7q11.23 Duplication Syndrome

Clinical characteristics.

7q11.23 duplication syndrome is characterized by distinctive facial features; cardiovascular disease (dilation of the ascending aorta in 46%); neurologic abnormalities (hypotonia, adventitious movements, and abnormal gait and station); speech sound disorders including motor speech disorders (childhood apraxia of speech and/or dysarthria) and phonologic disorders; behavior problems including anxiety disorders (especially social anxiety disorder [social phobia]), selective mutism, attention deficit hyperactivity disorder (ADHD), oppositional disorders, physical aggression, and autism spectrum disorders (ASD); delayed motor, speech, and social skills in early childhood; and intellectual ability ranging from intellectual disability (~18%) to borderline intellectual ability (~20%) to low average to high average (the remainder). Approximately 30% of individuals with the 7q11.23 duplication have one or more congenital anomalies.

Diagnosis/testing.

The diagnosis of the 7q11.23 duplication syndrome is established by detection of a recurrent 1.5- to 1.8-Mb heterozygous duplication of the Williams-Beuren syndrome critical region (WBSCR).

Management.

Treatment of manifestations: Aortic dilation is treated with beta blocker therapy and/or surgery as needed. Constipation should be aggressively managed at all ages to prevent encopresis and impaction. Address developmental disabilities, including ASD, through early intervention programs (including speech/language therapy, physical therapy, and occupational therapy), special education programs, and vocational training. Address ASD with applied behavior analytic interventions and other empirically supported psychosocial approaches. Address childhood apraxia of speech (CAS) or manifestations of this disorder with intensive speech/language therapy to maximize effective oral communication and prevent or limit later language impairment and/or reading disorder. Address emotional and behavioral disorders (aggression, social anxiety, selective mutism) with cognitive-behavioral therapy, applied behavior analysis behavior modification intervention, and psychotropic medications as needed.

Surveillance: Routine monitoring of head circumference in infancy. Annual monitoring of aortic diameter (including Z scores in children) and behavior. Annual assessment by occupational and physical therapists and speech and language pathologists until age six years.

Genetic counseling.

The 7q11.23 duplication syndrome is transmitted in an autosomal dominant manner. About 27% of probands have an affected parent. When a parent has the 7q11.23 duplication, the risk to each sib of inheriting the duplication is 50%. If the 7q11.23 duplication identified in the proband is not identified in 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. Prenatal testing for pregnancies at increased risk is possible using genomic testing that will detect the 7q11.23 duplication; however, it is not possible to reliably predict the phenotype based on the results of such testing.

Suggestive Findings

The 7q11.23 duplication syndrome is suspected in individuals with the following findings:

• Distinctive craniofacies. Macrocephaly, brachycephaly, broad forehead, straight eyebrows, deep-set eyes, long eyelashes, broad nasal tip, low insertion of the columella, short philtrum, thin vermilion of the upper lip, high-arched palate, and minor ear anomalies (overfolded helix, lateral protrusion) are observed at all ages (Figure 1). Facial asymmetry and low-hanging columella become more evident/are more common in older children and adults (Figure 2).
• Cardiovascular disease. Dilation of the ascending aorta, found in 46% of individuals with the 7q11.23 duplication syndrome, has been reported at all ages and may be progressive [Morris et al 2015].
• Growth abnormalities
  • Macrocephaly is present in 50% of affected individuals.
  • Although linear growth is in the normal range for most individuals; about 17% (half of whom have growth hormone deficiency) have short stature.
• Neurologic abnormalities include hypotonia, adventitious movements, and abnormalities of gait and station. Children typically have developmental coordination disorder. Abnormalities found on brain MRI include ventriculomegaly, decreased white matter volume, and cerebellar vermis hypoplasia. Seizures are present in 19%.
• Speech sound disorder. Almost all young children have speech delay or disorder. Childhood apraxia of speech or manifestations of this disorder are common. Dysarthria or manifestations of dysarthria, primarily resulting from low muscle tone, are fairly common.
• Behavior problems include anxiety disorders (>50%), selective mutism (29%), attention deficient hyperactivity disorder (ADHD) (35%), oppositional disorders (25%), and physical aggression. Autism spectrum disorders (ASD) are present in ~20% based on gold-standard assessment (i.e., Autism Diagnostic Observation Schedule-2 [ADOS-2] [Lord et al 2012] and Autism Diagnostic Interview-Revised [ADI-R] [Lord et al 1994], plus clinical judgment).
• Developmental delay. Most individuals have delayed motor, speech, and social skills in early childhood. Expressive language is usually more delayed than receptive language. Although the majority of school age children have intellectual ability in the low average to average range and a few children score even higher, about 20% have borderline intellectual ability and about 18% have intellectual disability.

