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Congenital, Developmental, and Neurocutaneous Disorders
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CHAPTER 426 CONGENITAL, DEVELOPMENTAL, AND NEUROCUTANEOUS DISORDERS
426 CONGENITAL, DEVELOPMENTAL, AND NEUROCUTANEOUS DISORDERS JONATHAN W. MINK
CONGENITAL DISORDERS Malformations of Cerebral Cortex Developmental malformations of the cerebral cortex arise from a wide variety of etiologies, including genetic mutations, intrauterine infections, intrauterine ischemia, and toxic exposures. These malformations are heterogeneous and can result from disrupted neuronal proliferation, migration, or cortical organization. In general, disorders that arise early in development are more severe than those that arise after the basic architecture of the brain has developed. When small areas of the brain are involved, the patient may have minor impairment of neurologic function. When larger areas of the brain are involved, patients often have cognitive deficits and more severe neurologic dysfunction. Epilepsy (Chapter 410), which is the most common manifestation of abnormal cortical development, may occur with or without other neurologic signs or symptoms.
Disorders of Neuronal Proliferation
Neuronal proliferation can be abnormally increased or decreased owing to a variety of mechanisms. These disorders can manifest with megalencephaly or
CHAPTER 426 CONGENITAL, DEVELOPMENTAL, AND NEUROCUTANEOUS DISORDERS
microcephaly, or head size can be normal. Abnormal proliferation can involve specific cell types, thereby resulting in focal or multifocal areas of dysplasia or in the formation of hamartomas (see Tuberous Sclerosis, later).
FOCAL CORTICAL DYSPLASIA WITH BALLOON CELLS
Focal cortical dysplasia is caused by abnormal proliferation of both neurons and glia. Its neuropathology is characterized by the presence of giant dysmorphic neurons and “balloon cells” associated with altered cortical lamination, but some lesions have abnormal cortical layering with ectopic neurons in white matter. Affected patients typically present with partial seizures that are often intractable to medical therapy. These seizures can begin at any age but most commonly present during childhood or adolescence. The type of seizure depends on the anatomic location of the dysplasia. Other neurologic manifestations, such a sensory, motor, or cognitive impairments, depend on the extent of the dysplasia and whether multiple brain regions are affected. The diagnosis of focal cortical dysplasia is usually made with brain magnetic resonance imaging (MRI), which demonstrates focal thickening of a gyrus or alteration of the gray-white matter junction. Management includes medical treatment of seizures, but surgical resection of the epileptic focus may be required for complete remission (Chapter 410).
Disorders of Neuronal Migration
Disorders of neuronal migration typically result in disruption of the normal laminar organization of the cerebral cortex. Defects include impaired initiation of neuronal migration, impaired orderly migration, and impaired termination of migration. All result in abnormal cortical organization and function.
LISSENCEPHALY AND BAND HETEROTOPIA
The lissencephalies (smooth brain) are a group of disorders that are caused by arrested migration of neurons to the cerebral cortex. Lissencephaly genes include LIS1 (chromosome 17p13.3) and DCX (chromosome Xq22), both of which are thought to be involved in the regulation of microtubule organization and function. Individuals with mutations of LIS1 typically have severe malformations that are most prominent in the posterior cerebrum. More extensive mutations in the region of LIS1 result in Miller-Dieker syndrome, a condition characterized by lissencephaly and distinctive facial features that include a prominent forehead, midface hypoplasia, low-set and abnormally shaped ears, and a small jaw. Males with DCX mutations typically have a severe lissencephaly that is most prominent in the anterior cerebrum. Lissencephaly is typically diagnosed in infancy or early childhood, usually accompanied by microcephaly, severe global developmental delay, cerebral palsy, and intractable epilepsy. Diagnosis of lissencephaly is made by brain MRI that shows a smooth cortex with minimal sulcation. Genetic testing for LIS1 and DCX is available. Management consists of seizure control, genetic counseling, and supportive care. Band heterotopia (double cortex) is a less severe form of lissencephaly that is usually seen in women with DCX mutation. Clinical manifestations of band heterotopia range from mild to severe and include seizures, intellectual disability, and developmental delay. Women with a DCX mutation are at risk of having male children with severe lissencephaly. Brain MRI demonstrates a band of gray matter underlying a nearly normal-appearing cerebral cortex. Management consists of seizure control and genetic counseling.
NODULAR HETEROTOPIA
Nodular heterotopias are characterized by nodular ectopic collections of neurons and glia in the subependyma or in the subcortical white matter. The most important form is subependymal nodular heterotopia, a condition characterized by multiple gray matter nodules in the walls of the lateral ventricles bilaterally. This X-linked condition is due to a mutation in FLNA (chromosome Xq28), which codes for filamin A, an actin-cross-linking phosphoprotein that is critical for the initiation of migration. As a result of this mutation, many neurons do not migrate out of the subventricular zone. Most affected individuals are heterozygous females. Males are severely affected and often die in infancy. Most affected females present with seizures during childhood or adolescence. Females may be intellectually normal or have mild disability. Individuals with subependymal nodular heterotopia appear to be at increased risk for aortic or carotid dissection and for cardiac valvular abnormalities. The diagnosis is based on brain MRI, which shows gray matter nodules along the walls of the lateral ventricles. Genetic testing for FLNA is available. Management consists of seizure control and genetic counseling.
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Disorders of Cortical Organization
Disorders of cortical organization include conditions such as polymicrogyria and schizencephaly. These disorders are not due to abnormal numbers of neurons or impaired migration but instead include abnormalities of gyration, sulcation, connectivity, or synaptogenesis. The best understood of these disorders are polymicrogyria and schizencephaly.
POLYMICROGYRIA
Polymicrogyria is characterized by regions of complex cortical convolutions with miniature gyri that are fused and superimposed together. Polymicrogyria is caused by failure of cortical organization as a result of in utero injury or genetic mutation; it has been associated with prenatal infections, such as cytomegalovirus, and possible vascular abnormalities, but often it is idiopathic. A single gene, GPR56 (chromosome 16q13), has been associated with bilateral frontoparietal polymicrogyria. GPR56 codes for a G protein– coupled receptor that appears to be important for human cerebral cortical development. Clinical manifestations include epilepsy, developmental delay, cerebral palsy, and intellectual disability, depending on the location and extent of the abnormality. The diagnosis of polymicrogyria is made by brain MRI. Clinical management consists of seizure management and supportive therapies.
SCHIZENCEPHALY
Schizencephaly is characterized by infolding of cortical gray matter along a hemispheric cleft near the primary cerebral fissures. It is thought to represent a more extensive injury than what leads to polymicrogyria. In most cases, the cause cannot be determined, but it has been associated with in utero insult. A rare familial form has been described, but no gene has been identified. Clinical features include developmental delay, cerebral palsy, dysarthria, and epilepsy. The clinical abnormalities are more severe with large open-lip schizencephaly and with bilateral lesions than with small unilateral closed-lip schizencephaly. Diagnosis is made by brain MRI. Management consists of seizure control and supportive therapies when indicated.
Malformations of Cerebellum and Brain Stem
Developmental abnormalities of the hindbrain are less well understood than are abnormalities of cerebral cortical development. Two of the better known and important syndromes are Joubert’s syndrome and Dandy-Walker malformation.
