Phelan-McDermid Syndrome - 22q13 deletion

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Phelan-McDermid Syndrome - 22q13 deletion

Postby patoco » Sat Jun 10, 2006 2:40 am

Phelan-McDermid Syndrome - 22q13 deletion

Our Home Page: Lymphedema People


Key Words: Trisomy 22, 22ql3 deletion, lymphedema

In our section titled Syndrome of Lymphatic Dysplaysia, we cover a condition known as Trisomy 22, Trisomy Mosiac

In our committment to providing an extensive resource base for all conditions that have relate in any manner to lymphedema, I wanted to share with our members an visitors a related condition that also has lymphedema as a complication. It too is associated with Chromosome 22.


Phelan-McDermid Syndrome

National Organization for Rare Disorders


It is possible that the main title of the report Phelan-McDermid Syndrome is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.


Deletion 22q13 Syndrome
Disorder Subdivisions
General Discussion

Phelan-McDermid syndrome is a rare chromosomal disorder in which a portion of the long arm (q) of chromosome 22 is missing (deleted or monosomic). Although the range and severity of symptoms may vary, Phelan-McDermid syndrome is generally thought to be characterized by low muscle tone, normal to accelerated growth, absent to severely delayed speech, moderate to profound mental retardation, and minor dysmorphic features. A rare number of cases with much smaller (submicroscopic) deletions of 22q13 are reported to result in mild developmental delay Current research indicates that the inability of the gene involved to produce sufficient protein for normal functioning (haploinsufficiency) may be responsible for most of the neurologic symptoms (developmental delay and absent speech) associated with this disorder.

Chromosome Deletion Outreach, Inc.
P.O. Box 724
Boca Raton, FL 33429-0724
Tel: 8882366880



UNIQUE - Rare Chromosome Disorder Support Group
P.O. Box 2189
Surrey, Intl CR3 5GN
United Kingdom
Tel: 4401883 330766
Fax: 4401883 330766



Chromosome 22 Central
237 Kent Avenue
Ontario, P4N 3C2
Tel: 705-268-3099
Fax: 705-267-3374


For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc. ® (NORD). A copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see

The information provided in this report is not intended for diagnostic purposes. It is provided for informational purposes only. NORD recommends that affected individuals seek the advice or counsel of their own personal physicians.

It is possible that the title of this topic is not the name you selected. Please check the Synonyms listing to find the alternate name(s) and Disorder Subdivision(s) covered by this report.

This disease entry is based upon medical information available through the date at the end of the topic. Since NORD's resources are limited, it is not possible to keep every entry in the Rare Disease Database completely current and accurate. Please check with the agencies listed in the Resources section for the most current information about this disorder.

For additional information and assistance about rare disorders, please contact the National Organization for Rare Disorders at P.O. Box 1968, Danbury, CT 06813-1968; phone (203) 744-0100; web site or email

Last Updated: 1/26/2005
Copyright 2004, 2005 National Organization for Rare Disorders, Inc.


Findings in patients with 22q13 Deletion have included (in no particular order):

developmental delay
speech difficulties
Epicanthal folds
high arched palate
mild dilitation of cerebral ventricles
dysplastic ears
delay in gross motor milestones
normal or accelerated growth
mild facial dysmorphic features
downslanting palpebral fisuures
simian crease


Support for Chromosome 22 Related Disorders



Randy Riddle
5501 Vista Sandia NE
Albuquerque, NM 87111
telephone: 505-323-9574


For more information:

Mary C. (Katy) Phelan, Ph.D.
Molecular Pathology Laboratory Network
250 East Broadway
Maryville, TN 37804
Phone: 1-800-932-2943
FAX: 1-865-380-9191





Additional Information



Further delineation of the 22q13 deletion syndrome.

Lindquist SG, Kirchhoff M, Lundsteen C, Pedersen W, Erichsen G, Kristensen K, Lillquist K, Smedegaard HH, Skov L, Tommerup N, Brondum-Nielsen K.

The John F. Kennedy Institute, Glostrup, Denmark.

