsevier.

Workup

The evaluation and management of NF1 patients are summarized in Table E3. Workup of both NF1 and schwannomatosis is largely dictated by clinical symptoms and usually includes MRI evaluation.⁸

TABLE E3 Evaluation and Management of Neurofibromatosis 1 (NF1) Patients

At Time of Diagnosis and Annually During Childhood and Adolescence (Unless Otherwise Indicated)
Dermatologic examination (especially if a plexiform neurofibroma [PNF] is present)
•Surgical consultation if painful or disfiguring neurofibromas •PET-CT if rapid growth, increased firmness, or persistent pain within an established PNF or the development of a new neurologic deficit * •Ophthalmologic examination with visual assessment (prior to age 8 yr) •Orbital/brain MRI if signs/symptoms of optic glioma •Evaluation for scoliosis and tibial bowing •Referral to orthopedics if scoliosis develops •Neurologic examination, developmental/behavioral evaluation, and (in young children) measurement of head circumference •Orbital/brain and/or spinal MRI if neurologic signs/symptoms develop ^† •Comprehensive developmental assessment prior to starting school and if problems arise •Cardiac assessment and measurement of blood pressure •Referral to cardiology if murmur is detected •Renal arteriography and 24-h urine collection for catecholamines and metanephrines if hypertension develops •Assessment for pubertal development •Orbital/brain MRI and referral to endocrinology if precocious puberty develops
Minimum Annual Evaluation for Adults With Uncomplicated Disease
Dermatologic evaluation if PNF is present PET-CT for indications described above Neurologic examination (especially if a PNF is present) MRI and/or other studies as indicated if neurologic signs/symptoms develop Measurement of blood pressure Evaluation as described above if hypertension develops In women, screening for breast cancer with clinical examination + mammography ± MRI (beginning by age 40)
Potentially Affected Family Members
Dermatologic examination for cutaneous manifestations of NF1 Ophthalmologic examination for Lisch nodules Consider genetic testing if a mutation has been identified in the proband

CT, Computed tomography; MRI, magnetic resonance imaging; PET-CT, positron emission tomography-computed tomography.

^*Immediate assessment is required for any of these findings.

^†The role of neuroimaging in asymptomatic patients is controversial.

From Bolognia JL: Dermatology, ed 4, Philadelphia, 2018, Elsevier.

Laboratory Tests

•Genetic testing is recommended to distinguish among the various NF conditions.⁴
•Genetic testing is possible in individuals who desire prenatal diagnosis for NF1. There is no single standard test, and multiple tests are required. Results can tell only if an individual is affected but cannot predict the severity of the disease due to variable expression.
•Pathologic evaluation of tissue samples for definitive tumor typing.⁹

Imaging Studies

•MRI with and without gadolinium is the imaging study of choice in NF patients. MRI increases detection of optic gliomas, tumors of the spine, acoustic neuromas, and "bright spots" believed to represent hamartomas.
•In NF1, localized MRI is recommended if nonsuperficial plexiform neurofibromas are suspected. X-ray, computed tomography (CT), and ultrasound may also be indicated based on localized area of interest. The decision to utilize imaging should be directed by clinical symptoms.
•In SWN, baseline MRIs of the brain and spine are recommended. In some cases, whole-body MRI may be indicated for tumor staging and burden.⁹

Other Tests

•Detailed skin examination; consider utilizing Wood’s lamp in patients with very pale skin for visualizing café-au-lait spots
•Comprehensive neurologic examination
•Complete ophthalmologic examination, including slit lamp
•Audiology examination in NF2-related SWN

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Basic Information ⬇

Diagnosis ⬆ ⬇

Treatment ⬆ ⬇

Pearls & Considerations ⬆ ⬇

Reference(s) ⬆