Child Neurology
7th Edition
© 2006 Lippincott Williams & Wilkins
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Chapter 12
Neurocutaneous Syndromes
Bernard L. Maria
John H. Menkes
The neurocutaneous syndromes are marked by the conjoined abnormalities of skin and nervous system. The term phakomatoses (phakomatosis from fakos, Greek for lentil) is reserved for a group of diseases in which the subject is predisposed to tumors of the skin, nervous system, and other organs. The major entities included among the phakomatoses are the neurofibromatoses, tuberous sclerosis (TS), Sturge-Weber syndrome (SWS), von Hippel–Lindau disease, ataxia-telangiectasia (AT), and hypomelanosis of Ito (HI).
Additionally, numerous other conditions exist, many of uncertain heredity and some extremely rare, in which abnormalities of skin are linked with those of the nervous system. These are detailed in a book edited by Gomez (1).
Though a common pathogenesis of all neurocutaneous syndromes has eluded investigators for a century because the various diseases in this category have very different clinical presentations, genetic transmissions, and pathological findings, a unifying etiology has recently been proposed. This suggests that all neurocutaneous syndromes are disorders of neural crest (i.e., neurocristopathies) that can affect all three primitive germ layers. The known genes that regulate neural crest formation, migration or terminal differentiation also serve as tumor-suppressor genes (e.g., NF1, TSC1,2), hence the high incidence of neoplasms, both benign and malignant, in these diseases (1a).
NEUROFIBROMATOSIS (VON RECKLINGHAUSEN DISEASE)
No longer considered to be a single disorder, neurofibromatosis has been divided into at least two genetically distinct forms. The common form, once known as peripheral neurofibromatosis, is called neurofibromatosis 1(NF1). The other, rarer form, once termed central neurofibromatosis, is now called neurofibromatosis 2(NF2). Additionally, several authorities distinguish segmental neurofibromatosis, in which the features of NF1 are confined to one part of the body; spinal neurofibromatosis, characterized by the late appearance of spinal cord tumors; and a condition marked by autosomal dominant café au lait spots. Oh and colleagues have recently reported that a subset of patients may meet diagnostic criteria for both NF1 and NF2 (2).
Neurofibromatosis 1
NF1 is characterized by multiple tumors within the central and peripheral nervous systems, cutaneous pigmentation, and lesions of the vascular system and viscera. Additionally, a tendency exists for a variety of tissues to undergo malignant transformation. Although it was described initially in the eighteenth century, and more succinctly in 1849 by Smith (3), von Recklinghausen in 1882 first combined the various features of the condition and termed it neurofibromatosis (4). The disease occurs in approximately 2 to 3 per 10,000 live births and is transmitted as a dominant trait with variable expression but virtually complete penetrance by the age of 5 years (5). It is the most common single-gene defect to affect the nervous system. Approximately one-half of the cases appear to be sporadic, and the mutation rate has been estimated at 1 in 10,000 gametes per generation, one of the highest mutation rates in humans (6). Stephens and coworkers found that 93% of new mutations were in the paternally derived chromosome (7). For as yet unknown reasons, no parental age effect occurs. As determined by linkage analysis and translocation breakpoints, the gene for NF1 is located on the long arm of chromosome 17, near the centromere (q11.2). It has been cloned and consists of 60 exons that are spread out over 350 kb of genomic DNA and gives rise to three alternative-spliced messenger RNA transcripts (8,9). NF1 is heterogeneous at the mutation level, with more than 300 independent mutations having been reported (10). The gene encodes a cytoplasmic protein, named neurofibromin, which contains a 2818 amino acid segment whose only demonstrated function is down-regulation of the Ras signal transduction. The peptide domain encoded by exons 21 to 27 activates the intrinsic guanosine triphosphatase of Ras proteins (N-, K-, and H-ras), which leads to hydrolysis of bound guanosine triphosphate and inactivation of downstream signaling. Neurofibromin inactivates the
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tumor gene p21ras by stimulating its GTPase activity and converting the active form of p21ras into its inactive form. Inasmuch as the active form of p21ras is a specific growth regulator for astrocytes, the NF1 gene functions as a tumor-suppressor gene (11,12,13). This is confirmed by the observation that loss of NF1 gene expression occurs in at least some neurofibroma, in neurosarcoma, and in leukemic cells derived from NF1 subjects (11,14,15). Neurofibromin also has been shown to be associated with cytoplasmic microtubules in the brain and is believed to be involved in signaling within the central nervous system (CNS).
The NF1 gene is large and is intrinsically hypermutable; more than 300 mutations have been described, and only rarely has the same mutation been identified in unrelated patients. Mutations include large deletions seen in 7.5% to 17% of patients (16,17), frame shifts, stop mutations, and point mutations. The majority (60% to 70%) of mutations result in the formation of truncated and nonfunctioning neurofibromin. Somatic mosaicism is fairly common; its exact frequency has not been ascertained (16). NF1 gene expression is complex and is modulated post-transcriptionally by numerous alternative splicings and RNA editing (18). Some of the alternative transcripts lack tumor suppressor activity and are developmentally regulated. Their role in producing the clinical phenotype of NF1 is not understood (9,18,19).
It, therefore, comes as no surprise that there is much variability in the expression of NF1, even within the same family. Since the NF1 gene was cloned in 1990, two major pathogenetic mechanisms have been considered: (a) loss of NF1 function as a tumor suppressor gene, and (b) heterozygous mutation of the gene leads to haploinsufficiency of the gene product (20). A detailed review of the pathogenesis is beyond the scope of this text. The interested reader is referred to a chapter by Huson and Korf (5).
Correlation between the genetic mutation and the clinical expression is still poor. However, a significant proportion of subjects with severe manifestations, including dysmorphic features, have large deletions in the NF1 gene (21).
Pathology
The most striking neuropathologic feature of neurofibromatosis 1 is the presence of tumors along the major peripheral nerves, with the ulnar and radial nerves being involved most frequently. Neurofibromas are the most common tumor type, but schwannomas also can be seen. Tumors that are prone to develop within the CNS include primarily optic gliomas; pilocytic astrocytomas of the third ventricle, cerebellum, and spinal cord; and high-grade astrocytomas (22,23). Additionally, neurofibromatosis has been associated with a number of other neoplastic processes with a greater than random frequency (24). These include leukemia, Wilms tumor, neuroblastoma, and pheochromocytoma (25). A syndrome of multiple endocrine neoplasia characterized by bilateral pheochromocytomas, medullary thyroid carcinoma, and multiple neuromas and café au lait lesions has been delineated (26). Although generally benign, both central and peripheral neurofibromas can undergo malignant degeneration. This is particularly likely to occur with the plexiform neurofibroma, for which the risk for malignant transformation to neurofibrosarcoma has been estimated at 5% (27).
Clinical Manifestations
NF1 is a progressive disease process that can affect almost every organ. When many peripheral lesions are present, few lesions tend to be within the CNS. The reverse also is true (28).
The most common skin lesions are the café au lait spots. These are numerous light brown areas, usually located over the trunk, with smooth, well-defined borders and uniform pigmentation. They are seen in virtually every patient with NF1, and they result from an aggregation of neural crest-derived pigmented melanoblasts in the basal layer of the epidermis (5). They are present at birth, and their number and size increase until puberty. According to Crowe and associates, at least six such lesions are necessary for a diagnosis of NF1 (29). There is no correlation between the number of spots and the severity of the NF1. Less frequent are diffuse freckling, freckling in the armpits and groin that tends to begin between 3 and 5 years of age, and large areas of faintly increased pigmentation (melanoderma). Although usually present before the onset of neurologic symptoms, these pigmentary abnormalities are not striking during infancy but intensify with age, particularly after puberty.
Various types of cutaneous tumors can be found (Fig. 12.1). The most characteristic for NF1 is the pedunculated molluscum fibrosum and the subcutaneous neurofibromas. The latter consist of an overgrowth of Schwann cells admixed with tortuous nerve fibers and perineural fibroblasts. The number of neurofibromas is highly variable, and they are located singly or in groups along nerve trunks. Generally, cutaneous tumors tend to enlarge slowly throughout life, and they occur at an unpredictable rate (20). Plexiform neurofibromas can occur in all affected tissues and lead to exophthalmos, or defects of the skull and orbit, or hypertrophy of one or more extremity, sometimes with overlying hyperpigmentation. Plexiform neurofibromas can be quite extensive and infiltrative and can be associated with soft tissue overgrowth. There is a risk that a neurofibroma will transform into a malignant peripheral nerve sheath tumor, which is associated with anaplastic changes and multiple mitoses. The lifetime risk for malignant peripheral nerve sheath tumor is estimated to be 5 to 10% (30).
Multiple nodules within the iris (iris hamartomas) (Fig. 12.2) were first described by Lisch (31). Lisch nodules are seen in almost all affected individuals aged 21 or more
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years, but only in one-half of children aged 5 to 6 years (32). Initially light colored, these melanocytic hamartomas become darker with time. They do not affect vision, but they are helpful diagnostic markers (32).
FIGURE 12.1. Lisch nodules of iris (L). (Courtesy of Dr. Bronwyn Bateman, Department of Ophthalmology, University of Colorado School of Medicine, Denver.)
Short stature is common. It was seen in 31.5% of patients in the series of Huson and Korf (5). In some children, a number of risk factors, including suprasellar lesions and skeletal deformities are responsible. In addition, growth hormone deficiency can be common; Vassilopoulou-Sellin and coworkers found defective growth hormone levels in 79% of children who had no obvious medical or radiologic lesions to account for their short stature (33).
Macrocephaly is common, and 16% of children in Riccardi’s series (27), 45% of children in the series of Huson and Korf (5), and 38% of children in Young and coworkers (35) series had a head circumference at or above the 98th percentile (34). Only rarely is there associated hydrocephalus, typically owing to aqueductal stenosis. Various skeletal abnormalities not associated with tumors have been described. The most common location for dysplasia of a long bone is the tibia, although other long bones can be affected (36). Low cervical or thoracic kyphoscoliosis can result in a narrow angulation of the spine that may require surgery in 5% of patients (35,37). Scoliosis was noted in 32% of children in the series of Holt, and its incidence increases with age (38). Less commonly, one observes scalloping of the posterior portion of the vertebral bodies. This scalloping is caused by a dural ectasia, the
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consequence of congenital weakness of the dura and the resulting pressure on the vertebral bodies. Anterior and lateral meningoceles, which are more common in adults, also result from the dural weakness. Bony rarefactions, the consequence of subperiosteal neurofibromas, can arise within the spine, the pelvis, particularly the iliac wings, or the skull. These rarefactions can induce pathologic fractures. Bony overgrowth, often with contiguous elephantiasis, is seen in approximately 10% of patients. Radiographic findings are reviewed by Holt (38), Klatte and coworkers (39) and Ippolito and coworkers (40).