A chromosomal deletion syndrome associated with a 22q13 microdeletion has previously been reported in approximately 75 children. We report six cases from Denmark with a deletion of 22q13. One was cytogenetically visible by conventional karyotyping, one was diagnosed by high resolution karyotyping after the demonstration of low arylsulfatase A activity. Two were diagnosed by high resolution CGH analysis, one was diagnosed by multisubtelomeric FISH analysis and one was diagnosed serendipitously as lack of the control signal in a FISH analysis for 22q11 deletion. One of the cases was a mosaic with 16% of cells showing two signals. The phenotype of the children included: generalized developmental delay, compromised language development, hypotonia, normal or accelerated growth and minor facial dysmorphism. Other features were partial agenesis of the corpus callosum, bilateral ureteropelvic stricture, gastroesophageal reflux and hearing loss. One case had a different phenotype, and showed a deletion as well as a duplication. The extent of the deletion was studied by quantitative PCR analysis of a number of DNA markers in the 22q13 region. The deletions varied in size, extending from 4.0 to 9.0 Mb. The clinical phenotype seemed rather similar although some specific features might be attributable to differences in deletions.

PMID: 15770125 [PubMed - in process]


Cryptic subtelomeric translocations in the 22q13 deletion syndrome.

Praphanphoj V, Goodman BK, Thomas GH, Raymond GV.

Department of Pediatrics, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA.

Cryptic subtelomeric rearrangements are suspected to underlie a substantial portion of terminal chromosomal deletions. We have previously described two children, one with an unbalanced subtelomeric rearrangement resulting in deletion of 22q13-->qter and duplication of 1qter, and a second with an apparently simple 22q13-->qter deletion. We have examined two additional patients with deletions of 22q13-->qter. In one of the new patients presented here, clinical findings were suggestive of the 22q13 deletion syndrome and FISH for 22qter was requested. Chromosome studies suggested an abnormality involving the telomere of one 22q (46,XX,?add(22)(q13. 3)). FISH using Oncor D22S39 and Vysis ARSA probes confirmed a terminal deletion. A multi-telomere FISH assay showed a signal from 19qter on the deleted chromosome 22. Results were confirmed with 19qtel and 22qtel specific probes. The patient is therefore trisomic for 19qter and monosomic for 22qter. The patient's mother was found to have a translocation (19;22)(q13.42;q13.31). We also re-examined chromosomes from two patients previously diagnosed with 22q deletions who were not known to have a rearrangement using the multi-telomere assay. One of these patients was found to have a derivative chromosome 22 (der(22)t(6;22)(p25;q13)). No evidence of rearrangement was detected in the other patient. Thus we have found the 22q13 deletion to be associated with a translocation in three of four patients. This report illustrates the usefulness of examining patients with hypotonia, severe language delay, and mild facial dysmorphism for this syndrome and suggests that most of these deletions may be unbalanced subtelomeric rearrangements.

Publication Types:
Case Reports

PMID: 10633138 [PubMed - indexed for MEDLINE]


22q13 deletion syndrome

Phelan MC, Rogers RC, Saul RA, Stapleton GA, Sweet K, McDermid H, Shaw SR, Claytor J, Willis J, Kelly DP.

Greenwood Genetic Center, Greenwood, South Carolina,

We have recently collected clinical information on 37 individuals with deletion of 22q13 and compared the features of these individuals with 24 previously reported cases. The features most frequently associated with this deletion are global developmental delay, generalized hypotonia, absent or severely delayed speech, and normal to advanced growth. Minor anomalies include dolicocephaly, abnormal ears, ptosis, dysplastic toenails, and relatively large hands. As with many terminal deletions involving pale G-band regions, the deletion can be extremely subtle and can go undetected on routine cytogenetic analysis. In fact, 32% of the individuals in our study had previous chromosome analyses that failed to detect the deletion. Eight of 37 individuals had deletion of 22q13 secondary to an unbalanced chromosome translocation. In the newborn, this deletion should be considered in cases of hypotonia for which other common causes have been excluded. In the older child, this syndrome should be suspected in individuals with normal growth, profound developmental delay, absent or delayed speech, and minor dysmorphic features. We recommend high-resolution chromosome analysis and fluorescence in situ hybridization studies, or molecular analysis to exclude this diagnosis. Copyright 2001 Wiley-Liss, Inc.

PMID: 11391650 [PubMed - indexed for MEDLINE] ... query_hl=6


Pubmed links page for 22q13 - PHELAN-McDERMID SYNDROME ... d=15770125


22q13.3 Deletion Syndrome

Author: Katy Phelan, PhD, FACMG

Posted: 11 May 2005


Disease characteristics. Deletion 22q13.3 is a microdeletion syndrome in which the affected individuals have neonatal hypotonia, normal to accelerated growth, absent to severely delayed speech, global developmental delay, and minor dysmorphic facial features. Other features include large, fleshy hands, dysplastic toenails, sacral dimple, and decreased perspiration. Behavior characteristics include mouthing or chewing non-food items, increased tolerance to pain, and autistic-like affect.

