Agenesis of the Corpus Callosum
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consists of a heterogeneous group of disorders that vary in expression from severe
intellectual and neurologic abnormalities to the asymptomatic and normally intelligent
patient
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The corpus callosum develops from the commissural plate that lies in proximity to the
anterior neuropore
When agenesis of the corpus callosum is an isolated phenomenon, the patient may
be normal. When it is accompanied by brain anomalies due to cell migration defects,
such as heterotopias, microgyria, and pachygyria (broad, wide gyri), patients often
have significant neurologic abnormalities, including mental retardation, microcephaly,
hemiparesis, diplegia, and seizures.
Absence of the corpus callosum may be inherited as an X-linked recessive trait or as
an autosomal dominant trait and on occasion as an autosomal recessive trait.
The condition may be associated with specific chromosomal disorders, particularly
trisomy 8 and trisomy 18.
Agenesis of the corpus callosum is also seen in metabolic disorders.
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Aicardi syndrome
represents a complex disorder that affects many systems and is typically associated
with agenesis of the corpus callosum, distinctive chorioretinal lacunae, and infantile
spasms.
Patients are almost all female, suggesting a genetic abnormality of the X
chromosome (it may be lethal in males during fetal life).
Seizures become evident during the 1st few months and are typically resistant to
anticonvulsants
All patients have severe mental retardation and can have abnormal vertebrae that
may be fused or only partially developed (hemivertebra).
Abnormalities of the retina, including circumscribed pits or lacunae and coloboma of
the optic disc, are the most characteristic findings of Aicardi syndrome.
Colpocephaly
refers to an abnormal enlargement of the occipital horns of the ventricular system
and can be identified as early as the fetal period
is often associated with agenesis of the corpus callosum, but it can occur in isolation
also associated with microcephaly. It can also be seen in anatomic megalencephaly
such as in Sotos syndrome.
HOLOPROSENCEPHALY
- is a developmental disorder of the brain that results from defective formation of the
prosencephalon and inadequate induction of forebrain structures.
- The abnormality is classified into 3 groups:
o Alobar
 is characterized by a single ventricle, an absent falx, and
nonseparated deep cerebral nuclei
 affected children with the alobar type have high mortality rates, but
some live for years
o semilobar
o lobar
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A fourth type, the middle interhemispheric fusion (MIHF) variant or syntelencephaly,
involves a segmental area of noncleavage, actually a nonseparation, of the posterior
frontal and parietal lobes. Facial abnormalities including cyclopia, synophthalmia,
cebocephaly, single nostril, solitary central incisor tooth, and premaxillary agenesis
are common in severe cases
Alobar holoprosencephaly is characterized by a single ventricle, an absent falx, and
nonseparated deep cerebral nuclei.
The incidence of holoprosencephaly ranges from 1/5,000 to 1/16,000
The cause of holoprosencephaly is often not identified. There appears to be an
association with maternal diabetes. Chromosomal abnormalities, including deletions
of chromosomes 7q and 3p, 21q, 2p, 18p, and 13q, as well as trisomy 13 and 18,
account for upwards of 50% of all cases
Agenesis of the Cranial Nerves and Dysgenesis of the Posterior
Fossa
CONGENITAL CRANIAL DYSINNERVATION DISORDERS
- Absence of the cranial nerves or the corresponding central nuclei has been
described in several conditions and includes the optic nerve, congenital ptosis,
Marcus Gunn phenomenon (sucking jaw movements causing simultaneous eyelid
blinking; this congenital synkinesis results from abnormal innervation of the trigeminal
and oculomotor nerves), the trigeminal and auditory nerves, and cranial nerves IX, X,
XI, and XII. Increased understanding of these disorders and their genetic causes has
led to the term congenital cranial dysinnervation disorders (CCDD).
- Optic nerve hypoplasia can occur in isolation or as part of the septo-optic dysplasia
complex (De Morsier syndrome).
- Septooptic dysplasia can be caused by a mutation in the HESX1 gene.
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Möbius syndrome
is characterized by bilateral facial weakness, which is often associated with paralysis
of the abducens nerve
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Hypoplasia or agenesis of brainstem nuclei as well as absent or decreased numbers
of muscle fibers has been reported.
Affected infants present in the newborn period with facial weakness, causing feeding
difficulties owing to a poor suck
The facial appearance of Möbius syndrome has been improved by facial surgery.
Duane retraction syndrome
characterized by congenital limitation of horizontal globe movement and some globe
retraction on attempted adduction and is believed to be the result of abnormal
innervations by the oculomotor nerve of the lateral rectus muscle.
