Phelan-McDermid Syndrome – 22q13 deletion – Page One
Posted October 30, 2008on:
Phelan-McDermid Syndrome – 22q13 deletion – Page One
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:
Normal to accelerated growth
Absent to severely delayed speech
Global developmental delay
Normal head circumference
Minor dysmorphic facial features including:
Wide nasal bridge
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.
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
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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
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.
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
Increased tolerance to pain
Prominent or large ears
Full or puffy cheeks
Full or puffy eyelids
Wide nasal bridge
Decreased perspiration with tendency to overheat
Malocclusion/wide spaced teeth
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 tocommunicate 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. Thephenotypically 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].