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Phelan-McDermid Syndrome

Synonyms: 22q13.3 Deletion Syndrome, Chromosome 22q13.3 Deletion Syndrome, Deletion 22q13 Syndrome

, PhD, FACMG and , MD, FACMG.

Author Information
, PhD, FACMG
Hayward Genetics Center and Department of Pediatrics
Tulane University School of Medicine
New Orleans, Louisiana
, MD, FACMG
Senior Clinical Geneticist
Greenwood Genetic Center
Greenwood, South Carolina

Initial Posting: ; Last Update: August 25, 2011.

Summary

Disease characteristics. Phelan-McDermid syndrome (22q13.3 deletion syndrome) is characterized by neonatal hypotonia, global developmental delay, absent to severely delayed speech, and normal to accelerated growth. Most individuals have moderate to profound intellectual disability. Other features include large fleshy hands, dysplastic toenails, and decreased perspiration that results in a tendency to overheat. Behavior characteristics include mouthing or chewing non-food items, decreased perception of pain, and autistic-like affect.

Diagnosis/testing. Clinical diagnostic criteria for Phelan-McDermid syndrome have not been established. Phelan-McDermid syndrome results from terminal or interstitial deletion of chromosome 22q13.3. On rare occasion an apparently balanced chromosome rearrangement or a mutation disrupts SHANK3. Prior to about 2006, deletion of 22q13.3 was commonly diagnosed by high resolution chromosome analysis and fluorescence in situ hybridization (FISH); since 2006, chromosome microarray analysis (CMA), a more sensitive and accurate method for detecting this deletion, is preferred.

Management. Treatment of manifestations: Oral-motor therapy for chewing and swallowing problems; standard treatment of gastroesophageal reflux, seizures, recurrent ear infection and ophthalmic, cardiac, renal, respiratory, and immunologic issues; physical and occupational therapy and exercise to improve coordination and strength; augmented communication strategies; orthodontic therapy for malocclusion; medication for hyperactivity, anxiety, and self-stimulatory behavior.

Surveillance: Baseline renal ultrasound examination for identification of presymptomatic kidney abnormalities; baseline brain imaging for the presence of arachnoid cysts with evaluation by a neurologist if behavior problems or regression of skills become evident; attention to symptoms of possible increased intracranial pressure; routine follow up of cardiac abnormalities; routine dental and eye examinations; monitoring for lymphedema which may appear in adolescence or adulthood.

Agents/circumstances to avoid: Exposure to high temperatures and extended periods in the sun because of decreased perspiration.

Genetic counseling. Phelan-McDermid syndrome results from a de novo or inherited chromosome abnormality, which can be determined by parental chromosome analysis. Prenatal testing for 22q13.3 deletion is possible for pregnancies at increased risk.

Diagnosis

Clinical Diagnosis

Phelan-McDermid syndrome (22q13.3 deletion syndrome) is suspected in children with the following:

  • Neonatal hypotonia
  • Normal to accelerated growth
  • Absent to severely delayed speech
  • Global developmental delay
  • Normal head circumference
  • Minor dysmorphic facial features including:
    • Dolichocephaly
    • Full brow
    • Flat midface
    • Ptosis
    • Puffy eyelids
    • Long eyelashes
    • Wide nasal bridge
    • Bulbous nose
    • Puffy cheeks
    • Pointed chin
    • Large or prominent ears

Other features that raise suspicion of Phelan-McDermid syndrome include relatively large and fleshy hands, dysplastic toenails, sacral dimple, and decreased perspiration. Behavior characteristics include mouthing or chewing non-food items, decreased perception of pain, and autistic-like affect and behavior.

Causes of Phelan-McDermid syndrome

  • Terminal or interstitial deletion involving 22q13.3 [Phelan et al 2010]. Approximately 80% of individuals with Phelan-McDermid syndrome have one of the following:
    • A terminal deletion involving 22q13.3 (i.e., a single break in the chromosome arm with loss of the segment distal to the break)
    • An interstitial deletion involving 22q13.3 (i.e., two breaks within the same chromosome arm and loss of the intervening segment)
  • Unbalanced chromosome translocation or other structural chromosomal rearrangement [Phelan et al 2010]. Approximately 20% of individuals with Phelan-McDermid syndrome have deletions resulting from an unbalanced chromosome translocation or other structural chromosomal rearrangement. Unbalanced chromosome translocations are characterized by deletion of 22q13.3 and partial trisomy of a second unrelated chromosomal segment.
  • Apparently balanced chromosome translocation. Disruption of SHANK3 resulting from a de novo, apparently balanced translocation t(12;22)(q24.1;q13.3) was reported in a male with features of Phelan-McDermid syndrome [Bonaglia et al 2001]. The breakpoints localized to chromosome 22 within exon 21 of SHANK3 and to chromosome 12 within an intron of APPL2. The translocation led to no loss of genetic material.
  • Truncation of SHANK3. Misceo et al [2011] described an intragenic deletion of SHANK3 associated with a translocation between 22q13.33 and Xq21.33 in a 20-year-old woman with physical and developmental features of Phelan-McDermid syndrome. The last two exons (exons 22 and 23) of SHANK3 were truncated; disruption of Xq21 resulted in premature ovarian insufficiency.

Critical region. The diagnosis of Phelan-McDermid syndrome is confirmed by demonstration of a heterozygous deletion at chromosome 22q13.3. The size of the 22q13.3 deletion in Phelan-McDermid syndrome ranges from 95 kb to more than 9 Mb (see Molecular Genetic Pathogenesis).

Genes. The consensus among investigators is that SHANK3, ACR, and RABL2B, the three q terminal genes on chromosome 22, are included in the critical region.

Testing

Cytogenetic testing

  • G-banded chromosome analysis can identify the 22q13.3 deletion if the deletion is 2 Mb or greater in size and the chromosome resolution is at or above the 650-band level. Note: The quality of the stain and the skill of the technical staff also influence the ability to visualize the deletion at the microscope.
  • Chromosome analysis can detect unbalanced rearrangements involving 22q13.3 with the exception of cryptic abnormalities. Note: Chromosome changes are considered cryptic if they cannot be visualized at the microscope by high-resolution chromosome analysis at the 650-band level of resolution.
  • Chromosome analysis can detect balanced rearrangements (that have no net gain or loss of chromosome material) involving a breakpoint within 22q13, which cannot be detected by chromosomal microarray analysis (CMA) [Bonaglia et al 2001].

