22q13 deletion syndrome

22q13 deletion syndrome
Specialty	Genetics

Phelan-McDermid syndrome (PMS), also called 22q13 deletion syndrome, is a rare genetic condition characterized by global developmental delay, intellectual disability (ID), absent or delayed speech, autism spectrum disorder (ASD), hypotonia and mild dysmorphic features.   Affected individuals present in addition with an array of medical, neurological and behavioral symptoms (tables 1 and 2)^,.  The core clinical and neurobehavioral symptoms in PMS syndrome are caused by the loss of one functional copy of the SHANK3 gene (haploinsufficiency)¹, which is located in the distal segment of the long arm of chromosome 22 (figure 1).   The SHANK3 gene encodes a protein that is critical for neuronal communication and synapse formation.    About 80% of cases result from a spontaneous, or de novo mutation, and is not inherited from parents.

History

The first case of PMS was described in 1985 by Watt et al., who described a 14 year old boy with severe intellectual disability, mild dysmorphic features and absent speech, which was associated with terminal loss the distal arm of chromosome 22(9).  In 1988, Phelan et al. described a similar clinical presentation associated with a de novo deletion in 22q13.3(4).  Subsequent cases where described in the following years with a similar clinical presentation.  Phelan et al (2001)(4), compared 37 subjects with 22q13 deletions with features of 24 cases described in the literature finding that the most common features were global developmental delay, absent or delayed speech and hypotonia.  In 2001, Bonaglia et al.(10), described a case that associated the 22q.13 deletion syndrome with a disruption of the SHANK3 gene (also called ProSAP2).  The following year, Anderlid et al. (2002)(11), refined the area in 22q13 presumably responsible for the common phenotypic presentation of the syndrome to a 100kb  in 22q13.3 (image).  Out of the three genes affected, SHANK3 was identified as the critical gene due to its expression pattern and function.  Wilson et al. (2003)(12) evaluated 56 patients with the  clinical presentation of PMS, all of whom had a functional loss of one copy of the SHANK3 gene, further confirming the role of SHANK3 in the major neuropsychiatric manifestations of the syndrome.  Since then multiple other studies have reported similar findings with smaller deletions of the region or mutations of the gene(13).

Epidemiology

The true prevalence of PMS has not been determined. More than 1200 people have been identified worldwide according the Phelan-McDermid Syndrome Foundation. However, it is believed to be underdiagnosed due to inadequate genetic testing and lack of specific clinical features. It is known to occur with equal frequency in males and females(7).   Studies using chromosomal microarray for diagnosis indicate that at least 0.5% of cases of ASD can be explained by mutations or deletions in the SHANK3 gene(14). In addition when ASD is associated with ID, SHANK3 mutations or deletions have been found in up to 2% of individuals(15,16).  The rate of SHANK3 insufficiency in ID and ASD is still being determined; however, these findings imply that it is one of the most common single gene causes.

Etiology

The loss of one copy of SHANK3 can result from chromosomal abnormalities in the terminal end of chromosome 22 or from a mutation in SHANK3 leading to a loss of function in the protein.  The SHANK3 gene codes for a protein (SHANK3) that is vital for synaptic formation and plasticity(17,18) (figure 2). It is expressed widely in the brain early in the postnatal period and its expression peaks during synaptic formation and maturation(13).   The protein is found in the hippocampus, the striatum, cerebellar granular cells, olfactory bulb and the thalamic nuclei(13,19).  SHANK proteins are critical for the architectural make-up of the dendritic spines and their expression is essential for cognition and learning(17).  SHANK3 is a scaffolding protein located in the postsynaptic density of excitatory synapses (figure 2)(7,13).  Genetic manipulation of Shank3 in animal model systems leads to changes in the key components of glutamatergic synapse and dendritic spine density.

Chromosomal abnormalities leading to the loss of the terminal arm of chromosome 22 include unbalanced chromosomal translocations, terminal or interstitial deletions involving the 22q13.3 region, a ring chromosome, or other structural changes (figure 3). Terminal deletions account for about 75% of the cases of PMS(7).  Some studies suggest a relationship between deletion size and the extent or severity of certain clinical features, but this has not been well established and remains the focus of clinical research(1,20–24).    

