These disorders are believed to arise from a defect in midline development. The result is a failure of midline structures, like the corpus callosum, to form. Included are also abnormalities in the separation of the neural tube into two hemispheres. This later defect is believed to result in holoprosencephaly and related disorders.
Pathogenesis and Pathophysiology. Completion of neural tube closure is followed by segmentation in the anteroposterior axis. Although these segments were originally defined morphologically, recent data have demonstrated a coordinated expression of a variety of developmentally regulated genes, mostly members of transcription factor families such as the homeobox genes. In more general terms, these data have suggested that the segmental organization of the nervous system is established through a combinatorial regional expression and regulation of specific
Figure 28-3 Semilobar and alobar holoprosencephaly. In semilobar and lobar holoprosencephaly there is an apparent midline sagittal (interhemispheric) fissure (coronal section of brain). However, coronal sections reveal the cerebral cortex to be continuous across the midline. Furthermore, no corpus callosum is present. The thalamus is abnormally shaped, with marked midline fusion. Alobar holoprosenceph ha s no indication of a midline fissure on coronal sections or when viewing the brain dorsally. Again there is no evidence of a corpus callosum, only subcortical white matter across the midline.
developmental genes.y , y These segments form the progenitors to all structures recognized in the adult nervous system. In addition to the anteroposterior organization of the nervous system, bilateral symmetry arises in the cerebral hemispheres. At approximately 5 to 6 weeks after fertilization, the prosencephalon, the most rostral segment of the nervous system, shows differential growth as two distinct hemispheres. The most anterior point of the neural tube, the lamina terminalis, is the location from which the major crossing fibers between the cerebral hemisphere will arise. Both the anterior commissure and the corpus callosum have their anlagen in the lamina terminalis. From there, the corpus callosum grows back over the top of the third ventricle to form its genu, body, and splenium. Failure of the prosencephalon to grow into two symmetrical hemispheres and defects in the region of the lamina terminalis are believed to give rise to the class of defects commonly referred to as cleavage defects or midline defects.
Epidemiology and Risk Factors. Although several teratogenes and maternal factors have been reported as risk factors for the midline defects, these associations are weak and at present no definite causality has been established. On the other hand, holoprosencephaly is sometimes found segregating in families and linkage to specific chromosomal loci has been established. Evidence from this linkage analysis and from deletion mapping indicates that at least chromosomes 2p21, 7q36, 18p11.3, and 21q22.3 may harbor genes responsible for holoprosencephaly. 'd The gene for autosomal dominant familial holoprosencephaly at 7q36 (HPE3) has been identified by two groups led by Belloni and Roessler as the human Sonic hedgehog homolog, a member of an important family of developmental signalling molecules. In addition to these loci, trisomy 13 is closely linked to midline malformations, including arrhinencephaly, agenesis of the corpus callosum, and holoprosencephaly, and is the single most common chromosomal defect underlying holoprosencephaly. Other cytogenetic etiologies in holoprosencephaly include deletions of 13q, triploidy, and duplications of 3p.
Clinical Features and Associated Disorders. Holoprosencephaly is frequently divided into subtypes according to the extent of cerebral hemisphere involvement, but these distinctions are probably artificial. The most commonly used classification scheme defines three subtypes--alobar, semilobar, and lobar holoprosencephaly. y
Alobar holoprosencephaly is the most severe of these (. Fig, 2.8:3 ). The brain shows no evidence of a midsagittal fissure. The corpus callosum is absent, and the olfactory bulbs and tracts are almost always absent as well. Varying degrees of fusion of the basal ganglia and thalamus are present. This form of holoprosencephaly is most frequently associated with severe facial malformations (see later). Semilobar holoprosencephaly is characterized by an incomplete fusion of the cerebral hemispheres. The occipital and parietal lobes (see Fig 28-3. ) tend to be more or less separated, whereas the frontal lobes show varying degrees of fusion. Again, the corpus callosum is absent in all cases and the olfactory bulbs and tracts are absent in most. The basal ganglia and thalamus (see Fig 28-3 ) are variably involved but at least partially fused in all cases. In lobar holoprosencephaly, a midline fissure is present over the entire dorsal aspect of the brain; however, in at least the medio-orbital region of the frontal lobe, there is fusion across the midline. The olfactory bulbs and tracts are again absent in the vast majority of cases as is the corpus callosum. The posterior fossa contents are often unremarkable in holoprosencephaly. Only in the most severe cases of alobar holoprosencephaly can anomalous development of the cerebellum occasionally be seen. On the other hand, absence of the corticospinal tracts is a common finding and is believed to be the consequence of the severe malformation of the cerebral cortex with subsequent failure of formation of proper motor projections.
