Disorder	Genetics and Etiology	Clinicopathologic features
Chromosomal abnormalities
Down syndrome	Trisomy 21 or translocation of chromsome 21 to other chromosome, usually 14 or 21. Triplication of the 21q21-q22.3 is critical.
Klinefelter syndrome	Genotype is 47, XXY.
Multiple Y chromosome syndrome	Genotypes include 47, XYY and 48 XXYY.
Turner syndrome	Genotype is 46, X.
Multiple X syndromes	Genotype is 47, XXX; 48, XXXX, and 49 XXXXX.
Deletion and mutation
Angelman syndrome	Genetic changes: Most common is microdeletion of the long arm of chromosome 15q11-13 that is of maternal origin (identifiable in approximately 60% of cases) which is the same site as the chromosomal defect in Prader-Willi syndrome. Uniparental disomy: About 2% of them are due to paternal uniparental disomy (the child has two copies of the father’s chromosome 15 but Is missing the mother’s chromosome 15). Imprinting mutation: the patient shows an exclusively paternal methylation pattern on the maternally derived alleles.	Summary: Angelman syndrome is also known as the "Happy puppet syndrome". These patients are euphoric, frequently simile and with paroxysms of laughter. They also have unusual but characteristic posture characterized by flexion at the wrists and elbows when the arms are raised such that they resemble on a string. Clinically the patients have developmental delay and severe mental retardation, ataxia, seizure, hypotonia, postnatally developing microbrachyencephaly, and a characteristic facial appearance with macrostomia and prognathia. Abnormalities in the cerebrum have been revealed by Golgi impregnantation but very few cases have been studied histologically.
Prader-Willi syndrome	Genetics: Microdeletion of the long arm of chromosome 15q11-13 that is of paternal origin. The maternal gene is silenced by genetic imprinting. Hypopigmentation is more often seen in aptients with a deletion. The hypopigmentation in the eye and elsewhere is thought to be associated with hemizygosity of the P gene that is located within the 15q11-13 region.	Summary: Most of the clinical features of Prader-Willi syndrome are believed to be a result of hypothalamic insufficiency. This syndrome is characterized by severe infantile hypotonia, subsequent hyperphagia (overeating with a lack of satiation) and rapid weight gain after the first year, morbid obesity, obsessive compulsive behavior, mild to moderated developmental delay, and hypogonadism. Neuropathologic changes are usually limited to the paraventricular nuclei.
22q deletion syndrome	Deletion in chromosome 22q11.
William’s (William-Beuren) syndrome	Genetics: Submicroscopic deletion of elastin gene (ELN) at chromosome 7q11.23. Deletion in classic William’s syndrome is usually >500 kb. This is probably a contiguous gene syndrome. Deletion can be detected by cytogenetics or FISH. Physical features are probably secondary to the deletion of ELN gene.	Summary: Williams syndrome is clinically characterized by typical elfin face, dental problem characteristic stenotic cardiovascular problem, hypercalcemia. Although their mean IQ is only about 60, patients with Williams syndrome are associated with many cognitive strengths that are better than the cognitively matched control. They also has a charactertic tendency to approach strangers indiscriminately. Geneticlly, it is associated with the deletion of elastin gene.
Smith-Magenis syndrome	Genetics: Deletion at chromosome 17p11.2. The deletion vary from 1.5 MB to 9 MB. Most cases are due to de novo deletion. Haplotype insufficiency: Deletion occurs on only one chromosome. Genes involved: Only a few genes have been demonstrated to be consistently deleted in Smith-Magenis syndrome.	Summary: Smith-Magenis syndrome is a syndrome characterized by mental retardation and multiple congenital anomalies. A a deletion at chromosome 17p11.2 is seen in most patients by cytogenetics or, in smaller deletion, by FISH. The deletion occurs in only one chromosome and almost all of the patients have de novo deletions. Smith-Magenis syndrome is characterized by typical craniofacial features, peripheral neuropathy, mental retardation, and hyperactivity disorder or ADHD. Other typical problems include onychotillomania, spasmodic upper body squeezing, and sleep behavior. Typically, these patients also have aggression, self –destruction, and tantramus. Renal, musculoskeletal, cardiac, and ophthalmological abnormalities may also be present.
Fragile X syndrome	Genetics: Trinucleotide (CGG repeats) expansion of FMR1 gene on chromosome Xq27.3.	Summary: This is the most common form of inherited mental retardation. It affects both male and female. The fragile site is on chromosome Xq27.3 where the fragile X mental retardation 1 (FMR1) gene locates. The molecular defect involves the presence of a large amplification of a trinucleotide CGG tandem repeat, often with methylation that leads to silicencing of the gene, in the untranslated area. The fragile site appears as a gap at Xq27, and the chromosome is apt to break from a triradial at this point. The FMR protein coded by the gene is a mRNA binding protein that modulates RNA translation. Clinically, most male carriers are mentally retarded and also have macro-orchidism, high forehead, prominent nose, and large protruding ears. Most heterozygous female carriers are normal but with slight mental retardation. Severely mentally retarded female carriers have also been described. There are no consistent changes of the CNS associated with this syndrome, however, abnormal dentritic morphology has been described in several cases.
Toxic exposure
Fetal alcohol syndrome	Etiology: In utero exposure to alcohol.	Summary: Fetal alcohol syndrome is resulted from the teratogenic effects of alcohol on human fetuses. The classic cases have the clinical triad of growth retardation, characteristic facial dysmorphology and dysfunction of the central nervous system. The degree of involvement is highly variable.
Unknown
Tourette syndrome	Genetics: Probably hereditary but the genetic mechanism is not clear.	Summary: Tourette syndrome should not be viewed as a neurodevelopmental disorder because significant developmental delay mental retardation is usually not present. Clinical features include motor and vocal tics with onset before 18 years of age; obsessive compulsive behavior and attention deficits hyperkinetic disorder (ADHD)