FIGURE 12.2. Neurofibromatosis. Posterior view demonstrating various types of cutaneous tumors. These include the pedunculated molluscum fibrosum and subcutaneous neurofibromas. Note the area of hyperpigmentation of the right elbow and a typical café au lait lesion. (Courtesy of Dr. V. M. Riccardi, Neurofibromatosis Institute, La Crescenta, CA.)
Headache is common in children with NF1 and usually occurs in the absence of structural lesions (41). Severe migrainelike headache occurs in 20% to 25% of children with NF1, but because of the risk of CNS tumors, prompt neuroimaging with MRI is warranted. Hypertension can develop owing to the presence of a pheochromocytoma, which is seen in 1% to 4% of subjects. It also can be the result of renal artery stenosis, the most common of a variety of arterial abnormalities seen in neurofibromatosis (42,43). The microscopic picture of these arterial abnormalities is one of an intense subintimal proliferation of the spindle cells, which are believed to be of Schwann cell origin. Congenital heart disease has been reported in NF1 as well.
Neurologic manifestations can be grouped into five major categories (44,45).
Cognitive Disabilities
Although as many as 30% to 60% of children with neurofibromatosis have learning disabilities, only a small proportion are severely retarded (27,34,46). Thus, in the series of Ferner and colleagues, only 8% of patients with NF1 had an IQ below 70 (47). All studies designed to investigate the cognitive deficits of NF1 subjects have shown a significant lowering in full-scale IQ when compared with unaffected siblings. As a rule, children tend to do better on verbal tasks rather than performance tasks and show deficits in visuospatial areas, attention, short-term memory, and reading (47,48). Both nonverbal and verbal learning problems occur, and the children may be easily distractible and poorly organized (49). Mental retardation is only slightly more common in patients with NF1 than in the general population (4% to 8%) (46). These deficits are believed to result from cortical heterotopias and other malformations of cerebral architecture such as glial nodules and other hamartomatous lesions (50) as well as from the presence of abnormal myelin. Studies conducted by Costa and Silva suggest that learning disabilities associated with NF1 are associated with excessive Ras activity that leads to increased γ-aminobutyric acid (GABA) inhibition and to decreased long-term potentiation (51).
Malformations have been demonstrated by magnetic resonance imaging (MRI) as small focal areas of increased signal (unidentified bright objects—UBOs) on T2-weighted scans in 60% to 70% of patients with neurofibromatosis (35,52). Areas of increased signal (isointense on T1-weighted images) are located with particular frequency in the globus pallidus, brainstem, optic tracts, thalamus, and cerebellum (53,53a). They exert no mass effect, do not enhance with contrast, and are not visible on CT scan; they are asymptomatic and unrelated to the presence of macrocephaly. UBOs tend to diminish or disappear over the years and are rare in subjects older than 30 years of age. In the experience of DiMario and Ramsby, lesions in the basal ganglia and cerebellum decrease in size and number over time, whereas lesions in the brainstem tended to increase in both number and size (54). Pathologic studies suggest that these hyper-intense areas on MRI may represent dysmyelination or increased water content in the brain. Jurkiewicz and colleagues have shown that proton magnetic resonance spectroscopy may distinguish UBOs from astrocytomas in NF1 (55). Studies present conflicting data as to whether the number of abnormalities seen on MRI correlate with the severity of cognitive deficits (49,56). The most recent series, published in 2003 by Feldmann and colleagues, suggest that as a rule, patients with focal areas of increased signal on T2-weighted MRI studies do worse on cognitive and fine motor performance than NF-1 patients who do not show these lesions (56a). When lesions are seen in the brainstem, they should not be confused with a neoplasm (50).
Intracranial Tumors
Children with NF1 are at risk for optic pathway gliomas and brainstem gliomas. In addition, there appears to be an increased risk for the occurrence of benign and malignant neoplasms in other locations (the cerebrum or cerebellum), ependymomas, meningiomas, PNET/MBs, and malignant schwannomas arising from the cranial nerves (57).
Optic Pathway Gliomas.
Intracranial tumors can arise at any time of life, the optic pathway being the most common and the earliest site of involvement (58). In the series of Holt, optic pathway gliomas were found in 23% of children with neurofibromatosis (38). This compares with an incidence of 15% in the series of Huson and Korf (5) 20% in the series of Poyhonen (58a), and 19% in the series of Listernick and colleagues (59). The tumor is benign and histologically corresponds to a pilocytic astrocytoma. It is more common in girls, with a female to male ratio of 2:1 (59). Approximately one-half of patients who harbor optic pathway tumors develop signs or symptoms, and the tumor can involve any portion of the optic pathway (60). Bilateral optic nerve gliomas are seen almost exclusively in NF1 (61). Although optic pathway gliomas are an incidental finding in the majority of children with NF1, these neoplasms occasionally enlarge to distort and compress local structures, causing decreased visual acuity, visual field cuts, afferent papillary defect, decreased color vision, proptosis, strabismus, papilledema, optic nerve atrophy, and optic disk pallor. Precocious puberty is seen in
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approximately 40% of subjects and results from compression of the hypothalamus and interference with the tonic central nervous system inhibition of the hypothalamic-pituitary-gonadal axis. The presence of precocious puberty in a child with NF1, therefore, should always arouse the suspicion of an enlarging chiasmatic glioma. The diencephalic syndrome also may be seen but is much more common in hypothalamic tumors in patients without NF1 (62).
Decreased visual acuity is rarely a presenting complaint in children, even though it can be demonstrated by examination. The natural history of these optic pathway tumors in subjects with NF1 is not known, and their growth rate differs considerably from one patient to the next. In the series of Listernick and colleagues (59), no tumor growth was seen as determined by MRI over a mean interval of 2.4 years. Only a small proportion of intraorbital tumors progress, whereas tumors that involve the optic chiasm are more likely to progress. The consensus statement from the NF1 Optic Pathway Glioma Task Force has concluded that MRI screening of children with NF1 for optic pathway gliomas has only limited value, and even though asymptomatic tumors are often found, these only rarely progress. Riccardi believes that if an MRI study does not demonstrate an optic glioma by one year of age, these studies will remain negative (62a). Optic pathway gliomas also have been noted to spontaneously regress in patients with and without NF1, providing further evidence of their benign nature. Serial visual acuity examinations in asymptomatic children with NF1 under age 6 years and in symptomatic children are preferable and less costly than repeated MRIs. Accelerated linear growth or the appearance of premature secondary sexual characteristics should prompt an immediate work-up. Listernick and colleagues recommend that even for stable lesions, an MRI should be performed at 3, 9, 15, 24, and 36 months after diagnosis. Ophthalmologic exams should be performed at 3, 6, 12, 18, 24, and 36 months (63).
It is unusual for optic pathway gliomas to become aggressive, and tumors may even regress though they are symptomatic. One must carefully weigh the risks and benefits of any intervention in these children, attempting to preserve visual function while causing the least amount of harm. Treatment options include surgery, radiation, and chemotherapy, alone or in combination (23). The benefits of radical versus conservative surgery in these tumors have been debated in the literature (64). Radiotherapy has been shown to halt tumor progression, but there has been concern that it could transform the tumor to a higher-grade glioma and cause a vasculopathy (63). Reservations regarding the dangers of surgical resection and the potential toxicities of radiation therapy have led to the use of chemotherapy in progressive chiasmatic/hypothalamic gliomas, as reviewed by Rosser and Packer (23).
Focal or generalized seizures can appear early in childhood and were seen in 7% of patients in the series of Huson and Korf (5). Some of these patients had an electroencephalographic picture consistent with hypsarrhythmia. Because a significant proportion of patients with seizures and neurofibromatosis are ultimately found to have intracranial tumors, a child with cutaneous neurofibromatosis and seizures should be suspected of harboring a tumor and should receive imaging studies.
Brainstem Gliomas.
The true incidence of brainstem gliomas in NF1 is difficult to estimate because they are often mistaken for brainstem and cerebellar UBOs (65). Brainstem gliomas in NF1 cause neurologic symptoms such as headaches, hydrocephalus, and cranial neuropathies in 88% of patients. The medulla represents the primary tumor site in 80% of patients. Patients may require cerebrospinal fluid diversion, but unlike brainstem glioma in non-NF1 patients, radiotherapy or chemotherapy is rarely required. In fact, such tumors behave much like optic pathway gliomas in NF1 in that they have a relatively benign course and can regress spontaneously after becoming symptomatic. Pollack and colleagues reviewed the course of 21 children (mean age 9.5 years) with NF1 and brainstem gliomas (66). Twelve patients (57%) had clinically symptomatic lesions, with cranial neuropathies and hydrocephalus as most common symptoms. Only 4 children required specific intervention such as biopsy, resection, or adjuvant radiation. All children were alive at the time of the report, and radiographic progression was seen in only 9 children (3 clinically deteriorated).
Tumors of the Peripheral Nerves
Tumors of the peripheral nerves can arise at any age and can involve any of the major nerves. Even though these tumors are occasionally painful, surgical removal must be weighed carefully against the possibility of the procedure producing considerable neurologic deficit. Malignant degeneration of neurofibromas occurs in less than 3% of children, but appears more frequently in adults (27). Tumors also can arise within the autonomic nerve supply of various viscera. According to Kissel and Schmitt, the stomach, tongue, mediastinum, large intestines, and adrenal medulla are the most common sites (67). Treatment options for patients with progressive plexiform neurofibromas have been limited, with surgery as the only proven modality. Trials that have evaluated antihistamines, maturation agents, and antiangiogenic agents have had mixed results that are difficult to interpret, and therapy is moving toward a more biologically based approach (68).
Intraspinal Tumors
Intraspinal tumors are generally slower to develop than intracranial tumors, and asymptomatic spinal cord tumors are commonly detected on routine neuroimaging studies. The youngest patient with a symptomatic intraspinal tumor in Canale’s series was 20 years of age (44). Approximately one-half of intraspinal tumors are multiple, and occasionally, they are accompanied by malformations
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such as syringomyelia. Familial spinal neurofibromatosis is a variant of NF1. The condition is marked by the development of multiple spinal cord tumors during adult life (67,69,70).