JOUBERT’S SYNDROME
Joubert’s syndrome is characterized by a distinctive pattern of cerebellar and brain stem developmental malformation. Four causative genes (NPHP1, CEP290, AHI1, and TMEM67 [MKS3]) together account for approximately 30% of cases. Clinical features include hypotonia, truncal ataxia, developmental delay, abnormal eye movements, and disordered breathing. The combination of signs and severity can be variable. Some individuals with Joubert’s syndrome also have retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, or hepatic fibrosis. No formal diagnostic criteria exist. The diagnosis is usually based on the combination of hypotonia in infancy with later development of ataxia, intellectual impairment, and abnormal breathing pattern, or abnormal eye movements in combination with a characteristic MRI finding known as the molar tooth sign. The molar tooth sign results from hypoplasia of the cerebellar vermis and accompanying brain stem abnormalities on axial imaging through the junction of the midbrain and pons. Genetic testing is available for the four identified genes. Management is supportive. Caffeine can be helpful for periodic hypoventilation, but some patients require tracheostomy.
DANDY-WALKER MALFORMATION
Dandy-Walker malformation is characterized by cerebellar vermis hypoplasia and cystic dilation of the fourth ventricle. Rare familial cases have been reported, but a genetic basis has not been identified. This heterogeneous disorder is usually accompanied by hypotonia, delayed motor development, and ataxia. Intellectual disability is present in about 50% of affected individuals. In some cases, hydrocephalus requires shunting. Diagnosis is based on characteristic findings on brain MRI. Treatment is supportive, with cerebrospinal fluid (CSF) shunting when indicated.
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growth in childhood or adolescence. However, tethered spinal cord syndrome may go undiagnosed until adulthood, when sensory and motor problems and loss of bowel and bladder control emerge. Erectile dysfunction may occur in males. Symptoms are typically progressive. Diagnosis is made with MRI, which shows a low conus medullaris (i.e., below the bottom of the L2 vertebral body) or a thickened or fat-containing filum terminale. Diminished pulsations of the spinal cord may also be seen. Treatment consists of surgical release of the tethered cord. With successful surgery, symptoms typically do not progress and may improve.
SYRINGOHYDROMYELIA
FIGURE 426-1. Chiari I malformation. A sagittal magnetic resonance image shows low, pointed cerebellar tonsils (i.e., Chiari I malformation, T) that extend to the level of C1 (black arrow) and a dilated central canal of the spinal cord (i.e., syringohydromyelia, S). (From Barkovich AJ, Kuzniecky RI. Congenital, Developmental, and Neurocutaneous Disorders. In Goldman L, Ausiello D, eds. Cecil Textbook of Medicine, 23rd ed. Philadelphia: Saunders Elsevier; 2008:2790.)
CHIARI MALFORMATIONS
Four types of Chiari malformation have been described. The most common of these are Chiari types I and II. Chiari I malformations are most often diagnosed in adulthood, whereas Chiari II malformations are associated with spina bifida and are usually diagnosed in childhood. Chiari I malformations are characterized by downward displacement of the cerebellar tonsils through the foramen magnum, often first accompanied by compression of the tonsils. Chiari I is a developmental abnormality that is thought to be congenital in most cases, even though symptoms may not present until adulthood, typically in the third or fourth decade of life. The abnormality is often asymptomatic and discovered only as an incidental finding. However, clinical manifestations can result from compression of neural structures at the cranial-cervical junction or obstruction of CSF flow. Signs and symptoms include headaches that worsen with straining or coughing, lower cranial nerve findings, downbeat nystagmus, ataxia, or long-tract signs. Chiari I malformations are accompanied by syringomyelia (see later) in up to 80% of cases. Diagnosis is made with brain MRI, which shows the cerebellar tonsils extending through the foramen magnum 5 mm or more (Fig. 426-1). Surgical treatment with craniocervical decompression is recommended for symptomatic patients but usually not for asymptomatic individuals or patients whose only symptom is headache. Chiari II malformations, commonly called Arnold-Chiari malformations, are characterized by descent of the cerebellar tonsils, the inferior vermis, and portions of the cerebellar hemispheres into the spinal canal along with elongation and displacement of the brain stem and fourth ventricle. Chiari II malformations are almost always associated with meningomyelocele and spina bifida. Hydrocephalus requiring shunting occurs in most cases. Brain stem dysfunction may result from intrinsic malformation or from compression of neural structures at the craniocervical junction. Treatment is surgical repair of the myelomeningocele, relief of hydrocephalus, and occasionally, cervical bone decompression. The prognosis depends on the level and extent of the myelomeningocele and on the severity of brain anomalies.
Malformations of Spinal Cord Tethered Spinal Cord
Tethered spinal cord syndrome is a disorder caused by an anomalous filum terminale that restricts the normal ascent of the conus medullaris and limits the movement of the spinal cord within the spinal column. The result is an abnormal stretching of the spinal cord with neurologic symptoms referable to the lower spinal cord. Tethering may also develop after spinal cord injury. Associated spinal anomalies are common and may include diastematomyelia, spinal lipomas, dermal sinuses, and fibrolipomas of the filum terminale. Symptoms can occur at any age but usually develop during periods of rapid
Syringohydromyelia is a condition in which the central canal of the spinal cord (hydromyelia) or the substance of the spinal cord (syringomyelia) is expanded by the accumulation of CSF. In many cases, both hydromyelia and syringomyelia are present (syringohydromyelia). The proximate cause of syringes probably is altered flow of CSF with variations in pressure in different parts of the subarachnoid space. The pressure variations create forces that drive CSF into the spinal cord. Possible causes include narrowing of the foramen magnum, Chiari I and II malformations, intramedullary and extramedullary spinal cord tumors, and subarachnoid scarring. Subsequent extension of the cyst may result from rapid changes in intraspinal pressure owing to such events as coughing or sneezing. Symptoms of syringohydromyelia most commonly begin in late adolescence or early adulthood and progress irregularly, with long periods of stability. The classic presentation is asymmetrical weakness and atrophy in the upper extremities, loss of upper limb deep tendon reflexes, and loss of pain and temperature sensation (with preservation of vibration and proprioception) in the neck, arms, and upper part of the trunk. With progression, spasticity and hyperreflexia develop in the lower extremities. Progressive ascending and descending levels of weakness and sensory impairment typically occur over time. The diagnosis is made by spinal MRI (see Fig. 426-1). If syringohydromyelia is identified, it is important to perform a brain MRI to look for associated abnormalities of the craniocervical junction. Occasionally, mild central canal dilation is discovered incidentally in patients without spinal cord symptoms or signs. If no associated cause is found, the prognosis of such incidentally discovered anomalies is generally good. Treatment is directed at the cause, if one can be identified. Syringopleural or syringoperitoneal shunting is sometimes performed with variable benefit.
DEVELOPMENTAL DISORDERS
Disorders that result from impaired postnatal neurodevelopmental function range from specific disorders such as fragile X syndrome and Rett’s syndrome, to complex syndromes such as autism, to nonspecific developmental delay and learning disabilities.
Fragile X Syndrome
Fragile X syndrome is an X-linked trinucleotide repeat disorder that is characterized by nonsyndromic mental retardation in most affected males. The pathogenesis of fragile X syndrome is not well understood. The classic disorder is seen in males with full mutations (>200 repeats) in the FMR1 gene. Fragile X syndrome may present as only moderate to severe mental retardation, but it is often associated with a prominent forehead, large ears, prominent jaw, and macro-orchidism. Postpubertal males often have poor impulse control, perseveration, and poor eye contact. Up to 25% of affected males have autism. Heterozygous females may be asymptomatic or may have a syndrome similar to what is seen in males, depending on repeat size and random X-inactivation. Other disorders associated with FMR1 include the fragile X ataxia syndrome, which is characterized by the late onset, usually after age 50 years, of progressive cerebellar ataxia and intention tremor in individuals who have an FMR1 premutation (60 to 200 repeats). It occurs equally in males and females. Diagnosis is by molecular genetic testing. Cytogenetic testing for fragile sites is no longer recommended because it is less sensitive and more expensive than molecular testing. Treatment is symptomatic and supportive. Genetic counseling is recommended for affected individuals and their families.
