Malformations and Neurocutaneous Disorders

Tumors and Developmental

Disorders

CHAPTER 70

Malformations and Neurocutaneous Disorders M. Bahr and B. L. Schlaggar

Malformations of the central nervous system (CNS) are irreversible structural defects caused by disturbances of normal prenatal or postnatal development. Normal maturation of the CNS involves a predictable sequence of stages, each precisely timed in its evolution. With an insult to one or more of those stages, a brain malformation can result. The specific types of malformations seen are determined by the timing of the insult to the brain, the duration of that insult, and its severity (Barth, 1992; Volpe, 2001a;b). Some insults are brief (e.g., a one time exposure to a toxin), whereas others may occur over many weeks or throughout an entire gestation (e.g., recurrent uterine bleeding, gestational diabetes mellitus, maternal alcohol abuse, genetic defects). The clinical consequences of these events are determined by the regions of brain affected and the extent of any cerebral malformation that results. The neurological deficits caused by some cerebral malformations are rarely apparent immediately after birth, because subtle neurological abnormalities usually cannot be appreciated at that time, even by the most skilled examiner. Thus, these cerebral dysplasias are often not detected until later in life, not uncommonly by chance when neuroradiological studies are done for unrelated reasons (e.g., in a school child who is having difficulty learning to read). The rate of developmental abnormalities of the brain may be as high as 3 % (Kalter and Warkany, 1983). The most definitive way to confirm the presence of a CNS malformation and to delineate its pathology is by direct histopathological examination (Friede, 1989). In the absence of such examination, high-resolution imaging techniques—computed cranial tomography (CCT) and especially magnetic resonance imaging (MRI)—will almost always demonstrate those developmental CNS disorders that are of greatest clinical importance (Barkovich, 1995). Neurological Disorders: Course and Treatment, Second Edition Copyright 2003, Elsevier Science (USA). All rights reserved.

CLASSIFICATION An understanding of the sequence of events in neuroembryology provides a framework for an appropriate classification scheme for the array of malformations seen clinically (for excellent and detailed textbook reviews see Sarnat and Menkes, 2000 and Volpe, 2001a,b). The neurons and glia of the CNS are derived from a specialized region of ectoderm called the neural plate. Adjacent mesoderm induces the neural plate to form the neural tube during the first 4 weeks of gestational life, a process called neurulation. Between the third and fourth gestational weeks, the lateral margins of the neural plate close over dorsally to form the neural tube. During this closure, the neural crest cells are formed, and these give rise to dorsal root ganglia, sensory ganglia of cranial nerves, autonomic ganglia, Schwann cells, and cells of the pia and arachnoid. The neural tube gives rise to the CNS and spinal cord. Closure of the neural tube proceeds rostrally and caudally; the rostal end closes at approximately 23-25 days, the caudal end at about 25-27 days (McLone and Dias, 1994). With an insult or a genetic defect acting during this time, a disorder of neurulation can result (Table I). The rostral end of the neural tube later gives rise to antecedents of the telencephalon. Lesions that interfere with CNS development when the rostral neural tube is closing are expressed mainly as midline defects and malformations of the prosencephalon (telencephalon and diencephalon) (Table I). Accordingly, interference with closure of the caudal neural tube manifests as meningomyelocele, for example. The cavity of the neural tube gives rise to the ventricular system, while dividing neuroepithelial cells located at the ventricular surface in the wall of the neural tube generate progenitors for neurons and glia. Most of these progenitors migrate outward from the 947

948 TABLE I

TUMORS AND DEVELOPMENTAL DISORDERS Gestational Timing of Some CNS Malformations

Type of malformation

II,

III.

IV.

V.

VI.

Disorders of neurulation Craniorachischisis totalis Anencephaly Encephaloceles Meningomyeloceles Malformations of the prosencephalon Atelencephaly, aprosencephaly Holoprosencephaly Septooptic dysplasia Disorders of proliferation and/or migration Schizencephalies Lissencephalies (agyria) Pachygyria, polymicrogyria Disturbances of differentation Microcephaly, megalencephaly Neurocutaneous disorders Corpus callosum hypo-/aplasia Aicardi syndrome Colpocephaly Congenital vascular malformations and CNS tumors Aqueduct stenosis Encephalo clastic Porencephaly Multicystic encephalopathies, Hydranencephaly Cerebellar malformations Chiari malformations Cerebellar hemisphere hypoplasia and aplasia Cerebellar vermis hypoplasia and aplasia Dandy-Walker malformations Disorders of myelination Hypomyelination, dysmyelination, delayed myelination

Gestational stage 3-4 weeks of gestation 3 weeks 4 weeks 4 weeks 4 weeks 5-10 weeks of gestation 5 weeks 5-6 weeks 6-7 weeks 2-5 months of gestation 2 months 3 months 3-5 months 1-6 months of gestation 2-4 months 2-4 months or later 3-5 months 2-3 months 2-3 months 4 months 3 months-perinatal

4 weeks-1 year postnatal 4 weeks 6 weeks 6-10 weeks 7-10 weeks

7 months-first years postnatal

Disorders described in the text appear in italics.

neutral tube between the 6th and 24th gestational week. When normal proliferation or migration of these progenitors is disrupted, disturbances of normal organization (i.e., gyral formation, lamination) of the cerebral cortex are seen (Table I). On reaching their final destination, neurons and glia differentiate to their characteristic mature forms; if this process is disturbed, errors of differentiation result (Table I). The cerebellum is a portion of brain with a relatively protracted development (between the first gestational month and the first postnatal year), making it vulnerable to malformation over a long developmental period (Table I). Malformations of the cerebellum are frequently associated with cerebral malformations. One of the latest stages in maturation of the CNS is myelination of the fiber tracts. CNS myelination can be interfered with between the late stages of pregnancy and through the first postpartum years (Table I). (Disorders of myelination are not dis-

cussed in this chapter. Interested readers are referred to Lyon et aL [1996]. This is a brief but excellent textbook on the neurology of hereditary neurological diseases of childhood, including leukodystrophies.) Abnormalities of the ventricular system and disorders of the cerebrovascular system are described elsewhere (Chapters 41 and 60). Developmental malformations of the leptomeninges can result in CSF-fiUed arachnoid cysts, which are usually classified according to their location along the neuraxis (Table I). PRINCIPLES OF THERAPY General Principles The therapeutic options for treatment of CNS malformations are presently limited to prevention and symptomatic management. Because disorders of neurulation can be caused by folic acid-deficient states, prevention of folic acid deficiency is of utmost importance (Fishman, 2000). Hence, periconceptional folic acid (0.4mg/day) use is recommended*** (Thompson et aL, 2000). In addition, avoidance of folic acid antagonists (such as some anticonvulsants and antibiotics) by women of child-bearing age is recommended** (Hernandez-Diaz et aL, 2000). Most instances of brain malformations are sporadic, but specific genetic disorders are increasingly recognized (see later). Hence another form of prevention is genetic counseling. Most cerebral malformations, particularly the migrational disorders and many of the neurocutaneous disorders (discussed later), are accompanied by seizures that require treatment with anticonvulsants and/or neurosurgery (see Chapter 20 and 21). Interferences with normal CSF flow typically manifest as hydrocephalus and may require medical treatment to slow the formation of CSF (e.g., acetazolamide or furosemide for the treatment of communicating hydrocephalus) or surgical shunting of CSF, usually from a lateral ventricle to the peritoneum (e.g., V-P shunting for treatment of noncommunicating hydrocephalus caused by DandyWalker, Chiari, or other malformation or from an aqueductal stenosis or interventricular foraminal blockade as in tuberous sclerosis) (for treatment of hydrocephalus see Chapter 60). Other disorders that are associated with intracranial tumors (such as acoustic neuromas in neurofibromatosis 2) or with arachnoid cysts (as in Aicardi syndrome) may call for surgical treatment. On occasion, direct surgical intervention may result in a cure (as with a Chiari I malformation). DISORDERS OF NEURULATION Among the most frequent CNS malformations are disorders caused by incomplete or defective formation

MALFORMATIONS AND NEUROCUTANEOUS DISORDERS

of the neural tube. Incomplete closure of the cranial end of the neural tube results in anencephaly (which is lethal) or in meningoceles or meningoencephaloceles (also known as encephalomeningoceles). Defective closure of the caudal neural tube results in spinal meningoceles or more frequently, spinal meningomyeloceles (also known as myelomeningoceles). Complete failure of neural tube closure results in cranioraschisis totalis, which is fatal. The prenatal diagnosis of these disorders is usually quite easily accomplished with an ultrasonographic examination, although serum alphafetoprotein screening seems to yield a greater diagnostic sensitivity (Pilu et aL, 2000).

Encephaloceles Meningoencephaloceles (usually shortened in name to encephaloceles) are less common than meningomyeloceles, with a prevalence of about 1 in 10,000. Roughly two dozen inherited syndromes associated with encephalocele are listed on the Online Medelian Inheritance in Man (OMIM) (www3,ncbiMlm.gov/Omim), In Western countries, 85% of encephaloceles are posterior in location, whereas anterior encephaloceles are more common in Asia (Aicardi, 1992a). With the posterior lesions, tissue from the occipital lobe, cerebellum, or brainstem can be contained within the sac, and not uncommonly there are also accompanying malformations of brain (often agenesis of the corpus callosum but also other malformations of cerebrum, cerebellum, or mesencephalon). In half of the cases, there is associated hydrocephalus. Somatic malformations are frequent as well. Hamartomatous cerebral tissue is frequently found within the wall of the encephalocele. When the walls of the sac are thinned, CSF may escape, and meningitis can develop. The treatment of choice for smaller encephaloceles that do not contain viable brain tissue (10%-20% of the occipital lesions) (i.e., cranial meningoceles) is surgical excision and closure of the underlying cutaneous defect. With encephaloceles that contain brain tissue, and particularly those where the sac is large, the prognosis even with surgery is generally poor (Date et al., 1993). In general, outcome is more favorable for patients with anterior than with posterior encephaloceles (Brown and Sheridan-Pereira, 1992). For a discussion of surgical treatment strategies, see Mori (1985) and Humphreys (1994).

