Phelan-McDermid Syndrome – 22q13 deletion – Page Two
Posted October 30, 2008on:
Genotype-Phenotype CorrelationsAlthough 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.For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.Evaluations at Initial DiagnosisGenetic 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.Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.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.firstname.lastname@example.orgChromosome 22 Central
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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].
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 shortarm 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).
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 ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
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.
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 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 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
606230 PROLINE-RICH SYNAPSE-ASSOCIATED PROTEIN 2
606232 CHROMOSOME 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.
Phelan-McDermid Syndrome/22q13 Deletion Syndrome Foundation
250 East Broadway
Maryville, TN 37804
Pediatrics, August, 2004