Rett’s Syndrome
Rett’s syndrome is a neurodevelopmental disorder that occurs in females with mutations in the MECP2 gene. MECP2 mutations are generally lethal in male embryos, but Rett’s syndrome has been reported in males with XXY karyotype or with somatic mosaicism. MECP2 is thought to mediate
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transcriptional silencing of methylated DNA. Most mutations are probably de novo or may reflect germline mosaicism; 99% of cases represent a single occurrence within a family. Affected girls are usually normal at birth and have apparently normal development for the first 6 to 18 months of life. Brain growth decelerates, and development stagnates, followed by rapid regression of language and motor skills. A classic feature of Rett’s syndrome is the loss of purposeful hand use and the development of repetitive stereotyped hand movements that usually have the appearance of wringing or clapping. Other features present to variable degree are bruxism, episodic apnea and hyperpnea, seizures, gait disorders, and tremor. Non-neurologic features include growth failure and wasting, bowel dysmotility, scoliosis, osteopenia, and vasomotor changes in the limbs. Diagnosis is by molecular genetic methods. Treatment is symptomatic.
Autism
Autism is a neurodevelopmental syndrome characterized by impaired communication, impaired social interaction, and restricted interests or repetitive behaviors. Fragile X syndrome and tuberous sclerosis are two important entities in which an autistic phenotype can occur and in which autism may be the most prominent feature. Symptoms typically present before 3 years of age and persist into adulthood. Autism is a spectrum ranging from severe, with impairment in all domains, to mild with normal intellect and language but with impaired social interactions and repetitive behaviors or restricted interests. Autism has many causes but in most cases is idiopathic. Epilepsy is common in autism. Diagnosis is based on careful diagnostic interview and examination. When epilepsy is present, treatment with antiepileptic medications is indicated. Behavioral therapy can help individuals learn rules for social interaction and can improve communication. It can also help with problematic behavior. Educational support is important. Medications such as atypical antipsychotics, selective serotonin reuptake inhibitors, and anxiolytics (Chapter 404) can help with aggressive behavior, repetitive behaviors, and anxiety.
FIGURE 426-2. Multiple neurofibromas covering the back of a patient with neurofibromatosis type 1.
TABLE 426-1 DIAGNOSTIC CRITERIA FOR NEUROFIBROMATOSIS TYPE 1 Two or more of the following clinical features signify the presence of neurofibromatosis type 1: Six or more cafe au lait macules (>0.5 cm at largest diameter in prepubertal individuals or >1.5 cm in individuals past puberty) Axillary freckling or freckling in inguinal regions Two or more neurofibromas of any type or ≥1 plexiform neurofibroma Two or more Lisch nodules (iris hamartomas) A distinctive osseous lesion A first-degree relative with neurofibromatosis type 1 diagnosed by using the above-listed criteria
NEUROCUTANEOUS DISORDERS
Neurocutaneous disorders are congenital syndromes characterized by dysplastic and neoplastic lesions primarily involving the nervous system and skin. The more than 40 described syndromes include neurofibromatosis, tuberous sclerosis, Sturge-Weber syndrome, and von Hippel-Lindau disease.
Neurofibromatosis
Neurofibromatosis encompasses a spectrum of syndromes with distinctive neural and cutaneous lesions. The two major forms of neurofibromatosis are genetically and clinically distinct.
NEUROFIBROMATOSIS TYPE 1
Neurofibromatosis type 1, which is the classic disorder described by von Recklinghausen, is an autosomal dominant condition with an incidence of 1 per 2500 to 3000 births. Although it is an autosomal dominant disease, approximately 50% of cases are due to new mutations. Most mutations in NF1 occur in the parental germline. The NF1 gene, which is located on chromosome 17q11.2, codes a protein called neurofibromin, which is thought to function as a tumor suppressor by acting as a negative regulator of the Ras signaling pathway. Neurofibromatosis type 1 is characterized by multiple cafe au lait spots, axillary and inguinal freckling, multiple discrete cutaneous neurofibromas (Fig. 426-2), and Lisch nodules (Table 426-1). Subcutaneous neurofibromas may be painful or disfiguring. Learning disabilities are present in at least 50% of individuals. Other manifestations include plexiform neurofibromas, optic nerve and other central nervous system (CNS) gliomas, malignant peripheral nerve sheath tumors, tibial dysplasia, and vasculopathy. Management of patients depends on the specific manifestations and often requires multidisciplinary collaboration. Most patients with neurofibromatosis type 1 do not require treatment, but all require surveillance (Table 426-2). Subcutaneous, intraspinal, and intracranial tumors can be treated surgically. Optic nerve gliomas may be treated with chemotherapy; both cisplatin and temozolomide have shown some benefit. Radiation is not recommended. Genetic counseling should be provided to all patients and their families.
NEUROFIBROMATOSIS TYPE 2
Neurofibromatosis type 2, which is often referred to as central neurofibromatosis, is an autosomal dominant condition with an incidence of approximately 1 in 25,000 individuals. The NF2 gene is located on chromosome 22q12.2. Its gene product, merlin, is cytoskeletal protein that is thought to act as a
TABLE 426-2 RECOMMENDED SURVEILLANCE IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 1 Annual physical examination by a physician who is familiar with the individual and with the disease Annual ophthalmologic examination in early childhood, less frequent examination in older children and adults Regular developmental assessment by screening questionnaire (in childhood) Regular blood pressure monitoring Other studies only as indicated on the basis of clinically apparent signs or symptoms Monitoring of those who have abnormalities of the central nervous system, skeletal system, or cardiovascular system by an appropriate specialist
membrane-stabilizing protein. The specific function of merlin is unknown. Neurofibromatosis type 2 is characterized by bilateral vestibular schwannomas, which usually present with symptoms of tinnitus, hearing loss, and imbalance. The age at onset is usually in young adulthood, but some individuals may develop posterior subcapsular lens opacities or mono-neuropathy in childhood. Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years (Table 426-3). Affected individuals may also develop schwannomas of other cranial and peripheral nerves, meningiomas, and, rarely, ependymomas or astrocytomas. Posterior subcapsular lens opacities are the most common ocular abnormality. Management is dependent on the specific manifestations and complications. In individuals who either have tested positive for known NF2 mutations or have a family history of neurofibromatosis type 2 and whose genetic status cannot be determined with genetic testing, annual brain MRI is recommended starting between ages 10 and 12 years and continuing until at least age 40 years. Hearing evaluations may be useful in detecting changes in auditory nerve function before changes can be visualized by MRI. Routine complete eye examinations should be part of the care of all individuals. Bevacizumab, a vascular endothelial growth factor inhibitor (5 mg/kg intravenously every 2 weeks), can improve hearing in some patients with neurofibromatosis type 2 and vestibular schwannomas. 1 Surgical treatment of schwannomas and meningiomas may be indicated to preserve function or to relieve compression of adjacent structures, especially in patients with intramedullary spinal tumors. Genetic counseling should be provided to affected individuals and their families.
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TABLE 426-3 DIAGNOSTIC CRITERIA FOR NEUROFIBROMATOSIS TYPE 2 Presence of one or more of the following makes the diagnosis of neurofibromatosis type 2: • Bilateral vestibular schwannomas • A first-degree relative with neurofibromatosis type 2, and Unilateral vestibular schwannoma, or Any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities* • Unilateral vestibular schwannoma, and Any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities* • Multiple meningiomas, and Unilateral vestibular schwannoma, or Any two of: schwannoma, glioma, neurofibroma, cataract* *“Any two of ” refers to two individual tumors or cataracts.