TABLE 12.1 Neurological Complications in Patients with NF-1
Complication Incidence (%)
Educational difficulties 62
Cutaneous neurofibroma 59
High signals on T2 MRI 54
Macrocephaly (≥2 SD) 29
Optic gliomas (ascertained by neuroimaging) 20
Plexiform neurofibroma 15
Epilepsy 5.6
Spinal neurofibroma 5.0
Visceral neurofibroma 3.0
Astrocytomas 1.5
Other CNS tumors 4.0
Aqueductal stenosis 1.2
Vestibular schwannoma 0
SD = standard deviation.
After Pyhonen (58a), and McGaughran et al. (72a).
Cerebral Infarction
Cerebral infarctions are common and can be responsible for the abrupt evolution of neurologic signs. They result from cerebrovascular occlusive disease and most commonly affect the supraclinoid portion of the internal carotid artery or one of its major branches (71,72). More than one-half of the patients with occlusive disease of the internal carotid have the arteriographic picture of moyamoya disease (71,72).
The incidence of some of the neurologic complications encountered in NF1 and NF2 is presented in Table 12.1 (58a,72a).
Several conditions are related to NF1. Watson syndrome—characterized by dominantly transmitted pulmonary valve stenosis, café au lait spots, and low to normal intelligence—is believed to be allelic with NF1 (73). The concurrence of Noonan syndrome with NF1 may represent either a contiguous gene syndrome or the coincidental segregation of two autosomal dominant conditions (see Chapter 4 (73a)).
Diagnosis
Despite the advances in understanding the molecular biology for NF1 and NF2, the diagnosis for both conditions is still largely based on clinical criteria. The diagnosis of NF1 cannot be made with certainty before 1 year of age in almost half of affected children with a negative family history (74). The appearance of most signs of NF1 is age dependent, and reliability of diagnostic criteria improves as the child grows older (75). At this time, expert consensus does not support the use of UBOs as a diagnostic criterion because adding it the the National Institutes of Health (NIH) Diagnostic Criteria does not improve their sensitivity significantly (74a). The NIH diagnostic criteria for NF1 are two or more of the following:
  • Six or more café au lait macules whose greatest diameter is more than 5 mm in prepubertal patients and more than 15 mm in postpubertal patients
  • Two or more neurofibromas of any type, or one or more plexiform neurofibroma
  • Freckling in the axillary or inguinal region (Crowe’s sign)
  • An optic pathway tumor
  • Two or more Lisch nodules (iris hamartomas)
  • A distinctive osseous lesion such as sphenoid wing dysplasia or thinning of the cortex of the long bones (with or without pseudoarthrosis)
  • A first-degree relative (parent, sibling, or offspring) with NF1 according to the previously mentioned criteria (76,77,78,79).
At the moment, DNA-based testing is unnecessary to make a diagnosis if the NIH criteria are met. DNA testing for the diagnosis of NF1 is limited because present techniques detect only approximately 70% of mutations (5), and detection of a specific mutation does not predict the severity of the disease. Although a solitary café au lait spot can occur in the normal population, the incidence of more than four such lesions in nonaffected persons is low, and in the absence of other symptoms of neurofibromatosis, the lesions can indicate a partial penetrance of the disease (80). Conversely, some 75% of individuals with proven NF1 have six or more café au lait spots 1 cm or more at the largest diameter (29).
Both parents should be examined with particular attention to the presence of café au lait spots, subcutaneous neurofibromas, and Lisch nodules. Detection of Lisch nodules often requires slit-lamp examination by an ophthalmologist. If one parent has the stigmata of NF1, the condition in the offspring is not a new mutation, and a 50% chance exists for it to occur in each subsequent sibling. The risk for the patient’s own potential offspring is the same. If neither parent has any abnormalities, a new mutation is presumed, and the recurrence risk for NF1 is no greater than in the general population. Prenatal diagnosis of the condition can be made by linkage analysis, if two or more family members are affected (79).
Treatment and Prognosis
Therapy is symptomatic. Most pediatric patients with NF1 should be seen in a multispecialist clinic at intervals of at least 6 months to 1 year to detect and manage the various potential complications. The necessity or value of routine cranial MRI scans is a matter of debate because it is becoming apparent that the detection of asymptomatic lesions may not alter clinical management (79). However,
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the detection of asymptomatic optic pathway gliomas may alter the intensity of ophthalmologic monitoring. When tumors are confined to peripheral nerves, the long-term prognosis is generally good. The prognosis for intracranial tumors depends on their location and whether they are single or multiple. In a follow-up study of patients with NF1 first reported in 1951, Sorensen and coworkers found that survival was limited by an incidence of neoplasms that was four times greater than seen in the normal population. Thus, 84% of patients developed a glioma, and second tumors were seen five to eight times more frequently than expected. Malignancies were encountered in one-third of the cohort, with female subjects having a higher incidence than male subjects. Second neoplasms were seen in 83% of patients with optic gliomas and in 43% of patients with other types of gliomas (81). NF1 is a progressive disease, and more manifestations are usually present in older patients. The clinical variability and natural history of the burden of disease in NF1 has been reviewed by Friedman (75) and Young, Hyman, and North (35).
Neurofibromatosis 2
NF2 is genetically and clinically distinct from NF1. It is far less common, with an estimated incidence of 1 in 33,000 to 40,000, and it is characterized by the development of CNS tumors, notably bilateral vestibular schwannomas (77). The gene for NF2 has been mapped to the long arm of chromosome 22 (22q11) and has been cloned. Its gene product, merlin (schwannomin), shares significant homology with several actin-associated proteins (78). Merlin is localized to the cell membrane and is believed to act as a membrane-cytoskeletal linker. It serves as a tumor suppressor by playing a role in the regulation of cell-cell adhesion and in the reorganization of the actin cytoskeleton in response to growth factors, confluency, and changes in the shape of the cell (82,83). Merlin is widely expressed in human brain; it is absent from almost all schwannomas and from many meningiomas and ependymomas isolated from subjects with NF2 (83a). A large number of gene mutations have been documented. Some 90% of patients have gross truncations of merlin as a result of nonsense or frame-shift mutations (84). These patients tend to be younger at onset of symptoms and at diagnosis and tend to harbor a large number of tumors (85).
Clinical Manifestations
In contrast to NF1, clinical manifestations and age of onset are similar within a given family, but differ considerably between families (86). The clinical manifestations of NF2 are highlighted by the presence of bilateral vestibular schwannomas (acoustic neuromas), which become manifest in more than 95% of genetically affected subjects (87). Generally, these tumors become symptomatic at puberty or thereafter. In addition, schwannomas occur in the other cranial nerves and the spinal and cutaneous nerves. Other tumors of the CNS seen in this condition include cranial and spinal meningiomas and multiple tumors of glial and meningeal origin. These tumors are readily detectable by imaging studies, with the acoustic neuromas appearing as a mass in the cerebellopontine angles or enlargement of the gasserian ganglia (52,88). As a rule, the mean age of onset of symptoms is in the second decade of life. In the series of Mautner and colleagues it was 17 years, with the age ranging from 2 to 36 years (88). In the same series, 44% of patients presented with deafness. Café au lait lesions were present in only 43% and in this series as in others they rarely number more than six (89,90). Cataracts (posterior subcapsular or cortical) were seen in 81%, and seizures were presenting complaints in 8%. Peripheral nerve tumors were seen in 68%. These are predominantly schwannomas, but also can be neurofibromas (89). These appear as discrete, well-circumscribed slightly raised lesions with a roughened, slightly pigmented surface. Other skin lesions such as nodular tumors or neurofibromas also are less common than in NF1. According to Riccardi, acoustic neuromas and optic glioma never coexist in a patient (27). The various neurological complications are summarized in Table 12.2 (90a).
TABLE 12.2 Neurological Complications in Patients with NF-2
  Incidence (%)
Presentation at 15 years or less 18
Presentation at 10 years or less 9
Complications in Children 15 years or less
Vestibular schwannoma (Hearing loss, tinnitus, facial palsy) 43
Meningioma (Headaches, seizures) 31
Spinal tumor 11
Unilateral facial palsy 10
From Evans et al. (90a).
Diagnosis
As is the case for NF1, the diagnosis of NF2 rests on clinical grounds. The criteria for NF2 are one or more of the following conditions:
  • Bilateral eighth nerve masses (vestibular schwannomas) seen with imaging techniques
  • A parent, sibling, or child with NF2 and either unilateral eighth nerve mass or any two of the following conditions: neurofibroma, meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacity (76,89,91)
  • Patients with unilateral vestibular schwannomas and cataracts, or meningioma, glioma, or schwannoma are suspect for NF2, as are patients with multiple meningiomas plus unilateral vestibular schwannoma, cataracts, or glioma (89).
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  • In 10% of cases of NF2, there is an identifiable mutation in merlin; for the remainder of patients, prenatal diagnosis requires a linkage study using DNA derived from at least two affected family members, if these are available.
Tuberous Sclerosis
Although the earliest report of a patient with TS is said to have been made by von Recklinghausen in 1863 (92), its first complete, albeit mainly pathologic, description is attributed to Bourneville, who, in 1880, was the first to call it TS (93). This is a protean disorder, chiefly manifested by mental deficiency, epilepsy, and skin lesions. It occurs with a frequency of 1 in 6,000 to 9000 and is transmitted as an autosomal dominant gene (94,95,96,97). Approximately one-third of cases have inherited a mutated TS gene from one of the parents; the rest are new mutations.
TS is genetically heterogeneous, with loci on chromosome 9q34.3 (TSC1), and 16p13.3 (TSC2) near the mapped location of the adult polycystic kidney disease gene (APKD1). Each locus accounts for approximately 50% of familial cases (96). The phenotypic expression of the two genetic defects appears to be similar, aside from the observation that TSC2 patients appear more prone to neurologic problems. TSC1 codes for hamartin, a 130-kd protein with no significant homology to any other known vertebrate protein (98). TSC2 codes for tuberin, a 200-kd protein, which functions as a tumor-suppressor gene (99). It acts as a GTPase activator for rap1, which is an effective proliferation signal, expressed in several tissues, notably astrocytes. Rap1 also is involved in morphogenesis and cell migration (100). Tuberin is most abundant in cerebral gray matter and increases during prenatal and postnatal development (101). The protein also may be involved in neuronal differentiation (102). The similarity in phenotypes produced by mutations in the TSC1 and TSC2 genes suggests that the genes somehow function together, and direct interaction between the two proteins has been shown (103). Hamartin and tuberin associate physically in vivo, and inactivation of either is believed to prevent the formation of a functional protein complex that regulates cell growth and proliferation (104,105). Nearly 1,000 mutations have been discovered to date, and genotype/phenotype correlation studies could provide guidance for optimal medical care in affected individuals. Relevant animal models, including conventional and conditional knockout mice, are valuable tools for studying the normal functions of tuberin and hamartin and how disruption of their expression gives rise to the variety of clinical features that characterize TS.
