Neurofibromatosis

Introduction to neurofibromatosis Neurofibromatosis (NF) is an autosomal dominant hereditary disease that occurs in the nerve trunk or peripheral axon sheath nerve cells and benign tumor cells. basic knowledge The proportion of illness: the incidence rate is 0.03% - 0.08% Susceptible people: no special people Mode of infection: non-infectious Complications: Epilepsy Neurofibromatosis Pneumonia

Cause of neurofibromatosis

(1) Causes of the disease

NF is a gene defect that causes abnormal development of neural crest cells and causes multiple systemic damage. It can be classified into neurocutaneous syndrome. According to clinical manifestations and gene localization, it is divided into neurofibromatosis type I (NFI) and type II (NFII), NFI. The main features are skin milk coffee plaque and peripheral nerve multiple neurofibromatosis, high penetrance rate, the gene is located on chromosome 17q11.2, NFII is also called central neurofibromatosis or bilateral acoustic neuroma disease, the gene is located on chromosome 22q, the disease is Autosomal dominant genetic disease, about half of the children of the patient can be ill, NF may occur due to genetic mutation, the function of the gene with growth regulation is lost, so that the cell loses control and proliferates into a tumor, which is grown in the nerve trunk. A benign tumor dominated by fibroblasts, the NFI genome spans 350Kb, the cDNA is 11Kb long, contains 59 exons, encodes 2818 amino acids, and constitutes 327kD of neurofibroprotein, distributed in neurons, except for type 5 NF. Probably a post-zygotic somatic mutation, about 50% of cases represent a new gene mutation, and the NFI gene is a tumor suppressor. Gene, translocation, deletion, rearrangement or point mutation, the tumor suppressor function is lost and pathogenic, the type 1 NF gene is in the center of the chromosome 17q11.2, the gene encodes neurofibromin is a A protein transformed from ras protein with growth regulation function. The gene of type 2 NF is located on the long arm of chromosome 22q11-q13. The gene encoding schwannomin is an actin scaffold (aclincytoskeleton). Glycoproteins attached to the cell surface also play a role in growth regulation, and NFII gene deletion mutations cause Schwann cell tumors and meningiomas.

(two) pathogenesis

The pathogenesis of this disease is unclear, may be abnormal development of neural crest, late thought and excessive production of nerve growth factor or hyperactivity, promote abnormal proliferation of nerve fibers, leading to tumor growth, the main pathological features of ectodermal nerve tissue dysplasia, Hyperplasia and tumor formation, NFI neurofibromatosis occurs in the distal end of the peripheral nerve, spinal nerve roots, especially the cauda equina, cranial nerves are more common in the auditory nerve, optic nerve and trigeminal nerve, intraspinal tumors include ependymoma and astroglioma The most common intracranial tumors are gliomas, which vary in size, and the cells are arranged in a nucleus like a fence.

1. Generally seen neurofibromatosis is not connected with the large nerve trunk, but also from small unmyelinated fibers, loose and translucent thin capsule, no external or light reaction zone, invasive fibroids The disease can infiltrate the surrounding normal tissue, and the blunt dissection is difficult to reach the extracapsular capsular mass excision. For example, the tumor is connected to the main nerve trunk and often invades the nerve tissue. When the capsule is separated, the nerve fiber enters and penetrates the tumor. Unlike schwannomas, which do not invade nerve fibers, it is difficult to remove the nerves without damaging the nerves. Large tumors are mostly stage III lesions. It is also common for tumors to retreat into cysts containing yellow fluid. Neurofibromas are not enveloped. However, the boundary is clear, located in the dermis and subcutaneous tissue. The tumor is mainly composed of nerve membrane cells and nerve sheath cells, and many hyperplastic axons and abundant small blood vessels are visible. The fibrous tissue is fine, closely arranged and light. The degree of curling is wavy, and sometimes the mucoid degeneration of the fiber is observed. In the milk coffee stain, the melanin of the basal cell layer of the epidermis increases, and huge pigment particles are visible.

