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Last updated: 8/15/2023
Years published: 1996, 2003, 2016, 2019, 2023
NORD gratefully acknowledges Dr. Charlotte Ockeloen, Clinical Geneticist, Clinical Pharmacologist, Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands, for her assistance in updating this report.
KBG syndrome (KBGS) is a rare genetic disorder characterized by large front teeth (macrodontia), characteristic facial features, short to normal stature, developmental delay or intellectual disability (the level of intellectual disability is usually mild, and there are also people with KBGS who have a normal development). Behavioral issues are common. People with KBGS can have skeletal abnormalities (such as short fingers, delayed closure of the fontanelle or scoliosis), hearing loss and feeding difficulties (particularly in infancy), and some have epilepsy (seizures) or brain malformations. The specific symptoms may vary from one person to another. KBG syndrome is caused by a change (variant or mutation) in the ANKRD11 gene or a loss of genetic material (microdeletion) on chromosome 16q that involves the ANKRD11 gene. Variants of this gene can occur spontaneously with no family history or be inherited in an autosomal dominant manner. KBG syndrome is named after the initials of the last names of the first three families identified with this disorder in the medical literature in 1975.
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; prominent ears; and/or a triangularly shaped face. There is typically a full tip of the nose with upturned nostrils. Characteristic features may also include 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 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 disabilities 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.
People (especially children) with KBGS may have hearing loss. This can be sensorineural or perceptive and might require treatment such as hearing aids. Children experience recurrent ear infections (otitis media), which may contribute to hearing loss.
Some children have behavioral issues 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 issues is variable.
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.
About 40% of people with KBGS have a short stature. Affected children may have delayed bone age, which means that a childโs 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). Scoliosis (sideways curve of the spine) is quite common.
In some children, associated features may include a sunken, pushed-in appearance of the chest (pectus excavatum or โfunnel chestโ); 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 has been reported in some children. Some infants have sleep difficulties.
Feeding difficulties are present in about 20% of people with KBGS and can include vomiting, constipation and gastroesophageal reflux disease.
Some children with KBGS have been reported to have incomplete closure of certain bones of the spinal column (spina bifida) or inelastic tissue on the caudal spinal cord (tethered cord). People with KBG might have various eye and vision problems such as crossed eyes (strabismus), cloudy lenses of the eyes (congenital cataracts), blurred vision or other vision problems. Some patients have skin or hair differences including dark spots on the skin (hyperpigmentation); dry, itchy skin; excess body hair (hypertrichosis); abnormal hair patterns on the scalp and/or deformed, thickened or discolored nails.
Delayed closure of the โsoft spotsโ or fontanelles has also been reported. An infantโs 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 infantโs โsoft spotsโ. The seven bones of an infantโs 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. The fontanelle can also be unusually large at birth.
KBG syndrome is caused by either an alteration (variant or 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 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 gene 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 gene change in the affected individual. This may be referred to as a โde novoโ 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 actual number of patients worldwide is much higher. The disorder can go undiagnosed or misdiagnosed, making it difficult to determine 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, (pediatric) neurologists, physical therapists, speech therapists, orthodontists or dentists and other healthcare professionals may need to plan an affected childโs treatment systematically and comprehensively.
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:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
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 growth 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.
TEXTBOOKS
Dowling PA, Fleming P, Gorlin RJ. KBG Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:210.
Gorlin RJ, et al., eds. Syndromes of the Head and Neck, 3rd ed. New York, NY: Oxford University Press; 1990:840-1.