Meningomyeloceles Incomplete closure of the caudal neural tube occurs most often in the lumbar region (80%) and results in the formation of meningoceles or meningomyeloceles. The treatment of these lesions is determined to some

949

extent by their severity, following therapeutic guidelines similar to those applied to meningoencephaloceles earlier. Most physicians advocate early surgery, because the likelihood of reversing any associated deficits tends to decrease with age (May, 1992). With rare exceptions, meningoceles and meningomyeloceles should be surgically excised. Lumbar (including thoracolumbar and lumbosacral) meningomyeloceles are often associated with a paraplegia and usually a neurogenic bladder disorder as well. By contrast, most patients with lesions that extend below SI are ultimately able to walk unaided (Liptak et al., 1992). About 90% of patients with lumbar meningomyeloceles have hydrocephalus develop from an associated Chiari malformation (accompanied by an aqueductal stenosis in 4 0 % - 7 5 % of cases); by contrast, with occipital, cervical, thoracic, or sacral lesions, the incidence of hydrocephalus is about 60% (this occurs only with meningomyeloceles, not with uncomplicated meningoceles [Aicardi, 1992a]) (see Chapter 60 for treatment of hydrocephalus). Long-term neuropediatric, neurosurgical, urological, and orthopedic follow-up is required for all patients in whom a myelocele and especially a meningomyelocele is repaired. It is important to watch for late complications, (such as retethering of the cord or hind brain herniation), so these can be dealt with promptly. The question of optimal mode of obstetrical delivery for fetal meningomyelocele has been raised. Many centers act on the belief that the long-term outcome is bolstered by cesarean section and avoid vaginal delivery (Luthy et al., 1991). A recent retrospective study suggests that in isolated fetal meningomyelocele mode of delivery has no clear impact on outcome (Merrill et al., 1998). Tulipan and colleagues have argued that in utero repair of meningomyelocele may reduce the degree of hindbrain herniation normally seen in patients with myelomeningocele, thereby decreasing the morbidity associated with the Chiari type II malformation (see later), including brainstem dysfunction, hydrocephalus, and syringomyeha (Tulipan et ai, 1998).

MIDLINE MALFORMATIONS, DEVELOPMENTAL MALFORMATIONS OF T H E PROSENCEPHALON Holoprosencephaly (Disorder of Prosencephalon Cleavage) Several variants of holoprosencephaly (HPE; an undivided forebrain) have been described, based on the appearance of the observed defects. These include alobar, semilobar, lobar, and abortive lobar forms and aplasia of the olfactory bulbs and tracts. In alobar, the most severe form, one finds absence of the interhemi-

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TUMORS AND DEVELOPMENTAL DISORDERS

spheric fissure with a single-sphered cerebrum and a common ventricle, a membranous roof over the third ventricle, undivided basal ganglia, absent olfactory bulbs and tracts, and hypoplasia of the optic nerves, v^ith the cerebral cortex surrounding the single ventricle exhibiting the cytoarchitecture of the hippocampus and other limbic structures; the cortex often also show^s disordered neuronal migration. The diencephalon is also undivided. In semilobar, the interhemispheric fissure is evident posteriorly. In lobar, there is absence of the anterior corpus callosum and continuity of the frontal lobes and basal ganglia. There are often accompanying cranial malformations (e.g., microcephaly), and facial malformations (e.g., hypotelorism, flattened nose, bilateral cleft lip and palate, single central incisor), as well as frequent developmental defects of the cardiac, gastrointestinal, genitourinary, and musculoskeletal systems (Volpe, 2001a). The severity of the facial feature dysmorphism correlates fairly well with the degree of cerebral malformation leading to the axiom that "the face predicts the brain." For example, cyclopia, predicts alobar pathosis, whereas mild hypotelorism is more consistent with semilobar or lobar pathosis. The frequency of HPE is 1 in 15,000 live births, with a 60-fold greater incidence (~1 in 250) in aborted embryos (Cohen, 1989; Kinsman et aL, 2000). Chromosome abnormalities are increasingly recognized. At least 12 different loci have been associated with HPE (Walhs and Muenke, 2000). Familial instances have shown varied patterns of inheritance, including autosomal dominant, autosomal recessive, X-linked recessive. Being the infant of a diabetic mother seems to increase the risk of HPE 10-fold (Volpe, 2001b). Disturbances of several factors/genes have recently been implicated as potential causes of holoprosencephaly, such as mutations of telencephalin; a telencephalon-specific glycoprotein, SIX3; a homeobox gene of the sine oculis family of transcription factors, sonic hedgehog; ZIC2 or TGIF, a homeodomain protein that represses transcription of certain proteins (Kinsman et al., 2000; Wallis and Muenke, 2000). The clinical pictures seen are extremely variable and include a wide spectrum of abnormalities of the cranium, brain, and extracranial structures, with the lobar forms typically relatively less affected. The patients are usually severely mentally retarded and frequently have seizures. Infants with alobar HPE ususally die within the first few months. The prenatal diagnosis of HPE is usually relatively easy and can be made from the 16th week of pregnancy by ultrasonography (Chervenak et aL, 1985). Management of HPE is directed at the attendant neurological problems of seizures, nonprogressive encephalopathy, pulmonary aspiration, blindness, and spastic para/tetraparesis and hydrocephalus.

Hypothalamic/pituitary axis abnormalities such as deficient thyroid-, growth-, adrenocorticotropic-, and antidiuretic-hormones must be suspected, and, if present, specific interventions are needed (Cameron etal., 1999).

Septo-Optic Dysplasia Septo-optic dysplasia (SOD) represents a disorder of development of the midline prosencephalic structures. These structures include the commisural, chiasmatic, and hypothalamic plates. Differential involvement of these plates produces the array of malformations seen clinically. For example, in SOD, which typically includes underdevelopment or absence of the septum pellucidum, optic nerves, and optic chiasm, the commisural and chiasmatic plates are involved. Accordingly, agenesis of the corpus callosum can be seen. With involvement of the hypothalamic plate there can be hypothalmic/pituitary dysfunction. The constellation of absent septum pellucidum, optic nerve hypoplasia, hypothalamic/pituitary insufficiency is called DeMorsier syndrome. Minor forme frustes have been recognized such as isolated agenesis of the corpus callosum and septum pellucidum cyst. There may be accompanying malformations of the olfactory system, other parts of the rhinencephalon, and other midline structures. Midline prosencephalon malformations can also be seen with disorders of cerebral cortex proliferation/migration such as SOD and schizencephaly and Aicardi syndrome. Clinical features of SOD include varying degrees of visual disturbances, developmental delay, and endocrine abnormalities (especially growth hormone deficiency and central diabetes insipidus) (Aicardi, 1992a) (for treatment, see Chapters 102-104). Hypotensive and or hypoglycemic crisis accounts for two out of three deaths in these patients (Cameron et aL, 1999). The etiology is unknown. Recently, a novel homeobox gene called Hesxl on chromosome 3p21.1-p21.2 has been implicated in the development of septo-optic dysplasia (Dattani et al,, 2000). Nonetheless, familial SOD is decidedly uncommon, suggesting that most cases are sporadic, with risk of recurrence less than 5%.

DISORDERS OF PROLIFERATION A N D / O R MIGRATION Schizencephaly This deficit, also referred to in the literature as agenetic porencephaly and familial porencepahly, occurs when there is complete agenesis of a portion of the neuronal germinative zone, resulting in unilateral or bilateral clefts extending through the entire cerebral

MALFORMATIONS AND NEUROCUTANEOUS DISORDERS

hemisphere from the ependymal Uning of the lateral ventricles to the pial covering of cortex (Barkovich, 1995). Frequently classified as a defect in migration, schizencephaly also likely represents a disorder of proliferation taking into account the apparent failure of portion(s) of the neuronal germinative zone. A vascular insult has been implicated (Barkovich and Kjos, 1992). The clefts are lined by thickened pachygyric or polymicrogyric cortex; their lips can be fused (closed-lip schizencephaly) or separated (open-lip schizencephaly), w^ith hydrocephalus a frequent accompaniment of the latter variety (Byrd et al, 1989; Yakovlev and Wadsv^orth, 1946). Motor disabilities and seizures are present in most cases, whether bilateral or unilateral (Barkovich and Kjos, 1992). With a unilateral cleft w^ith fused lips, intelligence is often normal; with a unilateral cleft with open lips, there is usually mild-to-moderate developmental retardation; with bilateral clefts, there is usually severe retardation, early onset of seizures, major motor handicaps, and frequent blindness (often secondary to optic nerve hypoplasia) (Barkovich, 1995). Recent findings support the role of germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly (Brunelli et al., 1996). The role of EMX2 in the development and differentiation is not yet clear, but a recent study suggests its contribution in the differentiation of neocortical areas (Bishop et al.^ 2000).

