KBG Syndrome

Disease Overview

KBG syndrome (KBGS) is a rare genetic disorder characterized by large front teeth (macrodontia), characteristic facial features, short to normal stature, developmental delay and intellectual disability. The level of intellectual disability is usually mild, and there are people with KBGS who have normal intelligence. 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) 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 (de novo) with no family history or can be inherited in an autosomal dominant manner.

Treatment is directed toward the specific symptoms that an affected person has.

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.

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Synonyms

• short stature-facial and skeletal anomalies-intellectual disability-macrodontia syndrome
• ANKRD11-related disorder
• short stature, facial/skeletal anomalies-retardation-macrodontia

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Signs & Symptoms

People with KBG syndrome usually present with skeletal abnormalities, distinct facial features and intellectual delays. The following signs and symptoms may be present in people with KBG syndrome:

• Craniofacial differences: Children with KBG syndrome may have characteristic physical abnormalities of the head and face
  • The shape of the skull can be abnormal with a flat back of the head (brachycephaly)
  • Distinctive face:
    • Eyes that appear widely spaced apart (hypertelorism) or crossed (strabismus)
    • Wide, bushy eyebrows
    • Thin, bow-shaped lips
    • Prominent ears
    • Triangularly shaped face
    • Full tip of the nose with upturned nostrils
    • Large teeth (macrodontia) which are particularly common in KBG syndrome and often affect the two upper middle teeth (upper central incisors) and sometimes other teeth as well
    • Jagged, crowded or misaligned teeth
    • Unusually short, flattened, supporting bones or sockets of the jaw (mandible) that house the teeth (alveolar ridges)
  • Small head size (microcephaly)–in only a few people, as most have a normal head size
  • Speech and hearing impairments
    • Deafness can be sensorineural (also known as perceptive) and might require treatment such as hearing aids
    • Recurrent ear infections (otitis media) which may contribute to hearing loss
  • Mild to moderate levels of intellectual disability and developmental delays, which are delays in reaching developmental milestones
    • Most children only have mild learning disabilities
    • Some children do not have intellectual disabilities or issues with learning or thinking
    • Some adults with KBG syndrome can live independently but others need help or live in assisted facilities
  • Behavioral issues such as:
    • Impulsivity or poor concentration
    • Attention deficit/hyperactivity disorder (ADHD)
    • Temper tantrums
    • Anxiety or shyness, or compulsive and sometimes aggressive behavior
    • Autism spectrum disorder or autistic traits
  • 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
    • Brain abnormalities in MRI scans of the brain
    • Short stature (in about 40% of people)
    • Delayed bone age which means that a child’s bones mature at a slower rate
    • Other malformations of the bones including:
      • Spinal abnormalities (abnormal vertebrae or ribs)
      • Abnormal spinal curve (scoliosis)– most common
      • Shortened middle portion of the thigh bones (femoral neck)
      • Abnormally developed hip bones (hip dysplasia/Perthes disease)
      • Shortened, hollow finger bones (metacarpals)
      • Sunken, pushed-in appearance of the chest (pectus excavatum or “funnel chest”)
      • Short bones of the hands (brachydactyly), pinkies that are unusually short and/or may be stuck in a bent position (clinodactyly)
    • Single deep crease across the palms of the hands (simian crease)
    • Feeding difficulties (present in about 20% of people with KBGS) which can include vomiting, constipation and gastroesophageal reflux disease

Less commonly, additional findings have been reported in some children including:

• Congenital heart defects
• Anomalies of the roof of the mouth (palate)
• Webbing or fusion (syndactyly) of the middle toes
• Webbed, short neck
• Undescended testicles (cryptorchidism)
• Early puberty also known as precocious puberty, a condition where a child experiences the physical changes of puberty (like breast development in girls or testicular growth in boys) earlier than the typical age range (puberty usually starts before age 8 in girls and age 9 in boys)
• Sleep difficulties
• Incomplete closure of certain bones of the spinal column (spina bifida) or inelastic tissue on the caudal spinal cord (tethered cord)
• Other vision problems such as cloudy lenses of the eyes (congenital cataracts), blurred vision or other
• 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 ‘soft spots’ or fontanelles
  • The skull has seven bones and several joints called sutures which 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 and the sutures normally remain flexible until this point but in some infants, this fusion is delayed, and the fontanelle can also be unusually large at birth.