2. Microscopic morphometric electron microscopy showed that these tumors were formed by the proliferation of fibroblasts or peripheral nerve cells. The main manifestation was that the loose spindle cells produced a fine fibrous eosin matrix with undulating waves. Regular, there are phagocytic cells, containing lipids and hemosiderin; there are Verocay bodies, vascular proliferation, mature fat, mature fiber nodules, etc., called mixed neurofibroma, NFII more common bilateral acoustic neuroma And multiple meningiomas, tumor cells are loosely arranged, common megakaryocytes.

Histopathological examination revealed two types of pathological changes.

(1) cutaneous neurofibromatosis: the tumor has no capsule, consists of nerve-sheath cells and nerve sheath cells. The nerve-coat cells are immature collagen fiber bundles. The fibrils in the bundle are fine, some have mucus between them, and the nerve sheath cells are Slender diamond shape or slightly curved waveform, the cell boundary is unclear, the cytoplasm is lightly eosin, and there are obvious filamentous processes with different lengths at both ends; the nucleus is often deeply stained, and most of them are arranged in parallel with the loose bundle of collagen fibers. It is in the shape of a wave or a vortex.

(2) subcutaneous plexiform neurofibroma: invasion of the surrounding large nerves, and see irregular nerve bundles, proliferating nerve sheath cells and collagen fibers composed of curved strips around the mucus-like amorphous interstitial.

Immunohistochemical neurofibroma has different antigen expression according to its main cell type. S-100 protein and type 4 collagen are positive for nerve sheath cells, epidermal membrane antigen is positive for nerve-stained cells, vimentin is for fibroblasts. Positive expression of nerve sheath cells, neurofilament and myelin basic protein were positive for axon and myelin sheath.

In addition, the disease may also have meningeal bulging, syringomyelia, and congenital malformations and other diseases, some patients still have lesions other than the nervous system, such as metabolic bone disease caused by bone hyperplasia, cranial occlusion, due to normal bone Substitute by fibroblasts and fibroblasts to make the bones sparse, cyst formation, and congenital spinal abnormalities, bone cysts, humeral pseudoarthrosis, can also have a limb and half of the tongue or face hypertrophy, the vertebral side Bend, etc., there are reports of cerebral cortical histology abnormalities, gray matter ectopic islands and localized gliosis, which may be the cause of mental retardation.

Tumors are usually benign and slow to grow, about 3% to 4% can cause malignant transformation, especially large plexiform neuroma is more malignant, malignant transformation is mostly peripheral tumors, central tumors rarely have malignant transformation, skin fibroids and fibers Soft tumors are formed by fibrous tissue hyperplasia, mostly located in the dermis or subcutaneous tissue, without cell membranes, and the skin pigmentation spots are caused by melanin deposition in the basal cell layer of the epidermis.

Neurofibromatosis prevention

Genetic counseling, prevention measures include avoidance of close relatives, carrier genetic testing and prenatal diagnosis and selective abortion to prevent the birth of children.

Early diagnosis and treatment of the sprinkler can prolong survival.

Neurofibromatosis complications Complications epileptic neurofibromatosis pneumonia

With the development of the disease, the symptoms and signs appear diverse, which can be the manifestation of the disease, but also can be seen as a complication.

1. Fracture or dislocation of the tumor invading the skeletal system, can cause fractures, dislocation, spinal deformity, can be complicated by scoliosis, congenital sacral pseudoarthrosis and congenital clavicular pseudoarthrosis, when the tumor compresses the common peroneal nerve can cause foot drop.

2. When epilepsy tumors invade the central nervous system, there may be epileptic seizures, and attention should be paid to prevent trauma.

3. Neurofibromatosis can sometimes rupture itself, or it can cause massive hemorrhage inside the tumor. In severe cases, it can cause shock.

4. Huge tumors on the limbs can often rupture, leading to infection and suppuration, and even amputation.

5. Diffuse interstitial pneumonia can occur in a small number of patients with lung damage.

6. Malignant tumors Skin neurofibromas can develop into neurofibrosarcoma and malignant schwannomas, and have been reported to be associated with wilm tumors, striated muscle tumors, and chronic myelogenous leukemia.

