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Ehlers-Danlos syndrome (kyphoscoliotic)
kEDS is characterised by marked joint hypermobility, fragile and hyperextensible skin, and progressive curvature of the spine. It is a lifelong condition affecting individuals from birth, and its severity can vary.
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Overview
Ehlers-Danlos syndrome (kyphoscoliotic), often referred to as kEDS, is a rare genetic disorder that impacts connective tissue. Connective tissue provides strength and elasticity to many parts of the body, including skin, joints, blood vessels, and internal organs. In kEDS, a fault in the development of collagen, a key protein in connective tissue, leads to its characteristic features [PMID:33678703]. This can result in symptoms such as very flexible joints, skin that stretches easily, and a curved spine.
kEDS is one of the rarer types of Ehlers-Danlos syndromes. It is present from birth, though some symptoms may become more apparent as a child grows. The specific set of symptoms and their severity can differ significantly between individuals, even within the same family.
Symptoms & clinical features
The main features of kEDS include pronounced joint hypermobility, fragile and easily stretched skin, and kyphoscoliosis, which is a combination of outward (kyphosis) and sideways (scoliosis) curvature of the spine. Joint hypermobility means that joints can move beyond the typical range, leading to dislocations or subluxations, where joints partially come out of place [PMID:33678703].
Skin involvement typically manifests as skin that is soft, smooth, easily bruised, and prone to poor wound healing, often resulting in wide, atrophic (thinned) scars. Other potential symptoms can include fragile blood vessels, eye abnormalities such as scleral fragility (weakness in the white part of the eye), and problems with muscle tone (hypotonia) [PMID:28723696]. This low muscle tone can contribute to developmental delays in infants, such as sitting and walking later than expected.
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Affected organs
kEDS primarily affects organs and systems rich in collagen, which is widespread throughout the body. The skeletal system is notably impacted, leading to issues like kyphoscoliosis, joint hypermobility, and a tendency for bone fractures. The skin is also significantly affected, becoming thin, fragile, and prone to easy bruising and scarring.
Less commonly, other systems may be involved. Ocular (eye) issues, such as fragility of the sclera, can occur. Some individuals may experience vascular fragility, meaning blood vessels are weaker and more susceptible to damage. Connective tissue weakness can also affect various internal organs, potentially leading to complications, though these are generally less common than the musculoskeletal and skin manifestations.
Risks & severity
The severity of kyphoscoliotic Ehlers-Danlos syndrome can vary widely among affected individuals. Spinal curvature (kyphoscoliosis) is often progressive and may become severe over time, potentially impacting breathing and heart function in some cases. Joint dislocations are common and can contribute to chronic pain and reduced mobility.
While kEDS is considered a lifelong condition, careful management can help improve quality of life. The risk of serious vascular complications, such as arterial rupture, appears to be lower in kEDS compared to some other types of Ehlers-Danlos syndrome, but fragile blood vessels can still be a concern for some individuals. The exact prevalence of kEDS is not well established, but it is considered a very rare condition.
Genetic causes
Kyphoscoliotic Ehlers-Danlos syndrome is caused by pathogenic variants (sometimes called mutations) in specific genes involved in collagen synthesis and modification. The most commonly identified genes are PLOD1 and FKBP14.
The PLOD1 gene provides instructions for making an enzyme called procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1. This enzyme is crucial for modifying collagen after it has been produced, ensuring it gains the necessary strength and stability. Pathogenic variants in PLOD1 lead to a deficiency of this enzyme, resulting in improperly formed collagen that lacks structural integrity [PMID:28723696].
The FKBP14 gene provides instructions for making the FKBP14 protein, which also plays a role in processing and folding collagen. Pathogenic variants in FKBP14 disrupt this process, leading to the production of faulty collagen. Both genetic causes result in defective collagen, which underlies the symptoms observed in kEDS.
- FKBP14 FKBP prolyl isomerase 14
- PLOD1 procollagen-lysine,2-oxoglutarate 5-dioxygenase 1The PLOD1 gene provides instructions for producing lysyl hydroxylase 1, an enzyme vital for the proper formation and stability of collagen, a key component of connective tissues.
Inheritance pattern
kEDS is inherited in an autosomal recessive pattern. This means that a person must inherit two copies of a pathogenic variant - one from each parent - to develop the condition. If a person inherits only one copy of a pathogenic variant, they are considered a carrier. Carriers typically do not show symptoms of the condition themselves, but they can pass the variant on to their children.
