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Costello syndrome
Costello syndrome is a rare genetic disorder characterised by developmental delay, distinctive facial features, skin and musculoskeletal abnormalities, and an increased risk of certain tumours. It is typically identified in infancy or early childhood.
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Overview
Costello syndrome is a rare condition that affects many parts of the body, including intellectual development, growth, and the heart. It is one of a group of conditions known as RASopathies, which share some common features and are caused by genetic changes affecting the RAS/MAPK signalling pathway [PMID:33651700]. Individuals with Costello syndrome often have characteristic facial features, soft skin, and problems with growth and feeding. The condition can also lead to a higher risk of developing certain benign and malignant tumours.
First described in 1977, Costello syndrome is rare, with exact prevalence figures not well established. It affects individuals from birth and its features can become more apparent as a child grows. Management typically involves a multidisciplinary team of specialists to address the wide range of potential health concerns.
Symptoms & clinical features
The symptoms of Costello syndrome can vary widely among individuals, but common features often include developmental delay, which can affect intellectual and motor skills. Speech development is frequently impacted. Babies with Costello syndrome may experience feeding difficulties, often requiring tube feeding, and have a slower than typical weight gain.
Distinctive physical features commonly associated with the syndrome include coarse facial traits, such as a large mouth and full lips, along with loose, soft skin, particularly on the hands and feet. Musculoskeletal issues, such as joint hypermobility and tight Achilles tendons, are also often observed. Heart abnormalities, including structural defects and rhythm disturbances, are seen in a significant number of individuals [PMID:24077963].
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Affected organs
Costello syndrome can affect a number of body systems. The heart is frequently involved, with potential for structural defects and problems with heart rhythm. The skin often appears loose and soft, with redundant folds, especially on the palms and soles.
The musculoskeletal system can be affected, leading to joint flexibility or stiffness, and sometimes bone abnormalities. The brain and nervous system are impacted, contributing to developmental delay and learning difficulties. Additionally, the gastrointestinal system can be affected, causing feeding challenges in infancy. Certain benign and cancerous tumours, including rhabdomyosarcoma and neuroblastoma, have a higher incidence in individuals with Costello syndrome [PMID:24077963].
Risks & severity
The severity of Costello syndrome can vary considerably between individuals. While many experience developmental delay and significant feeding issues in early life, the specific challenges and their impact differ. The condition is associated with a lifelong risk of certain tumours. Research suggests this risk is elevated compared to the general population, although the exact percentage can vary based on specific tumour types [PMID:24077963].
The most common types of tumours associated with Costello syndrome include rhabdomyosarcoma (a type of muscle cancer) and neuroblastoma (a cancer of nerve cells). Benign (non-cancerous) papillomas, which are wart-like growths, are also frequently observed, particularly around the mouth and nose. Regular monitoring for these tumour types typically forms part of ongoing medical care.
Genetic causes
Costello syndrome is caused by pathogenic variants in the HRAS gene. The HRAS gene provides instructions for making a protein called H-Ras, which is a member of the RAS protein family. These proteins act as molecular switches that are crucial for cell signalling pathways.
The H-Ras protein plays a vital role in controlling important cellular processes such as cell growth, division (proliferation), specialisation (differentiation), and programmed cell death. When the HRAS gene has a pathogenic variant, it typically leads to an overactive H-Ras protein. This overactivity disrupts the normal regulation of cell signalling, which can result in the developmental and physical features seen in Costello syndrome, as well as increasing the risk of tumour formation [PMID:26786192].
- HRAS HRas proto-oncogene, GTPaseThe HRAS gene encodes the H-Ras protein, a key regulator of cell growth, division, and differentiation, involved in signal transduction pathways that influence cellular behaviour.
Inheritance pattern
Costello syndrome is inherited in an autosomal dominant pattern. This means that a person only needs one copy of the HRAS gene to have a pathogenic variant in order to develop the condition. In most cases of Costello syndrome, the genetic change occurs spontaneously (de novo) in the affected individual and is not inherited from either parent. This means that neither parent carries the pathogenic variant.
If a parent has Costello syndrome, there is a 50% chance in each pregnancy that their child will also inherit the pathogenic variant. Genetic counselling is often recommended for families affected by the condition to understand the inheritance patterns and potential risks for future pregnancies.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of Costello syndrome is typically suspected based on characteristic clinical features observed in an individual. This suspicion is then confirmed through genetic testing. Genetic testing involves analysing the HRAS gene to identify specific pathogenic variants.
