Partial deletion of the long arm of chromosome 22
-Rare developmental defect during embryogenesis
-Rare genetic disease
Rare intellectual deficit with developmental anomaly
-Rare neurologic disease
Phelan-McDermid syndrome is a developmental disorder with variable features. Common features include neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, autistic behavior (see 209850), and minor dysmorphic features (Precht et al., 1998; ... Phelan-McDermid syndrome is a developmental disorder with variable features. Common features include neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, autistic behavior (see 209850), and minor dysmorphic features (Precht et al., 1998; Prasad et al., 2000; Durand et al., 2007).
Phelan et al. (2001) compared the phenotypes of 37 patients with 22q13 deletion syndrome with those of 24 published cases. All 37 patients presented with global developmental delay and absent or severely delayed expressive speech. Hypotonia was present ... Phelan et al. (2001) compared the phenotypes of 37 patients with 22q13 deletion syndrome with those of 24 published cases. All 37 patients presented with global developmental delay and absent or severely delayed expressive speech. Hypotonia was present in 97% of patients, and 95% showed normal to accelerated growth. Other less common features associated with this syndrome included increased tolerance to pain, dysplastic toenails, chewing behavior, fleshy hands, dysplastic ears, pointed chin, dolichocephaly, ptosis, tendency to overheat, and epicanthic folds. Bonaglia et al. (2001) studied a 4.5-year-old boy with all the features of terminal 22q13.3 deletion syndrome. He had only slight delay in early motor milestones and severely compromised language development, in that he was unable to utter single words until he was 2 years old. At age 4.5 years, his verbal expression was limited to a few words. The boy had mild mental retardation (overall IQ of 54) and sharply limited verbal abilities (verbal IQ of 32 and performance IQ of 70). Neurologic examination showed mild hypotonia and minor dysmorphic features (dolichocephaly, epicanthic folds, and saddle nose with bulbous tip). Wilson et al. (2003) noted that very few organ malformations had been reported in patients with 22q13 deletion syndrome. Lindquist et al. (2005) reported the clinical features of 6 cases of 22q13 deletion in Denmark. Consistent phenotypic features were generalized developmental delay, hypotonia, compromised language development, normal or accelerated growth, and minor facial dysmorphisms. Other features included partial absence of corpus callosum, bilateral ureteropelvic structure, gastroesophageal reflux, and hearing loss. Tabolacci et al. (2005) reported 2 brothers, born of nonconsanguineous parents, with features suggestive of Clark-Baraitser syndrome (300602). FISH screening revealed a cryptic subtelomeric deletion of chromosome region 22q13, and segregation analysis revealed the deletion to be of maternal origin, mostly likely due to germinal mosaicism. Tabolacci et al. (2005) suggested that patients diagnosed with Clark-Baraitser syndrome be tested for submicroscopic 22qter deletion.
In their study of 32 cases of telomeric 22q13 deletions resulting from rings, simple deletions, and translocations, Luciani et al. (2003) found no gross phenotypic differences between the 22q13 deletion and the ring 22 syndromes for similarly sized ... In their study of 32 cases of telomeric 22q13 deletions resulting from rings, simple deletions, and translocations, Luciani et al. (2003) found no gross phenotypic differences between the 22q13 deletion and the ring 22 syndromes for similarly sized deletions. Nevertheless, behavioral disorders were a constant feature and increased in severity with age. Although patients with simple 22q13 terminal deletion had a general tendency to overgrowth, the patients with a ring 22 often showed growth failure. Lindquist et al. (2005) reported that the clinical phenotype of 6 patients with 22q13 deletion in Denmark was similar, although some specific features might have been attributable to differences in deletions. The phenotype in the patient with a deletion and a duplication was different from that in the other 5 patients; he showed severe failure to thrive and growth failure as well as significantly dysmorphic facial features. Wilson et al. (2003) determined the deletion size and parent of origin in 56 