TABLE 426-4 DIAGNOSTIC CRITERIA FOR TUBEROUS SCLEROSIS COMPLEX Definite—Two major features or one major feature plus two minor features Probable—One major feature plus one minor feature Possible—One major feature or two or more minor features
FIGURE 426-3. Subependymal nodules and multiple cortical tubers in a patient with tuberous sclerosis.
Major features Facial angiofibromas or forehead plaque Nontraumatic ungual or periungual fibromas More than three hypomelanotic macules (ash leaf spots) Shagreen patch (connective tissue nevus) Multiple retinal nodular hamartomas Cortical tuber Subependymal nodule Subependymal giant cell astrocytoma Cardiac rhabdomyoma, single or multiple Lymphangiomyomatosis Renal angiomyolipoma Minor features Multiple dental enamel pits Hamartomatous rectal polyps Bone cysts Cerebral white matter radial migration lines Gingival fibromas Nonrenal hamartoma Retinal achromic patch “Confetti” skin lesions Multiple renal cysts
Tuberous Sclerosis Tuberous sclerosis complex is characterized by abnormalities of the brain, kidney, and heart. Tuberous sclerosis may occur as an autosomal dominant syndrome or result from spontaneous mutation. Two tuberous sclerosis genes have been identified. TSC1 (chromosome 9q34) codes for a protein called hamartin, a protein that interacts with the product of the TSC2 gene to inhibit the mammalian target of rapamycin (mTOR). TSC2 (chromosome 16p13) codes for tuberin, which interacts with hamartin. TSC2 mutations account for about 60% of individuals with clinical tuberous sclerosis. The specific findings vary across individuals, and severity ranges from minimal to severe. Skin lesions are seen in almost 100% of affected individuals, but CNS lesions are the leading cause of morbidity and mortality. Epilepsy is seen in as many as 80% of patients with CNS lesions. Intellectual impairment and developmental delay are common, and up to 40% of patients have an autism spectrum disorder. Giant cell astrocytoma is the leading cause of death. Up to 80% of children with tuberous sclerosis have an identifiable renal lesion (Chapter 203) by 10.5 years of age, and renal disease is the second leading cause of early death in individuals with tuberous sclerosis. Cardiac rhabdomyomas, which can occur in up to 50% of patients, are usually present at birth and typically regress over time. Diagnosis of tuberous sclerosis (Table 426-4) is usually clinical and confirmed by identification of calcified or uncalcified hamartomas on imaging studies (Fig. 426-3). Treatment is directed at complications of the disease, particularly epilepsy (Chapter 410). Neurosurgical intervention may sometimes be indicated for epilepsy and for symptomatic treatment of complications, such as hydrocephalus, which results from midline giant cell tumors. In a small,
FIGURE 426-4. Sturge-Weber syndrome. This patient has a classic diffuse capillary hemangioma in the distribution of the ophthalmic, nasociliary, and maxillary branches of the trigeminal nerve. The lesion extends backward over the anterior two thirds of the crown of the head. (From Forbes CD, Jackson WD. Color Atlas and Text of Clinical Medicine, 2nd ed. London: Mosby; 1996.)
nonrandomized study, treatment with sirolimus (dosed to achieve blood levels of 1 to 5 ng/mL) for 1 year reduced the size of the angiomyolipomas during the year of treatment. Rapamycin has shown promise in early investigations for treatment of giant cell astrocytomas. Serial brain MRI and renal ultrasound screening may be indicated in some patients because benign tumors of these organs may enlarge rapidly. Genetic counseling is an important part of management.
Sturge-Weber Syndrome
Sturge-Weber syndrome is a sporadic disorder characterized by facial vascular nevi, epilepsy, cognitive impairment, and sometimes hemiparesis, hemianopsia, or glaucoma. The characteristic CNS feature of this disorder is capillary angiomatosis of the pia mater. Cerebral cortical calcifications are generally seen in a pericapillary distribution and are progressive. Most patients with Sturge-Weber syndrome have epilepsy. The diagnosis is usually based on the presence of a facial nevus (Fig. 426-4), which is manifested as a typical portwine stain, and confirmatory imaging on a contrast brain MRI showing leptomeningeal enhancement. Regular ophthalmologic examination is warranted because of the risk for glaucoma. Treatment is usually aimed at the epilepsy, which can be medically
intractable. In patients with intractable epilepsy and infantile-onset hemiplegia, hemispherectomy can improve the seizures and the neurodevelopmental outcome.
Von Hippel-Lindau Disease
Von Hippel-Lindau disease (i.e., CNS angiomatosis) is an autosomal dominant disorder caused by a defective tumor suppressor gene at chromosome 3p25-p26. It is characterized by retinal angiomas, brain (usually cerebellar) and spinal cord hemangioblastomas, renal cell carcinomas, endolymphatic sac tumors, pheochromocytomas, papillary cystadenomas of the epididymis, angiomas of the liver and kidney, and cysts of the pancreas, kidney, liver, and epididymis. Both sexes are affected equally. Symptoms typically begin during the third or fourth decade. Retinal inflammation with exudate, hemorrhage, and retinal detachment from the retinal angiomas typically precedes the cerebellar complaints, but the order is not constant. The ocular findings are nonspecific, and the retinal detachment may mask the underlying lesion. Headache, vertigo, and vomiting result from cerebellar tumors. Cerebellar signs such as ataxia, dysdiadochokinesis, and dysmetria are common. Rare patients present with symptoms of spinal cord or visceral lesions, or may have hearing loss from tumors of the endolymphatic sac. Clinical diagnosis is established if the patient has more than one CNS hemangioblastoma, one hemangioblastoma with a visceral manifestation of the disease, or one manifestation of the disease and a known family history. Molecular genetic testing detects mutations in the VHL gene in nearly 100% of affected individuals. For patients with von Hippel-Lindau disease and for those with a diseasecausing VHL mutation, surveillance is recommended with annual ophthalmologic examination, annual blood pressure monitoring, measurement of urinary catecholamine metabolites beginning at age 5 years in families with pheochromocytoma, and annual abdominal ultrasound examination beginning at age 16 years with evaluation of suspicious lesions by computed tomography or MRI. Treatment is symptomatic. Retinal detachments and tumors are treated by laser therapy. Large brain tumors (Chapter 195), renal cell carcinomas (Chapter 203), pheochromocytomas (Chapter 235), epididymal tumors (Chapter 206), and endolymphatic sac tumors are treated surgically; smaller CNS tumors may be treated by gamma knife.
1. Plotkin SR, Stemmer-Rachamimov AO, Barker FG 2nd, et al. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med. 2009;361:358-367.
SUGGESTED READINGS Evans GR, Lloyd SK, Ramsden RT. Neurofibromatosis type 2. Adv Otorhinolaryngol. 2011;70:91-98. Review emphasizing the role of surgery. Ferner RE. The neurofibromatoses. Pract Neurol. 2010;10:82-93. Review. Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-call astrocytomas in tuberous sclerosis. N Eng J Med. 2010;363:1801-1811. In a nonrandomized study, oral everolimus decreased the volume of subependymal giant-cell astrocytomas and the frequency of seizures in patients with tuberous sclerosis. Nordstrom-O’Brien M, van der Luijt RB, van Rooijen E, et al. Genetic analysis of von Hippel-Lindau disease. Hum Mutat. 2010;31:521-537. Review of mutations and their clinical manifestations.
