Although chromosome 22q11.2 deletions can be inherited inan autosomal dominant fashion, most cases arise de novo. Common features include clefting of the palate with velopharyngealinsufficiency; conotruncal cardiac defects (including truncusarteriosus, ventriculoseptal defect, tetralogy of Fallot, and right-sided aortic arch); and a characteristic facial appearance, including a prominent nose and a broad nasal root. Speech and languagedifficulties are common, as is mild intellectual impairment. Morethan 200 additional abnormalities have been identified in individuals with these conditions. About 70% have immunodeficiencies, largely related to T-cell dysfunction. A wide spectrumof psychiatric disturbances, including schizophrenia and bipolardisorder, has been seen in more than 33% of affected adults.
Damage to the third and fourth pharyngeal pouches, embryonic structures that form parts of the cranial portion of thedeveloping embryo, leads to abnormalities in the developingface (clefting of the palate, micrognathia), the thymus gland,the parathyroid glands, and the conotruncal region of the heart.This spectrum of findings, called the DiGeorge malformationsequence, is an important chromosome 22 deletion syndrome.
The deletion that occurs in chromosome 22q11 is usually too small to be seen by standard chromosome analysis; either fluorescent in situ hybridization or chromosomal microarray is needed to identify the deletion. A gene called TBX1 is within the deleted sequence. It is believed that deletion of one copy of TBX1 is responsible for many of the features of the various 22q11 deletion syndromes.
Duplications and deletions occur secondary to misalignment and unequal crossing over during meiosis. Small extra chromosomes are found in a small percentage of the population (0.06%). These “marker” chromosomes sometimes are associated with mental retardation and other abnormalities, and other times they have no apparent phenotypic effects.
Chromosome 15 is the most common of all marker chromosomes, and its inverted duplication accounts for almost 40% of this group of chromosomal abnormalities. Features seen in children with 47,XX,+inv dup (15q) or 47,XY,inv dup(15q) depend on the size of the extra chromosomal material present: the larger the region, the worse the prognosis. Children with this disorder tend to have a variable degree of developmental disability and autism spectrum disorders; seizures are common, as are behavior problems. The phenotype shows minimal dysmorphic features, with a sloping forehead, short and downward-slanting palpebral fissures, a prominent nose with a broad nasal bridge, a long and well-defined philtrum, a mid-line crease in the lower lip, and micrognathia.
Named for the iris coloboma that gives patients’ eyes a catlikeappearance, cat eye syndrome is due to a small, supernumerarychromosome with an inversion duplication of 22q11. The twocopies of 22q11 on this extra chromosome plus the two normal copies of chromosome 22 result in four copies of this region.Although the colobomas name the syndrome, they occur infewer than 50% of individuals with the marker chromosome. Other clinical features include mild mental retardation, behavioral disturbances, mild ocular hypertelorism, downward-slanting palpebral fissures, micrognathia, auricular pits and/or tags,anal atresia with rectovestibular fistula, and renal agenesis.