Other Segmentation And Cleavage Disorders

Septo-optic dysplasia is pathologically defined as absence of the septum pellucidum and hypoplastic optic nerves. This clinical constellation of symptoms and signs has also been referred to as de Morsier's syndrome. Other abnormalities are variably reported, suggesting considerable heterogeneity underlying this phenotype. Clinically, there are optic nerve hypoplasia resulting in visual impairment, endocrine abnormalities resulting from hypothalamic-pituitary insufficiency, and frequently seizures, especially in cases in which there has been disruption of cortical development as well. The degree of visual impairment can vary from blindness, with the development of amaurotic nystagmoid eye movements after a few months, to normal vision in a few cases. The endocrine insufficiencies can lead to

symptomatic hypoglycemias and diabetes insipidus; later, growth hormone deficiency may become apparent. These endocrine insufficiencies can and should be treated by standard endocrine replacement protocols. Although retardation of cognitive development occurs especially in patients with obvious concomitant cortical anomalies, a number of cases with normal cognitive development are on record. Most cases of septo-optic dysplasia have been sporadic; however, there are two observations in sibs and in cousins suggesting the existence of a form with autosomal recessive inheritance. It is an important consideration in the differential diagnosis in children presenting with optic hypoplasia. y

Agenesis of the corpus callosum can be found as an isolated malformation or in association with other malformations. y A growing number of inborn errors of metabolism also include agenesis of the corpus callosum. In complete agenesis of the corpus callosum, the cingulate gyrus is altogether absent and sulci are found radiating down the medial aspect of the brain from the dorsal surface to the high-riding roof of the third ventricle ( F.!.g, „2.8z4 ). Coronal sections or images often reveal slightly dilated ventricles with an irregular batwing-like contour (see Fig.^S-.^ ). A white matter tract, known as the bundle of Probst, can frequently be found running anteroposterior just above the lateral ventricle, where the fibers of the corpus callosum would normally collect into the commissure. Partial agenesis is recognized by the absence to variable degrees of the posterior corpus callosum, with sparing of the rostrum and genu (see Fig, 2.8.-4 ). In cases of partial agenesis of the corpus callosum, the cingulate gyrus is present only to the extent that the corpus callosum exists. The anterior commissure, also derived from the lamina terminalis, may be absent in cases of complete agenesis of the corpus callosum, although it is usually spared with partial agenesis of the corpus callosum.

Isolated agenesis of the corpus callosum is sometimes discovered incidentally either on imaging studies that were obtained for other reasons, such as trauma, or at autopsy. In isolation, the abnormality clinically is largely silent and deficits may be discovered only on careful neuropsychological assessment. Findings resembling disconnection syndromes have been described in some patients; however, this is by no means a constant feature and in the majority of patients this characteristic cannot be demonstrated. Patients with agenesis of the corpus callosum have a higher incidence of seizures and mental retardation, partially reflecting the slightly higher incidence of neuronal migrational abnormalities also seen in these patients. It should be noted, however, that patients with mental retardation or seizures, or both, are also more likely to undergo CNS imaging, which skews the ascertainment of the clinicopathological correlations in agenesis of the corpus callosum.

Because it can be assumed that the clinical manifestations of agenesis of the corpus callosum most often depend on the associated CNS anomalies rather than on the lack of the corpus callosum itself, careful assessment for such associated malformations is mandatory. Although agenesis