patients with the 22q13 deletion syndrome. Similar to other terminal deletion syndromes, there was an overabundance of paternal deletions. The deletions varied widely in size, from 130 kb to more than 9 Mb; however, all 45 patients who could specifically be tested for the terminal region containing the PSAP2 (SHANK3) gene showed a deletion of this gene. Comparison of clinical features to deletion size showed few correlations. Some measures of developmental assessment did correlate with deletion size; however, all patients showed some degree of mental retardation and severe delay or absence of expressive speech, regardless of deletion size. Because the SHANK3 gene encodes a structural protein of the postsynaptic density, the analysis supported haploinsufficiency of this gene as a major causative factor in the neurologic symptoms of 22q13 deletion syndrome. Wilson et al. (2008) reported 2 unrelated patients with interstitial deletions of chromosome 22q13 that did not include the SHANK3 gene; both patients had 2 copies of SHANK3. The phenotype was similar to that observed in 22q13 deletion syndrome, including psychomotor retardation, hypotonia, speech delay, and overgrowth. One child was more severely affected; the second child was able to open a computer by himself and use a mouse, and he could feed and dress himself. Neither child had high pain tolerance, upper respiratory problems, or toenail abnormalities. The mother of the second child also carried the deletion; she had speech problems and was slow to walk, but attended normal school. Microsatellite and FISH analysis showed that both deletions were entirely contained within the largest terminal 22q13 deletion reported, but did not overlap with the 9 smallest deletions of 22q13 previously reported. Wilson et al. (2008) concluded that genes on chromosome 22q12 other than SHANK3 can have a major effect on cognitive and language development and noted the general nonspecificity of the phenotype. Sarasua et al. (2011) used high-resolution oligonucleotide array CGH to delineate precisely the breakpoints in 71 patients with Phelan-McDermid syndrome who had a terminal deletion of chromosome 22q13. Patient deletion sizes were highly variable, ranging from 0.22 to 9.22 Mb, and there were no common breakpoints. SHANK3 was deleted in all cases, and MAPK8IP2 (607755) was deleted in all but 2 individuals. Larger deletions including regions proximal to SHANK3 were significantly associated with 16 features: neonatal hypotonia, neonatal hyporeflexia, neonatal feeding problems, speech/language delay, delayed age at crawling, delayed age at walking, severity of developmental delay, male genital anomalies, dysplastic toenails, large or fleshy hands, macrocephaly, tall stature, facial asymmetry, full brow, atypical reflexes, and dolichocephaly. Patients with autism spectrum disorders were found to have smaller deletion sizes (median of 3.39 Mb) than those without autism spectrum disorders, although this may have reflected difficulty in assessing autism in patients with severe developmental delay.
Bonaglia et al. (2006) studied 2 patients, 1 previously reported by Anderlid et al. (2002), with cardinal features of the 22q13.3 deletion syndrome associated with a deletion involving the last 100 kb of chromosome 22q13.3. Both patients showed ... Bonaglia et al. (2006) studied 2 patients, 1 previously reported by Anderlid et al. (2002), with cardinal features of the 22q13.3 deletion syndrome associated with a deletion involving the last 100 kb of chromosome 22q13.3. Both patients showed a breakpoint within the same 15-bp repeat unit, overlapping results obtained by Wong et al. (1997) and suggesting that a recurrent deletion breakpoint exists within the SHANK3 gene. Bonaglia et al. (2006) stated that this was the first instance of terminal deletions having a recurrent breakpoint, and noted that because the deletion partially overlaps the commercial subtelomeric probe, FISH results are difficult to interpret and similar cases may be overlooked. Durand et al. (2007) reported evidence showing that abnormal gene dosage of SHANK3 is associated with severe cognitive deficits, including language and speech disorder and autism spectrum disorder. They reported 3 families with autism spectrum disorder and unambiguous alteration of 22q13 or SHANK3. In the first family, the proband with autism, absent language, and moderate mental retardation carried a de