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426 CONGENITAL, DEVELOPMENTAL, AND NEUROCUTANEOUS DISORDERS JONATHAN W. MINK
CONGENITAL DISORDERS Malformations of Cerebral Cortex Developmental malformations of the cerebral cortex arise from a wide variety of etiologies, including genetic mutations, intrauterine infections, intrauterine ischemia, and toxic exposures. These malformations are heterogeneous and can result from disrupted neuronal proliferation, migration, or cortical organization. In general, disorders that arise early in development are more severe than those that arise after the basic architecture of the brain has developed. When small areas of the brain are involved, the patient may have minor impairment of neurologic function. When larger areas of the brain are involved, patients often have cognitive deficits and more severe neurologic dysfunction. Epilepsy (Chapter 410), which is the most common manifestation of abnormal cortical development, may occur with or without other neurologic signs or symptoms.
Disorders of Neuronal Proliferation
Neuronal proliferation can be abnormally increased or decreased owing to a variety of mechanisms. These disorders can manifest with megalencephaly or
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microcephaly, or head size can be normal. Abnormal proliferation can involve specific cell types, thereby resulting in focal or multifocal areas of dysplasia or in the formation of hamartomas (see Tuberous Sclerosis, later).
FOCAL CORTICAL DYSPLASIA WITH BALLOON CELLS
Focal cortical dysplasia is caused by abnormal proliferation of both neurons and glia. Its neuropathology is characterized by the presence of giant dysmorphic neurons and “balloon cells” associated with altered cortical lamination, but some lesions have abnormal cortical layering with ectopic neurons in white matter. Affected patients typically present with partial seizures that are often intractable to medical therapy. These seizures can begin at any age but most commonly present during childhood or adolescence. The type of seizure depends on the anatomic location of the dysplasia. Other neurologic manifestations, such a sensory, motor, or cognitive impairments, depend on the extent of the dysplasia and whether multiple brain regions are affected. The diagnosis of focal cortical dysplasia is usually made with brain magnetic resonance imaging (MRI), which demonstrates focal thickening of a gyrus or alteration of the gray-white matter junction. Management includes medical treatment of seizures, but surgical resection of the epileptic focus may be required for complete remission (Chapter 410).
Disorders of Neuronal Migration
Disorders of neuronal migration typically result in disruption of the normal laminar organization of the cerebral cortex. Defects include impaired initiation of neuronal migration, impaired orderly migration, and impaired termination of migration. All result in abnormal cortical organization and function.
LISSENCEPHALY AND BAND HETEROTOPIA
The lissencephalies (smooth brain) are a group of disorders that are caused by arrested migration of neurons to the cerebral cortex. Lissencephaly genes include LIS1 (chromosome 17p13.3) and DCX (chromosome Xq22), both of which are thought to be involved in the regulation of microtubule organization and function. Individuals with mutations of LIS1 typically have severe malformations that are most prominent in the posterior cerebrum. More extensive mutations in the region of LIS1 result in Miller-Dieker syndrome, a condition characterized by lissencephaly and distinctive facial features that include a prominent forehead, midface hypoplasia, low-set and abnormally shaped ears, and a small jaw. Males with DCX mutations typically have a severe lissencephaly that is most prominent in the anterior cerebrum. Lissencephaly is typically diagnosed in infancy or early childhood, usually accompanied by microcephaly, severe global developmental delay, cerebral palsy, and intractable epilepsy. Diagnosis of lissencephaly is made by brain MRI that shows a smooth cortex with minimal sulcation. Genetic testing for LIS1 and DCX is available. Management consists of seizure control, genetic counseling, and supportive care. Band heterotopia (double cortex) is a less severe form of lissencephaly that is usually seen in women with DCX mutation. Clinical manifestations of band heterotopia range from mild to severe and include seizures, intellectual disability, and developmental delay. Women with a DCX mutation are at risk of having male children with severe lissencephaly. Brain MRI demonstrates a band of gray matter underlying a nearly normal-appearing cerebral cortex. Management consists of seizure control and genetic counseling.
NODULAR HETEROTOPIA
Nodular heterotopias are characterized by nodular ectopic collections of neurons and glia in the subependyma or in the subcortical white matter. The most important form is subependymal nodular heterotopia, a condition characterized by multiple gray matter nodules in the walls of the lateral ventricles bilaterally. This X-linked condition is due to a mutation in FLNA (chromosome Xq28), which codes for filamin A, an actin-cross-linking phosphoprotein that is critical for the initiation of migration. As a result of this mutation, many neurons do not migrate out of the subventricular zone. Most affected individuals are heterozygous females. Males are severely affected and often die in infancy. Most affected females present with seizures during childhood or adolescence. Females may be intellectually normal or have mild disability. Individuals with subependymal nodular heterotopia appear to be at increased risk for aortic or carotid dissection and for cardiac valvular abnormalities. The diagnosis is based on brain MRI, which shows gray matter nodules along the walls of the lateral ventricles. Genetic testing for FLNA is available. Management consists of seizure control and genetic counseling.
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Disorders of Cortical Organization
Disorders of cortical organization include conditions such as polymicrogyria and schizencephaly. These disorders are not due to abnormal numbers of neurons or impaired migration but instead include abnormalities of gyration, sulcation, connectivity, or synaptogenesis. The best understood of these disorders are polymicrogyria and schizencephaly.
POLYMICROGYRIA
Polymicrogyria is characterized by regions of complex cortical convolutions with miniature gyri that are fused and superimposed together. Polymicrogyria is caused by failure of cortical organization as a result of in utero injury or genetic mutation; it has been associated with prenatal infections, such as cytomegalovirus, and possible vascular abnormalities, but often it is idiopathic. A single gene, GPR56 (chromosome 16q13), has been associated with bilateral frontoparietal polymicrogyria. GPR56 codes for a G protein– coupled receptor that appears to be important for human cerebral cortical development. Clinical manifestations include epilepsy, developmental delay, cerebral palsy, and intellectual disability, depending on the location and extent of the abnormality. The diagnosis of polymicrogyria is made by brain MRI. Clinical management consists of seizure management and supportive therapies.
SCHIZENCEPHALY
Schizencephaly is characterized by infolding of cortical gray matter along a hemispheric cleft near the primary cerebral fissures. It is thought to represent a more extensive injury than what leads to polymicrogyria. In most cases, the cause cannot be determined, but it has been associated with in utero insult. A rare familial form has been described, but no gene has been identified. Clinical features include developmental delay, cerebral palsy, dysarthria, and epilepsy. The clinical abnormalities are more severe with large open-lip schizencephaly and with bilateral lesions than with small unilateral closed-lip schizencephaly. Diagnosis is made by brain MRI. Management consists of seizure control and supportive therapies when indicated.
Malformations of Cerebellum and Brain Stem
Developmental abnormalities of the hindbrain are less well understood than are abnormalities of cerebral cortical development. Two of the better known and important syndromes are Joubert’s syndrome and Dandy-Walker malformation.
JOUBERT’S SYNDROME
Joubert’s syndrome is characterized by a distinctive pattern of cerebellar and brain stem developmental malformation. Four causative genes (NPHP1, CEP290, AHI1, and TMEM67 [MKS3]) together account for approximately 30% of cases. Clinical features include hypotonia, truncal ataxia, developmental delay, abnormal eye movements, and disordered breathing. The combination of signs and severity can be variable. Some individuals with Joubert’s syndrome also have retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, or hepatic fibrosis. No formal diagnostic criteria exist. The diagnosis is usually based on the combination of hypotonia in infancy with later development of ataxia, intellectual impairment, and abnormal breathing pattern, or abnormal eye movements in combination with a characteristic MRI finding known as the molar tooth sign. The molar tooth sign results from hypoplasia of the cerebellar vermis and accompanying brain stem abnormalities on axial imaging through the junction of the midbrain and pons. Genetic testing is available for the four identified genes. Management is supportive. Caffeine can be helpful for periodic hypoventilation, but some patients require tracheostomy.
