Agenesis and dysgenesis of the corpus callosum

Agenesis and Dysgenesis of the Corpus Callosum Guillermo Davila-Gutierrez Agenesis and dysgenesis of the corpus callosum is a frequent anomaly that presents with a spectrum of clinical features and exhibits variable findings in neurological studies. Clinical signs and symptoms are the result of cerebral and extracerebral malformations associated with callosal dysgenesis. Callosal agenesis may be an isolated anomaly or may be syndromic as part of more extensive malformations, metabolic and genetic disorders. The advent of modern techniques and equipment for neuroimaging have allowed us to define with more precision the type and severity of the callosal dysgenesis and accompanying other cerebral malformations. Molecular genetic studies allow the recognition and confirmation of new syndromes that until now were incompletely defined. In the context of these new pathologic entities, a new classification is proposed that may prove to be more useful than the traditional single category, "agenesis of the corpus callosum" and can serve as a basis for a later, more detailed, etiologic classification that integrates morphology and molecular genetics. Copyright 2002, Elsevier Science (USA). A l l rights reserved.

S THE CEREBRAL hemispheres develop, commissural fibers interconnect corresponding areas between them. The most important of these commissures cross in the primitive lamina terminalis (terminal plate), the rostral part of the forebrain. This plate extends from the diencephalic roof to the optic chiasm. The first commissures formed are the anterior and hippocampal, interconnecting the phylogenetically older parts of the forebrain. The anterior commissure joins the olfactory bulb, whereas the hippocampal commissure (psalterium) joins the formations of the same name. The largest cerebral commissure is the corpus callosum that connects neocortical areas, at first it is located at the level of the lamina terminalis; as the brain grows and fibers aggregate it extends beyond the lamina terminalis. The first callosal fibers form at day 74 of gestation, and formation is complete by 115 days. Fibers of the anterior commissure cross the midline on the 54 th day. To provide a pathway across the midline, a large glial barrier derived from the lamina terminalis must first undergo apoptotic breakdown and create a bridge along which the callosal axons may be guided. In one murine model of callosal agenesis, failure of apoptosis of this glial wall results in inability of axons to cross the midline, but whether

A

this same mechanism accounts for any human cases is unknown. Myelination of the human corpus callosum is initiated at about 4 months postnatally and continues into adolescence. An adult corpus callosum contains about 180 million axons, of which 40% are myelinated.l'2 Most of the fibers have an inhibitory function, and two loci responsible for the formation have been identified in the experimental model "mouse without a corpus callosum"; however, these corresponding loci have not yet been identified in the human. 2 Agenesis refers to the total lack of development of this commissure; dysgenesis, the more frequent condition, is a partial callosal agenesis, often associated with heterotopic fibers crossing the midline in other commissures and at aberrant sites. EPIDEMIOLOGY

Agenesis and dysgenesis of the corpus callosum (ADCC) occurs in about one to three infants per 1,000 births, is usually sporadic, 3 but may be transmitted as x-linked, autosomal-dominant, or autosomal-recessive traits. 4 ADCC have a prevalence, in studies based on cerebral tomography, of 2.3% in North American subjects, 0.79% in Japan, and 0.74% in France. In countries of Latin America, the statistical prevalence remains unknown. CLASSIFICATION

From the lnstituto Nacional de Pediatrfa, Servicio de Neurologia, Mexico. Address reprint requests" to Guillermo Ddvila-Gutidrrez, MD, lnstituto Nacional de Pediatr[a, Servicio de Neurologia, lnsurgentes Sur 3700-C, M~xico, D.F. 04530, Mexico. Copyright 2002, Elsev&r Science (USA). All rights reserved. 1071-9091/02/0904-0005535.00/0 doi: l O.1053/sper~2002.32505 292

At the moment there is no universally accepted classification of corpus callosal dysgenesis. For this reason I propose the following: 1. Agenesis and dysgenesis of the corpus callosum, isolated 2. Agenesis and dysgenesis of the corpus callosum, associated:

Seminars in Pediatric Neurology, Vol 9, No 4 (December), 2002: pp 292-301

AGENESIS AND DYSGENESIS OF THE CORPUS CALLOSUM

2.1. Agenesis and dysgenesis of the corpus callosum associated with other malformations of the brain (eg, holoprosencephaly; lissencephaly; hemimegalencephaly). 2.2. Agenesis and dysgenesis of the corpus callosum with cyst formation: 2.2.1. Cysts appear to be an extension or diverticuli of the third or lateral ventricles. 2.2.1. a. Associated with presumed communicating hydrocephalus but without other cerebral malformations. 2.2.1. b. Associated with hydrocephalus secondary to diencephalic malformations prohibiting egress of CSF from the third ventricle into the cerebral aqueduct (of Sylvius). 2.2.1. c. Associated with small head size and apparent cerebral hemispheric dysplasia or hypoplasia. 2.2.2. Cysts are loculated and do not communicate with the ventricles. 2.2.2. a. Multiloculated cysts not associated with abnormalities other than callosal agenesis/hypogenesis. 2.2.2. b. Associated with deficiencies of the falx cerebri, subependymal heterotopia, and polymicrogyria (Aicardi syndrome). 2.2.2. c. Associated with subcortical heterotopia. 2.2.2. d. Consists of interhemispheric arachnoidal cysts. 2.2.3. Agenesis and dysgenesis of the corpus callosum associated with sensory-motor neuropathy (Andermann syndrome). 2.3. Agenesis and dysgenesis of the corpus callosum associated with other neuropathies. 2.4. Agenesis and dysgenesis associated with metabolic diseases. 2.5. Agenesis and dysgenesis associated with fetal exposure to toxins. 2.6. Lipoma of the corpus callosum. 2.7. Agenesis and dysgenesis associated with other less frequent malformations. Point 2.2 is included in the classification by Barkovich et al 5 because callosal agenesis and dysgenesis with cysts constitute a heterogeneous group of situations that require special mention. Barkovich et al 5 based their classification on the imaging studies of 25 cases of corpus callosal

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agenesis with interhemispheric cysts, associated or without any other anomaly. CLINICAL FEATURES

The spectrum of clinical features that appear in patients with agenesis or dysgenesis of the corpus callosum are extremely variable and are more related to associated cerebral or extracerebral malformations than to the callosal agenesis itself. Nevertheless, many children with isolated callosal agenesis have hypertelorism since birth, and this mild facial dysmorphism may be a clue to the neuroanatomic anomaly and further justify neuroimaging studies. The hypertelorism associated with callosal agenesis also may include other midfacial dysmorphic features of the nose in particular, as in the frontonasal dysplasia sequence (median cleft face syndrome) of DeMyer. 6 The neurological features result from the manifestations caused by ADCC, including those originating in the severity and variety of the accompanying cerebral malformations: epilepsy, mental retardation, hydrocephalus, and morphologic and growth abnormalities that vary from hypotonia to severe spasticity, ataxia, autistic behavior, learning disabilities, and behavioral disorders. When ADCC presents as an isolated condition, intelligence usually is normal and clinical features are mild and frequently can go unnoticed by the clinician. Mental retardation can exist as Serur et al4 described in 1988. More thorough neurological examination reveals defects in transfer of information. A patient may be unable to name objects placed in the left hand while exhibiting normal stereognosis and naming of objects in the right hand because the epicritic tactile perception in the right hemisphere cannot be transferred to the left hemisphere for speech (naming), even though the patient understands what the object is. Other more subtle neuropsychological, perceptual, and motor defects also are evident. 7 Friefeld et al 8 evaluated interhemispheric somatosensory functions in children from 2 years 8 months to 11 years 9 months of age, who presented ADCC. They compared their findings with those found in an age-matched population who did not have neurodevelopment alterations. The tests included manual and bimanual stereognostic quantitation, visual discrimination, kinesthesia, and texture distinction. Children with callosal agenesis showed significant deficiencies at the test, com-