When both parents are carriers of the same pathogenic variant for kEDS, there is a 25% (1 in 4) chance with each pregnancy that their child will inherit two copies of the variant and develop the condition. There is a 50% (1 in 2) chance that their child will be a carrier, and a 25% (1 in 4) chance that their child will inherit two unaffected copies of the gene and neither have the condition nor be a carrier.
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
A diagnosis of kEDS typically begins with a clinical evaluation based on characteristic signs and symptoms, such as significant joint hypermobility, skin fragility, and progressive kyphoscoliosis. A clinical geneticist, who specialises in inherited conditions, often performs this initial assessment.
Genetic testing is used to confirm the diagnosis by identifying pathogenic variants in the PLOD1 or FKBP14 genes [PMID:33678703]. This can involve a blood test to analyse DNA. The NHS Genomic Medicine Service offers genetic testing for inherited conditions, including kEDS, which falls under specific R-codes for rare disease testing. Referral for genetic testing is usually made by a specialist clinician, such as a geneticist, orthopaedic surgeon, or rheumatologist, particularly when kEDS is suspected based on clinical findings.
Management & lifestyle
Management of kEDS focuses on addressing symptoms and improving quality of life, as there is currently no cure for the underlying genetic defect. Physiotherapy and occupational therapy are often crucial to help manage joint hypermobility, strengthen muscles, and improve stability, aiming to prevent dislocations and maintain function. Orthopaedic interventions, including bracing or surgery, may be considered for severe or progressive kyphoscoliosis to support the spine and prevent further curvature [PMID:28723696].
Regular monitoring for potential complications, such as eye problems or vascular fragility, is important. Skin care, including careful wound management and protection from injury, is also a key aspect of ongoing care. An individual's care plan is typically coordinated by a multidisciplinary team of specialists within the NHS, often involving geneticists, orthopaedists, physiotherapists, and other relevant professionals. Genetic counsellors can provide support and information to individuals and families regarding the condition and its inheritance.
UK care pathway
In the UK, individuals suspected of having kEDS can be referred to a clinical genetics service through their GP or another specialist. Clinical geneticists and genetic counsellors are key to guiding families through the diagnostic process, including discussing the appropriateness of genetic testing within the NHS Genomic Medicine Service (GMS).
Genetic testing for Ehlers-Danlos syndromes, including kEDS, is available through the GMS under specific R-codes. If a diagnosis is confirmed, care typically involves a multidisciplinary team to manage the various symptoms. Genetic counsellors play a vital role in providing information, support, and discussing the implications of genetic diagnoses for patients and their families.
Frequently asked questions
Is kEDS the same as 'classic' Ehlers-Danlos syndrome?
No, kEDS is a specific type of Ehlers-Danlos syndrome. While all EDS types affect connective tissue, they have different genetic causes and specific sets of symptoms. kEDS is distinct from classical EDS, which is typically caused by variants in the COL5A1 or COL5A2 genes.
Can kEDS be prevented?
kEDS is a genetic condition present from birth, caused by inherited pathogenic variants. It cannot be prevented. For families with a known history of kEDS, genetic counselling can provide information about inheritance patterns and reproductive options.
Will my children inherit kEDS?
kEDS is inherited in an autosomal recessive pattern. This means if you have kEDS, both of your gene copies have pathogenic variants. If your partner is not a carrier, your children will be carriers but are unlikely to have the condition. If your partner is a carrier, there is a chance your children could inherit kEDS. Genetic counselling can provide personalised risk assessments.
What kind of exercise is safe with kEDS?
Physical activity is important, but it needs to be carefully managed to avoid joint injuries. Low-impact exercises like swimming, cycling, and walking are often recommended. A physiotherapist experienced with Ehlers-Danlos syndromes can provide tailored advice and help develop a safe exercise plan.
How is kEDS managed in childhood?
Management in children typically involves a multidisciplinary team. This includes regular monitoring of spinal curvature, physiotherapy for joint stability, and occupational therapy to support daily activities. Careful skin protection and prompt treatment of any injuries are also crucial.
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
- 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
- Solinski MA, Blair MP, Dietz H. FEVR findings in patients with Loeys-Dietz syndrome type II. Ophthalmic genetics. 2018. PMID: 30406707