Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1), also known as phakomatosis, is a neurocutaneous disorder that is most commonly of autosomal dominant inheritance due to mutations in the NF1 gene. Neurofibromatosis type 1 presents a range of clinical manifestations with the most prominent features being various pigmented skin lesions called café au lait macules (CALMs), benign nerve-sheath tumors called neurofibromas, freckling of the inguinal and axillary regions, and iris hamartomas, referred to as Lisch nodules. At least half of the individuals with NF1 have learning disabilities. Neurofibromatosis type 1 may also cause osteodysplasia and malignant transformation of tumors. The diagnosis is based on the typical clinical presentation and can be confirmed with genetic testing. Management depends on the clinical presentation and may vary from surgical removal to chemotherapy/radiotherapy for tumors, occupational therapy and PT for motor impairments, treatment with growth hormone, and bracing in the case of bone abnormalities.

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Overview

Epidemiology

  • Neurofibromatosis type 1 (NF1) is the most common type of neurofibromatosis.
  • Incidence: approximately 1 in 2,600–3,000 individuals, regardless of ethnicity and gender
  • Inherited in about half of the cases
  • Life expectancy:
    • The mean age at death is 54.4 years.
    • The median age at death is 59 years.

Etiology

  • Autosomal dominant inheritance
  • Less commonly, de novo mutations (primarily in paternally derived chromosomes)

Pathophysiology

  • Mutations in the NF1 gene located on chromosome 17
  • NF1 encodes neurofibromin, a cytoplasmic protein.
    • Predominantly expressed in neurons, Schwann cells, oligodendrocytes, leukocytes
    • Multidomain molecule regulating several important intracellular processes:
      • RAS-cyclic AMP pathway
      • Extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) cascade
      • Adenylyl cyclase
      • Cytoskeletal assembly
    • Also functions as a tumor suppressor
  • Involvement of neurofibromin in various pathways explains the wide range of clinical manifestations.

Clinical Presentation

  • Café au lait macules (CALMs):
    • Flat, uniformly hyperpigmented macules
    • Appear in the 1st year after birth
    • Increase during early childhood
  • Freckling:
    • Appears in the axillary or inguinal regions
    • Apparent by 3–5 years of age
  • Lisch nodules:
    • Raised tan-colored hamartomas of the iris
    • More common in adults than in children
  • Tumors:
    • Peripheral neurofibromas:
      • Cutaneous
      • Plexiform
      • Nodular
    • Optic pathway gliomas:
      • Low-grade pilocytic astrocytomas
      • Occur in children < 6 years of age
      • Rare in older children and adults
      • Most children have normal vision.
      • Some gliomas may be symptomatic with progressive visual loss.
    • Other CNS neoplasms:
      • Low-grade astrocytomas
      • Brainstem gliomas
    • Soft tissue sarcomas:
      • Malignant peripheral nerve sheath tumors
      • Rhabdomyosarcoma
      • GI stromal tumors
      • Glomus tumors
    • Other tumors:
      • Juvenile myelomonocytic leukemia
      • Pheochromocytoma
      • Breast cancer
  • Bone abnormalities:
    • Long bone dysplasia and pseudoarthrosis
    • Other bone lesions:
      • Vertebral defects
      • Nonossifying fibromas within long bones
      • Sphenoid wing dysplasia
    • Short stature
    • Scoliosis
    • Osteoporosis
  • Neurologic abnormalities:
    • Cognitive deficits and learning disabilities
    • Seizures
    • Macrocephaly
    • Peripheral neuropathy
  • Congenital heart disease
  • Hypertension
  • Vasculopathy
  • Other manifestations:
    • Constipation
    • Irritable bowel syndrome
    • Pulmonary hypertension
    • Pulmonary artery stenosis
    • Interstitial lung disease
    • Bullous lung disease
    • Arterial dissection (rare)
Café-au-lait macules (calms)

Café au lait macules (CALMs):
Image showing well-circumscribed, light-brown, pigmented CALMs that are commonly found in the general population. Macules can be few millimeters to several centimeters (> 20 cm) in size and may appear at birth or early life. The development of multiple CALMs may be associated with genetic syndromes such as neurofibroma type 1. Macules can be treated with laser therapy for cosmetic purposes.

Image: “Case one: photograph of café-au-lait spots.” by Khalil J. et al. License: CC BY 4.0

Diagnosis

The diagnosis of NF1 is usually made clinically based on the typical clinical presentation and confirmed by genetic testing.

  • Diagnostic criteria: At least 2 features must be present:
    • ≥ 6 CALMs:
      • > 5 mm in diameter in prepubertal individuals
      • > 15 mm in diameter in postpubertal individuals
      • The longest diameter is measured.
      • Ordinary room light is used.
    • ≥ 2 neurofibromas of any type or 1 plexiform neurofibroma
    • Freckling in the axillary or inguinal regions
    • Optic glioma
    • ≥ 2 Lisch nodules
    • A distinctive bony lesion (e.g., sphenoid dysplasia, thickening of the cortex of long bones with or without pseudoarthrosis)
    • A 1st-degree relative (parent, sibling, or offspring) with NF1 defined by the above criteria
  • Genetic testing
  • Screening of family members
  • Prenatal testing
  • Neuroimaging (MRI or CT), potential findings:
    • Focal bright spots on T2-weighted images (disappear with age)
    • Increased brain volume
    • Abnormal cerebral vasculature