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pared with the results found in the control population. They concluded that children with ADCC have a lower capacity for processing somatosensory information. Symptoms of interhemispheric disconnection were less severe in simple callosal agenesis than in patients in whom a callosotomy had been performed as a therapeutic procedure for epilepsy. Two factors may explain this difference: (1) corpus callosum section is performed in a brain with maximal functional plasticity associated with early development stages; and (2) surgical division of the corpus callosum results in more disruption to functional cerebral organization that the natural developmental anomalies of this commissure. This is why it is suggested that a functional compensation in corpus callosotomy is not as great compared with hypoplasias of the corpus callosum. 9J~ ADCC is present in the presence of other neurodevelopment anomalies neuroblast migrational disorders including lissencephaly, ~ holoprosencephalyl Chiari II malformation, hydrocephalus, interhemispheric cysts, 4 arachnoidal cysts, neurocutaneus syndromes, schizophrenia, and others. This diversity of causes explains why patients show manifestations of the associated conditions: epilepsy, mental retardation, and alterations in muscle tone. When ADCC is correlated with other extracerebral anomalies, the accompanying manifestations bear a relation to the involved organs (Table 1). DIAGNOSIS BY NEUROIMAGING

Corpus callosum agenesis is an important anomaly in children with neurodevelopment handicaps, usually detected by neuroimaging. Computed tomography is as diagnostic as magnetic resonance, even if it does not provide as much detail of cortical and subcortical architecture. Modern sonography, both prenatal and postnatal, also can be diagnostic in many cases. In the past, the diagnosis of dysgenesis of the corpus callous was generally made at autopsy. Pneumoencephalograms and angiograms of the brain were used in the pre-imaging era in living patients, but these were highly invasive procedures. The advances in the last decades in the field of the neuroimaging and cytogenetic studies have allowed a recognition of the high frequency of developmental malformations of the corpus callosum and the diagnosis of entities previously unknown (Table 1). Fetal sonography has allowed diagnosis in utero of dys-

genesis and lipomas of the corpus callous, with postnatal confirmation by computed tomography or magnetic resonance imaging. Studies of morphometric imaging of the brain by ultrasonography, as with magnetic resonance imaging, better quantitate alterations in the development of the corpus callosum. Chaco et al 3 demonstrated, in a population of 2,164 children with various neurological problems who underwent computerized tomography brain from January 1993 to December 1997, that 1% of the cerebral tomographic studies showed callosal agenesis (22 cases), in most cases it was not possible to disclose a specific syndrome; 33% presented with epilepsy; 64% were male. Barkovich et al 5 used morphology of the brain with magnetic resonance to propose a classification of the associated ADCC with cerebral cysts. Yasushi et al ~2 concluded that there is a significant difference in the thickness of the corpus callosum in children with developmental delay, compared with normal children, in a magnetic resonance study. At times the corpus callosum can be absent, totally or partially, and this situation results in easily demonstrable lesions in sagittal MRI views at the midline, but axial and coronal views also are diagnostic (Fig 1). The terms "partial agenesis" and "hypogenesis" have been used synonymously; however, some authors assert that dysgenesis is the preferred term. 13 Kier and Truwit 14 pointed out that the largest part of the corpus callosum in hypogenesis is the anterior portion of the body and genu. Callosal agenesis may coexist with normal cerebral cortical gyration or with generalized, focal, or multifocal abnormalities of the convolutions (Fig 2). Atypical cases of corpus callosal hypogenesis have been noted in the literature, for example, absence of the anterior part, with preservation of the posterior parts, in children with holoprosencephaly (Fig 3). Elongation of the anterior commissure or hippocampal commissural in patients with corpus callosal dysgenesis has been observed.a 3 Colpocephaly, a selective ventriculomegaly of the occipital horns more than the frontal or temporal horns of the lateral ventricles, is a common finding in agenesis of the corpus callosum, and callosal agenesis is probably the second most frequent cause of colpocepbaly after periventricular leukomalacia (Fig 4). 2 The cause is the deficiency