novo deletion of 22q13. The deletion breakpoint was located in intron 8 of SHANK3 and removed 142 kb of the terminal 22q13. In a second family, 2 brothers with severely impaired speech, severe mental retardation, and a diagnosis of autism had a heterozygous 1-bp insertion in the SHANK3 gene (606230.0001), resulting in a truncated protein. The mutation was absent in an unaffected brother and in the unaffected parents. In a third family studied by Durand et al. (2007), a terminal 22q deletion was found in a girl with autism and severe language delay, and a 22qter partial trisomy in her brother with Asperger syndrome who demonstrated precocious language development and fluent speech. These unbalanced cytogenetic abnormalities were inherited from a paternal translocation, t(14;22)(p11.2;q13.33). Studies with informative SNPs and quantitative PCR permitted mapping of the breakpoint on 22q13 between ALG12 (607144) and MLC1 (605908). The deletion and duplication rearrangement observed in both sibs involved 25 genes, including SHANK3, located in the 800-kb terminal segment of 22q13. Durand et al. (2007) concluded that gene dosage of SHANK3 is important for speech and language development as well as social communication. Moessner et al. (2007) identified deletions in the SHANK3 gene on chromosome 22q13 in 3 (0.75%) of 400 unrelated patients with an autism spectrum disorder. The deletions ranged in size from 277 kb to 4.36 Mb; 1 patient also had a 1.4-Mb duplication at chromosome 20q13.33. The patients were essentially nonverbal and showed poor social interactions and repetitive behaviors. Two had global developmental delay and mild dysmorphic features. A fourth patient with a de novo missense mutation in the SHANK3 gene had autism-like features but had diagnostic scores above the cutoff for autism; she was conceived by in vitro fertilization. Dhar et al. (2010) carried out clinical and molecular characterization of 13 patients with varying sizes of deletion in the 22q13.3 region. Developmental delay and speech abnormalities were common to all and comparable in frequency and severity to previously reported cases. Array-based comparative genomic hybridization showed the deletions to vary from 95 kb to 8.5 Mb. Two patients had a smaller 95-kb terminal deletion with breakpoints within the SHANK3 gene while 3 other patients had a similar 5.5-Mb deletion, implying the recurrent nature of these deletions. The 2 largest deletions were found in patients with ring chromosome 22. No correlation could be made with deletion size and phenotype although complete/partial SHANK3 was deleted in all patients. By specific screening of the SHANK3 gene in 221 patients with autism spectrum disorders, Boccuto et al. (2013) identified 5 (2.3%) index patients with heterozygous pathogenic changes in that gene (see, e.g., 606230.0004-606230.0006). Three patients had autistic disorder, 1 had pervasive developmental disorder-not otherwise specified (PDD-NOS), and 1 had Asperger syndrome. Most had some additional features including seizures, developmental delay, and mild facial dysmorphism. The mutations included a 106-kb deletion encompassing only the SHANK3 gene, 2 frameshift mutations, 1 missense mutation, and a splice site mutation. Screening of this gene in an independent cohort of 104 patients identified 1 (0.9%) with a SHANK3 missense mutation. No cell lines were available from the patients, so functional or expression studies could not be performed. Boccuto et al. (2013) also identified a c.1304+48C-T transition (dbSNP rs76224556) in 17 (7.7%) cases, including 5 with autistic disorder and 12 with PDD-NOS. Four (23.5%) of these patients had an affected sib who also carried the variant. The variant was demonstrated to be inherited from an apparently unaffected parent in 15 cases. However, this variant was significantly more frequent in the patient cohort than in the combined control population (7.7% vs 1.4%, p value less than 0.0002). In the replication cohort, 8 (7.7%) of 104 patients carried the c.1304+48C-T variant. This change occurs in a highly CG-rich region and causes the loss of a CpG dinucleotide, which may affect methylation status. Boccuto et al. (2013) concluded that variation in the SHANK3 gene increases the basal susceptibility to autism spectrum disorders, which have a complex etiology.
Phelan-McDermid syndrome (22q13.3 deletion syndrome) is suspected in children with the following:...
