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Revision as of 19:11, 13 October 2010
Introduction
Contiguous gene syndromes is a group of disorders caused by deletion that spans several genes, located near each other. Deletions on some chromosomes are more common and produce recognized phenotypes:- Williams syndrome (chromosome 7q genes deletion)
- Angelman syndrome and Prader-Willi syndrome (15q11-13 deletion)
- DiGeorge syndrome (22q11.2 deletion)
- WAGR syndrome (11p13 deletion)
Most can be diagnosed by careful history and physical exam. Karyotyping is usually not sufficient to diagnose small deletions, and fluorescent in situ hybridization (FISH) is needs for genetic diagnosis.
Williams syndrome
Williams syndrome is a neurodevelopmental disorder characterized by "elfin" facial dysmorphisms, variable MR, and cognitive deficits. Cognitive problems include, most prominently, visual-spatial deficits, affecting handwriting, drawing, gait, and ability to assemble jigsaw puzzles. (This is often contrasted with fragile X syndrome, where cognitive deficits are uniform, and Down syndrome, where visual-spatial abilities may be spared). Notably, many patients with Williams syndrome demonstrate superior musical abilities.
Associated dysmorphic features include short upturned nose, flat nasal bridge, long philtrum, wide mouth and full lips.
Behaviorally, children are often inattentive, hyperactive, overly friendly and hyperverbal (blurting). At the same time many exhibit social and communicative difficulties seen in autism spectrum disorders.
Elastin protein insufficiency accounts for significant cardiovascular disease and arterial stenosis. Hypercalcemia is another clinical feature of the syndrome.
Angelman Syndrome
Each autosomal gene is represented by two copies (alleles), one from each parent; in some instances only one copy is expressed, while the other is silenced. This phenomenon is referred to as genetic imprinting. Chromosomal region 15q11-13 contains genes whose expression depends on whether the chromosome is maternal or paternal in origin. For example UBE3A gene is only expressed by the maternal chromosome, and invariably silenced on the paternal copy. A loss of 15q11-13 segment of the maternal chromosome will result in Angelman syndrome, since the normal paternal copy contains a silenced copy of UBE3A. A deletion of the same segment occuring on the paternal chromosome will result in Prader-Willi syndrome.
If the deletion is relatively small, genetic diagnosis requires analysis of methylation patterns using Southern Blot of PCR.
Individuals with Angelman syndrome are hypotonic as infants, and develop with significant motor delays and MR. Speech and expressive language are delayed or absent. A characteristic gait ataxia and a happy, easily excitable demeanor were captured in the older term happy puppet syndrome, which is no longer considered appropriate. Early seizures and microcephaly are common features.
Associated dysmorphic features include large mandible, wide mouth, and wide-spaced teeth.
Prevalence is about 1 in 10,000 births.
Prader-Willi Syndrome
Prader-Willi syndrome (PWS) results from 15q11-13 deletion on the paternal chromosome. The corresponding genes on the maternal chromosome are silenced and thus, not expressed. Infants are lethargic and hypotonic at birth; they often have feeding difficulties resulting in failure to thrive. Speech and other developmental delays follow. Hyperphasia becomes significant by second or third year of life, contributing to obesity. Scoliosis and hypogonadism are features that often go unrecognized. Children with PWS have mild to moderate MR, behavioral difficulties and temper tantrums, obsessive-compulsive and skin picking behaviors.
Characteristic dysmorphic features include elongated face, narrow forehead, prominent nasal bridge, and smooth philtrum.
Prevalence is about 1 in 10,000 births.
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