Mutations in the TSC2 genes are more readily detected in sporadic than in familial cases (106). Penetrance is variable. No family with two or more affected offspring has been encountered in which one parent did not have adenoma sebaceum or some other skin lesion characteristic for TS (107). Conversely, the risk of having more than one affected child is low when both parents are clinically unaffected because under such circumstances, the condition is probably a new mutation.
FIGURE 12.3. Tuberous sclerosis. A large intraventricular tuber produces increased intracranial pressure, flattening of the gyri, and herniation of the right temporal uncus (U). (Courtesy of Dr. P. Cancilla, Department of Pathology, University of California, Los Angeles, UCLA School of Medicine.)
Pathology
Abnormalities can be found in the brain, eyes, skin, kidneys, bones, heart, and lungs. In the brain, three types of abnormalities occur: cortical tubers, subependymal nodules, and disorders of myelination. The most characteristic gross abnormality is the presence of tubers. These are numerous hard areas of gliotic tissue of varying size, after which this condition is named. Tubers can be located in the convolutions of any part of the cerebral hemispheres (Fig. 12.3). Less commonly, they are in the cerebellum, brainstem, or spinal cord. The highest frequency of tubers is in the frontal lobes, but the highest density is in the parietal regions (108). On histologic examination, tubers are sclerotic areas that consist of an overgrowth of atypical giant cells that exhibit cytomegaly (109) and express both gial and neuronal markers. Adjacent to these giant cells are dysplastic neurons that are characterized by aberrant dendritic arborizations and a dysmorphic cell body. Tubers may be dynamic lesions characterized by populations of cells undergoing proliferation, migration, and death. Crino recently showed that there is cell-specific activation of the mTOR/p70-S6 kinase/ribosomal S6 cascade in tubers and that giant cells express activated (phosphorylated) p70-S6-kinase and ribosomal S6 protein (110). The tuberin/hamartin complex regulates mTOR, and Rheb (Ras homologue enriched in brain), a Raslike GTPase, has been identified as a target of tuberin GAP activity (111,112,113,114,115,116). These findings support impaired hamartin/tuberin–mediated mTOR pathway and Rheb regulation.
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Tubers likely form a constitutive activation of mTOR cascade during brain development as a consequence of impaired hamartin (TSC1) or tuberin (TSC2) function.
FIGURE 12.4. Noncontrast computed tomographic scan of tuberous sclerosis, taken at several levels, shows typical calcified subependymal tubers at the margins of the lateral ventricles and projecting slightly into the ventricles. (Courtesy of Dr. Hervey D. Segall, Children’s Hospital of Los Angeles.)
Rapamycin, a specific inhibitor of mTOR, is currently in clinical trials and may prove useful in some TS-related tumors, including those that affect the brain. Similarly, farnesyltransferase inhibitors may prove useful in disrupting Rheb activation (117). Blood vessels in sclerotic regions show hyaline degeneration of their walls. In approximately one-half of subjects, calcium is deposited within the gliotic areas to an extent as to be visible on plain radiography of the skull or on computed tomographic (CT) scanning (Fig. 12.4). Subependymal nodules are found in the caudate nucleus and the ventricular walls, particularly in the region of the foramen of Monro. Tuber and nodule volumes are significantly positively correlated. Subependymal nodules are multiple small, tumorlike nodules that project into the ventricles and that because of their appearance on pneumoencephalography were described as “candle drippings.” Calcification of these nodules is common and increases with age. Subependymal giant cell astrocytomas arise from subependymal nodules, particularly in the area surrounding the foramen of Monro, and transitions between gliosis and astrocytomas are common. Their incidence in TS is approximately 10% to 15% (118). Although only rarely malignant, they often obstruct the foramen of Monro. It is of note that approximately one-half of high-grade and low-grade sporadic adult astrocytomas show reduced or absent expression of tuberin (119). In the remainder, the majority have an increased expression of rap1.
Myelination usually is diminished in the gliotic areas within and surrounding the cortical tubers. In addition, islets occur consisting of heterotopic cells within white matter. These are distributed in a linear pattern that follows the normal migratory path of primitive neurons between the germinal layer of the ventricles and the cortical surface.
Tumors also can arise from various viscera. In the heart, the characteristic lesion is the rhabdomyoma. The incidence of these tumors in children with TS can be as high as 50%. Characteristically, they are multiple and well circumscribed. Rhabdomyomas cause as many as one-fourth of infants to die from circulatory failure during the first few days of life, well before developing other stigmata of TS. Between 50% and 80% of patients develop multiple renal tumors, which are usually benign and of mixed embryonal type. Lungs are rarely involved, but when lesions are present in the lungs, they are usually cystic or fibrous. Other organs can be the seat of fibrocellular hamartomas (1). The pathologic features of the disease are extensively reviewed by Bender and Yunis (120).
Clinical Manifestations
Manifestations of TS vary considerably with respect to age of onset, severity, and rate of progression, and natural history studies have yet to be conducted to investigate cell lineage and identify the point at which cortical development of TS is initiated as well as determine whether these lesions continue to evolve after birth. The four main types of manifestations are mental retardation, seizures, cutaneous lesions, and tumors in various organs including the brain. The frequency of the major signs and symptoms is given in Table 12.3 (121).
The degree of mental retardation varies widely, and for unknown reasons, a significant proportion of youngsters develops autistic features. Approximately one-third of patients diagnosed as having TS on the basis of other clinical manifestations maintain a normal intelligence. In the most
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recent population-based study, 55% of those with TS had an IQ >70, while 30.5% had an estimated IQ <21 (122). Individuals with TS in the normal range of intellectual abilities showed a normal distribution of IQ, but with a mean IQ 12 points lower than their unaffected siblings. Even normal-intelligent individuals with TS without a lifetime history of seizures had mean IQs below that of their non-TS siblings. In others, language and perceptual development is slowed. Of retarded patients studied by Borberg, 15% developed normally for the first few years of life, showing the first signs of intellectual deterioration between 8 and 14 years of age (123). This deterioration can be the consequence of either frequent, uncontrolled seizures or the development of increased intracranial pressure caused by an obstruction at the foramen of Monro. In some series, the number of tubers is greater in subjects with mental retardation than in those with normal intelligence, whereas in others, there is no consistent relationship between intelligence and the number of tubers, and mental retardation reflects the early onset of seizures (118,124). In addition to the concerns of global inellectual problems, there is a higher prevalence of behavioral problems, psychiatric diagnoses, learning disorders, and specific neuropsychologic deficits. The behavioral and cognitive aspects of TS have been recently reviewed by Prather and Petrus (125). Because of the potential for behavioral and cognitive regression in TS, most experts in the field recommend that children with TS have a neuropsychologic evaluation when entering school, in the fourth grade, and again in the ninth grade.
TABLE 12.3 Clinical Picture in 71 Patients with Tuberous Sclerosis
Manifestation 43 Patients with Mental Retardation 26 Patients with Average Intelligence
Seizures 43 26
   Major motor seizures 19 6
   Minor seizures 6 5
   Major and minor seizures 7 3
      Seizure onset before 1 year of age 28 4
      Seizure onset before 5 years of age 38 8
Adenoma sebaceum (facial angiofibroma) 37 22
   Appearance of skin lesion before 2 years of age 17 9
   Appearance of skin lesion after 9 years of age 2 3
Retinal tumors 21 13
Intracranial calcifications 20 15
From Lagos JC, Gomez MR. Tuberose sclerosis: reappraisal of a clinical entity. Mayo Clin Proc 1967;42:26. With permission.
Seizures, the most common presenting complaint in all patients with TS, occur at some time in all patients who are retarded. Almost all seizure types are seen in TS though typical absence seizures are not observed. Infantile spasms are the most common seizures during infancy (126). Between one-fourth and one-half of children presenting with this type of seizure ultimately develop TS (127). Later, generalized convulsions or focal seizures can occur. Seizures can appear as early as the first week of life. The earlier the onset of seizures, the more likely the infant is to be mentally retarded (Table 12.3). Of 90 children whose seizures began before 1 year of age, only 8% were deemed to have average intelligence (128). Gomez and colleagues have postulated the presence of an epileptogenic factor, independent of cerebral TS, that facilitates the early onset of seizures and, in turn, impairs normal CNS development (129). Abnormalities in glutamatergic and γ-aminobutyric acid (GABA) receptor subunits have been identified in cortical tuber samples, and abnormal glutamatergic transport in astrocytes had been observed in mouse models of TS (130,131). Several studies have characterized the neurophysiologic activity of cortical tubers at the time of epilepsy surgery, with some studies finding cortical tubers electrically silent, but others finding frequent epileptiform activity associated with the tuber or the region around the tuber (132,133). The severity of the seizures is unpredictable (134). Interestingly, up to 10% of individuals with TS and intractable epilepsy have normal brain MRI scans, with no evidence of cortical tubers or other dysgenetic features (125). As is discussed in Chapter 14, vigabatrin (150 mg/kg per day) is extremely effective in the management of infantile spasms caused by TS and is now considered to be the treatment of choice (135).
Autism or pervasive developmental disorder is a prominent feature of TS (136). In a series of TS patients from the University of California, Los Angeles, 28.5% satisfied the clinical features for autism, and a further 14.2% met the criteria for pervasive developmental disorder (137). In other series of patients with TS, the incidence of autistic disorders was even higher (138). Bolton and Griffiths have commented on the association of autism with tubers within the temporal lobes (139). In a later report of a larger series, Bolton and coworkers stated that risk factors for autism spectrum disorders were temporal lobe tubers associated with temporal lobe epileptiform activity and infantile spasms having an early onset and persistence (140).
