Bakri H. Elsheikh, MBBS, FRCP

Puja Aggarwal, MD

DESCRIPTION

• Neurofibromatosis type I (NF1) is a progressive autosomal dominant genetic disorder characterized primarily by various cutaneous manifestations and the tendency to develop tumors of the peripheral and CNS.
• NF1 clinical presentation and severity are extremely variable, even within the same family.
• It was known as Von Recklinghausen's disease in the past.
• The diagnosis of NF1 can be made, using the National Institute of Health criteria, if there are 2 or more of the following:
  • 6 or more café-au-lait spots that are greater than 5 mm in a prepubertal child and greater than 15 mm in diameter in a postpubertal individual.
  • 2 or more neurofibromas or 1 plexiform neurofibroma.
  • 2 or more Lisch nodules (iris hamartomas).
  • Axillary or inguinal freckling.
  • Optic glioma.
  • Distinctive bony lesions including sphenoid dysplasia or thinning of the long-bone cortex with or without pseudoarthrosis.
  • Definitive diagnosis of NF1 in a first degree relative based upon the above criteria.
• Segmental NF1 with involvement of a limited body region can occur.

EPIDEMIOLOGY

Incidence

• Approximately 1 in 3000 live births.

Prevalence

• NF1 is the most common neurocutaneous disorder affecting about 100,000 Americans.
• NF1 has no particular racial, ethnic, or gender predilection.

RISK FACTORS

Having a parent diagnosed with NF1

Genetics

• NF1 is an autosomal dominant genetic disorder characterized by a complete penetrance with variable expression.
• There is 100% penetrance after childhood.
• About 50% of patients have new mutations; the other 50% have a parent with NF1.
• The severity of NF1 is not different between inherited and new mutations.

GENERAL PREVENTION

• There are no interventions that prevent NF1.

PATHOPHYSIOLOGY

• A mutation in the large 60-exon NF1 gene on chromosome 17 q11.2 accounts for most NF1.
• Neurofibromin, the NF1 gene product, controls cellular proliferation and functions as a tumor suppressor gene. It activates GTPase that downregulates the Ras proto-oncogene which plays a role in cell growth and proliferation.
• The absence of neurofibromin leads to increased cell proliferation and tumor formation.
• Neurofibromin is found in many tissues including kidney, brain, spleen, and thymus.

ETIOLOGY

• Inheritance pattern is autosomal dominant.
• Spontaneous new mutations of unknown cause occur in half of the patients.
• Neurofibromin, the gene responsible for NF1, is a tumor suppressor gene located on chromosome 17q11.2. Mutations result in loss of tumor suppressor function of neurofibromin.

COMMONLY ASSOCIATED CONDITIONS

• Hypertension
  • Essential
  • Renal artery stenosis
  • Pheochromocytoma
• Epilepsy
• Malignant peripheral nerve sheath tumors
• CNS tumors
  • Astrocytomas and brainstem gliomas
• Osteopenia
• Learning disabilities in children

HISTORY

• Careful history regarding an abnormal skin findings, freckles, rapidly or slowly enlarging growths to suggest neurofibromas, visual complains, headaches, seizures, scoliosis, focal neurological complaints, and paresthesias should be sought.
• Careful history should also be obtained regarding learning disabilities, behavioral and growth abnormalities.

PHYSICAL EXAM

• Café-au-lait macules
  • Flat hyperpigmented spots of various sizes and shapes, more often found in the trunk.
• Neurofibromas
  • Most common tumors in NF1.
  • Benign tumors arising from peripheral nerve.
  • Pain might occur in the nerve distribution but can be asymptotic.
• Plexiform neurofibromas
  • 5% lifelong risk of malignant transformation.
  • Cause distortion of involved structures.
  • Often develop in the face.
• Lisch nodules (iris hamartomas)
  • Asymptomatic (no visual symptoms).
• Axillary or inguinal freckling
• Optic glioma
  • The most common CNS tumor in NF1.
  • Can be an incidental finding or patients might present with progressive vision loss and optic atrophy. Pain and proptosis can occur.
• Kyphoscoliosis
• Short stature
• Skeletal anomalies
• Macrocephaly
• Precocious puberty

Pediatric Considerations

• Only half of the children with NF1 and no family history of NF1 meet the NIH criteria for diagnosis of NF1 by age 1. However, most children meet the criteria for diagnosis by age 8.
• The diagnosis of NF1 in a child, whose parent is confirmed to have NF1, only requires the presence of 1 more item of the NIH criteria.
• In children with many café-au-lait spots and no known family history of NF1, the clinician should suspect NF1 and follow the child clinically.
• Children with NF1 might have normal intelligence, but learning disabilities often occur. Also poor social skills, behavioral and personality changes can be seen.

DIAGNOSTIC TESTS AND INTERPRETATION

Lab

Initial Lab Tests

• Genetic testing confirms the diagnosis
• Slit lamp examination of the eye helps detect iris hamartomas

Follow-Up & Special Considerations

• Dictated by findings on clinical exam

Imaging

Initial Approach

• It is debated at this time whether a brain MRI should be obtained at initial diagnosis.
• Abnormal signals on T2-weighted MRI referred to as “Unidentified Bright Objects” can occur in the optic tracts, basal ganglia, brainstem, cerebellum, and cortex. Their prognostic significance is unknown.
• MRI can help identify bony dysplasia in the cranium and the presence of optic glioma or other tumors.