Symptoms of neurofibromatosis Common symptoms Lipoma Horner syndrome Bone destruction Cortical bone thinning Dark spot lens opacity slow growth

Most of the patients are adults, the incidence of men and women is equal, neurofibromatosis can have three benign stages, that is, delayed, active and invasive; but can also be converted into sarcoma.

1. Clinical classification There are seven types of clinical manifestations of this disease.

Type 1 NF (typical neurofibromatosis): accounts for more than 85% of all NF patients. Most neurofibromas appear in patients ranging in size from a few millimeters to several centimeters, with most widely distributed coffee spots, little or no nervous system. Damage, about 1/4 of children under 6 years of age and almost all elderly patients have iris Lisch nodules.

Type 2 NF (central or acoustic neuroma): The difference from type 1 is the presence of bilateral acoustic neuroma.

Type 3 NF (mixed) and type 4 NF (variant): Similar to type 2 NF, but with more neurofibromas.

The above 4 types of optic glioma, schwannomas, meningioma are more dangerous, and are autosomal dominant.

Type 5 NF (segmental or cutaneous ganglia neurofibromatosis): usually non-hereditary, considered to be caused by mutations in the somatic zygotic cells, which may be bilateral.

Type 6 NF (no neurofibromatosis): clinically no neurofibromatosis, only coffee spots, the diagnosis of coffee spots must occur in two generations.

Type 7 NF (late-type neurofibroma): Neurofibroma occurs only after the age of 20, and it is still unknown whether it is hereditary.

2. Clinical features Characteristic lesions are mainly neurofibromatosis, followed by coffee spots, crotch freckles, giant pigmented edema (neural spasm), sacral hirsutism, cranial gyrus and giant tongue.

(1) Skin symptoms:

1 coffee spot: almost all cases can be seen at the time of birth, skin milk coffee spots, pigmentation is the hallmark of the disease, is one of the characteristics of neurofibroma, shape and size, the edge is not complete, does not protrude the skin, good hair In the non-exposed part of the trunk, the pigment is uniform in light brown or dark brown irregular round or oval, the number is variable, the size can range from a wide range of dark spots to scattered plaques, and the tumor can also contain pigment cells. Coffee spots with a diameter of 1.5 to 5 cm (the minimum diameter of children is 0.5 cm) are found in babies born one year old. Pre-puberty >5mm skin milk coffee spots (>15mm after puberty) have a high diagnostic value, usually indicated as type l NF, part of the normal skin tone, or slightly reddish.

2 cutaneous fibroids and fibroids: cutaneous neurofibromas are dermal tumors that develop in childhood, single (as shown in Figure 3) or multiple skin or subcutaneous masses, highlighting the surface of the skin or subcutaneously accessible Shape, fusiform or irregular mass, texture can be soft and soft, the surface of the tumor is smooth or rough, and the size is different. The small ones are rice grains, mostly sesame, mung bean to citrus size, pedicle or pedicle, the larger It weighs several kilograms and can be loosely suspended on the body surface. It is band-shaped and mainly distributed on the trunk and facial skin. It is also found in the limbs. It is mostly pink, flesh-colored, and fruit-red. The number is variable and can be as many as several thousand. Soft as a scorpion, soft tumor fixed or pedicled, soft and elastic to touch, neurofibroma of superficial epithelium resembles a bead-like nodule, movable, can cause pain, tenderness, radiation pain or paresthesia, with fingers Light pressure can push the soft tumor to the fat layer, and release the finger to bounce back, which can be differentiated from lipoma.

A. Soft sputum-like hyperplasia: The soft, sputum-like tumors on the skin are proliferated, scattered throughout the body, ranging from a few to several thousand.

B. Subcutaneous spindle neuroma.

C. plexiform neurofibroma: rare, is a nerve trunk and its branch diffuse neurofibroma, often accompanied by a large number of skin and subcutaneous tissue hyperplasia, causing diffuse hypertrophy of the region or limb, called neurofibromatous elephantiasis, around the circumference The nodules that slowly grow out of the nerve are diffusely swollen and the boundary is unclear. The tumor can be highly proliferated, wrinkles, bloated and drooping. It is like a bag of worms when touched. Plexus neuroma often appears in a certain nerve distribution area. Such as the median nerve of the hand, the fifth or eighth cranial nerve, or the distribution of the upper cervical nerve, etc. When the eighth brain nerve wave is timely, it can cause unilateral or bilateral deafness. Deep tissue begins to have a tight fixation or rapid growth, or local severe pain, the possibility of malignant transformation should be suspected.

