PCR in diagnosing ASD

• A child who has a triplication of four genes in the WBSCR plus a duplication of the remaining genes in the WBSCR has been reported [Zarate et al 2014].
• A large family including 11 individuals in three generations who had a triplication of ELN and LIMK1 has been identified [Guemann et al 2015]; ten of the 11 had a supravalvar aortic aneurysm.

Penetrance

Penetrance is complete and is the same for males and females. Expression of phenotypic features is variable.

Prevalence

Prevalence has been estimated at 1:7,500-1:20,000 [Van der Aa et al 2009, Velleman & Mervis 2011].

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Genetically Related Disorders

Williams syndrome (WS) is caused by deletion of the contiguous genes in the WBSCR. WS is characterized by dysmorphic facial features, intellectual disability, elastin arteriopathy (most commonly supravalvar aortic stenosis), hypercalcemia, connective tissue abnormalities, and a specific cognitive and behavioral profile. In contrast to the 7q11.23 duplication syndrome, which is associated with social anxiety disorder, selective mutism, and separation anxiety, WS is characterized by overly friendly, socially disinhibited behavior.

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Differential Diagnosis

The 7q11.23 duplication syndrome should be distinguished from other syndromes that include developmental delay, macrocephaly, hypotonia, distinctive craniofacies, and behavior problems. Examples include fragile X syndrome andSotos syndrome.

The 7q11.23 duplication syndrome should be added to the list of syndromes that are associated with aortic dilation:Marfan syndrome, Loeys-Dietz syndrome, Ehlers-Danlos syndromes (see Ehlers-Danlos Syndrome, Classic Type,Ehlers-Danlos Syndrome, Hypermobility Type, Ehlers-Danlos Syndrome, Kyphoscoliotic Form, and EDS vascular type), and familial thoracic aneurysm. The distinctive facial features and developmental and behavioral phenotype of the 7q11.23 duplication syndrome distinguish it from these conditions.

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Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with the 7q11.23 duplication syndrome and to guide medical management, the following evaluations are recommended:

• Complete physical and neurologic examination
• Plotting of growth parameters. Individuals with short stature should be evaluated for growth hormone deficiency.
• Consideration of neuroimaging especially in individuals with macrocephaly and/or abnormal neurologic examination: brain MRI to evaluate for ventriculomegaly/hydrocephalus, cerebellar vermis hypoplasia, and/or white matter abnormalities. Note: Because sedation is likely to be necessary, this should be considered carefully and may not be necessary in every patient.
• Cardiology evaluation
• Evaluation by a cardiologist
• Echocardiogram, including measurement of the aortic root and ascending aorta with computation of Zscores to monitor for progressive aortic dilation
• Genitourinary system evaluation
• Ultrasound examination of the kidneys
• Physical examination of males for cryptorchidism
• In females with unilateral renal agenesis, evaluation of müllerian structures
• Baseline ophthalmologic evaluation
• Baseline audiologic evaluation
• Clinical genetics evaluation/consultation for individualized assessment/recommendations and discussion of clinical manifestations, natural history, and recurrence risks
• Multidisciplinary developmental evaluation
• Speech and language (preferably by an examiner who is experienced in evaluating children for childhood apraxia of speech)
• Physical therapy
• Occupational therapy (including assessment for sensory integration difficulties)
• Social skills
• Intellectual abilities
• Adaptive behavior
• Vocational skills
• Assessment of behavior (preferably by a licensed psychologist) including:
• Anxiety (especially social anxiety disorder, selective mutism, separation anxiety, generalized anxiety disorder)
• Attention problems
• Oppositional behavior/aggression. If indicated, refer for a functional behavioral assessment, preferably by a board-certified behavior analyst.
• Autism spectrum disorder screening. If indicated, refer for gold-standard autism assessment (ADOS-2 [Lord et al 2012] and ADI-R [Lord et al 1994], plus clinical judgment) preferably by an examiner who is experienced with individuals who have social anxiety disorder.

Treatment of Manifestations

Developmental disabilities should be addressed by early intervention programs, special education programs, and vocational training. Recommendations include speech/language therapy, physical therapy, and occupational therapy. Hippotherapy should be considered, especially for children who have difficulty with balance and children who have an autism spectrum disorder.

