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Basics ⬇

Pathogenesis ⬆ ⬇

Clinical Manifestations ⬆ ⬇

Neurofibromatosis Type 1 !!navigator!!

  • Café au lait macules (CALMs), often called café au lait spots, are the earliest clinical manifestation of NF.

  • A CALM is a light brown to tan macule or patch. The CALMs that are associated with NF1 typically have smooth borders (Fig. 11.1).

  • Axillary or inguinal freckling (Crowe sign) consists of small, pigmented tan macules and when present is considered to be pathognomonic for NF1 (Fig. 11.2).

  • Cutaneous neurofibromas are soft, rubbery, skin-colored or tan-pink papules and nodules (Figs. 11.3 and 11.4) and usually present after puberty.

  • Plexiform neuromas manifest as large drooping tumors, which on palpation feel like a “bag of worms” and occur in 30% to 50% of patients with NF1 (Fig. 11.5).

  • Ocular lesions (Lisch nodules) are asymptomatic, pigmented iris hamartomas seen in 80% of patients with NF.

  • Macrocephaly is also an early sign of NF1 and may be present in up to 16% of patients.

  • Benign and malignant tumors of the CNS and peripheral nervous system may occur in up to 10% to 20% of patients with NF1.

  • An optic glioma is the most common benign tumor associated with NF1. Other tumors include malignant peripheral nerve sheath tumors, meningiomas, and glioblastomas.

  • Many patients with NF1 have seizure disorders and mental retardation.

  • Musculoskeletal findings can occur including osteopenia, scoliosis, sphenoid wing dysplasia, congenital tibial dysplasia, and pseudarthrosis.

  • Endocrine disorders occur; 3% to 5% of affected children have sexual precocity associated with short stature.

  • Gastrointestinal symptoms may result from stromal tumors in the GI tract.

  • Patients with NF1 have an increased risk of malignancies including breast cancer, leukemia and lymphoma, and pheochromocytoma (<1% of patients with NF1).

Neurofibromatosis Type 2 !!navigator!!

  • CALMs occur less frequently in NF2, but are found in 33% of patients. Usually affected patients have <5 lesions.

  • Skin tumors including schwannomas or neurofibromas are often the presenting sign of NF2 and can occur in 30% to 50% of patients.

  • Tumors including vestibular and cranial schwannomas, cranial meningiomas, and spinal cord tumors.

  • Hearing loss and visual impairment may occur as a result of tumor burden. Hearing impairment occurs in 75% of affected children.

  • Presentation in childhood is associated with a worse prognosis.

Outline

Diagnosis ⬆ ⬇

Neurofibromatosis TYPE 1 !!navigator!!

  • The diagnosis of NF1 can be made based on clinical findings and requires two or more of the following:

    • 6 café au lait macules (must be >5 mm if prepubertal and >15 mm if postpubertal)

    • Axillary or inguinal freckling

    • 2 neurofibromas or 1 plexiform neurofibroma

    • Optic glioma

    • 2 Lisch nodules

    • Bony lesions (sphenoid dysplasia, pseudarthrosis)

    • First-degree relative with NF1

Neurofibromatosis TYPE 2 !!navigator!!

  • Diagnostic criteria for NF2 include the following:

    • Bilateral vestibular schwannomas seen by magnetic resonance imaging (MRI) scan OR a first-degree relative with NF2

      AND

    • Unilateral vestibular schwannoma OR two of the following:

      • Meningioma

      • Glioma

      • Schwannoma

      • Juvenile posterior subcapsular cataract

Outline

Other Information ⬆

Laboratory Evaluation

  • Genetic testing is now more readily available through commercial laboratories and is often covered by insurance. Laboratories that perform genetic testing for NF1 and NF2 can be found on www.genetests.org

  • MRI studies of the brain and cervical spine may be helpful in NF1 patients with symptoms of CNS disease and in patients with suspected NF2 disease.

Diagnosis-icon.jpg Differential Diagnosis

Café au lait macules

  • CALMs are a common birthmark seen in 10% to 20% of the general population (seeChapter 1: Birthmarks), most persons have one to three lesions.

  • Isolated CALMs usually have irregular or smudgy borders.

Segmental Neurofibromatosis

  • CALMs and neurofibromas localized to one segment of the body.

  • Absence of CNS tumors.

  • Lack of inheritance (somatic mutation).

McCune-Albright Syndrome (also called Polyostotic Fibrous Dysplasia)

  • A genetic condition caused by mutations in GNAS that results in skin, bone, and endocrine problems.

  • Associated with a large pigmented macular lesion (resembling a CALM) that is usually located on the trunk or abdomen and has a typical geographic (“coast of Maine”) border.

  • Precocious puberty and bone lesions usually occur.

NF1-like Syndrome (or Legius Syndrome)

  • Most patients with Legius syndrome have six or more CALMs and intertriginous freckling, thus meeting the criteria for NF1. However, patients never develop neurofibromas, Lisch nodules, optic gliomas, or bony lesions.

  • Macrocephaly and learning disabilities are common.

  • Caused by mutations in SPRED1 gene.

Management-icon.jpg Management

  • Education on neurofibromatosis, its natural history and clinical heterogeneity is key.

  • It is often helpful to inform parents of the estimated relative risk of the different associations. For example, not all patients with NF1 will develop a glioblastoma or severe mental retardation.

  • Children with NF1 should have complete physical examinations including head circumference, height, weight, and blood pressure twice yearly.

  • Surveillance for learning disabilities, tumors, and ophthalmologic examinations should occur yearly.

  • Symptomatic or disfiguring neurofibromas can be removed surgically.

  • Treatment of NF2 is primarily surgical.

  • Genetic counseling for patients and their families is an important aspect of treatment.

Helpful-Hint-icon.jpg Helpful Hints

  • At present, genetic testing is used for unusual presentations and for reproductive counseling.

  • Numerous support networks exist for NF patients and their families including the National Neurofibromatosis Foundation, Inc. and the Children's Tumor Foundation (http://www.ctf.org).