Microcephaly Child

Skin Tag Penis

Figure 19.34 Organizing center in the isthmus at the boundaries between the midbrain and hindbrain. This region secretes FGF-8 in a circumferential ring that induces expression of engrailed I and 2(EN1 and EN2) in gradients anteriorly and posteriorly from this area. ENI regulates development of the dorsal midbrain, and both genes participate in formation of the cerebellum. WNTI, another gene induced by FGF-8, also assists in development of the cerebellum. N, notochord; P, prechordal plate.

Figure 19.34 Organizing center in the isthmus at the boundaries between the midbrain and hindbrain. This region secretes FGF-8 in a circumferential ring that induces expression of engrailed I and 2(EN1 and EN2) in gradients anteriorly and posteriorly from this area. ENI regulates development of the dorsal midbrain, and both genes participate in formation of the cerebellum. WNTI, another gene induced by FGF-8, also assists in development of the cerebellum. N, notochord; P, prechordal plate.

development of the hypothalamus. Interestingly, SHH signaling requires cleavage of the protein. The carboxy terminal portion executes this process, which also includes covalent linkage of cholesterol to the carboxy terminus of the amino terminal product. The amino terminal portion retains all of the signaling properties of SHH, and its association with cholesterol assists in its distribution.

Dorsal (lateral) patterning of the neural tube is controlled by bone mor-phogenetic proteins 4 and 7 (BMP4 and BMP7) expressed in the nonneural ectoderm adjacent to the neural plate. These proteins induce expression of MSX1 in the midline and repress expression of BF1 (Fig. 19.33).

Expression patterns of genes regulating anterior-posterior (craniocaudal) and dorsoventral (mediolateral) patterning of the brain overlap and interact at the borders of these regions. Furthermore, various brain regions are competent to respond to specific signals and not to others. For example, only the cranial part of the neural plate expresses NKX2.1 in response to SHH. Likewise, only the anterior neural plate produces BF1 in response to FGF-8; midbrain levels express EN2 in response to the same FGF-8 signal. Thus, a competence to respond also assists in specifying regional differences.


Holoprosencephaly (HPE) refers to a spectrum of abnormalities in which a loss of midline structures results in malformations of the brain and face. In severe cases, the lateral ventricles merge into a single telencephalic vesicle (alobar HPE), the eyes are fused, and there is a single nasal chamber along

Figure 19.35 Holoprosencephaly and fusion of the eyes (synophthalmia). A loss of the midline in the brain causes the lateral ventricles to merge into a single chamber and the eye fields to fail to separate. Mutations in the gene sonic hedgehog (SHH), which specifies the midline of the central nervous system at neural plate stages, is one cause for this spectrum of abnormalities.

with other midline facial defects (Fig. 19.35). In less severe cases, some division of the prosencephalon into two cerebral hemispheres occurs, but there is incomplete development of midline structures. Usually the olfactory bulbs and tracts and the corpus callosum are hypoplastic or absent. In very mild cases, sometimes the only indication that some degree of HPE has occurred is the presence of a single central incisor. HPE occurs in 1 in 15,000 live births, but is present in 1 in 250 pregnancies that end in early miscarriage. Mutations in SHH, the gene that regulates establishment of the ventral midline in the CNS, result in some forms of holoprosencephaly. Another cause is defective cholesterol biosynthesis leading to Smith-Lemli-Opitz syndrome. These children have craniofacial and limb defects, and 5% have holoprosencephaly. Smith-Lemli-Opitz syndrome is due to abnormalities in 7-dehydrocholesterol reductase, which metabolizes 7-dehydrocholesterol to cholesterol. Many of the defects, including those of the limbs and brain, may be due to abnormal SHH signaling, since cholesterol is necessary for this gene to exert its effects (see page 466). Other genetic causes include mutations in the transcription factors sine occulis homeobox3 (SIX3), TG interacting factor (TGIF) and the zinc finger protein ZIC2. Yet another cause of holoprosencephaly is alcohol abuse, which at early stages of development selectively kills midline cells.

Schizencephaly is a rare disorder in which large clefts occur in the cerebral hemispheres, sometimes causing a loss of brain tissue. Mutations in the homeobox gene EMX2 appear to account for some of these cases.

Meningocele, meningoencephalocele, and meningohydroencephalo-cele are all caused by an ossification defect in the bones of the skull. The most frequently affected bone is the squamous part of the occipital bone, which may be partially or totally lacking. If the opening of the occipital bone is small, only meninges bulge through it (meningocele), but if the defect is large, part of the brain and even part of the ventricle may penetrate through the opening into the meningeal sac (Figs. 19.36 and 19.37). The latter two malformations are known as meningoencephalocele and meningohydroen-cephalocele, respectively. These defects occur in 1/2000 births.