Psychological evaluation, psychiatric evaluation, and speech-language evaluation should guide therapy for the individual.

• Childhood apraxia of speech. Intensive speech-language therapy (preferably by a speech-language pathologist who has specific training in treating this disorder) is recommended for children who have childhood apraxia of speech or signs of this disorder, in order to maximize effective oral communication and prevent or limit later language impairment and/or reading disorder.
• Anxiety/selective mutism. Cognitive-behavioral intervention for anxiety (preferably by a licensed clinical psychologist) is recommended for those with social anxiety or selective mutism. Educators should be made aware of the signs and symptoms of social anxiety disorder and selective mutism and the appropriate educational interventions and support for children with these disorders. Psychotropic medication may also be indicated. For children who have selective mutism, co-treatment by the speech-language therapist and the psychologist should be strongly considered.
• Autism spectrum disorder (ASD). Applied behavior analysis (preferably conducted by a board-certified behavior analyst) or other empirically supported intervention for ASD is recommended for those with co-morbid ASD to address social communication difficulties.
• Attention deficit hyperactivity disorder (ADHD). Behavioral modifications in the home and school settings are recommended. Psychotropic medication may also be indicated.
• Aggression. When shown, physical aggression should be assessed and treated immediately to prevent development of a long-standing pattern of aggression. Applied behavior analysis intervention is recommended. Psychotropic medication may also be indicated.
• Oppositionality. Behavioral interventions are recommended to address oppositionality, with an emphasis on reinforcing positive behaviors. Psychotropic medication may also be indicated.

Specific medical problems are treated in the following ways:

• Hydrocephalus as needed with ventriculo-peritoneal shunting
• Aortic dilation with beta blocker therapy in some affected individuals. Some with severe aortic dilation have required surgery [Zarate et al 2014, Morris et al 2015, Parrott et al 2015].
• Strabismus in the usual manner
• Recurrent otitis media in the usual manner
• Poor feeding in infants. Feeding therapy
• Constipation. Aggressive management at all ages to prevent encopresis and impaction
• Growth hormone deficiency. Human growth hormone replacement therapy
• Club feet. Casting

Surveillance

Table 2.

Surveillance for Individuals with the 7q11.23 Duplication Syndrome

Interval/Age	Test/Measurement
Infancy	Measurement of head circumference at every visit or at least every 3 months Hearing evaluation
Annual	Medical evaluation Vision screening to monitor for refractive errors & strabismus Cardiology evaluation Echocardiogram to measure the aortic root & ascending aorta with calculation of Z scores to monitor for progressive aortic dilation. Significant dilation may require more frequent monitoring and/or CT angiography or magnetic resonance angiography. Occupational & physical therapy assessment (through age 6 years) Speech & language assessment (through age 6 years; annual assessment beyond age 6 years if moderate or severe speech/language disorder is present) Behavior assessment (attention, anxiety, opposition, aggression)
Every 3 years	Assessment of intellectual abilities & academic achievement
Adolescents/adults	Genetic counseling

Based on Mervis et al [2015], Morris et al [2015], and Parrott et al [2015]

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

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.

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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

The 7q11.23 duplication syndrome is transmitted in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• About 27% of probands have an affected parent [Morris et al 2015].
• Genetic counseling and evaluation of the parents by genomic testing that will detect the 7q11.23 duplicationpresent in the proband is recommended.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the parents:

• If the 7q11.23 duplication identified in the proband is not identified in one of the parents, the risk to sibs is low (<1%) but greater than that of the general population because of the possibility of parental germline mosaicism for the duplication [Bakker et al 1987].
• If one of the parents has the 7q11.23 duplication, the risk to each sib of inheriting the duplication is 50%. However, it is not possible to reliably predict the phenotype of the individual.

Offspring of a proband. Offspring of an individual with 7q11.23 duplication syndrome have a 50% chance of inheriting the duplication.

Other family members. The risk to other family members depends on the genetic status of the proband’s parents: if a parent has the 7q11.23 duplication, his or her family members may also have the duplication.

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. Similarly, decisions about testing to determine the genetic status of at-risk family members are best made before pregnancy.

It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with 7q11.2