Less common than Duane retraction syndrome and Möbius syndrome are the group
of disorders known as congenital fibrosis of the extraocular muscles (CFEOM).
CFEOM is characterized by severe restriction of eye movements and ptosis from
abnormal oculomotor and trochlear nerve development and/or from abnormalities of
extraocular muscle innervations.
BRAINSTEM AND CEREBELLAR DISORDERS
- Disorders of the posterior fossa structures include abnormalities of not only the
brainstem and cerebellum but also the cerebrospinal fluid spaces. Commonly
encountered malformations include Chiari malformation, Dandy-Walker
malformation, arachnoid cysts, mega cistern magna, persisting Blake pouch, Joubert
syndrome, rhombencephalosynapsis, Lhermitte-Duclos disease, and pontocerebellar
hypoplasias.
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Chiari malformation
the most common malformation of the posterior fossa and hindbrain.
It consists of herniation of the cerebellar tonsils though the foramen magnum.
Cases are either asymptomatic or symptomatic. When symptoms develop, they often
do not do so until late childhood.
Symptoms include headaches that are worse with straining and other maneuvers that
increase intracranial pressure. Symptoms of brainstem compression such as
diplopia, oropharyngeal dysfunction, tinnitus, and vertigo can occur.
Obstructive hydrocephalus and/or syringomyelia can also occur.
Dandy-Walker malformation
is part of a continuum of posterior posterior fossa anomalies that include cystic
dilatation of the fourth ventricle, hypoplasia of the cerebellar vermis, hydrocephalus,
and an enlarged posterior fossa with elevation of the lateral venous sinuses and the
tentorium.
The etiology of Dandy-Walker malformation includes chromosomal abnormalities,
single gene disorders, and exposure to teratogens.
Arachnoid cysts of the posterior fossa can be associated with hydrocephalus.
Mega cistern magna is characterized by an enlarged CSF space inferior and dorsal
to the cerebellar vermis and when present in isolation may be considered a normal
variant.
Persisting Blake pouch is a cyst that obstructs the subarachnoid space and is
associated with hydrocephalus.
Joubert syndrome
is an autosomal recessive disorder with significant genetic heterogeneity that is
associated with cerebellar vermis hypoplasia and the pontomesencephalic molar
tooth sign (a deepening of the interpeduncular fossa with thick and straight superior
cerebellar peduncles).
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It is associated with hypotonia, ataxia, characteristic breathing abnormalities
including episodic apnea and hyperpnea, global developmental delay, nystagmus,
strabismus, and oculomotor apraxia.
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Rhombencephalosynapsis
is an absent or small vermis associated with a nonseparation or fusion of the deep
midline cerebellar structures.
Ventriculomegaly or hydrocephalus is often seen.
Lhermitte- Duclos disease is a dysplastic gangliocytoma of the cerebellum leading
to focal enlargement of the cerebellum and macrocephaly, cerebellar signs, and
seizures.
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Pontocerebellar hypoplasias
are a group of disorders characterized by impairment of cerebellar and pontine
development together with histopathologic features of neuronal death and glial
replacement.
Clinical features tend to be nonspecific and include hypotonia, feeding difficulties,
developmental delay, and breathing difficulties.
Causes include:
o type I (with features of anterior horn cell involvement)
o type II (with extrapyramidal features, seizures, and acquired
microcephaly)
o Walker-Warburg syndrome
o muscle-eye-brain disease
o congenital disorders of glycosylation type 1A
o mitochondrial cytopathies
o teratogen exposure
o congenital cytomegalovirus (CMV) infection
o 3-methylglutaconic aciduria
o PEHO syndrome (progressive encephalopathy with edema,
hypsarrhythmia, and optic atrophy)
o autosomal recessive cerebellar hypoplasia in the Hutterite population
o lissencephaly with cerebellar hypoplasia
o other subtypes of pontocerebellar hypoplasia
Microcephaly
Microcephaly is defined as a head circumference that measures more than 3 standard
deviations below the mean for age and sex. This condition is relatively common, particularly
among developmentally delayed children. Although there are many causes of microcephaly,
abnormalities in neuronal migration during fetal development, including heterotopias of
neuronal cells and cytoarchitectural derangements, are often found. Microcephaly may be
subdivided into 2 main groups: primary (genetic) microcephaly and secondary (nongenetic)
microcephaly. A precise diagnosis is important for genetic counseling and for prediction for
future pregnancies.
ETIOLOGY
- Primary microcephaly refers to a group of conditions that usually have no associated
malformations and follow a mendelian pattern of inheritance or are associated with a
specific genetic syndrome. Affected infants are usually identified at birth because of a
small head circumference.