Diagnosis/testing. The diagnosis of 22q13.3 syndrome is confirmed by demonstration of a deletion or disruption of 22q13.3; approximately 75% of individuals have "simple" deletions, either terminal or interstitial, and about 25% have deletions resulting from an unbalanced translocation or other structural rearrangement. Many 22q13.3 simple deletions can be detected by routine chromosome analysis at the 500-550 band level (and confirmed by FISH studies), but high-resolution analysis may not detect subtle deletions. The minimum region of overlap of deletions leading to 22q13.3 syndrome is a 100-kb region delineated proximally by cosmid n85a3 and distally by cosmid n1g3. The cosmid clone n85a3 is distal to the ARSA locus and overlaps the 3' half of SHANK3 (PROSAP2), the candidate gene for neurological deficits in 22q13.3 syndrome. Commercially available FISH probes for detecting deletion of 22q13 include the ARSA probe and subtelomere probes; the combined use of these probes detects nearly 100% of deletions resulting in 22q13.3 deletion syndrome.

Management. Management of 22q13.3 deletion syndrome includes neurologic consultation for neonatal hypotonia; oral-motor therapy to alleviate chewing and swallowing problems and orthodontic therapy for malocclusion; medication to reduce hyperactivity, anxiety, and self-stimulatory behavior; antiepileptic drugs for individuals with seizures; treatment with typanostomy tubes for recurrent ear infection; treatment for visual impairment and cardiac, renal, respiratory, immunologic, and other medical issues by standard protocols; removal of ingrown toenails to prevent infection; pressure stockings to treat lymphedema; physical and occupational therapies and exercise programs to improve coordination and strengthen muscles; augmentation of communication with sign language, picture exchange systems, and computer touch screens; and treatment of gastroesophageal reflux by thickening of formula, smaller feedings, and positioning in infants and avoidance of spicy or irritating foods in older children. Individuals should avoid exposure to high temperatures and extended periods in the sun as they do not perspire normally.

Genetic counseling. 22q13.3 deletion syndrome can be the result of a de novo chromosome deletion or of an inherited chromosome abnormality. Most probands have a de novo chromosome deletion; familial chromosome rearrangements have been identified in 15-20% of probands. Prenatal testing by chromosome analysis and/or FISH for pregnancies at increased risk is available clinically.


Deletion 22q13.3 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:
Full brow
Flat midface
Puffy eyelids
Long eyelashes
Wide nasal bridge
Puffy cheeks
Pointed chin
Large or prominent ears

Other features that raise suspicion of 22q13.3 include relatively large and fleshy hands, dysplastic toenails, sacral dimple, and decreased perspiration. Behavior characteristics include mouthing or chewing non-food items, increased tolerance to pain, and autistic-like affect.


Cytogenetic Testing
The diagnosis of 22q13.3 syndrome is confirmed by demonstration of a deletion or disruption of 22q13.3.

Approximately 75% of individuals have "simple" deletions which are either:

A "terminal" deletion: A single break in the chromosome arm with loss of the segment distal to the break
An "interstitial" deletion: Two breaks within the same chromosome arm and loss of the intervening segment

Approximately 25% of individuals 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 many 22q13.3 simple deletions can be detected by routine chromosome analysis (500-550 band level), even high resolution analysis (>550 bands) may fail to detect subtle deletions. In over 30% of affected individuals, two or more G-banded chromosome studies are performed to detect this deletion [Phelan, personal observation]. Indications that led to repeat chromosome studies that revealed deletion 22q13 included:

Postnatal findings of hypotonia, failure to thrive, and/or dysmorphic features in infants who had had normal prenatal cytogenetic studies.
Band resolution of the first study inadequate to detect subtle rearrangements.
High-resolution 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 sub-telomere FISH studies.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by at least one US CLIA-certified laboratory or a clinical laboratory outside the US. GeneTests does not independently verify information provided by laboratories and does not warrant any aspect of a laboratory's work; listing in GeneTests does not imply that laboratories are in compliance with accreditation, licensure, or patent laws. Clinicians must communicate directly with the laboratories to verify information. —ED.