Molecular Genetic Testing

Deletion/duplication analysis. The 22q13.3 deletion can be detected by any number of molecular methods that determine the copy number of sequences within the deleted region. Either whole-genome or targeted approaches can be used.

  • Genomic microarray technologies. Array-based comparative genomic hybridization (aCGH) or chromosomal microarray analysis (CMA) using BAC or oligonucleotide arrays can detect the 22q13.3 deletion. Although more sensitive than high-resolution chromosome analysis in detecting a microdeletion, CMA may fail to detect low-level mosaicism for a deletion or duplication [Miller et al 2010].
    Note: (1) The ability to size the deletion depends on the type of microarray used and the density of probes in the 22q13.3 region. (2) CMA can never detect a balanced chromosome rearrangement.
  • Targeted deletion analysis. Targeted methods including fluorescence in situ hybridization (FISH) or multiplex ligation-dependent probe amplification (MLPA) can be used to identify 22q13.3 deletion if the Phelan-McDermid syndrome is suspected clinically, to confirm a deletion identified on genomic microarray analysis, and/or to evaluate those relatives of a proband (with a known deletion) who have findings that suggest the diagnosis of Phelan-McDermid syndrome.
    Note: It is not possible to size the deletion routinely by use of FISH.

    Two commercially available FISH probes:
    • A probe for ARSA, the gene encoding arylsulfatase A (e.g., 310-kb probe at 22q13.33, Vysis® Part #32-190012). Note: ARSA is not within the critical region; thus, this probe may fail to detect very small distal deletions of chromosome 22 [Wong et al 1997].
    • A 22q subtelomere probe (e.g., D22S1726, Vysis® Part #33-27000), 80 kb in size and estimated to be within 300 kb of the end of chromosome 22

Table 1. Summary of Molecular Genetic Testing Used in Phelan-McDermid Syndrome

Test MethodMutations Detected 1Mutation Detection Frequency by Test Method 2
FISHDeletion 22q13.3~100% when both ARSA and subtelomere 22q probes are used
Deletion/duplication analysis 3Variable depending on the loci analyzed 4

1. See Molecular Genetics for additional information.

2. The ability of the test method used to detect the indicated deletion

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

4. Detection frequency may be equivalent to that obtained by FISH, depending on location and density of sequences examined and the inclusion of appropriate 22q subtelomeric loci.

Interpretation of test results. Results of FISH studies of deletion 22q13 may be misleading: (1) the use of a probe for ARSA, which is not within the critical deletion region for Phelan-McDermid syndrome, may yield a false negative result [Bonaglia et al 2006]; and (2) the use of a subtelomere probe as the sole diagnostic tool can fail to detect an interstitial deletion of 22q13.

Testing Strategy

To establish the diagnosis of deletion 22q13.3 in a proband requires detection of a 70-kb minimal critical deletion common in the 22q13.3 deletion syndrome [Wong et al 1997, Bonaglia et al 2001]. The deletion can be detected by:

  • Chromosomal microarray analysis (CMA) performed as part of the evaluation of developmental delay or intellectual disability;
  • A targeted technique (e.g., FISH, MLPA, targeted GH) if the 22q13.3 deletion is suspected based on the clinical features;
  • G-banded chromosome analysis if the deletion is at least 2 Mb in size and the chromosome resolution is at or above the 650 band level.

Carrier testing for parents and at-risk relatives

  • Chromosome analysis and/or FISH should be offered to the parents of all children with deletion 22q13.3 to determine if one of the parents has a balanced rearrangement involving 22q13.3.
  • If a balanced rearrangement is identified in one parent, chromosome analysis and/or FISH can be offered to other relatives at risk of being carriers. See Genetic Counseling.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior confirmation of the 22q13.3 deletion in the proband and/or of balanced carrier status in a parent.

Clinical Description

Natural History

Males and females are equally affected with no apparent parent-of-origin effect (Table 2).

Table 2. Features of Phelan-McDermid Syndrome

PrevalenceFeatures
>95%Neonatal hypotonia
Global developmental delay
Absent or severely delayed speech
>75%Normal to accelerated growth
Large, fleshy hands
Dysplastic toenails
Long eyelashes
Decreased sensitivity to pain
Mouthing/chewing/tooth grinding
Autism/autistic-like behavior
>50%Dolichocephaly
Prominent or large ears
Full brow
Full or puffy cheeks
Full or puffy eyelids
Deep-set eyes
Flat midface
Wide nasal bridge
Bulbous nose
Pointed chin
Sacral dimple
Decreased perspiration with tendency to overheat
Feeding difficulties
>25%Strabismus
Renal problems
Gastroesophageal reflux
Malocclusion/wide-spaced teeth
Epicanthal folds
Long philtrum
High-arched palate
Seizures

Hypotonia. Newborns with Phelan-McDermid syndrome have generalized hypotonia that may be associated with weak cry, poor head control, and feeding difficulties leading to failure to thrive.

Developmental delay. Although a few individuals with small subtelomeric deletions are reported to have mild delays, most individuals with 22q13.3 deletion are described as having "global developmental delay" or "moderate to profound intellectual disability." Development assessment using the Developmental Profile II (DPII) and the Scales of Independent Behavior-Revised – Full Scale (SIB-R) demonstrated that all participants in the study of Wilson et al [2003] had moderate to profound intellectual disability but compared to most children with this level of impairment, children with 22q13.3 deletion had less frequent and less severe problematic behaviors.

Major milestones are delayed: the average age for rolling over is approximately eight months, for crawling approximately 16 months, and for walking approximately three years. Poor muscle tone, lack of balance, and decreased upper body strength contribute to the delay in walking. Gait is typically broad-based and unsteady.

Toilet training is difficult to achieve and requires extreme vigilance by parents and caregivers. Children may stay dry at night but become wet or soiled during the day because they are unable to communicate their needs.

Speech delay. Infants typically babble at the appropriate age and children may acquire a limited vocabulary. However, by approximately age four years many children have lost the ability to speak. With intensive occupational, speech, and physical therapy they may regain speech and increase their vocabularies. Physical therapy strengthens muscle tone, improves coordination, and generally increases the individual's awareness of his/her surroundings. Although speech remains impaired throughout life, individuals can learn to communicate with the aid of aggressive therapy and communication training.

