NORD gratefully acknowledges Dr. Charlotte Ockeloen, Clinical Geneticist, Clinical Pharmacologist in training, Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands, for her assistance in updating this report.
Children with KBG syndrome may display characteristic physical abnormalities of the head and face (craniofacial dysmorphism). The shape of the skull can be abnormal, with a flat back of the head (brachycephaly). Characteristic facial features may include eyes that appear widely spaced apart (hypertelorism) or crossed (strabismus); wide, bushy eyebrows; thin, bow-shaped lips; and/or a triangularly-shaped face. There is typically a full tip of the nose with upturned nostrils. Characteristic features may also include abnormally large teeth (macrodontia). Macrodontia is particularly common in KBG syndrome and often affects the two upper middle teeth (upper central incisors) and sometimes other teeth as well. Affected individuals may also have jagged, crowded, or misaligned teeth and/or unusually short, flattened, supporting bones or sockets of the jaw (mandible) that house the teeth (alveolar ridges). Microcephaly has been described in some children. Microcephaly is a condition in which the circumference of the head is smaller than would be otherwise expected based on age and gender. However, most children with KBG syndrome have a normal head size.
A child with KBG syndrome may also be of short stature, have speech and hearing impairments, and/or have mild to moderate levels of intellectual disability. Children with intellectual disability may experience delays in reaching developmental milestones. Most children will only experience mild learning disabilities. Other children will not have intellectual disability and have no issues with learning or thinking that are related to KBG syndrome. Part of the adults with KBG syndrome can live independently, but other adults with KBG need external help or live in assisted facilities.
Children experience recurrent ear infections (otitis media), which may contribute to hearing loss.
Some children experience behavioral anomalies such as impulsivity or poor concentration, sometimes with a diagnosis of attention deficit hyperactivity disorder (ADHD), temper tantrums, anxiety or shyness, or compulsive and sometimes aggressive behavior. Autism spectrum disorder or autistic traits can also be present in children with KBG syndrome. The nature of the behavioral abnormalities is variable and can be mild.
Some children have epilepsy, usually during childhood. The type of epilepsy can vary from generalized or partial seizures that respond well to therapy, to more complex forms of epilepsy that are difficult to treat. Some children also have EEG abnormalities without signs of seizures. Sometimes MRI scans of the brain show abnormalities.
Affected children may have delayed bone age, which means that a child’s bones mature at a slower rate. Other malformations of the bones can be present, such as spinal abnormalities (abnormal vertebrae or ribs); the shortened middle portion of the thigh bones (femoral neck); abnormally developed hip bones (hip dysplasia/Perthes disease); and/or shortened, hollow finger bones (metacarpals).
In some children, associated features may include a sunken, pushed-in appearance of the chest (pectus excavatum or “funnel chest”); a single deep crease across the palms of the hands (simian crease); certain bones of the hands may be short (short tubular bones of the hands), pinkies that are unusually short (brachydactyly) and/or that may be stuck in a bent position (clinodactyly).
Less commonly, additional findings have been reported in some children including congenital heart defects, defects affecting the roof of the mouth (palate), webbing or fusion (syndactyly) of the middle toes, and a webbed, short neck. Some males may have undescended testicles (cryptorchidism). Advanced puberty had been reported in some children. Some infants have feeding difficulties or sleep difficulties.
Delayed closure of the ‘soft spots’ or fontanelles has also been reported. An infant’s skull has seven bones and several joints called sutures. Sutures are made of tough, elastic fibrous tissue and separate the bones from one another. Sutures meet up (intersect) at two spots on the skull called fontanelles, which are better known as an infant’s “soft spots”. The seven bones of an infant’s skull normally do not fuse together until around age two or later. The sutures normally remain flexible until this point. In some infants, this fusion is delayed.
KBG syndrome is caused by either an alteration (mutation) in the ANKRD11 gene, or a loss of genetic material from chromosome 16q that includes the ANKRD11 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
The ANKRD11 gene contains instructions for creating a protein that is active in nerve cells (neurons). The exact role of this protein is not fully understood. When the ANKRD11 is altered or missing, individuals cannot produce enough functional copies of this protein. More research is necessary to determine how low levels of the protein product of the ANKRD11 gene causes the symptoms of KBG syndrome.
KBG syndrome is inherited in an autosomal dominant pattern. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an altered or missing gene is necessary to cause a particular disease. The affected gene can be inherited from either parent or can be the result of a new, spontaneous mutation (gene change) in the affected individual. This may be referred to as a “de novo” change. The risk of passing the altered gene or missing chromosome segment from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
KBG syndrome is a rare disorder that affects males and females. Currently, more than 150 cases have been reported in the medical literature. The disorder can go undiagnosed or misdiagnosed, making it difficult to determining the true frequency of KBG syndrome in the general population.
A diagnosis of KBG syndrome may be suspected after a thorough clinical evaluation, a detailed patient and family history, and the identification of characteristic physical findings. The diagnosis can also be made by gene panel analysis or next generation sequencing techniques, where multiple genetic causes of intellectual disability are investigated at the same time.
Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedists, orthopedic surgeons, neurologists, physical therapists, speech therapists, orthodontists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.
Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family may be beneficial as well.
Orthopedic surgery may be particularly helpful to correct hip and spine abnormalities of affected individuals. Hearing aids, speech therapy, and comprehensive dental care may also be beneficial.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Some children with KBG syndrome have been treated with growth hormone therapy. Initial results have been promising in helping children who are experiencing delays or diminished growth. More research is necessary to determine the long-term safety and effectiveness of growth hormone therapy in children with KBG syndrome.
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