Gene. The minimum region of overlap of deletions leading to 22q13.3 syndrome is a 100-kb region delineated proximally by cosmid n85a3 and distally by cosmid n1g3. The cosmid clone n85a3 is distal to the ARSA locus and overlaps the 3' half of SHANK3 (PROSAP2), the candidate gene for the neurological deficits (developmental delay and absent speech) in 22q13.3 syndrome.

Molecular genetic testing: Clinical uses

Prenatal diagnosis

Molecular genetic testing: Clinical method

Fluorescence in situ hybridization (FISH). The commercially available FISH probes for detecting deletion of 22q13 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 the majority of individuals with deletion 22q13.3, 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 [Flint et al 1995].

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 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.

Molecular genetic testing: Research. Although polymorphisms exist within SHANK3, no clinically significant mutations have been identified [McDermid, personal communication].

Table 1. Molecular Genetic Testing Used in 22q13.3 Deletion Syndrome

Test Method Mutations Detected Mutation Detection Rate Test Availability

FISH Deletion 22q13.3 ~100% when both ARSA and subtelmorere 22q probes are used Clinical

Testing Strategy for a Proband

Cytogenetic analysis at or above the 550-band level should be performed to determine if an obvious cytogenetic abnormality is present.

If deletion 22q13.3 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 syndrome is strong.

Genetically Related Disorders
No other known phenotypes are associated with deletion 22q13.3.

Clinical Description

Natural History

Males and females are equally affected with no apparent parent-of-origin effect.

Table 2. Features of Deletion 22q13.3 Syndrome 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
Increased tolerance 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
GE reflux
Malocclusion/wide spaced teeth
Epicanthal folds
Long philtrum
High arched palate


Hypotonia. Newborns with deletion 22q13.3 have generalized hypotonia that may be associated with weak cry, poor head control, and feeding difficulties leading to failure to thrive. Head size is typically within normal range with microcephaly reported in fewer than 5% of individuals.

Developmental delay. Most affected individuals have moderate-to-profound developmental delay, although a few individuals with small subtelomeric deletions are reported to have mild delays. Major milestones are delayed: the average age for rolling over is about eight months, for crawling about 16 months, and for walking about 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 about four years of age many children lose their ability to speak. With intense occupational, speech, and physical therapy they may regain speech and increase their vocabularies. Although speech remains impaired throughout life, individuals can learn to communicate with the aid of aggressive therapy and communication training. Receptive communications 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.

Individuals with 22q13.3 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, over 80% of affected individuals have normal hearing.

Growth manifestations. Intrauterine growth in deletion 22q13.3 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 so that children appear tall and thin. The hands appear large and fleshy. Toenails are often dysplastic, thin, and flaky and tend to become ingrown. Fingernails are usually normal.

Atypical 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, increased tolerance to pain, and sleep disturbance. Affected individuals may have difficulty falling asleep and staying asleep, although sleep apnea is not a problem. 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. Individuals may suffer ear infections, GE reflux, increased intracranial pressure, or other painful medical conditions without indicating discomfort. Aggressive behavior such as biting, hair pulling, or pinching is seen in about 25% of affected individuals.

Vision impairment. 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 about 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.

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

Gastrointestional findings. Gastroesophageal reflux is seen in about 30% and cyclic vomiting in about 25% of individuals.

Dental malocclusion. 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 manifestations. Arachnoid cysts occur in about 15% of individuals compared to about 1% in the general population. Other neurological problems include reduced myelination, frontal lobe hypoplasia, agenesis of the corpus callosum, ventriculomegaly, and seizures. 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 deletion 22q13.3.

Lymphedema. Both lymphedema and recurrent cellulitis have been observed in about 10% of individuals, typically becoming problematic during the teenage and adult years.

Fertility. No individuals diagnosed with 22q13.3 syndrome have been known to reproduce. Nonetheless, no fertility studies have been performed that would exclude the possibility of reproduction. Females with deletion 22q13.3 go through puberty and begin their menstrual periods at the normal age.

Life span impact. 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 syndrome reflects the difficulty in establishing this diagnosis prior to the advent of high-resolution chromosome analysis and FISH.

Mosaic deletion 22q13.3. The 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].