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Table 1. Syndromes Associated With Agenesis/Dysgenesis of the Corpus Callosum and Extracerebral Manifestations Syndrome

Extracerebral Manifestations

Leopard syndrome 46

Cutaneous scaling lesions Neural-sensory hypoacusis Growth disturbance Hypertelorism Pulmonic stenosis Aicardi syndrome 19'2~ Micro-ophthalmia Chorioretinitis with lacunae Vertebral anomalies Coloboma of the optic disk Shapiro syndrome47 Episodic hypothermia Hyponatremia Andermann Skeletal dysplasia syndrome 2e Menkes disease2e Tricorrhexis nodosa Pill torti Urinary disorders Fetal alcohol Hypoacusis syndromeal Congenital cardiopathies Strabismus Cong. muscle fiber-type disproportion Vinci syndrome 4e Oculocutaneous albinismo Cardiomyopathy Recurrent respiratory infections

Miller-Dieker syndrome 2

Prominent forehead Anteverted nares Long filtrum (upper lip) Bitemporal scalloping CRASH syndrome 49'5~ Adducted thumbs

Preaxia polysyndactyly Double hallux Diabetes insipidus Diaphragmatic defects Pulmonary hypoplasia Cleft lip and palate Cardiopathies with septal defects Anomalies of the aortic arch Hypoplasia genital Hypoplasia of distal phalanges Renal dysplasia Polysyndactyly

Acrocallosal syndrome 51 Fryns syndrome 52

MeckeI-GrLiber syndrome 5a Hemimegalencephaly

TM

Cranial or facial asymmetry (some)

of white matter around the occipital horns due to absence of the posterior fornix of the corpus callosum. Axons from the occipital lobes do not form part of the bundle of Probst in agenesis of the corpus callosum, and their pathway and destination, and even whether they exist, are unknown.

Neurological Manifestations

Transmission

Infantile spasms Mental retardation

Autosomal recessive

Infantile spasms Mental retardation Disturbance in neuroblast migration

X-linked dominant Lethal in males Deletion or translocation at Xp22

Polyuremic syndrome Mental retardation Sensory-motor neuropathy Mental retardation Myoclonic epilepsy Cerebellar hypoplasia Mental retardation Craniofacial alterations Language disorder Microcephaly Microcephaly Hypoplasia of vermis Heterotopia Schizencephaly Psychomotor delay Mental retardation Epilepsy Hypotonia Psychomotor delay Mental retardation Spasticity Hydrocephalus Craniofacial anormalies Epilepsy Mental retardation Die in neonatal period

Holoprosencephaly Occipital encephalocele Multiple dysgeneses Dysplastic hypertrophy of one hemisphere

Autosomal recessive in French-Canadian children

X-linked recessive

Toxic; not genetic

Autosomal recessive

Deletion at 17p13.3

X-linked recessive Mutation of L1 gene at Xq28 Autosomal recessive

Autosomal recessive

Autosomal recessive

No genetic trait except in syndromic forms

ELECTROENCEPHALOGRAPHIC FEATURES The electroencephalography (EEG) in agenesis of the corpus callosum has no distinguishing features in the neonatal period or the first year. The most characteristic feature is the continued asyn-

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Fig1. Tl-weighted axial, coronal, and sagittal MRI showing partial agenesis of the corpus callosum, predominantly the posterior portion, in a 3-year-old boy with infantile myocionic epilepsy. Multifocal pachygyria suggests a disturbance of neuroblast migration.