- Primary microcephaly is also associated with at least 7 loci, and 4 single etiologic
genes have been identified. It is known as autosomal recessive primary microcephaly
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(MCPH) and has autosomal inheritance. Many X-linked causes of microcephaly are
caused by gene mutations that lead to severe structural brain malformations such as
lissencephaly, and these should be sought on MRI.
Secondary microcephaly results from a large number of noxious agents that can
affect a fetus in utero or an infant during periods of rapid brain growth, particularly the
1st 2 yr of life. Acquired microcephaly can be seen in conditions such as Rett
syndrome and in genetic conditions known also to cause primary microcephaly.
CLINICAL MANIFESTATIONS AND DIAGNOSIS
- It is important to measure a patient’s head circumference at birth to diagnose
microcephaly as early as possible
An insult to the brain that occurs later in life, particularly beyond the age of 2 yr, is
less likely to produce severe microcephaly.
- The head circumference of each parent and sibling should be recorded.
- Laboratory investigation of a microcephalic child is determined by the history and
physical examination. If the cause of the microcephaly is unknown, the mother’s
serum phenylalanine level should be determined. High phenylalanine serum levels in
an asymptomatic mother can produce marked brain damage in an otherwise normal
nonphenylketonuric infant.
- A karyotype and/or array-comparative genomic hybridization (array-CGH) study is
obtained if a chromosomal syndrome is suspected or if the child has abnormal facies,
short stature, and additional congenital anomalies.
- MRI is useful in identifying structural abnormalities of the brain such as
lissencephaly, pachygyria, and polymicrogyria, and CT scanning is useful to detect
intracerebral calcification
TREATMENT
Once the cause of microcephaly has been established, the physician must provide accurate
and supportive genetic and family counseling. Because many children with microcephaly are
also mentally retarded, the physician must assist with placement in an appropriate program
that will provide for maximal development of the child.
Hydrocephalus
Hydrocephalus is not a specific disease; it represents a diverse group of conditions that
result from impaired circulation and absorption of CSF or, in rare circumstances, from
increased production of CSF by a choroid plexus papilloma.
PHYSIOLOGY
- The CSF is formed primarily in the ventricular system by the choroid plexus, which is
situated in the lateral, 3rd, and 4th ventricles
- In a normal child, about 20 mL/hr of CSF is produced.
- The total volume of CSF approximates 50 mL in an infant and 150 mL in an adult.
- Most of the CSF is extraventricular.
- CSF is absorbed primarily by thearachnoid villi through tight junctions of their
endothelium by the pressure forces that were noted earlier
- Hydrocephalus resulting from obliteration of the subarachnoid cisterns or malfunction
of the arachnoid villi is called nonobstructive or communicating hydrocephalus.
PATHOPHYSIOLOGY AND ETIOLOGY
- Obstructive or noncommunicating hydrocephalus develops most commonly in
children because of an abnormality of the aqueduct or a lesion in the 4th ventricle.
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Aqueductal stenosis results from an abnormally narrow aqueduct of Sylvius that is
often associated with branching or forking
Lesions or malformations of the posterior fossa are prominent causes of
hydrocephalus, including posterior fossa brain tumors, Chiari malformation, and the
Dandy-Walker syndrome.
Nonobstructive or communicating hydrocephalus most commonly follows a
subarachnoid hemorrhage, which is usually a result of intraventricular hemorrhage in
a premature infant. Blood in the subarachnoid spaces can cause obliteration of the
cisterns or arachnoid villi and obstruction of CSF flow
CLINICAL MANIFESTATIONS
- The clinical presentation of hydrocephalus is variable and depends on many factors,
including the age at onset, the nature of the lesion causing obstruction, and the
duration and rate of increase of the intracranial pressure (ICP).
In an infant, an accelerated rate of enlargement of the head is the most prominent
sign
- the anterior fontanel is wide open and bulging, and the scalp veins are dilated
- The forehead is broad, and the eyes might deviate downward because of
impingement of the dilated suprapineal recess on the tectum, producing the settingsun eye sign
- In an older child, the cranial sutures are partially closed so that the signs of
hydrocephalus may be subtler. Irritability, lethargy, poor appetite, and vomiting are
common to both age groups, and headache is a prominent symptom in older patients
- Percussion of the skull might produce a cracked pot sound or MacEwen’s sign,
indicating separation of the sutures
- A foreshortened occiput suggests Chiari malformation, and a prominent occiput
suggests the Dandy-Walker malformation
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Chiari malformation
consists of two major subgroups:
o Type I
- typically produces symptoms during adolescence or adult life and is usually
not associated with hydrocephalus
- Patients complain of recurrent headache, neck pain, urinary frequency, and
progressive lower extremity spasticity
- The deformity consists of displacement of the cerebellar tonsils into the
cervical canal
- Although the pathogenesis is unknown, a prevailing theory suggests that
obstruction of the caudal portion of the 4th ventricle during fetal development
is responsible.
