6. Turner syndrome (XO). Only females affected. Triangular face, small chin, occasionally hypertelorism and epicanthal folds, widely spaced nipples, clinodactyly, cubitus valgus, hypoplastic nails, short stature, webbed neck, delayed sexual development, mild developmental delay. The manner of inheritance of the X chromosome may have bearing on the patient’s personality and level of functioning, as noted in Chap. 20.
7. Colpocephaly. A rare type of malformation of the brain consisting of marked dilatation of the occipital horns of the lateral ventricles, thickening of the overlying rim of cortical gray matter, and thinning of the white matter. The associated clinical picture comprises developmental delay, spasticity, seizures, and visual abnormalities (because of optic nerve hypoplasia). This disorder is probably of diverse causation, but it is listed here with the chromosomal abnormalities because some cases have been associated with the mosaicism for trisomy 8 (Herskowitz et al). The term colpocephaly is often used incorrectly to apply to all forms of ventricular enlargement (including hydrocephalus) associated with abnormal development of the brain.
8. Fragile X syndrome (see further on for additional clinical details in the section on developmental delay). This abnormality is among the most common inherited forms of developmental delay, estimated to occur in 1 of every 1,500 male live births and accounting for 10 percent of severe developmental delay in males. Females, with two X chromosomes, are affected about half as frequently, and then only to a slight degree. With the advent of new markers for the detailed structure of chromosomes, Lubs observed an unusual site of frequent breakage (“fragility”) on the X chromosome and related it to a syndrome that included developmental delay, flaring ears, elongated facies, slightly reduced cranial perimeter, normal stature, and enlarged testes. More recently, rare progressive ataxia has been reported in adults who harbor the chromosomal abnormality and had displayed little or no cognitive deficiency.
The chromosomal fragility appears to be due to a heritable, unstable CGG repeating sequence in the X chromosome. Affected individuals have over 230 repeats and carriers have 60 to 230 repeats. The prolonged sequence inactivates a gene (FMR1) that codes for an RNA-binding protein of as yet an unknown connection to brain function. The genetics of this and other retardations was reviewed by Nokelainen and Flint. Rousseau and colleagues described a simple and sensitive test using DNA analysis for the diagnosis of the syndrome both prenatally and after birth. Because of mosaicism, the length of the triplet repeat does not directly relate to the degree of expression of cognitive impairment, and the fragile X alteration occasionally turns up in cognitively normal males; in some instances, the male children of their daughters have the disease. In some of the cases we have observed, the cognitive impairment has been mild in degree and the main abnormalities have taken the form of troublesome behavior, logorrhea, an autistic type of gaze aversion, and asociality. These and other neurobehavioral features of the syndrome and its unique pattern of inheritance (it is neither recessive nor dominant) have been discussed by Shapiro.
9. Williams syndrome. Described by J.C.P. Williams and colleagues of Australia from the perspective of a supravalvular aortic stenosis and a year later by Beuren and colleagues, this unique combination of cerebral maldevelopment and cardiovascular abnormalities has been traced in most patients to a microdeletion on chromosome 7 in the region of the gene that codes for the protein elastin. Its frequency is 1 in 20,000 newborns. Further discussion of clinical features of this syndrome is found later in the chapter.