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GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. Diagnosis of 22q13.3 deletion syndrome is established by demonstration of a deletion or disruption of 22q13.3 by routine chromosome analysis or fluorescence in situ hybridization (FISH) testing. Approximately 75% of deletions are "simple" (either terminal or interstitial), and approximately 25% are complex, resulting from an unbalanced translocation or other structural chromosome rearrangement. Although many 22q13.3 simple deletions can be detected by routine chromosome analysis at the 500- to 550-band level, even high-resolution analysis may not detect subtle deletions. FISH testing detects nearly 100% of deletions.
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. Agents/circumstances to avoid: exposure to high temperatures and extended periods in the sun because of decreased perspiration.
Genetic counseling. 22q13.3 deletion syndrome results from a de novo chromosome deletion in 80%-85% of affected individuals or an inherited chromosome rearrangement in 15%-20%. Prenatal testing for pregnancies at increased risk is possible by chromosome analysis and/or FISH.
22q13.3 deletion syndrome is a microdeletion syndrome 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
Puffy cheeks
Pointed chin
Large or prominent ears
Other features that raise suspicion of 22q13.3 deletion 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.
The diagnosis of 22q13.3 deletion syndrome is confirmed by demonstration of a deletion or disruption of 22q13.3.
Approximately 75% of individuals with 22q13.3 deletion syndrome have one of the following "simple" deletions:
A "terminal" deletion, i.e., a single break in the chromosome arm with loss of the segment distal to the break
An "interstitial" deletion, i.e., two breaks within the same chromosome arm and loss of the intervening segment
Approximately 25% of individuals with 22q13.3 deletion syndrome have deletions resulting from an unbalanced translocation or other structural rearrangement. Unbalanced translocations are characterized by deletion of 22q13.3 and partial trisomy of a second chromosomal segment.
Note: Although routine chromosome analysis (500-550 band level) can detect many 22q13.3 simple deletions, in some cases even high-resolution analysis (>550 bands) may fail to detect a subtle deletion [Phelan et al 2001].
Other methods that can be used to detect microdeletion 22q13.3:
Array comparative genomic hybridization (CGH), which can aid in the detection of simple deletions and in identification of derivative chromosomes resulting from translocations involving chromosome 22 and a second chromosome
Fluorescence in situ hybridization (FISH) testing, which can be used to confirm the presence of a deletion when 22q13.3 deletion syndrome is suspected clinically but a deletion is not detected by routine cytogenetic analysis
If the results of conventional chromosome analysis are normal, reflex testing to FISH or array CGH is warranted for the following indications:
Postnatal findings of hypotonia, failure to thrive, and/or dysmorphic features in infants who had normal prenatal cytogenetic studies
Band resolution of the first cytogenetic study inadequate to detect subtle rearrangements
High-resolution cytogenetic analysis targeted to examine a specific chromosome based on clinical findings
High clinical suspicion of a chromosomal disorder leading to repeated chromosome analyses, often accompanied by subtelomere FISH studies
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Critical region. The 22q13.3 break point has been delineated at the base pair level in only a few cases. The minimum region of overlap for deletions of SHANK3 is a 100-kb region delineated proximally by cosmid n66c4, which is distal to the ARSA locus and overlaps the 5' half of SHANK3, and distally by cosmid n94h12, which overlaps the 3' end [Bonaglia et al 2006].
Polymorphisms were present within the highly polymorphic region D22S163, the site of the break points in three individuals with 22q13.3 deletion syndrome; their break points were no more than 15 base pairs apart inside a short simple repeat between exons 8 and 9 of SHANK3 [Bonaglia et al 2006].
Another individual had a break point in exon 21 [Bonaglia et al 2001].
Gene. SHANK3(PROSAP2) is the candidate gene for the neurologic deficits (developmental delay and absent speech) in 22q13.3 deletion syndrome. Two brothers had a SHANK3 frameshift mutation resulting from a guanine insertion in exon 21. The mother was inferred to have germline mosaicism for the mutation [Durand et al 2007].
