Neurofibromatosis Generalisata

Neurofibromatosis (NF) type I (NF-I), also called von Recklinghausen disease, is a rare genetic disorder characterized by the development of multiple neurofibromas of the nerves and skin. The presence of café-au-lait spots on the skin of the trunk and other regions, as well as freckling, particularly in the axillary region and in the inguinal area is characteristic of this medical condition. Often evident by age 1 year, the café-au-lait spots tend to increase in size and number over time. At birth or early childhood, plexiform neurofibromas may be present. Benign tumor-like nodules of the colored regions of the eyes (Lisch nodules) may be present. Other features include macrocephaly, seizures, scoliosis, and bowing of the lower legs.

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Type I: Neurofibromatosis von Recklinghausen; Fibromatosis Molluscum Multiplex; Elephantiasis Neuromatoses.

Neurofibromatosis is more a spectrum of disorders classified as follows:

• NF-I, or peripheral NF, is best known as von Recklinghausen neurofibromatosis (VRNF).
• NF-II, or central NF, is bilateral acoustic neuroma NF (BANF).
• NF-III appears to combine at least some features of types I and II.
• NF-IV also represents a heterogeneous category (Lisch nodules in the iris are absent).
• NF-V, or segmental NF, is restricted in its involvement of the body.
• NF-VI manifests primarily as café-au-lait spots without neurofibromas.
• NF-VII is a late-onset variety.
• NF-NOS represents forms of NF that do not appear to fit into categories I to VII.

In a review article published in JAMA in 1997, Gutmann et al. seem to categorize forms other than NF-I and NF-II as mosaic NF. These individuals may require more detailed counseling than patients with the usual presentation.

Approximately 1:3000 in the general population. One million patients estimated in 1987 worldwide. NF-I = 1:4000, NF-II = 1:50,000 in the general population.

Usually autosomal dominant but heterogenic (half of probands represent new mutations). The NF-I defect is on chromosome 17q11.2, and NF-II is caused by a change in the long arm of chromosome 22. NF-I gene produces neurofibromin, which is considered a tumor suppressor gene controlling cell proliferation, differentiation, and interaction. NF-II gene produces merlin or schwannomin.

Differential diagnosis is difficult. NF-I may be associated with Ehlers-Danlos Syndrome (EDS), which is also situated on chromosome 17. The neurofibromatosis-Noonan syndrome is related and associated with chromosome 22 damage, as is the Watson syndrome. Differential diagnosis also should be made with the proteus syndrome, McCune-Albright syndrome, and multiple endocrine neoplasia type IIB.

Café-au-lait spots may appear in syndromes as different as Bannayan-Riley-Ruvalcaba, Jaffe-Campanacci, LEOPARD Syndrome (lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, growth retardation, and deafness), and Tuberous Sclerosis.

NF-I patients should have two or more of the following criteria: (A) six or more patchy hyperpigmented skin lesions called café-au-lait spots larger than 5 mm in prepuberty or larger than 15 mm after puberty; (B) two or more neurofibromas of any type or one or more plexiform neurofibromas; (C) skin-fold freckling in the axilla or groin; (D) optic pathway tumor; (E) two or more iris Lisch nodules (benign iris hamartomas); (F) a characteristic bony lesion (dysplasia of the sphenoid bone, dysplasia or thinning of long bone cortex); (G) a first-degree relative with NF-I.

NF-II patients should have (A) bilateral vestibular schwannomas visualized by MRI or (B) a parent, sibling, or child with NF-II, plus (1) unilateral vestibular schwannoma detected before age 30 years or (2) any two of the following: meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity.

NF-I presents with café-au-lait spots, multiple cutaneous or subcutaneous neurofibromas, or iris Lisch nodules, which are rare in children younger than 3 years. Nodular plexiform neurofibromas are similar to subcutaneous neurofibromas but involve nerve plexuses or dorsal nerve roots; they may grow in the mediastinum. Diffuse plexiform neurofibromas involve all skin levels and are usually hyperpigmented. Neurofibromas may appear anywhere and grow with age. They all carry a risk of functional or anatomical complication by compression or invasion. Other common findings are the following. Skeletal anomalies: Sphenoid wing dysplasia, early-onset and rapidly progressive thoracic scoliosis (in 10%) with kyphosis; patients with kyphoscoliosis are at high risk for cervical vertebral anomalies (e.g., dysplasia with or without paraspinal neurofibromas), which can be asymptomatic. Vascular Anomalies: Systemic hypertension is very frequent and caused by renal artery stenosis, pheochromocytoma, or catecholamine-secreting nodular plexiform neurofibromas. Pheochromocytoma: 5% of patients. Optic Gliomas: In 15% of patients with NF-I but only one third become symptomatic and require treatment. Seizures: Usually caused by a brain tumor or hydrocephalus, but no anatomical cause is found in 6% of patients. Learning disabilities caused by developmental delay: motor problems, hypotonia. Pseudarthrosis (usually of the tibia) or pathologic limb fracture in 2% of patients with NF-I. Congenital glaucoma is present in 0.5% of neonates with NF-I. Increased risk of developing certain types of malignancy: juvenile chronic myelogenous leukemia, Wilms tumor, rhabdomyosarcoma. Short stature. Enlarged spinal canal on CT scans is not uncommon with or without diastematomyelia. Secondary involvement of the spinal cord occurs in a variety of ways: compression by adjacent neurofibromas, vertebral collapse from neurofibroma-associated erosions, and compression from severe untreated kyphoscoliosis. Neurofibrosarcomas can occur anywhere; already established neurofibromas develop, probably most often in the large plexiform variety. Visceral nerves are also involved, and the large bowel may demonstrate a nonneurofibroma hyperganglionosis that is functionally similar to Hirschsprung disease.

