Neurofibromatosis, type 1
 (von Recklinghausen disease)

CONDITION

Neurofibromatosis, type 1 
(von Recklinghausen disease)


CLINICAL BOTTOM LINE 


• Neurofibromatosis, type 1 (NF1) is an autosomal dominant multisystem disorder caused by mutations in the NF1 gene. 


• Family history is useful if present in a parent, but half of cases are new diagnoses.


• Clinical manifestations are variable and include cutaneous (multiple café au lait spots, axillary and inguinal freckling, neurofibromas [Figure 1]), neurologic (neuropathies secondary to neurofibromas), orthopedic (skeletal dysplasia, scoliosis, osteoporosis), and ophthalmologic (Lisch nodules on the iris [Figure 2], optic gliomas). Malignant tumors of neuroectodermal origin as well as pheochromocytoma are possible.


• Diagnosis is usually clinically based using NIH criteria. Genetic testing is available but has limitations. Fifty percent of diagnoses represent new mutations in patients with no prior family history.¹


• Manifestations of the disorder occur over time and require referral to multiple specialists: ophthalmology, neurology, orthopedics, cardiology, and surgery. Learning disabilities range from mild to severe in >50% of those affected.


• Follow-up should include an annual examination by a clinician familiar with the patient and the disease. Children with NF require a multidisciplinary team approach with regular developmental assessment and monitoring of manifestations. Regular BP monitoring for both children and adults is necessary because of increased prevalence of essential hypertension in adults and, rarely, renovascular hypertension.


WHAT IS NEUROFIBROMATOSIS?


NF1 is an autosomal dominant condition with an incidence of 1:2,600-3,000; all races and both genders are affected equally. It exemplifies pleiotropy, the genetic effect of a single gene on multiple phenotypic traits. The disorder affects multiple systems. 


The list of potential complications associated with NF1 is extensive, ranging from benign to severe, involving any of the affected organ systems:² 


• Optic/ophthalmologic: Optic glioma, visual deficits

• Skin: Cutaneous and subcutaneous neurofibromas, plexiform 
neurofibromas

• Neurodevelopmental: Cognitive 
deficits, learning disabilities, seizures, and neuroimaging abnormalities (NF "bright spots," cerebrovascular dysplasia), speech deficit, short stature

• Oncologic: Development of malignant peripheral nerve sheath tumors, sarcomatous degeneration with a 10% lifetime risk of neurofibrosarcoma, astrocytic tumors is possible. Women with NF1 appear to have a 5-fold increased risk of developing breast cancer before 
age 50 years and a 3.5-fold increased risk of developing breast cancer overall

• Skeletal: Scoliosis (with or without kyphosis), congenital tibial pseudarthrosis, limb abnormalities, spinal cord compression, osteoporosis

• Endocrine: Precocious puberty possible

• Neurologic: Compressive peripheral neuropathy, focal neurologic deficits, cerebral arteriopathy

• Cardiovascular: Hypertension 
(essential and renovascular), pheochromocytoma, early-onset cardiovascular disease, aneurysms

• Psychosocial: Disfiguration, macrocephaly, megalencephaly, pain, psychosocial burden.


Many persons develop only cutaneous manifestations of the disease and Lisch nodules, but the frequency of more serious complications increases with age. Adolescence for boys and girls often precipitates the development of subcutaneous and cutaneous neurofibromas.


DIFFERENTIAL DIAGNOSIS

• Mosaic/segmental NF1

• Neurofibromatosis, type 2 (NF2) 

• Café au lait spots

• Legius syndrome

• McCune-Albright syndrome 

• Noonan syndrome

• MEN2b (multiple endocrine neoplasia, type IIb)


DIAGNOSIS

• The diagnosis is clinical and requires the presence of at least two of seven National Institutes of Health (NIH)-established criteria. 


• Diagnosis is difficult in children <8 years using the NIH diagnostic criteria as several manifestations do not appear until later childhood or adolescence, often delaying confirmation of the diagnosis; the usual order of appearance of the clinical features is: café au lait spots, axillary freckling, Lisch nodules, and neurofibromas.³


MANAGEMENT

• Children should be evaluated by a multidisciplinary team that includes genetics, pediatric neurology, and 
ophthalmology. Referrals to der­matology, neurosurgery, plastic surgery, and pediatric endocrinology may be indicated.


• The American Academy of Pediatrics Committee on Genetics has published diagnostic and health supervision guidelines for children with NF1.⁴


• Surveillance


–General clinical evaluation should be provided regularly by professionals familiar with the patient and with increased frequency in patients with disease complications. 


–Recommendations for ongoing assessment and periodic review throughout life should include


■ Evaluation for new neurofibromas and progression of lesions


■ Annual BP measurement 
and formal ophthalmologic evaluation


■ Neurodevelopmental 
assessment


■ Evaluation for skeletal changes
—ie, scoliosis, vertebral angulation, and limb abnormalities.


–Clinicians should be aware of signs and symptoms that require immediate referral:²


■ Pain of unknown etiology


■ Weakness, numbness, tingling in the extremities


■ Change in balance or 
coordination


■ Change in vision


■ Change in intensity or frequency of headaches


■ Neurofibromas that change rapidly in size and/or color, or cause pain


■ Abnormal neurologic 
examination


■ Sudden onset of hypertension


■ Regression of cognitive skills or loss of developmental 
milestones


■ Significant deviation from established pattern of growth.


• Referral to a clinical geneticist or genetic counselor for


–More in-depth discussions regarding clinical findings, recurrence risk, future reproductive options


–Evaluation of risk of disease for other family members.¹