Figure 1.

Children with classic 7q11.23 duplication syndrome Top row: age 1 year, age 2 years, age 2 years, age 2 years, age 4 years.

Figure 2.

Adolescents and adults with classic 7q11.23 duplication syndrome Top row: Age 12 years (front and profile), age 14 years, age 21 years.

Establishing the Diagnosis

The diagnosis of the 7q11.23 duplication syndrome is established by detection of a 1.5- to 1.8-Mb heterozygous duplication of the Williams-Beuren syndrome critical region (WBSCR) (Table 1).

For this GeneReview, the 7q11.23 duplication syndrome is defined as the presence of a recurrent 1.5- to 1.8-Mb duplication at the approximate position of chr7:72,744,454-74,142,513 in the reference genome (NCBI Build hg19).

Note: The phenotype of significantly larger or smaller duplication within this region may be clinically distinct from the 7q11.23 duplication syndrome (see Genotype-Phenotype Correlations).

Although several genes of interest are within the 1.5- to 1.8-Mb recurrent microduplication, no single gene has been definitively identified as causing individual clinical features (see Molecular Genetics for genes of interest in this region).

Genomic testing methods that determine the copy number of sequences can include chromosomal microarray (CMA) or targeted duplication analysis by fluorescence in situ hybridization (FISH). Note: The 7q11.23 duplication cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques.

Chromosomal microarray (CMA) using oligonucleotide arrays or SNP genotyping arrays can detect the recurrent duplication in a proband. The ability to size the duplication depends on the type of microarray used and the density of probes in the 7q11.23 region.

Note: (1) Most individuals with the 7q11.23 duplication syndrome are identified by CMA performed in the context of evaluation of developmental delay, intellectual disability, and/or autism spectrum disorders. (2) This microduplication can be detected by BAC arrays.

Targeted duplication analysis. FISH analysis, quantitative PCR (qPCR), multiplex ligation-dependent probe amplification (MLPA), or other targeted quantitative methods may be used to test relatives of a proband known to have the 7q11.23 duplication.

Note: (1) Targeted duplication testing is not appropriate for an individual in whom the 7q11.23 duplication was not detected by CMA designed to target this region. (2) It is not possible to size the duplication routinely by use of targeted methods.

Evaluating at-risk relatives. FISH, qPCR, or other quantitative methods of targeted duplication analysis can be used to identify the 7q11.23 duplication in at-risk relatives of the proband. Testing parental samples is important in determining recurrence risk (see Genetic Counseling).

Clinical Description

Infancy. Median birth weight is at the 75^th centile, median birth length is at the 80^th centile, and median head circumference is at the 75^th centile (30% of newborns have an OFC ≥95^th centile). Infants with the 7q11.23 duplication syndrome are hypotonic and may have joint laxity, resulting in delayed attainment of motor milestones. Median age of walking is 1.33 years [Morris et al 2015].

Approximately 30% of individuals with the 7q11.23 duplication syndrome have one or more congenital anomalies. Congenital malformations that have been reported in more than one individual include cleft lip and/or palate, congenital heart disease, diaphragmatic hernia, unilateral renal agenesis, vertebral anomalies, cryptorchidism, and talipes equinovarus; however, no consistent specific pattern of malformations has been observed [Berg et al 2007, Van der Aa et al 2009, Dixit et al 2013, Morris et al 2015].

Speech is significantly delayed with median age of single words at 2.00 years based on parental report. Among probands who eventually are diagnosed with the 7q11.23 duplication syndrome, the most common reason for evaluation was developmental delay; the second most common reason was autism spectrum disorder (ASD) [Morris et al 2015].

