Neurofibromatosis type 1
Updates to Article Attributes
Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is a multisystem neurocutaneous disorder, the the most common phakomatosis, and a RASopathy. Additionally, it is also one of the most common inherited CNS disorders, autosomal autosomal dominant disorders, and inherited tumour syndromes.
Individual systemic manifestations are discussed individually:
The remainder of this article pertains to a general discussion of neurofibromatosis type 1.
Epidemiology
Neurofibromatosis affects 1:2500-3000 individuals 3. In In half of the cases, the disease is inherited as an autosomal dominant condition. In the other half, the disease is due to a de novo mutation 6. There is a 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 the following are required 2:
≥2 neurofibromas
oror ≥1 plexiform neurofibromadistinctive osseous lesion (such as sphenoid wing dysplasia
oror thinning of long bone cortex with or without pseudoarthrosis)>6 café au lait spots evident during one year (prepubertal >0.5 cm, postpubertal >1.5 cm in size)
axillary or inguinal freckling
≥2 iris hamartomas (Lisch nodules)
a primary relative with NF1
A mnemonic to help remember these features is CAFE SPOT.
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 the inactivation of a tumour suppressor gene (see below) is also associated with an increased incidence of numerous tumours 1-6:
malignant peripheral nerve sheath tumour (MPNST)(~10% of patients)7
-
glioma
juvenile pilocytic astrocytoma(~20% of patients) 13
Pathology
The NF1 gene locus is on chromosome 17q11.2 and the gene product is neurofibromin, which acts as a tumour suppressor of the Ras/MAPK pathway; inactivation of the gene thus predisposes to tumour development 6,12,13. For this reason, the disorder is classified as a RASopathy12.
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;
theythey 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
oror optic pathway glioma (may manifest as enlarged optic foramen)progressive sphenoid wing dysplasia
lambdoid suture defects
dural calcification at the vertex
moya-moya phenomenon(rare)
Cutaneous
cutaneous and subcutaneous neurofibromas:
benignbenign peripheral nerve sheath tumours
Skeletal
posterior vertebral scalloping
hypoplastic posterior elements
ribbon rib deformity, rib notching, and dysplasia
tibial pseudoarthrosis
oror, less commonly, ulnar pseudoarthrosisbony dysplasias: especially affecting the tibia
severe bowing, gracile bones 11
multiple non-ossifying fibromas
Thoracic
-
mediastinal masses
lateral thoracic meningocele: typically on the convex side of scoliosis (through widened neural foramina)
extra-adrenal phaeochromocytoma (paraganglioma)
-
lung parenchymal disease: ~20%
diffuse interstitial fibrosis:
lowerlower zonebullae 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 life expectancy is approximately half that of non-affected individuals. Tumours or cardiovascular complications are the most common causes of mortality 8.
History and etymology
The first name of this condition was von Recklinghausen disease because in 1882, Friedrichvon Recklinghausen described described cases of neurofibromatosis and recognised it as a nosological entity 14.
See also
-<p><strong>Neurofibromatosis type 1 (NF1)</strong>, also known as <strong>von Recklinghausen disease</strong>, is a multisystem neurocutaneous disorder, the most common <a href="/articles/phakomatoses">phakomatosis</a>, and a <a href="/articles/rasopathy-1">RASopathy</a>. Additionally, it is also one of the most common inherited CNS disorders, autosomal dominant disorders, and inherited tumour syndromes. </p><p>Individual systemic manifestations are discussed individually: </p><ul>- +<p><strong>Neurofibromatosis type 1 (NF1)</strong>, also known as <strong>von Recklinghausen disease</strong>, is a multisystem neurocutaneous disorder, the most common <a href="/articles/phakomatoses-1">phakomatosis</a>, and a <a href="/articles/rasopathy-1">RASopathy</a>. Additionally, it is also one of the most common inherited CNS disorders, autosomal dominant disorders, and inherited tumour syndromes. </p><p>Individual systemic manifestations are discussed individually: </p><ul>