Adenoma sebaceum (angiofibroma) is the characteristic cutaneous lesion of TS (Fig. 12.5). These lesions consist of a red, papular rash over the nose, chin, cheeks, and malar region, appearing between ages 1 and 5 years. In the experience of Pampiglione and Moynahan, 12% of affected children developed this skin lesion by 1 year of age, and 40% by 3 years of age (141). Depigmented nevi, resembling vitiligo, in the form of oval areas with irregular margins (ash leaf) over the trunk and extremities are equally
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common. Generally, they appear earlier than the adenoma sebaceum. They can be noted at birth and are seen before 2 years of age in more than one-half of the subjects (141,142). They are more readily visualized when the skin is illuminated with ultraviolet light (Wood lamp). Depigmented nevi differ from vitiligo in that in vitiligo, the melanocytes are absent, whereas in depigmented macules, the melanocytes are normal but the melanosomes are reduced and contain less melanin. Hypopigmented macules are seen in 0.8% of apparently healthy newborns (143).
FIGURE 12.5. Tuberous sclerosis. Characteristic fibrous plaque of the forehead and facial angiofibroma in a boy with an early stage of the condition. (From Gomez MR, ed. Neurocutaneous diseases. A practical approach. Boston: Butterworths, 1987. With permission.)
Of the other cutaneous abnormalities, flattened fibromas are the most common. They appear in a variety of areas, including the trunk, gingivae, and periungual regions. In some infants, fibromas are found along the hairline or eyebrows. Another striking, but less common, lesion is the shagreen patch. This is an uneven thickening of skin, grayish green or light brown, raised above the surrounding surface, usually in the posterior lumbosacral region. Café au lait spots are seen in 7% to 16% of subjects. Their incidence is not much greater than in the general population, and their presence in isolation should not prompt the diagnosis of neurofibromatosis. A significant percentage of subjects have patches of gray or white hair. Their presence can precede that of the depigmented nevi and thus can be the earliest clinical manifestation of TS (144). The abnormality is seen in 0.3% of apparently healthy newborns (143).
Intracranial tumors are less frequent in TS than in neurofibromatosis, but occurred in 15% of the series of Kapp and coworkers (145). Although the numerous intraventricular nodules are technically tumors, they usually do not grow to the extent of producing increased intracranial pressure. Tumors are found in the neighborhood of the foramen of Monro, arising from either the walls of the lateral ventricles or the anterior portion of the third ventricle. On the basis of their histology, they have been classified as giant cell astrocytomas.
The usual symptoms indicating the presence of an expanding mass in a patient with TS are headache, vomiting, and diminished vision. Papilledema is common, and occasionally lateralizing signs such as hemiparesis can develop. In as many as 50% of patients, tumors are detected in the retina, where they usually arise from the nerve head (146). Other common retinal anomalies are hyaline or cystic nodules (147). Further sites for neoplasms include the skin, lung, kidneys, bone, liver, and spleen (148,149). Patients require lifelong follow-up for early detection of potentially life-threatening conditions. The major causes of death include status epilepticus, renal disease, brain tumors, and lymphangiomyomatosis of the lung (150).
The non-neurologic manifestations of TS often present in adulthood. After neurologic manifestations, renal lesions are the most common cause of morbidity and mortality in TS. Two types of renal involvement are seen. Polycystic kidney disease occurs in 3% to 5% of individuals and reflects a contiguous gene syndrome with involvement of the APKD1 gene adjacent to the TSC2 gene on chromosome 16. Such patients develop progressive renal failure and require transplantation. More commonly, patients with TS and renal disease have single or multiple renal cysts that may be associated with angiomyolipomas and do not cause renal failure (151). Pulmonary disease in TS includes lymphangiomyomatosis of the lung, a progressive and often fatal disease seen almost exclusively in women; approximately 40% of women with TS develop the condition, and screening high-resolution chest CTs are recommended in adult women with TS. TS patients also may have pulmonary disease with multifocal micronodular pneumocyte hyperplasia and clear cell tumors of the lung, both of which are benign conditions detected radiographically. Cardiac lesions occur in 50% of all individuals with TS, but in contrast to lymphangiomyomatosis and angiomyolipomas, such lesions are of maximal size and clinically symptomatic during intrauterine life or in early infancy; they are rich in glycogen and usually regress spontaneously within 2 to 3 years (151,97). Patients with TS develop gingival fibromas and dental pits and craters.
Diagnosis
As a rule, the diagnosis of TS is based on the characteristic skin lesions, seizures, and intellectual impairment or deterioration. In infants, the combination of depigmented areas of skin, infantile spasms, and delayed development is diagnostic. Griffiths and Martland suggest that the role of neuroimaging is to confirm the clinical suspicion of TS, evaluate the extent of the abnormality, look for associated but clinically unsuspected abnormalities, and follow the progression of the disease (152). Definite TS, as defined
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by the 1998 consensus conference sponsored by the TS Alliance and the National Institutes of Health, is diagnosed when at least two major, or one major and two minor, features are present. Probable TS includes one major and one minor feature. Possible TS includes one major or two or more minor features Table 12.4) (153). The 1998 criteria do not include symptoms such as seizures or mental retardation, to avoid “double counting” (i.e., central nervous system lesions cause seizures, and including both in the criteria leads to counting the same symptom twice) (153). Associated neurologic features include seizures, autism or pervasive developmental disorders, mental retardation, and various learning and behavioral disorders (97).
TABLE 12.4 Diagnostic Features of Tuberous Sclerosis
Major features
Skin Manifestions
   Facial angiofibromas
   Ungual fibroma
   More than three hypomelanotic macules
   Shagreen patch
Brain Lesions
   Cortical tuber
   Subependymal nodules
   Subependymal giant cell astrocytoma
Eye Lesions
   Multiple retinal nodual hamartomas
Tumors of Other Organs
   Cardiac rhabdomyoma
   Lymphangioleiomyomatosis
   Renal angiomyolipoma
Minor features
Multiple randomly distributed pits in dental enamel
Rectal polyps
Bone cysts
Cerebral white matter migration abnormalties on brain imaging
Gingival fibromas
Non-renal hamartomas
Retinal achromic patches
Confetti skin lesions
Multiple renal cyts
From Roach ES, Sparagana SP. Diagnosis of tuberous sclerosis complex. J Child Neurol 2004;19:643–649.
The clinical criteria outlined above are useful, despite the availability of a genetic test for TS, because they are quick, accurate, and inexpensive. Phenotypic variability may be related to the following factors: (1) the stronger phenotypic presentation in patients with TSC2 gene mutations, (2) somatic mosaicism, and (3) the specific type of genetic mutation. Genetic testing for TSC1 and TSC2 mutations has been available since 2002. Confirmatory testing for TS is helpful in individuals who fail to meet the criteria for definite TS as well as to improve genetic counseling. Prenatal genetic testing for TS also is possible when there is a defined TS mutation in a specific family. Preimplantation genetic diagnosis testing also is feasible (154,155,156). Genetic testing for TS has a false negative rate of 15% to 20%.
MRI is the simplest way to confirm the diagnosis of TS. Ninety percent of people with TS exhibit at least one supratentorial brain lesion, including cortical tubers, subependymal nodules, subependymal giant cell astrocytoma, white matter linear migration lines, corpus callosum agenesis or dysplasia, and transmantle cortical dysplasia (157). Infratentorial brain lesions are seen in less than 2% of patients. CT scanning demonstrates multiple scattered calcium deposits varying in size up to several centimeters and located close to the wall of the lateral and third ventricles near the foramen of Monro (see Fig. 12.4). In the series of Kingsley and coworkers, only 5% of patients with clinical features of TS had a normal CT scan result (118). Calcified masses within the cortex and white matter also are seen, as is cerebral cortical atrophy and ventricular dilatation, but the CT does not show cortical tubers unless they have become calcified (118). Whereas MRI is inferior to CT scanning for the detection of calcified lesions, it is preferable for the visualization of cortical tubers, the various white matter lesions, areas of heterotopias, and hamartomas. MRI also demonstrates islets of abnormal heterotopic giant cells that extend radially from the ependyma to the cortex. These are particularly common in the frontal lobes and the cerebellum (53,158). Cortical tubers can be found in 95% to 100% of patients with TS. They appear as thickened cortical gray matter that is hyperintense on T2-weighted images with indistinct gray-white differentiation. Fluid attenuated inversion recovery (FLAIR) sequences, which suppress the signal from cerebrospinal fluid (CSF), can be used to demonstrate smaller tubers (159). Subependymal nodules are hypointense on T1-weighted images. They are seen in approximately 95% of TS subjects, with the amount of calcification increasing with age. Gadolinium-enhanced MRI can be helpful in distinguishing a subependymal giant cell astrocytoma from a benign subependymal nodule (53,160) (Fig. 12.6). Hence, both CT and MRI studies are necessary for the complete evaluation of the child with TS, particularly for the detection of the heterotopias, which in our experience have proven to be troublesome seizure foci. There is evidence that the number of subependymal nodules and tubers is associated with increased frequency of seizures, cognitive impairment, and adaptive functioning (157).
Equally diagnostic for TS are the cystlike foci in the phalanges in approximately two-thirds of subjects. These are not seen at birth, but appear around puberty. A periungual or subungual fibroma (Koenen tumor), also characteristically appearing after puberty, is virtually diagnostic of TS, as are retinal hamartomas, which can be visualized in approximately one-half of patients (128).
Electroencephalography and the CSF are of relatively little diagnostic importance. Approximately one-third of
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children have hypsarrhythmia, which can persist in a modified form in patients up to 8 years of age (141). Focal and multifocal paroxysmal discharges and diffuse slowing also are seen. Slow-wave abnormalities are often indicative of large intracerebral calcifications or masses.
FIGURE 12.6. Magnetic resonance imaging of tuberous sclerosis. A large cortical tuber is seen as a signal void corresponding to the calcification seen on computed tomographic scan. This area is surrounded by a fine hyperintense rim (white arrow). An area of high signal intensity with blurred margins corresponds to another large cortical tuber (arrowheads). (Courtesy of Dr. Nadine Martin, Départment de Neuroradiologie, Capital Beaujon, Clichy, France.)
The CSF protein content can be elevated, particularly in patients in whom intraventricular nodules have expanded, interfering with CSF circulation.