Lissencephaly (Agyria) and Pachygyria The most severe migrational abnormality is lissencephaly (smooth brain), which can be diagnosed by CCT scan and particularly well by MRI (Barkovich, 1995). In lissencephaly the brain has few if any gyri (hence agyria in the extreme). Two general types of lissencephaly have been distinguished. In type I, or classical lissencephaly, the cerebral wall is like that of a 12week old fetus, with an outermost cell-poor layer, a diffuse cellular layer (containing neurons characteristic of lower layers of cortex), a zone of columns of heterotopic neurons, and an innermost band of white matter. Additional findings can include enlarged ventricles and hypoplasia of the corpus callosum. In type II lissencephaly, the cortex consists of clusters and circular arrays of neurons, with no recognizable lamination or other organization, separated by glial and vascular septa, with prominent neuronal heterotopias (thus the term "cobblestone hssencephaly"). A striking feature of cobblestone lissencephaly is the apparent loss of integrity of the pial surface that typically defines the outermost surface of the cortical mantle. It seems that migrating neurons stream through the compromised pia and then travel haphazardly and tangentially once beyond the compromised pial boundary. Recognized

951

syndromes consistently involving type II lissencephaly commonly have an associated muscular dystrophy and can have retinal abnormalities (discussed later) (Volpe, 2001b). In pachygyria, the features are similar to those of lissencephaly but less marked, with a paucity of gyri that are unusually broad and with an abnormally thickened and poorly organized cerebral cortex. However, the number of neurons is not clearly fewer (Volpe, 2001b). Most commonly, type I lissencephaly occurs either alone (isolated lissencephaly sequence; ILS) or with accompanying craniofacial and extracranial abnormalities (Miller-Dieker syndrome; MDS). Children with isolated type I lissencephaly show bitemporal hollowing, a small jaw, and early hypotonia, with later spastic quadriparesis, seizures beginning in the first year, and severe mental retardation. These children characteristically become microcephalic during their first year. In isolated pachygyria, similar but milder clinical findings are seen. The radiological findings in type I lissencephaly are best seen with MRI, which shows a smooth cortical surface with disorganization of the cortical architecture and accompanying colpocephaly (discussed later) in all cases. Type I lissencephaly is usually sporadic, although occasionally it is of autosomal recessive inheritance (Dobyns, 1989). In MDS, in addition to bitemporal hollowing and a small jaw, there is a characteristic facies, with a short, upturned nose; a long, thin, and protuberant upper lip; and a flattened midface. Accompanying genital, cardiac, and limb abnormalities are seen. The neurology of MDS is similar to that of ILS, although in MDS the neurological abnormalities tend to be even more severe. These abnormalities consist of severe mental retardation, seizures, and spastic quadriparesis. Death before 1 year of age is common. ILS seems to be a microdeletion of 17pl3.3 involving the LISl locus (Ledbetter et al., 1992), whereas MDS is due to a larger deletion/translocation involving LISl and encompassing surrounding gene(s) in the sub-band pl3.3 (Dobyns et aL, 1993). The gene product of LISl, the regulatory gamma subunit of platelet activating factor (PAF) acetylhydrolase, is directly implicated in neuronal migration in the neopallium and cerebellum (Sweeney et aL, 2000). The diagnosis of MDS can be made by commercially available fluorescent in situ hybridization. In addition to somatic line mutations in LISl, type I lissencephaly can also be seen in men with mutation of the doublecortex (DCX) gene located at Xq22.3-q23. The name "double cortex" comes from the cortical appearance in affected women. Whereas men have a typically lissencephalic brain, affected women can have subcortical band heterotopia where there is a concentric but subcortical "band" of neurons that have failed to migrate to the cortical plate proper, thus a "double

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TUMORS AND DEVELOPMENTAL DISORDERS

cortex." The overlying cortex might be thin and simpHfied, but it can also appear normal. The explanation for the gender difference stems from the fact that women, by virtue of random inactivation of one X chromosome in each somatic cell (lyonization; Barr body formation), are mosaic for the mutation. Cortical neurons whose inactivated X chromosome contains the wild-type allele will express only mutant gene product and consequently have abnormal migration. Those cortical neurons whose inactivated X chromosome contains the mutant allele will make normal gene product and migrate normally. The gene product of DCX is doublecortin, a microtubule-associated protein required for neuronal migration to the cerebral cortex (Gleeson, 2000). Mutation analysis for LISl and DCX is essential in determining the etiology of the disease in patients and can be helpful in determining the recurrence risk in families since LIS-1 is autosomal and doublecortin is Xlinked (Gleeson, 2000). An interesting neuroimaging clue that can help distinguish LIS-1 from DCX involvment is that the agyria appears more profound occipitally in LIS-1 cases, whereas it is more impressive frontally in DCX cases. The neurobiological significance of this observation has not been explained but is likely to relate to molecular gradients in the developing telencephalon already demonstrated to function in the differentiation of the neocortex (e.g.. Bishop et ai, 2000). The three disorders most strongly associated with type II lissencephaly are the Walker-Warburg syndrome (WWS), Fukuyama congenital muscular dystrophy (FCMD), and muscle-eye-brain disease (MEB). Each is inherited by autosomal recessive patterns (Dobyns, 1987). As noted earlier, these conditions each involve type II lissencephaly and congenital muscular dystrophy. In Walker-Warburg syndrome, there is /hydrocephalus, agyria, retinal dysplasia, ± ^ncephalocele (thus the acronym HARD ±E syndrome) with accompanying macrocrania (congenital or less often, developing in the first year), hypoplasia, or absence of the cerebellar vermis with or without Dandy-Walker malformation, and muscular dystrophy. Neurologically, severe seizures and mental retardation are seen, as in type I lissencephaly, to which marked hypotonia and weakness are added, because of the accompanying muscle disease. The putative locus for WWS is 9q31 (Toda et al., 199S). In contrast to WWS, FCMD has less severe lissencephaly and no retinal dysplasia. Myocardial fibrosis can be seen. FCMD is seen more commonly in Japanese people. The gene locus for FCMD is also known to be at 9q31, raising the possiblity that FCMD and WWS are "genetically identical" (Toda et aL, 1995). The predicted protein of the FCMD gene, called fukutin, is thought to be a secreted extracellular matrix component (Kobayashi et aL, 1998). This putative func-

tion could account for both loss of pial integrity and muscular dystrophy when fukutin is deficient. Although MEB is phenotypically very similar to WWS, a genetic locus has recently been identified at Ip34-p32 (Cormand et aL, 1999). In principle, WWS may be allelic to both FCMD and MEB. Most children with type II lissencephaly die in early infancy (Aicardi, 1992a).

Polymicrogyria In polymicrogyria the cerebral cortex is subdivided by a large number of very small folds causing its external surface to look like that of a wrinkled chestnut. The polymicrogyria can be of four distinct layers (as seen in destructive encephalopathies of ischemic or infectious type [e.g., in hydranencephaly or cytomegalovirus disease]), perhaps occuring during cortical migration. The polymicrogyria can be nonlayered as with disorders of peroxisomes such as Zellweger syndrome and neonatal adrenoleukodystrophy. In patients with Zellweger syndrome, a lethal panperoxisomal disorder, and in mice lacking the Pxrl import receptor for peroxisomal matrix proteins, the absence of peroxisomes leads to abnormal neuronal migration (Gressens et aL, 2000). Children with polymicrogyria typically have frequent seizures and severe developmental delay. Symmetrical forms of polymicrogyria have been noted in both sporadic and familial forms. In these patients one might find bilaterial perisylvian, frontal, or occipital polymicrogyria. Deficits can range from extremely mild and localized to severe mental retardation and seizures. The causes of symmetrical polymicrogyrias are not known but are presumed to be genetic. Seizures accompanying the neuronal migratory disorders are often refractory to anticonvulsants. When hydrocephalus coexists, for example, with lissencephaly, shunting may be needed, although the clinical outcome is unlikely to be influenced substantially. Because neuronal migration that gives rise to formation of the cerebral cortex is associated temporally and causally with development of the corpus callosum, the migrational disorders discussed previously are frequently accompanied by underdevelopment or agenesis of the corpus callosum.

DISTURBANCES OF DIFFERENTIATION The disorders classically listed as malformations of differentiation (Table I) (Friede, 1989) could be included in other categories as well, but for the sake of

MALFORMATIONS AND NEUROCUTANEOUS DISORDERS

simplicity they will be addressed here. Note that the neurocutaneous disorders are discussed in a separate section later. Agenesis of the corpus callosum is a common malformation with a prevalence determined by CCT scanning, ranging from 0.74%-2.3% (Sarnat, 1992). From a developmental standpoint, it can be the result of the aberrant development of the prosencephalic commisural plate, as discussed earlier. The agenesis can be either complete or can occur in partial form, with the missing portion usually the posterior part, because the corpus callosum develops in an anteroposterior direction. Although cases may occur in isolation, other brain abnormalities, such as Chiari II malformation or neuronal migrational disorders, frequently coexist (Barkovich and Norman, 1988). Dysmorphic-appearing cingulate cortex, commonly with everted gyri and misdirected Probst bundles, is frequently seen in patients with complete agenesis of the corpus callosum (Barkovich and Norman, 1988). This observation is consistent with the notion that the cingulate callosal fibers pioneer the corpus callosum (Koester and O'Leary, 1994). When accompanied by chorioretinal lacunae, vertebral abnormalities, infantile spasms, and developmental delay in a girl, the combination is called Aicardi syndrome. There are many other causes of callosal agenesis, including a variety of chromosome defects (e.g., trisomy 8), toxins (e.g., maternal alcohol abuse), and metabolic disorders (e.g., nonketotic hyperglycinemia) (Aicardi, 1992a). When agenesis of the corpus callosum occurs alone, accompanying symptoms may be absent or mild. In such cases, the agenesis is often found by chance when a CCT or MRI scan is done, often for unrelated reasons. When there are accompanying cerebral abnormalities, mental retardation and seizures are frequent findings. Extracranial malformations can coexist and can affect the face as well as the cardiovascular, genitourinary, gastrointestinal, and musculoskeletal systems (Kozlowski and Ouvrier, 1993). Agenesis of the corpus callosum is accompanied by elevation of the third ventricle, a radial rather than horizontal orientation of cerebral gyri (producing a "sunburst" appearance), and very often a malformed lateral ventricular system, which maintains its fetal morphology with enlargement of the occipital horns, an appearance called colpocephaly (Yakovlev and Wadsworth, 1946). Colpocephaly also occurs with other brain pathosis, including destructive encephalomalacias, with particular involvement of periventricular white matter (e.g., periventricular leukomalacia) and a number of developmental disorders of brain in which myelination is impaired. (Aicardi, 1992a; Herskowitz etal, 1985). Isolated cysts of the septum pellucidum or a cavum vergae are usually unaccompanied by any clinical symptoms.