Receptive communication skills are more advanced than expressive language skills as demonstrated by the ability of affected children to follow simple commands, demonstrate humor, and express emotions.

Hearing. Individuals with Phelan-McDermid syndrome have a delayed response to verbal cues. They also have difficulty discerning spoken words from background noise. These two factors, along with the frequent occurrence of ear infections, contribute to the perception that hearing may be impaired. In fact, more than 80% of affected individuals have normal hearing.

Growth. Intrauterine growth in Phelan-McDermid syndrome is appropriate for gestational age; the mean gestational age is 38.2 weeks. Postnatal growth is normal or accelerated. Height is often advanced for age but remains within two to three standard deviations from the mean. Weight is not increased so children appear tall and thin.

Whereas children have increased height for age, adults tend to fall within the normal range for height. Most adults are also within the normal range for weight, although inactivity and overeating (possibly a manifestation of compulsive mouthing) result in increased weight gain in approximately 10% of individuals.

Head size is typically within normal range with microcephaly reported in fewer than 5% of individuals.

Behavior. Philippe et al [2008] examined the neurobehavioral profiles of eight children with 22q13 deletion syndrome who ranged in age from four years, three months to 11 years, four months. Behavior problems included hyperactivity, short attention span, restlessness, clumsiness, ignorance of the consequences, resistance to change, and repetitive activities.

Other abnormal behaviors described in Phelan-McDermid syndrome include habitual chewing or mouthing, tooth grinding, decreased perception of pain, and sleep disturbance. Although sleep apnea is not a problem, affected individuals may have difficulty falling asleep and staying asleep. Affected individuals may become agitated in unfamiliar, noisy, or crowded surroundings.

While Philippe et al [2008] concluded that behavior exhibited by children with Phelan-McDermid syndrome did not meet the DSM IV criteria for autism, other investigators have described the behavior as autistic or autistic-like with poor eye contact, stereotypic movements, and self-stimulation.

As a result of high pain tolerance and lack of expressive communication skills, affected individuals may suffer cuts, scrapes, or even broken bones without indicating that they are in pain. They may suffer ear infections, gastroesophageal reflux, increased intracranial pressure, or other painful medical conditions without indicating discomfort.

Aggressive behavior including biting, hair pulling, or pinching is seen in approximately 25% of affected individuals.

Vision. Most affected individuals have normal vision although hyperopia and myopia are observed. Cortical visual impairment, characterized by extensive use of peripheral vision, difficulty in processing cluttered images, problems with depth perception, and the tendency to look away from objects before reaching for them, has been reported in approximately 6% of affected individuals. The quality of vision fluctuates, being better at some times than others. Blindness and optic nerve hypoplasia have been associated with cortical visual impairment [Phelan et al 2010].

Renal. Kidney function is typically normal although frequent urinary tract infections, cystic kidneys, dysplastic kidney, hydronephrosis, and vesicoureteral reflux have been reported.

Gastrointestinal. Gastroesophageal reflux is seen in approximately 30% and cyclic vomiting in approximately 25% of individuals.

Dental. The most frequently encountered dental problems are malocclusion and crowding. Poor muscle tone, incessant chewing, tooth grinding, and tongue thrusting may contribute to malocclusion. Malocclusion may be accompanied by difficulty swallowing and drooling, and may contribute to difficulties in verbalization.

Neurologic. Arachnoid cysts occur in approximately 15% of individuals with Phelan-McDermid syndrome compared to an estimated 1% in the general population. Other neurologic problems include reduced myelination, frontal lobe hypoplasia, agenesis of the corpus callosum, ventriculomegaly, focal cortical atrophy, and seizures [Tabolacci et al 2005].

Brain imaging studies on eight children with 22q13.3 deletion syndrome revealed normal MRI in three children with interstitial deletions of fewer than 270 kb; four of the remaining five had thinning of the corpus callosum; and one of the five had atypical morphology of the corpus callosum [Philippe et al 2008]. PET studies of the eight children demonstrated localized dysfunction of the left temporal polar lobe and significant hypoperfusion of the amygdala compared to 13 children with idiopathic intellectual disability.

Between 25% and 50% have seizures, many of which are febrile and do not require medication; however, grand mal seizures, focal seizures, and absence seizures have been described. No characteristic EEG findings are associated with Phelan-McDermid syndrome.

Lymphedema. Both lymphedema and recurrent cellulitis have been observed in approximately 10% of individuals, typically becoming problematic during the teen and adult years. Progressive lymphedema leading to pleural effusions has been reported in a female with deletion 22q13 resulting from a ring chromosome r(22)(p11.2q12.3). FISH studies demonstrated that ARSA was deleted on the ring 22 [McGaughran et al 2010].

Craniofacial. Among the most common and striking craniofacial features are dolichocephaly, large or prominent ears, epicanthal folds, long eyelashes, supraorbital fullness, full cheeks, and short or bulbous nose. More subtle features are deep-set eyes, flat midface, full brow, wide nasal bridge, pointed chin, and long philtrum. The features may change over time, particularly if the individual is on anticonvulsants that tend to coarsen the features. Adults have a more prominent, square jaw and less bulbous-appearing nose.

Other

Fertility. No individuals with Phelan-McDermid syndrome have been known to reproduce, although no fertility studies that would exclude the possibility of reproduction have been performed. Females with Phelan-McDermid syndrome go through puberty and begin menstruation at the normal age.

Life span. Longitudinal data are insufficient to determine life expectancy. However, life-threatening or life-shortening cardiac, pulmonary, or other organ system defects are not common. The paucity of older adults with Phelan-McDermid syndrome reflects the difficulty in establishing the diagnosis prior to the advent of high-resolution chromosome analysis, FISH, and CMA.

Mosaic deletion 22q13.3. Mosaic deletion 22q13.3 has been reported on occasion. The level of mosaicism for deletion 22q13.3 varies among affected individuals. Note: Because most testing is performed on blood samples, because the level of mosaicism in blood can change over time, and because the level of mosaicism in the blood is not representative of the level of mosaicism in the brain and other tissues, the level of mosaicism that is sufficient for expression of the major features of Phelan-McDermid syndrome is unknown.