chrony of sleep spindles after 18 months of age, when spindles should become synchronous. However, this asynchrony is not an overall asymmetry, and the morphology and number of spindles in the two hemispheres are relatively equal over an extended period of stage 2 sleep. 2 If callosal agenesis is associated with other cerebral malformations, the EEG shows characteristics of those malformations in addition. Even in simple callosal agenesis, loci of sharp wave activity or even epileptiform complexes may be present, and correlates with the higher than normal incidence of seizure disorders in children with agenesis of the corpus callosum. These focal electrographic abnormalities are probably due to anatomic foci of microdysgenesis. 2 DIFFERENTIAL DIAGNOSIS

ADCC can occur as an isolated neurodevelopmental condition, associated with mental retardation or normal intelligence (point 1), it can occur as

an X-linked or autosomal-recessive condition, or can present as an incidental finding during imaging in apparently normal patients. However, ADCC frequently coexists with central nervous system malformations (point 2.2). Klass et al v described concomitant findings in 13 children with partial agenesis of the corpus callosum, who also had hydrocephalus caused by stenosis of the cerebral aqueduct and with meningomyelocele (point 2.1). Among the malformations most commonly associated with partial or complete callosal dysgenesis, holoprosencephaly has already been mentioned above in relation to the absence of a bundle of Probst. Many cases of lissencephaly, both type I as the Miller-Dieker syndrome and type II as Walker-Warburg syndrome have partial to complete agenesis of the corpus callosum. In hemimegalencephaly, the part of the corpus callosum on the side of the enlarged, dysplastic hemisphere also is dysplastic, distorted, enlarged, small, or bilater-

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Fig 2. Aicardi syndrome in an 8-month-old girl who presented with myoclonic epilepsy, severe psychomotor delay, hypotonia, and an extensive congenital dermal melanosis. The axial CT demonstrates agenesis of the corpus callosum and extensive bilateral cortical dysplasias.

ally absent.15 Hemimegalencephaly may be an isolated malformation or syndromic, associated most commonly with epidermal nevus, Proteus, KlippelTrenauny-Weber syndromes. 15 The presence of ADCC has been documented in Chiari II malformation, Dandy-Walker syndrome, and arachnoideal cyst. It also is recognized in about 25 secondary syndromes neuroblast migrational disorders (Fig 1), with variable and nonspecific clinical features, the most important of which are psychomotor retardation, epilepsy, craniofacial dysmorphism, alterations in muscular tone and stretch reflexes, and frequently in hypotonia with hyperreflexia, a The association of ADCC with cysts can be present in a great quantity of demonstrable and classifiable pathological processes, confirmed by imaging studies (point 2.2). Examples of these associations are found in several studies. Tange et a116 described a neonate with an interhemispheric

glial-ependymal cyst that was associated with corpus callosal agenesis and obstructive hydrocephalus; the cyst was extirpated and the hydocephalus resolved. Cysts can be loculated or multiloculated. Uematsu et a117 reported a case by fetal ultrasonography, later confirmed with cerebral MRI, that actually was due to multiloculated neuroepithelial cysts. An association of ADCC with subarachnoidal cysts also has been recognized (point 2.2.2). For example, Hendriks et al ~8 reported two sisters that presented corpus callosal agenesis, neuralsensory deafness, and subarachnoideal cysts with hydrocephalus, the cysts being located in the pineal region and obstruct the cerebral aqueduct, as an autosomal-recessive trait. At point 2.2.2 b is Aicardi syndrome, described at 1965 by Aicardi and Lafebvre. To date, about 170 cases are documented in the literature, j9 The syndrome is characterized by myoclonic epilepsy, infantile spasms, and corpus callosal agenesis (Fig 2) that is a total

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Fig 3. Tl-weighted MRI, in eagittel end axial planes, of a 2-year-old boy with holoproeencephaly and generalized tonic seizures. In the sag!ttal view, agenesis of the anterior part of the corpus callosum is associated with deficiency of the frontal lobes and the possible presence of a large anterior cyst. The posterior part of the corpus callosum end occipital lobes are partially formed.