NF-II is characterized by bilateral acoustic neuromas in at least 90% of patients. Café-au-lait spots are likely to be pale but larger, and usually are fewer in number than in NF-I. Neurofibromas are minimal on the skin but numerous around the vertebras. Meningiomas (intracranial and paraspinal) are frequent, unlike in NF-I, in which they are very rare. The illness may not be obvious until the second or even the fourth decade of life.

NF-III is a mixed form with the cutaneous finding of NF-I, but there is a definite and high risk for intracranial and paraspinal tumors as in NF-II (more likely schwannomas, acoustic neuromas, and meningiomas). Iris Lisch nodules are absent. Palmar neurofibromas are characteristic for the NF-IIIa type, and the intestinal manifestations are more common in the NF-IIIb type.

Prior to anesthesia, the stability of the cervical spine and the integrity of the spinal cord should be assessed to eliminate compression neuromas. Blood pressure measurements should be obtained to assess the association of a pheochromocytoma (Multiple Endocrine Neoplasm (MEN) IIb). Development of significant scoliosis may cause severe restrictive lung disease. Presymptomatic screening by CT scan of the brain is advocated for NF-I. MRI is more difficult to assess because 30 to 60% of NF-I patients demonstrate high-signal-intensity lesions in the basal ganglia, thalamus, cerebellum, and brainstem; however, their clinical relevance is still a matter of debate. Presymptomatic screening by MRI of the brain and cervical spine is better for patients with NF-II to search for acoustic neurofibromas, meningiomas, and glials tumors as ependymomas. Cervical spine involvement is frequent. Radiography of the chest (especially in the newborn) must be obtained to exclude the presence of a mediastinal mass. In presence of hypertension, investigate the cause (pheochromocytoma, abdominal of thoracic coarctation, renal arteries stenosis).

Problems with the airway in the presence of some laryngeal or pharyngeal neurofibromas have been described; face-mask ventilation, direct laryngoscopy and tracheal intubation may be difficult. During direct laryngoscopy, one must remember that neck extension could lead to the possibility of cervical spine compression by intramedullary neuromas. Given the high incidence of spinal cord involvement, spinal or epidural techniques should be used only when neuroimaging has shown the absence of compressing lesions. Neuromuscular monitoring is mandatory. In case of sudden intraoperative hypertension, the presence of a pheochromocytoma should be suspected, blood sample drawn for further analysis, and therapy started as if catecholamine discharge was present.

Some controversy exists about use of muscle relaxants because responses have been described as increased, decreased, or normal. The retrospective article by Richardson et al. suggests no dosing alterations of either succinylcholine or nondepolarizing agents.

McCune-Albright Syndrome: Characterized by bone dysplasia and spontaneous fractures, increasing pain, and limited mobility. Other clinical features include early puberty and café-au-lait spots, hyperthyroidism, and other endocrine abnormalities.

Tuberous Sclerosis: Characterized by seizures, mental retardation, developmental delays, ocular and skin lesions, and brain tumors. Onset is during infancy or early childhood. Approximately 60 to 90% of infants have café-au-lait or white hypomelanotic spots on the skin at birth. Seizures and myoclonic jerks are the most consistent symptoms and affect more than 80% of affected children. Benign periungual or subungual fibromas may be present.

Proteus Syndrome: Characterized by abnormal and asymmetrical growth in any system of the body. Hypertrophic abnormalities of the skin, face, eyes, ears, lungs, skeletal muscles, and nerves occur. The clinical manifestations are usually present during the first year of life and may include large nevi, hemangiomas, lipomas, and lymphangiomas. Mental impairment, seizures, visual abnormalities, and pulmonary cysts are part of this medical condition.

Noonan Syndrome: Characterized by distinctive craniofacial anomalies (e.g., ocular hypertelorism, ptosis, prominent low-set ears), pterygium colli, dwarfism, characteristic abnormalities of the sternum, cryptorchidism and/or congenital heart defects (e.g., pulmonary stenosis, atrial septal defects). Other features include improper development of certain blood or lymph vessels, coagulation disorders and platelet dysfunction, and/or mental retardation. Nevi, skin lentigines, and/or café-au-lait spots help make the diagnosis. It is inherited as an autosomal dominant trait.

Watson Syndrome: Extremely rare inherited disorder characterized by café-au-lait spots, lentigines, dwarfism, pulmonary stenosis, and developmental delay. In some cases, the association of macrocephaly, limited movements of the ankles and knees, neurofibromata in certain areas of the body, and/or iris Lisch nodules must be considered. Watson syndrome has been often confused with NF-I. It results from a genetic mutation in the NF-1 gene located on the long arm of chromosome 17 (17q11.2). It is inherited as an autosomal dominant.

Neurofibromatosis-Noonan Syndrome (Quattrin McPherson Syndrome): Association of NF-I and the clinical manifestations of Noonan syndrome. Clinical features include multiple benign tumors of the nerves and skin, dwarfism, pterygium colli, muscle weakness, and/or cognitive disabilities. Congenital heart defects often seen in Noonan syndrome may be present (e.g., pulmonary valve stenosis, atrial septal defect). Whether neurofibromatosis-Noonan syndrome is a rare variant of NF-I is unclear.