DiagnosisClinical DiagnosisPhelan-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 nosePuffy 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.SHANK3 (previously known as PROSAP2) is completely or partially deleted in virtually all cases; rarely, it is disrupted by an apparently balanced translocation [Bonaglia et al 2001] (see Molecular Genetics).ACR RABL2B TestingCytogenetic testingG-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 View in own windowTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityFISHDeletion 22q13.3~100% when both ARSA and subtelomere 22q probes are usedClinical Deletion / duplication analysis 2Variable depending on the loci analyzed 31. The ability of the test method used to detect the indicated deletion2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. 3. 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 StrategyTo 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 relativesChromosome 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. Genetically Related (Allelic) DisordersSHANK3 mutations are observed in autism spectrum disorders:In their investigation of autism spectrum disorders, Durand et al [2007] identified three families with loss or disruption of SHANK3:Family 1. An individual with autism, absent speech, and intellectual disability had a de novo microdeletion of 22q13.3. The deletion break point was within intron 8 of SHANK3, resulting in loss of the distal 142 kb of 22q. The deleted segment includes the minimal critical deletion for Phelan-McDermid syndrome as defined by Wong et al [1997] and Bonaglia et al [2001].Family 2. Two brothers with autism, severely delayed speech, and severe intellectual disability were heterozygous for the insertion of a guanine nucleotide into exon 21 of SHANK3. The guanine insertion created a frameshift mutation at nucleotide 3680 leading to a truncated protein lacking crucial domains involved in the synaptic targeting and postsynaptic assembly of SHANK3 multimers. Neither the parents nor an unaffected brother had the mutation. Results of molecular studies suggested maternal germline mosaicism. Family 3. A paternal t(14;22)(p11.2;q13.33) resulted in a terminal deletion of chromosome 22 in a daughter and partial trisomy of 22q in a son. The daughter had autism and severe language delay; the brother had Asperger syndrome with precocious language development and fluent speech but severe impairment in social communications. The deletion and duplication involved 25 genes and was located in the 800-kb terminal sequence of 22q13. The deleted segment in the affected daughter included the minimal critical deletion for Phelan-McDermid syndrome as defined by Wong et al [1997] and Bonaglia et al [2001]. According to Betancur et al [2009] this study confirms that haploinsufficiency of SHANK3 accounts for the neurodevelopmental phenotype in the 22q13 deletion syndrome.In their study of SHANK3 in autism spectrum disorders, Moessner et al [2007] identified three deletions of 22q13.3: a de novo, approximately 227-kb deletion in family 1; a 3.2-Mb deletion in family 2 inherited from the father who had a balanced translocation; and a 4.4-Mb deletion in family 3 presumed to be inherited from the mother, who was presumed to have germline mosaicism. Note: Testing for 22q13.3 microdeletion and SHANK3 deletions/mutations are often included in panels designed for testing of individuals with autism spectrum disorders.
Males and females are equally affected with no apparent parent-of-origin effect (Table 2)....
Natural HistoryMales and females are equally affected with no apparent parent-of-origin effect (Table 2).Table 2. Features of Phelan-McDermid SyndromeView in own windowPrevalenceFeatures>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 SeizuresCusmano-Ozog et al [2007], Dhar et al [2010], Phelan et al [2010]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.OtherThe hands appear large and fleshy. Toenails are often dysplastic, thin, and flaky and tend to become ingrown. Fingernails are usually normal. An atypical teratoid/rhabdoid tumor was reported in an infant with a 7.2-Mb deletion of 22q13 [Sathyamoorthi et al 2009].Arylsulfatase A deficiency (metachromatic leukodystrophy) was observed in a child with deletion 22q13 and mutation of ARSA on the homologous chromosome 22 [Bisgaard et al 2009].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].
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....
Differential DiagnosisHypotonia 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Phelan-McDermid syndrome, the following evaluations are recommended: ...
ManagementEvaluations Following Initial DiagnosisTo 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 ManifestationsTreatment 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 SurveillanceThe following are appropriate:Ongoing pediatric care with regular immunizations Evaluation by a neurologist for changes in behavior or regression of skillsMonitoring 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 AvoidExposure 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 RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationIntranasal 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 realted 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. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDNot applicable22q13.3Not applicable SHANK322q13.33SH3 and multiple ankyrin repeat domains protein 3SHANK3 @ LOVDSHANK3Data 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) View in own window 606230SH3 AND MULTIPLE ANKYRIN REPEAT DOMAINS 3; SHANK3 606232PHELAN-MCDERMID SYNDROMEMolecular Genetic PathogenesisThe 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.