Follow-Up & Special Considerations

• Should be based upon clinical exam

Diagnostic Procedures/Other

• Should be based upon clinical exam

Pathological Findings

• N/A

DIFFERENTIAL DIAGNOSIS

• Noonan syndrome
• Neurofibromatosis type 2
  • Schwannomatosis
  • Multiple café-au-lait spots
  • McCune–Albright syndrome
  • Congenital generalized fibromatosis
  • Lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retarded growth, deafness (LEOPARD) syndrome
  • Legius syndrome

MEDICATION

First Line

• There is no treatment to cure or halt progression of NF1. The hallmark of current treatment is monitoring and treatment of complications and genetic counseling.
• Pain associated with neurofibromas could benefit from NSAIDs or antiepileptic medication such as gabapentin.
• Seizures, if present, are treated with appropriate antiepileptic drugs.

Second Line

• N/A

ADDITIONAL TREATMENT

General Measures

• Patients benefit from referral to a neurofibromatosis multidisciplinary clinic.

Issues for Referral

• Ophthalmological referral for optic gliomas and vision assessment.
  • Referral to neurosurgeons for possible removal of plexiform neurofibromas or other peripheral or CNS tumors.
  • Referral to spine surgeon for possible correction of scoliosis.
  • Referral to epileptologists for control of seizures.

Additional Therapies

• Patients may need referral to physical, speech, or occupational therapy based upon neurological deficits.

COMPLEMENTARY AND ALTERNATIVE THERAPIES

• N/A

SURGERY/OTHER PROCEDURES

• When neurofibromas become very large causing pain or disfigurement, surgical removal should be considered.
  • With skeletal abnormalities including scoliosis, patients may consider seeing a spinal surgeon for spinal fusion.

IN-PATIENT CONSIDERATIONS

Initial Stabilization

• N/A

Nursing

• N/A

FOLLOW-UP RECOMMENDATIONS

• Should follow-up yearly with a neurologist and ophthalmologist; follow-up with other specialties based on findings.

Patient Monitoring

• Yearly neurological exams to monitor progression of NF1
• Yearly ophthalmological exams to monitor for optic gliomas
• Regular blood pressure monitoring as hypertension is associated with NF1
• Yearly physical exam with increased attention to skin, skeleton, cardiovascular, and neurological systems
  • Developmental progress in children including height, weight, head circumference, and school progress

DIET

• N/A

PATIENT EDUCATION

• Patients should be offered genetic counseling and explained that if 1 parent has NF1, there is a 50% chance each offspring will have it.
• Prenatal diagnostic testing is available. DNA can be extracted from fetal cells through amniocentesis at 15–18 weeks gestation or chorionic villus sampling at 8–12 weeks gestation
• With severe NF1, prenatal ultrasound may be able to help with diagnosis
• Sources for more information:
  • NINDS: Neurofibromatosis fact sheet. Website: http://www.ninds.nih.gov/disorders/neurofibromatosis/detail_neurofibromatosis.htm
  • Neurofibromatosis, Inc. (NF Inc.), P.O. Box 66884, Chicago, IL 60666. Website: http://www.nfinc.org

PROGNOSIS

• Prognosis of NF1 is difficult to estimate as the disease course is highly variable; however, it is progressive in the majority of patients with a small number having stable symptoms.

COMPLICATIONS

• Disease-associated tumors including neural tumors such as malignant peripheral nerve sheath tumors (neurofibrosarcomas, malignant schwannomas, angiosarcomas), optic gliomas, cerebellar astrocytomas, cerebral gliomas, and brainstem gliomas
• Disease-associated tumors including nonneural malignant tumors such as pheochromocytoma, xantholeukemia and rhabdomyosarcoma
• Disease-associated epilepsy with an overall risk of 2–5% due to abnormalities of the cortex
• Cerebrovascular disease including
  • Stroke due to stenosis or occlusion of major blood vessels, especially in the supraclinoid internal carotid or proximal anterior or middle cerebral arteries with an increased risk of Moyamoya disease
  • Cerebral aneurysms and subarachnoid hemorrhage
• Cognitive deficits can occur along with learning disabilities with an IQ 5 to 10 points lower than the general population.
• Cardiovascular effects may include essential hypertension or hypertension secondary to coarctation of the aorta, pheochromocytoma, or renal artery stenosis
• Respiratory complaints may occur with plexiform neurofibromas of the head and neck with growth into the upper airway. Also, scoliosis associated with NF1 may decrease lung volumes and impair ventilation
• Gastrointestinal disease may include carcinoid tumors in the duodenum near the ampulla of Vater. Also, ganglioneuromatosis may affect the myenteric plexus of NF1 patients causing abdominal pain and constipation.
• Urogenital disease including neurofibromas in the retroperitonium can compress the urinary tract or compress the bladder causing urinary complaints.
• Skeletal disease including scoliosis, kyphosis, and long bone deformation

• Ferner RE, Huson SM, Thomas N, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet 2007;44:81–88.
• Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 1997;278:51–57.
• National Institutes of Health Consensus Development Conference. Neurofibromatosis conference statement. Arch Neurol 1988;45:575–578.

SEE-ALSO

• N/A

ICD9

237.71 Neurofibromatosis, type 1 [von Recklinghausen's disease]

• NF1 is a complex genetic disease that requires a multidisciplinary team approach to the diagnosis and management.
• Despite the absence of specific preventive treatment, some of the disease complications can be prevented by timely intervention.