Genotype-Phenotype Correlations

Although the size of the deletion in 22q13.3 syndrome ranges from 100 kb to more than 9 Mb, Wilson et al (2003) found that deletion size showed little correlation with the clinical features of this disorder. Their analysis of 56 individuals with deletions ranging from 130 kb to more than 9 Mb revealed that all individuals showed the characteristic neurological features of developmental delay and absent or delayed speech. While all other individuals in the study showed moderate-to-profound mental retardation, the individual with the smallest (130 kb) deletion exhibited milder delays, less severe speech delay, and few of the typical dysmorphic features [Flint et al 1995 , Wong et al 1997]. In a report by Anderlid et al (2002), a 30-year-old woman with a 100-kb deletion of 22q13 also showed mild mental retardation and speech delay with minor dysmorphic features consistent with 22q13.3 syndrome. With increasing age, she experienced a decline in speech, onset of abnormal behavior with autistic features, and deterioration of daily living skills.


Features of 22q13.3 syndrome are apparent in all individuals with deletion 22q13.3 in a significant proportion of cells.


No true synonyms exist for 22q13.3 deletion, but some have used the term Phelan-McDermid syndrome after the individuals who originally described the disorder.


The prevalence of deletion 22q13.3 is unknown. Deletion 22q13.3 remains underdiagnosed due to the failure to detect the deletion of chromosome 22 in routine chromosome studies and the failure 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].

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

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 ring chromosome 22, loss of short arm and satellite material is of no clinical significance. In individuals with ring chromosome 22, 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 syndrome: global developmental delay, severe speech deficit, hypotonia, and minor dysmorphic features. Unlike 22q13.3 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 syndrome. Many families with ring chromosome 22 are members of the Phelan-McDermid Syndrome/Deletion 22q13.3 Syndrome Foundation.

Other disorders. 22q13.3 syndrome should be suspected in any infant with neonatal hypotonia of unknown etiology. As in Prader-Willi syndrome , neonatal hypotonia and feeding difficulty can be the earliest presenting symptoms. Any neonate referred for chromosome analysis, FISH, or molecular studies to rule out Prader-Willi syndrome should also be tested for 22q13.3 syndrome.

The diagnosis of 22q13.3 syndrome should also be suspected in individuals with "atypical" Angelman syndrome . Features common to both 22q13.3 syndrome and Angelman syndrome include global developmental delay, absent speech, unsteady gait, and minor dysmorphic features. De Vries et al (2002) evaluated 44 individuals with features of Angelman syndrome but without the characteristic chromosome 15 abnormality and found no evidence of deletion 22q13.3. In the study group, 73% of individuals had severe developmental delay, 77% had serious speech impairment, and almost 50% had microcephaly. The failure to find deletion of 22q13.3 was not surprising since the features of the study group were not highly suggestive of 22q13.3 syndrome, in which global developmental delay and absent or severely delayed speech are present in over 95% of individuals and microcephaly is found in fewer than 10%.

Other chromosomal and non-chromosomal diagnoses have been applied to individuals prior to the diagnosis of 22q13.3 syndrome. These diagnoses include velocardiofacial syndrome (see 22q11.2 Deletion Syndrome), Williams syndrome , trichorhinophalangeal syndrome, Smith-Magenis syndrome , fragile X syndrome , F-G syndrome, cerebral palsy, spastic paraplegia (see Hereditary Spastic Paraplegia Overview), and autism (See Autism Overview).


Evaluations at Initial Diagnosis

Upon initial diagnosis, the following evaluations should be performed to identify findings of 22q13.3 syndrome:

A complete physical and neurological examination
Determination of head circumference, height, weight, and other anthropometric measurements

A family history to determine if any relatives are similarly affected

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 audiological examination

A medical genetics consultation to discuss clinical manifestations, prognosis, natural history, therapies, and recurrence risks

Treatment of Manifestations

Neurologic consultation for neonatal hypotonia

Evaluation of feeding problems (usually consisting of swallowing or sucking difficulties) by a feeding specialist and/or occupational therapist and speech pathologist

Evaluation by a child development specialist if autistic-like features are present. Medication to reduce hyperactivity, anxiety, and self-stimulatory behavior can be helpful in some individuals.

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.

Ocular 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.

Regular dental evaluations, routine brushing, and fluoride. Oral-motor therapy may alleviate chewing and swallowing problems. A pediatric orthodontist should be consulted to monitor malocclusion and determine if orthodontic therapy is required.

