22q13 deletion syndrome

22q13 Deletion Syndrome (spoken as twenty two q thirteen), also known as Phelan-McDermid Syndrome, is a genetic disorder caused by deletions or rearrangements on chromosome 22. The deletion occurs at the terminal end of the chromosome at the location designated q13.3. Some terminal deletions can be uncovered by karyotype analysis, but many deletions are too small (microdeletions). The availability of DNA microarray technology, and microarray's utility in looking for multiple genetic problems simultaneously, have made this technology the diagnostic tool of choice. However, fluorescence in situ hybridization (FISH) tests are valuable for diagnosing cases of mosaicism (mosaic genetics) and chromosomal rearrangements (e.g., ring chromosome, unbalanced chromosomal translocation). There is a great deal of interest in one of the gene that is usually deleted in Phelan-McDermid Syndrome, SHANK3 (also known as PROSAP2). Errors in this gene have been associated with Autism Spectrum Disorder (ASD) and Schizophrenia. However, there is a growing interest in other genes that are deleted in PMS (see Etiology, below).

Phelan-McDermid Syndrome is characterized by global developmental delay, absent or severely delayed speech, and neonatal hypotonia. There are approximately 600 reported cases of Phelan-McDermid Syndrome worldwide.

Characteristics
The core characteristics of 22q13 Deletion Syndrome (listed above) have a major impact on the individual. However, in addition to these characteristics, there are other manifestations than may range from mild to severe:

Physical
 * Absent to severely delayed speech: 99%
 * Hypotonia (poor muscle tone): 97%
 * Normal to accelerated growth: 95%
 * Increased tolerance to pain: 86%
 * Thin, flaky toenails: 78%
 * Large, fleshy hands: 68%
 * Prominent, poorly formed ears: 65%
 * Pointed chin: 62%
 * Dolichocephaly (elongated head): 57%
 * Ptosis (eyelid) (droopy eyelids): 57%
 * Poor thermoregulation: 51%

Behavioral
 * Chewing on non food items (clothing, bedding, toys):70%
 * Teeth grinding: (percent undetermined)
 * Autistic behaviors: (percent undetermined)
 * Tongue thrusting: (percent undetermined)
 * Hair pulling: (percent undetermined)
 * Aversion to clothes: (percent undetermined)

Etiology
The deletion affects the terminal region of the long arm of chromosome 22 (the paternal chromosome in 75% of cases), from 22q13.3 to 22qter. Although the deletion is most typically a result of a de novo mutation, there is an inherited form resulting from familial chromosomal translocations involving the 22 chromosome. In the de novo form, the size of the deletion is variable and can go from 130kbp (130,000 base pairs) to 9Mbp (9,000,000 base pairs). At one time it was thought that deletion size was not related to the core clinical features. That observation lead to an emphasis on the SHANK3 gene. More recent studies with larger cohorts, however, have demonstrate that the core features do depend upon deletion size. More to the point, cases of PMS that do not affect SHANK3 have been reported. A landmark study of iPS neurons cultured from patients with PMS shows that restoration of the SHANK3 protein levels will rescue fewer than half the glutamate neurons of neocortex. This result has fueled a growing interest in the MAPK8IP2 (also called IB2) and other genes commonly lost in PMS. MAPK8IP2 is especially interesting because it regulates the balance between NMDA receptors and AMPA receptors.

Incidence
The incidence of the 22q13 deletion syndrome is uncertain. The National Institutes of Health Office of Rare Diseases (http://rarediseases.info.nih.gov/) lists Phelan-McDermid syndrome as a rare disease.