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Cornelia de Lange syndrome
CdLS is a genetic condition typically characterised by distinctive facial features, slow growth before and after birth, limb abnormalities, and intellectual disability. Its severity varies widely among affected individuals.
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Overview
Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that can affect many parts of the body. It is often apparent from birth, presenting with a range of physical, developmental, and cognitive challenges. The features of CdLS can vary significantly, even within the same family [PMID:31855913]. Some individuals may have mild symptoms, while others experience more severe health issues and greater developmental delays.
CdLS is estimated to affect between 1 in 10,000 and 1 in 30,000 newborns. The condition is usually diagnosed based on a combination of characteristic physical features, developmental assessment, and genetic testing. Early diagnosis allows for timely interventions and support to help manage the various aspects of the syndrome.
Symptoms & clinical features
Individuals with Cornelia de Lange syndrome commonly exhibit a range of characteristic features. These often include distinctive facial traits such as thick, arched eyebrows that may meet in the middle (synophrys), long eyelashes, a short nose with an upturned tip, and thin lips turned downwards [PMID:31855913]. Growth delays are typical, often starting before birth (intrauterine growth restriction) and continuing throughout childhood, resulting in short stature.
Skeletal abnormalities, particularly affecting the limbs, are also common. These can range from small hands and feet to more noticeable differences like fused or missing fingers, and forearm bone differences. Other potential symptoms include intellectual disability, which can vary from mild learning difficulties to more severe cognitive impairment. Gastrointestinal issues, hearing loss, heart defects, and seizures may also affect some individuals with CdLS [PMID:31855913].
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Affected organs
Cornelia de Lange syndrome can impact various organ systems throughout the body. Growth plates and bones are often affected, leading to short stature and limb abnormalities. The brain is also consistently involved, resulting in intellectual disability and developmental delays, and sometimes seizures. The gastrointestinal system may experience issues such as feeding difficulties, gastro-oesophageal reflux, and bowel problems.
Other organs that can be affected include the heart, with some individuals having congenital heart defects. The kidneys and urinary system may also be impacted. Hearing impairment, often due to abnormalities in the ear structures, is another common feature. Vision problems, such as short-sightedness or drooping eyelids, can also occur.
Risks & severity
The severity of Cornelia de Lange syndrome can vary considerably, from very mild presentations that may go undiagnosed for some time, to severe forms requiring extensive medical care. The specific gene involved and the type of genetic change can influence the spectrum of symptoms an individual experiences. For instance, changes in the NIPBL gene are generally associated with more typical and often more severe forms of CdLS [PMID:20301725].
Individuals with CdLS may have an increased risk of certain medical complications, including recurrent infections, gastrointestinal complications, and, less commonly, heart or kidney problems. The life expectancy for individuals with CdLS is variable and depends largely on the severity of the associated medical issues and the availability of appropriate medical care. Early intervention and supportive therapies can play a crucial role in improving outcomes and quality of life.
Genetic causes
Cornelia de Lange syndrome is primarily caused by genetic changes (variants) in genes that are involved in the cohesin complex. This complex of proteins is crucial for maintaining the structure of chromosomes and regulating various cell processes, including cell division and gene expression. Approximately 60-70% of individuals with CdLS have a variant in the NIPBL gene [PMID:20301725]. The NIPBL gene provides instructions for making a protein called delangin, which helps load the cohesin complex onto chromosomes.
Other genes associated with CdLS include SMC1A and SMC3. These genes encode components of the cohesin complex itself. When there are pathogenic variants in NIPBL, SMC1A, or SMC3, the cohesin complex may not function correctly. This disruption can lead to problems with normal development, affecting many parts of the body and resulting in the characteristic features of CdLS.
- NIPBL NIPBL cohesin loading factorThe NIPBL gene provides instructions for producing the delangin protein, which is critical for chromosome organisation during cell division and plays a key role in human development.
- SMC1A structural maintenance of chromosomes 1AThe SMC1A gene is crucial for chromosome organisation and DNA repair, and plays a role in conditions such as Cornelia de Lange syndrome and specific forms of epilepsy.
- SMC3 structural maintenance of chromosomes 3The SMC3 gene provides instructions for a protein that is a key component of the cohesin complex, which plays a critical role in chromosome structure, cell division, and DNA repair.
Inheritance pattern
Cornelia de Lange syndrome typically follows an autosomal dominant inheritance pattern. This means that a person only needs one copy of an altered gene in each cell to develop the condition. In most cases of CdLS, the genetic change occurs spontaneously (de novo) in the affected individual, meaning it is not inherited from either parent [PMID:20301725].
When a genetic change is de novo, the parents typically do not carry the altered gene, and the chance of having another child with CdLS is very low. However, in a small number of families, one parent may have a very mild form of CdLS or 'germline mosaicism', where the genetic variant is present in some, but not all, of their reproductive cells. In such rare instances, the chance of having another affected child can be higher. Genetic counselling is important for families to understand these risks.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
The diagnosis of Cornelia de Lange syndrome is often first suspected based on the presence of characteristic physical features and developmental delays. A healthcare professional, typically a paediatrician or clinical geneticist, will examine the individual and review their medical history. If CdLS is suspected, genetic testing is usually recommended to confirm the diagnosis.
