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1999-06-15-18 Agenesis of the corpus callosum © Pilu www.thefetus.net/
Agenesis of the corpus callosum

Gianluigi Pilu, MD

Bologna, Italy pilu@mbox.queen.it

Definition: Complete or partial absence of the corpus callosum

Epidemiology: Uncertain. The incidence varies in different studies, depending upon the population investigated and the method of ascertainment. Estimates of 0.3-0.7 % in the general population[1] and 2-3 % in the developmentally disabled[2],[3] are usually quoted.

Codes: MESH Corpus callosum BDE 0220 ICD9 742.2 CDC 742.210

Etiology: Heterogeneous. Genetic factors are probably predominant. Autosomal dominant, autosomal recessive and sex-linked transmission have all been documented.[4],[5]. Agenesis of the corpus callosum is also a part of Mendelian syndromes (Table 1), including Walker-Warburg syndrome[6]; Andermann"s syndrome[7]; acrocallosal syndrome [8]; F.G. syndrome[9], Fryns syndrome.[10] Callosal agenesis is also found in two conditions with sex linked dominant etiology and lethality in males: the orofaciodigital type I syndrome[11] and Aicardi syndrome.[12] Frontonasal dysplasia or median cleft face syndrome is also frequently associated with agenesis of the corpus callosum. This condition is usually a sporadic disease, but a few familial cases consistent with an autosomal dominant transmission have been described.[13] A high frequency of agenesis of the corpus callosum has been documented in infants with inborn errors of metabolism.[14] Various teratogens have also been implicated as a possible cause of agenesis of the corpus callosum, including alcohol,[15] valproate, [16] cocaine[17], rubella[18] and influenza virus.[19]

Table 1. Syndromes featuring agenesis of the corpus callosum.
(Modified from Blum et al38)

Frequent in:

·         Acrocallosal syndrome (AR)

·         Aicardi syndrome (X-linked dominant)

·         Andermann syndrome (AR)

·         Cerebro-oculo-facio-skeletal (COFS) syndrome (AR)

·         Fryns syndrome (AR)

·         Marden-Walker syndrome(AR)

·         Meckel Gruber syndrome (AR)

·         Microphtalmia-linear skin defects syndrome (X-linked dominant)

·         Miller Diexer syndrome (lissencephaly syndrome)

·         Neu-Laxova syndrome(AR)

·         Septo-Optic dysplasia sequence

·         Walker-Warburg syndrome (X-linked dominant)

·         Zellweger syndrome (AR)

Occasional in:

·         Apert syndrome (AR)

·         Baller-Gerold syndrome (AR)

·         Calloso-genital dysplasia syndrome (AR)

·         Coffin-Siris syndrome (?AR)

·         Congenital microgastria-limb reduction complex (unknown)

·         Crouzon syndrome (AD)

·         Duplication 4p syndrome

·         Fetal alcohol syndrome

·         Fetal warfarin syndrome

·         FG syndrome (X-linked recessive)

·         Fronto-nasal dysplasia sequence (sporadic/AD)

·         Gorlin syndrome (AD)

·         Greig cephalopolysyndactyly syndrome (AD)

·         Hydrolethalus syndrome(AR, X-linked dominant)

·         Lens dysplasia (X-linked recessive)

·         Marshall-Smith syndrome (unknown)

·         Oculo-auricolo-vertebral spectrum (unknown)

·         Oculo-cerebro-cutaneous syndrome (Delleman syndrome) (unknown)

·         Opitz syndrome (AD, X-linked recessive)

·         Oral-facio-digital syndrome type 1 (X-linked dominant)

·         Peters’-Plus syndrome (AR)

·         Radial aplasia-thrombocytopenia syndrome (AR)

·         Rubinstein –Taybi syndrome 8SPORADIC)

·         Shapiro syndrome (X-linked recessive)

·         Simpson-Golabi-Behmel syndrome (X-linked recessive)

·         Trisomy 8 syndrome

·         Trisomy 13 syndrome

·         Trisomy 18 syndrome

·         X-linked hydrocephalus spectrum (X-linked recessive)

·         XO syndrome

·         XXXXY syndrome (hypoplastic)

·         Yunis-Varon syndrome

·         Metabolic disorders

AR, AD autosomal recessive, autosomal dominant

Recurrence risk: Dependent upon the etiology in the specific case. Many cases have an autosomal recessive or sex-recessive transmission.

Embryology: The corpus callosum is the largest commissure connecting the cerebral hemispheres. It is a broad plate of dense myelinated fibers, located deep in the longitudinal fissure, that reciprocally interconnect regions of the cortex in all lobes with corresponding regions of the opposite hemispheres (Figure 1).

