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KBG syndrome
KBG syndrome is a rare genetic condition that can impact growth, development, and intellectual ability. It often leads to distinctive facial features and can present with a wide range of symptoms, affecting individuals from birth.
Overview
KBG syndrome is a rare genetic condition characterised by a combination of developmental differences, distinctive facial features, and skeletal anomalies [PMID:33671049]. It is named after the initials of the first families in whom the condition was identified. While the specific features can vary significantly among individuals, common findings include developmental delay, short stature, and certain tooth abnormalities [PMID:24603952].
The condition is typically diagnosed in childhood, often when parents or healthcare professionals notice developmental milestones are not being met, or when specific physical characteristics become apparent. As a rare condition, the exact number of people affected by KBG syndrome is not well established, but it is thought to be very uncommon.
Symptoms & clinical features
The symptoms of KBG syndrome are varied and can affect many parts of the body. Developmental delay is a common feature, which can include delays in speech, motor skills like walking, and learning. Intellectual disability, ranging from mild to severe, is also frequently observed [PMID:33671049].
Distinctive facial features are often present, though they can be subtle. These may include a triangular-shaped face, wide-set eyes (hypertelorism), a broad nasal bridge, and a long philtrum (the groove between the nose and upper lip). Dental abnormalities, such as widely spaced teeth or abnormally shaped front teeth (macrodontia of the upper central incisors), are also common [PMID:24603952]. Skeletal issues can include short stature, a curved spine (scoliosis), and abnormalities in the ribs or hands.
Other potential symptoms can include behavioural differences, hearing loss, and, less commonly, heart problems or seizures. The specific combination and severity of symptoms are unique to each individual with KBG syndrome.
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Affected organs
KBG syndrome can affect several organ systems. The central nervous system is frequently impacted, leading to developmental delay and intellectual disability. The skeletal system is also commonly involved, resulting in short stature, and various bone anomalies including those affecting the spine, ribs, and hands.
Dental issues primarily affect the teeth, with characteristic features such as macrodontia. Sensory organs can also be affected, as hearing loss is sometimes observed. Although less common, some individuals may experience cardiac issues affecting the heart, or neurological conditions like seizures.
Risks & severity
The severity of KBG syndrome varies considerably between individuals. Some people may have mild developmental delays and subtle physical features, while others experience more significant intellectual disability and a broader range of health challenges. The age of onset for symptoms is typically in early childhood, as developmental delays often become noticeable during infancy or toddlerhood.
While KBG syndrome is a lifelong condition, it is not generally considered life-threatening. The main risks are related to the potential for developmental and intellectual disability, which can impact independence and require ongoing support. Associated medical issues like hearing loss or heart problems, if present, also require management. There are no specific lifetime cancer risks commonly associated with KBG syndrome.
Genetic causes
KBG syndrome is caused by genetic changes in the ANKRD11 gene, located on chromosome 16. The ANKRD11 gene provides instructions for making a protein called ankyrin repeat domain-containing protein 11. This protein is believed to play a critical role in the regulation of gene expression and chromatin remodelling, processes essential for normal growth and development of many tissues, particularly the brain [PMID:33671049].
When there is a pathogenic (disease-causing) variant in the ANKRD11 gene, the protein may not be produced correctly, or it may not function as it should. This disruption to gene regulation during development is thought to be the underlying cause of the diverse symptoms seen in KBG syndrome. Most cases result from a new, spontaneous genetic change (de novo variant) in the affected individual, meaning it was not inherited from either parent.
- ANKRD11 ankyrin repeat domain 11
Inheritance pattern
KBG syndrome is inherited in an autosomal dominant pattern. This means that only one copy of the altered ANKRD11 gene in each cell is sufficient to cause the condition. If a parent has KBG syndrome, there is a 50% chance with each pregnancy that their child will also inherit the condition.
However, in many cases, KBG syndrome occurs due to a new genetic change that arises spontaneously (a de novo variant) in the affected individual and is not present in either parent's genes. In such cases, the parents typically do not have the condition and the risk of having another child with KBG syndrome is low, although genetic counselling is recommended for accurate risk assessment.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of KBG syndrome is typically confirmed through genetic testing. If a doctor suspects KBG syndrome based on a person's clinical features - such as developmental delay, distinctive facial features, or skeletal anomalies - they may recommend genetic testing to look for pathogenic variants in the ANKRD11 gene. This often involves a blood test for DNA analysis.