Genetic testing for CdLS commonly involves testing for variants in the NIPBL, SMC1A, and SMC3 genes. This testing is crucial as it can confirm the specific genetic cause, which may help predict the range of features an individual might experience and inform genetic counselling. In the UK, genetic testing for suspected inherited intellectual disability and related developmental disorders, including CdLS, can be accessed via the NHS Genomic Medicine Service (GMS) pathways, often initiated by referral from a specialist to regional Clinical Genetics services. The relevant R-code for genomic testing in these contexts would be determined by the regional Genomic Laboratory Hub.
Management & lifestyle
While there is currently no cure for Cornelia de Lange syndrome, management focuses on addressing specific symptoms and developmental challenges to improve an individual's quality of life. This often involves a multidisciplinary team approach, including paediatricians, geneticists, developmental specialists, gastroenterologists, cardiologists, and other relevant specialists.
Management strategies can include therapies such as speech therapy, occupational therapy, and physical therapy to support developmental progress. Regular monitoring for potential complications such as feeding difficulties, gastro-oesophageal reflux, heart defects, hearing loss, and seizures is important. In the UK, individuals with suspected or confirmed CdLS would typically be managed through local NHS services, with referrals to specialist centres as needed. Genetic counsellors can provide essential support and information to families regarding the genetics of the condition and future family planning.
UK care pathway
In the UK, individuals suspected of having Cornelia de Lange syndrome are typically referred to a clinical geneticist or a paediatric neurologist as part of the NHS Genomic Medicine Service (GMS) pathway. These specialists can assess clinical features, coordinate diagnostic genomic testing, and provide a confirmed genetic diagnosis. Genetic counsellors play a vital role in explaining inheritance patterns, recurrence risks, and supporting families through the diagnostic process and beyond.
Frequently asked questions
What causes Cornelia de Lange syndrome?
Cornelia de Lange syndrome is caused by changes in certain genes, most commonly NIPBL, SMC1A, and SMC3. These genes are important for how cells develop and function, particularly in forming and maintaining chromosome structure. These genetic changes usually occur by chance rather than being inherited from parents.
Are there different types of Cornelia de Lange syndrome?
While typically referred to as one syndrome, the severity and specific features of Cornelia de Lange syndrome can vary greatly. This variability is often linked to which gene has a change and the precise nature of that change. Healthcare professionals may refer to a 'spectrum' of CdLS due to this wide range of presentations.
Can Cornelia de Lange syndrome be inherited?
In most cases, Cornelia de Lange syndrome is not inherited; it results from a new genetic change in the affected individual. However, in rare situations, a parent might have a very mild form of the condition or carry the genetic change in some of their reproductive cells (germline mosaicism), which can lead to a slightly increased chance of having another affected child. Genetic counselling is available to discuss these risks.
What kind of support is available for individuals with CdLS in the UK?
In the UK, individuals with Cornelia de Lange syndrome can access support through various NHS services. This includes specialists such as paediatricians, geneticists, and therapists for developmental support. Advocacy groups and charities also offer valuable resources and community support for families affected by CdLS.
What is the life expectancy for someone with Cornelia de Lange syndrome?
Life expectancy for individuals with Cornelia de Lange syndrome varies significantly. It depends largely on the severity of the associated medical complications, such as heart defects or severe feeding issues. With good medical care and management of symptoms, many individuals with CdLS can live into adulthood, sometimes with a near-normal lifespan for milder forms.
References
- Kline AD, Moss JF, Selicorni A. Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement. Nature reviews. Genetics. 2018. PMID: 29995837
- Kaur M, Blair J, Devkota B. Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms. American journal of medical genetics. Part A. 2023. PMID: 37377026
- Parenti I, Mallozzi MB, Hüning I. ANKRD11 variants: KBG syndrome and beyond. Clinical genetics. 2021. PMID: 33955014
- Boyle MI, Jespersgaard C, Brøndum-Nielsen K. Cornelia de Lange syndrome. Clinical genetics. 2015. PMID: 25209348
- Olley G, Pradeepa MM, Grimes GR. Cornelia de Lange syndrome-associated mutations cause a DNA damage signalling and repair defect. Nature communications. 2021. PMID: 34035299
- Deschamps GN. Cornelia de Lange Syndrome. Neonatal network : NN. 2022. PMID: 35644361
- Liu J, Baynam G. Cornelia de Lange syndrome. Advances in experimental medicine and biology. 2010. PMID: 20687500
- Gupta D, Goyal S. Cornelia de-Lange syndrome. Journal of the Indian Society of Pedodontics and Preventive Dentistry. 2005. PMID: 15858306