Figure 1: The fully formed corpus callosum

It derives from the massa commissuralis, an embryological structure formed by the fusion of the lateral margins of the groove that separates the primitive telencephalic vesicles. Formation of the corpus callosum is a late event in cerebral ontogenesis, which takes place between 12 and 18 weeks" gestation. The most anterior portion, the rostrum, develops first and is followed by the genu, body and splenium. The corpus callosum is in close anatomic and embryological relationship with the underlying septum pellucidum. Although there is no a priori evidence to suggest that the development of the septum pellucidum cannot proceed independently of the corpus callosum, most observers claim that there can be no septum pellucidum without a corpus callosum.[20]

Pathology: Agenesis of the corpus callosum may be either complete (Figure 2) or partial.

Figure 2: Coronal section of the brain of a normal neonate (left) compared with complete agenesis of the corpus callosum (right).

In the latter case, also referred to as dysgenesis of the corpus callosum, the caudal portion (splenium and body) is missing to varying degrees. Complete agenesis of the corpus callosum is typically associated with significant distortion of the intracranial architecture. The lateral ventricles tend to be larger than normal, particularly at the level of the atria and occipital horns (Figure 3).

 

Figure 3: Magnetic resonance in a neonate with agenesis of the corpus callosum demonstrating the absence of the corpus callosum (left) with enlargement of the atria and occipital horns (right).

It has been postulated that the absence of the posterior portion of the corpus callosum results in distortion of the array of white matter tracts in the occipital lobes leading to caudal expansion of the ventricles.[21] Such ventricular enlargement tends per se to be stable and is not usually associated with intracranial hypertension. The frontal horns are usually normal in size but are more separated than normal from the midline. The third ventricle is often superiorly elongated, reaching the area normally occupied by the corpus callosum.  At times, it may be found to communicate with a large interhemispheric cyst (Figure 4).[22],[23]

 

Figure 4: Magnetic resonance in a neonate with agenesis of the corpus callosum with an interhemispheric cyst (left) and in another neonate with agenesis of the corpus callosum and an interhemispheric lipoma (left).

Absence of the corpus callosum also results in abnormal induction of medial cerebral convolutions, determining a radiate arrangement of cerebral sulci around the roof of the third ventricle, extending through the zone normally occupied by the cyngulate gyrus. The modifications of the arterial vascular supply in infants with agenesis of the corpus callosum has been investigated in depth with both angiography[24] and sonography[25] and are relevant for antenatal diagnosis.[26] Under normal condition, a branch of the anterior callosal artery runs along the superior surface of the corpus callosum, describing a semicircular loop. When the corpus callosum is absent such loop is lost and branches of the anterior cerebral artery are seen ascending linearly with a radiate arrangement.

Associated anomalies: The high frequency of associated malformations suggests that agenesis of the corpus callosum is frequently a part of a widespread developmental disturbance. In a large postnatal series[27], central nervous system anomalies, including microcephaly, abnormal convolutional patterns, heterotopia, intracranial lipomas, interhemispheric cysts, neural tube defects, Dandy-Walker malformation, aplasia or hypoplasia of the pyramidal tracts are found in 85% of the cases. Systemic anomalies including a variety of musculo-skeletal, cardiovascular, genitourinary and gastrointestinal malformations were found in 62% of cases.

Chromosomal anomalies are found in 20% of cases, and mostly include trisomy 18, trisomy 8 and trisomy 13. [28]

In antenatal series, anatomic anomalies were found in 50% of cases. The anomaly most frequently encountered was Dandy-Walker malformation. Cardiovascular anomalies mainly included cono-truncal malformations: tetralogy of Fallot, double outlet right ventricle. A detailed list of syndromes associated with agenesis of the corpus callosum is reported in Table 1.

Diagnosis: The sonographic diagnosis of fetal agenesis of corpus callosum is difficult for several reasons. First, the corpus callosum is a thin band of white matter that usually can not be demonstrated by the axial views that are commonly employed for standard sonographic examinations. Second, development of the corpus callosum is a late event, that is complete only by midgestation.

The available experience suggests that agenesis of the corpus callosum can be accurately identified by targeted examinations performed at 18-20 weeks or later. The sensitivity of non-targeted examinations is unknown, but it is probably very low, particularly in the early second trimester. In one antenatal series, 10/15 affected fetuses were found to have an unremarkable intracranial sonogram at 16-22 weeks’ gestation.[29]  However, failure to visualize the cavum septum pellucidum that under normal condition is usually seen without difficulty beyond 18 weeks gestation should raise the suspicion of agenesis of the corpus callosum (Figure 5).

 

Figure 5: An axial section in a normal midtrimester fetus demonstrating the cavum septi pellucidii (left) compared with a fetus with complete agenesis of the corpus callosum (right).