In the UK, suspected cases may be referred to a clinical genetics service through the NHS Genomic Medicine Service (GMS). Genetic testing for KBG syndrome falls under specific R-codes within the GMS testing directory, such as R27 (Intellectual disability), which covers conditions with developmental delay and distinctive features. A genetic counsellor or clinical geneticist can guide individuals and families through the testing process and explain the results.
Management & lifestyle
Management of KBG syndrome focuses on addressing the individual's specific symptoms and needs. There is no cure for KBG syndrome, so care is supportive and aims to optimise quality of life. This often involves a multidisciplinary team of healthcare professionals.
Developmental delays may be supported through early intervention programmes, including physiotherapy, occupational therapy, and speech and language therapy. Educational support is crucial for individuals with intellectual disabilities. Regular monitoring for hearing loss and dental issues is also recommended. Any specific medical concerns, such as heart problems or seizures, would be managed by relevant specialists following NHS guidelines. Genetic counsellors can provide ongoing support and information to families.
UK care pathway
In the UK, individuals suspected of having KBG syndrome would typically be referred by their GP or another specialist to a regional Clinical Genetics service within the NHS Genomic Medicine Service (GMS). These services provide expert assessment, diagnosis, and genetic counselling. Genetic testing for conditions like KBG syndrome is performed through the GMS testing directory, which includes specific R-codes for developmental disorders and intellectual disability where KBG syndrome may be considered. Genetic counsellors are integral to this pathway, offering information, support, and guidance to families.
Frequently asked questions
Is KBG syndrome always inherited from a parent?
No, not always. While it can be inherited in an autosomal dominant pattern from an affected parent, many cases of KBG syndrome occur spontaneously due to a new genetic change in the ANKRD11 gene that was not present in either parent.
How common is KBG syndrome?
KBG syndrome is considered a rare condition. The exact prevalence is not well established, but it is known to affect a very small number of individuals worldwide.
Are there treatments for KBG syndrome?
There is no cure for KBG syndrome, but management focuses on supporting the individual's specific symptoms. This can include therapies for developmental delays, educational support, and medical management for any associated health issues like hearing loss or heart problems.
What kind of doctors treat KBG syndrome?
Management often involves a team of specialists, which may include paediatricians, clinical geneticists, neurologists, speech and language therapists, occupational therapists, physiotherapists, and educational psychologists. Genetic counsellors also play a key role in supporting families.
Can KBG syndrome be diagnosed before birth?
In some specific circumstances, if a genetic variant has been identified in a family, prenatal genetic testing may be an option. However, it is not routinely performed without a known family history or specific indications.
References
- Parenti I, Mallozzi MB, Hüning I. ANKRD11 variants: KBG syndrome and beyond. Clinical genetics. 2021. PMID: 33955014
- Morel Swols D, Foster J 2nd, Tekin M. KBG syndrome. Orphanet journal of rare diseases. 2017. PMID: 29258554
- Brancati F, Sarkozy A, Dallapiccola B. KBG syndrome. Orphanet journal of rare diseases. 2006. PMID: 17163996
- Adam MP, Bick S, Mirzaa GM. ANKRD11-Related KBG Syndrome. 1993. PMID: 29565525
- Martinez-Cayuelas E, Blanco-Kelly F, Lopez-Grondona F. Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients. Journal of medical genetics. 2023. PMID: 36446582
- Bayat A, Grimes H, de Boer E. Natural history of adults with KBG syndrome: A physician-reported experience. Genetics in medicine : official journal of the American College of Medical Genetics. 2024. PMID: 38818797
- de Boer E, Ockeloen CW, Kampen RA. Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein. Genetics in medicine : official journal of the American College of Medical Genetics. 2022. PMID: 35833929
- Peluso F, Caraffi SG, Contrò G. Deep phenotyping of the neuroimaging and skeletal features in KBG syndrome: a study of 53 patients and review of the literature. Journal of medical genetics. 2023. PMID: 37586838