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Ehlers-Danlos syndrome (kyphoscoliotic)
kEDS is a rare inherited condition that affects the body's connective tissues, which provide strength and support. Individuals with kEDS typically experience severe spinal curvature, joint hypermobility, and fragile tissues, impacting various body systems from birth.
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Overview
Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is one of the rarer types within the Ehlers-Danlos syndromes (EDS), a group of inherited conditions affecting connective tissue. Connective tissue is the material that provides strength and support to many parts of the body, including skin, bones, blood vessels, and organs. In kEDS, the connective tissue is unusually fragile and stretchy, leading to a range of features that are typically present from birth or early childhood.
The most prominent features of kEDS include significant curvature of the spine (kyphoscoliosis), pronounced joint flexibility (hypermobility), and very soft, often fragile skin. The condition can also affect muscle tone and the eyes. Because connective tissue is widespread throughout the body, the impact of kEDS can be wide-ranging, although its severity can vary between individuals. This condition is considered rare, though exact prevalence figures are not well established.
Symptoms & clinical features
The clinical features of kEDS are typically evident from birth or early infancy. A hallmark symptom is congenital muscle hypotonia, meaning reduced muscle tone at birth, which can lead to delays in motor development such as sitting or walking. Progressive kyphoscoliosis, a combined sideways and forward curvature of the spine, is a defining feature and can become severe, often requiring intervention [PMID:27876121].
Joint hypermobility is another prominent symptom, leading to frequent joint dislocations or subluxations (partial dislocations). The skin is often described as soft, velvety, and stretchy, and may be prone to easy bruising and scarring. Other signs can include scleral fragility, making the whites of the eyes appear bluish, and abnormalities in blood vessels, although these are generally less severe than in some other EDS types. Respiratory complications due to severe kyphoscoliosis can also occur.
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Affected organs
kEDS primarily affects the skeletal system, leading to severe and progressive kyphoscoliosis, joint instability, and dislocations. The muscles are also affected, with generalised hypotonia present from birth. The skin is commonly involved, being soft, hyperextensible, and fragile, leading to easy bruising and poor wound healing.
While less common, some individuals may experience complications related to blood vessels or ocular tissues. For example, the sclera (the white outer layer of the eyeball) can be thin and fragile, potentially leading to blue sclera. In rare cases, arterial rupture has been reported, highlighting the systemic nature of connective tissue dysfunction, although this is not as characteristic as in vascular EDS [PMID:27876121].
Risks & severity
The severity of kEDS can vary, but it is generally considered a severe form of Ehlers-Danlos syndrome. The progressive nature of kyphoscoliosis means that spinal curvature can worsen over time, potentially leading to respiratory and cardiac complications if severe enough to restrict lung function. The age of onset for most features is typically at birth or during early childhood.
Individuals with kEDS face lifelong challenges due to joint instability, chronic pain, and potential complications from fragile tissues. While the risk of life-threatening vascular events is generally lower than in vascular EDS, it remains a consideration in some cases. Early diagnosis and ongoing medical management are crucial to address symptoms, prevent complications, and improve quality of life.
Genetic causes
Kyphoscoliotic Ehlers-Danlos syndrome is caused by pathogenic variants (genetic changes) in specific genes involved in the processing of collagen, a key protein in connective tissue. The two genes most commonly associated with kEDS are PLOD1 and FKBP14.
Pathogenic variants in PLOD1 account for the majority of kEDS cases. This gene provides instructions for making an enzyme called procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (also known as lysyl hydroxylase 1). This enzyme plays a critical role in modifying collagen by adding hydroxyl groups to lysine residues, a process essential for collagen to form stable cross-links. When PLOD1 is not functioning correctly, collagen cross-linking is impaired, leading to unstable connective tissue [PMID:20301725]. More recently, pathogenic variants in FKBP14 have been identified as a cause of kEDS. The FKBP14 gene provides instructions for making a protein that assists in the folding and processing of collagen. Changes in FKBP14 can also disrupt the normal structure and function of collagen, leading to the characteristic features of kEDS.
- FKBP14 FKBP prolyl isomerase 14
- PLOD1 procollagen-lysine,2-oxoglutarate 5-dioxygenase 1The PLOD1 gene provides instructions for an enzyme called lysyl hydroxylase 1, which plays a crucial role in the proper formation and stability of collagen fibres, essential for connective tissue strength.
Inheritance pattern
kEDS is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of a pathogenic variant - one from each parent - to develop the condition. People who have only one copy of a pathogenic variant in a gene associated with kEDS are called carriers. Carriers typically do not show symptoms of the condition because their other working copy of the gene can compensate.
If both parents are carriers of a pathogenic variant for kEDS, there is a 25% (1 in 4) chance with each pregnancy that their child will inherit two altered copies and develop kEDS. There is a 50% (2 in 4) chance that their child will be a carrier, and a 25% (1 in 4) chance that their child will inherit two normal copies of the gene and neither have the condition nor be a carrier. Family members of an affected individual may be offered genetic counselling to understand their own carrier status and reproductive risks.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
The diagnosis of kEDS is typically suspected based on characteristic clinical features, including severe kyphoscoliosis, generalised joint hypermobility, muscle hypotonia from birth, and skin fragility. However, because other connective tissue disorders can share some of these features, genetic testing is usually required to confirm the diagnosis and identify the specific genetic cause.
