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Kleefstra syndrome
Kleefstra syndrome is a rare genetic condition that usually results in developmental delay, intellectual disability, and particular facial characteristics. It often involves difficulties with speech and can affect several body systems.
Overview
Kleefstra syndrome is a rare genetic disorder that impacts development, leading to a range of features including intellectual disability, developmental delay, and often distinctive facial appearances [PMID:27072911]. The condition was first described in 2004 and is named after Dr. Tjitske Kleefstra, who led the initial research. Individuals with Kleefstra syndrome typically experience varying degrees of developmental challenges.
While the specific features can differ significantly between individuals, common characteristics include global developmental delay, which means reaching developmental milestones later than expected, and intellectual disability. Many affected individuals also present with speech and language difficulties. Although rare, understanding Kleefstra syndrome is important for providing appropriate support and care.
Symptoms & clinical features
The symptoms of Kleefstra syndrome are wide-ranging and can vary in severity. Developmental delay is a core feature, affecting areas such as motor skills, social interaction, and language acquisition [PMID:27072911]. Intellectual disability is almost universally observed, often ranging from moderate to severe. Speech and language impairment is particularly common, with some individuals having very limited verbal communication.
In addition to developmental challenges, individuals with Kleefstra syndrome often have distinctive facial features. These can include a prominent jaw, a short nose with an upturned tip, and widely spaced eyes (hypertelorism) [PMID:22095277]. Other features might include heart defects, kidney problems, epilepsy, and hearing loss. Behavioural differences, such as autistic-like traits, sleep disturbances, and sometimes aggressive behaviour, have also been reported in some individuals.
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Affected organs
Kleefstra syndrome can affect various body systems, though the primary impact is on brain development, leading to neurological and neurodevelopmental symptoms. The brain is therefore the most significantly affected organ, resulting in intellectual disability and developmental delay. Epilepsy, a condition affecting the brain's electrical activity, is also seen in some cases.
Beyond the brain, other organs can be involved. Congenital heart defects are reported in a subset of individuals. Kidney abnormalities, ranging from mild structural changes to more significant problems, may also occur. Hearing loss, affecting the auditory system, and respiratory issues have also been noted in some individuals with the syndrome.
Risks & severity
Kleefstra syndrome presents with a broad spectrum of severity. While all individuals experience developmental delay and intellectual disability, the degree of impairment can vary considerably. Some individuals may achieve limited speech, while others remain non-verbal. The severity of associated medical issues, such as heart defects or kidney problems, also differs.
The condition is present from birth, with developmental delays typically becoming apparent in early childhood. While there are no specific lifetime risk figures for the general population, once diagnosed, the condition requires ongoing medical and supportive care throughout life. The severity and range of symptoms are influenced by the specific genetic change, but precise predictions for any individual are challenging due to the variability observed.
Genetic causes
Kleefstra syndrome is caused by changes (pathogenic variants) in the EHMT1 gene [PMID:22095277]. The EHMT1 gene provides instructions for making a protein called euchromatic histone lysine methyltransferase 1. This protein plays a crucial role in a process called chromatin remodelling, which helps to control how genes are turned on or off in cells.
Specifically, the EHMT1 protein is involved in adding a chemical tag (a methyl group) to a protein called histone H3. This modification is important for regulating gene expression, particularly in the developing brain [PMID:27072911]. When there is a pathogenic variant in the EHMT1 gene, the EHMT1 protein either doesn't work correctly or isn't produced in sufficient amounts. This disruption to gene regulation during development leads to the wide range of features seen in Kleefstra syndrome.
- EHMT1 euchromatic histone lysine methyltransferase 1
Inheritance pattern
Kleefstra syndrome is inherited in an autosomal dominant pattern. This means that a person only needs one altered copy of the EHMT1 gene to develop the condition. In most cases of Kleefstra syndrome, the genetic change occurs spontaneously, meaning it is a new change (a de novo mutation) in the affected individual and is not inherited from either parent. In such instances, the parents typically do not carry the gene change and therefore have a very low risk of having another child with the condition.
However, in rare situations, one parent may have a very mild form of the condition that was previously undiagnosed, or a parent might have germline mosaicism, where the gene change is present in some of their reproductive cells but not in other body cells. If a person with Kleefstra syndrome has children, there is a 50% chance for each child to inherit the altered EHMT1 gene and therefore develop the condition.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
A diagnosis of Kleefstra syndrome is typically suspected based on an individual's clinical features, such as developmental delay, intellectual disability, and distinctive facial characteristics. Confirmation of the diagnosis requires genetic testing. The NHS Genomic Medicine Service (GMS) offers genomic testing for individuals suspected of having genetic conditions like Kleefstra syndrome.