DANDY-WALKER MALFORMATION
Dandy-Walker malformation is characterized by cerebellar vermis hypoplasia and cystic dilation of the fourth ventricle. Rare familial cases have been reported, but a genetic basis has not been identified. This heterogeneous disorder is usually accompanied by hypotonia, delayed motor development, and ataxia. Intellectual disability is present in about 50% of affected individuals. In some cases, hydrocephalus requires shunting. Diagnosis is based on characteristic findings on brain MRI. Treatment is supportive, with cerebrospinal fluid (CSF) shunting when indicated.
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CHAPTER 426 CONGENITAL, DEVELOPMENTAL, AND NEUROCUTANEOUS DISORDERS
growth in childhood or adolescence. However, tethered spinal cord syndrome may go undiagnosed until adulthood, when sensory and motor problems and loss of bowel and bladder control emerge. Erectile dysfunction may occur in males. Symptoms are typically progressive. Diagnosis is made with MRI, which shows a low conus medullaris (i.e., below the bottom of the L2 vertebral body) or a thickened or fat-containing filum terminale. Diminished pulsations of the spinal cord may also be seen. Treatment consists of surgical release of the tethered cord. With successful surgery, symptoms typically do not progress and may improve.
SYRINGOHYDROMYELIA
FIGURE 426-1. Chiari I malformation. A sagittal magnetic resonance image shows low, pointed cerebellar tonsils (i.e., Chiari I malformation, T) that extend to the level of C1 (black arrow) and a dilated central canal of the spinal cord (i.e., syringohydromyelia, S). (From Barkovich AJ, Kuzniecky RI. Congenital, Developmental, and Neurocutaneous Disorders. In Goldman L, Ausiello D, eds. Cecil Textbook of Medicine, 23rd ed. Philadelphia: Saunders Elsevier; 2008:2790.)
CHIARI MALFORMATIONS
Four types of Chiari malformation have been described. The most common of these are Chiari types I and II. Chiari I malformations are most often diagnosed in adulthood, whereas Chiari II malformations are associated with spina bifida and are usually diagnosed in childhood. Chiari I malformations are characterized by downward displacement of the cerebellar tonsils through the foramen magnum, often first accompanied by compression of the tonsils. Chiari I is a developmental abnormality that is thought to be congenital in most cases, even though symptoms may not present until adulthood, typically in the third or fourth decade of life. The abnormality is often asymptomatic and discovered only as an incidental finding. However, clinical manifestations can result from compression of neural structures at the cranial-cervical junction or obstruction of CSF flow. Signs and symptoms include headaches that worsen with straining or coughing, lower cranial nerve findings, downbeat nystagmus, ataxia, or long-tract signs. Chiari I malformations are accompanied by syringomyelia (see later) in up to 80% of cases. Diagnosis is made with brain MRI, which shows the cerebellar tonsils extending through the foramen magnum 5 mm or more (Fig. 426-1). Surgical treatment with craniocervical decompression is recommended for symptomatic patients but usually not for asymptomatic individuals or patients whose only symptom is headache. Chiari II malformations, commonly called Arnold-Chiari malformations, are characterized by descent of the cerebellar tonsils, the inferior vermis, and portions of the cerebellar hemispheres into the spinal canal along with elongation and displacement of the brain stem and fourth ventricle. Chiari II malformations are almost always associated with meningomyelocele and spina bifida. Hydrocephalus requiring shunting occurs in most cases. Brain stem dysfunction may result from intrinsic malformation or from compression of neural structures at the craniocervical junction. Treatment is surgical repair of the myelomeningocele, relief of hydrocephalus, and occasionally, cervical bone decompression. The prognosis depends on the level and extent of the myelomeningocele and on the severity of brain anomalies.
Malformations of Spinal Cord Tethered Spinal Cord
Tethered spinal cord syndrome is a disorder caused by an anomalous filum terminale that restricts the normal ascent of the conus medullaris and limits the movement of the spinal cord within the spinal column. The result is an abnormal stretching of the spinal cord with neurologic symptoms referable to the lower spinal cord. Tethering may also develop after spinal cord injury. Associated spinal anomalies are common and may include diastematomyelia, spinal lipomas, dermal sinuses, and fibrolipomas of the filum terminale. Symptoms can occur at any age but usually develop during periods of rapid
Syringohydromyelia is a condition in which the central canal of the spinal cord (hydromyelia) or the substance of the spinal cord (syringomyelia) is expanded by the accumulation of CSF. In many cases, both hydromyelia and syringomyelia are present (syringohydromyelia). The proximate cause of syringes probably is altered flow of CSF with variations in pressure in different parts of the subarachnoid space. The pressure variations create forces that drive CSF into the spinal cord. Possible causes include narrowing of the foramen magnum, Chiari I and II malformations, intramedullary and extramedullary spinal cord tumors, and subarachnoid scarring. Subsequent extension of the cyst may result from rapid changes in intraspinal pressure owing to such events as coughing or sneezing. Symptoms of syringohydromyelia most commonly begin in late adolescence or early adulthood and progress irregularly, with long periods of stability. The classic presentation is asymmetrical weakness and atrophy in the upper extremities, loss of upper limb deep tendon reflexes, and loss of pain and temperature sensation (with preservation of vibration and proprioception) in the neck, arms, and upper part of the trunk. With progression, spasticity and hyperreflexia develop in the lower extremities. Progressive ascending and descending levels of weakness and sensory impairment typically occur over time. The diagnosis is made by spinal MRI (see Fig. 426-1). If syringohydromyelia is identified, it is important to perform a brain MRI to look for associated abnormalities of the craniocervical junction. Occasionally, mild central canal dilation is discovered incidentally in patients without spinal cord symptoms or signs. If no associated cause is found, the prognosis of such incidentally discovered anomalies is generally good. Treatment is directed at the cause, if one can be identified. Syringopleural or syringoperitoneal shunting is sometimes performed with variable benefit.
DEVELOPMENTAL DISORDERS
Disorders that result from impaired postnatal neurodevelopmental function range from specific disorders such as fragile X syndrome and Rett’s syndrome, to complex syndromes such as autism, to nonspecific developmental delay and learning disabilities.
Fragile X Syndrome
Fragile X syndrome is an X-linked trinucleotide repeat disorder that is characterized by nonsyndromic mental retardation in most affected males. The pathogenesis of fragile X syndrome is not well understood. The classic disorder is seen in males with full mutations (>200 repeats) in the FMR1 gene. Fragile X syndrome may present as only moderate to severe mental retardation, but it is often associated with a prominent forehead, large ears, prominent jaw, and macro-orchidism. Postpubertal males often have poor impulse control, perseveration, and poor eye contact. Up to 25% of affected males have autism. Heterozygous females may be asymptomatic or may have a syndrome similar to what is seen in males, depending on repeat size and random X-inactivation. Other disorders associated with FMR1 include the fragile X ataxia syndrome, which is characterized by the late onset, usually after age 50 years, of progressive cerebellar ataxia and intention tremor in individuals who have an FMR1 premutation (60 to 200 repeats). It occurs equally in males and females. Diagnosis is by molecular genetic testing. Cytogenetic testing for fragile sites is no longer recommended because it is less sensitive and more expensive than molecular testing. Treatment is symptomatic and supportive. Genetic counseling is recommended for affected individuals and their families.