Some tumors have no capsule, the tumor grows outward, and the surrounding boundary is not clear, which often leads to the displacement of local and adjacent organs, resulting in obvious deformity and dysfunction (Fig. 6), called neuroma elephantiasis (elephantiasis). Neuromatosa).

3 other skin lesions: systemic and axillary freckles (crowe sign) is also one of the characteristics, large and black pigmentation suggest clustered neurofibroma, located in the midline suggesting spinal cord tumor, clinically misdiagnosed as melanin, axillary freckles can be stretched To the neck, it occurs in the groin and can extend to the perineum. In addition, the skin can be seen with bronze coloration and hyperpigmentation, as well as those with yellow granuloma.

(2) nervous system damage: mental retardation, dementia, epilepsy and a variety of intracranial malignant tumors can occur, about 50% of patients with neurological symptoms, mainly caused by central or peripheral nerve tumor compression, followed by gliosis , caused by vascular hyperplasia and skeletal deformities.

1 intracranial tumor: acoustic neuroma is the most common, bilateral acoustic neuroma is the main feature of NFII, often with meningeal meningioma, multiple meningioma, glioma, ventricular ependymoma, meningeal bulging and hydrocephalus , spinal nerve posterior root schwannomas, etc., optic nerve, trigeminal nerve and posterior group of cranial nerves can occur, a small number of cases may have mental decline, memory disorders and seizures.

2 intraspinal tumors: single or multiple neurofibromas, meningioma, spinal deformity, spinal bulging and syringomyelia can occur in any plane of the spinal cord.

3 peripheral nerve tumors: peripheral nerves can be involved, the horsetail is good, the tumor is beaded along the nerve trunk distribution, generally no obvious symptoms, such as sudden growth or severe pain may be malignant.

(3) Eye symptoms Iris Lisch nodules are found in all adult patients. Fibrosis or plexiform neurofibroma can be seen in the upper eyelids. The eyelids can be paralyzed and the masses and pulsations are pulsating. The slit lamp can be seen in the iris miliary orange-yellow circle. Nodules, which are hamartomas, also known as Lisch nodules, can increase with age, and are unique to NFI. Gray-white tumors and optic disc lordosis can be seen at the fundus; optic glioma can cause exophthalmos and loss of vision.

(4) Bone damage: adjacent bone can compress the bone, usually erosive, can cause skeletal deformities, common congenital bone dysplasia including scoliosis, lordosis and kyphosis, skull asymmetry, defect And depression, congenital ankle joint, spina bifida, dislocation and non-traumatic fracture, causing excessive limb hypertrophy, etc. Direct tumor compression can lead to bone changes, such as acoustic neuroma caused by enlarged internal auditory canal, spinal neuroma caused by enlarged intervertebral foramen Bone destruction; long bone, facial bone and sternum overgrowth, long bone hyperplasia, backbone bending and pseudoarticular formation are also common; adrenal gland, heart, lung, digestive tract and mediastinum, etc., can occur tumor, isolated deep nerve Fibroids grow slowly, and are found due to asymmetry or compression of the nerves. Growing at the proximal end of the humerus can compress the common peroneal nerve and cause foot drop, with little pain, but it is not uncommon to switch to fibrosarcoma.

(5) Other:

1 endocrine damage: visible acromegaly, cretinism, mucous edema, hyperthyroidism, pheochromocytoma, precocious puberty, etc.

2 lung damage: diffuse interstitial pneumonia can occur in a small number of patients.

3 malignant tumors: cutaneous neurofibromatosis can sometimes develop into neurofibrosarcoma and malignant schwannomas, and has been reported to be associated with wilm tumors, striated muscle tumors and chronic myelogenous leukemia.

3. TCM syndrome differentiation TCM believes that this disease is mostly due to congenital quality defects, or labor injury, lung qi, inferiority, external evils, blood and blood, block the meridians and hair.