absence in 75% of patients, severe psychomotor retardation and disturbances of muscular tone, the most frequent being hypotonia. Epilepsy and psychomotor or mental retardation find their anatomic

Fig 4. Axial CT of an 11-month-old boy showing colpocephaly associated with csllosal agenesis. This selective enlargement of the occipital horns is due to an absence of the periventriculer white matter formed by the posterior fornix of the corpus callosum. (Courtesy of Dr. Laura Flores-Sarnat.)

basis in the severity of the cerebral dysgenesis, involving the lower part of the vermis, anomalies of hippocampal orientation, periventricular heterotopia, polymicrogyria, lissencephaly-pachygyria, holoprosencephaly, agenesis of the pineal gland, Chiari malformations and Dandy-Walker syndrome, 2~ vertebral dysplasias, micro-ophthalmia, and optic nerve coloboma. They can also be associated with the presence of neoplastic tumors, including choroid plexus papilloma, benign teratoma of the soft palate, hepatoblastoma, and parapharyngeal carcinoma; however, this relationship can be f o r t u i t o u s . 21-24 The disease is lethal for males, which is why almost all reported cases are female. 2'19"2~ It is transmitted as an X-linked dominant disease, and it is suspected that an autosomal deletion or translocation of Xp22 may occur in some cases, which has been reported in 47XXY males. The callosal agenesis seen in holoprosencephaly is unique, by contrast with its presence as a component of other extensive cerebral malformations (point 2.1). In holoprosencephaly, the bundle of Probst never forms. This large aberrant tract consists of diverted callosal axons in the dorsomedial part of the ipsilateral hemisphere, where they pass posteriorly after being unable to cross the midline. 2 Despite the absence of a bundle of Probst in holoprosencephaly, the small pyramidal neurons of

AGENIESIS AND DYSGENESIS OF THE CORPUS CALLOSUM

layer 3 of the neocortex are present. In normal brains, their axons form most of the fibers of the corpus callosum, but the destination of the axons of layer 3 in holoprosencephaly, in those lateral parts of the cortex where lamination often is still recognizable, is unknownY Holoprosencephaly is associated with at least six known distinctive genetic mutations. ADCC can be present in children with peripheral neuropathy (point 2.3) in French-Canadian children, an autosomal-recessive, progressive neuropathy that results from a mutation at the 15q 13q15 locus. 26

There are many genetic syndromes (point 2.4) that associate ADCC with cerebral and extracerebral malformations; for example, Guzzetta et a127 reported an association with polysyndactyly and trigonocephaly with corpus callosal dysgenesis in an 11-month-old child. It has been reported that ADCC occurs in chromosomopathies, as in the 13, 16, and 18 trisomies, in l lq monosomy as an X-linked recessive form, and in aneuploidies such as 47XXY. In Table 1 some genetic syndromes associated with ADCC are presented, and it is important to mention other genetic syndromes associated as examples of the pathologies classified at this point. Others examples of syndromes that associate ADCC with extracerebral malformations in at least a proportion of cases are: Walker-Warburg syndrome (lissencephaly type 2 and sometimes occipital encephalocele), Rubinstein-Taybi syndrome, thanatophoric dwarfism, Smith-Lemi-Opitz syndrome (metabolic block in cholesterol synthesis that affects the Sonic hedgehog gene), Menkes kinky hair disease, Marshall-Smith syndrome, Kallmann syndrome, Goldenhar syndrome, CoffinSifts syndrome, Apert disease, Baller-Gerold syndrome, among many others. ADCC has been described with congenital metabolic diseases (point 2.5) including nonketotic hyiperglyicinemia, organic acidurias, pyruvate decarboxylase deficiency, Zellweger cerebro-hepatorenal disease (peroxisomal disease with secondary mitochondrial disorder), with primary mitochondrial cytopathies such as Leigh encephalopathy and Leber optic atrophy. It has also been reported with macromolecular metabolic disease, as in Hurler disease. 28-3~ At point 2.6 toxic products are mentioned as causes of dysgenesis of the corpus callosum.

