10. Prader-Willi and Angelman syndromes. The Prader-Willi syndrome was already mentioned in relation to the hyperphagia of hypothalamic disorders (adiposogenital dystrophy, Froehlich syndrome). It is not uncommon (1 in 20,000 births) and affects both sexes equally. Hypotonia (floppy infant), areflexia, small stature, dysmorphic facies, and hypoplastic genitalia are evident, and arthrogryposis may be present at birth. After the first year, developmental delay becomes obvious and obesity, due to hyperphagia, becomes prominent. Patients are identified by the “H3O” mnemonic, referring to hypomentia, hypotonia, hypogonadism, and obesity. The disorder is associated with a deletion at 15q11-q13 (a so-called microdeletion, as in Williams syndrome), which can be identified by a combination of cytogenetic and DNA analyses. In 70 percent of cases the disease is caused by a noninherited deletion from the paternal X chromosome.
11. The Angelman syndrome, another cause of severe developmental delay, is associated with the identical chromosomal abnormality to that found in the Prader-Willi syndrome, but there is usually a maternally inherited single-gene defect. The difference in phenotype derives from a complex genetic phenomenon termed spatially restricted imprinting. The phenotype comprises severe developmental delay, microcephaly, refractory seizures, absence of speech, ataxia, inappropriate laughter, prominent jaw, thin upper lip, and prolonged tongue. Outstanding in its clinical presentation is an unusual marionette-like stance coupled with a persistent tendency to laugh and smile (hence the old name “happy puppet syndrome”).
12. Rett syndrome, discussed more fully further on, is mentioned here because it is to the result of a dominant defect on the X chromosome. It affects 1 of every 10,000 to 15,000 girls. After 6 to 18 months of normal development, motor skills and mental abilities seem slowly to regress. Certain handwringing and other stereotyped hand movements appear as the disease progresses and are characteristic. This disorder is discussed more extensively later in the chapter.
Several generalizations can be made about these chromosomal dysgeneses. First, the autosomal ones are often lethal (Rett syndrome is an exception), and they almost always have a devastating effect on cerebral growth and development, whether the infant survives or not. Anomalies of nonneural and a degree of externally visible dysmorphism structures are regularly present—an association so constant that one may safely predict that an otherwise normally formed infant will not have a detectable chromosomal defect. However, only in the Down syndrome and trisomy 13 (and possibly trisomy 18) are the physiognomy and bodily configuration highly characteristic. Surprisingly, some of the most grotesque disfigurements, such as anencephaly and multiple severe congenital anomalies, are not related to a morphologic abnormality of chromosomes. By contrast, an insufficiency of sex chromosomes induces only subtle effects on the brain, affecting intellect and personality; to some extent this is true of supernumerary sex chromosomes (e.g., XYY).
The basic abnormality of the brain underlying the developmental delay in many of these chromosomal dysgeneses has not been ascertained. The cerebrum is slightly small, but only minor changes are seen in the convolutional pattern and cortical architecture in conventional microscopic preparations. Neurocellular methodologies to date are not sufficiently advanced to reveal the fundamental cerebral abnormality.
Teratologic Deformations of the Nervous System