Clinical Description

Affected individuals present with a broad array of medical and behavioral manifestations (tables 1 and 2).  Patients are consistently characterized by global developmental delay, intellectual disability, speech abnormalities, ASD, hypotonia and mild dysmorphic features.    Table 1 summarizes the dysmorphic and medical conditions that have been reported in individuals with PMS.  Table 2 summarize the psychiatric and neurological associated with SHANK3 deficiency and PMS (1,4,21,23–33).  Most of the studies include small samples or relied on parental report or medical record review to collect information, which can account in part for the variability in the presentation of some of the presenting features.  Larger prospective studies are needed to further characterize the disorder genetic. It is likely that as the awareness, of PMS and the role of SHANK3 deficiency in ASD and ID, increases among the medical community more individuals will be identified which will provide a better understanding of the disorder.

Dysmorphic Feature	Percentage (%)	Medical Comorbidities	Percentage (%)
Macrocephaly	7-31	Hypothyroidism	3-6
Microcephaly	11-14	Sleep disturbance	41-46
Dolichocephaly	23-86	Gastroesophageal reflux	42-44
Long eyelashes	43-93	Increased pain threshold	10-88
Bulbous nose	47-80	Constipation/diarrhea	38-41
High arched palate	25-47	Brain imaging abnormalities	7-75
Malocclusion/widely spaced teeth	19	Recurrent upper respiratory infections	8-53
Full cheeks	25	Renal abnormalities	17-26
Pointed chin	22-62	Lymphedema	8-53
Large fleshy hands	33-68	Seizures	14-41
Hypoplastic/dysplastic nails	3-78	Strabismus	6-26
Hyper-extensibility	25-61	Short stature	11-13
Abnormal spine curvature	22	Tall stature/accelerated growth	3-18
Sacral dimple	13-37	Cardiac defects	3-25
Syndactyly of toes 2 and 3	9-48	Precocious or delayed puberty	12

Table 1: Dysmorphic features and medical comorbid conditions that have been reported in individuals with Phelan McDermid Syndrome.

Psychiatric and Neurologic Manifestations	Percentage (%)
Autism Spectrum disorder	>50
Intellectual Disability	>75
Global Developmental Delay	>75
Absent or severely affected speech	>75
Sensory seeking behaviors (mouthing of objects)	>25
Teeth grinding	>25
Hyperactivity and inattention	>50
Stereotypical movements	>50
Hypotonia	>50
Fine and gross motor abnormalities	>90
Poor fine motor coordination	>90
Gait Abnormalities	>90
Visual tracking abnormalities	>85
Seizure disorder	17-41
Brain structural abnormalities	44-100
Sleep problems	>40

Table 2: Psychiatric and Neurologic Manifestations associated with Phelan McDermid Syndrome

1.     Diagnosis and Management

a.       Clinical Genetics and Genetic Testing

Genetic testing is necessary to confirm SHANK3 deficiency and the diagnosis of PMS.  A prototypical terminal deletion of 22q13 can be uncovered by karyotype analysis, but many terminal and interstitial deletions are too small to detect with this method(14,33). Chromosomal microarray should be ordered in children with suspected developmental delays or ASD(34,35).  Most cases will be identified by microarray; however, small variations in the SHANK3 gene might be missed.  If SHANK3 is highly suspected, Sanger or next generation sequencing or autism specific panels that include SHANK3 are warranted.  The falling cost for whole exome sequencing may replace DNA microarray technology for candidate gene evaluation.  Biological parents should be tested with fluorescence in situ hybridization (FISH) to rule out balanced translocations or inversions.  Balanced translocation in a parent increases the risk for recurrence and heritability within families (figure 3)(36).

Clinical genetic evaluations and dysmorphology exams should be done to evaluate growth, pubertal development, dysmorphic features (table 1) and screen for organ defects (table 2).

b.      Cognitive and Behavioral Assessment

All patients should undergo comprehensive developmental, cognitive and behavioral assessments by clinicians with experience in developmental disorders(1). Special emphasis should be placed on evaluating autism spectrum disorder (ASD) symptoms.  Gold standard assessment tools such as the Autism Standard Observation Schedule (ADOS), and the Autism Diagnostic Interview (ADI) are recommended; however, given the limitations of these tests in patients with profound intellectual disability results should be carefully integrated with expert clinical evaluation and results of cognitive testing.  Cognitive evaluation should be tailored for individuals with significant language and developmental delays(33). All patients should be referred for specialized speech/language, occupation and physical therapy evaluations.