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ENCEPHALOCLASTIC LESIONS: HYDRANENCEPHALY A N D PORENCEPHALY The cerebral ventricles can dilate because of loss of brain parenchyma (hydrocephalus ex vacuo) or can be enlarged on a maldevelopmental basis, as in some cases of colpocephaly (discussed earlier). The term porencephaly refers to a cavity or cavities in cerebrum (Gr. porus = hole), acquired either in utero or in early postnatal life. Although such lesions can be consequences of trauma, infection, and hemorrhage, ischemia is the most common cause. Porencephalic cysts of ischemic causation are usually found in the territory of middle cerebral artery supply (when unilateral, left-sided in 80%). Such ischemia has many possible causes, including vascular maldevelopment, vasospasm (as with cocaine exposure), embolic vascular occlusion (as from placental fragments with placental infarction), or vascular thrombosis (as with hypernatremic dehydration, disseminated intravascular coagulation, or a variety of hypercoagulable states) (Volpe, 2001c). True porencephalies always communicate with the cerebral subarachnoid space, and they often communicate with the ventricular system as well. The porencephalic defects are sometimes surrounded by microgyria, the presence or absence of which probably depends on the time of the insult (Aicardi, 1992a). Most porencephalic cysts do not need treatment, but occasionally they enlarge and cause an increase in intracranial pressure because of an accompanying ball valve that interferes with CSF outflow from the cyst. In that circumstance, surgical extirpation or shunting is needed. Furthermore, these cysts can be intimately associated with epileptogenic foci in medically intractable epilepsy requiring surgical removal. Bilateral porencephaly that is extreme in degree, with most of the cerebral hemispheres reduced to CSFfiUed sacs, is called hydranencephaly. When caused by ischemia, hydranencephaly is usually a sequel to bilateral cerebral infarction in the distribution of both internal carotid arteries (Halsey, 1987). Hydrocephalus often coexists with hydranencephaly and is amenable to treatment, but the cerebral defects of hydranencephaly are not. On occasion, severe hydrocephalus alone may mimic hydranencephaly; in such instances, even with extreme hydrocephalus, the outlook is much better than with hydranencephaly. When ischemic stroke in the perinate is suspected, a comprehensive screen for genetic and acquired risk factors is recommended (Gunther et aL, 2000). The risk of recurrence of ischemic stroke or other manifestations of thrombophilia after perinatal ischemic stroke is presently under investigation but is likely to be low. Accordingly, the role of antiplatelet and anticoagulation therapy in these patients is not known.

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TUMORS AND DEVELOPMENTAL DISORDERS

CEREBELLAR MALFORMATIONS Chiari Malformations Chiari malformations are complex disorders of early embryonic development. These are the most common dysplasias of the cerebellum and are associated with a wide variety of malformations of the rhombencephalon, mesencephalon, diencephalon, and telencephalon in different combinations. The Chiari malformations are classified into types I, II, III, and IV. Chiari I Malformation Clinical Aspects and Natural Course. Chiari I malformations are unilateral or bilateral herniations of the cerebellar tonsils down through the foramen magnum, with or without accompanying caudal displacement

of the medulla oblongata (Figure 1). Hydrocephalus, syringomyelia/bulbia, and malformation of the skull base and upper cervical spine (i.e., atlantoaxial dislocation, platybasia) are frequently associated. Clinical symptoms are often delayed until late in the third or fourth decade of life. Occipital headaches are frequent, and lower cranial nerve signs can be seen, with horizontal gaze evoked and downbeat nystagmus particularly characteristic. Ten percent of the patients have cerebellar signs. Paroxysmal bulbar signs and or headache brought on with cough or the Valsava moreover should prompt consideration of Chiari I malformation. Chiari I can be seen dramatically in infancy, with bulbar dysfunction such as dysphagia, stridor, apnea, and aspiration. A particularly concerning complication is development of sleep apnea, which can be the only clinical appearance of the syndrome (Zolty et uL^ 2000). A reversible acquired Chiari I malforma-

Chiari I Malformation

hydrocephalus

upward displacement of the lateral sinuses and tentorium enlargement of the foramen magnum herniation of the cerebellar tonsilles

Dandy-Walker Malformation hydrocephalus upward displacement of the lateral sinuses and tentorium

enlarged posteria fossa

cerebellar hypoplasia cystic dilatation of the 4. ventricle

FIGURE 1 Typical features of a Chiari I and a Dandy-Walker malformation. On the left side, a schematic drawing of the main neuroradiological findings in the sagittal plane and on the right side, original sagittal MR pictures are shown.

MALFORMATIONS AND NEUROCUTANEOUS DISORDERS

tion has been described with CSF leakage after lumbar puncture (Samii et al.^ 1999). Most centers with an MRI facility are equipped to perform CSF flow studies to demonstrate expected flow diminution at the foramen magnum; a finding consistent with symptomatic Chiari I malformations (Bhadelia et aL, 1995). Principles of Therapy. If the malformation is symptomatic, suboccipital decompression is recommended with exploration of the fourth ventricle and its outlet foramina and duraplasty (Munshi et al., 2000; see also treatment recommendations for Chiari II malformation). This intervention will reverse the symptoms in more than two thirds of patients, although up to one third of those treated will relapse within the next 3 years (Levy et al,^ 1983). The benefit from a surgical decompression in general seems to be greatest in patients who have only cerebellar symptoms and when the cerebellar dislocation is not below the CI level (Stevens et aL, 1993), although evidence for relief of pediatric headache exists (Weinberg et aL, 1998). Chiari II Malformation Clinical Aspects and Natural Course. The Chiari II malformation consists of inferior displacement of the medulla, fourth ventricle, and cerebellar vermis through the foramen magnum into the upper cervical canal. This displacement is accompanied by elongation and thinning of the upper medulla and lower pons and persistence of the embryonic flexure of these structures, along with bony defects of the foramen magnum, occiput, and upper cervical vertebrae. An accompanying myelomeningocele, most often in the lumbosacral region, with hydrocephalus is almost invariably present. Symptoms of brainstem dysfunction are of particular concern. These include vocal cord paralysis with laryngeal stridor, obstructive and central apnea, and dysphagia (with the last sometimes resulting aspiration pneumonia). There may be associated torticollis or retrocoUis, scoliosis, and hydromyelia (Paul et aL^ 1983). Maldevelopment of the skull base and upper cervical spine, as with Chiari I, can be seen. The symptoms are usually present at birth, but in some cases they may be first diagnosed later in childhood. In most cases of myelomeningocele with Chiari malformation, there are also accompanying abnormalities of cerebral cortical development, most often polymicrogyria, with or without disordered lamination, and neuronal heterotopias. Migrational anomalies of the cerebellum and brainstem are also noted (Gilbert et al., 1986). Mental retardation is often a consequence, caused either by the accompanying cerebral dysgenesis or by the hydrocephalus, especially if the latter has been shunted.

955

and complicating infections have necessitated shunt revisions (Aicardi, 1992a). Principles of Therapy. Accompanying meningomyeloceles should be treated surgically during the first days of life, and associated hydrocephalus should be shunted. If there is evidence for brainstem compression, with paraparesis, tetraparesis, dysphagia, torticollis, or retrocoUis, suboccipital decompression should be carried out (Carmel, 1983; Haines and Berger, 1991). This decompressive surgery can result in complete reversal of the neurological signs. Most patients with type II Chiari malformations need placement of a V-P shunt, particularly if there is an associated aqueductal stenosis (Mori, 1985). These shunts not uncommonly obstruct, and the resulting increase in intracranial pressure—if unrelieved—can be damaging to the brain and lifethreatening. Thus, blocked shunts should be revised promptly. All patients with surgically treated Chiari II malformations should be followed carefully long term, because delayed complications (such as retethering of the spinal cord or hindbrain herniation) are not infrequent and call for reoperation. In general, indications for surgical decompression of Chiari II malformations are similar to those for type I (Venes et aL, 1986). The outcome of patients with a Chiari II malformation who undergo surgical decompression, however, seems to be less favorable compared with patients with Chiari I malformations, depending on the grade of cerebellar ectopia (Stevens et al., 1993). Thus, patients with a level of the cerebellar ectopia below the C2 level have a 69% risk of deterioration by 18 months compared with an improvement of symptoms in about 50% of the patients with a cerebellar ectopia not below the CI level.

Chiari HI Malformation Clinical Aspects and Natural Course. Encephaloceles located in the low occipital or high cervical regions, when combined with deformities of the lower brainstem, skull base, and upper cervical vertebrae characteristic of the Chiari type II malformation, comprise the Chiari III malformation. This type of encephalocele contains cerebellum in virtually all cases and occipital lobe in about one half. Partial or complete agenesis of the corpus callosum occurs in two thirds (Volpe, 20001a). The treatment strategies of encephaloceles have already been delineated.

Chiari IV Malformation This type of malformation consists only of cerebellar hypoplasia and is not part of the Chiari deformity as it is now understood (Friede, 1989).