Clinical testing
Fluorescence in situ hybridization (FISH). The commercially available FISH probes for detecting deletion of 22q13.3 include the arylsulfatase A (ARSA) probe and subtelomere probes. One of the commonly used ARSA probes is 310 kb in size and maps to 22q13.33 [Vysis, Downers Grove, IL, Part #32-190012]. The subtelomere probe (D22S1726) is 80 kb in size and is estimated to be within 300 kb of the end of chromosome 22 [Vysis, Downers Grove, IL, Part #33-27000]. The combined use of the probes for ARSA and for the subtelomere region should detect 100% of the deletions resulting in this syndrome.
Deletion 22q13.3 observed on routine cytogenetic studies should be confirmed with FISH studies.
Although deletion of ARSA is seen in most individuals with 22q13.3 deletion syndrome, FISH analysis for ARSA may fail to identify more distal deletions involving the telomeric region.
22q subtelomeric probes detect deletions more distal to ARSA but could miss interstitial deletions.
Note: (1) Commercially available probe sets designed for detection of deletion 22q11.2 (velocardiofacial/DiGeorge syndrome) typically use the ARSA gene as the control probe. (2) If clinical suspicion of 22q13.3 deletion syndrome is strong and if the deletion is not demonstrated by the initial cytogenetic analysis, probes for ARSA and for the subtelomere region of 22q should be used sequentially.
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. 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.
To confirm the diagnosis in a proband
Cytogenetic analysis at or above the 550-band level should be performed to determine if an obvious cytogenetic abnormality is present.
If 22q13.3 deletion syndrome is suspected, FISH testing should accompany cytogenetic analysis.
Even if previous chromosome studies have been reported as normal, repeat chromosome studies (with FISH for ARSA and/or the 22q subtelomere) are indicated when clinical suspicion of 22q13.3 deletion syndrome is strong.
Prenatal diagnosis for at-risk pregnancies requires prior confirmation of the diagnosis of 22q13.3 deletion syndrome in the proband and/or of balanced carrier status in a parent.
No other phenotypes are known to be associated with deletion 22q13.3.
| Prevalence | Features |
|---|---|
| >95% | Neonatal hypotonia Global developmental delay Absent or severely delayed speech Normal to accelerated growth |
| >75% | Large, fleshy hands Dysplastic toenails Long eyelashes Decreased sensitivity to pain Mouthing/chewing/tooth grinding |
| >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 |
| >25% | Strabismus Renal problems Gastroesophageal reflux Malocclusion/wide-spaced teeth Epicanthal folds Long philtrum High-arched palate |
Hypotonia. Newborns with 22q13.3 deletion 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 syndrome are described as having "global developmental delay" or "moderate to profound mental retardation." Results of formal IQ testing are often not reported. In the study by Phelan et al (2001), the Vineland Adaptive Behavior Scales (VABS) and Battelle Developmental Inventory (BDI) were used to test cognitive ability and adaptive behavior. Fifteen of 20 children (75%) demonstrated severe to profound mental retardation, with standard scores below 40. The other five children (25%) scored in the mild to moderate range of mental retardation, with standard scores between 40 and 70. These five children were the youngest children in the sample and most likely received higher scores because the tests do not score low enough for the younger age groups. As children age their scores relative to their peers' continue to decrease and they may eventually fall within the severe to profound range of mental retardation. The highest age equivalent on the VABS composite was 18 months and the highest on the BDI was 21 months.
Similarly, Bonaglia et al (2006) described an individual age 13 years whose overall VABS was 18 months with receptive and expressive language skills below the bottom of the scale, socialization age equivalent 18 months, learning skills 32 months, and motor skills 23 months.
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 22q13.3 deletion 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 22q13.3 deletion syndrome is appropriate for gestational age; the mean gestational age is 38.2 weeks. Postnatal growth is normal or accelerated. Height is advanced for age, but weight is not increased; thus, children appear tall and thin.
