Neurofibromatosis

Neurofibromatosis type 1 (NF1, or von Recklinghausen disease) is most prevalent, occurring in 1 of 4650 people in a study done in the United Kingdom (2 Types references Neurofibromatosis refers to several related genetic disorders that have overlapping clinical manifestations. It causes various types of benign or malignant tumors that involve central or peripheral... read more ). It causes neurologic, cutaneous, and sometimes soft-tissue or bone manifestations. The NF1 gene is located on band 17q11.2 and encodes synthesis of neurofibromin; > 1000 mutations have been identified. Although it is an autosomal dominant disorder Autosomal Dominant Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more , 20 to 50% of cases are caused by a de novo germ cell mutation.

NF2-related schwannomatosis (NF2) accounts for 10% of cases, occurring in about 1 of 25,000 people in a study from the North West of England (3 Types references Neurofibromatosis refers to several related genetic disorders that have overlapping clinical manifestations. It causes various types of benign or malignant tumors that involve central or peripheral... read more ). It manifests primarily as congenital bilateral vestibular schwannoma Vestibular Schwannoma A vestibular schwannoma (acoustic neuroma) is a Schwann cell–derived tumor of the 8th cranial nerve. Symptoms include unilateral hearing loss. Diagnosis is based on audiology and confirmed by... read more (acoustic neuroma). The NF2 gene is located on band 22q11 and encodes synthesis of merlin, a tumor suppressor; 200 mutations have been identified. Approximately half of patients with NF2 inherit a mutation from an affected parent (4 Types references Neurofibromatosis refers to several related genetic disorders that have overlapping clinical manifestations. It causes various types of benign or malignant tumors that involve central or peripheral... read more ).

Non-NF2 schwannomatosis (schwannomatosis) is a rare disorder. It is classified as a third type of neurofibromatosis. In 15% of cases, this type is familial and related to a germline mutation in the SMARCB1 or LZTR1 gene. These genes are tumor-suppressor genes and both are located on chromosome 22 very close to the NF2 gene (1 Types references Neurofibromatosis refers to several related genetic disorders that have overlapping clinical manifestations. It causes various types of benign or malignant tumors that involve central or peripheral... read more ). In the remaining cases, the genetic basis is not well-understood, but in tissue from some patients, other mutations in the same gene are involved. Two or more schwannomas develop in spinal and peripheral nerves and are sometimes quite painful; however, vestibular schwannomas do not develop. Schwannomatosis used to be considered a form of NF2 because multiple schwannomas are present in both conditions; however, the clinical picture is different, and the genes involved are distinct.

Tumors may be peripheral or central.

Peripheral tumors are common in NF1 and can develop anywhere along the course of peripheral nerves. The tumors are neurofibromas, which develop from nerve sheaths and consist of mixtures of Schwann cells, fibroblasts, neural cells, and mast cells. Most appear during adolescence. Occasionally, they transform to malignant peripheral nerve sheath tumors. There are multiple forms:

Central tumors have several forms:

Most patients with NF1 are asymptomatic. Some present with neurologic symptoms or bone deformities. In > 90%, characteristic skin lesions are apparent at birth or develop during infancy.

Café-au-lait lesions are medium-brown (café-au-lait), freckle-like macules, distributed most commonly over the trunk, pelvis, and flexor creases of elbows and knees. Although children who do not have neurofibromatosis may have 2 or 3 café-au-lait spots, children who have NF1 have ≥ 6 such macules and often many more. These macules are > 5 mm in affected prepubertal children and > 15 mm in postpubertal patients (see table ).

Cutaneous neurofibromas, which arise along small peripheral nerves, are common. During late childhood, these cutaneous tumors of various sizes and shapes appear, ranging in number from several to thousands. They may appear skin-colored or have a pink or tan discoloration and are usually asymptomatic.

Plexiform neurofibromas can develop and have a tendency to grow to large sizes, causing irregularly thickened, distorted structures, sometimes with grotesque deformities that can impinge on nerves and other structures. Plexiform neurofibromas can also involve cranial nerves, typically the 5th, 9th, and 10th.

Neurologic symptoms vary, depending on location and number of neurofibromas. Larger neurofibromas may press on their nerve of origin and cause distal paresthesia, pain, and sensory loss or weakness, depending on the function of the nerve that is involved. Neurofibromas that form along spinal nerve roots, especially where the nerve roots are contained by bone, can compress the nerve roots and cause radicular pain, weakness, or widespread sensory loss in that nerve distribution. Plexiform neurofibromas that compress cranial nerves cause deficits typical of those nerves.

Bone abnormalities include

An optic glioma and Lisch nodules (iris hamartomas) occur in some patients. Optic gliomas are typically asymptomatic and do not require treatment unless they progressively increase in size.

Patients with NF1 can also have changes in their arterial walls that may lead to Moyamoya syndrome (stenosis or occlusion of arteries in and around the circle of Willis with formation of small collateral arteries) or intracranial aneurysms Brain Aneurysms Brain aneurysms are focal dilations in the cerebral arteries. In the United States, brain aneurysms occur in 3 to 5% of people. Brain aneurysms can occur at any age but are most common among... read more .

Some children have cognitive deficits, learning disorders, and slightly larger heads.

Children and adolescents with NF1 may have childhood chronic myelomonocytic leukemia Pathophysiology The myelodysplastic syndrome (MDS) is group of clonal hematopoietic stem cell disorders typified by peripheral cytopenia, dysplastic hematopoietic progenitors, a hypercellular or hypocellular... read more (juvenile myelomonocytic leukemia) and rhabdomyosarcoma Rhabdomyosarcoma Rhabdomyosarcoma is a cancer arising from embryonal mesenchymal cells that have potential to differentiate into skeletal muscle cells. It can arise from almost any type of muscle tissue in any... read more . Pheochromocytomas Pheochromocytoma A pheochromocytoma is a catecholamine-secreting tumor of chromaffin cells typically located in the adrenals. It causes persistent or paroxysmal hypertension. Diagnosis is by measuring catecholamine... read more may occur at any age.

Malignant tumors are much less common but still more common than in the general population; they include supratentorial or brain stem gliomas Gliomas Gliomas are primary tumors that originate in brain parenchyma. Symptoms are diverse and vary by location, manifesting as focal neurologic deficits, encephalopathy, or seizures. Diagnosis is... read more and transformation of plexiform neurofibromas to malignant peripheral nerve sheath tumors. These tumors may develop at any age.

In NF2, bilateral vestibular schwannomas Vestibular Schwannoma A vestibular schwannoma (acoustic neuroma) is a Schwann cell–derived tumor of the 8th cranial nerve. Symptoms include unilateral hearing loss. Diagnosis is based on audiology and confirmed by... read more develop and become symptomatic during childhood or early adulthood. They cause hearing loss, unsteadiness, and sometimes headache or facial weakness. Bilateral 8th cranial (vestibulocochlear) nerve masses may be present.

Family members may have gliomas, meningiomas Meningiomas Meningiomas are tumors of the meninges that can compress adjacent brain tissue. Symptoms depend on the tumor’s location. Diagnosis is by MRI with contrast agent. Treatment may include excision... read more , or schwannomas.

In schwannomatosis, multiple schwannomas develop on cranial, spinal, and peripheral nerves. Vestibular schwannomas do not develop, and patients do not become deaf. Also, the other types of tumors that sometimes occur in neurocutaneous disorders do not develop.

The first symptom of schwannomatosis is usually pain, which may become chronic and severe. Other symptoms may develop, depending on the location of the schwannomas.