NORD gratefully acknowledges Kia Hutchins, MMSc, NORD Editorial Intern from the Emory University Genetic Counseling Training Program and Cecelia A. Bellcross, PhD, MS, CGC, Associate Professor, Director, Genetic Counseling Training Program, Emory University School of Medicine, for assistance in the preparation of this report.
Weaver Syndrome (WS) is a genetic condition which causes fast growth. Children usually start having symptoms before birth (prenatal onset). The primary symptom is growth and bone development (maturation) that occurs faster than usual, so affected individuals are taller than average. Intellectual disability, loose muscles (hypotonia) of the core, and rigid muscles (hypertonia) of the limbs with poor coordination are also seen. Physical differences of the face and feet are common. Babies with this syndrome have a hoarse low-pitched cry.
The main symptom of WS is fast growth and bone development (maturation). Children with WS may be tall, they have a normal or high weight for their height. A large head size (macrocephaly) is also common. Some children with WS may not show symptoms until several months after birth. People with WS may have muscles that get more rigid over time (hypertonia), especially in the arms and legs. However, the muscles in their core may be looser (hypotonia). Due to their rigid muscles, individuals with WS may have poor coordination. Babies with this syndrome have a hoarse and low-pitched cry.
People with WS may have eyes that are far apart (hypertelorism), extra skin over the inner corner of the eyes (epicanthal folds) or eyelids that slant down (down-slanting palpebral fissures). The back of the head (occiput) may be flat, the forehead wide and the ears larger than usual. The groove located above the upper lip and below the nose (philtrum) may be longer than average. People with WS may have a smaller jaw than normal (micrognathia). Other physical features can include thin hair, inverted nipples and loose skin.
People with WS usually have wide thumbs. One or more fingers may be permanently bent (camptodactyly). Nails may be deep-set and thin. The pads of the fingertips are usually raised. People with WS may have differences of the feet. These may include misshapen toes (clinodactyly), a very high arch of the foot (pes cavus), a clubfoot or a twisted foot (metatarsus adductus). The clubfoot may have the sole of the foot turned inward and upward towards the heel (talipes equinovarus) or towards the toes (talipes calcaneovalgus). People with WS may not be able to fully extend their elbows or knees.
Other symptoms associated with WS include varying levels of intellectual ability, from normal intelligence to severe intellectual disability. There also seems to be an increased chance for umbilical hernias and, more rarely, a type of brain cancer called neuroblastoma.
WS is usually caused by harmful changes (mutations) in the EZH2 gene. These harmful changes cause the EZH2 gene to work incorrectly. The function of the EZH2 gene is to turn other genes on and off in a process called methylation. The EZH2 gene’s influence on the function of many other genes explains why WS affects many body systems. However, it is not known how these changes cause the specific symptoms of WS. Some people with WS do not have a mutation in the EZH2 gene.
WS is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular condition. In about half of patients, the non-working gene is inherited from an affected parent. In the other half, it occurs as a new (de novo) change one of the EZH2 genes in the affected individual. The chance of passing the non-working gene from an affected parent to a child is 50% for each pregnancy. The chance is the same for males and females.
WS is a very rare disorder – only about 50 affected individuals have been identified.
The growth changes seen with WS are broad and could be caused by many overgrowth syndromes. Genetic testing can diagnose WS and finding a harmful change in the EZH2 gene confirms WS. Because the symptoms of WS are not specific, genetic testing may include many genes that cause overgrowth syndromes (gene panel).
Clinical Testing & Workup
People with WS need many clinical assessments after diagnosis. A neurology assessment can identify delays and rigid muscles. Psychologists can identify behavior issues. Examinations by specialists are needed to look for problems with the heart, hands or feet. Results from these evaluations will help guide what other testing should be done.
Treatment of WS involves management of symptoms and is supportive. Physical therapy may be helpful for rigid muscles, foot differences and bent fingers or toes. Surgery may be needed to correct problems with the fingers, toes or feet. Therapies or individual education plans (IEPs) may be helpful for children with WS.
Genetic counseling is recommended for patients and their families.
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