Genetic testing for kEDS involves looking for pathogenic variants in the PLOD1 and FKBP14 genes. This can be performed through DNA sequencing, often as part of a larger gene panel for connective tissue disorders or Ehlers-Danlos syndromes. In the UK, such testing is generally accessed through the NHS Genomic Medicine Service following a referral to a clinical genetics specialist. The relevant NHS National Genomic Test Directory R-codes would guide which specific tests are available.
Management & lifestyle
Management of kEDS is multidisciplinary and focuses on addressing symptoms and preventing complications. Due to the progressive nature of kyphoscoliosis, regular orthopaedic assessment is essential, and surgical intervention may be required to correct severe spinal curvature. Physiotherapy is crucial for managing muscle hypotonia, improving muscle strength, and maintaining joint function, while occupational therapy can help with daily living activities.
Skin fragility requires careful management to prevent injury and promote wound healing. Eye examinations are important, especially if blue sclera or other ocular concerns are present. Regular follow-up with a team of specialists, including orthopaedic surgeons, physiotherapists, geneticists, and potentially ophthalmologists, is essential. There is no specific cure for kEDS, so management aims to optimise quality of life through supportive care, symptom relief, and early intervention for potential complications.
UK care pathway
In the UK, individuals suspected of having kEDS are typically referred to a clinical genetics service by their GP or another specialist. A clinical geneticist will assess symptoms, review family history, and may arrange for genetic testing through the NHS Genomic Medicine Service. The NHS National Genomic Test Directory outlines the available genetic tests, identified by specific R-codes, that laboratories can offer.
Following a diagnosis, ongoing care is generally coordinated through specialist centres or multidisciplinary teams, involving various healthcare professionals such as orthopaedic surgeons, physiotherapists, and paediatricians (for children). Genetic counsellors play a vital role in providing information and support to individuals and families regarding the condition, inheritance patterns, and reproductive options.
Frequently asked questions
What is the life expectancy for someone with kEDS?
Life expectancy for individuals with kEDS can vary. While severe forms of kEDS can lead to significant complications, especially related to respiratory function due to spinal curvature, advancements in medical and surgical management have improved outcomes. Regular monitoring and proactive treatment of complications are important.
Can kEDS be prevented?
No, kEDS is a genetic condition present from birth and cannot be prevented. If you have a family history of kEDS, genetic counselling can help you understand the inheritance pattern and the risk of passing the condition on to future children.
Is kEDS the same as hypermobile Ehlers-Danlos syndrome (hEDS)?
No, kEDS and hypermobile EDS (hEDS) are different types of Ehlers-Danlos syndrome. While both involve joint hypermobility, kEDS is specifically characterised by severe kyphoscoliosis and muscle hypotonia from birth, and it has known genetic causes (PLOD1 or FKBP14). hEDS is currently diagnosed based on clinical criteria and its genetic cause is largely unknown.
How is the kyphoscoliosis managed in kEDS?
Management of kyphoscoliosis in kEDS often involves regular orthopaedic assessments. Depending on the severity and progression of the spinal curve, treatment options can range from bracing, especially in childhood, to surgical correction to stabilise the spine and prevent further complications, such as respiratory compromise.
What kind of exercise is safe for someone with kEDS?
Physical activity for individuals with kEDS should be carefully tailored by physiotherapists experienced in connective tissue disorders. Low-impact exercises that strengthen muscles around joints without putting excessive strain on them are generally recommended. Activities that involve high impact, sudden twisting, or extreme joint movements should typically be avoided to prevent dislocations and injuries.
References
- Quade A, Wiesmann M, Weis J. Stroke in Ehlers-Danlos Syndrome Kyphoscoliotic Type: Dissection or Vasculitis? Pediatric neurology. 2017. PMID: 28739362
- Semyachkina AN, Nikolaeva EA, Galeeva NM. Ehlers-Danlos syndrome kyphoscoliotic type 2 caused by mutations in the FKBP14 gene: an analysis of five cases. F1000Research. 2021. PMID: 34504686
- Solinski MA, Blair MP, Dietz H. FEVR findings in patients with Loeys-Dietz syndrome type II. Ophthalmic genetics. 2018. PMID: 30406707
- van Dijk FS, Mancini GMS, Maugeri A. Ehlers Danlos syndrome, kyphoscoliotic type due to Lysyl Hydroxylase 1 deficiency in two children without congenital or early onset kyphoscoliosis. European journal of medical genetics. 2017. PMID: 28757364
- Liang B, Yu D, Zhao W. Prenatal diagnosis of fetuses with region of homozygosity detected by single nucleotide polymorphism array: a retrospective cohort study. Journal of human genetics. 2022. PMID: 35896820