Mosaicism is particularly common in 22q13 deletion associated with ring chromosomes because of the instability of the ring structure during cell division.

  • One adult with characteristic features of 22q13.3 deletion syndrome showed ring 22 in only 8% of blood cells [Phelan, unpublished data].
  • Bonaglia et al [2009] reported mosaicism for ring chromosome 22 in two individuals with deletions of 8.8-8.9 Mb. Patient 1 had a ring derived from the maternal chromosome 22 in 45% of cells as well as paternal isodisomy for the segment 22q13.2-qter, which resulted from gene conversion in the cells that did not have the ring chromosome 22. Patient 2 had a ring derived from the paternal chromosome 22 in 73% of peripheral blood cells. Psychomotor delay was more severe in patient 2 than patient 1.

In at least three instances mosaicism in asymptomatic mothers resulted in 22q13.3 deletion syndrome in their offspring:

  • Two brothers with features suggestive of Clark-Baraitser syndrome (see Differential Diagnosis) were found to have deletion of approximately 3.5 Mb at 22q13. It was inferred that the deletion had been inherited from the mother because the brothers had not inherited the same paternal chromosome 22 [Tabolacci et al 2005].
  • A phenotypically normal mother of two affected children was mosaic for deletion 22q13.3, resulting from an unbalanced translocation with the satellite region of an unidentified acrocentric chromosome. The derivative chromosome 22 was observed in 6% of cells from maternal peripheral blood [Phelan, unpublished data].
  • The mother of a child with non-mosaic ring chromosome 22 had ring chromosome 22 in fewer than 2% of peripheral blood cells [Phelan, unpublished data].

Genotype-Phenotype Correlations

Although several studies to determine genotype-phenotype correlations in those with 22q13.3 deletion failed to show a relationship between microdeletion size and severity of features, the study by Wilson et al [2003] reported a statistically significant correlation between deletion size and the degree of developmental delay and severity of hypotonia.

Penetrance

As expected, features of Phelan-McDermid syndrome are apparent in all individuals with non-mosaic deletion 22q13.3.

  • Individuals with "smaller" deletions have been reported to have milder expression of the features, although intellectual deficits and speech impairment are universally present [Wilson et al 2003].
  • Full manifestation of features has been seen in individuals with as low as 8% mosaicism for the 22q13.3 deletion in peripheral blood [Phelan, personal observation].

Nomenclature

Previously referred to as 22q13.3 deletion syndrome to reflect the chromosomal basis of this deletion, the condition is now commonly called Phelan-McDermid syndrome, a more comprehensive term that includes individuals with 22q13.3 deletion and those without a detectable deletion who have a mutation of SHANK3.

Prevalence

The prevalence of 22q13.3 microdeletion is unknown. With the advent of CMA, the number of individuals diagnosed with Phelan-McDermid syndrome in increasing; nonetheless, it remains underdiagnosed. It is the second most common subtelomeric imbalance found in individuals with intellectual disability [Delahaye et al 2009].

Differential Diagnosis

Hypotonia and developmental delay are nonspecific findings and cannot be used to differentiate Phelan-McDermid syndrome from other common disorders. However, the association of these features with absent or severely delayed speech and autistic-like behavior increases the likelihood of Phelan-McDermid syndrome [Manning et al 2004]. The concurrent finding of other minor dysmorphic features seen in this syndrome should strengthen the suspicion of the diagnosis.

Ring chromosome 22. Ring chromosomes are usually accompanied by the loss of genetic material from the distal long (q) arm and distal short (p) arm. For individuals with ring chromosome 22, loss of short arm and satellite material is of no clinical significance; the size of the deleted segment of 22q determines the phenotype, which ranges from normal to severely affected. Phenotypic expression may further be complicated by instability of the ring chromosome 22 during mitosis, which may cause the chromosome to become broken, lost, or duplicated.

Regardless of which autosome is involved, the general phenotype of the ring chromosome syndrome includes growth retardation, cognitive impairment, and minor dysmorphic features. Individuals with ring chromosome 22 often show features similar to Phelan-McDermid syndrome, including global developmental delay, severe speech deficit, hypotonia, and minor dysmorphic features. Unlike Phelan-McDermid syndrome, ring chromosome 22 is characterized by delayed growth (20%-24% of individuals) and microcephaly (33% of individuals) [Ishmael et al 2003, Luciani et al 2003].

Ring chromosomes are difficult to characterize cytogenetically; molecular characterization is complicated by instability of the ring. Nonetheless it is reasonable to assume that individuals with a ring chromosome who are missing 22q13.3 would have the phenotype of Phelan-McDermid syndrome. Many families with ring chromosome 22 are members of the Phelan-McDermid Syndrome/Deletion 22q13.3 Syndrome Foundation (see Resources).

Other disorders

Prader-Willi syndrome (PWS). Phelan-McDermid syndrome should be suspected in any infant with neonatal hypotonia of unknown etiology. As in PWS, neonatal hypotonia and feeding difficulty can be the earliest presenting findings of Phelan-McDermid syndrome. Testing for 22q13.3 deletion is recommended for any child with these findings in whom genetic testing for PWS is normal.

Angelman syndrome. The diagnosis of Phelan-McDermid syndrome should also be suspected in individuals with "atypical" Angelman syndrome. Features common to both syndromes include infantile hypotonia, global developmental delay, absent speech, unsteady gait, and minor dysmorphic features. Genetic testing for Angelman syndrome includes chromosome 15q11-q13 methylation analysis plus molecular genetic testing of UBE3A. When the diagnosis of Angelman syndrome is not confirmed by these studies, testing for 22q13.3 deletion is recommended [Precht et al 1998, Van Tuinen et al 2000].

Velocardiofacial syndrome (VCFS) (see 22q11.2 Deletion Syndrome). Similarities between VCFS and Phelan-McDermid syndrome include hypotonia, epicanthal folds, narrow palpebral fissures, broad nasal root, speech delay, renal abnormalities, and developmental delay. The neurologic problems observed in VCFS are not as severe as those in Phelan-McDermid syndrome. Unlike Phelan-McDermid syndrome, VCFS is frequently associated with cardiac and/or palatal defects, immune deficiency, and hypocalcemia. 22q11.2 deletion syndrome is diagnosed by FISH using the N25 or Tuple probe set using ARSA as the control probe. Because ARSA maps to 22q13.3, the N25 or Tuple probe set detects deletion of 22q13.3, resulting in the diagnosis of 22q13.3 deletion in a number of individuals tested for VCFS.

