Neurofibromatosis type 1
Updates to Article Attributes
Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is a multisystem neurocutaneous disorder and the most common phakomatosis. Additionally, it is also one of the most common inherited CNS disorders, autosomal dominant disorders and inherited tumour syndromes.
Individual systemic manifestations are discussed individually:
- breast manifestations of NF1
- central nervous system manifestations of NF1
- cutaneous manifestations of NF1
- musculoskeletal manifestations of NF1
- pulmonary manifestations of NF1
- orbital manifestations of NF1
The remainder of this article pertains to a general discussion of neurofibromatosis type 1 (NF1).
Epidemiology
Neurofibromatosis affects 1:2500-3000 individuals 3. In half of cases, the disease is inherited as an autosomal dominant condition. In the other 50% of cases the disease is due to a new mutation 6. There is variable expression but 100% penetrance by 5 years of age 6.
Clinical presentation
As is the case with many phakomatoses, NF1 results in a variety of abnormalities of variable severity. To make the clinical diagnosis two or more of following are required 2:
- >6 cafe au lait spots evident during one year
- two or more neurofibromas or one plexiform neurofibroma
- optic nerve glioma
- distinctive osseous lesion
- (such as sphenoid wing dysplasia or thinning of long bone cortex with or without pseudoarthrosis)
- two or more iris hamartomas (Lisch nodules)
- axillary or inguinal freckling
- primary relative with NF1 with above criteria
In addition ~45% (range 30-60%) of patients have learning disabilities, and approximately 1% have hypertension due to renal artery stenosis.
It is important to consider that NF1 has a much earlier age of onset than schwannomatosis and NF2, with approximately 50% of patients meeting the diagnostic criteria for NF1 by the age of 1 year and approximately 97% meeting the criteria by the age of 8 years 10.
Neoplasms
It should come as no surprise that a disease due to inactivation of a tumour suppressor gene (see below) is also associated with increased incidence of numerous tumours 1-6:
- pheochromocytoma
-
malignant peripheral nerve sheath tumour (MPNST)
- previously known as neurofibrosarcoma
- overal risk of developing a MPNST is ~10% 7
- Wilms tumour
- rhabdomyosarcoma
- renal angiomyolipoma
- glioma
- carcinoid tumour(s)
- leiomyoma(s)
- leiomyosarcoma
- ganglioglioma
- leukaemia
Pathology
The NF1 gene locus is on chromosome 17q11.2 and the gene product is neurofibromin, acts as a tumour suppressor; inactivation of the gene thus predisposes to tumour development 6.
The disease primarily is a hamartomatous disorder that involves the ectoderm and mesoderm. Usually three types of neurofibromas occur in this disorder and are distinguished on the basis of their gross and microscopic appearances.
- localised neurofibroma (cutaneous neurofibroma): the most common type, is a focal lesion that typically is located in the dermis and subcutis
- diffuse neurofibroma (subcutaneous neurofibroma): localised in the subcutis, usually in the head and neck region.
- plexiform neurofibroma: considered pathognomonic if present ; they may be seen in virtually any location but usually occur in the neck, pelvis, and extremities
Radiographic features
Breast
Central nervous system
- FASI (focal areas of signal intensity): occur in deep white matter and basal ganglia or corpus callosum 5, areas of T2/FLAIR hyperintensity with no contrast enhancement
- optic nerve glioma or optic pathway glioma (may manifest as enlarged optic foramen)
- progressive sphenoid wing dysplasia
- lambdoid suture defects
- dural calcification at vertex
- moya moya phenomenon (rare)
- buphthalmos
Cutaneous
- cutaneous and subcutaneous neurofibromas: benign peripheral nerve sheath tumours
Skeletal
- kyphoscoliosis
- posterior vertebral scalloping
- hypoplastic posterior elements
- enlarged neural foramina
- ribbon rib deformity, rib notching and dysplasia
- dural ectasia
- tibial pseudoarthrosis or less commonly ulnar pseudoarthrosis
- bony dysplasias: especially affecting tibia
- severe bowing, gracile bones 11
- multiple NOF
- limb hemihypertrophy
Thoracic
- mediastinal masses
- neurofibroma
- lateral thoracic meningocoeles: typically on convex side of scoliosis (through widened neural formina)
- extra adrenal pheochromocytoma
- lung parenchymal disease: ~20%
- diffuse interstitial fibrosis: lower zone
- bullae formation: upper zone
- secondary pulmonary arterial hypertension and cor pulmonale
Vascular
Treatment and prognosis
No single treatment exists, and a combination of supportive and surgical therapies are employed depending on the specific tumours and anomalies present.
Although prognosis is very variable, overall patients with neurofibromatosis type I have a life expectancy approximately half that of non affected individuals, usually succumbing to tumours or cardiovascular complications 8.
See also
-<li>distinctive osseous lesion</li>-<li><a href="/articles/sphenoid-wing-dysplasia">sphenoid wing dysplasia</a></li>- +<li>distinctive osseous lesion (such as <a href="/articles/sphenoid-wing-dysplasia">sphenoid wing dysplasia</a> or thinning of long bone cortex with or without <a href="/articles/congenital-pseudoarthrosis-of-the-tibia">pseudoarthrosis</a>)</li>
-</ul><p>In addition ~45% (range 30-60%) of patients have learning disabilities.</p><p>It is important to consider that NF1 has a much earlier age of onset than schwannomatosis and NF2, with approximately 50% of patients meeting the diagnostic criteria for NF1 by the age of 1 year and approximately 97% meeting the criteria by the age of 8 years <sup>10</sup>. </p><h6>Neoplasms</h6><p>It should come as no surprise that a disease due to inactivation of a tumour suppressor gene (see below) is also associated with increased incidence of numerous tumours <sup>1-6</sup>:</p><ul>- +</ul><p>In addition ~45% (range 30-60%) of patients have learning disabilities, and approximately 1% have hypertension due to <a href="/articles/renal-artery-stenosis">renal artery stenosis</a>.</p><p>It is important to consider that NF1 has a much earlier age of onset than schwannomatosis and NF2, with approximately 50% of patients meeting the diagnostic criteria for NF1 by the age of 1 year and approximately 97% meeting the criteria by the age of 8 years <sup>10</sup>. </p><h6>Neoplasms</h6><p>It should come as no surprise that a disease due to inactivation of a tumour suppressor gene (see below) is also associated with increased incidence of numerous tumours <sup>1-6</sup>:</p><ul>
-<a href="/articles/tibial-pseudoarthrosis">tibial pseudoarthrosis</a> or less commonly ulnar pseudoarthrosis</li>- +<a title="Tibial pseudoarthrosis (congenital)" href="/articles/congenital-pseudoarthrosis-of-the-tibia">tibial pseudoarthrosis</a> or less commonly ulnar pseudoarthrosis</li>
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