956

TUMORS AND DEVELOPMENTAL DISORDERS

Dandy-Walker

Malformation

Clinical Aspects and Natural Course. The DandyWalker malformation includes partial or complete absence of the cerebellar vermis, cystic dilation of the fourth ventricle, enlargement of the posterior fossa, upward displacement of the intracranial torcular and lateral venous sinuses and tentorium cerebelli, and accompanying hydrocephalus; findings are best seen v^ith MRI (Figure 1). The disturbance in Dandy-Walker malformation seems to be primarily a delay or total failure of the foramen of Magendie (exiting from the fourth ventricle) to open, leading to a build-up of CSF pressure and cystic dilation of the fourth ventricle. Despite subsequent opening of the foramina of Lushka (usually patent in Dandy-Walker malformation), cystic dilation of the fourth ventricle and impairment of CSF flow persist (Volpe, 2001a). Prenatal diagnosis is relatively easy from the 18th to 20th week (Newman, 1982). The prevalence of Dandy-Walker malformation is between 1 in 25,000 and 1 in 35,000, with girls more often affected than boys. Most cases are sporadic (Aicardi, 1992a). The dominant clinical feature in Dandy-Walker malformation is development of hydrocephalus early in life, usually with striking enlargement of the occipital skull. The neurological signs are those of increased intracranial pressure and others more specifically related to posterior fossa abnormalities, including lower cranial nerve palsies, nystagmus, and ataxia. Associated abnormalities of the cerebrum occur in up to 70% of cases, the most important being agenesis of the corpus callosum and disordered neuronal migration. As a result, mental retardation is frequent. Systemic abnormalities (e.g., cardiac, urinary) are present in 2 0 % - 8 0 % of cases (Volpe, 2001a). In the absence of developmental abnormalities of the cerebrum and with successful treatment of the hydrocephalus, the outlook is generally good. The mortality in such cases has varied from 10% (Hirsch et aL, 1984) to 40% (Pascual-Castroviejo et al.^ 1991), with the presence or absence of accompanying cerebral and extracranial malformations a major determinant of these outcome figures. For those cases detected in utero or in the neonatal period, the outcome is usually unfavorable, with about a 4 0 % mortality and cognitive deficits in 7 5 % of the survivors (Volpe, 2001a). Even with treatment, only 50% of children with Dandy-Walker malformation achieve an IQ of 80 or greater. With early surgery, the outlook for cognitive development is usually better. Principles of Therapy. Surgical treatment of the Dandy-Walker malformation is complicated by the presence of the fourth ventricular cyst. Unroofing of the cyst is usually not effective (Edwards and Raff el, 1987). Placement of a cystoperitoneal shunt is also usually not

effective, because the aqueduct in Dandy-Walker malformations typically does not allow adequate CSF flow. Thus, the preferred approach is to shunt both the cyst and the lateral ventricle at the same time, connecting the two catheters by a Y-connector to the peritoneal catheter (Osenbach and Menezes, 1992).

Arachnoid Cysts Clinical Aspects and Natural Course Arachnoid cysts are a common finding on CCT or MRI, with a frequency of 4 % ; they are seen more often in males. These cysts are fluid-filled cavities that develop within a duplication or anomolous splitting of the arachnoid membrane or between the arachnoid and the pia (Sarnat and Menkes, 2000) They may or may not communicate with the subarachnoid space (Aicardi, 1992c), which may be differentiated by uptake of contrast-enhancing substances from the CSF. Symptoms occur in only 10%-30% of cases (Harsh et al, 1986). These cysts are usually classified according to their location on the neuraxis. They are more often supratentorial than infratentorial, with 5 0 % - 6 0 % of the total found in the middle cranial fossa (Sarnat and Menkes, 2000) (Figure 2). They vary greatly in size. Location and size determine the presence or absence of clinical symptoms. Even large cysts can be asymptomatic. When located in the midline, they can compress the cerebral aqueduct or a foramen of Monro and cause obstructive hydrocephalus (Raimondi et aL, 1980). If located in the posterior fossa, they may simulate a tumor and can cause hydrocephalus by obstructing CSF flow. A minority of arachnoid cysts, similar to porencephalic cysts, have a ball-valve type opening and can accumulate CSF, causing progressive enlargement. Clinical symptoms associated with arachnoid cysts are extremely variable. In addition to those of intracranial hypertension from secondary hydrocephalus, there may be visual impairment, cranial nerve palsies, gait ataxia, seizures, endocrine abnormalities, and deformation of the skull (De Meyer, 1985). Focal symptoms can be caused by local pressure effects, hemorrhage into a cyst, or rupture of a cyst wall.

Principles of Therapy Symptomatic arachnoid cysts should be treated. When there is accompanying obstructive hydrocephalus, the cyst and the ventricular system should both be shunted with a common valve adapted to both systems to circumvent pressure differences between the two (Raimondi et aL, 1980). Complications include shunt failure, infection, and subdural hematoma (from

MALFORMATIONS AND NEUROCUTANEOUS DISORDERS

FIGURE 2

Typical location of an arachnoid cyst (arrows indicate the position of the cyst on the MR pictures).

957

958

TUMORS AND DEVELOPMENTAL DISORDERS

excessive or rapid decompression of the cerebral hemispheres). As an ahernative to shunting, these cysts can sometimes be treated effectively by fenestration of their walls into the surrounding normal CSF spaces (Baskin and Wilson, 1984; Raffel and McComb, 1994). Some of the cysts can be surgically excised, but the location of others results in a high rate of complication with attempted removal (Rappaport, 1993).

N E U R O C U T A N E O U S DISORDERS The skin, eye, and central nervous system share a common neuroectodermal origin. The neurocutaneous disorders or phakomatoses (Gr. phakoma = birth spot or mother spot) are a complex group of conditions affecting two or three of these neuroectodermal derivatives simultaneously and other organs as well. Most are genetic. Systemic manifestations of these disorders commonly include skeletal overgrowth, hamartomatous tumors (such as fibromas and myomas), and vascular malformations (particularly angiomas) that can involve the skin, eye, or CNS. The degree to which different tissues are involved is extremely variable. Therapies differ depending on the symptoms that are present or the ones that can be anticipated and may include excision of tumors or angiomas that are causing seizures and shunting of CSF for treatment of accompanying hydrocephalus. Genetic linkage studies have been useful in diagnosing these disorders in more mildly affected patients in whom the diagnosis might otherwise not have been appreciated. Table II summarizes the known patterns of inheritance in different neurocutaneous disorders.

TABLE II

Neurocutaneous Disorders

Autosomal dominant inheritance Neurofibromatosis Tuberous sclerosis V, Hippel-Lindau disease Nevoid basal cell carcinoma syndrome (Gorlin-Goltz syndrome) [Hypomelanosis Ito] Autosomal recessive inheritance Ataxia teleangiectatica Louis-Bar* [Xeroderma pigmentosum] Cockayne syndrome* [Fucosidose] [Phenylketonuria] [Homozystinuria] [Argininosuccinaciduria and Citrullamia] [Carboxylase-deficency] [Neuroichthyosis] Sjogren-Larsson syndrome* Refsum's disease* Giant-Axon neuropathy* [Werner Syndrome] [Progeria] Familiar dysautonomia* [Chediak-Higashi disease] X-chromosomal inheritance Fabry's disease* [Kinky hair disease] [Incontinentia pigmenti] Sporadic [Neurocutaneous melanosis] Sturge-Weber syndrome Klippel-Trenaunay syndrome* Syndromes that are indicated with an asterisk (*) are described in other chapters, rare disorders, indicated with [ ] should be further studied in the specialized literature of neuropediatrics. Disorders described in the text appear in italics. Modified according to Gomez (1991).

Neurofibromatosis (NF) Neurofibromatosis refers mainly to two different disorders, both of autosomal dominant inheritance, NF 1 and NF 2. Each has a broad range of clinical expression. Following the recommendations of the National Institutes of Health Consensus Development Conference (1988), classical neurofibromatosis (von Recklinghausen disease) has been referred to as NF 1, whereas neurofibromatosis restricted to the CNS, with accompanying bilateral VIII nerve tumors, is referred to as NF 2. Other variants described, accounting for less than 1% of all cases of NF (Pont and Elster, 1992), are referred to as NF 3-8 (Mackool and Fitzpatrick, 1992). NF 1 is the most frequent form, with a prevalence of 1 in 3000 to 1 in 4000 (Braffman and Naidich, 1994a; Gomez, 1991; Listernick and Charrow, 1990), accounting for 90% of all NF cases. N F l has a penetrance of almost

100% and variable expressivity; its mutation rate of 50% (Aoki et al, 1989) is one of the highest among all autosomal dominant diseases. The responsible gene has been mapped to band 11.2 of the long arm of chromosome 17 (Barker et ai, 1987), with the protein normally encoded by this gene called neurofibromin. Neurofibromin has sequence similarities to a family of proteins called guanidine triphosphatase-activating proteins (GAPs), which are involved in the inactivation of the proto-oncogene ras. Ras proteins are important for a variety of cellular processes, including cell proliferation and differentiation, and tumor formation. Neurofibromin acts as a tumor-suppressor gene by inhibiting Ras activity. Biochemical analysis of tumors in NF 1 gave evidence of hyperactive Ras, which may be a target for future therapies (Weiss et al,^ 1999). Neurofibromin is expressed at different levels in several organs, which

MALFORMATIONS AND NEUROCUTANEOUS DISORDERS

may explain the heterogeneity of the pathologic condition in NF 1. The clinical variability may also be contributed to by secondary somatic mutations (Gutmann and Collins, 1993). NF 2 is an autosomal dominant disorder that has been mapped to the 11.2 band of the long arm of chromosome 22 (Aicardi, 1992b). It affects about 1 in 50,000 individuals and is typically manifested at a later age than NF 1 (Mulvihill et aL, 1990), usually during or soon after puberty (Elster, 1992). NF 2 patients typically have bilateral vestibular schw^annomas develop, which are sometimes associated w^ith schwannomas at other locations, meningeomas, ependymomas, or juvenile subcapsular lenticular opacities. The disease is caused by inactivating mutations in a tumor suppressor gene on 22ql2, which encodes Merlin, a member of the protein 4.1 superfamily (Rouleau et al., 1993), which regulates differentiation and proliferation in various cell types (McCartney et al., 2000). Clinical Aspects The initial diagnosis of NF 1 is usually made by detection of multiple light brown, typically oval, skin lesions or cafe-au-lait spots (present in 99% of patients, but often not seen until infancy or later childhood), axillary TABLE m

959

or inguinal freckles (usually very numerous), and cutaneous or subcutaneous neurofibromas. The 1988 NIH criteria for the diagnosis of NF 1 are listed in Table III. Intracranial and Intraspinal

Tumors

About 5%-10% of NF 1 patients eventually develop intracranial tumors. The most common of these are optic pathway gliomas (OPT; optic pathway tumor). OPTs occur in 5 % - 1 5 % of children with NF 1 (Braffman and Naidich, 1994a; Gomez, 1991) and are one of the most frequent tumors in the first decade of life. Of all patients presenting with an OPT, about 2 5 % have NF 1 (Pont and Elster, 1992). Gliomas are also found in NF 1 in the brainstem and hypothalamus (Braffman and Naidich, 1994a). Neurofibromas, and less often, schwannomas, can involve spinal nerve roots in NF 1. When spinal nerve roots are involved it is typically the dorsal more often than the ventral root. Optic gliomas are not found in NF 2, but other intracranial tumors (meningiomas and schwannomas) and spinal tumors (schwannomas and ependymomas) are seen. The most characteristic intracranial tumor in NF 2, however, is the acoustic schwannoma, present in at least 90% of cases, almost always bilaterally. These tumors are rarely found in NF 1. Cutaneous manifestations are uncommon in NF 2, with few or no cafe-au-lait spots found in most patients (Aicardi, 1992b).