Williams syndrome. Although the features of an older child with Williams syndrome are fairly distinct (characteristic facies, loquaciousness), the newborn with Williams syndrome has features that overlap with Phelan-McDermid syndrome, including hypotonia, global developmental delay, and puffy eyelids. In contrast to Phelan-McDermid syndrome, Williams syndrome is associated with cardiovascular anomalies (elastin arteriopathy, peripheral pulmonary stenosis, supravalvular aortic stenosis, and hypertension) and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism, and early puberty). Williams syndrome can be diagnosed with FISH for the 7q11.23 deletion that includes ELN, the gene in which mutation is causative. Inheritance is autosomal dominant; however, most affected individuals have a de novo mutation.

Trichorhinophalangeal syndrome (TRPS) is classified as type I or type II (Langer-Giedion syndrome), which is characterized by multiple cartilaginous exostoses. Features of TRPS that tend to overlap with Phelan-McDermid syndrome include hypotonia, intellectual deficit, bulbous nose, large or prominent ears, deep-set eyes, and thin hypoplastic toenails. Features that distinguish TRPS from Phelan-McDermid syndrome include redundant skin, prominent philtrum, thin upper lip, sparse hair, small jaw, and growth retardation. TRPS type II results from a microdeletion of 8q24.11-q24.13 leading to loss of TRPSI and EXT1. TRPS type I results from an even smaller deletion of 8q24.12. Inheritance of TRPS type I is autosomal dominant.

Smith-Magenis syndrome (SMS). Overlap between SMS and Phelan-McDermid syndrome include hypotonia, speech delay, psychomotor retardation, flat midface, and decreased sensitivity to pain. Infants with SMS also have failure to thrive, hyporeflexia, and generalized lethargy. SMS is characterized by inattention and hyperactivity, distinctive facial features, and behavioral abnormalities (significant sleep disturbance, stereotypies, and maladaptive and self-injurious behaviors) that are generally recognized after age 18 months. Self-injurious behaviors include self-hitting, self-biting, and/or skin picking, inserting foreign objects into body orifices, and yanking fingernails and/or toenails. The diagnosis of SMS is confirmed by detection of an interstitial deletion of 17p11.2 by cytogenetic analysis and/or FISH testing.

Fragile X syndrome. Infants and young children with fragile X syndrome may have hypotonia, significant speech delay, and autistic-like behavior. In addition to global delays, tall stature and some facial features are similar to those of Phelan-McDermid syndrome. A male with fragile X syndrome has a characteristic appearance (large head, long face, prominent forehead and chin, protruding ears), connective tissue findings (joint laxity), and large testes (post-pubertally). Behavioral abnormalities, sometimes including autism spectrum disorder, are common. Fragile X syndrome is identified by molecular testing for the CGG repeat in FMR1. Inheritance is X-linked.

FG syndrome. Overlap between FG syndrome and Phelan-McDermid syndrome includes hypotonia, intellectual disability, delayed speech, autistic-like behavior, and gastroesophageal reflux. Characteristic features of FG syndrome that are not associated with Phelan-McDermid syndrome include intestinal/anal atresia, chronic constipation, short stature, vertebral malformations, simple low-set ears, and characteristic personality traits that include outgoing, talkative, and impulsive behavior. FG syndrome is a heterogeneous disorder with several X-linked forms; although the vast majority of cases are inherited, it can occur as a de novo mutation in a family. See MED12-Related Disorders.

Sotos syndrome (cerebral gigantism), like Phelan-McDermid syndrome, is associated with physical "overgrowth." At birth individuals with Sotos syndrome are of normal weight and length and have hypotonia and difficulty feeding. During the first few years of life they begin to grow at an accelerated pace and have mild intellectual disability, delays in motor development, and dysmorphic features that include dolicocephaly, pointed chin, and large hands. They may have autistic-like behavior, receptive language skills that are more advanced than expressive language skills, attention deficit disorder, and/or aggressiveness. Unlike children with Phelan-McDermid syndrome, children with Sotos syndrome become more similar to their peers with age. They may be within the normal range for height, although at the high end of the height curve. The degree of intellectual impairment is variable, ranging from mild (in which children attend mainstream schools and are likely to be independent in adulthood) to severe. Approximately 80%-90% of individuals with Sotos syndrome have a demonstrable mutation or deletion of NSD1, the only gene in which mutations are known to cause Sotos syndrome. Inheritance is autosomal dominant; more than 95% of affected individuals have a de novo mutation.

Clark-Baraitser syndrome is presumed to be X-linked based on the reported cases being male and related in a pattern consistent with X-linked inheritance. Two males suspected of having Clark-Baraitser were subsequently found on FISH testing to have a subtelomeric deletion of 22q13. Individuals with Clark-Baraitser typically present with intellectual disability and thick hands and feet, but do not usually have hypotonia. They also have obesity, macrocephaly, and macroorchidism, which are not reported in Phelan-McDermid syndrome.

Cerebral palsy is not a single disorder but a "catch-all" name for a variety of neurologic disorders that are usually present at birth and affect body movements. Because children with Phelan-McDermid syndrome exhibit neonatal hypotonia, poor coordination, and delayed and unsteady walking, a clinician may apply the term cerebral palsy. The many causes of cerebral palsy include birth trauma, prematurity, low birth weight, infections, intrapartum asphyxia, jaundice, intracranial hemorrhage, and placental abruption. Cerebral palsy can also be caused after birth by asphyxia related to choking, near drowning, poisoning, or other events that reduce the oxygen supply to the brain. Physical injury, including shaken baby syndrome, can also lead to cerebral palsy. Genetic testing that reveals microdeletion of 22q13.3 is often the manner in which individuals erroneously diagnosed with cerebral palsy receive the correct diagnosis.