Figure 28-4 Partial and complete agenesis of the corpus callosum. A midsagittal MRI of a patient with complete agenesis of the corpus callofA) The medial gyri are seen radiating to the third ventricle. A midsagittal section of the brain from a patient with complete agenesis of the corpus callosurfBj. A comparison of(A) and (B) shows remarkable similar findings. A coronal MRI of another patient with agenesis of the corpus callosfc;. The lateral ventricles show the classic batwing form, and dilation is seen in the temporal horns of the lateral ventricles and the third ventricle. A midsagittal section of a brain with partial agenesis of the corpus callcfDu. The partial corpus callosum presen(arrowheads) extends from the lamina terminalis posteriorly. The cingulate (partially obscured by the arrowheads) extends the length of the corpus callosum. A sulcufarrow) extends from the dorsal surface of the brain to the third ventricle only posterior to the formed corpus callosc, Courtesy of Dr. R. Robertson)

of the corpus callosum can be diagnosed on a CT scan (high riding third ventricle, parallel configuration of the lateral ventricles, and colpocephaly), MRI is far superior in diagnosing associated structural abnormalities. Partial agenesis is also seen very clearly on sagittal MRI images. Midline cysts not associated with agenesis of the corpus callosum, holoprosencephaly, and extreme hydrocephalus without agenesis of the corpus callosum need to be considered in the differential diagnosis. In secondary disruption of the corpus callosum, developmental features, such as lack of the cingulate gyrus and presence of a bundle of Probst, are not found. The potential of an underlying metabolic disorder (e.g., nonketotic hyperglycinemia, infantile lactic acidosis associated with pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency, and Smith-Lemli-Opitz and Zellweger's syndromes) have to be considered in clinical context. In patients with additional malformations of the brain and/or extraneural structures, a karyotype should be performed as well. A special problem is posed by the prenatal detection of the absence of the corpus callosum on ultrasound. The presence of additional abnormalities and an abnormal karyotype is a poor prognostic indicator for developmental outcome, whereas outcome can be favorable if the agenesis of the corpus callosum is a truly isolated malformation. y

Absence of the olfactory bulbs and tracts, or arrhinencephaly, is also considered in the midline defects, although the pathogenesis may be distinct. Arrhinencephaly can be found as an isolated malformation or in conjunction with a variety of malformation syndromes. Clinically, bilateral arrhinencephaly manifests as anosmia. Although arrhinencephaly is frequently included in the midline dysplasias and can represent a mild manifestation of the holoprosencephaly spectrum, it would be incorrect to conclude that every isolated case of arrhinencephaly belongs with this spectrum. Possibly, arrhinencephaly can result from a number of independent mechanisms. One example of a non-holoprosencephaly-sequence syndrome associated with arrhinencephaly is Kallmann's syndrome. This syndrome is characterized by a combination of arrhinencephaly, resulting in anosmia, and hypogonadotropic hypogonadism, resulting from gonadotropin-releasing hormone

Figure 28-5 Lissencephaly type I and type I (A), A brain from an 8-month-old infant with Walker-Warburg syndrome demonstrating type II lissencephaly. Note the smooth surface of the brain; slight irregularities of the cortical surface can best be appreciated in areas of light reflection on the specimerfC), A histological section through the cerebral mantle of a 20-week-old gestational age fetus with the Walker-Warburg syndrome. One half of the thickness of this section is taken up by the totally disorganized cortical plates (white bar). In addition, there are subcortical heterotopias pointed out by the arrowD shows an age matched control. Here the cortical platwhite bar) takes up only a fraction of the whole thickness of the mantlB and E are examples of type I lissencephaly, as can be seen in the Miller-Dieker syndrome) is a coronal section stained for myelin that demonstrates the four layers of this type of lissencephaly: 1 corresponds to the molecular layer, 2 is a cellular layer with mostly large neurons, 3 is a layer containing myelinated fibers, and 4 is a broad heterogeneous cell rich layer. Note that the cortical plate takes up more then half of the total thickness of the cerebral m in a T2-weighted coronal MRI scan of a brain with type I lissencepha(e, Courtesy of Dr. R. Robertson)

deficiency.y Other neurological features may be associated. The syndrome can be inherited in an autosomal dominant, recessive, or X-linked recessive pattern. The gene for the X-linked form has been identified; it shares homology with neural cell adhesion molecules, and the developmental defect has been linked to the failure of gonadotropin- releasing hormone (GnRH)-producing neurons to reach the hypothalamus. y

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