In numerous patients, incomplete forms of TS have been recognized by means of genetic surveys. These include isolated adenoma sebaceum, isolated retinal hamartomas, adenoma sebaceum with intracranial tumors but no seizures or intellectual deterioration, and visceral tumors without cerebral involvement (107,121,134). In the experience of Roach, who used MRI to screen apparently normal parents of children with TS, only 0.8% of the parents had typical MRI findings but a normal physical examination (161). Thus, a careful physical examination of parents is nearly as sensitive and much more cost effective than imaging studies. Incompletely affected individuals can have children with complete TS, a fact that should be kept in mind when offering genetic counseling. When both parents appear to be unaffected, the recurrence risk for a second child with TS has been calculated to be 1 in 22 after one affected offspring and 1 in 3 after two affected offspring (5).
The genetic diagnosis of TS has limited application. Two-thirds of the cases are sporadic, and a substantial fraction of even the most severe cases could be caused by mosaicism and missed by screening of leukocytes (162). Genetic testing has not been used routinely for the prenatal diagnosis of TS.
Treatment and Prognosis
No specific treatment for TS is available. As stated elsewhere in this section, seizures are managed with anticonvulsant medications. Although vigabatrin’s availability is limited in the United States because of its retinal toxicity and nonapproval by the Food and Drug Administration, it is the most effective antiepileptic drug in children with infantile spams and TS. In selected patients, resection of a single cortical epileptogenic tuber by stereotactic techniques or open craniotomy can result in a marked reduction of seizure frequency (163). Studies are currently under way to examine the impact of neurosurgery on the quality of life in TS. Whether pertussis immunizations provoke the onset of infantile spasms in subjects with TS predisposed to such seizures is a matter of considerable controversy (164). In view of studies that suggest as much and the observations of Gomez and associates that pertussis immunization can precede the onset of infantile spasms by less than 24 hours in infants with TS, pertussis immunization with whole cell vaccine is best withheld (129).
Resection of intraventricular tumors is reserved for children who develop ventricular obstruction. In view of the long survival of patients who do not receive radiation therapy for their mass lesions, we cannot draw any conclusions about its usefulness as an adjunct to surgery.
Whether patients should undergo periodic neuroimaging to detect the development of subependymal giant cell astrocytomas is a matter of debate (165). Whatever position a clinician wishes to take on this issue, regular neurologic examinations of the patient with TS are indicated. The management of cardiac rhabdomyomas and the various renal tumors that can develop in TS is outside the scope of this text.
Sturge-Weber Syndrome
Sturge-Weber Syndrome (SWS), as described by Sturge in 1879 (166) and Kalischer in 1897 (167), is a sporadic condition characterized by a port-wine vascular nevus on the upper part of the face, saltatory neurologic deterioration, and eventual neurodevelopmental delay. No convincing evidence for hereditary transmission has been
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found. The hallmark intracranial vascular anomaly is a leptomeningeal angiomatosis that involves one or more lobes in one or both hemispheres (166). Although a port-wine stain on the face is a relatively common malformation, occurring in approximately 3 in 1,000 births (frequency of 1/50,000), only 5% of infants affected with this type of a cutaneous lesion have SWS (168). Conversely, 13% of patients with cerebral manifestations of SWS do not have a facial nevus (169).
Pathogenesis and Pathology
In SWS, abnormalities of the skin, leptomeninges, choroid, and cortex can be traced to malformation of an embryonic vascular plexus, arising within the cephalic mesenchyme between the epidermis (neuroectoderm) and the telencephalic vesicle. Interference with the development of vascular drainage of these areas at approximately 5 to 8 weeks of gestation subsequently affects the face, eye, leptomeninges, and brain. Imaging findings in SWS can best be explained by the model of low-flow angiomatosis involving the leptomeninges (170). The angiomatosis is accompanied by poor superficial cortical venous drainage, with enlarged regional transmedullary veins developing as alternate pathways (Fig. 12.7). The ipsilateral choroid plexus may become engorged. Vascular stasis promotes chronic hypoxia of both cortex and underlying white matter. Ultimately, tissue loss and dystrophic calcification occur. Key radiologic features, therefore, are leptomeningeal enhancement of the angiomatosis, enlarged transmedullary
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veins, enlarged choroid plexus, white matter abnormalities, atrophy, and cortical calcifications.
FIGURE 12.7. Magnetic resonance imaging (A) in axial plane shows contrast-enhancing angiomatosis overlying the right cerebral hemisphere. Note hypertrophy of the choroid plexus in the coronal section (B) . Axial T2-weighted magnetic resonance imaging (C) shows widespread atrophy of the right hemisphere.
Two structural aspects of SWS compromise cerebral blood flow. First, obstruction in the angiomatosis creates stasis, decreased venous return, and hypoxia. Under such conditions, neuronal metabolism suffers. Second, the lack of normal leptomeningeal vessels hinders neuroglial oxygenation, particularly at times of increased demand, such as when seizures occur. The resulting hypoxia is associated with several physiologic changes: abnormal drainage into the deep plexus and hypertrophy of the choroid plexus, increased capillary permeability, alterations in pH, calcium deposition, cerebral atrophy, and disruption of the blood–brain barrier (171,172,173). Poor venous drainage in one or both hemispheres is indicated by the presence of enlarged cortical vessels that extend beyond the borders of the leptomeningeal angiomatosis (174). The vascular compromise accounts for neurologic deterioration and eventual neurodevelopmental delay. The phenomenon of saltatory neurologic deterioration has been explained by the development of repeated thromboses, which are caused by microcirculatory stasis in the leptomeningeal angiomatosis. The stasis results in progressive, recurrent infarction that underlies loss of neurologic function.
On pathologic examination of the brain, the essential feature is a leptomeningeal angiomatosis with a predilection for the occipital or occipitoparietal region of one cerebral hemisphere (175). On microscopic examination, the walls of these vessels are encrusted with iron and calcium deposits. Cortical calcifications usually are found in the degenerated cortex underneath the vascular malformations; in the less affected areas, calcifications are localized to the cortical tissue surrounding the walls of the smaller blood vessels. Calcification of microglia and neurons is a less common finding.
Clinical Manifestations
SWS is a progressive disease. The cutaneous port-wine nevus is present at birth and involves at least one eyelid or the supraorbital region of the face (172). It is initially pale red and gradually assumes the deep port-wine color. The angiomas also commonly affect the mucous membranes of the pharynx and other viscera. An angioma of the choroid membrane of the eye is often associated with unilateral congenital glaucoma and buphthalmos. Bilateral facial nevi are not uncommon and were seen in 33% of patients in the series of Pascual-Castroviejo and colleagues (176). Approximately one-fourth of these patients had bilateral cerebral lesions on imaging studies. It is important to note that most children with a facial cutaneous vascular malformation do not have SWS. When the cutaneous malformation is unilateral or bilateral and includes the ophthalmic division of the trigeminal nerve, the likelihood of SWS increases. The overall risk of SWS associated with any kind of facial cutaneous vascular malformation is approximately 8%. Children with involvement of the eyelids are at elevated risk for eye and brain disease (177). Rarely, some children with SWS lack a facial cutaneous vascular malformation but have the neurologic and/or ophthalmic components. The intracranial leptomeningeal angiomatosis is a key diagnostic feature in SWS.
Some 75% to 90% of affected patients develop focal or generalized seizures (178,179). These are usually the initial neurologic manifestation and frequently begin in the first year of life. Seizures can progressively become more refractory to medication and can be followed by transient or permanent hemiparesis. Hemiparesis, often with homonymous hemianopia, ultimately develops. In the Mayo Clinic series, some 67% of patients with a unilateral lesion and seizures were mentally handicapped (169). This is comparable with the data of Sujansky and Conradi, who found that 71% of SWS subjects with seizures required special education (178), and that of Pascual-Castroviejo and colleagues, who found that the IQ of 70% of SWS subjects was less than 90 (176). By contrast, all patients without seizures were mentally normal (169,178). Of the longitudinal studies published, none shows that early onset of seizures indicates poor prognosis. In fact, retrospective studies do not support the widely held belief that seizure frequency early in life in patients who have SWS is a prognostic indicator. However, some patients do develop intractable epilepsy, permanent weakness, hemiatrophy, and visual field cuts, glaucoma, and mental retardation (180,181). The hemiparesis and hemiatrophy are thought to arise from chronic cerebral hypoxia. Other findings common to patients with SWS are vascular headache (40% to 60%), developmental delay and mental retardation (50% to 75%), glaucoma (30% to 70%), hemianopsia (40% to 45%), and hemiparesis (25% to 60%) (182).
Diagnosis
Diagnosis of SWS is made on the basis of the presence or absence of ophthalmologic or neurologic disease. The disease course, however, is variable, and the patient must be continually monitored for complications. Glaucoma can be present at birth or develop over the years in up to 60% of patients (178). Less commonly, symptoms owing to hemangiomas involve the viscera. These include hematuria and gastrointestinal hemorrhages. Intracranial hemorrhages are rare.
Most port-wine stains occur as an isolated anomaly. However, the coincidence of a facial vascular nevus and seizures should suggest SWS. Neuroimaging studies document the gradual but inexorable progression of the disease. This is particularly true for those children who develop seizures. MRI is presently the diagnostic modality of choice. In infants, the unenhanced MRI can be normal, and the most reliable diagnostic features are leptomeningeal enhancement on MRI after gadolinium administration, enlarged transmedullary veins, and unilateral hypertrophy of
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the choroid plexus (see Fig. 12.7) (179,183,184). CT scan can reveal the localization and extent of intracranial calcifications (Fig. 12.8). Rarely present at birth, these become evident in nearly 90% of patients by the end of the second decade of life (169). Characteristically, calcifications are arranged in parallel lines (“railroad tracks”) or serpentine convolutions that are most striking in the occipital and parieto-occipital areas (see Fig. 12.8). In older subjects, MRI not only shows the pial angiomatosis, but also adjacent cerebral atrophy and enlargement of the lateral ventricles ipsilateral to the vascular nevus. Depending on the age when the study is performed, arteriography or MR arteriography can demonstrate abnormalities in approximately 50% of subjects. These include venous angiomas, thrombotic lesions, and other vascular anomalies (185,186). Functional cerebral imaging by means of a positron emission tomography (PET) or a single photon emission CT (SPECT) scan shows hypometabolism and hypoperfusion (Fig. 12.9) (187). The affected area is more extensive than the area of CT or MRI abnormalities (184). In infants who have not yet experienced a seizure, generally accelerated myelination and hyperperfusion of the affected region is seen (174,184,188).
FIGURE 12.8. Computed tomographic scan in axial plane shows widespread calcification in right hemisphere of the same patient in Figure 12.7.
The characteristic intracranial calcifications and seizures unaccompanied by a facial nevus also are seen in some patients with celiac disease (189). This condition is covered in Chapter 17.
