Neurofibromatosis Type 1 (NF1) or von Recklinghausen disease is an autosomal dominant condition affecting the skin and peripheral nerves. It is:
- a common genetic condition with an incidence of 1 in 2500
- accounts for 90% of cases of neurofibromatosis
- distinct from NF2 which is less common, and can also present with cutaneous neurofibromas
- is caused by mutations in the NF1 gene that encodes the protein neurofibromin, and
- is associated with congenital anomalies and age related abnormal tissue proliferation.
Complications can affect many body systems.
Genetics
NF1 is fully penetrant. This means everyone with a mutant gene will eventually show signs of NF1, although it is a very variable condition even within families, so that some family members can be much more severely affected than others. 50% of cases are due to new mutations and so have no family history of the condition. Occasionally mosaicism for the condition can occur due to the gene mutation only occurring in a proportion of a person’s body cells. This means that only certain parts of the body are affected, usually in a unilateral distribution.
Clinical features
Cutaneous manifestations are the commonest features. Many of the features of NF1 only become apparent as the patient gets older. Average lifespan is reduced to the mid fifties mainly due to the occurrence of malignant soft tissue tumours.
- Common Features: the cardinal features are multiple café au lait spots, neurofibromas (benign tumours arising from peripheral nerves) and iris hamartomas (Lisch Nodules). Axillary and inguinal freckling and Campbell de Morgan spots may also be present. Learning difficulties are common as well as short stature and macrocephaly.
- Possible Complications: The following complications may occur depending on the site of the lesions. They include seizures, hydrocephalus due to aqueduct stenosis, precocious puberty, optic pathway tumors (usually under 7 yrs), glaucoma, scoliosis, malformation of skull bone (sphenoid wing dysplasia) and long bone bowing.
- Cardiovascular complications such as hypertension due to renal artery stenosis or pheochromocytoma and pulmonary stenosis may also occur. Benign and malignant tumours can occur such as plexiform neurofibromas (complex fibromas which run along the course of nerves and may develop into malignant peripheral nerve sheath tumours), CNS glioma, rhabdomyoma, neuroblastoma and myelogenous leukaemia.
Diagnostic criteria
Two or more of the following criteria are required for a diagnosis of NF1:
- 6 or more café au lait macules (0.5cm in children and 1.5cm in adults). Note that one or two café au lait macules in an individual is common in the general population, and of no clinical significance.
- 2 or more cutaneous/subcutaneous neurofibromata or one plexiform neurofibromata
- Axillary or inguinal frecking
- Optic pathway glioma
- Two or more Lisch nodules (iris hamartomas)
- Bony dysplasia (sphenoid wing dysplasia, bowing of long bone with or without pseudoarthrosis)
- First degree relative (parent, child or sibling) with NF1
Café au lait patches tend to arise within the first year of life. Optic gliomas, skeletal dysplasias and plexiform neurofibromata tend to occur in early childhood. Neurofibromata and Lisch nodules tend to occur in teenagers.
Diagnosis is usually clinical, although mutation testing is available. Prenatal testing is also possible but will not indicate how severely affected the child would be.
In those with equivocal diagnosis, brain MRI imaging may be useful. The parents of affected children should be examined carefully. Due to the variable phenotype they may not always be aware of the condition if they have minimal symptoms and signs.
Surveillance
There is a risk of serious complications arising throughout life, and regular surveillance is required to try and detect these at an early time when they are potentially treatable.
