Armstrong and also Naidu, who have reviewed the neuropathology of Rett syndrome, have drawn attention to a number of subtle cortical abnormalities, most of which are consistent with disruption of the postnatal integrative phase of cerebral development; however, not all cases showed these abnormalities. There is generally a decrease in brain size, most marked frontally. Dendritic branching is reduced in several areas. MRI studies have shown reduced volume in dorsal parietal gray matter with preserved occipital volume, and reduction of anterior frontal lobe volume that correlates with symptom severity.
This is yet another X-linked type of developmental delay, which in its fully expressed form is associated with prominent dystonia of the hands and sometimes of the feet, or ataxia. Like Rett syndrome, discussed above, variations in gene expression appear to cause other syndromes including myoclonic epilepsy, West syndrome, autism, and nonspecific retardation, as well as lissencephaly. The mutated gene, termed Aristaless-related homeobox (ARX), is involved with regulation of protein-DNA interactions. The subject is reviewed by Sherr.
A similar type of hereditary, male-sex-linked developmental delay was described by Renpenning and associates (and subsequently associated with Renpenning’s name). The originally described family comprised 21 males in 2 generations of Mennonites in western Canada whose IQs ranged from 30 to 40. It has now been described in at least 60 individuals from 15 families. As with the fragile X syndrome, female siblings may show slight degrees of retardation. Affected members were small in stature and slightly microcephalic but otherwise free of somatic and neurologic abnormalities. The mutated gene responsible is PQBP1, the polyglutamine binding protein of which produces the syndrome through unknown means.
This inherited form of developmental delay is manifest in both males and females and was mentioned earlier. It is characterized by mild and variable developmental delay but with sometimes striking retention and even precocity or superiority of musical aptitude and social amiability. In some instances, a retained facility for writing permits the production of long, written descriptions; yet at the same time, these subjects are barely able to draw simple objects. The child is physically slow and has minor but distinctive somatic changes (wide mouth, almond-shaped eyes, short upturned nose, flat nasal bridge, long philtrum, delicate chin, and small pointed ears), together imparting an “elfin appearance” that is nonetheless variable and not as apparent in adulthood as the facial features coarsen. There is often an unusual sensitivity to auditory stimuli. The delay in acquisition of communicative speech and defects in visual, spatial, and motor skills make these children seem more deficient than they actually are. Striking sociability and empathy set them apart; they represent virtually the converse of autism in this respect. Memory for musical scores—such as memorizing parts of a complete symphony after one hearing—may be prodigious.
By the use of high-resolution cytogenetics, the disease was traced in over 90 percent of cases to a deletion on chromosome 7 in the ELN gene that controls the production of elastin (Nickerson et al). This is of interest because one index feature of these cases is supravalvular aortic stenosis and variations (but not necessarily deletions) in the same gene account for cases of familial supravalvular stenosis without developmental delay. This cardiovascular disease is the main cause of death in these individuals.
It is not known whether there is a characteristic brain pathology, but one 35-year-old patient examined by Golden and associates showed no cerebral abnormalities except for Alzheimer changes, mainly plaque formation in the entorhinal cortex and amygdala. The laboratory diagnosis can be established by the use of ELN-specific probes or other techniques that show only one allele of the gene. A most interesting related finding by Somerville and colleagues is that duplication at the same site on chromosome 7 implicated in Williams syndrome can cause a delay in the acquisition of expressive speech. The reader is referred to an extremely thorough clinical and genetic review of the syndrome by Pober.