Rett’s Syndrome
Rett’s syndrome is a neurodevelopmental disorder that occurs in females with mutations in the MECP2 gene. MECP2 mutations are generally lethal in male embryos, but Rett’s syndrome has been reported in males with XXY karyotype or with somatic mosaicism. MECP2 is thought to mediate
CHAPTER 426 CONGENITAL, DEVELOPMENTAL, AND NEUROCUTANEOUS DISORDERS
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transcriptional silencing of methylated DNA. Most mutations are probably de novo or may reflect germline mosaicism; 99% of cases represent a single occurrence within a family. Affected girls are usually normal at birth and have apparently normal development for the first 6 to 18 months of life. Brain growth decelerates, and development stagnates, followed by rapid regression of language and motor skills. A classic feature of Rett’s syndrome is the loss of purposeful hand use and the development of repetitive stereotyped hand movements that usually have the appearance of wringing or clapping. Other features present to variable degree are bruxism, episodic apnea and hyperpnea, seizures, gait disorders, and tremor. Non-neurologic features include growth failure and wasting, bowel dysmotility, scoliosis, osteopenia, and vasomotor changes in the limbs. Diagnosis is by molecular genetic methods. Treatment is symptomatic.
Autism
Autism is a neurodevelopmental syndrome characterized by impaired communication, impaired social interaction, and restricted interests or repetitive behaviors. Fragile X syndrome and tuberous sclerosis are two important entities in which an autistic phenotype can occur and in which autism may be the most prominent feature. Symptoms typically present before 3 years of age and persist into adulthood. Autism is a spectrum ranging from severe, with impairment in all domains, to mild with normal intellect and language but with impaired social interactions and repetitive behaviors or restricted interests. Autism has many causes but in most cases is idiopathic. Epilepsy is common in autism. Diagnosis is based on careful diagnostic interview and examination. When epilepsy is present, treatment with antiepileptic medications is indicated. Behavioral therapy can help individuals learn rules for social interaction and can improve communication. It can also help with problematic behavior. Educational support is important. Medications such as atypical antipsychotics, selective serotonin reuptake inhibitors, and anxiolytics (Chapter 404) can help with aggressive behavior, repetitive behaviors, and anxiety.
FIGURE 426-2. Multiple neurofibromas covering the back of a patient with neurofibromatosis type 1.
TABLE 426-1 DIAGNOSTIC CRITERIA FOR NEUROFIBROMATOSIS TYPE 1 Two or more of the following clinical features signify the presence of neurofibromatosis type 1: Six or more cafe au lait macules (>0.5 cm at largest diameter in prepubertal individuals or >1.5 cm in individuals past puberty) Axillary freckling or freckling in inguinal regions Two or more neurofibromas of any type or ≥1 plexiform neurofibroma Two or more Lisch nodules (iris hamartomas) A distinctive osseous lesion A first-degree relative with neurofibromatosis type 1 diagnosed by using the above-listed criteria
NEUROCUTANEOUS DISORDERS
Neurocutaneous disorders are congenital syndromes characterized by dysplastic and neoplastic lesions primarily involving the nervous system and skin. The more than 40 described syndromes include neurofibromatosis, tuberous sclerosis, Sturge-Weber syndrome, and von Hippel-Lindau disease.
Neurofibromatosis
Neurofibromatosis encompasses a spectrum of syndromes with distinctive neural and cutaneous lesions. The two major forms of neurofibromatosis are genetically and clinically distinct.
NEUROFIBROMATOSIS TYPE 1
Neurofibromatosis type 1, which is the classic disorder described by von Recklinghausen, is an autosomal dominant condition with an incidence of 1 per 2500 to 3000 births. Although it is an autosomal dominant disease, approximately 50% of cases are due to new mutations. Most mutations in NF1 occur in the parental germline. The NF1 gene, which is located on chromosome 17q11.2, codes a protein called neurofibromin, which is thought to function as a tumor suppressor by acting as a negative regulator of the Ras signaling pathway. Neurofibromatosis type 1 is characterized by multiple cafe au lait spots, axillary and inguinal freckling, multiple discrete cutaneous neurofibromas (Fig. 426-2), and Lisch nodules (Table 426-1). Subcutaneous neurofibromas may be painful or disfiguring. Learning disabilities are present in at least 50% of individuals. Other manifestations include plexiform neurofibromas, optic nerve and other central nervous system (CNS) gliomas, malignant peripheral nerve sheath tumors, tibial dysplasia, and vasculopathy. Management of patients depends on the specific manifestations and often requires multidisciplinary collaboration. Most patients with neurofibromatosis type 1 do not require treatment, but all require surveillance (Table 426-2). Subcutaneous, intraspinal, and intracranial tumors can be treated surgically. Optic nerve gliomas may be treated with chemotherapy; both cisplatin and temozolomide have shown some benefit. Radiation is not recommended. Genetic counseling should be provided to all patients and their families.
NEUROFIBROMATOSIS TYPE 2
Neurofibromatosis type 2, which is often referred to as central neurofibromatosis, is an autosomal dominant condition with an incidence of approximately 1 in 25,000 individuals. The NF2 gene is located on chromosome 22q12.2. Its gene product, merlin, is cytoskeletal protein that is thought to act as a
TABLE 426-2 RECOMMENDED SURVEILLANCE IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 1 Annual physical examination by a physician who is familiar with the individual and with the disease Annual ophthalmologic examination in early childhood, less frequent examination in older children and adults Regular developmental assessment by screening questionnaire (in childhood) Regular blood pressure monitoring Other studies only as indicated on the basis of clinically apparent signs or symptoms Monitoring of those who have abnormalities of the central nervous system, skeletal system, or cardiovascular system by an appropriate specialist
membrane-stabilizing protein. The specific function of merlin is unknown. Neurofibromatosis type 2 is characterized by bilateral vestibular schwannomas, which usually present with symptoms of tinnitus, hearing loss, and imbalance. The age at onset is usually in young adulthood, but some individuals may develop posterior subcapsular lens opacities or mono-neuropathy in childhood. Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years (Table 426-3). Affected individuals may also develop schwannomas of other cranial and peripheral nerves, meningiomas, and, rarely, ependymomas or astrocytomas. Posterior subcapsular lens opacities are the most common ocular abnormality. Management is dependent on the specific manifestations and complications. In individuals who either have tested positive for known NF2 mutations or have a family history of neurofibromatosis type 2 and whose genetic status cannot be determined with genetic testing, annual brain MRI is recommended starting between ages 10 and 12 years and continuing until at least age 40 years. Hearing evaluations may be useful in detecting changes in auditory nerve function before changes can be visualized by MRI. Routine complete eye examinations should be part of the care of all individuals. Bevacizumab, a vascular endothelial growth factor inhibitor (5 mg/kg intravenously every 2 weeks), can improve hearing in some patients with neurofibromatosis type 2 and vestibular schwannomas. 1 Surgical treatment of schwannomas and meningiomas may be indicated to preserve function or to relieve compression of adjacent structures, especially in patients with intramedullary spinal tumors. Genetic counseling should be provided to affected individuals and their families.
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TABLE 426-3 DIAGNOSTIC CRITERIA FOR NEUROFIBROMATOSIS TYPE 2 Presence of one or more of the following makes the diagnosis of neurofibromatosis type 2: • Bilateral vestibular schwannomas • A first-degree relative with neurofibromatosis type 2, and Unilateral vestibular schwannoma, or Any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities* • Unilateral vestibular schwannoma, and Any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities* • Multiple meningiomas, and Unilateral vestibular schwannoma, or Any two of: schwannoma, glioma, neurofibroma, cataract* *“Any two of ” refers to two individual tumors or cataracts.