Although 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.
Unusual behavior. Behavior may be autistic-like with poor eye contact, stereotypic movements, and self-stimulation. Other abnormal behaviors 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.
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 2005].
Renal. Renal function is typically normal although frequent urinary tract infections, cystic kidneys, dysplastic kidney, hydronephrosis, and vesicoureteral reflux have been reported.
Gastrointestional. 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 22q13.3 deletion 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]. Many seizures 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 22q13.3 deletion syndrome.
Lymphedema. Both lymphedema and recurrent cellulitis have been observed in approximately 10% of individuals, typically becoming problematic during the teenage and adult years.
Other physical findings. The hands appear large and fleshy. Toenails are often dysplastic, thin, and flaky and tend to become ingrown. Fingernails are usually normal. 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.
Fertility. No individuals with 22q13.3 deletion syndrome have been known to reproduce, although no fertility studies that would exclude the possibility of reproduction have been performed. A female with 22q13.3 deletion syndrome goes through puberty and begins 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 22q13.3 deletion syndrome reflects the difficulty in establishing the diagnosis prior to the advent of high-resolution chromosome analysis, FISH, and array CGH.
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. Because most testing is performed on blood samples and the level of mosaicism in blood can change over time, it is not known what level of mosaicism is "required" for expression of the major features of 22q13.3 deletion syndrome.
One adult with characteristic features of the syndrome showed ring 22 in only 8% of blood cells [Phelan, unpublished data].
There have been at least three reported instances of maternal mosaicism leading to 22q13.3 deletion in their offspring:
Two brothers with features of Clark-Baraitser syndrome were found to have deletion 22q13. The deletion was inferred to come from the mother because the brothers did not inherit the same chromosome 22 from their father [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.
The mother of a child with non-mosaic ring chromosome 22 had ring 22 in fewer than 2% of peripheral blood cells [Phelan, unpublished data].
| Number of Individuals | Deletion Size | Comment | Reference |
|---|---|---|---|
| 1 | 130 kb | Mild features 1 | Wong et al 1997 |
| 1 | 100 kb | Mild features that became more severe with age | Anderlid et al 2002 |
| 56 | 130 kb - 9 Mb | No correlation | Wilson et al 2003 |
| 33 | 160 kb - 8 Mb | Luciani et al 2003 2 | |
| 6 | 4 Mb - 9 Mb | Lindquist et al 2005 | |
| 9 | 3.3 Mb - 8.4 Mb | Koolen et al 2005 | |
| 35 | <67 kb - 10.2 Mb | Jeffries et al 2005 3 |
1. Milder delays, less severe speech delay, and fewer of the typical dysmorphic features compared to individuals with larger deletions
2. Included simple deletions, rings, and unbalanced translocations
3. Study of ring chromosomes
As expected, features of 22q13.3 deletion 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 mental deficits and speech impairment are universally present.
Full manifestation of features has been seen in individuals with as low as 8% mosaicism for the deletion [Phelan, personal observation].
No true synonyms exist for 22q13.3 deletion syndrome, but some have used the term Phelan-McDermid syndrome after the individuals who originally described the disorder.
The prevalence of 22q13.3 deletion syndrome is unknown. The disorder remains underdiagnosed as a result of failure (1) to detect the deletion of chromosome 22 in routine chromosome studies and (2) to recognize the phenotype on clinical examination. In surveys of subtelomeric deletions, deletion of 22q13.3 is the second most common deletion, after deletion 1p36.3 [Heilstedt et al 2003].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Hypotonia and developmental delay are nonspecific findings and cannot be used to differentiate 22q13.3 deletion 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 22q13.3 deletion 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 22q13.3 deletion syndrome, including global developmental delay, severe speech deficit, hypotonia, and minor dysmorphic features. Unlike 22q13.3 deletion 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 who are missing 22q13.3 would have the phenotype of 22q13.3 deletion syndrome. Many families with ring chromosome 22 are members of the Phelan-McDermid Syndrome/Deletion 22q13.3 Syndrome Foundation.