Diagnostic Criteria of NF 1 and 2

NF-1 Two or more of the following: 1. Six or more cafe-au-lait macules more than 5 mm in greatest diameter in prepubertal individuals and more than 15 mm in greatest diameter in postpubertal individuals 2. Two or more neurofibromas of any type or one plexiforme neurifibroma 3. Freckling in the axillary or inguinal regions 4. Optic glioma 5. Two or more Lisch nodules (iris-hamartomas) 6. A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex with or without pseudoarthrosis 7. A first-degree relative (parent, sibling, or offspring) with NF-1 by the above criteria NF-2 Either of the following 1. Bilateral eight nerve masses seen with appropriate imaging techniques (e.g., CT or MRI) or 2. A first-degree relative with NF-2 and either a unilateral eighth nerve mass, or two of the following: — Neurofibroma — Meningeoma — Glioma — Schwannoma — Juvenile posterior subcapsular lenticular opacity

Other Tumor Manifestations

in NF

Adolescents with NF also have an increased frequency of pheochromocytomas ( 0 . 5 % - l % ) , ganglioneuromas, carotid glomus tumors, rhabdomyosarcomas, Wilms' tumors and leukemia. In about 5% of patients with NF 1, a neurofibroma will undergo malignant transformation to a fibrosarcoma. This usually occurs after the age of 10 years and occurs most often with plexiform neurofibromas, the most common extracranial tumor in NF 1 (Pont and Elster, 1992). Plexiform neuromas are locally aggressive tumors with a tendency to centripetal growth (Braffman and Naidich, 1994a). Plexiform neurofibromas can undergo malignant transformation to one of the clinically most aggressive cancers associated with neurofibromatosis 1 (NFl), the malignant peripheral nerve sheath tumor (MPNST) (King et al, 2000). The development of MPNST occurs in about 5 % of identified plexiform neurofibromas. Thus when a patient with a plexiform neurofibroma notes an acute change in that tumor or new pain associated with it, a concerted effort to identify a malignant transformation is recommended. This includes MRI of the plexiform tumor, CT of the chest, and referral to a surgical oncologist (Gutmann, 1998). By contrast, cutaneous neuro-

960

TUMORS AND DEVELOPMENTAL DISORDERS

fibromas are not thought to undergo transformation. Other Neurological

maUgnant

Symptoms

Frequent brain-based neurological findings in NF 1 include mental retardation (8%) and learning problems (40%). There is an increased frequency of macrocrania (15%-45%) in NF 1 (Aicardi, 1992b), usually secondary to macrencephaly (large brain) or less often from hydrocephalia (usually from aqueductal stenosis). The brains of such children, in addition to being large, often show abnormalities in gyral formation and cortical architecture, which can explain the cognitive and learning deficits that are frequently found (Rosman and Pearce, 1975). GUal nodules are often found in the cerebral cortex of NF 1 patients and may be important contributors to the increased frequency of seizures seen in NF 1. MRI scans of patients with NF 1 show small punctate or confluent foci of increased signal intensity within brain parenchyma on T2-weighted images, especially in cerebellum, brainstem, globus pallidus, thalamus, and supratentorial white matter. These foci, probable hamartomas, occur in 60%-80% of patients (Duffner et aL, 1989; Elster, 1992). They are more frequent in younger NF 1 patients, resolving with increasing age, and are rarely seen after age 20 (Aoki et al.^ 1989). Their precise significance is unknown, but the degree of their distribution (i.e., widespread versus focal) correlates with measured intelligence in children with NF 1. A more widespread distribution correlates with lower measured intelligence (Denckla et aL, 1996). Anomalies of the Skeleton About 0 . 5 % - l % of all NF 1 patients have congenital pseudoarthroses (usually of the tibia or radius). In about 2 % of NF 1 patients, scoliosis or kyphoscoliosis develops, usually in the second decade of life. This occurs most often in the lower cervical and upper thoracic regions. Cardiorespiratory compromise may result. Underdevelopment of the greater wing of the sphenoid bone, which forms the posterior wall of the orbit, is not uncommonly seen in NF 1 and causes a pulsatile exophthalmos. Malformations

artery stenosis or by a pheochromocytoma. Cardiovascular malformations are found in 2 . 3 % of NF patients (Lin et aL, 2000).

of the Vasculature

Vaso-occlusive disease can be seen in NF, with the abdominal aorta, and the iliac, mesenteric, renal, or cerebral arteries beeing common sites for such involvement. A Moya-Moya vascular syndrome can develop with or without a history of radiation therapy. Arterial hypertension is found in about 1 % of NF patients, most often in adolescence; this is usually caused by renal

Natural Course Except for optic glioma, which usually is seen in the first decade of life, most of the clinical signs of NF develop after puberty. As indicated earlier, these signs are extremely variable, because they depend on the nature and location of the causative pathosis. Overall, life expectancy in NF is somewhat shortened. Principles of Therapy The treatment of NF is entirely symptomatic. Anticipation of the wide array of potential problems is a necessity. Surgical treatment may be cosmetic or may be needed to remove tumors from one or more body sites. Radiation of the tumors is usually without benefit in NF 1 (optic glioma is a possible exception) and should generally be avoided, because the consequences of encephalopathies and other complications of radiation can be more severe than those of the underlying lesions (Gomez, 1991). The biological behavior of OPTs in NF 1 varies with their location and age of presentation. Hence the management of children with OPT and NF 1 depends on the location of the tumor and age of the child at presentation. Tumors anterior to the chiasm frequently remain stable for many years, whereas more posteriorly located gliomas tend to be invasive. OPT, which is seen before the age 6, is more likely to grow rapidly and progress (Schroder et aL, 1999). Several authors have cautioned, however, that spontaneous improvement/regression of OPTs occurs, also more commonly in younger patients (Perilongo et al., 1999; Rossi et aL, 1999). In general, surgery has played a limited role in the management of OPT, reserved for the most aggressive or poorly located. Until recently, the most experience has been with the use of radiation therapy localized to the tumor. However, the use of radiation therapy in younger children (<6 years old) is highly associated with endocrinological, cerebrovascular (e.g., Moya-Moya syndrome) and neuropsychological adverse sequelae (Cappeli et al.^ 1998). Recently, the usefulness of chemotherapeutics, carboplatinum and vincristine, has been advocated, particularly in younger children (Listernick et aL, 1999; Silva et al.y 2000). At this time, a reasonable approach to OPT in children with NF 1 is to document progression before intervention. If intervention is warranted, chemotherapy should be considered, particularly for younger children. Surgery and radiation therapy should be limited to selected cases. Therefore, depending on a variety of circumstances, treatment of OPT in NF 1

MALFORMATIONS AND NEUROCUTANEOUS DISORDERS

should include regular ophthalmological and neuroradiological (MRI) follow-up with the possiblity of no intervention, chemotherapy, radiation therapy, surgery, or some combination of these modalities (Aicardi, 1992a; Gutmann, 1998). Shunting is frequently needed for hydrocephalus caused by third ventricular obstruction (from an optic glioma) or from aqueductal stenosis. Acoustic neuromas should be surgically excised, which is accomplishable in most cases. When excision is not possible, radiation therapy can be considered, particularly in elderly patients, in others at high surgical risk, and in those who have been operated on one side with development of a contralateral tumor with hearing that is still satisfactory on that side (Flickinger et al., 1993; Maire et aL, 1992). Table IV provides an overview of the major craniocerebral manifestations of NF and therapeutic options to be considered. Special educational assistance and behavior modification should be provided to children with NF who have learning and behavioral problems. Recently, application of vitamin D3 analogues was found effective in improving the pigmentation of the cafe au lait spots in NF patients (Nakayama et aL, 1999).

Tuberous Sclerosis (TS) Tuberous sclerosis (eponym: Bourneville-Fr ingle disease) is another neurocutaneous disorder of autosomal dominant inheritance. Multiple organ systems are affected with hamartomas seen in brain, retina, skin.