Neurologic problems. Neurologic examination of children with the 7q11.23 duplication syndrome is abnormal in 89%; findings include hypotonia (60%), abnormalities in gait and station such as wide-based gait and difficulty with balance (62%), and adventitious movements such as involuntary motor overflow (83% of children age >14 years). Developmental coordination disorder is present in 74% [Morris et al 2015].

Seizures are present in 19% [Berg et al 2007, Torniero et al 2007, Van der Aa et al 2009, Değerliyurt et al 2012, Morris et al 2015].

Hydrocephalus requiring shunting was present in 5.6% in one series [Morris et al 2015].

When asked to indicate behavioral concerns regarding their child, 25% of parents reported that he/she exhibited high pain tolerance [Morris et al 2015].

Neuroimaging. Common MRI findings include varying degrees of ventriculomegaly, thin corpus callosum, increased extra-axial spaces, thin white matter, delayed myelination, posterior fossa cysts, and cerebellar vermis hypoplasia [Berg et al 2007, Depienne et al 2007, Torniero et al 2007, Orellana et al 2008, Torniero et al 2008, Van der Aa et al 2009, Dixit et al 2013, Prontera et al 2014, Morris et al 2015].

Craniofacial features. The characteristic craniofacial phenotype including macrocephaly, brachycephaly, broad forehead, straight eyebrows, deep-set eyes, long eyelashes, broad nasal tip, low insertion of the columella, short philtrum, thin vermilion of the upper lip, high-arched palate, and minor ear anomalies (overfolded helix, protruding ears) is observed at all ages (Figure 1). Facial asymmetry and low-hanging columella become more evident/are more common in older children and adults (Figure 2).

Cardiovascular disease. Patent ductus arteriosus is present in 15%-21% [Van der Aa et al 2009, Morris et al 2015] and septal defects are present in 2%.

Aortic dilation may be detected at any age; surgical correction has been required in some adolescents and adults. Some individuals with dilation of the ascending aorta also have had dilation of the aortic root [Zarate et al 2014, Morris et al 2015, Parrott et al 2015]. The prevalence of aortic dilation is 46% [Morris et al 2015].

Cognitive abilities. Median IQ is 85 (low average), with a range from severe intellectual disability to superior ability. On average, verbal, nonverbal reasoning, and spatial abilities are at about the same level, although a variety of patterns of relative strengths and weaknesses occur. Median reading achievement performance is at the bottom of the average range (varying from severe disability to superior) and median mathematics achievement performance is at the bottom of the low average range (also varying from severe disability to superior) [Mervis et al 2015].

Speech and language difficulties. Severe delay in expressive language was the presenting feature in the first individual reported with the 7q11.23 duplication syndrome [Somerville et al 2005].

DSM-5 speech sound disorder, present in 82%, includes articulation disorders (motor speech disorders such as childhood apraxia of speech) and phonologic disorders (cognitive-linguistic disorders reflecting inaccurate or incomplete phonologic representations or inappropriate phonologic rules).

The most common speech sound disorder in children with 7q11.23 duplication is childhood apraxia of speech (a neurologic speech disorder not due to muscle weakness or muscle tone differences but rather due to problems of planning and coordinating the muscle movements needed to pronounce words) or manifestations of this disorder.

Childhood dysarthria or its manifestations (usually resulting from low muscle tone) are also common [Velleman & Mervis 2011, Mervis et al 2015]. "Developmental" speech problems, such as distortions of /s/ or /r/, may persist past typical ages.

On omnibus tests of language abilities (including receptive and expressive modalities and vocabulary and grammar) overall performance is most commonly in the range of mild to moderate language disorder but can range from severe language disorder to average language ability. For most children vocabulary abilities are stronger than grammatic abilities [Velleman & Mervis 2011].

School-age children who had had consistent speech-language therapy from late infancy or early toddlerhood had considerably stronger language and literacy skills than children who had not. Children who were taught to read using a strong phonics approach had better reading skills than children taught with sight-word or whole-word approaches [Velleman & Mervis 2011].

Adaptive behavior. Adaptive skills are more limited than expected for IQ. Median performance is at the mild adaptive deficit to borderline level, ranging from severe adaptive deficit to average. Executive functioning difficulties also may be observed [Mervis et al 2015].