Klippel-Trenaunay syndrome is a nonhereditary condition that shares a number of clinical features with SWS. In essence, it consists of cutaneous vascular nevi, which can appear at any site of the body and vary in size, venous varicosities, and hypertrophy of the bone and soft tissues (190,191). In some instances, the syndrome is associated with seizures, facial hemihypertrophy, and intracerebral calcifications (192) (see Chapter 13).
An association of large facial hemangiomas and abnormalities of the posterior fossa, notably the Dandy-Walker syndrome, posterior fossa arachnoid cyst, or cerebellar hypoplasia, has been recorded (193). There also is an autosomal dominant condition characterized by cerebral or cerebellar arteriovenous malformations, cutaneous vascular malformations, and seizures (194).
Treatment
Patients with SWS require consistent and thorough monitoring for development of glaucoma, seizures, headache, and strokelike episodes. Medical and surgical management of glaucoma associated with SWS continues to be challenging. Lifelong medical treatment coupled with frequent surgeries is standard. The goal is to control intraocular pressure in order to prevent optic nerve damage. Medications should be given to decrease the production of aqueous fluid or promote the outflow of aqueous fluid. Beta-antagonist eye drops, adrenergic eye drops, and carbonic anhydrase inhibitors are the treatments of choice. Trabeculectomy and goniotomy are typical surgical options.
Laser therapy for facial cutaneous vascular malformation should be started soon after diagnosis for the best prospect of success. A vascular-specific pulsed dye laser can improve the appearance of the facial cutaneous vascular malformation, typically within 10 treatments. The location of the facial cutaneous vascular malformation predicts the response to laser therapy. Central forehead lesions respond best, whereas central facial lesions do not respond as well (195,196,197,198,199). Many patients benefit psychologically from removal of the facial cutaneous vascular malformation (200). Without laser therapy, the lesion grows and typically darkens, developing vascular ectasias that promote nodularity and superficial blebbing. This may lead to overgrowth of the soft tissue and bone beneath the lesion. Hypertrophy and nodularity within the lesion develop in 65% of patients by the fifth decade (200).
Prevention of recurrent seizures may diminish effects of hypometabolism and hypoxia; therefore, the goal is complete seizure control. Management principles for recurrent seizures associated with other conditions also apply to seizure prophylaxis in SWS (see Chapter 14). Children who
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receive no relief from frequent, debilitating seizures are candidates for epilepsy surgery. Although there is no conclusive evidence that surgical management in infancy provides a better prognosis, delay of surgical treatment may result in further cognitive deterioration (201). A retrospective clinicopathologic review of infants requiring epilepsy surgery indicated that in 7 of 8 patients, epilepsy was absent or significantly diminished postoperatively, supporting the benefits of early surgery (202). Arzimanoglou and colleagues had similar good results with surgery. They found that almost all patients benefited. All children with a pre-existing hemiparesis became seizure-free following hemispherectomy (202a). However, most candidates for the procedure have significant developmental delay, and there is a significant operative risk (203). Few data are available, but anecdotal experience suggests that surgical relief of catastrophic epilepsy may result in resumption of developmental progression. For each patient, the timing of surgery must be carefully considered after fully assessing the procedure’s relative risks and benefits (204). The retrospective study of Kossoff and colleagues showed that the age when hemispherectomy was performed or the type of surgical procedure did not affect the outcome (205).
FIGURE 12.9. Sturge-Weber disease. Computed tomographic scan and fluorodeoxyglucose positron emission tomography scans of a 13-month-old girl with bilateral capillary hemangiomas affecting all three divisions of the fifth cranial nerve. The hemangioma was more intense on the left, and there was left-sided glaucoma. Seizures began at 1 year of age, developmental milestones were normal, and no hemiparesis was seen. A: Computed tomographic scan showing early left occipital calcifications. B: Positron emission tomography scan indicating marked hypometabolism of occipital, temporal, and posterior parietal regions of the left hemisphere. (Courtesy of Dr. Harry Chugani, Division of Pediatric Neurology, Wayne State University, Detroit, MI.)
Transient focal deficits presenting with hemiparesis or visual field defects not directly linked to epileptic incidences should be monitored diligently. Prophylactic
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aspirin is recommended for the prevention of these episodes. Aspirin may delay the neurologic deterioration that often accompanies SWS. Anecdotal data suggest that aspirin therapy is safe and effective. However, no randomized, controlled clinical trials have tested its use in children with SWS. We recommend the antiplatelet dose of 3 to 5 mg/kg/d for children with recurrent strokelike episodes.
Headaches can be debilitating in patients with SWS. The frequency and severity of headaches is higher in SWS than in the general population. Many children report a temporal relationship between their headaches and seizure activity. The leptomeningeal angioma may predispose children to neuronal hyperexcitability, which could account for the migraines. Children with SWS often respond to standard abortive and preventive migraine management in order to cope with headaches. To the best of knowledge, there are no reported serious adverse events from the use of triptans in SWS.
Prognosis
The prognosis in SWS varies widely. Although patients with widespread hemispheric disease or bihemispheric disease are at greatest risk for neurologic complications, many function virtually normally. Clearly, a subgroup of patients with limited central nervous system involvement as defined by neuroimaging studies has a particularly malignant clinical course, with intractable epilepsy, headache, strokelike episodes, and cognitive deterioration. A longitudinal study must be conducted to identify risk factors for neurologic deterioration.
Von Hippel–Lindau Disease
The association of cerebellar hemangioblastomas with angiomas of the spinal cord, multiple congenital cysts of the pancreas, and kidney and renal carcinoma was first recorded by Lindau in 1926 (206), although retinal hemangiomas had already been described by Collins (207) and more definitively by von Hippel in 1904 (208). The condition is transmitted as a dominant trait with variable penetrance. Its prevalence is 1 in 40,000 to 50,000 (209). The von Hippel–Lindau (VHL) gene has been localized to the tip of the short arm of chromosome 3 (3p25–p26). It codes for two different tumor-suppressor proteins (210,210a,211).
As a rule, VHL disease does not present during the pediatric years, although cerebellar hemangioblastomas can be seen as early as 9 years of age (211a). More often symptoms are delayed until the second or third decade. They can be referred to the eye with sudden intraocular hemorrhage or to the posterior fossa with increased intracranial pressure or cerebellar signs (212). Of the gene carriers, 51% have retinal hemangiomatosis, and 46% have CNS hemangioblastoma. Most commonly (52% of cases), the neoplasm is located in the cerebellum. It can be found in the spinal cord in 44% and in the brainstem in 18% of patients with CNS hemangioblastoma (213). Vortmeyer and colleagues found angiomesenchymal tumorlets in the nerve roots, spinal cord, and cerebellum in postmortem CNS tissue from four patients with VHL (214). Antiangionenic treatments with interferons and thalidomide are being tested in progressive CNS hemangioblastomas (215).
Associated with the retinal and cerebral lesions are a number of systemic lesions that tend to progress and become apparent during adult life. These include pancreatic cysts, found in 72% of autopsied patients with VHL, and various other pancreatic endocrine lesions (216); kidney cysts, seen in 59% of autopsies; juvenile renal carcinoma (217); liver cysts, seen in 17% of autopsies; and epididymal cystoadenomas, seen in 7% of autopsies. VHL also is associated with the adult form of renal carcinoma, seen in 45% of autopsies, and pheochromocytomas, seen in 17% of autopsies. The high incidence of pheochromocytomas, which are often bilateral, appears to be limited to certain families in whom pheochromocytomas are usually the first expression of the disease, becoming manifest as early as 5 years of age (218).
A high CSF protein content is seen in the majority of subjects, and approximately 50% of patients with cerebellar tumors have polycythemia, the consequence of erythropoietin production by the tumor. MRI appears to be an excellent means for screening and follow-up examinations of affected family members in that it can detect neoplasms before the development of symptoms (219).
Ataxia-Telangiectasia
Ataxia-telengiectasia (AT) is characterized by slowly progressive cerebellar ataxia, ocularmotor apraxia, choreoathetosis, telangiectasis of the skin and conjunctivae, susceptibility to sinobronchopulmonary infections, lymphoreticular neoplasia, other malignancies, and sensitivity to ionizing radiation (220). It was described by Syllaba and Henner in 1926 (221), by Louis-Bar in 1941 (222), and more definitively in 1958 by Boder and Sedgwick (223), who presented the first clinical and neuropathologic delineation of the disease and named it AT. AT has a frequency of approximately 1 in 40,000 births in the United States.
Pathology and Pathogenesis
The gene for AT (ATM, AT, mutated) has been mapped to the long arm of chromosome 11 (11q23.3). It has been cloned, and it codes for a nuclear serine/threonine protein kinase ATM, which activates the cellular response to double-stranded breaks in the DNA (224,225). These proteins are involved in the cellular responses to DNA damage, cell-cycle control, and maintaining telomere length (226,227). The ATM protein is localized in both the nucleus and cytoplasm. Screening for the gene has disclosed
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a large variety of mutations, most of which are unique for a given family, with nonconsanguinous patients being compound heterozygotes (226,228). The majority of mutations give rise to a truncated and nonfunctioning protein (228). As a result, a number of biochemical and cellular abnormalities occur.
One basic lesion results in a marked increase in cellular sensitivity to ionizing radiation. This sensitivity is accompanied by a normal response to ultraviolet irradiation. Radiosensitivity of AT cells appears to result from an inability to recognize and respond to the presence of DNA damage by inhibition of DNA synthesis. In normal cells, reduced DNA synthesis provides time for DNA repair before DNA synthesis is resumed at its preinjury rate. Although there is no defect in the ability to repair or remove strand breaks, fibroblasts derived from patients with AT contain increased amounts of topoisomerase II, an enzyme involved in inducing the transient breaks in double-stranded DNA (229).
Another feature of AT that arises from cellular sensitivity to ionizing radiation is the increased incidence of chromosomal breaks and rearrangements. Spontaneous intrachromosomal recombination rates are 30 to 200 times higher in fibroblasts derived from patients with AT than in normal cells (230). Translocations between chromosomes 7 and 14 are particularly frequent and can occur in the vicinity of the genes that code for the T-cell receptor and IgG genes (226).