Other disorders
Prader-Willi syndrome (PWS). 22q13.3 deletion 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 symptoms of 22q13.3 deletion syndrome. Testing for 22q13.3 deletion syndrome is recommended for any child with these findings in whom genetic testing for PWS is normal.
Angelman syndrome. The diagnosis of 22q13.3 deletion 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 15q11-13 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 syndrome is recommended [Precht et al 1998, Van Tuinen et al 2000].
Velocardiofacial syndrome (VCFS) (see 22q11.2 Deletion Syndrome). Similarities between VCFS and 22q13.3 deletion 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 22q13.3 deletion syndrome. Unlike 22q13.3 deletion 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, the N25 or Tuple probe set detects deletion of 22q13, resulting in the diagnosis of 22q13.3 deletion syndrome 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 22q13.3 deletion syndrome, including hypotonia, global developmental delay, and puffy eyelids. In contrast to 22q13.3 deletion 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 the ELN gene. Although inheritance is autosomal dominant, 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 22q13.3 deletion syndrome include hypotonia, intellectual deficit, bulbous nose, large or prominent ears, deep-set eyes, and thin hypoplastic toenails. Features that distinguish TRPS from 22q13.3 deletion 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 TRPI 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 22q13.3 deletion 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 22q13.3 deletion 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 the FMR1 gene. Inheritance is X-linked.
FG syndrome. Overlap between FG syndrome and 22q13.3 deletion syndrome includes hypotonia, mental retardation, delayed speech, autistic-like behavior, and gastroesophageal reflux. Characteristic features of FG syndrome that are not associated with 22q13.3 deletion 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 new mutation in a family.
Sotos syndrome (cerebral gigantism). Sotos syndrome, like 22q13.3 deletion syndrome, is associated with physical "overgrowth." At birth individuals with Sotos syndrome are 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, have mild mental retardation, 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 22q13.3 deletion 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 known to be associated with Sotos syndrome. Inheritance is autosomal dominant; more than 95% of affected individuals have a de novo mutation.
Cerebral palsy. 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 22q13.3 deletion 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 deletion of 22q13.3 is often the manner in which individuals erroneously diagnosed with cerebral palsy attain the correct diagnosis.
Spastic paraplegia (see Hereditary Spastic Paraplegia Overview). Because children with 22q13.3 deletion 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 22q13.3 deletion 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 (see Autism Overview). Several studies have reported autism or autistic-like behavior in individuals with 22q13.3 deletion syndrome [Anderlid et al 2002, Manning et al 2004, Jeffries et al 2005, Phelan et al 2005, Durand et al 2007].
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 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.
22q13.3 deletion syndrome should be considered in the differential diagnosis of autism, particularly when subtle dysmorphic features are present.
Duplication 22q syndrome. Duplication of 22q12-q13 results in severe psychomotor retardation, pre- and postnatal growth retardation, cleft palate with or without cleft lip, micrognathia, ocular hypertelorism, low-set ears, congenital heart defects, renal and genital anomalies, skeletal anomalies, and hypotonia. Almost half of all individuals die before age 12 years.
Although more than 20 cases of duplication of distal 22q have been described, many of them have break points within 22q12 rather than 22q13. Persons with the more distal break point (22q13) generally have derivative chromosomes resulting from unbalanced translocations, which complicates clinical characterization of duplication 22q13 because the person also has a deletion of a second chromosome. Nonetheless, in comparing two persons with pure duplication 22q13, Feenstra et al (2006) determined that psychomotor retardation, short stature, and small palpebral fissures were present in both. Other features were hypotonia, macrocephaly, dysplastic ears, long philtrum, micrognathia, short neck, genital malformation, and slender fingers in one and microcephaly, epicanthal folds, short philtrum, low-set ears, webbed neck, hypoplastic nipples, dysplastic right hip, pulmonary valvular stenosis, ectopic left kidney, mucous cleft palate, frontal bossing, and flat midface in the other.