Referral for genetic testing would typically be made by a paediatrician, neurologist, or clinical geneticist. The relevant NHS Genomic Medicine Service 'R-code' for testing for intellectual disability and related conditions would usually be applied. Genetic testing, often involving whole exome sequencing or specific gene panel testing, will look for pathogenic variants in the EHMT1 gene to confirm the diagnosis.
Management & lifestyle
Management of Kleefstra syndrome is supportive and focuses on addressing the individual's specific symptoms and needs. There is no cure for the condition, so care aims to maximise quality of life and developmental potential. Management usually involves a multidisciplinary team of healthcare professionals, including paediatricians, neurologists, geneticists, speech and language therapists, occupational therapists, and physiotherapists.
Interventions may include early developmental therapies to support motor skills and communication, educational support tailored to intellectual disability, and behavioural therapies for challenging behaviours. Regular medical check-ups are important to monitor for associated conditions such as heart defects, kidney problems, epilepsy, and hearing difficulties. Genetic counselling is also recommended for families to understand the inheritance pattern and implications for future pregnancies.
UK care pathway
In the UK, individuals suspected of having Kleefstra syndrome would typically be referred to a clinical genetics service or a specialist paediatrician via their GP. This initiates the pathway for diagnostic genomic testing through the NHS Genomic Medicine Service (GMS). Genetic counsellors play a vital role in explaining the condition, inheritance patterns, and supporting families through the diagnostic process and beyond. The specific genetic test for Kleefstra syndrome would be covered under relevant GMS 'R-codes' for developmental disorders and intellectual disability.
Frequently asked questions
Is Kleefstra syndrome inherited?
Most cases of Kleefstra syndrome are caused by a new genetic change (de novo mutation) that occurs spontaneously in the affected individual and is not inherited from their parents. However, in rare instances, it can be inherited from a parent, usually if they have a very mild or undiagnosed form, or if they have germline mosaicism.
What kind of support is available for individuals with Kleefstra syndrome?
Support for individuals with Kleefstra syndrome is tailored to their specific needs and can include developmental therapies like speech and language therapy, occupational therapy, and physiotherapy. Educational support, behavioural interventions, and regular medical check-ups for associated health issues are also important.
What are the common developmental challenges in Kleefstra syndrome?
Common developmental challenges include global developmental delay, meaning slower progress in motor skills, social interaction, and cognitive abilities. Intellectual disability is almost always present, often accompanied by significant speech and language difficulties.
How is Kleefstra syndrome diagnosed in the UK?
Diagnosis in the UK typically begins with clinical suspicion by a paediatrician or geneticist. Confirmation requires genetic testing, usually performed through the NHS Genomic Medicine Service, which identifies pathogenic variants in the EHMT1 gene.
Can the severity of Kleefstra syndrome vary?
Yes, the severity of Kleefstra syndrome can vary significantly between individuals. While all affected individuals have developmental delay and intellectual disability, the degree of these challenges and the presence of other medical issues like heart or kidney problems can differ widely.
References
- Rots D, Choufani S, Faundes V. Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes. American journal of human genetics. 2024. PMID: 39013459
- Adam MP, Bick S, Mirzaa GM. Kleefstra Syndrome. 1993. PMID: 20945554
- Perrot A, Rickert-Sperling S. Human Genetics of Ventricular Septal Defect. Advances in experimental medicine and biology. 2024. PMID: 38884729
- Aydin H, Bucak IH, Bagis H. Kleefstra Syndrome. Journal of the College of Physicians and Surgeons--Pakistan : JCPSP. 2022. PMID: 35633020
- Rots D, Bouman A, Yamada A. Comprehensive EHMT1 variants analysis broadens genotype-phenotype associations and molecular mechanisms in Kleefstra syndrome. American journal of human genetics. 2024. PMID: 39013458
- Bouman A, Gaasterland CMW, Sloof-Enthoven C. International clinical evidence-based guideline for Kleefstra syndrome. Genetics in medicine : official journal of the American College of Medical Genetics. 2026. PMID: 41578867
- Ren R, Liu Y, Liu P. Clinical characteristics and genetic analysis of four pediatric patients with Kleefstra syndrome. BMC medical genomics. 2024. PMID: 39696517
- Morison LD, Kennis MGP, Rots D. Expanding the phenotype of Kleefstra syndrome: speech, language and cognition in 103 individuals. Journal of medical genetics. 2024. PMID: 38290825