-</ul><p>The remainder of this article pertains to a general discussion of neurofibromatosis type 1. </p><h4>Epidemiology</h4><p>Neurofibromatosis affects 1:2500-3000 individuals <sup>3</sup>. In half of the cases, the disease is inherited as an autosomal dominant condition. In the other half, the disease is due to a de novo mutation <sup>6</sup>. There is a variable expression but 100% penetrance by 5 years of age <sup>6</sup>.</p><h4>Clinical presentation</h4><p>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 the following are required <sup>2</sup>:</p><ul>-<li><p>≥2 <a href="/articles/neurofibroma">neurofibromas</a> or ≥1 <a href="/articles/plexiform-neurofibroma">plexiform neurofibroma</a></p></li>- +</ul><p>The remainder of this article pertains to a general discussion of neurofibromatosis type 1. </p><h4>Epidemiology</h4><p>Neurofibromatosis affects 1:2500-3000 individuals <sup>3</sup>. In half of the cases, the disease is inherited as an autosomal dominant condition. In the other half, the disease is due to a de novo mutation <sup>6</sup>. There is a variable expression but 100% penetrance by 5 years of age <sup>6</sup>.</p><h4>Clinical presentation</h4><p>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 the following are required <sup>2</sup>:</p><ul>
- +<li><p>≥2 <a href="/articles/neurofibroma">neurofibromas</a> or ≥1 <a href="/articles/plexiform-neurofibroma">plexiform neurofibroma</a></p></li>
-<li><p>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>)</p></li>- +<li><p>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>)</p></li>
-<li><p>≥2 iris hamartomas (Lisch nodules) </p></li>- +<li><p>≥2 iris hamartomas (Lisch nodules) </p></li>
-</ul><p>A mnemonic to help remember these features is <a href="/articles/neurofibromatosis-type-1-mnemonic">CAFE SPOT</a>.</p><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 <a href="/articles/neurofibromatosis-type-2-3">NF2</a>, 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 the inactivation of a tumour suppressor gene (see below) is also associated with an increased incidence of numerous tumours <sup>1-6</sup>:</p><ul>- +</ul><p>A mnemonic to help remember these features is <a href="/articles/neurofibromatosis-type-1-mnemonic">CAFE SPOT</a>.</p><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 <a href="/articles/neurofibromatosis-type-2-3">NF2</a>, 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 the inactivation of a tumour suppressor gene (see below) is also associated with an increased incidence of numerous tumours <sup>1-6</sup>:</p><ul>
-<li><p><a href="/articles/malignant-peripheral-nerve-sheath-tumour">malignant peripheral nerve sheath tumour (MPNST)</a> (~10% of patients) <sup>7</sup></p></li>- +<li><p><a href="/articles/malignant-peripheral-nerve-sheath-tumour">malignant peripheral nerve sheath tumour (MPNST)</a> (~10% of patients) <sup>7</sup></p></li>
-<li><p><a href="/articles/pilocytic-astrocytoma">juvenile pilocytic astrocytoma</a> (~20% of patients) <sup>13</sup></p></li>- +<li><p><a href="/articles/pilocytic-astrocytoma">juvenile pilocytic astrocytoma</a> (~20% of patients) <sup>13</sup></p></li>
-<li><p><a href="/articles/spinal-astrocytoma">spinal astrocytoma</a> and <a href="/articles/spinal-pilocytic-astrocytoma">spinal pilocytic astrocytoma</a> <sup>9</sup></p></li>- +<li><p><a href="/articles/spinal-astrocytoma">spinal astrocytoma</a> and <a href="/articles/spinal-pilocytic-astrocytoma">spinal pilocytic astrocytoma</a> <sup>9</sup></p></li>
-</ul><h4>Pathology</h4><p>The NF1 gene locus is on chromosome 17q11.2 and the gene product is neurofibromin, which acts as a tumour suppressor of the <a href="/articles/mapk-pathway">Ras/MAPK pathway</a>; inactivation of the gene thus predisposes to tumour development <sup>6,12,13</sup>. For this reason, the disorder is classified as a <a href="/articles/rasopathy-1">RASopathy</a> <sup>12</sup>.</p><p>The disease primarily is a <a href="/articles/hamartoma">hamartomatous</a> 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. </p><ul>- +</ul><h4>Pathology</h4><p>The NF1 gene locus is on chromosome 17q11.2 and the gene product is neurofibromin, which acts as a tumour suppressor of the <a href="/articles/mapk-pathway">Ras/MAPK pathway</a>; inactivation of the gene thus predisposes to tumour development <sup>6,12,13</sup>. For this reason, the disorder is classified as a <a href="/articles/rasopathy-1">RASopathy</a> <sup>12</sup>.</p><p>The disease primarily is a <a href="/articles/hamartoma">hamartomatous</a> 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. </p><ul>
-<li><p><a href="/articles/diffuse-neurofibroma">diffuse neurofibroma</a> (subcutaneous neurofibroma): localised in the subcutis, usually in the head and neck region. </p></li>-<li><p><a href="/articles/plexiform-neurofibroma">plexiform neurofibroma</a>: considered pathognomonic if present; they may be seen in virtually any location but usually occur in the neck, pelvis, and extremities </p></li>- +<li><p><a href="/articles/diffuse-neurofibroma">diffuse neurofibroma</a> (subcutaneous neurofibroma): localised in the subcutis, usually in the head and neck region. </p></li>
