The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome)

Abstract

The 22q13.3 deletion syndrome, also known as Phelan-McDermid syndrome, is a contiguous gene disorder resulting from deletion of the distal long arm of chromosome 22. In addition to normal growth and a constellation of minor dysmorphic features, this syndrome is characterized by neurological deficits which include global developmental delay, moderate to severe intellectual impairment, absent or severely delayed speech, and neonatal hypotonia. In addition, more than 50% of patients show autism or autistic-like behavior, and therefore it can be classified as a syndromic form of autism spectrum disorders (ASD). The differential diagnosis includes Angelman syndrome, velocardiofacial syndrome, fragile X syndrome, and FG syndrome. Over 600 cases of 22q13.3 deletion syndrome have been documented. Most are terminal deletions of ∼100 kb to >9 Mb, resulting from simple deletions, ring chromosomes, and unbalanced translocations. Almost all of these deletions include the gene SHANK3 which encodes a scaffold protein in the postsynaptic densities of excitatory synapses, connecting membrane-bound receptors to the actin cytoskeleton. Two mouse knockout models and cell culture experiments show that SHANK3 is involved in the structure and function of synapses and support the hypothesis that the majority of 22q13.3 deletion syndrome neurological defects are due to haploinsufficiency of SHANK3, although other genes in the region may also play a role in the syndrome. The molecular connection to ASD suggests that potential future treatments may involve modulation of metabotropic glutamate receptors.

Phelan–McDermid Syndrome and SHANK3: Implications for Treatment

“…The behavioral abnormalities in PMS vary, including repetitive use and spinning of objects, chewing, stereotypic motor mannerisms, stereotypic vocalizations, unusual sensory interests and sensitivities, sleep disturbances, and negative reactions to changes in routine [10,43]. ASD is also common in PMS and, in addition to the restrictive and repetitive behaviors noted, includes the characteristic symptoms of language delay and impaired social interactions [7,21].…”

“…Virtually every organ system can be affected, and recent practice parameters were published to provide guidelines for assessment and monitoring [51]. Developmental delays may not be apparent in the first 12 months of life, but a common presenting symptom in infants is hypotonia, which can also contribute to poor feeding, weak cry, and poor head control [43,51]. Low muscle tone and coordination deficits also contribute to significant delays in achieving major motor milestones like rolling over, crawling, and walking [46,[52][53][54].…”

“…Low muscle tone and coordination deficits also contribute to significant delays in achieving major motor milestones like rolling over, crawling, and walking [46,[52][53][54]. The degree to which gross and fine motor coordination is affected in PMS can vary by location and severity, but gait is almost uniformly affected [10,43], with some reports of inability to ambulate [10,51]. Language delays are present in>75 % of patients, with expressive language affected more than receptive language [43].…”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…There are also a number of microRNA-related loci in this region, including miR-185 and DiGeorge syndrome chromosomal (or critical) region 8, a component of the microprocessor complex that is involved in the initial step of miRNA biogenesis [110]. 22q13 22q13 deletion syndrome, also known as Phelan-McDermid syndrome, is characterized by global developmental delay, absent or severely delayed speech, ASD, neonatal hypotonia, normal or accelerated growth, and dysmorphic features [150,151]. Dysmorphic facial features include dolicocephaly, flat midface, wide nasal bridge, and bulbous nose.…”

Phelan‐McDermid syndrome data network: Integrating patient reported outcomes with clinical notes and curated genetic reports

“…One such rare neuropsychiatric disorder is Phelan‐McDermid Syndrome (PMS) or 22q13 deletion syndrome (OMIM 606232) (Cusmano‐Ozog, Manning, & Eugene Hoyme, 2007; Phelan, 2008; Phelan & McDermid, 2012), with approximately 1,400 cases diagnosed worldwide, mostly in children. PMS is caused by deletion of the terminal end of the long arm of chromosome 22 or by mutation and loss of function of the SHANK3 gene (Macedoni‐Lukšič, Krgović, Zagradišnik, & Kokalj‐Vokač, 2013), which is also implicated in ASD (Gauthier et al, 2008; Uchino & Waga, 2013).…”