7q11.23 Duplication Syndrome

Clinical characteristics: 7q11.23 duplication syndrome is characterized by delayed motor, speech, and social skills in early childhood; 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 issues including anxiety disorders (especially social anxiety disorder [social phobia]), selective mutism, attention-deficit/hyperactivity disorder, oppositional disorders, physical aggression, and autism spectrum disorder; and intellectual disability in some individuals. Distinctive facial features are common. Cardiovascular disease includes dilatation of the ascending aorta. Approximately 30% of individuals have one or more congenital anomalies.

Diagnosis/testing: The diagnosis of 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.

Management: Treatment of manifestations: Address developmental delays through early intervention programs (including speech-language therapy, physical therapy, and occupational therapy), special education programs, and vocational training. Address childhood apraxia of speech 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, autism spectrum disorder) with cognitive-behavioral therapy, applied behavior analysis behavior modification intervention, and psychotropic medications as needed. Standard treatment for seizures and congenital heart disease. Ventriculo-peritoneal shunt as needed for hydrocephalus. Aortic dilatation is treated with beta-blocker therapy and/or surgery as needed. Feeding therapy and gastrostomy tube placement may be required. Constipation should be aggressively managed. Human growth hormone replacement therapy for growth hormone deficiency. Treatment per nephrologist and/or urologist for genitourinary malformations. Standard treatments for vision and hearing issues and recurrent otitis. Casting and treatment per orthopedist for clubfeet. Social work support for families.

Surveillance: Assessment of growth and nutrition at each visit. Annual assessment by occupational and physical therapists and speech-language pathologists until at least age six years. Annual assessment of intellectual ability and academic achievement. Head circumference at every visit in infancy or at least every three months. Assess for new-onset seizures or monitor those with seizures as clinically indicated. Behavior assessment annually. Annual monitoring of aortic diameter (including z scores in children). Annual monitoring for constipation, hearing and vision issues, and kyphoscoliosis. Assess need for additional genetic counseling and family support.

Genetic counseling: 7q11.23 duplication syndrome is transmitted in an autosomal dominant manner. About 27% of individuals diagnosed with 7q11.23 duplication syndrome have an affected parent; about 73% of individuals have the disorder as the result of a de novo genetic alteration. If one of the parents has the 7q11.23 duplication identified in the proband, the risk to each sib of inheriting the duplication is 50%. It is not possible to reliably predict the phenotype in sibs who inherit a 7q11.23 duplication because manifestations of 7q11.23 duplication syndrome may vary in affected family members. If the 7q11.23 duplication identified in the proband cannot be detected in parental leukocyte DNA and neither parent has a balanced chromosome rearrangement, the recurrence risk to sibs is low but greater than that of the general population because of the possibility of parental germline mosaicism. Once a 7q11.23 duplication has been identified in an affected family member, prenatal and preimplantation genetic testing are possible; however, the manifestations of 7q11.23 duplication syndrome cannot be reliably predicted on the basis of prenatal test results or family history.