- +<li><p><a href="/articles/plexiform-neurofibroma">plexiform neurofibroma</a>: considered pathognomonic if present; they may be seen in virtually any location but usually occur in the neck, pelvis, and extremities </p></li>
-<li><p><a href="/articles/fasi">FASI</a> (focal areas of signal intensity): occur in deep white matter and basal ganglia or corpus callosum <sup>5</sup>, areas of T2/FLAIR hyperintensity with no contrast enhancement</p></li>-<li><p><a href="/articles/optic-pathway-glioma">optic nerve glioma</a> or optic pathway glioma (may manifest as enlarged optic foramen)</p></li>- +<li><p><a href="/articles/fasi">FASI</a> (focal areas of signal intensity): occur in deep white matter and basal ganglia or corpus callosum <sup>5</sup>, areas of T2/FLAIR hyperintensity with no contrast enhancement</p></li>
- +<li><p><a href="/articles/optic-pathway-glioma">optic nerve glioma</a> or optic pathway glioma (may manifest as enlarged optic foramen)</p></li>
-<li><p><a href="/articles/moyamoya-disease-1">moya-moya phenomenon</a> (rare)</p></li>- +<li><p><a href="/articles/moyamoya-disease-1">moya-moya phenomenon</a> (rare)</p></li>
-</ul><h5>Cutaneous</h5><ul><li><p>cutaneous and subcutaneous <a href="/articles/localised-neurofibroma">neurofibromas</a>: benign peripheral nerve sheath tumours</p></li></ul><h5>Skeletal</h5><ul>- +</ul><h5>Cutaneous</h5><ul><li><p>cutaneous and subcutaneous <a href="/articles/localised-neurofibroma">neurofibromas</a>: benign peripheral nerve sheath tumours</p></li></ul><h5>Skeletal</h5><ul>
-<li><p><a href="/articles/ribbon-rib-deformity">ribbon rib deformity</a>, <a href="/articles/rib-notching">rib notching</a>, and dysplasia </p></li>- +<li><p><a href="/articles/ribbon-rib-deformity">ribbon rib deformity</a>, <a href="/articles/rib-notching">rib notching</a>, and dysplasia </p></li>
-<li><p><a href="/articles/congenital-pseudoarthrosis-of-the-tibia">tibial pseudoarthrosis</a> or, less commonly, ulnar pseudoarthrosis</p></li>- +<li><p><a href="/articles/congenital-pseudoarthrosis-of-the-tibia">tibial pseudoarthrosis</a> or, less commonly, ulnar pseudoarthrosis</p></li>
-<p>mediastinal masses </p>- +<p>mediastinal masses </p>
-<li><p><a href="/articles/pulmonary-fibrosis" title="Pulmonary fibrosis">diffuse interstitial fibrosis</a>: lower zone</p></li>- +<li><p><a href="/articles/pulmonary-fibrosis" title="Pulmonary fibrosis">diffuse interstitial fibrosis</a>: lower zone</p></li>
-<li><p><a href="/articles/aneurysm">aneurysms</a> / <a href="/cases/arteriovenous-malformation-cerebral-2">arteriovenous malformations</a></p></li>- +<li><p><a href="/articles/aneurysm">aneurysms</a> / <a href="/cases/arteriovenous-malformation-cerebral-2">arteriovenous malformations</a></p></li>
-</ul><h4>Treatment and prognosis</h4><p>No single treatment exists, and a combination of supportive and surgical therapies are employed depending on the specific tumours and anomalies present. </p><p>Although prognosis is very variable, overall life expectancy is approximately half that of non-affected individuals. Tumours or cardiovascular complications are the most common causes of mortality <sup>8</sup>.</p><h4>History and etymology</h4><p>The first name of this condition was von Recklinghausen disease because in 1882, <strong>Friedrich</strong> <strong>von Recklinghausen</strong> described cases of neurofibromatosis and recognised it as a nosological entity <sup>14</sup>. </p><h4>See also</h4><ul><li><p><a href="/articles/paediatric-mediastinal-masses">paediatric mediastinal masses</a></p></li></ul>- +</ul><h4>Treatment and prognosis</h4><p>No single treatment exists, and a combination of supportive and surgical therapies are employed depending on the specific tumours and anomalies present. </p><p>Although prognosis is very variable, overall life expectancy is approximately half that of non-affected individuals. Tumours or cardiovascular complications are the most common causes of mortality <sup>8</sup>.</p><h4>History and etymology</h4><p>The first name of this condition was von Recklinghausen disease because in 1882, <strong>Friedrich</strong> <strong>von Recklinghausen</strong> described cases of neurofibromatosis and recognised it as a nosological entity <sup>14</sup>. </p><h4>See also</h4><ul><li><p><a href="/articles/paediatric-mediastinal-masses">paediatric mediastinal masses</a></p></li></ul>
Image 25 MRI (FLAIR) ( create )
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