Spastic paraplegia. Because children with Phelan-McDermid syndrome have delayed motor milestones and may walk with an unsteady, "spastic" gait, they may be misdiagnosed as having spastic paraplegia. However, individuals with hereditary spastic paraplegia are distinguished by progressive weakness and spasticity of the lower extremities. Individuals with complex spastic paraplegia may also display neurologic dysfunction including seizures, dementia, and amyotrophy. Spastic paraplegia encompasses a number of neurologic disorders with X-linked, autosomal recessive, or autosomal dominant inheritance. Individuals with Phelan-McDermid syndrome do not demonstrate progressive neurologic symptoms characteristic of hereditary spastic paraplegia, yet they may carry this diagnosis until genetic testing that identifies the 22q13.3 deletion is performed.

Autism. Several studies have reported autism or autistic-like behavior in individuals with Phelan-McDermid syndrome [Anderlid et al 2002, Manning et al 2004, Jeffries et al 2005, Durand et al 2007, Phelan et al 2010]. Phelan-McDermid syndrome should be considered in the differential diagnosis of autism spectrum disorders, particularly when subtle dysmorphic features are present.

The causes of autism have been divided into "idiopathic" and "secondary." Secondary autism describes cases of autism in which a known etiology, such as a chromosome disorder, has been identified. Autism that is associated with dysmorphic features, microcephaly, and/or a structural brain malformation has been called "complex autism" [American Psychiatric Association 1994]. Using this nosology, the autism in deletion 22q13.3 would be considered both secondary and complex as opposed to idiopathic and essential (having no associated physical abnormalities). Cohen et al [2005] suggested the term "syndromal" rather than "complex" for autism associated with other clinical signs and used 22q13.3 deletion syndrome (Phelan-McDermid syndrome) as an example of a genetic disorder consistently associated with autism.

Jacquemont et al [2006] reported that 5% of individuals with autism have a chromosomal disorder and listed 22q13.3 deletion among the three most common chromosomal defects associated with autism.

Schaefer & Mendelsohn [2008] listed 22q13 as a chromosomal “hot spot” for autism spectrum disorders.

Lintas & Persico [2009] reported that 1.1% of individuals with autism spectrum disorders have a SHANK3 mutation, deletion, or duplication and suggested that persons with autism and severe language and social impairment may be good candidates for SHANK3 molecular genetic testing.

22q11.2 duplication is defined in the GeneReview on this topic as the presence of a common 3-Mb or 1.5-Mb proximal nested duplication. The 22q11.2 duplication phenotype appears to be generally mild and highly variable; findings range from apparently normal to intellectual/learning disability, delayed psychomotor development, growth retardation, and/or hypotonia. The high frequency with which the 22q11.2 duplication is found in an apparently normal parent of a proband suggests that many individuals can harbor a duplication of 22q11.2 with no discernible phenotypic effect. Whether duplication 22q11.2 could be a non-pathogenic polymorphism or a real syndrome with a great clinical variability and reduced penetrance is uncertain at this time.

The phenotype is not sufficiently distinct to be specifically suspected on clinical grounds alone. 22q11.2 duplication is not detectable by routine G-banded karyotyping. Most individuals with 22q11.2 duplication are identified either by CMA testing or by other types of deletion/duplication analysis.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Phelan-McDermid syndrome, the following evaluations are recommended:

  • A complete physical and neurologic examination
  • Determination of head circumference, height, weight, and other anthropometric measurements
  • A medical history, focusing on feeding problems, increased incidence of infection, evidence of kidney malfunction and/or gastroesophageal reflux, and symptoms of increased intracranial pressure
  • Renal ultrasound examination to evaluate for ureteral reflux, dysplastic kidney, multicystic kidneys, and other renal problems
  • Liver function tests may be warranted given that two individuals had autoimmune hepatitis and liver failure [Tufano et al 2009, Bartsch et al 2010]
  • Brain imaging studies (MRI, CT scan) in individuals with microcephaly and in individuals with symptoms suggestive of increased intracranial pressure from arachnoid cysts, including irritability, incessant crying, severe headache, cyclic vomiting, and seizures
  • Multidisciplinary developmental evaluation to assess motor, cognitive, social, and vocational skills
  • Comprehensive speech/language evaluation including an audiologic examination
  • A medical genetics consultation to discuss clinical manifestations, prognosis, natural history, therapies, and recurrence risks
  • Neurologic consultation to evaluate delays secondary to hypotonia and to monitor acquisition of major milestones
  • An EEG in individuals with seizures to help determine the appropriate antiepileptic drugs (AEDs). An EEG may also be used to detect subclinical seizure activity.
  • Evaluation of feeding problems (usually consisting of swallowing or sucking difficulties) by a feeding specialist and/or occupational therapist and speech pathologist
  • Evaluation of a child with autistic-like features by a child development specialist to identify early intervention programs to meet the child's developmental needs and to minimize atypical behaviors such as tactile defensiveness, anxiety, and self-stimulation
  • Evaluation for hypothyroidism in individuals who experience changes in behavior including lethargy, decreased activity, cognitive regression, and loss of coordination
  • Evaluation by an audiologist experienced in testing severely delayed children if hearing deficits are suspected because of recurrent ear infections and lack of expressive speech
  • Ophthalmologic examination in individuals with strabismus or other indications of visual impairment; assessment of cortical visual impairment by a team including physical therapists, occupational therapists, orientation and mobility specialists, pediatric neurologists, and pediatric ophthalmologists
  • Sleep study to evaluate for sleep apnea if sleep disturbance is present

Treatment of Manifestations

Treatment includes the following:

  • Regular professional dental hygiene, routine brushing, and fluoride treatment
  • Oral-motor therapy to alleviate chewing and swallowing problems
  • Consultation with a pediatric orthodontist regarding malocclusion and need for orthodontic intervention
  • Routine protocols to alleviate sleep apnea. If other sleep disturbances are present, establishing a bedtime routine can calm and soothe the child. Melatonin has been used to treat insomnia in children with autism spectrum disorders with 85% of parents reporting improved or normal sleep [Anderson et al 2008]. Although no controlled studies have been performed in Phelan-McDermid syndrome, melatonin treatment has been used to improve sleep in some children.
  • Tympanostomy tube placement for recurrent ear infections. If hearing is impaired, management with hearing aids should be considered.
  • Resolution of cardiac, renal, respiratory, immunologic, thyroid, and other medical issues according to standard protocols
  • Surgical removal of ingrown toenails to prevent infection
  • Use of pressure stockings and elevation of the foot of the bed for lymphedema.
  • Early intervention programs, intensive physical and occupational therapies, adaptive exercise and sports programs, and other therapies to improve coordination and strength
  • Therapies to improve verbal and nonverbal communication because perceptive language is often more advanced than expressive language. Sign language, picture exchange systems, and computer touch screens may augment communication.
  • Educational programming directed to the specific disabilities identified
  • Walkers or other assistive walking devices
  • Nutritional assessment for individuals with persistent gastroesophageal reflux (GER) and/or cyclic vomiting. GER may be treated in infants by thickening formula, smaller feedings, and positioning, and in older children by avoiding spicy food and refraining from eating within two to three hours of bed time. In some cases, medication is required to control GER. In the most persistent cases, surgery (fundoplication) may be required.
  • As in the general population, medication as indicated to help reduce hyperactivity, anxiety, and self-stimulatory behavior
  • Intravenous fluids to prevent dehydration in individuals with recurrent vomiting; neurologic evaluation to assess cyclic vomiting, particularly to address issues of increased intracranial pressure. If increased intracranial pressure is caused by an arachnoid cyst, surgery may be warranted.
  • Vigilance by parents or caregivers in monitoring children, particularly those who can walk or run independently, as children may be impulsive and unaware of the consequences of their behavior

Surveillance

The following are appropriate:

  • Ongoing pediatric care with regular immunizations
  • Evaluation by a neurologist for changes in behavior or regression of skills
  • Monitoring for symptoms (e.g., vomiting, incessant crying, irritability, severe headaches) that may indicate increased intracranial pressure secondary to a subarachnoid cyst
  • Routine monitoring of cardiac abnormalities
  • Monitoring for lymphedema that may occur in teenage or adult years; in severe cases, monitoring by a vascular surgeon
  • Routine dental examinations to monitor problems such as malocclusion, crowding, and accelerated tooth decay caused by poor enamel formation attributable to recurrent antibiotic therapy, acid reflux, and extended use of bottle feeding
  • Ophthalmologic examination at routine intervals by a specialist trained in evaluating individuals with developmental delay

Agents/Circumstances to Avoid

Exposure to high temperatures and extended periods in the sun should be avoided because individuals with 22q13.3 deletion have reduced perspiration and tend to overheat easily.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Intranasal insulin (INIT). Schmidt et al [2009] reported improved motor skills, cognition, and behavior in five of six children with Phelan-McDermid syndrome given INIT.

Risperidone. Pasini et al [2010] reported that low-dose risperidone treatment improved behavior, mood, and sleep in an 18-year-old female with Phelan-McDermid syndrome. Risperidone has been shown to exert a dose-dependent effect on glutamate receptors in animal models. These authors suggest that the therapeutic effects they observed may be related to the dose-dependent effects on a subset of glutamate receptors altered by SHANK3 haploinsufficiency.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Phelan-McDermid syndrome results from either a de novo or inherited deletion of chromosome 22q13.3.

On rare occasion an apparently balanced chromosome rearrangement or a mutation disrupts SHANK3.

Risk to Family Members

Parents of a proband

  • Chromosome analysis and/or FISH should be offered to the parents of all children with deletion 22q13.3.
    • Most terminal or interstitial deletions of 22q13.3 are de novo; thus, parents are most likely to have normal karyotypes.
    • Approximately 50% of unbalanced structural rearrangements that include 22q13 (e.g., reciprocal translocations, insertional translocations, inversions) are de novo and approximately 50% are inherited from a parent who is a carrier for a balanced chromosome rearrangement.
    • Although the probability of parental mosaicism for 22q13 deletion is low, it is important that parental mosaicism be considered when parental chromosome studies are performed. See Natural History, Mosaic deletion 22q13.3.

Sibs of a proband

  • The risk to sibs of a proband with 22q13.3 deletion depends on the chromosome findings in the parents.
    • When the parents have normal chromosomes, the risk to sibs of having 22q13.3 deletion is negligible.
    • When a parent has a balanced chromosome rearrangement, the risk to sibs of having 22q13.3 deletion is increased and depends on the specific chromosome rearrangement and the possibility of other variables.

Offspring of a proband. No individuals diagnosed with 22q13.3 deletion syndrome have been known to reproduce.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent has a balanced chromosome rearrangement, his or her family members may be at risk and should be offered chromosome analysis and/or FISH.

Carrier Detection

If a parent of the proband has a balanced chromosome rearrangement, at-risk family members can be tested by chromosome analysis and/or FISH.

Note: CMA does not detect a balanced chromosome rearrangement (as there is no loss or gain of chromosome material) and should not be used for carrier detection.

Related Genetic Counseling Issues

Phelan-McDermid syndrome resulting from an apparently balanced chromosome rearrangement or a mutation that disrupts SHANK3 requires formal genetic consultation.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with Phelan-McDermid syndrome.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for 22q13.3 deletion is possible by CMA and/or FISH of fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or by chorionic villus sampling at approximately ten to 12 weeks' gestation. The choice of test method(s) (i.e., CMA chromosome analysis and/or FISH) is based on which method(s) detected the deletion in the affected family member(s). Both mosaic and non-mosaic deletions of 22q13.3 have been successfully identified prenatally [Riegel et al 2000, Phelan 2001, Maitz et al 2008, Koc et al 2009].

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Phelan-McDermid Syndrome Foundation
    PO Box 1016
    Venice FL 34284
    Phone: 941-485-8000
    Fax: 941-485-8000
    Email: diannawalston@gmail.com
  • Chromosome 22 Central
    338 Spruce Street North
    Timmins Ontario P4N 6N5
    Canada
    Phone: 705-268-3099
    Email: steph.stpierre@c22c.org
  • Chromosome Disorder Outreach (CDO)
    PO Box 724
    Boca Raton FL 33429-0724
    Phone: 561-395-4252 (Family Helpline)
    Email: info@chromodisorder.org
  • National Dissemination Center for Children with Disabilities (NICHCY)
    1825 Connecticut Avenue NW
    Suite 700
    Washington DC 20009
    Phone: 800-695-0285 (Toll-free Voice/TTY); 202-884-8200 (Voice/TTY)
    Fax: 202-884-8441
    Email: nichcy@aed.org
  • Unique: The Rare Chromosome Disorder Support Group
    PO Box 2189
    Caterham Surrey CR3 5GN
    United Kingdom
    Phone: +44 (0) 1883 330766
    Fax: +44 (0) 1883 330766
    Email: info@rarechromo.org; rarechromo@aol.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Phelan-McDermid Syndrome: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
Not applicable22q13​.3Not applicable
SHANK322q13​.33SH3 and multiple ankyrin repeat domains protein 3SHANK3 @ LOVDSHANK3

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Phelan-McDermid Syndrome (View All in OMIM)

606230SH3 AND MULTIPLE ANKYRIN REPEAT DOMAINS 3; SHANK3
606232PHELAN-MCDERMID SYNDROME

Molecular Genetic Pathogenesis

The size of the 22q13.3 deletion in Phelan-McDermid syndrome ranges from 95 kb to more than 9 Mb.