The presence of ventriculomegaly is another important risk factor. Prenatal studies suggest that agenesis of the corpus callosum is found in 3% of all fetuses with ventriculomegaly[30] and in almost 10% of those with mild ventriculomegaly[31].

Ventricular enlargement is predominant at the level of the occipital horns, resulting in a teardrop configuration of the lateral ventricles (also referred to as colpocephaly) (Figure 6-7).

 

Figure 6: Schematic representation of the "teardrop" sign associated with agenesis of the corpus callosum.

Figure 7: The “teardrop” sign in a third trimester fetus with agenesis of the corpus callosum

The definitive diagnosis of callosal agenesis depends upon direct demonstration of the absence of the complex formed by the corpus callosum and cavum septum pellucidum by midsagittal or midcoronal views of the fetal brain (Figure 8-10).

Figure 8: Schematic representation of the findings associated with agenesis of the corpus callosum that can be demonstrated with coronal and sagittal views of the brain.

 

Figure 9: Midcoronal scan in a normal fetus  (left) and with agenesis of the corpus callosum (right).

 

Figure 10: Median scan in a normal fetus  (left) and with agenesis of the corpus callosum (right).

There are however a number of indirect findings that may prove helpful from time to time:

·       the absence of the main cerebral commissure may results in increased separation of the hemispheres with a prominent interhemispheric fissure. Under such circumstance, sonography will reveal three echogenic lines running parallel in the upper cranium, the middle one representing the falx cerebrii, the lateral ones representing the medial borders of the separated hemispheres (Figure 11)

Figure 11: Axial and midcoronal views of the brain with agenesis of the corpus callosum demonstrating that the midline echo has become a three line complex due to distension of the interhemispheric fissure.

·       upward displacement of the third ventricle, that can be identified by demonstrating that this structure reaches superiorly the level of lateral ventricles is a very specific sign, that however only occurs in about 50% of cases, either a coronal or axial scan (Figure 12).

Figure 12: Coronal and axial views of the brain of a fetus with callosal agenesis demonstrating that the third ventricle has been displaced upward and can be seen at the same level as the bodies of lateral ventricles.

·       abnormal midline lesions occur frequently, including lipomas and cysts. Lipomas appear as brightly echogenic lesions (Figure 13). A lipoma in the anterior midline is associated with agenesis of the corpus callosum in 50% of cases. [32] It is worth noting however that lipomas are not usually demonstrable in the second trimester and tend to appear only in late gestation.26 Interhemispheric cysts associated with agenesis of the corpus callosum are of neuroepithelial origin,23 and probably represents the consequence of overdistension of the third ventricle (Figure 14).

Figure 13: Intracranial lipoma with complete agenesis of the corpus callosum. Symmetric lipomas are found within the bodies of lateral ventricles.

Figure 14: Agenesis of the corpus callosum with an interhemispheric cyst.

·       Under normal condition, a midsagittal view of the brain will reveal the pericallosal artery, a branch of the anterior callosal artery running along the superior surface of the corpus callosum and describing a semicircular loop. When the corpus callosum is absent such loop is lost and branches of the anterior cerebral artery are seen ascending linearly with a radiate arrangement.26 (Figure 15)

Figure 15: Color Doppler demonstration of anterior cerebral artery branching in a normal fetus (left) and in a fetus with agenesis of the corpus callosum (right).

A distinction should be made between complete and partial agenesis of the corpus callosum. Complete agenesis of the corpus callosum is commonly regarded as a malformation, deriving from faulty embryogenesis, while partial agenesis of the corpus callosum may represent both a true malformation and a disruptive event occurring at any time during pregnancy. Partial agenesis of the corpus callosum has been described antenatally in three cases.26,[33],34All fetuses had a "teardrop" configuration of lateral ventricles. The natural history of partial agenesis of the corpus callosum is nevertheless uncertain, and the cerebral findings associated with it are probably more subtle than with the complete form. It is expected that antenatal diagnosis will not be possible in all cases.

Although current ultrasound equipment allows identifying with certainty agenesis of the corpus callosum in the vast majority of cases, magnetic resonance may be helpful, both for validating the diagnosis in dubious cases, and for identifying associated cerebral anomalies. For example, it has been demonstrated that antenatal magnetic resonance can recognize, at least in the third trimester, heterotopia of the gray matter, which is very frequently associated with neurologic sequelae and seizures.[34]

Differential diagnosis: agenesis of the corpus callosum must be distinguished from other causes of ventriculomegaly; agenesis of the corpus callosum with an interhemispheric cyst must be differentiated from other intracranial fluid-filled lesions, such as arachnoid cyst, porencephaly or an aneurysm of the vein of Galen.