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type II Chiari malformation
- is characterized by progressive hydrocephalus with a myelomeningocele.
- this lesion represents an anomaly of the hindbrain, probably owing to a
failure of pontine flexure during embryogenesis, and results in elongation of
the 4th ventricle and kinking of the brainstem, with displacemen of the inferior
vermis, pons, and medulla into the cervical canal
- Approximately 10% of type II malformations produce symptoms during
infancy, consisting of stridor, weak cry, and apnea, which may be relieved by
shunting or by decompression of the posterior fossa
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Dandy-Walker malformation
consists of a cystic expansion of the 4th ventricle in the posterior fossa and midline
cerebellar hypoplasia, which results from a developmental failure of the roof of the
4th ventricle during embryogenesis
Approximately 90% of patients have hydrocephalus, and a significant number of
children have associated anomalies, including agenesis of the posterior cerebellar
vermis and corpus callosum
The Dandy-Walker malformation is managed by shunting the cystic cavity (and on
occasion the ventricles as well) in the presence of hydrocephalus
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
- Examination includes careful inspection, palpation, and auscultation of the skull and
spine
- The occipitofrontal head circumference is recorded and compared with previous
measurements. The size and configuration of the anterior fontanel are noted, and the
back is inspected for abnormal midline skin lesions, including tufts of hair, lipoma, or
angioma that might suggest spinal dysraphism.
- The presence of a prominent forehead or abnormalities in the shape of the occiput
can suggest the pathogenesis of the hydrocephalus
- The CT scan and/or MRI along with ultrasonography in an infant are the most
important studies to identify the specific cause and severity of hydrocephalus
- Measurement of parents’ head circumferences is necessary to establish the
diagnosis.
MEGALENCEPHALY
Megalencephaly is an anatomic disorder of brain growth defined as a brain weight:volume
ratio >98th percentile for age (or ≥2 standard deviations [SD] above the mean) that is usually
accompanied by macrocephaly (an occipitofrontal circumference [OFC] >98th percentile).
The most common cause of anatomic megalencephaly is benign familial megalencephaly.
This condition is easily diagnosed by careful family history and measurement of the parents’
head circumferences (OFCs). Anatomic megalencephaly is usually apparent at birth, and
head growth continues to run parallel to the upper percentiles. Common megalencephalyassociated macrocephaly syndromes include syndromes with prenatal and/or postnatal
somatic overgrowth such as Sotos, Simpson-Golabi-Behmel, fragile X, Weaver, M-CMTC,
and Bannayan-Ruvalcaba-Riley syndromes and syndromes without somatic overgrowth
such as FG, Greig cephalopolysyndactyly, acrocallosal, and Gorlin syndromes. Hypotonia,
poor coordination, and speech delay are common. Most children show mental retardation,
ranging from mild to severe.
HYDRANENCEPHALY
- Hydranencephaly may be confused with hydrocephalus. The cerebral hemispheres
are absent or represented by membranous sacs with remnants of frontal, temporal,
or occipital cortex dispersed over the membrane. The midbrain and brainstem are
relatively intact.
- The cause is unknown, but bilateral occlusion of the internal carotid arteries during
early fetal development would explain most of the pathologic abnormalities.
- Affected infants can have a normal or enlarged head circumference at birth that
grows at an excessive rate postnatally.
TREATMENT
- Therapy for hydrocephalus depends on the cause
- Medical management, including the use of acetazolamide and furosemide, can
provide temporary relief by reducing the rate of CSF production, but long-term results
have been disappointing.
- The major complications of shunting are occlusion (characterized by headache,
papilledema, emesis, mental status changes) and bacterial infection (fever,
headache, meningismus), usually due to Staphylococcus epidermidis
PROGNOSIS
- Prognosis depends on the cause of the dilated ventricles and not on the size of the
cortical mantle at the time of operative intervention, except in cases in which the
cortical mantle has been severely compressed and stretched.
- Hydrocephalic children are at increased risk for various developmental disabilities.
- Many children have abnormalities in memory function.
- Vision problems are common, including strabismus, visuospatial abnormalities, visual
field defects, and optic atrophy with decreased acuity secondary to increased ICP.
