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  Disease summary:

  
  
  
  
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    Neurofibromatosis type 1 (NF1) is a common (∼1/3000), progressive neurocutaneous disorder primarily of increased tumor predisposition, but also pigmentary abnormalities, osseous dysplasia, and impaired cognitive function that arises secondary to mutations in the tumor suppressor gene NF1.

    
    
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    NF1 is a pleiotropic disorder, affecting different organ systems (central and peripheral nervous systems, bone, vasculature) with wide variation in severity of clinical features, even among members of the same family. There is limited genotype-phenotype correlation (see Counseling).

    
    
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    NF1 affects all ethnic groups and both sexes equally.

    
    
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    As a population, individuals with NF1 have a reduced lifespan.

  
  
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  Hereditary basis:

  
  
  
  
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    NF1 is a monogenic disorder with an autosomal dominant pattern of inheritance. It is 100% penetrant, typically by late adolescence. Approximately half of the individuals affected with NF1 have a family history of the disorder.

  
  
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  Differential diagnosis:

  
  
  
  
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    The diagnosis is rarely mistaken in a patient with numerous café-au-lait macules, neurofibromas, and axillary freckling. Certain features, especially when present in isolation or in a younger patient, may present a diagnostic challenge (Table 108-1). Consideration of a missense NF1 mutation, or a de novo NF1 mutation present in a segmental or mosaic state (see Counseling) should be made when confronted with either café-au-lait macules only or neurofibromas only, especially in a limited distribution. A diagnosis of Legius syndrome should be considered in older individuals with pigmentary findings only and absence of neurofibromas.

Diagnostic Criteria for NF1

The NIH Consensus Criteria for the diagnosis of NF1 were developed in 1987.

Neurofibromatosis type 1 is present in a patient who has two or more of the following:

1. 
   

   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

   
   
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   Two or more neurofibromas of any type or one plexiform neurofibroma

   
   
3. 
   

   Freckling in the axillary or inguinal regions

   
   
4. 
   

   Optic glioma

   
   
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   Two or more Lisch nodules (iris hamartomas)

   
   
6. 
   

   A distinctive osseous lesion such as sphenoid wing dysplasia or thinning of the long bone cortex with or without pseudarthrosis

   
   
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   A first-degree relative (parent, sibling, offspring) with NF1 by the above criteria

The criteria were reviewed in 1997 and were left unchanged. More recently, Huson has suggested that the diagnostic criteria be changed to (1) include NF1 pathogenic mutations, (2) recognize segmental NF1, and (3) distinguish numerous café-au-lait macules arising from DNA mismatch repair and ring chromosome syndromes (Table 108-1).

In adults, the diagnosis of NF1 can usually be made based on history and physical examination findings. A Wood (ultraviolet) lamp is necessary for a thorough skin examination. Biopsy and pathologic examination of skin “lumps and bumps” is occasionally required. Referral to ophthalmology for a slit-lamp examination of the irides for Lisch nodules is prudent.

In younger children without a family history of NF1, multiple examinations over several years may be needed to establish the diagnosis (see Counseling). Although café-au-lait macules are present in greater than 95% of children by age 1 year, there is typically delay before the appearance of other features. In this situation, genetic testing of NF1 may be useful to expedite diagnosis. By age 5 years, approximately 50% of children with NF1 will have three or more of the seven diagnostic features.

Clinical Characteristics

Neurofibroma

This is the hallmark lesion of NF1, and is a soft, fleshy benign tumor of the Schwann cell. They may develop from essentially any nerve in the body, although they have a predilection for the back, abdomen, arms, and face. They may number in the thousands and vary in size from pinhead to large pedunculated masses. It is difficult to predict neurofibroma burden. They typically appear in adolescence and the number of lesions often increases with puberty and pregnancy, suggesting hormonal influence. They are usually asymptomatic but may itch (Table 108-2).