The majority of terminal deletions of 22q13.3 (69%-74%) occur on the paternal chromosome 22 [Luciani et al 2003, Wilson et al 2003].

The genes included in the critical region are SHANK3, ACR, and RABL2B, the three q-terminal genes on chromosome 22.

Molecular characterization of terminal deletions in three unrelated individuals with Phelan-McDermid syndrome identified the same 15-base pair repeat unit in the D22S167 sequence variant between exons 8 and 9 as a recurrent breakpoint [Wong et al 1997, Anderlid et al 2002, Bonaglia et al 2006].

Heterozygous inactivation of SHANK3 is responsible for the majority of neurologic features of Phelan-McDermid syndrome [Wilson et al 2003]. Analysis of deletion breakpoints in SHANK3 suggests the presence of a deletion hot spot [Bonaglia et al 2006].

Evidence for a role for SHANK3 in Phelan-McDermid syndrome:

  • Bonaglia et al [2001] reported a child with a de novo balanced translocation t(12;22) (q24.1;q13.3) that disrupted SHANK3.
  • Anderlid et al [2002] described the disruption of SHANK3 resulting from a 100-kb deletion in an individual with the Phelan-McDermid syndrome phenotype.
  • In a study of two unrelated individuals with 100-kb deletions of 22q13, one of whom was the individual described by Anderlid et al [2002], Bonaglia et al [2006] concluded that the direct repeat within SHANK3 may form slipped (hairpin) structures with a strong potential for forming tetraplexes, suggesting a possible mechanism for the occurrence of a common break point.
  • Two studies, one involving 56 individuals with 22q13.3 deletion [Wilson et al 2003] and the other 32 individuals [Luciani et al 2003], proposed SHANK3 as a candidate gene for the neurologic deficits of Phelan-McDermid syndrome (developmental delay and impaired speech) because it is located in the critical region, is preferentially expressed in the cerebral cortex and the cerebellum, and encodes a protein in the postsynaptic density (PSD) of the excitatory synapses.
  • Thirty four of 35 individuals in a study of ring 22 were hemizygous for SHANK3 and demonstrated typical features of Phelan-McDermid syndrome including moderate to profound developmental delay, absent or delayed speech, autistic traits, and variable dysmorphic features. The single individual whose ring chromosome did not disrupt SHANK3 was a phenotypically normal female. This study lends further credence to the role of SHANK3 in normal neurologic development and supports the observation that hemizygosity for SHANK3 leads to intellectual disability, language deficits, and atypical behavior [Jeffries et al 2005].

Boccuto [personal observation] examined SHANK3 in 44 individuals with clinical features of Phelan-McDermid syndrome but with no apparent deletion of chromosome 22 by CMA, subtelomere FISH, or MPLA. Two loss-of-function mutations were identified: c.3931delG (p.Glu1311fs) and a partial-gene deletion (detected by customized FISH using cosmids n66c4 and n85a3).

Together these data provide compelling evidence that SHANK3 is the gene responsible for at least the developmental delay and speech deficit associated with 22q13.3 deletion syndrome. The contribution of epigenetic factors to the phenotypic expression in Phelan-McDermid syndrome is yet unknown.

SH3 and multiple ankyrin repeat domains protein 3 (Shank3) belongs to a family of proteins that interact with receptors of the postsynaptic membrane. These multidomain proteins are important scaffolding molecules in the postsynaptic density (PSD) and function to receive and integrate synaptic signals and transduce them into postsynaptic cells. In addition to their role in the assembly of the PSD during synaptogenesis, the Shank proteins may play a role in synaptic plasticity and in the regulation of dendritic spine morphology [Boeckers et al 2002].

In addition to deletion/disruption of SHANK3, deletion/disruption of other nearby genes as a cause of Phelan-McDermid syndrome seems possible. MAPK8IP2 is approximately 70 kb proximal to SHANK3 and is deleted in the majority of individuals with Phelan-McDermid syndrome [Giza et al 2010]. Experiments in mice demonstrate that Mapk8ip2 is highly expressed in the brain and is an essential component of the postsynaptic density. Mice lacking Mapk8ip2 demonstrate cognitive deficits reminiscent of those in individuals with deletion of 22q13.

Wilson et al [2008] reported two unrelated children with interstitial deletions of 22q13 proximal to, but not overlapping, SHANK3. The children had intellectual disability, severe language delay, hypotonia, and advanced height. The mother of one of the children who had the same deletion as her affected child had mild speech delay.

References

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Suggested Reading

  1. Buxbaum JD. Multiple rare variants in the etiology of autism spectrum disorders. Dialogues Clin Neurosci. 2009;11:35–43. [PMC free article: PMC3181906] [PubMed: 19432386]
  2. Hallschmid M, Benedict C, Schultes B, Perras B, Fehm HL, Kern W, Born J. Towards the therapeutic use of intranasal neuropeptide administration in metabolic and cognitive disorders. Regul Pept. 2008;149:79–83. [PubMed: 18442862]
  3. Phelan MC. Deletion 22q13.3 syndrome. Orphanet J Rare Dis. 2008;3:14. [PMC free article: PMC2427010] [PubMed: 18505557]

Chapter Notes

Acknowledgments

Dr. Phelan gratefully acknowledges the members of the Phelan-McDermid Syndrome/Deletion 22q13 Syndrome Foundation for their participation in research and for their generous sharing of information.

Revision History

  • 25 August 2011 (me) Comprehensive update posted live
  • 25 October 2007 (me) Comprehensive update posted to live Web site
  • 11 May 2005 (me) Review posted to live Web site
  • 22 November 2004 (kp) Original submission
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