Another basic characteristic of AT is a variety of immunologic abnormalities involving both the cellular and the humoral arms of the immune system (226). Low levels of serum and secretory IgA are found in 70% to 80% of patients (231). Additionally, low or borderline values for IgG2 and IgG4 are almost invariable (232). IgE is decreased or absent in 80% to 90% of patients, whereas IgM, IgG1, and IgG3 levels tend to be high (232). In most subjects, the deficiency of IgA and IgE results from impaired synthesis, although a high catabolic rate, the consequence of circulating anti-IgA antibodies, also has been noted (233). As a consequence of these humoral deficits, antibody response to various bacterial and viral antigens is deficient. Impaired cellular immunity is common in older children and is reflected in hypoplastic, embryonic-appearing tonsils, adenoids, and lymphoid tissue. In spite of the high prevalence of laboratory immunologic abnormalities, systemic bacterial, severe viral, and opportunistic infections are uncommon in AT, and the immune defect is rarely progressive (234).
ATM protein is believed to also be involved in a complex system that prevents apoptosis after DNA damage (235). A defect in this system could be responsible for cell death within the nervous system as well as within the thymus and the vascular endothelium (226,236).
Such a cell loss is the most striking finding on neuropathologic examination. This is most clearly seen in the cerebellar cortex where extensive loss of both Purkinje cells and internal granular cells occurs. Surviving Purkinje cells contain eosinophilic cytoplasmic inclusion bodies. Older patients show demyelination of the posterior columns and the dorsal spinocerebellar tracts (237,238). In some instances, loss of anterior horn cells also occurs. Examination of peripheral nerves can reveal lipid inclusions in Schwann cells and a slight degree of axonal degeneration (238). Vascular malformations have been found inconsistently within the nervous system and the meninges (239).
Clinical Manifestations
AT is not a rare condition. Next to tumors of the posterior fossa, it is the most common cause for progressive ataxia in children younger than 10 years of age.
Cerebellar signs appear in infancy or early childhood. The telangiectases, which are characteristically located over the exposed areas, bulbar conjunctivae, bridge of the nose, ears, neck, and antecubital fossae, are first seen at between 3 and 10 years of age (Fig. 12.10) and become more marked with exposure to sunlight (240,241). Thinning and premature graying of the hair and loss of skin elasticity and subcutaneous fat also are prominent.
Approximately 85% of patients develop choreoathetosis, apraxia of eye movements, and nystagmus. Hypotonia, diminished reflexes, and generalized muscular weakness also have been observed and occur later. Imaging studies show cerebellar atrophy. Although normal initially, intelligence usually becomes impaired as the illness progresses, perhaps owing to diminished stimulation. Most patients experience recurrent sinopulmonary infections. Neoplastic disease is common. In particular, children
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with AT are 40 to 100 times more likely to develop lymphoma, leukemia, lymphosarcoma, and Hodgkin’s disease than their peers (242). Other associated neoplasms include basal cell carcinoma, adenocarcinoma of the stomach, ovarian dysgerminoma, and a variety of brain tumors. In obligatory heterozygotes, the incidence of malignancies is increased threefold, with breast cancer being the most likely malignancy to be encountered in an AT heterozygote (243,244). Approximately one-half of patients develop an unusual form of diabetes in adolescence, characterized by hyperglycemia with only rare glycosuria, absence of ketosis, hypersecretion of insulin, and peripheral resistance to the action of insulin (245).
FIGURE 12.10. Telangiectasia of the bulbar conjunctiva in a 12-year-old child with ataxia-telangiectasia. (From Boder E, Sedgwick RP. Ataxia-telangiectasia. In: Goldensohn ES, Appel S, eds. Scientific approaches to clinical neurology. Philadelphia: Lea & Febiger, 1977. With permission.)
As expected from their in vitro fibroblast radiation sensitivity, children with AT are unusually sensitive to radiotherapy (246). It is unknown whether this radiosensitivity extends to the malignant cell lines derived from AT subjects.
Generally, the clinical course is downhill, although neurologic deterioration decelerates after adolescence. Death results from bronchopulmonary infection or malignancies.
Diagnosis
The diagnosis of AT is not difficult when the oculocutaneous lesions and the neurologic picture, particularly the oculomotor apraxia, are fully developed. In their absence, a young child often presents with progressive cerebellar ataxia. Friedreich ataxia, the late infantile or juvenile neuronal ceroid lipofuscinoses, Refsum disease, and abetalipoproteinemia must all be considered.
Several laboratory tests assist in the diagnosis. A clinical diagnosis can now be confirmed by radiosensitivity testing (colony survival assay), immunoblotting, and mutation detection (247). Elevated α-fetoprotein levels are found in up to 95% of patients and precede by several years the appearance of telangiectases (248,249). An elevated carcinoembryonic antigen also was present in nearly all patients with AT. The characteristic defect in serum immunoglobulins, the demonstration of impaired delayed hypersensitivity responses, and the demonstration of spontaneous chromosome breaks also can assist in the diagnosis. MRI of the brain shows cerebellar atrophy. Prenatal diagnosis of the disease is available by showing mutations in the AT gene (250).
Milder forms of AT have been recognized (251). These patients have a later onset of neurologic symptoms, absence of telangiectatic lesions, less severe ataxia, and a longer life span (228). In these patients, the ATM protein is present but in reduced amounts.
The Nijmegen breakage syndrome (NBS) is an autosomal recessive disorder characterized by microcephaly, a birdlike facies, growth retardation, immune deficiency, an increased incidence of lymphoid cancers, and cellular sensitivity to ionizing radiation. The gene (NBS1) for this disorder differs from the AT gene; it has been localized to chromosome 8q21 (252). It encodes a protein called nibrin, which is involved in the repair of DNA double-stranded breaks. The pathologic characteristic of this disorder is an oligyric microcephaly, an indication that the NBS1 gene is involved in corticogenesis (252a). While ATM and NBS regulate several genes in common, both of these proteins have distinct patterns of gene regulation—findings consistent with the functional overlap and distinctiveness of these two conditions (235).
Treatment
No specific treatment prevents the neurologic progress of AT. Intercurrent sinopulmonary infections can be prevented by γ-globulin therapy or treated with antibiotics and postural drainage using a regimen similar to that used for cystic fibrosis.
Incontinentia Pigmenti and Hypomelanosis of Ito
Incontinentia pigmenti and hypomelanosis of Ito (HI) have considerable clinical similarity. Incontinentia pigmenti (Bloch-Sulzberger syndrome) is an X-linked disorder with lethality in male subjects. It is characterized by incontinence of melanin from the melanocytes in the basal layer of the epidermis into the superficial dermis. The skin lesions are erythematous and bullous at birth, crusting with residual pigmentation. They tend to follow a dermatome distribution. Neurologic symptoms are seen in up to 30% of patients (253). These include seizures, spasticity, microcephaly, and mental retardation (254). MRI discloses a variety of abnormalities. These include hypoplasia of the corpus callosum, neuronal heterotopias, and small or large vessel occlusion (255).
HI is characterized by hypopigmented lesions occurring in whorls and located on the trunk, head, or extremities, following a dermatome distribution, the lines of Blaschko. In the series of Pascual-Castroviejo and colleagues, mental retardation and seizures were found in 76% of subjects, macrocephaly in 23%, and hemihypertrophy in 20% (256). Some 10% of patients showed infantile spasms during the first year of life, and another 10% had autistic behavior. In addition, a variety of ophthalmologic abnormalities occur, notably microphthalmos and choroidal atrophy. Gray matter heterotopias, cerebellar atrophy, and intracranial arteriovenous malformations are occasionally seen on imaging studies (257). The disorder is probably heterogeneous, and in some instances, the phenotype may result from the loss of pigmentation genes (258).
Recent evidence convincingly indicates that HI is not a discrete disorder as originally believed but instead is a nonspecific pigmentary disorder caused by chromosomal mosaicism. It almost always occurs sporadically, and it
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seems to be caused by a de novo mutation in early embryogenesis. Although HI is often considered the fourth most common neurocutaneous syndrome, it is an uncommon condition, with only 1 affected individual in every 600 to 1,000 new patients in a pediatric neurology service.
TABLE 12.5 Some Neurocutaneous Syndromes
Condition Signs and Symptoms Reference
Angiomatoses
   Wyburn-Mason syndrome Facial nevus flammeus, telangiectases intracranial cirsoid aneurysm, racemose angioma of retina, seizure disorder, and variable degree of mental retardation 259,260
   Cutaneomeningospinal angiomatosis (Cobb syndrome) Vascular skin nevus at birth, angioma of spinal cord, neurologic symptoms appearing in childhood (see Chapter 12) 261
   Riley-Smith syndrome Macrocephaly, pseudopapilledema, multiple hemangiomas 262,263
   Osler-Weber-Rendu disease Telangiectases on tongue, face, mucous membranes, liver, and brain, epistaxes, intracranial hemorrhage, autosomal dominant hereditary pattern Chapter 13
   Gass syndrome Cavernous hemangiomas of retina, intracranial cavernous hemangiomas, angiomatous hamartomas of skin 264
Linear nevus sebaceus Yellow papules in linear patches (may be evident at birth), mental retardation, seizures, various developmental and vascular anomalies of CNS 265,266
Leopard syndrome Lentigenes, electrocardiographic abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation, sensorineural deafness, autosomal dominant gene 269,271,270
Xeroderma pigmentosum (De Sanctis–Cacchione syndrome) Neurologic abnormalities (20%; 90% in Japan), microcephaly, mental deterioration, ataxia, choreoathetosis sensorineural hearing loss, peripheral neuropathy Chapter 4
Klippel-Trenaunay syndrome Capillary hemangioma, lymphedema, angioma of gut and bladder, hypertrophy of long bones, macrocephaly, intracranial and intraspinal angiomas Chapter 13
Neurocutaneous melanosis Multiple pigmented skin nevi present at birth, meningeal melanosis tending to become malignant, hydrocephalus, seizures 267,268
Treatment for HI is symptomatic. The skin lesions require no special treatment, and individuals do not have to take extra precautions with exposure to ultraviolet light. For children without additional neurologic manifestations, an annual follow-up appointment is recommended. The hypopigmented lesions tend to darken with time. Children with HI and neurologic complications will benefit from special education services. Dentists can frequently treat abnormalities of the teeth. Surgery, corrective glasses, vision therapy, and medication may help some of the ophthalmologic conditions seen in HI. Patients suffering from seizures may benefit from antiepileptic drugs, but almost 30% of patients with HI have refractory epilepsy.
Some of the other less common neurocutaneous syndromes are presented in Table 12.5 (259,260,261,262,263,264,265,266,267,268,269,270,271).
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