Exencephaly is characterized by failure of the cephalic part of the neural tube to close. As a result, the vault of the skull does not form, leaving the malformed brain exposed. Later this tissue degenerates, leaving a mass of necrotic tissue. This defect is called anencephaly, although the brainstem remains intact (Fig. 19.38, A and B). Since the fetus lacks the mechanism for swallowing, the last 2 months of pregnancy are characterized by hydramnios. The abnormality can be recognized on a radiograph, since the vault of the skull is absent. Anencephaly is a common abnormality (1/1500) that occurs 4 times more often in females than in males. Like spina bifida, up to 70% of these cases can be prevented by having women take 400 ^g of folic acid per day before and during pregnancy.

Hydrocephalus is characterized by an abnormal accumulation of cere-brospinal fluid within the ventricular system. In most cases, hydrocephalus in the newborn is due to an obstruction of the aqueduct of Sylvius (aque-ductal stenosis). This prevents the cerebrospinal fluid of the lateral and third ventricles from passing into the fourth ventricle and from there into the sub-arachnoid space, where it would be resorbed. As a result, fluid accumulates y m m««

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Figure 19.36 A-D. Various types of brain herniation due to abnormal ossification of the skull.

Birth Defects Detected Ultrasound
Figure 19.37 Ultrasonogram (top) and photograph (bottom) of a child with a menin-goencephalocele. The defect was detected by ultrasound in the seventh month of gestation and repaired after birth. Ultrasound shows brain tissue (arrows) extending through the bony defect in the skull (arrowheads).

in the lateral ventricles and presses on the brain and bones of the skull. Since the cranial sutures have not yet fused, spaces between them widen as the head expands. In extreme cases, brain tissue and bones become thin and the head may be very large (Fig. 19.39).

The Arnold-Chiari malformation is caudal displacement and herniation of cerebellar structures through the foramen magnum. Arnold-Chiari malformation occurs in virtually every case of spina bifida cystica and is usually accompanied by hydrocephalus.

Microcephaly describes a cranial vault that is smaller than normal (Fig. 19.40). Since the size of the cranium depends on growth of the brain, the

Synophthalmia Pics
Figure 19.38 A. Anencephalic child, ventral view. This abnormality occurs frequently (1/1500 births). Usually the child dies a few days after birth. B. Anencephalic child with spina bifida in the cervical and thoracic segments, dorsal view.
Anencephalic Newborn

Figure 19.39 Child with severe hydrocephalus. Since the cranial sutures had not closed, pressure from the accumulated cerebrospinal fluid enlarged the head, thinning the bones of the skull and cerebral cortex.

Microcephaly Photos
Figure 19.40 Child with microcephaly. This abnormality, due to poor growth of the brain, is frequently associated with mental retardation.

underlying defect is in brain development. Causation of the abnormality is varied; it may be genetic (autosomal recessive) or due to prenatal insults such as infection or exposure to drugs or other teratogens. Impaired mental development occurs in more than half of cases.

Fetal infection by toxoplasmosis may result in cerebral calcification, mental retardation, hydrocephalus, or microcephaly. Likewise, exposure to radiation during the early stages of development may produce microcephaly. Hy-perthermia produced by maternal infection or by sauna baths may cause spina bifida and exencephaly.

The aforementioned abnormalities are the most serious ones, and they may be incompatible with life. A great many other defects of the CNS may occur without much external manifestation. For example, the corpus callosum may be partially or completely absent without much functional disturbance. Likewise, partial or complete absence of the cerebellum may result in only a slight disturbance of coordination. On the other hand, cases of severe mental retardation may not be associated with morphologically detectable brain abnormalities. Mental retardation may result from genetic abnormalities (e.g., Down and Klinefelter syndromes) or from exposures to teratogens, including infectious agents (rubella, cytomegalovirus, toxoplasmosis). The leading cause of mental retardation is, however, maternal alcohol abuse.

Figure 19.41 Segmentation patterns in the brain and mesoderm that appear by the 25th day of development. The hindbrain (coarse stipple) is divided into 8 rhombomeres (r1 to r8), and these structures give rise to the cranial motor nerves (m). P1-P4, pharyngeal (branchial) arches; t, telencephalon; d, diencephalon; m, mesencephalon.

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