In the UK, if Costello syndrome is suspected, a clinical genetics service can arrange for genetic testing. This usually involves a blood test to obtain DNA for analysis. The NHS Genomic Medicine Service (GMS) provides diagnostic testing for rare conditions like Costello syndrome, often accessed via R-codes such as R67 for overgrowth syndromes. A referral from a GP or another specialist, such as a paediatrician, is usually required to access these specialist genetic services.
Management & lifestyle
The management of Costello syndrome focuses on addressing the wide range of symptoms and potential health complications. This generally involves a multidisciplinary team of healthcare professionals, including paediatricians, cardiologists, gastroenterologists, and developmental specialists. Regular monitoring for cardiac issues and developmental progress is important.
Due to the increased risk of certain tumours, surveillance protocols are often put in place and may include regular imaging or screening tests, as advised by oncology specialists. Early intervention therapies, such as speech therapy, occupational therapy, and physiotherapy, are crucial to support developmental milestones. Nutritional support, including feeding tube insertion if necessary, can help address feeding difficulties. Management plans are tailored to each individual's specific needs and symptoms, within the framework of the NHS care pathway.
UK care pathway
In the UK, individuals suspected of having Costello syndrome are typically referred to a Clinical Genetics service. These services are part of the NHS Genomic Medicine Service (GMS) and can provide comprehensive assessment and diagnostic testing. Genetic counsellors within these services can offer support and information to families, helping them understand the condition, its inheritance, and implications for relatives.
Genetic testing for Costello syndrome falls under the scope of diagnostic testing for rare constitutional disorders within the NHS GMS. This can be accessed via specific R-codes for conditions presenting with features such as overgrowth or developmental delay. Following a confirmed diagnosis, ongoing care is coordinated by a paediatrician, who will refer to other specialist teams as needed.
Frequently asked questions
Is Costello syndrome always inherited from parents?
No, in most cases, Costello syndrome results from a spontaneous genetic change (de novo variant) in the HRAS gene, meaning it is not inherited from either parent. In rarer situations, an affected parent may pass the condition to their child.
What kind of medical care will a child with Costello syndrome need?
Children with Costello syndrome typically require care from many different specialists. This might include heart doctors (cardiologists), developmental paediatricians, speech and occupational therapists, and geneticists. Regular check-ups and monitoring for potential complications, such as heart problems and tumour risk, are important.
Are there any specific concerns for adults with Costello syndrome?
Adults with Costello syndrome continue to need medical follow-up, particularly regarding cardiac health and tumour surveillance. They may also benefit from ongoing support for developmental and learning needs, and management of any musculoskeletal issues.
What is the likelihood of having another child with Costello syndrome?
If the genetic change causing Costello syndrome occurred spontaneously (de novo) in the first child, the risk of it happening again in a subsequent pregnancy is generally considered low, similar to the general population. If a parent has the condition, the risk is 50% for each child. Genetic counselling can provide personalised risk assessments.
What types of tumours are associated with Costello syndrome?
Individuals with Costello syndrome have an increased risk of developing certain tumours. These can include benign papillomas (wart-like growths) and, less commonly, malignant tumours such as rhabdomyosarcoma and neuroblastoma. Regular screening and monitoring are often recommended.
References
- Hebron KE, Hernandez ER, Yohe ME. The RASopathies: from pathogenetics to therapeutics. Disease models & mechanisms. 2022. PMID: 35178568
- Zenker M. Clinical overview on RASopathies. American journal of medical genetics. Part C, Seminars in medical genetics. 2022. PMID: 36428239
- Rauen KA. The RASopathies. Annual review of genomics and human genetics. 2013. PMID: 23875798
- Bavle A, Shah R, Gross N. Encephalocraniocutaneous Lipomatosis. Journal of pediatric hematology/oncology. 2018. PMID: 29683947
- Perrino MR, Das A, Scollon SR. Update on Pediatric Cancer Surveillance Recommendations for Patients with Neurofibromatosis Type 1, Noonan Syndrome, CBL Syndrome, Costello Syndrome, and Related RASopathies. Clinical cancer research : an official journal of the American Association for Cancer Research. 2024. PMID: 39196581
- Scorrano G, David E, Calì E. The Cardiofaciocutaneous Syndrome: From Genetics to Prognostic-Therapeutic Implications. Genes. 2023. PMID: 38136934
- Jafry M, Sidbury R. RASopathies. Clinics in dermatology. 2020. PMID: 32972603
- Jaeger ZJ, Maverakis Ramirez NKA, Osborne AD. RASopathies. Part II: Cutaneous and extracutaneous manifestations. Journal of the American Academy of Dermatology. 2025. PMID: 40532825