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Hajdu-Cheney syndrome
This rare condition results from changes in the NOTCH2 gene, impacting bone growth and other bodily systems. Individuals with Hajdu-Cheney syndrome often present with distinctive facial features, skeletal abnormalities, and, in some cases, other health challenges.
Overview
Hajdu-Cheney syndrome is a very rare genetic condition that primarily affects the development of bones and connective tissues throughout the body [PMID:33679844]. It is characterised by a range of skeletal abnormalities, often leading to a distinctive appearance. Beyond the skeleton, the condition can also involve other body systems, though the severity and specific features can vary significantly among affected individuals [PMID:30138902].
The condition was first described in the mid-20th century, and its genetic basis was later identified. Because of its rarity, exact prevalence figures are not well established, but it is considered to be exceptionally uncommon. Awareness and understanding of Hajdu-Cheney syndrome help in early diagnosis and appropriate management.
Symptoms & clinical features
Individuals with Hajdu-Cheney syndrome typically exhibit a range of skeletal and other physical features. Common skeletal characteristics include acro-osteolysis, which is the progressive shortening and destruction of the bones at the ends of the fingers and toes [PMID:33679844]. Other bone anomalies can include osteoporosis (reduced bone density), short stature, and abnormalities of the skull and spine.
Characteristic craniofacial features may include a prominent forehead, widely spaced eyes, a small lower jaw, and a 'wormian' appearance of skull bones due to numerous small, irregular bones. Other potential features can involve loose joints, muscle weakness, and, in some cases, kidney problems, heart defects, or neurological issues such as developmental delay. The specific combination and severity of these symptoms vary greatly from person to person.
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Affected organs
Hajdu-Cheney syndrome primarily affects the skeletal system. This includes the bones of the hands, feet, skull, spine, and ribs. The process of bone resorption and formation is disrupted, leading to issues like acro-osteolysis and osteoporosis. Connective tissues, which provide support and structure to organs, can also be impacted.
While the skeleton is most prominently affected, other organs and systems can be involved. These may include the kidneys, leading to renal cysts or impaired function; the heart, with potential structural abnormalities; and the brain, sometimes resulting in developmental differences or neurological symptoms. Dental anomalies, such as delayed tooth eruption or missing teeth, are also commonly reported.
Risks & severity
Hajdu-Cheney syndrome presents with a broad spectrum of severity, even within the same family. Some individuals may have milder skeletal changes that are identified later in life, while others experience more pronounced and widespread issues from an early age. The progressive nature of acro-osteolysis means that bone changes in the extremities can worsen over time.
Complications such as frequent fractures due to osteoporosis, chronic pain, and mobility limitations are potential risks. The involvement of other organ systems, such as renal or cardiac issues, can contribute to the overall health challenges. While the condition can impact quality of life, careful monitoring and supportive management can help address many of these concerns. Life expectancy can be variable depending on the severity of organ involvement, particularly kidney or heart issues, but many individuals live into adulthood.
Genetic causes
Hajdu-Cheney syndrome is caused by pathogenic variants in the NOTCH2 gene [PMID:30138902]. This gene provides instructions for making a protein called Notch 2, which plays a critical role in cellular communication and the development of many tissues, particularly during embryonic development. Notch signalling is essential for the proper formation of bones, blood vessels, and other organs.
Pathogenic changes in NOTCH2 typically lead to a gain-of-function effect, meaning the altered protein becomes overactive or resistant to normal regulation [PMID:21671047]. This overactivity disrupts the normal balance of cell growth and differentiation, particularly in bone remodelling, where there is an imbalance between bone formation and bone breakdown. This leads to the characteristic features of Hajdu-Cheney syndrome, such as excessive bone resorption in the extremities and generalised osteoporosis.
- NOTCH2 notch receptor 2
Inheritance pattern
Hajdu-Cheney syndrome is inherited in an autosomal dominant pattern. This means that only one altered copy of the NOTCH2 gene in each cell is sufficient to cause the condition. In many cases, the genetic change occurs spontaneously (a 'de novo' variant) in the affected individual and is not inherited from a parent. However, if an affected individual has children, each child has a 50% chance of inheriting the altered gene and therefore developing the condition.
It is important for affected individuals and their families to discuss inheritance patterns with a clinical geneticist or genetic counsellor. This can help clarify the risks for other family members and inform family planning decisions. Genetic counselling can provide support and information regarding the genetic basis of the condition.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of Hajdu-Cheney syndrome is often suspected based on the characteristic clinical features, particularly the distinctive skeletal abnormalities and facial appearance. Imaging studies, such as X-rays, are crucial for identifying skeletal features like acro-osteolysis, osteoporosis, and skull anomalies.