A spectrum of distinctive facial dysmorphisms is part of the holoprosencephalic malformation sequence. These facial abnormalities are expressions of the underlying profound disturbance of midline development, affecting prechordal mesoderm that is important in facial development as well. The facial phenotypes can be ranked in descending order of their severity: (1) cyclopia (the eye and orbits are
fused or in various states of incomplete separation; agnathia may also be present); (2) ethmocephaly (instead of a nose, a proboscis is present and often located above the incompletely separated, or severely hypoteloric, eyes); (3) cebocephaly (the nose now is between and below the hypoteloric eyes, but there is only a single blindly ending nostril); (4) premaxillary agenesis or aplasia of the primary palate, associated with hypotelorism and often midline cleft lip and palate; (5) milder facial dysmorphism with hypotelorism, flat base of the nose, and milder midline or bilateral clefting; and (6) minimal forms such as single central incisor. Although it is generally true in the holoprosencephaly spectrum that the face predicts the brain, y exceptions do occur. In general, the severe facial dysmorphisms of cyclopia, cyclopia with agnathia, ethmocephaly, cebocephaly, and severe hypotelorism with agenesis of the primary palate and a median cleft lip and palate usually go along with the severe alobar form of holoprosencephaly. The correlation of severity of the facial appearance and brain morphology is less pronounced at the mild end of the spectrum of facial phenotypes. Thus, the brain does not necessarily predict the face. Although the full-fledged facial phenotypes seem to be always associated with holoprosencephaly, cases of agnathia (but without cyclopia), for example, or central cleft lip and palate, have been seen in patients with a morphologically normal-appearing brain and also with brains that have malformations distinct from the holoprosencephaly sequence.
The clinical presentation of holoprosencephaly is dependent on the degree of CNS involvement. Infants with severe alobar forms often die shortly after birth. Survivors frequently present with severe mental retardation, seizures (infantile spasms occur early), severe motor impairments, poikolothermia, and endocrine insufficiencies. In the milder forms of holoprosencephaly, longer survival with various degrees of psychomotor retardation is possible. Endocrine dysfunction may become apparent, with diabetes insipidus and growth hormone deficiency having been reported in a number of cases. It should be re-emphasized that only the classic facial phenotypes are predictive of the severe alobar holoprosencephaly with its associated very poor prognosis but that a number of partial facial phenotypes, such as midline cleft lip or midface hypoplasia, are not necessarily associated with the most severe malformations in the spectrum.
The diverse syndromic contexts in which holoprosencephaly can occur are listed in reference 25. In families with autosomal dominant holoprosencephaly, carriers of the gene with minimal expression of the defect (such as hypotelorism or a single central incisor) can be neurologically normal. There may be considerable variability of expression within a given family, with severely involved cases occurring alongside milder ones. Autosomal recessive holoprosencephaly has been reported as well and in some families is associated with heart and limb defects.
Evaluation. Most cases of holoprosencephaly occur sporadically but may also be a feature of one of several malformation sequences or syndromes. y , U Therefore, part of the clinical evaluation of a patient with holoprosencephaly should always include a careful workup for additional malformations, because this information may provide the diagnosis of a specific syndrome with potentially far-reaching genetic implications. Because of the associations with some deletion/microdeletion syndromes, high-resolution karyotype analysis (± fluorescent in situ hybridization [FISH] analysis) with special emphasis on chromosomes 2p21, 3p, 7q36, 13q,
18p11.3, and 21q22.3 is recommended in all cases of holoprosencephaly. If the affected proband is not available, chromosome analysis in the parents is important to rule out a carrier status for a balanced translocation. Possible misdiagnoses in the severe forms of alobar holoprosencephaly include hydranencephaly and hydrocephalus, as well as large and expanded interhemispheric cysts that sometimes are associated with agenesis of the corpus callosum. Expanded large posterior third ventricular cysts can be mistaken for semilobar holoprosencephaly. Bridging of cerebral cortex across the midline can be missed in very mild cases of lobar holoprosencephaly and is best evaluated on coronal T1-weighted MRI images. The prenatal diagnosis of holoprosencephaly is based largely on ultrasound examination. A first trimester diagnosis is possible based on ultrasound findings of a lack of a midline echo indicative of a monoventricle, cyclopia or marked hypotelorism, a flattened profile of the nose, and microcephaly. Transvaginal ultrasound enhances the visibility of these findings, especially early in gestation. Prenatal diagnosis of mild forms such as lobar holoprosencephaly may be impossible.
Management and Prognosis. The management of a patient with holoprosencephaly depends on the extent of clinical involvement and focuses predominately on seizure control (see Chapter52 ). The prognosis for all liveborn children with severe forms of holoprosencephaly is extremely poor. The rare cases associated with true hydrocephalus due to CSF flow obstruction need to be differentiated from vetriculomegaly as a feature of the malformation itself and treated with VP shunting. Prognosis similarly parallels the ability to control the seizures. Mental retardation may be mild in the least severely affected individuals but is almost always profound in the more severely affected individuals. In cases of holoprosencephaly with less complete CNS involvement, surgical correction of the craniofacial malformations, such as cleft lip or palate, may be appropriate. Endocrine dysfunctions respond to hormone replacement therapy.
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