A sleep study to evaluate for sleep apnea if sleep disturbance is present. Sleep apnea should be treated by routine protocols. If sleep apnea is not the cause of sleep disturbance, a bedtime routine to calm and soothe the child should be established.

Treatment with typanostomy tubes for recurrent ear infections. If hearing deficits are suspected because of recurrent ear infections and lack of expressive speech, hearing should be evaluated by a specialist who is experienced in testing severely delayed children. If hearing is impaired, management with hearing aids should be considered.

Treatment for cardiac, renal, respiratory, immunologic and other medical issues by standard protocols

Surgical removal of ingrown toenails to prevent infection
Use of pressure stockings, elevating the foot of the bed for treatment of lymphedema

Early intervention programs, intensive physical and occupational therapies, adaptive exercise and sports programs, and other therapies to improve coordination and strengthen muscles
Walkers or other assistive devices to aid in walking by ameliorating balance problems

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.

Nutritional assessment for individuals with persistent symptoms of gastroesophageal reflux (GER) or cyclic vomiting. In infants, GER may be treated by thickening formula, smaller feedings, and positioning. Older children should avoid spicy food and food than may cause irritation and should refrain 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.

Intravenous fluids to prevent dehydration in individuals with recurrent vomiting. A neurological evaluation is indicated 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 in monitoring children, particularly those who can walk or run independently, by the parents or caregivers; children may be impulsive and are not aware of the consequences of their behavior.


Ongoing pediatric care with regular immunizations
Evaluation by a neurologist for changes in behavior or regression of skills

Agents/Circumstances to Avoid

Exposure to high temperatures and extended periods in the sun should be avoided. Individuals with deletion 22q13.3 do not perspire normally and tend to overheat easily.

Therapies Under Investigation
Search for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

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

Mode of Inheritance

22q13.3 deletion syndrome can be the result of a de novo or of an inherited chromosome abnormality.

Risk to Family Members
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 to 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].
About 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 deletion 22q13.3.
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 is dependent upon the specific chromosome rearrangement and the possibility of other variables.
Because all phenotypically normal parents of probands have not 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 germline mosaicism has not been reported in deletion 22q13.3, although the possibility cannot be excluded.
Offspring of a proband. No individuals diagnosed with 22q13.3 syndrome have been known to reproduce.

Other family members. The risk to other family members depends upon 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.

Carrier Detection
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.

Related Genetic Counseling Issues
Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

Prenatal Testing
Prenatal diagnosis for pregnancies at increased risk is possible by chromosome analysis and/or FISH of fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or by chorionic villus sampling (CVS) at about 10-12 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.

Molecular Genetics

Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.

Molecular Genetics of 22q13.3 Deletion Syndrome Gene Symbol

Chromosomal Locus Protein Name
Unknown 22q13.3 Unknown

Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.

OMIM Entries for 22q13.3 Deletion Syndrome


Molecular Genetic Pathogenesis

The minimum region of overlap of deletions leading to 22q13.3 syndrome is a 100-kb region delineated proximally by cosmid n85a3 and distally by cosmid n1g3. The cosmid clone n85a3 is distal to the ARSA locus and overlaps the 3' half of SHANK3 (PROSAP2), the candidate gene for the neurological deficits (developmental delay and absent speech) in 22q13.3 syndrome [Anderlid et al 2002]. SHANK3 belongs to a family of proteins that interacts with receptors of the post-synaptic membrane. These multidomain proteins are important scaffolding molecules in the post-synaptic density (PSD) and function to receive and integrate synaptic signals and transduce them into post-synaptic 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]. SHANK3 is plausible as the candidate gene in 22q13.3 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 excitatory synapses [Luciani et al 2003 , Wilson et al 2003]. 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 a patient with the phenotype of 22q13.3 deletion syndrome.


GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

Phelan-McDermid Syndrome/22q13 Deletion Syndrome Foundation
250 East Broadway
Maryville, TN 37804
Phone: 800-932-2943
Fax: 865-380-9191


Chromosome 22 Central
237 Kent Avenue
Timmins, ON
Canada P4N 3C2
Phone: 705-268-3099


Chromosome Deletion Outreach, Inc
PO Box 724
Boca Raton, FL 33429-0724
Phone: 888-CDO-6880 (888-236-6680); 561-395-4252 (family helpline)


National Information Center for Children and Youth with Disabilities (NICHCY)
P.O Box 1492
Washington, CD 20013
Phone: 800-695-0285

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