Congenital malformations - Edocr

78 PART II CENTRAL NERVOUS SYSTEM MALFORMATIONS
in infants with fetal alcohol syndrome. Agenesis
of the corpus callosum may also be observed in
infants with congenital lactic acidosis secondary
to mitochondrial respiratory chain defects. Other
metabolic disorders in which it may be observed
include mupolysaccharidoses, mucolipidoses,
Zellweger syndrome, and Lowe syndrome.
Isolated agenesis of the corpus callosum
which cannot be linked to any teratogenic cause
and is not a component of a generalized malformation
syndrome nor associated with a metabolic
disorder is generally a sporadic occurrence.
However, familial cases have been reported both
in siblings and in parents of affected individuals.
In addition to genes for some of the multiple
malformation syndromes listed in Table 11-1,
two genes which are of importance in genetically
determined forms of agenesis of the corpus
callosum have been identified. One of these
is the LICAM gene on the X chromosome which
is also responsible for X-linked hydrocephalus
secondary to aqueductal stenosis. 5 Mutations in
this gene may lead to a wide range of effects on
the central nervous system, including isolated
agenesis of the corpus callosum or callosal agenesis
in conjunction with other malformations.
The second gene is the SLC12A6 gene, which is
mutated in patients with Andermann syndrome,
a disorder which occurs with high frequency in
the Charlevoix and Saguenay-Lac-St. Jean region
of Quebec. In addition to agenesis of the
corpus callosum, patients with this autosomal
recessive disorder have a progressive hereditary
neuropathy. 6 Clinical testing is available for mutations
in both LICAM and SLC12A6.
CLINICAL PRESENTATION
It is generally believed that the presenting findings
in patients with agenesis of the corpus callosum
are the result of associated anomalies and
that isolated agenesis of the corpus callosum is
asymptomatic. This conclusion is based on
the observation that many clinically normal
individuals have been found at autopsy or on
neuroimaging for indications such as headache
to have agenesis of the corpus callosum. Increasingly,
patients with agenesis of the corpus
callosum are being identified at birth because of
findings noted on prenatal ultrasonography.
Dysmorphic facial features may be present with
the most commonly observed facial features
being hypertelorism and a broad nose. Macrocephaly
and microcephaly both occur with increased
frequency. If not identified at birth, the
diagnosis usually follows neuroimaging obtained
for evaluation of developmental delay or
seizures later in infancy. Other neurologic findings
are common including poor coordination,
spasticity, quadriparesis, or hemiparesis. MRI is
the best modality for establishing the diagnosis
of agenesis of the corpus callosum and for delineating
the associated anomalies of the central
nervous system (CNS). (Fig. 11.1)
Prenatal diagnosis of agenesis of the corpus
callosum by ultrasonography cannot be reliably
accomplished prior to 20 weeks gestation. Findings
suggestive of agenesis of the corpus callosum
include ventriculomegaly, a high position of
the third ventricle, and failure to visualize the
cavum septum pellucidum. Agenesis of the corpus
callosum occurs in up to 10% of cases of mild
ventriculomegaly noted in utero but is less common
among cases of severe ventriculomegaly.
ASSOCIATED MALFORMATIONS
AND SYNDROMES
A large percentage of patients with agenesis of
the corpus callosum have associated anomalies.
Certainly all of those detected on the basis of
clinical signs and symptoms have associated
anomalies since isolated callosal agenesis is
asymptomatic. It is more difficult to determine
what fraction of fetuses with agenesis of the
corpus callosum detected in utero have associated
anomalies. Despite careful serial ultrasound
examinations, some of the associated abnormalities
cannot be visualized by prenatal ultrasound.
Therefore an anomaly that may appear