Neurofibromatosis Type 1 (NF1)
Neurofibromatosis Type 1 (NF1) is the most common single gene disorder to affect the human nervous system with an incidence of approximately 1 in 3,000 to 4,000 births. NF1 is characterized by the presence of neurocutaneous stigmata such as café-au-lait spots, auxillary freckling, cutaneous neurofibromas, and iris hamartomas (Lisch nodules). This disorder is associated with a wide variety of complications affecting almost every system of the body, including the nervous system (cognitive deficits, epilepsy, hydrocephalus, intracranial tumors), the eyes (optic glioma), the skeleton (short stature, scoliosis, pseudoarthrosis), the endocrine system (precocious puberty, hypothalamic dysfunction) and the circulation (hypertension, renal artery stenosis). NF1 occurs with equal frequency in males and females and has been identified in all ethnic groups.
While it is unlikely that any one person diagnosed with NF1 will experience all of these symptoms, it is difficult to predict the severity or progression of the disorder in any individual case.
Diagnostic Criteria for NF1
The diagnosis of NF1 is based on the presence of two or more of the following:
- Six or more café-au-lait spots 1.5 cm or larger in post pubertal individuals; 0.5 cm or larger in pre-pubertal individuals.
- Two or more neurofibromas of any type, or one or more plexiform neurofibromas
- Freckling in the axillary or inguinal region.
- Optic glioma (tumor of the optic pathway).
- Two or more Lisch nodules (benign iris hamartomas).
- A distinctive osseous lesion, Dysplasia of the sphenoid bone,
- Dysplasia or thinning of a long bone cortex (pseudoarthrosis).
- A first- degree relative with NF1 according to the preceding criteria.
Using the above criteria the diagnosis can be made with certainty in 94% of patients by the age of six years.
Clinical Features of NF1
Major Disorder Manifestations
- Café-au-lait spots are the hallmark feature of NF1 and usually become obvious during the first two years of life. These lesions are flat coffee coloured patches on the skin. They can become darker in sun-exposed areas, and have a regular border. Young children with no family history of NF1 and only six or more café-au-lait spots present a common diagnostic dilemma to the paediatrician. Spots with light or non-homogeneous pigmentation or irregular or shaded outlines were defined as “atypical”.
- Skin fold freckling is the most useful criteria, after café au lait spots, for making the diagnosis of NF1 in young children since freckling tends to appear during the first five years of life, while neurofibromas and Lisch nodules may not appear until adolescence. The reported frequency of axillary (armpit), freckling varies between 64% and 84%. Inguinal (or groin) freckling occurs in 52-56% of NF1 individuals. More generalized freckling may also occur on the trunk and neck and in the sub mammary region in women.
- Dermal neurofibromas (surface tumors) benign, usually small lumps in or under the skin, do not usually develop until preadolescence, with increasing tumor load during adolescent and young adult years. Early neurofibromas may appear as “divots” in the skin, with reddening of the skin due to dilatation or an increase in the number of capillaries.
Early appearance of neurofibromas may give some indication of the future severity of cutaneous manifestations for the individual patient; the earlier the onset, the more likely there will be a larger number and more extensive distribution of cutaneous neurofibromas. In females there is often a clear history of an increase in number of neurofibromas during puberty and pregnancy, with and increase during puberty noted in males. While cutaneous neurofibromas may become a major cosmetic problem for individuals with NF1, they are not pre-malignant lesions and do not transform into malignant tumors. Plexiform Neurofibromas on the other hand are usually congenital in origin and can undergo malignant transformation.
Age Group Percentage that have surface neurofibromas Less than 10 years old 14% 10 to 19 years old 44% 20 to 29 years old 85% Over 30 years of age 94%
- Lisch Nodules (small pigmented lumps in the iris – the coloured part of the eye) are often not visible, except by looking with a special eye examination microscope (slit lamp) and are characteristic of NF1. They do not cause symptoms but are extremely an useful as a diagnostic tool, particularly in adults. The incidence of Lisch nodules in NF1 increases markedly with age; by the age of five years, only 22% of patients had Lisch nodules, whereas by 20 years of age 96 to 100% of patients have the lesions on slit lamp examination.
Age Group Percentage that have Lisch nodules 0 to 4 years 22% 5 to 9 years 41% 10 to 19 years 85% Over 20 years 95%
Minor Disorder Manifestations include:
- Short stature – not usually associated with growth hormone deficiency
- Macrocephaly (enlarged brain) – is determined by brain size and not skull size.
- Specific Learning difficulties – this means that a child of normal intellect has specific problems in certain areas, for example, difficulty with reading or spelling or problems with fine motor co-ordination that lead to untidy school work. It is valuable for a child with NF1 who is having school difficulties, to have a psychological assessment to determine their strength and weaknesses and determine what educational help may be of benefit.
Frequency of Clinical Features of NF
|Clinical Feature||Frequency (%)|
|MAJOR DISORDER FEATURES|
|6 or more café-au-lait spots||More than 95%|
|MINOR DISEASE FEATURES|
|Short stature (height less than 3rd percentile)||30%|
|Macrocephaly (head circumference greater than 97th percentile)||45%|
|Surgical correction of scoliosis||5%|
|Optic pathway gliomas: All lesions||15-20%|
|Optic pathway gliomas: Symptomatic||5-7%|
|Plexiform neurofibromas – All lesions||25%|
|Plexiform neurofibromas – Large lesions of the head and neck||1-4%|
|Specific learning disability||30-60%|
|Pseudoarthrosis of the long bones||3%|
|Sphenoid wing Dysplasia||less than 1%|
|Malignant peripheral nerve sheath tumours||1-4%|
|Renal artery stenosis||1-2%|
|Noonan syndrome-like facies||7%|
|MRI T2- hyperintensities||60-70%|
Timeline for Detection of Signs and Complications
|Symptom||Congenital (0-2yrs)||Preschool (2-6yrs)||Late Childhood & Adolescence (6-16yrs)||Adulthood (16+yrs)|
|Plexiform neuromas diffuse||>||>|
|Optic pathway tumours||-||>|
|Malignant peripheral nerve sheath tumours||-||-||>||>|
How is NF1 Treated?
Treatments are presently aimed at controlling symptoms. Surgery can help some bone malformations. For problematic scoliosis, bone surgery may be combined with back braces. Surgery can also remove painful or disfiguring tumors; however, there is a chance that the tumors may grow back and in greater numbers. In the rare instances where tumors become malignant – 3 to 5 percent of all cases – treatment may include surgery, radiation or chemotherapy.