Examination of neurofibromatosis

1. Chromosome examination Autosomal 17q, 22q abnormalities, genetic analysis can determine NFI and NFII mutation types.

2. Immunohistochemical neurofibromatosis has different antigen expression according to its main cell type. S-100 protein and type 4 collagen are positive for sphincter cells, epidermal membrane antigen is positive for nerve-stained cells, and vimentin is positive. Fibroblasts and nerve sheath cells were positively expressed, and neurofilament and myelin basic protein were positively expressed on axons and myelin sheaths.

3. X-ray film can help to understand the bone involvement, X-ray film can be seen in a variety of skeletal deformities, neurofibroma in the bone can show long stripe morphology on the X-ray film, but X-ray examination often no positive findings.

4. Spinal angiography, CT and MRI examinations can find central nervous system tumors, CT is helpful to understand central nervous system involvement, benign neurofibromatosis is active stage II disease, no increase in radionuclide scan, such as compression of bone There is a moderate increase, angiography can be seen in the light neovascular response, in the late venous phase, there is no vascular area in the tumor, large blood vessel shift indicates that the tumor originated from the compression of the vascular nerve bundle.

5. Brainstem auditory evoked potential has a great diagnostic value for acoustic neuroma.

Diagnosis and diagnosis of neurofibromatosis

Diagnostic criteria

Diagnosis based on medical history, clinical manifestations, X-ray examination, radionuclide scanning and angiography, and ultimately rely on pathological diagnosis.

1. Qualitative diagnosis

(1) History and family history: This disease is autosomal dominant, irregularly inherited, and can be found in families with careful inquiry.

(2) Clinical features: verrucous hyperplasia, subcutaneous fusiform neuroma, plexiform neuroma, pigmentation are the four characteristics of this disease.

(3) Laboratory examination: autosomal abnormalities, histopathology can be confirmed.

2. Classification diagnosis

(1) Type 1 NF: It can be diagnosed by two or more of the following criteria.

16 or more coffee spots, the size of which is 5 cm before puberty and 15 cm in adults.

22 or more of any type of neurofibromatosis or 1 plexiform neurofibromatosis.

3 crotch and groin freckles.

4 optic glioma.

52 or more Lisch nodules.

6 Significant bone damage such as dysplasia of the butterfly and thin cortical bone with or without pseudo-osteoarthrosis.

7 First-degree relatives (parents, brothers and sisters, children) suffer from this disease.

(2) Type 2 NF: Diagnosis must have any of the following criteria.

1CT or MRI: confirmed bilateral bilateral auditory nerve tumors.

2 First-degree relatives suffering from type 2 neurofibromatosis or the following tumors, such as unilateral acoustic neuroma or the following tumors (neurofibroma, meningioma, glioma, schwannomas or juvenile posterior lens optic opacity) 2 One.

3. Chinese medicine believes that this disease is mostly due to congenital quality defects, or labor injury, lungs, unreasonable, external evils, blood and blood, block the meridians and hair.

Differential diagnosis

1. Hemangiomas are compressible, reddish or dark.

2. Lymphangioma surface often has transparent small particles protruding, and no skin melanin deposition.

3. Pigmented spot disease occurs only on the skin, without subcutaneous nodules and subcutaneous tissue hyperplasia.

4. Myxomatology is pathologically free of nerve axes and collagen fiber bundles.

5. Mucin-like lipoma can be seen in different stages of development of fat cells, nuclear infection, can have tumor giant cells, long spindle-shaped cells without corrugated nucleus, no axons and collagen fiber bundles.

6. Atypical cases of swine mites, which are found to be scattered in the subcutaneous multiple distribution, must be differentiated from the subcutaneous nodules of the swine mites.

7. The diffuse distribution volume is larger, it needs to be differentiated from cavernous hemangioma, lymphoma, schwannomas, elephantiasis, etc. The surface skin of these lesions is normal, and the skin color may be pale blue except for cavernous hemangioma. There was no significant change outside the plaque, and the surface skin of neurofibromatosis often had pigmentation and deepened.

8. The neurofibroma of the lower extremity is confused with the rubber leg and should also be identified.

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