Management

Tumors

  • Cutaneous and subcutaneous neurofibromas
    • Removal by surgery, laser, or electrodesiccation
    • Indications for removal include:
      • Pain
      • Bleeding
      • Interference with function
      • Disfigurement
    • Gabapentin (for pruritus)
  • Plexiform neurofibromas:
    • Selumetinib (for tumor regression)
    • Surgical resection (debulking)
    • Imatinib or pegylated interferon (shrinkage)
  • Optic pathway gliomas and other low-grade gliomas:
    • Chemotherapy:
      • Carboplatin
      • Vincristine
      • Vinblastine
    • Radiation (avoided in pediatric individuals)
  • High-grade gliomas:
    • Surgical resection
    • Conventional radiation + temozolomide
  • Malignant peripheral nerve sheath tumors:
    • Surgical resection
    • Adjunctive radiation therapy
  • Rhabdomyosarcoma:
    • Chemotherapy
    • Surgery, if feasible
    • Radiotherapy
  • GI stromal tumors: poorly responsive to imatinib

Neurologic abnormalities

  • Cognitive and learning deficits:
    • Learning disabilities: academic support
    • Speech deficits: speech therapy
    • Motor impairment: occupational therapy and PT
  • Seizures: antiseizure drugs
  • Peripheral neuropathy: Treat the underlying cause and alleviate symptoms.

Others

  • Psychosocial issues: counseling
  • Hypertension: antihypertensives
  • Genetic counseling for affected individuals and their families

Differential Diagnosis

  • Neurofibromatosis type 2: a neurocutaneous disorder that can arise from mutations in the NF2 gene. The main clinical features are bilateral vestibular schwannomas and intracranial/spinal meningiomas. Diagnosis is made clinically and confirmed based on genetic testing, MRI, and histopathology. Tumor surveillance, follow-up, and screening of at-risk family members are recommended. Management includes surgical intervention, radiation therapy, and/or monoclonal antibody therapy with bevacizumab.
  • Noonan syndrome: a genetic disorder that occurs following a mutation in one of several genes involved in the RAS signaling pathway, especially protein-tyrosine phosphatase, nonreceptor type. Clinical features include short stature, webbed neck, hypertelorism, downward eye slant, low-set ears, pulmonic stenosis, and CALMs. Management involves the identification and timely monitoring of various clinical presentations.
  • Tuberous sclerosis: an autosomal dominant disorder that mainly presents with neurocutaneous symptoms. Mutation in the TSC gene causes excessive tumor-like growth in the brain, eyes, heart, kidney, and lungs. Cutaneous manifestations include hypopigmentation (i.e., ash-leaf spots) or excessive growth (i.e., angiofibroma). The diagnosis is made clinically and confirmed by genetic testing. Management entails a multidisciplinary approach that targets the monitoring and treatment of various manifestations of the disorder.
  • Constitutional mismatch repair-deficiency syndrome: a rare autosomal recessive disorder resulting from the inheritance of deleterious mutations in both copies of 1 of the 4 mismatch-repair genes. Constitutional mismatch repair-deficiency syndrome results in early-onset (< 18 years of age) hematologic, brain, or colon cancers and may present with skin pigmentations similar to those in NF1. Diagnosis is made clinically. Management is centered around early screening for tumors and genetic counseling for families of affected individuals.

References

  1. Korf, B.R., et al. (2021). Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis. In Patterson, M.C. et al. (Ed.), UpToDate. Retrieved August 27, 2021, from https://www.uptodate.com/contents/neurofibromatosis-type-1-nf1-pathogenesis-clinical-features-and-diagnosis
  2. Korf, B.R., et al. (2021). Neurofibromatosis type 1 (NF1): Management and prognosis. In Patterson, M.C. et al. (Ed.), UpToDate. Retrieved August 27, 2021, from https://www.uptodate.com/contents/neurofibromatosis-type-1-nf1-management-and-prognosis
  3. Victorio, M.C. (2021). Neurofibromatosis. [Online] MSD Manual Professional Version. Retrieved August 28, 2021, from https://www.msdmanuals.com/professional/pediatrics/neurocutaneous-syndromes/neurofibromatosis
  4. Hsieh, D.T. (2020). Neurofibromatosis type 1. In Kao, A., et al. (Ed.), Medscape. Retrieved August 28, 2021, from https://emedicine.medscape.com/article/1177266
  5. Friedman, J.M. (2019). Neurofibromatosis 1. In: Adam, M.P., Ardinger, H.H., Pagon, R.A., et al. (Eds.), GeneReviews. Seattle (WA): University of Washington, Seattle; 1993–2021. Retrieved August 28, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK1109/
  6. Williams, V.C., et al. (2009). Neurofibromatosis type 1 revisited. Pediatrics, 123, pp. 124–133. Retrieved August 28, 2021, from https://doi.org/10.1542/peds.2007-3204 
  7. Jha, S.K., Mendez, M.D. (2021). Cafe Au Lait Macules. In StatPearls [Internet]. StatPearls Publishing. Retrieved August 28, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK557492/
  8. Friedman, J.M. (2019). Neurofibromatosis. In Adam, M.P., Ardinger, H.H., Pagon, R.A., et al. (Eds.), GeneReviews. Seattle (WA): University of Washington, Seattle; 1993–2021. Retrieved September 23, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK1109/ 
  9. OMIM (2020). Neurofibromin 1 (NF1). Retrieved Sep 23, 2021, from https://www.omim.org/entry/613113?search=nf1&highlight=nf1#description

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