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Causes

KBG syndrome is caused by either a change (variant) 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 variant 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, the person 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 cause the symptoms of KBG syndrome.

KBG syndrome is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

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Affected populations

KBG syndrome is a rare disorder that affects males and females.  As of 2023, around 400 cases have been reported in the medical literature. The actual number of patients worldwide is believed to be much higher. It is projected that the number of patients with ANKRD11 variants exceeds 800. The disorder can go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of KBG syndrome in the general population.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of KBG syndrome. Comparisons may be useful for a differential diagnosis:

Cornelia de Lange syndrome (CdLS): While CdLS and KBG syndrome have many similar facial and developmental features, particularly in early childhood, a single eyebrow (synophrys), severe upper limb anomalies, prenatal growth deficiency and a striking facial profile supports a diagnosis of CdLS. In contrast, findings like macrodontia, vertebral anomalies, and postnatal onset of growth delay, in the absence of classic CdLS features, are more suggestive of KBG syndrome. Genetic testing can confirm the diagnosis.

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Diagnosis

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. Diagnosis should be suspected in children who have the distinctive craniofacial features, short stature, developmental delay, intellectual disability and epilepsy.  The diagnosis can be confirmed with genetic testing identifying a ANKRD11 variant.

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Standard Therapies

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 child’s 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. Hearing aids, speech therapy and comprehensive dental care may also be beneficial.

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Clinical Trials and Studies

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.

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/

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References

TEXTBOOKS
Dowling PA, Fleming P, Gorlin RJ. KBG Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:210.

JOURNAL ARTICLES
Serra G, Elefante P, Gazzitano Y, et al. KBG syndrome: report and follow-up on three unrelated patients observed at different ages. Ital J Pediatr. 2025;51(1):54. Published 2025 Feb 21. doi:10.1186/s13052-025-01884-1

He D, Zhang M, Li Y, Liu F, Ban B. Insights into the ANKRD11 variants and short-stature phenotype through literature review and ClinVar database search. Orphanet J Rare Dis. 2024;19(1):292. Published 2024 Aug 12. doi:10.1186/s13023-024-03301-y

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

Peluso F, Caraffi SG, Contrò G, et al. Deep phenotyping of the neuroimaging and skeletal features in KBG syndrome: a study of 53 patients and review of the literature. J Med Genet. 2023;60(12):1224-1234. Published 2023 Nov 27. doi:10.1136/jmg-2023-109141

Ge XY, Ge L, Hu WW, Li XL, Hu YY. Growth hormone therapy for children with KBG syndrome: A case report and review of literature. World J Clin Cases. 2020;8(6):1172-1179. doi:10.12998/wjcc.v8.i6.1172

Low K, Ashraf T, Canham N, et al. Clinical and genetic aspects of KBG syndrome. Am J Med Genet A. 2016;170(11):2835-2846. doi:10.1002/ajmg.a.37842

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;170(11):2847-2859. doi:10.1002/ajmg.a.37878

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

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(3):547-552. doi:10.1002/ajmg.a.34436

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

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, D’Avanzo 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 – 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: Johns Hopkins University; Entry No:148050; Last Update: 10/11/2023. Available at: https://omim.org/entry/148050 Accessed June 25, 2025.

KBG Syndrome. Orphanet. September 2020. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=2332 Accessed June 25, 2025.

KBG Syndrome. MedlinePlus. January 1, 2018. Available at: https://medlineplus.gov/genetics/condition/kbg-syndrome/ Accessed June 25, 2025.

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