961

heart, kidneys, and lungs. Other organs can be involved as well, although less often. The disease is of dominant inheritance, but 60% of cases seem to arise by spontaneous mutation (Smirniotopoulos and Murphy, 1992). The prevalence varies from 1 in 10,000 to 1 in 40,000, figures that are probable underestimates because of the variability of symptoms, which are quite minor at times, and the frequency of entirely asymptomatic patients (Ahlsen et al.^ 1994). Gene loci have been identified on chromosome 9 (Gomez, 1991) and chromosome 16 (Nellist et aL, 1993), which encode the tuberous sclerosis complex (TSC) genes TSCl (hamartin) and TSC2 (tuberin), respectively (Crino and Henske, 1999). Both genes are expressed widely in the brain and interact in signalling pathways that regulate cellular differentiation and tumor suppression (Miloloza et aL, 2000). About 50% of the TSC families show linkage to TSCl and 50% to TSC2. Clinical Aspects Tuberous sclerosis is classically characterized by the clinical triad of mental retardation, epilepsy, and socalled adenoma sebaceum (facial angiofibroma), with onset before the age of 10. Many patients, rather than showing this classical triad, have incomplete forms. The most common skin lesions in TS are hypopigmented macules (present in 90%; seen best under ultraviolet light), facial angiofibromas (seen in about 50%, usually after 5 years of age), and fibrous plaques (usually found on the forehead or scalp, and sometimes at birth as the earliest diagnostic sign of TS) (Gomez, 1991). CNS

TABLE rV Craniocerebral Manifestations of NF, Clinical Relevance, and Therapeutic Options Type of manifestation 1. Tumors Neurofibromas, neurilemmomas Meningiomas

Preferred location

Cranial nerves VIII, V, IX-XII Convexity, falx cerebri

Vascular tumors of brain Astrocytomas

Cerebellum Optic pathways

Diffuse gliomatosis

Cerebrum, brainstem

Hamartomas 2. Malformations Migrational disorders Stenosis of the aqueductus cerebri Sceletal features

Vascular malformations

Clinical aspects

Often bilateral, Vlllth nerve symptoms Multiple tumors occur, recurrent manifestation

Principles of therapy

Excision, stereotactic radiation Surgical excision

Hypothalamus

Early manifestation of the disease Rare manifestation, no clinical signs Endocrine dysfunction

Surgical excision Chemotherapy radiation therapy (surgical excision) No treatment required, radiation without influence on natural course Surgical excision, if possible

Cerebrum Aqueductus cerebri

Epilepsy, mental retardation Occlusive hydrocephalus

Treatment of seizures V-P shunting

Pseudoarthrosis, absence of the greater sphenoidal wing Aorta, ihac, mesenteric, renal and cerebral arteries

Proptosis and pulsating exophthalmus

Plastic surgery

Secondary hypertension

Symptomatic

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TUMORS AND DEVELOPMENTAL DISORDERS

involvement includes three types of pathoses, cortical tubers, subependymal nodules, and cerebral white matter migration lines. Cortical tubers are hard nodules with increased astrocytes, decreased neurons, giant cells, and disturbed lamination. By radiological and histopathological methods, they may be indistinguishable from focal cortical dysplasia. Tubers are most commonly located in the cerebrum but can be found throughout the neuraxis. Subependymal astroglial nodules are frequently calcified, contrast-enhancing, and are found on MRI or CCT of the brain. They can transform to become subependymal giant cell astrocytomas. When located at the foramina of Monro (seen in 2 % - 2 6 % of cases) or the third ventricle, they can obstruct CSF flow and cause hydrocephalus; rarely, they undergo malignant transformation. Cerebral white matter migration lines are seen on MRI as white matter lesions containing clusters of heterotopic giant cells that produce an abnormal signal nearly identical to that produced by the cortical tubers (Braffman and Naidich, 1994a). They are likely indicative of aberrant neuronal migration contributing to the pathogenesis of TSC. One or more of the preceding neuroradiological findings is found in at least 90% of patients with TS. Almost half the patients have retinal or optic nerve hamartomas. One quarter have periungual or subungual fibromas develop (more frequent on the toes and in females, usually appearing after puberty). Grouped papules or shagreen patches (connective tissue naevus) usually occur on the dorsal trunk (seen in 20%) (Gomez, 1991). Despite the advances of molecular genetics of TSC, the diagnosis remains a clinical one. A National Institutes of Health Consensus Conference has recently updated the diagnostic criteria for tuberous sclerosis complex (Table V; adapted from Roach et ai, 1998). Note that these new diagnostic criteria do not include genetic or famililal criteria. The NIH consensus paper also includes recommendations for diagnostic and surveillance screening for TSC in both children and adults (Hyman and Whittemore, 2000) (Table VI). MRI is the brain imaging modality of choice for a suspected case or the initial diagnostic evaluation, although it is less sensitive for demonstrating subependymal nodules compared with CCT. CCT is recommended for screening an "asymptomatic" parent, child, or first-degree relative at the time of diagnosis of an affected individual as long as the physical examination is negative. Follow-up imaging in children should be on the order of every 1-3 years, but modified per clinical scenario (e.g., known nodule at foramen of Monro). In adults surveillance neuroimaging can be less frequent than in children. Neurodevelopmental testing should be performed in children as part of the initial

TABLE V Current Recommended Diagnostic Criteria for Tuberous Sclerosis Complex Major features Facial angiofibroma ("adenoma sebaceum") or forehead plaque Nontraumatic ungual or periungual fibroma Hypomelanotic macules (>3) Shagreen patch (nevus) Multiple retinal nodule hamartomas Cortical tuber* Subependymal nodule Subependymal giant cell astrocytoma Cardiac rhabdoyoma Lymphangiomyomatosis^ Renal angiomyolipoma^ Minor features Multiple randomly distributed dental enamel pits Hamartomatous rectal polyps (histologic confirmation suggested) Bone cysts (radiographic confirmation sufficient) Cerebral white matter migration lines* Gingival fibroma Nonrenal hamartoma (histological confirmation suggested) Multiple renal cysts (histological confirmation suggested) Retinal achromic patch "Confetti" skin lesions Definite TSC: either 2 major or 1 major and 2 minor features. Probable TSC: 1 major and 1 minor feature. Possible TSC: either 1 major or >1 minor features. *When cerebral cortical dysplasia and cerebral white matter migration tracts occur together, they should be counted as one rather than two features. ^When both lymphangioleiomyomatosis and renal angiomyolipomas are present, other features should be present before definite TSC can be diagnosed. Based on NIH Consenus, adapted from Roach et al., [1998], and published with permission.

evaluation and before primary school matriculation. An EEG should be performed when clinically driven and not as part of the initial evaluation. Funduscopic examination should be performed as part of the initial evaluation and then as indicated clinically (Hyman and Whittemore, 2000) (Table VI). Seizures develop in 8 0 % - 9 0 % of patients with TS and are the presenting symptom in as many as 75%. They usually begin in the first year of life and may be partial or generalized; common patterns are tonic/clonic seizures, atypical absences, and especially infantile spasms. Mental retardation is seen in about 50% of patients with TS and is closely linked with the occurrence of seizures, particularly when seizures are of early onset. TS patients without seizures, or those in whom seizures develop late, usually have normal intelligence (Wiss, 1992). Most patients with TS have behavioral/psychiatric problems, and some become frankly autistic (Ahlsen et aL, 1994; Curatolo et ai, 1991).

MALFORMATIONS AND NEUROCUTANEOUS DISORDERS

963

TABLE VI Diagnostic and Surveillance Screening in Tuberous Sclerosis Complex

Fundoscopic examination Brain MRI Brain EEC Cardiac ECG, Echo Renal CT, MRI, US Dermatological screen Neurodevelopment Pulmonary CT

"Asymptomatic" parent, child, or first-degree relative at time of diagnosis of affected individual

Suspected case or initial diagnostic evaluation

+ +'

+ +

J +' +

-

e

+ + + +^'

-

Known caseJ and no symptoms in referable organ Child

Known case and symptoms or findings previously documented

Adult

Child

Adult

+ + +' +^ + +' +^ +^

+' +'' +' +' +^ +'' +'' +''

_

_

+^

+'

V -

+'

+^

-

-

+'

^With negative physical examination results, CT is recommended. Every 1 to 3 years. ^Probably less frequently than in children. As clinically indicated. ^Unless seizures are suspected, this is generally not useful for diagnosis. 'Unless needed for diagnosis. ^Every 6 months to 1 year until involution or size stabilization occurs. Ultrasound is generally recommended because of cost, although local imaging expertise may vary. ^Every 3 years until adolescence. ^Generally for children only. Recommended for children at the time of beginning first grade. For women at age 18 years. Modified from, and published with permission, Hyman, M.H., Whittemore, V.H., Archives of Neurology. Volume 57, page 664. Copyright [2000], American Medical Association.

Systemic involvement in TS beyond that listed in the diagnostic criteria include periosteal nev^ bone formation, pulmonary cysts and fibrosis, and splenic cysts (Gomez, 1991). Cardiac rhabdomyomas and renal angiomyolipomas are quite common, occuring in nearly half of TSC patients (Gomez, 1991). Natural Course The neurocutaneous manifestations of TS are usually recognized early in childhood. Although the life expectancy in TS is shortened, patients v^ith no or minimal symptoms may have a normal life span. The clinical manifestations are protean, reflecting the multisystem involvement. Principles of Therapy Cognitive development is best in patients with TS who are treated early and effectively (Gomez, 1985). Infantile spasms (IS) are typically well managed with adrenocorticotrapic homone (ACTH), with sodium valproate, nitrazepam, and clonazepam as acceptable second-line drugs. Recently, vigabatrin has been successfully used in several studies with TSC patients with

complete cessation of the seizures in 9 5 % and complete cessation of the infantile spasms in 54% (Hancock and Osborne, 1999), suggesting that vigabatrin can be considered as an alternate first-line monotherapy of infantile spasms. Of course, the risk of irreversible peripheral retinal injury must be considered before initiating vigabitrin. At present, a prospective head-to-head study of vigabatrin and ACTH for IS in TSC is not available. However, such studies do exist for IS per se (reviewed in Wong and Trevathan, 2001). In general, vigabatrin and ACTH likely have comparable efficacy for the treatement of IS, with better tolerance reported for vigabatrin (Wong and Trevathan, 2001). Other seizure types are treated as outlined in Chapter 20. Excision of one or more cortical tubers may be indicated if they serve as seizure foci in patients in whom medical treatment has been ineffective (Koh et aL, 2000). Obstructive hydrocephalus is usually treated with shunting. Occasionally, a giant cell astrocytoma needs to be surgically resected from the region of a foramen of Monro. Facial angiofibromata can be treated with laser surgery. A point of controversy at present is the putative risk of whole cell pertussis vaccine facilitating onset of infantile spasms in susceptible TSC patients. It is probably

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TUMORS AND DEVELOPMENTAL DISORDERS

reasonable to withold the whole cell pertussis vaccine in susceptible patients at this time. Future work should be directed at evaluating the safety of the acellular pertussis vaccine. Referral to a genetic counsellor is recommended for parents who wish to have more children and for individuals with TSC who are of child-bearing age.

strating underlying cerebral calcifications (MartiBonmati et al.^ 1992). Angiographic study shows impaired superficial venous drainage and shunting of blood to the deep venous system, with development of abnormally dilated deep veins (Benedikt et al, 1993; Braffman and Naidich, 1994b; Vogl et al, 1993). Differential Diagnosis