c.       Neurological Management

Individuals with PMS should be followed by a pediatric neurologist regularly to monitor motor development, coordination and gait, as well as conditions that might be associated with hypotonia, like neuromuscular scoliosis and feeding problems(1,4,37).   Head circumference should be performed routinely up until 36 months.  Given the high rate of seizure disorders (up to 41% of patients) reported in the literature in patients with PMS and its overall negative impact on development, an overnight video EEG should be considered early to rule out seizure activity.  In addition, a baseline structural brain MRI should be considered to rule out the presence of structural abnormalities(22).

d.      Endocrinology

Growth should be monitored routinely due to reports of short stature and accelerated growth.  In addition, all patients should have baseline assessment of thyroid function(33).  If clinically indicated, nutritional assessments should be contemplated(5,31).

e.       Nephrology

All patients should have a baseline renal and bladder ultrasonography and a voiding cystourethrogram should be considered to rule out structural and functional abnormalities.  Renal abnormalities are reported in up to 38% of patients with PMS(1,38,39). Vesicouretral reflux, hydronephrosis, renal agenesis, dysplasic kidney, polycystic kidney and recurrent urinary tract infections have all been reported in patients with PMS.

f.       Cardiology

Congenital heart defects (CHD) are reported in samples of children with PMS with varying frequency (up to 25%)(29,36).  The most common CHD include tricuspid valve regurgitation, atrial septal defects and patent ductus arteriousus.  Cardiac evaluation, including echocardiography and electrocardiogram, should be performed to evaluate for CHD and cardiac function(33). 

g.      Gastroenterology

Gastrointestinal symptoms are common in individuals with PMS. Gastroesophageal reflux, constipation, diarrhea and cyclic vomiting are frequently described(1,5,40).

Medical Specialty	Assessment Recommended
Primary Care/Development Pediatrics	Careful and routine monitoring
	Hearing Assessment
	Visual Assessment
	Monitoring of height, weight and BMI
	Otolaryngology (ENT)
	Pediatric dentistry
	Physiatrist/physical therapy
Psychiatric and Psychology	Psychiatric evaluation with focus on autism spectrum disorder
	Autism Diagnostic Observation Schedule (ADOS)
	Cognitive or Developmental Assessment
	Speech and Language Evaluation/Therapy
	Adaptive Function Testing
	Educational Assessment
	Occupational Therapy
Neurology	Motor development, coordination and gait monitoring, as well as conditions that might be associated with hypotonia, like neuromuscular scoliosis and feeding problems
	Overnight video EEG
	Structural brain MRI
	Head circumference up to 36 months
Nephrology	Renal and bladder ultrasonography
Cardiology	Echocardiogram
	Electrocardiogram
Endocrinology	Thyroid function
	Nutritional assessment

Table 3: Clinical Assessment Recommendations in Phelan McDermid Syndrome. 

2.     Resources for Families 

1.     Phelan McDermid Foundation: 22q13.org

2.     http://www.shank3gene.org/

3.     Association Française du Syndrome Phelan-McDermid (France): http://22q13.fr

4.     Unique for Phelan McDermid Syndrome (UK):

http://www.rarechromo.org/information/Chromosome%2022/22q13%20deletions%20Phelan%20McDermid%20syndrome%20FTNW.pdf

References

• Bonaglia MC, Giorda R, Mani E, et al. (2006). "Identification of a recurrent breakpoint within the SHANK3 gene in the 22q13.3 deletion syndrome". J. Med. Genet. 43 (10): 822–8. doi:10.1136/jmg.2005.038604. PMC 2563164. PMID 16284256.
• Manning MA, Cassidy SB, Clericuzio C, et al. (2004). "Terminal 22q deletion syndrome: a newly recognized cause of speech and language disability in the autism spectrum". Pediatrics. 114 (2): 451–7. doi:10.1542/peds.114.2.451. PMID 15286229.
• Phelan MC, Rogers RC, Saul RA, et al. (2001). "22q13 deletion syndrome". Am. J. Med. Genet. 101 (2): 91–9. doi:10.1002/1096-8628(20010615)101:2<91::AID-AJMG1340>3.0.CO;2-C. PMID 11391650.
• 22q13.org "22q13 deletion syndrome home"
• Phelan MC, McDermid HE (2011). "The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome)". Mol Syndromol. 2 (1): 186–201. doi:10.1159/000334260. PMC 3366702. PMID 22670140.

External links

• DECIPHER database entry for 22q13 deletion syndrome
• 22q13.org, Support group for families of children affected by the 22q13 deletion syndrome.
• Alliance22 (in French)