V

Figure 1. Holoprosencephaly. MRI shows absence of the anterior corpus callosum (left) and continuity of the basal ganglia and frontal lobes (right).

Genetics

HPE occurs sporadically in children, but many families with multiple affected individuals have been reported. Autosomal dominant inheritance with incomplete penetrance and variable expressivity, autosomal recessive and X-linked forms are described. Recurrence risk to future siblings based on empiric data for sporadic HPE is 6% and appropriate genetic counseling should be given. The molecular basis of HPE is now understood in about 10% of patients who have mutations in one (or more) of the five known HPE genes. These include the SIX3 gene on chromosome 2p21, PTCH on 9q22.3, SHH on 7q36, TGIF on 18p11.3 and ZIC2 on 13q32. In addition, multiple loci have been mapped including HPE1 on 21q22.3, HPE2 on 2p21, HPE3 on 7q36 and HPE4 on 18p.

Agenesis of the Corpus Callosum

Diagnosis

Agenesis of the corpus callosum (ACC) is one of the most common brain malformations seen in humans. ACC is characterized by either complete absence of the corpus callosum or a foreshortened corpus callosum with absent posterior body and splenium. Some patients have interhemispheric cysts, which communicate with the third ventricle, while others have associated brain malformations such as hydro-cephalus, Dandy-Walker malformation, or polymicrogyria.

ACC occurs as an isolated anomaly, but is also seen in conjunction with other autosomal malformation syndromes (see Table 3). They include Walker-Warburg syndrome, lissencephaly, mutations of the L1CAM gene (including X-linked hydrocephalus with adducted thumbs), Lyon syndrome (which consists of necrotizing myopthy, cardiomyopathy and cataracts), and metabolic disorders including nonketotic hyperglycinemia and pyruvate dehydrogenase deficiency.

Table 3. Syndromes associated with specific brain anomalies

Structural Anomaly

Associated Syndrome

Holoprosencephaly

Agenesis of the Corpus Callosum

Dandy-Walker malformation

Trisomy 13

Deletion 13q, 18p Fetal hydantoin Pallister Hall Shprintzen Triploidy

Acrocallosal Aicardi

Cerebro-Oculo-Facial-Skeletal Fryns

Marden-Walker Meckel-Gruber Neu Laxova Walker-Warburg Zellweger

Aicardi

Walker-Warburg

Marden-Walker

Meckel-Gruber

Neu Laxova

Pallister-Hall

Coffin-Siris

Primary microcephaly

Smith-Lemli-Opitz Shprintzen

Maternal phenylketonuria

Aicardi

Angelman

Rubinstein-Taybi

Miller Dieker

Meckel-Gruber

Chromosomal abnormalities

Fetal alcohol

Marden-Walker

Clinical Course and Management

There is great variability in phenotype and prognosis for ACC, ranging from profound mental handicap to normal intelligence. Patients with severe handicaps often have associated brain malformations such as a cortical dysplasia or hydroceph-alus. Many children, especially those in whom ACC is recognized in the first few years of life, will have seizures. All affected children should have an ophthalmologi-cal exam searching for related anomalies, chromosome analysis, a full metabolic screen including serum and urine amino acids, organic acids, serum lactate and pyruvate. In children with less-severe cognitive defects, learning disabilities are often present and may be complex; neuropsychological testing is important.

Genetics

The genetics of ACC is complex because it has many potentials including chromosome aneuploidy syndromes and autosomal dominant, recessive and X-linked inheritance for isolated ACC and the ACC-associated malformation syndromes. Unfortunately, no studies of the empiric recurrence risk have been reported, although anecdotal evidence suggests a relatively low risk for isolated ACC when no syndrome has been recognized. No genes specifically causing isolated ACC have been identified.

Septo-Optic Dysplasia (DeMorsier Syndrome)

Diagnosis

Septo-optic dysplasia (SOD), or DeMorsier syndrome, is diagnosed when 2 of the following 3 major anomalies are present: absence of the septum pellucidum, optic nerve hypoplasia, and pituitary hypoplasia and insufficiency. The diagnosis of SOD is less likely when only one of the 3 major anomalies is present, as any one of the triad can be associated with multiple other anomalies and conditions. For example, congenital absence of the septum pellucidum occurs as part of several different brain malformations including basilar encephaloceles, holoprosencephaly, agenesis of the corpus callosum, SOD, severe hydrocephalus and hydranencephaly.