Sturge-Weber Syndrome (SWS, Encephalo-Trigeminal-Angiomatosis) Clinical Aspects Sturge-Weber syndrome (SWS) is a congenital malformation of the cranial vasculature. It is of sporadic occurrence. The prevalence is unknown but seems to be less common than NF or TS. The causative gene has not been found. In its complete form, there is a capillary/venous angioma of the face (nevus flammeus), most characteristically seen over the forehead and upper eyelid (the area supplied by first division of 5th cranial nerve, VI), with venous angiomatous involvement of the underlying leptomeninges (usually overlying the ipsilateral occipital lobe [Alexander and Norman, 1972]) and of the choroid in the ipsilateral eye. These findings can be unilateral or bilateral. Ischemic/hypoxic injury of the underlying brain (caused by stasis of blood in the overlying angioma and from impaired venous drainage from the cerebral cortex) frequently results in secondary calcifications, often paralleling pial blood vessels ("railroad track" appearance on cranial x-ray film). Also, abnormalities in gyral formation and cortical architecture can be seen (Wohlwill and Yakovlev, 1957). Reduced size of the underlying cerebral hemisphere can sometimes be seen on CCT or MRI soon after birth. Seizures, present in up to 90% of patients, are usually the first symptom of SWS and typically begin in early infancy. A hemiparesis contralateral to the cutaneous angioma is seen in up to two thirds of patients, a homonymous hemianopia is seen in almost all (Braffman and Naidich, 1994b). Mental retardation occurs in 60% (Pascual-Castroviejo et aL, 1993), particularly in those with seizures and bihemispheric disease (Gomez, 1991). By contrast, normal intelligence occurs when seizures are absent, even with bihemispheric lesions (Gomez and Bebin, 1987). The clinical diagnosis is usually not difficult, especially if typical signs such as a unilateral facial angioma, seizures, developmental delay, and a contralateral hemiparesis are found. Radiologically, the intracranial angiomas are best seen with contrast-enhanced MRI (which shows enhancing thickened leptomeninges) or by MRI angiography (which shows a pial blush overlying the affected hemisphere[s]), but CCT is better than MRI for demon-

The primary differential diagnosis of the facial angioma seen in SWS is the syndrome of KlippelTrenaunay, which includes facial/somatic hemihypertrophy, facial/somatic cutaneous nevi, seizures, and intracranial calcifications. In addition, celiac disease, Dandy-Walker syndrome, and hereditary neurocutaneous angiomatosis should be considered. Natural Course The prognosis of Sturge-Weber syndrome depends on the location and extent of the cerebral and ocular lesions. The neurological deterioration in SWS has been described as "saltatory," indicating abrupt changes in function with intervening periods of less-dramatic change. Patients at risk for neuro-ocular symptoms are only those in whom the cutaneous angioma involves the area supplied by VI (Enjolras et aL, 1985). The seizures are often partial, sometimes with secondary generalization, with a postictal paralysis (Todd) frequently found. The intracranial vascular malformations rarely bleed. With angiomatous involvement of the choroid, glaucoma is a common accompaniment. When this occurs in prenatal life, the child is typically born with congenital glaucoma with an accompanying large eye (buphthalmos). Angiomas can involve other organs as well. A unilateral facial angioma does not rule out bilateral cerebral involvement. Ten to 15% percent of patients with SWS do not have a facial angioma (Gomez and Bebin, 1987). Principles of Therapy Cerebral lesions, particularly when unilateral and accompanied by medically intractable seizures, can be treated surgically early in life (Gomez and Bebin, 1987). Corticectomy, lobectomy, or even hemispherectomy has been recommended. The greatest success is seen with operation on young patients in whom there has been no neurological deterioration. The cutaneous nevi can be treated with laser therapy with a good cosmetic result. Glaucoma can be treated medically and surgically. Enteric-coated aspirin at 3-5 mg/kg/day might be useful in patients with symptoms consistent with transient ischemic events. (Practitioners should follow guidelines comparable to those proposed for the treatment of chil-

MALFORMATIONS AND NEUROCUTANEOUS DISORDERS

dren with Kawasaki disease.) Genetic counseling should address the sporadic nature of the syndrome suggesting <5% chance of recurrence.

Von Hippel-Lindau Disease (VHL) Clinical Aspects and Natural Course Von Hippel-Lindau (VHL) disease is a disorder of autosomal dominant inheritance in which several organs of mesenchymal origin are affected. VHL patients typically have hemangioblastomas (vascular lesions with tumor cells) in the brain, particularly in the cerebellum (found in 3 5 % - 6 0 % of patients [Hubschmann et aL, 1981]); less often, hemangioblastomas are found in the medulla and in the retina. These patients also have tumor cysts (Lindau cysts) in other organs (particularly kidney, pancreas, and epididymis). They may also have renal cell carcinoma develop. Because 75% of the CNS hemangioblastomas are located in the posterior fossa, such patients usually are seen with headache, vomiting, and gait and limb ataxia, usually in the second to fourth decade (Braffman and Naidich, 1994b; Gomez, 1991) and rarely in the pediatric setting. Primary spinal involvement is rare, but spinal hemangioblastomas can be seen in as many as one quarter of the patients with brain involvement (Neumann et al.^ 1992). Once a cerebellar hemangioblastoma is found, it is important to search for these tumors outside the CNS, particularly in the retina, where hemangioblastomas are present in one half to two thirds of patients with VHL disease (Hardwig and Robertson, 1984). They are multiple in one third to two thirds of patients and bilateral in 2 0 % - 5 0 % (Huson et al.^ 1986). The diagnosis can be made under any one of the following three circumstances: (1) CNS and retinal hemangioblastomas; (2) CNS or retinal hemangioblastoma plus one of the following: renal, pancreatic, hepatic, or epididymal cysts; pheochromocytoma; renal cancer; (3) a definite family history of VHL plus one of the following: CNS or retinal hemangioblastoma; renal, pancreatic, hepatic, or epididymal cysts; pheochromocytoma; renal cancer (Michels, 1987). The earliest clinical evidence of VHL disease is often the finding of a retinal hemangioma, most frequently first seen in the third decade but sometimes as early as the first. The retinal lesions are often multiple. As they grow, the retina may detach. Ten to 20% of patients with retinal hemangioblastomas also have an intracranial tumor, and thus by definition have VHL disease (Gomez, 1991). Renal cell carcinoma (hypernephroma) occurs in 2 5 % - 4 0 % of patients with VHL (Horton et al, 1976), pheochromocytoma in about 10% (Hubschmann et aL, 1981). Polycythemia is often found with cerebellar

965

hemangioblastoma, and hematuria occurs in VHL patients with renal tumors. Polycythemia is likely due to excessive renal production of erythropoetin. The diagnosis of VHL disease is further supported by a positive family history. The incidence of the disorder is 1 in 50,000 (Neumann et al, 1992). The mean fife expectancy is about 50 years, with deaths from renal cell carcinoma or from cerebellar hemangioblastoma resulting in this reduced life expectancy. The gene locus for VHL has been mapped to chromosome 3p25-p26. The protein product is thought to have tumor suppressor function (Latif et aL, 1993). The VHL tumor suppressor gene has been demonstrated to be required for cell cycle exit (Pause et aL, 1998). Mutations in the gene result in constitutive up-regulation/expression of hypoxia-inducible genes like H I F l a , which in turn may be rseponsible for vascular tumors (Ohh et aL, 2000). Principles of Treatment Surgical removal of cerebellar hemangioblastoma is the treatment of choice in VHL patients. Radiotherapy is indicated in only those patients who have inoperable posterior fossa tumors (e.g., of the medulla) with progressing neurological signs. Stereotactic radiation may have a role to play. In 20% of patients, hemangioblastomas recur after initial surgery. Retinal angiomas are usually treated by cryosurgery or photocoagulation (Huson et al., 1986). VHL patients and others at risk for that disorder should be examined regularly, looking for (recurrent) hemangioblastomas and other evidence of the disease. When operable spinal tumors are found, they should be promptly excised, particularly if clinical symptoms are present. Therapeutic phlebotomy might be necessary in some cases of polycythemia.

Nevoid Basal Cell Carcinoma Syndrome (Gorlin-Goltz Syndrome) Clinical Aspects and Natural Course The nevoid basal cell carcinoma syndrome, or GorlinGoltz or Gorlin syndrome^ is of autosomal dominant inheritance. It is characterized by multiple basal cell carcinomas of the face, neck, and upper trunk that develop between puberty and age 35. The name nevoid basal cell carcinoma syndrome is misleading, however, because only 50% of these patients 20 years or older manifest the basal cell carcinomas, and it is only the rare lesion that becomes aggressive. Odontogenic keratocysts are characteristic of the disorder; they are seen late in the first decade and peak during the second or third decade (Gorlin, 1987). They are rarely symptomatic unless they become infected, although they can cause pathological

966

TUMORS AND DEVELOPMENTAL DISORDERS

fractures of the mandible or maxilla. Migrational abnormalities in the cerebrum occur, and seizures are frequent. Associated findings include skeletal abnormalities (such as frontal and parietal bossing, platybasia, and kyphoscoliosis); brain tumors (such as cerebellar medulloblastomas); other brain abnormalities (such as hydrocephalus); extraneural tumors (such as ovarian sarcomas); and endocrine abnormalities (such as hypogonadotrophic hypogonadism) (Gomez, 1991). Life expectancy is shortened. The pathogenesis of the disorder is unknown. Principles of Treatment The clinical course in nevoid basal cell carcinoma is extremely variable. Complications, such as hydrocephalus, should be treated actively. If the cysts found in this disorder are infected, antibiotics should be given. Larger cysts may require surgical removal. If there is an accompanying meduUoblastoma, it should be treated surgically rather than with radiation, because the latter predisposes to development of new skin lesions or malignant transformation of those already present (Gomez, 1991).

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