Behavior problems. Anxiety disorders are common, with approximately 60% meeting DSM criteria for at least one anxiety disorder other than specific phobia. The most common disorders are specific phobia (53%), social anxiety disorder (50%), selective mutism (29%), and separation anxiety disorder (13%) [Mervis et al 2015].

Approximately 35% met DSM criteria for ADHD and about 25% met DSM-IV criteria for oppositional defiant disorder or disruptive behavior disorder – not otherwise specified [Mervis et al 2015]. An elevated rate of physical aggression is also common.

The 7q11.23 duplication syndrome is associated with an elevated risk for autism [Sanders et al 2011]; autism spectrum disorder was the second most common indicator for genetic testing [Morris et al 2015]. Thirty-three percent screened positive for a possible autism spectrum disorder [Mervis et al 2015] and approximately 20% met criteria for an autism spectrum disorder based on a gold-standard assessment (ADOS-2 [Lord et al 2012] and ADI-R [Lord et al 1994], plus clinical judgment) with differential diagnosis taking into account selective mutism and social anxiety.

Eye, ear, nose, and throat

• Strabismus is present in 15%.
• Hearing loss has been reported in ~5%.
• Diastema is present in 31%, high-arched palate in 44%, and micrognathia in 30% [Morris et al 2015].
• Chronic otitis media affects 25% of children; ventilating tubes are placed in 15% and tonsillectomy and adenoidectomy are performed in 15%.

Gastrointestinal difficulties. Infants with the 7q11.23 duplication syndrome may have feeding problems such as difficulty with latching on, and 7.5% have persistent feeding problems requiring gastrostomy tube feeding. Chronic constipation is a significant problem in 66% of children and 27% of adults. Encopresis occurs in 20% of the children with constipation and 7.5% require hospitalization for disimpaction [Morris et al 2015].

Genitourinary tract abnormalities. Congenital anomalies of the urinary tract occur in 15%-18%, including hydronephrosis and unilateral renal agenesis [Zarate et al 2014, Morris et al 2015].

Females with unilateral renal agenesis may have abnormalities of müllerian structures [Morris et al 2015].

Approximately 15% of males have cryptorchidism [Orellana et al 2008, Van der Aa et al 2009, Morris et al 2015].

Musculoskeletal problems. Joint laxity may be present in young children. Talipes equinovarus (5%) responds to casting [Morris et al 2015].

Endocrine problems. Most affected individuals have normal stature. Growth hormone deficiency is found in 9% [Morris et al 2015].

Other. Cutis marmorata is present in 45% of children younger than age 14 years [Morris et al 2015].

Genotype/Phenotype Correlations

In classic Williams syndrome, the 7q11.23 deletion comprises 1.55 megabases (Mb) in 95% and 1.84 Mb in 5% [Bayés et al 2003]. Duplications of both sizes have been reported but the proportion of individuals with each of the two sizes has not been determined.

Longer duplications including HIP1 have been reported [Berg et al 2007, Dixit et al 2013, Zarate et al 2014]. Berg et al [2007] and Dixit et al [2013] noted that these individuals did not seem to differ phenotypically from individuals with the recurrent 7q11.23 duplication. However, systematic comparisons to a large group of individuals with the recurrent 7q11.23 duplication are needed to determine if longer duplications are associated with a more severe phenotype, considering that longer deletions of 7q11.23 including HIP1 are associated with more severe intellectual disability than is typical for individuals with classic deletions [Stock et al 2003].

Shorter 7q11.23 duplications have also been reported [Zarate et al 2014, Parrott et al 2015]. Systematic comparisons to a large group of individuals with the recurrent 7q11.23 duplication are needed to determine phenotypic similarities and differences as a function of the specific genes duplicated.

Given the small number of individuals identified with a 7q11.23 triplication and the variable size of the triplication, it is not yet known if the phenotype associated with the triplication is more severe than that associated with the duplication.

• A child age 38 months with a 7q11.23 triplication including almost all of the genes in the WBSCR has been reported [Beunders et al 2010]. The child had gross motor delay, severe language delay, anxiety, and aggressive behavior.
• 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].

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 Z scores 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

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 in the US and www.ClinicalTrialsRegister.eu in Europe 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.