Lindquist et al (2005) described an individual with duplication as well as deletion of 22q13 who had generalized developmental delay, delayed speech, hypotonia, dysmorphic features (including epicanthal folds, flat midface, puffiness around the eyes and cheeks), apneic spells with seizures, patent ductus arteriosis, and Pierre Robin sequence.
To establish the extent of disease in an individual diagnosed with 22q13.3 deletion 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
Brain imaging studies (MRI, CAT 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 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 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.
Tympanostomy tube placement for recurrent ear infections. If hearing is impaired, management with hearing aids should be considered.
Resolution of cardiac, renal, respiratory, immunologic, 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
Individuals with heat intolerance should be carefully monitored in warm weather to avoid hyperthermia and dehydration.
Direct exposure to sun should be avoided.
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
Exposure to high temperatures and extended periods in the sun should be avoided because individuals with deletion 22q13.3 have reduced perspiration and tend to overheat easily.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
22q13.3 deletion syndrome can be the result of a de novo chromosome deletion or of an inherited chromosome abnormality.
Parents of a proband
Most probands have a de novo chromosome deletion and their parents have normal karyotypes. Familial chromosome rearrangements have been identified in 15%-20% of probands.
The majority of simple deletions of 22q13.3 (69%-74%) occur on the paternal chromosome 22 [Luciani et al 2003, Wilson et al 2003].
Approximately 80% of the derivative chromosomes involving 22q13.3 are the result of familial translocations. Various parental chromosome rearrangements, including an insertional translocation, a pericentric inversion, and mosaicism have been observed [Watt et al 1985; Slavotinek et al 1997; Phelan, unpublished data].
Parents of a proband with a structurally unbalanced chromosome constitution (e.g., deletion or translocation) are at risk of having a balanced chromosome rearrangement.
Targeted chromosome analysis and FISH studies are warranted in parents of individuals with 22q13.3 deletion syndrome.
FISH studies should include the examination of a sufficient number of cells to rule out mosaicism in a parent.
Sibs of a proband
The risk to sibs of a proband with 22q13.3 deletion syndrome depends upon the chromosome findings in the parents.
As with other de novo chromosome rearrangements, the recurrence risk for future pregnancies is negligible when parental karyotypes are normal.
If a parent has a balanced structural chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
Because not all phenotypically normal parents of probands have been evaluated for mosaicism, the incidence of parental mosaicism is unknown. Based on data from 200 families, the finding of two sibs born to a parent who is mosaic for deletion 22q13.3 suggests that the risk to sibs of a proband is less than 0.5% [Phelan, unpublished data].
The occurrence of maternal germline mosaicism was suspected as a cause of 22q13.3 deletion syndrome in two brothers with features of Clark-Baraitser syndrome [Tabolacci et al 2005].
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 is found to have a balanced chromosome rearrangement, his or her family members may be at risk and should be offered chromosome analysis and FISH.
If a parent of the proband is found to have a balanced chromosome rearrangement, at-risk family members can be tested by chromosome analysis and/or FISH.
Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are known to be or at risk of being carriers of a balanced chromosome rearrangement.
Prenatal diagnosis for pregnancies at increased risk is possible by chromosome analysis and/or FISH of fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or by chorionic villus sampling at approximately ten to 12 weeks' gestation. Both mosaic and non-mosaic deletions of 22q13.3 have been successfully identified prenatally [Riegel et al 2000, Phelan 2001, Phelan et al 2001].