A definitive diagnosis is confirmed through genetic testing, which looks for pathogenic variants in the NOTCH2 gene. In the UK, genetic testing for suspected cases of Hajdu-Cheney syndrome can be requested by a clinical geneticist or other specialist via the NHS Genomic Medicine Service. This typically falls under specific R-codes for rare skeletal disorders. Referral to clinical genetics services is usually the first step for individuals with suspected genetic conditions.
Management & lifestyle
Management for Hajdu-Cheney syndrome is primarily supportive, focusing on addressing the specific symptoms and potential complications as they arise. This often involves a multidisciplinary team of specialists, including orthopaedic surgeons, endocrinologists, nephrologists, and physiotherapists.
For skeletal issues, treatments may include medication to improve bone density and reduce fracture risk, such as bisphosphonates. Pain management, physical therapy to maintain mobility, and orthopaedic interventions for severe skeletal deformities are also important. Regular monitoring for potential kidney or heart complications is recommended. Genetic counsellors can provide valuable support and information throughout the management pathway, helping families understand the condition and navigate care options within the NHS.
UK care pathway
In the UK, individuals suspected of having Hajdu-Cheney syndrome would typically be referred to a Clinical Genetics service. These services are part of the NHS Genomic Medicine Service, which provides specialised care for rare and genetic conditions. A clinical geneticist can confirm a diagnosis through genetic testing, often utilising relevant R-codes for skeletal dysplasias.
Once a diagnosis is made, ongoing care involves a multidisciplinary team coordinated through the NHS. Access to genetic counsellors is also available, offering support and detailed information about the condition, inheritance, and family planning considerations.
Frequently asked questions
Is Hajdu-Cheney syndrome always inherited from a parent?
No, not always. While it follows an autosomal dominant inheritance pattern, many cases of Hajdu-Cheney syndrome are due to a new genetic change (a 'de novo' variant) that occurs spontaneously in the affected individual and is not inherited from either parent. A clinical geneticist or genetic counsellor can discuss your specific family situation.
What kind of doctors treat Hajdu-Cheney syndrome?
Due to the varied symptoms, care for Hajdu-Cheney syndrome typically involves a team of specialists. This may include orthopaedic doctors for bone issues, endocrinologists for bone density, kidney specialists (nephrologists), heart specialists (cardiologists), and neurologists, all coordinated through your NHS care pathway.
Can the symptoms of Hajdu-Cheney syndrome get worse over time?
Some symptoms, particularly the bone changes like acro-osteolysis (shortening of finger and toe bones) and osteoporosis (reduced bone density), can be progressive and worsen over time. Regular monitoring and appropriate management are important to address these changes and help maintain quality of life.
Is there a cure for Hajdu-Cheney syndrome?
Currently, there is no cure for Hajdu-Cheney syndrome. However, management focuses on treating the specific symptoms and preventing complications. This can involve medications to strengthen bones, pain management, physical therapy, and interventions for organ-specific issues. Ongoing research may lead to new therapies in the future.
Where can I find support for Hajdu-Cheney syndrome in the UK?
For support in the UK, your NHS clinical genetics team and genetic counsellor can provide resources and connections to patient advocacy groups. Organisations dedicated to rare diseases or skeletal conditions may also offer valuable support networks and information for individuals and families affected by Hajdu-Cheney syndrome.
References
- Susin C, Stadler AF, Haas A. Periodontal Manifestations of Systemic Diseases. Journal of periodontal research. 2025. PMID: 40956006
- Canalis E, Zanotti S. Hajdu-Cheney syndrome: a review. Orphanet journal of rare diseases. 2014. PMID: 25491639
- Aida N, Ohno T, Azuma T. Progress and Current Status in Hajdu-Cheney Syndrome with Focus on Novel Genetic Research. International journal of molecular sciences. 2022. PMID: 36232677
- Samuel SS, Shetty S, Arunachal G. Hajdu Cheney Syndrome. Journal of clinical and diagnostic research : JCDR. 2016. PMID: 27042504
- Spodzieja K, Olczak-Kowalczyk D. Premature Loss of Deciduous Teeth as a Symptom of Systemic Disease: A Narrative Literature Review. International journal of environmental research and public health. 2022. PMID: 35329073
- Cortés-Martín J, Díaz-Rodríguez L, Piqueras-Sola B. Hajdu-Cheney Syndrome: A Systematic Review of the Literature. International journal of environmental research and public health. 2020. PMID: 32854429
- Canalis E. Clinical and experimental aspects of notch receptor signaling: Hajdu-Cheney syndrome and related disorders. Metabolism: clinical and experimental. 2018. PMID: 28941602
- Falls CJ, Page PS, Stadler JA. Craniospinal Surgery in Hajdu-Cheney Syndrome: A Review of Case Reports. Cureus. 2021. PMID: 35070539