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Church and Gerkin 31 describe it in the fetal alcohol syndrome. It also occurs among mothers exposed to valproic acid during pregnancy. Other possible associations of ADCC are less frequent and may be malformations of other organs (point 2.7): hematologic diseases, asplenia, anophthalmia, blepharophimosis, cleft lip and palate, albinism, bony lesions, congenital megacolon, and camptodactyly. 32 Verloes and Lesenfants 33 described a new syndrome in a 16-year-old teenager that presented corpus callosum agenesis with interventricular communication, 5 th digit camptodactyly, and obesity. It has been described as an association of ADCC with DiGeorge disease. 34 Pineda et a135 reported two brothers with agenesis of the corpus callosum, apneic spells, cyanosis, and hypothermia; both children (boy and girl) died in a few months and postmortem examination showed severe spongiosis of the white matter. Finally, some cases of aganglionic megacolon (Hirschsprung disease) also exhibit midline defects that include cleft palate, hypertelorism, and agenesis of the corpus callosum. This association of midline dysgenesis and defective neural crest migration is due to a nonsense and frameshift mutation in the ZFHX1B gene, that encodes SIP1 (Smad-interacting protein-I). 36"37 This "syndromic Hirschsprung disease" is another example of the advances being made in understanding the genetic pathogenesis of various causes of callosal agenesis. Recently a syndrome was described that associates ADCC with refractory thrombocytopenia and cerebellar hypoplasia, hypotonia, severe psychomotor retardation, and dysplasic megacaryocytes.38 An association of ADCC with asplenia, schizophrenia, vascular malformations of the pericallosal artery on the left side, hypogonadism, and gelastic seizures with diencephalic hamartoma has been documented. Imaging studies have demonstrated corpus callosal lipoma (point 2.8) even in the living fetus. 39 This congenital malformation is present in one in 17,000 individuals, and its diagnosis is possible at 26 weeks' gestation using ultrasonography, that shows colpocephaly. Its prognosis depends on accompanying malformations. Symptoms are sometimes delayed as late as the third decade. Symptoms in children appear as behavioral disturbances, partial or generalized seizures, headache, vomiting, and hydrocephalus. Frequently in young children,

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congenital frontal bossing is evident. Over time, calcification of the lipomatous tumor can occur and, in cases of refractory epilepsy, surgical intervention may be indicated. 4~ Lipomas and interhemispheric cysts that replace the middle part of the corpus callosum do not necessarily arise within the commissure, but in some cases may represent ectopic foci or loculations of meningeal or other mesodermal tissues during ontogenesis. PRENATAL DIAGNOSIS

Prenatal corpus callosal malformations initially were described by Comstock et a142 who identified the imaging features of laterally displaced lateral ventricles and atrium and upward movement of the third ventricle. Meizner et a143 noted absence or alteration of the cavum septum pellucidum as an

additional imaging sign and Lockwood et a144 diagnosed partial corpus callosal agenesis by posterior ventriculomegaly or colpocephaly. In 1996, Tepper and Zale145 described imaging findings in four cases, three with complete corpus callosal agenesis and one with partial agenesis. They assessed a relationship between the diameter of the frontal lobe radiation and biparietal diameter in 113 normal fetuses, and found that when complete corpus callosal dysgenesis exists, the frontal region is small and the cavum septi pellucidi is not evident. In about half the report fetal ultrasound studies, ADCC is an isolated finding. In the remaining studies, other abnormalities suggestive of specific syndromes may be found. Male fetuses are more likely to have an isolated ADCC that is considered benign in its clinical expression.

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