Craniosynostosis
Craniosynostosis is defined as premature closure of the cranial sutures and is classified as
primary or secondary. It is associated with varying types of abnormal skull shape. Primary
craniosynostosis refers to closure of one or more sutures owing to abnormalities of skull
development, whereas secondary craniosynostosis results from failure of brain growth and
expansion and is not discussed here. The incidence of primary craniosynostosis
approximates 1/2,000 births. The cause is unknown in the majority of children; however,
genetic syndromes account for 10-20% of cases.
DEVELOPMENT AND ETIOLOGY
- The bones of the cranium are well developed by the 5th mo of gestation (frontal,
parietal, temporal, and occipital) and are separated by sutures and fontanels.
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The brain grows rapidly in the 1st several years of life and is normally not impeded
because of equivalent growth along the suture lines.
The cause of craniosynostosis is unknown, but the prevailing hypothesis suggests
that abnormal development of the base of the skull creates exaggerated forces on
the dura that act to disrupt normal cranial suture development.
Genetic factors have been identified for some isolated and for many syndromic
causes of craniosynostosis
CLINICAL MANIFESTATIONS AND TREATMENT
- Most cases of craniosynostosis are evident at birth and are characterized by a skull
deformity that is a direct result of premature suture fusion.
- Palpation of the suture reveals a prominent bony ridge, and fusion of the suture may
be confirmed by plain skull roentgenograms, CT scan or bone scan in ambiguous
cases
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Scaphocephaly
Premature closure of the sagittal suture produces a long and narrow skull
the most common form of craniosynostosi
associated with a prominent occiput, a broad forehead, and a small or absent
anterior fontanel
The condition is sporadic, is more common in males, and often causes difficulties
during labor because of cephalopelvic disproportion
does not produce increased ICP or hydrocephalus, and results of neurologic
examination of affected patients are normal.
Frontal plagiocephaly
the next most common form of craniosynostosis and is characterized by unilateral
flattening of the forehead, elevation of the ipsilateral orbit and eyebrow, and a
prominent ear on the corresponding side
more common in females and is the result of premature fusion of a coronal and
sphenofrontal suture
Occipital plagiocephaly
most often a result of positioning during infancy and is more common in an immobile
child or a child with a disability, but fusion or sclerosis of the lambdoid suture can
cause unilateral occipital flattening and bulging of the ipsilateral frontal bone.
Trigonocephaly is a rare form of craniosynostosis caused by premature fusion of
the metopic suture. These children have a keel-shaped forehead and hypotelorism
and are at risk for associated developmental abnormalities of the forebrain. Milder
forms of metopic ridging are more common. Turricephaly refers to a cone-shaped
head due to premature fusion of the coronal and often sphenofrontal and
frontoethmoidal sutures. The kleeblattschädel deformity is a peculiarly shaped
skull that resembles a cloverleaf. Affected children have very prominent temporal
bones, and the remainder of the cranium is constricted. Hydrocephalus is a common
complication
Neurologic complications, including hydrocephalus and increased ICP, are more
likely to occur when two or more sutures are prematurely fused
The most prevalent genetic disorders associated with craniosynostosis:
include Crouzon, Apert, Carpenter, Chotzen, and Pfeiffer syndromes.
o Crouzon syndrome
- is characterized by premature craniosynostosis and is inherited as an
autosomal dominant trait
- The shape of the head depends on the timing and order of suture fusion but
most often is a compressed back-to-front diameter or brachycephaly due to
bilateral closure of the coronal sutures.
- The orbits are underdeveloped, and ocular proptosis is prominent.
- Hypoplasia of the maxilla and orbital hypertelorism are typical facial
features.
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Apert syndrome
- has many features in common with Crouzon syndrome
- is usually a sporadic condition, although autosomal dominant inheritance
can occur
- It is associated with premature fusion of multiple sutures, including the
coronal, sagittal, squamosal, and lambdoid sutures
- is characterized by syndactyly of the 2nd, 3rd, and 4th fingers, which may be
joined to the thumb and the 5th finger
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Carpenter syndrome
- is inherited as an autosomal recessive condition, and the many fusions of
sutures tend to produce the kleeblattschädel skull deformity
- Soft tissue syndactyly of the hands and feet is always present, and mental
retardation is common
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Chotzen syndrome
- characterized by asymmetric craniosynostosis and plagiocephaly
- the most prevalent of the genetic syndromes and is inherited as an
autosomal dominant\ trait
- It is associated with facial asymmetry, ptosis of the eyelids, shortened
fingers, and soft tissue syndactyly of the 2nd and 3rd fingers.
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Pfeiffer syndrome
- is most often associated with turricephaly.
- The eyes are prominent and widely spaced, and the thumbs and great toes
are short and broad
- Most cases appear to be sporadic, but autosomal dominant inheritance has
been reported.