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 available for families at risk of having a pregnancy with 22q13.3 deletion syndrome. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| Unknown | 22q13.3 | Unknown |
| 606230 | SH3 AND MULTIPLE ANKYRIN REPEAT DOMAINS 3; SHANK3 |
| 606232 | CHROMOSOME 22q13.3 DELETION SYNDROME |
The size of the deletion in 22q13.3 deletion syndrome ranges from 100 kb to more than 9 Mb. The minimum region of overlap of deletions leading to 22q13.3 syndrome is a 100-kb region delineated proximally by cosmid n66c4 and distally by cosmid n94h12 [Bonaglia et al 2006].
The cosmid clone n66c4 is distal to the ARSA locus and overlaps the 5' half of SHANK3 (PROSAP2), the candidate gene for the neurologic deficits (developmental delay and absent speech) in 22q13.3 deletion syndrome [Anderlid et al 2002, Bonaglia et al 2006]. The consequences of deletion or disruption of SHANK3, the characterization of deletion size, and the evidence for recurrent deletion sites provide compelling evidence that SHANK3 is the gene responsible for the developmental delay and speech deficit associated with 22q13.3 deletion syndrome.
SHANK3 belongs to a family of proteins that interacts 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].
Disruption of SHANK3 resulting in features of 22q13.3 syndrome was first reported by Bonaglia et al (2001) in a child with a de novo balanced translocation t(12;22) (q24.1;q13.3). Subsequently, Anderlid et al (2002) described the disruption of SHANK3 resulting from a 100-kb deletion in an individual with the phenotype of 22q13.3 deletion syndrome.
Two studies of 22q13.3 deletion syndrome, one involving 56 individuals [Wilson et al 2003] and the other 32 individuals [Luciani et al 2003], proposed SHANK3 as a candidate gene for the neurologic deficits (developmental delay and impaired speech) seen in 22q13.3 deletion syndrome. Because it is located in the critical region, it is preferentially expressed in the cerebral cortex and the cerebellum, and it encodes a protein in the PSD of the excitatory synapses.
In a study of 35 individuals with ring 22, 34 individuals were hemizygous for SHANK3 and demonstrated typical features of 22q13.3 deletion 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 mental retardation, language deficits, and atypical behavior [Jeffries et al 2005].
Deletion size and location have been investigated in a number of individuals. Lindquist et al (2005) used real-time polymerase chain reaction to map deletion size in six individuals. The deletion size ranged from 4.0 Mb to 8.5 Mb and the authors provide specific information regarding the position of the amplicons, showing reduced copy number in each individual. Tabolacci et al (2005) defined the deletion size in two brothers using three chromosome 22-specific BAC probes. Probe CTA-1109B5, which spanned approximately 3.5 Mb from the telomere, was deleted whereas probes RP1-102D24 (spanning ~5 Mb from the telomere) and CTA0397C4 (spanning ~6 Mb from the telomere) were present. Based on the physical map of these probes (www.Ensembl.org), the deletion spanned approximately 3.5 Mb and was the same size in the brothers.
In their investigation of autism spectrum disorders, Durand et al (2007) studied three families with loss or disruption of SHANK3:
In the first family, an individual with autism, absent speech, and mental retardation had a de novo deletion of 22q13. The deletion break point was within intron 8 of SHANK3, resulting in loss of the distal 142 kb of 22q.
In the second family, two brothers with autism, severely delayed speech, and severe mental retardation were heterozygous for the insertion of a guanine nucleotide into exon 21 of the SHANK3 gene. 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 pointed to maternal germline mosaicism.
In the third family, 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 segment of SHANK3.
In two unrelated individuals, Bonaglia et al (2006) investigated the break point within SHANK3 and determined that within SHANK3 the region containing the highly polymorphic locus D22S163 and its flanking repeats constitutes a tight deletion hot spot. D22S163 contains a mini-satellite repeat with an 88-base pair period (chr22: 4940821-49411525) and moderate size variability. Bonaglia et al concluded that the direct repeat within SHANK3 may form slipped (hairpin) structures and has a strong potential for forming tetraplexes, suggesting a possible mechanism for the occurrence of a common break point.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
The author 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.
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