SOD can occur as an isolated anomaly or in association with schizencephaly (SOD-SCH) or polymicrogyria, and these two conditions occur with approximately equal frequency. Patients with isolated SOD usually have a normal gyral pattern and cortex, complete absence of the septum pellucidum, diffuse although variable white matter hypoplasia with associated ventriculomegaly and, frequently, optic nerve hypo-plasia. Many present with symptoms of hypothalamic-pituitary dysfunction. Patients with SOD-SCH usually present with seizures or visual problems and have either unilateral or bilateral clefts extending from the pial surface to the ependymal surface, regions of polymicrogyria surrounding the clefts, partial absence of the septum pellucidum, normal lateral ventricles save for the clefts, and frequent optic nerve hy-poplasia.

Clinical Course and Management

The prognosis of SOD varies greatly, even among patients with isolated SOD. Most patients with isolated SOD present with pituitary insufficiency or mild developmental delay, and have normal intelligence or mild cognitive impairments, although some have more severe handicaps. Seizures are uncommon, but may occur during episodes of severe electrolyte disturbances. Patients with SOD-SCH usually present with visual loss, neurological abnormalities, or both. The neurological problems typically consist of developmental delay, mental retardation, either hemiplegia or quadriplegia depending on whether the cleft is unilateral or bilateral, and seizures.

Whenever any one of the triad is discovered, evaluations for the others are indicated. Testing for hypopituitarism is particularly important for patients with absent septum pellucidum or optic nerve hypoplasia.

Figure 2. Dandy Walker malformation. MRI shows hypoplasia of the corpus callosum, mild brainstem hypoplasia, small vermis, enlarged lateral, 3rd and 4th ventricles, and communication between the 4th ventricle and a moderate-sized retrocerebellar cyst.

Genetics

Although SOD appears to be a relatively common malformation, very few examples of familial recurrence have been reported. One pair of siblings reported to have SOD also had agenesis of the corpus callosum. Subsequent molecular studies revealed a homozygous mutation in the HESX1 gene on chromosome 3p21.1-p21.2. However, no mutations of this gene were found in 18 patients with sporadic SOD. No examples of familial SOD-SCH have been reported, although recurrence could be possible. Thus, parents should be counseled for a low recurrence risk of less than 5% and most likely less than 1%.

Dandy-Walker Malformation

Diagnosis

The Dandy-Walker malformation (DWM) consists of four abnormalities, including cerebellar vermis hypoplasia, a retrocerebellar cyst that communicates with the fourth ventricle, elevation of the torcula (confluence of the sinuses) by the large retrocerebellar cyst and hydrocephalus (Fig. 2). DWM has been reported in many different malformation syndromes, and combined with other brain anomalies, especially agenesis of the corpus callosum. The severity of the malformation and the associated neurological disabilities vary widely and reflect substantial causal heterogeneity.

Clinical Course and Management

While often considered a severe brain malformation, the severity of symptoms varies widely among patients with DWM. Many seem to have a generally good outcome and almost half have normal intelligence. The incidence of seizures is higher than in the normal population, but lower than the population of patients with most other brain malformations. Many children have congenital hydrocephalus, which frequently requires a shunt. In addition, the retrocerebellar cyst may enlarge, requiring a shunt, and children with normal lateral ventricles at birth or in early childhood may develop hydrocephalus later in life.

Genetics

Most patients with DWM have no other congenital anomalies except for related brain malformations. However, it has been observed in many multiple malformation syndromes such as Meckel syndrome. The empiric recurrence risk for isolated DWM is approximately 6%.

Pontocerebellar Hypoplasia

Diagnosis

Pontocerebellar hypoplasia (PCH) is characterized by a small brainstem with severe flattening of the pons and a small cerebellum involving both vermis and hemispheres. The sulci of the cerebellum are typically enlarged, which suggests atrophy rather than hypoplasia. Serial computed tomography (CT) and MRI scans in some patients have shown that the changes may be progressive, with later scans also showing some cerebral atrophy. PCH usually comprises a prenatal-onset degenerative disease or group of diseases and three types have been reported. PCH type 1 consists of combined PCH and anterior horn cell degeneration, compatible with spinal muscular atrophy. PCH type 2 consists of PCH and severe neurological disabilities, including severe mental retardation, spastic quadriparesis, ataxia and chorea. Features, that do not fit into either of the first two types characterize a possible third type of PCH.

Clinical Course and Management

All children with PCH type 1, with associated spinal muscular atrophy die early in life. Patients with PCH type 2 have severe spastic quadriparesis, opisthotonus, infancy-onset chorea, and at least half of them have epilepsy, which may be intractable. All survivors have had severe mental retardation and neurological disabilities, although many survive until at least late childhood. The prognosis for PCH is uniformly poor. The brainstem problems often make feeding very difficult, necessitating gastrostomy tube placement, and all patients should be monitored for seizures.

Genetics

PCH types 1 and 2 have autosomal-recessive inheritance. Some other PCH variants with multiple affected siblings have been reported, also supporting autosomal recessive inheritance. Some children appear to have non-progressive PCH, which may or may not be genetic.

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