TABLE 426-4 DIAGNOSTIC CRITERIA FOR TUBEROUS SCLEROSIS COMPLEX Definite—Two major features or one major feature plus two minor features Probable—One major feature plus one minor feature Possible—One major feature or two or more minor features
FIGURE 426-3. Subependymal nodules and multiple cortical tubers in a patient with tuberous sclerosis.
Major features Facial angiofibromas or forehead plaque Nontraumatic ungual or periungual fibromas More than three hypomelanotic macules (ash leaf spots) Shagreen patch (connective tissue nevus) Multiple retinal nodular hamartomas Cortical tuber Subependymal nodule Subependymal giant cell astrocytoma Cardiac rhabdomyoma, single or multiple Lymphangiomyomatosis Renal angiomyolipoma Minor features Multiple dental enamel pits Hamartomatous rectal polyps Bone cysts Cerebral white matter radial migration lines Gingival fibromas Nonrenal hamartoma Retinal achromic patch “Confetti” skin lesions Multiple renal cysts
Tuberous Sclerosis Tuberous sclerosis complex is characterized by abnormalities of the brain, kidney, and heart. Tuberous sclerosis may occur as an autosomal dominant syndrome or result from spontaneous mutation. Two tuberous sclerosis genes have been identified. TSC1 (chromosome 9q34) codes for a protein called hamartin, a protein that interacts with the product of the TSC2 gene to inhibit the mammalian target of rapamycin (mTOR). TSC2 (chromosome 16p13) codes for tuberin, which interacts with hamartin. TSC2 mutations account for about 60% of individuals with clinical tuberous sclerosis. The specific findings vary across individuals, and severity ranges from minimal to severe. Skin lesions are seen in almost 100% of affected individuals, but CNS lesions are the leading cause of morbidity and mortality. Epilepsy is seen in as many as 80% of patients with CNS lesions. Intellectual impairment and developmental delay are common, and up to 40% of patients have an autism spectrum disorder. Giant cell astrocytoma is the leading cause of death. Up to 80% of children with tuberous sclerosis have an identifiable renal lesion (Chapter 203) by 10.5 years of age, and renal disease is the second leading cause of early death in individuals with tuberous sclerosis. Cardiac rhabdomyomas, which can occur in up to 50% of patients, are usually present at birth and typically regress over time. Diagnosis of tuberous sclerosis (Table 426-4) is usually clinical and confirmed by identification of calcified or uncalcified hamartomas on imaging studies (Fig. 426-3). Treatment is directed at complications of the disease, particularly epilepsy (Chapter 410). Neurosurgical intervention may sometimes be indicated for epilepsy and for symptomatic treatment of complications, such as hydrocephalus, which results from midline giant cell tumors. In a small,
FIGURE 426-4. Sturge-Weber syndrome. This patient has a classic diffuse capillary hemangioma in the distribution of the ophthalmic, nasociliary, and maxillary branches of the trigeminal nerve. The lesion extends backward over the anterior two thirds of the crown of the head. (From Forbes CD, Jackson WD. Color Atlas and Text of Clinical Medicine, 2nd ed. London: Mosby; 1996.)
nonrandomized study, treatment with sirolimus (dosed to achieve blood levels of 1 to 5 ng/mL) for 1 year reduced the size of the angiomyolipomas during the year of treatment. Rapamycin has shown promise in early investigations for treatment of giant cell astrocytomas. Serial brain MRI and renal ultrasound screening may be indicated in some patients because benign tumors of these organs may enlarge rapidly. Genetic counseling is an important part of management.
Sturge-Weber Syndrome
Sturge-Weber syndrome is a sporadic disorder characterized by facial vascular nevi, epilepsy, cognitive impairment, and sometimes hemiparesis, hemianopsia, or glaucoma. The characteristic CNS feature of this disorder is capillary angiomatosis of the pia mater. Cerebral cortical calcifications are generally seen in a pericapillary distribution and are progressive. Most patients with Sturge-Weber syndrome have epilepsy. The diagnosis is usually based on the presence of a facial nevus (Fig. 426-4), which is manifested as a typical portwine stain, and confirmatory imaging on a contrast brain MRI showing leptomeningeal enhancement. Regular ophthalmologic examination is warranted because of the risk for glaucoma. Treatment is usually aimed at the epilepsy, which can be medically
intractable. In patients with intractable epilepsy and infantile-onset hemiplegia, hemispherectomy can improve the seizures and the neurodevelopmental outcome.
Von Hippel-Lindau Disease
Von Hippel-Lindau disease (i.e., CNS angiomatosis) is an autosomal dominant disorder caused by a defective tumor suppressor gene at chromosome 3p25-p26. It is characterized by retinal angiomas, brain (usually cerebellar) and spinal cord hemangioblastomas, renal cell carcinomas, endolymphatic sac tumors, pheochromocytomas, papillary cystadenomas of the epididymis, angiomas of the liver and kidney, and cysts of the pancreas, kidney, liver, and epididymis. Both sexes are affected equally. Symptoms typically begin during the third or fourth decade. Retinal inflammation with exudate, hemorrhage, and retinal detachment from the retinal angiomas typically precedes the cerebellar complaints, but the order is not constant. The ocular findings are nonspecific, and the retinal detachment may mask the underlying lesion. Headache, vertigo, and vomiting result from cerebellar tumors. Cerebellar signs such as ataxia, dysdiadochokinesis, and dysmetria are common. Rare patients present with symptoms of spinal cord or visceral lesions, or may have hearing loss from tumors of the endolymphatic sac. Clinical diagnosis is established if the patient has more than one CNS hemangioblastoma, one hemangioblastoma with a visceral manifestation of the disease, or one manifestation of the disease and a known family history. Molecular genetic testing detects mutations in the VHL gene in nearly 100% of affected individuals. For patients with von Hippel-Lindau disease and for those with a diseasecausing VHL mutation, surveillance is recommended with annual ophthalmologic examination, annual blood pressure monitoring, measurement of urinary catecholamine metabolites beginning at age 5 years in families with pheochromocytoma, and annual abdominal ultrasound examination beginning at age 16 years with evaluation of suspicious lesions by computed tomography or MRI. Treatment is symptomatic. Retinal detachments and tumors are treated by laser therapy. Large brain tumors (Chapter 195), renal cell carcinomas (Chapter 203), pheochromocytomas (Chapter 235), epididymal tumors (Chapter 206), and endolymphatic sac tumors are treated surgically; smaller CNS tumors may be treated by gamma knife.
1. Plotkin SR, Stemmer-Rachamimov AO, Barker FG 2nd, et al. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med. 2009;361:358-367.
SUGGESTED READINGS Evans GR, Lloyd SK, Ramsden RT. Neurofibromatosis type 2. Adv Otorhinolaryngol. 2011;70:91-98. Review emphasizing the role of surgery. Ferner RE. The neurofibromatoses. Pract Neurol. 2010;10:82-93. Review. Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-call astrocytomas in tuberous sclerosis. N Eng J Med. 2010;363:1801-1811. In a nonrandomized study, oral everolimus decreased the volume of subependymal giant-cell astrocytomas and the frequency of seizures in patients with tuberous sclerosis. Nordstrom-O’Brien M, van der Luijt RB, van Rooijen E, et al. Genetic analysis of von Hippel-Lindau disease. Hum Mutat. 2010;31:521-537. Review of mutations and their clinical manifestations.