JOURNAL ARTICLES
Hills S, Pugacheva A, Weltin P, et al. Tethered cord syndrome in KBG syndrome. Am J Med Genet A. 2023;191(5):1222-1226. doi:10.1002/ajmg.a.63128
Martinez-Cayuelas E, Blanco-Kelly F, Lopez-Grondona F, et al. Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients. J Med Genet. 2023;60(7):644-654. doi:10.1136/jmg-2022-108632
Low K, Ashraf T, Canham N, et al. Clinical and genetic aspects of KBG syndrome. Am J Med Genet A. 2016 [Epub ahead of print]. https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.37842/full
Goldenberg A, Riccardi F, Tessier A, et al. Clinical and molecular findings in 39 patients with KBG syndrome caused by deletion or mutation of ANKRD11. Am J Med Genet A. 2016; [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/27605097
Ockeloen CW, Willemsen MH, de Munnik S, et al. Further delineation of the KBG syndrome caused by ANKRD11 aberrations. Eur J Hum Genet. 2015;23:1270. https://www.ncbi.nlm.nih.gov/pubmed/26269249
Reynaert N, Ockeloen CW, Savedahl L, et al. Short stature in KBG syndrome: first responses to growth hormone treatment. Horm Res Paediatr. 2015;83:361-364. https://www.ncbi.nlm.nih.gov/pubmed/25833229
Sirmaci A, Spiliopoulos M, Brancati F, et al. Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia. Am J Hum Genet. 2011;89:289-294. https://www.ncbi.nlm.nih.gov/pubmed/21782149
Almandey AH, Anthonappa RP, King NM, Fung CW. KBG syndrome: clinical features and specific dental findings. Pediatr Dent. 2010;32:439-444. https://www.ncbi.nlm.nih.gov/pubmed/21070713
Brancati F, Sarkozy A, Dallapiccola B. KBG syndrome. Orphanet J Rare Dis. 2006;1:50. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1764006/
Tekin M, Kavaz A, Berberoglu M, et al. The KBG syndrome: confirmation of autosomal dominant inheritance and further delineation of the phenotype. Am J Med Genet A. 2004;130A:284-287. https://www.ncbi.nlm.nih.gov/pubmed/15378538
Dowling PA, Fleming P, Gorlin RG, et al. The KBG syndrome, characteristic dental findings: a case report. Int J Paediatr Dent. 2001;11:131-34. https://www.ncbi.nlm.nih.gov/pubmed/11310136
Sacharow S, Li D, Fan Ys, Tekin M. Familial 16q24.3 microdeletion involving ANKRD11 causes a KBG-like syndrome. Am J Med Genet A. 2012;158A:547-552. https://www.ncbi.nlm.nih.gov/pubmed/22307766
Mathieu M, Helou M, Morin G, et al. The KBG syndrome: an additional sporadic case. Genet Couns. 2000;11:33-35. https://www.ncbi.nlm.nih.gov/pubmed/10756425
Soekarman D, Volcke P, Fryns JP. The KBG syndrome: follow-up data on three affected brothers. Clin Genet. 1994;46:283-86. https://www.ncbi.nlm.nih.gov/pubmed/7834892
Zollarion M, Battaglia A, DโAvanzo MG, et al. Six additional cases of the KBG syndrome: clinical reports and outline of the diagnostic criteria. Am J Med Genet. 1994;52:302-07. https://www.ncbi.nlm.nih.gov/pubmed/7810561
Fryns JP, Haspeslagh M. Mental retardation, short stature, minor skeletal anomalies, craniofacial dysmorphism and macrodontia in two sisters and their mother. Another variant example of KBG syndrome? Clin Genet. 1984;26:69-72. https://www.ncbi.nlm.nih.gov/pubmed/6467660
Hermann J, Pallister PD, Tiddy W, Optiz JM. The KBG syndrome โ a syndrome of short stature, characteristic facies, mental retardation, macrodontia and skeletal anomalies. Birth Defects. 1975;11:7-18. https://www.ncbi.nlm.nih.gov/pubmed/1218237
INTERNET
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:148050; Last Update: 11/30/2022. Available at: https://omim.org/entry/148050 Accessed August 14, 2023.
Brancati F, Dallapiccola B, Sarkozy A. KBG Syndrome. Orphanet. September 2020. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=2332 Accessed August 14, 2023.
Genetics Home Reference. KBG Syndrome. January 2018. Available at: https://ghr.nlm.nih.gov/condition/kbg-syndrome Accessed August 14, 2023.
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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