Implications for targeted examinations: Expert sonography is extremely accurate in predicting complete agenesis of the corpus callosum. The examination should be performed at 18 weeks, and should include multiplanar imaging, to demonstrate the corpus callosum in both sagittal and coronal planes. Vaginal sonography is particularly helpful in vertex fetuses.

Implications for sonography screening: The sensitivity of non-targeted examinations is unknown, but it is probably very low, particularly in the early second trimester. In one antenatal series, 10/15 affected fetuses were found to have an unremarkable intracranial sonogram at 16-22 weeks’ gestation.[35] However, it is expected that by including the cavum septi pellucidi among the intracranial structures routinely visualized most cases with complete agenesis of the corpus callosum should be detected. It should be kept in mind however that visualization of the cavum septi pellucidi is usually possible only after 18 weeks’ gestation.

Prognosis: the corpus callosum is phylogenetically a recent structure, and its absence is not lethal. Isolated agenesis of the corpus callosum may be either a completely asymptomatic event or revealed during the course of a neurologic examination by subtle deficits, such as inability to match stimuli using both hands or to discriminate differences in temperature, shape, and weight in objects placed in both hands.

Persons with agenesis of the corpus callosum may have neurologic problems, such as seizures, intellectual impairment, and psychosis. However, these conditions are believed to be caused by abnormalities in associated cerebral anomalies rather than in the corpus callosum per se. In postnatal series, children with isolated agenesis of the corpus callosum are more frequently free from neurologic compromise. The worst outcomes are found in the presence of migrational disorder with or without Dandy-Walker malformation[36].

Counseling couples with fetuses that have isolated non-familial agenesis of the corpus callosum is a difficult task. Pediatric series are based upon investigation of symptomatic individuals and are therefore presumably biased. The experience with antenatal diagnosis thus far is limited, but seems more favorable than expected from postnatal data. A total of 37 infants with a prenatal diagnosis of isolated agenesis of the corpus callosum (no other malformations demonstrable at sonography and a normal karyotype) have been reported thus far.26,[37][38][39],[40]  The duration of postnatal follow-up studies ranges between a few months to 11 years. A normal or borderline development was present in 32, or 86%. In all cases with severe handicap other anomalies were present (ethmoidal cephalocele, CHARGE association, oral-facial-digital syndrome type I one case each, Aicardi syndrome in two).

The diagnosis of isolated agenesis of the corpus callosum in the fetus does arise concern about the possibility of association with either genetic syndromes, inborn errors of metabolisms or anatomic anomalies unpredictable by antenatal testing. However, the available experience suggest that callosal agenesis is compatible with a normal or borderline postnatal development in most cases. As some genetic conditions associated with agenesis of the corpus callosum, such as Aicardi syndrome, have sex-linked dominant etiology, it has been proposed that documentation of a male karyotype is reassuring.

Some intracranial findings have been found in excess in fetuses with a poor outcome, and are presumed to have prognostic value, albeit the experience thus far is limited. In our experience, upward displacement of the third ventricle and a distended interhemispheric fissure were most frequently associated with neurologic impairment, associated anomalies or both. Interestingly enough, no correlation was found between the degree of ventricular enlargement and the outcome. Similarly, the antenatal demonstration by MRI of heterotopia represents probably a poor prognostic factor.

It should be remembered that agenesis of the corpus callosum is a unique condition that even in the presence of a normal intelligence is associated with peculiar neurologic findings and subtle cognitive deficits. The interested reader is referred to specific works on this subject.[41],[42],[43],[44],[45] It has also been hypothesized a possible relationship between agenesis of the corpus callosum and psychotic disorders.[46]

Obstetric management: Agenesis of the corpus callosum is associated with an excess of both neural and extra-neural malformations as well as with chromosomal aberrations. Antenatal identification of callosal agenesis dictates therefore the need of a careful survey of the entire fetal anatomy, including echocardiography and karyotype. In continuing pregnancies, the management depends upon the sum of the different anomalies that are identified. Isolated agenesis of the corpus callosum does not require any modification of standard obstetric management. In one series,26 failure to progress in labor requiring cesarean delivery occurred on several occasions, and this was speculated to be  related to the high frequency of macrocrania in infants with callosal agenesis.

References

 

 

[1] Grogono JL (1968): Children with agenesis of the corpus callosum. Dev Med Child Neurol 10, 613-20.

 

 

[2] Han J, Benson JE, Kaufman B, Rekate HL, Alfidi RJ, Huss RG, Sacco D, Yoon YS, Morrison SC (1985). MR imaging of epdiatric cerebral abnormalities. J Computed Assist Tomogr 9, 103-14

 

 

[3] Jeret JS, Serur D, Wisniewski K, Fisch C (1986). Frequency of agenesis of the corpus callosum in the developmentally disabled population as determined by computerized tomography. Pediatr Neurosci 12, 101-6.

 

 

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