Introduction

Brief overview of ehlers-danlos syndrome 

Ehlers-Danlos Syndrome (EDS) is a group of heritable connective tissue disorders that affect the joints, skin and blood vessels. EDS has 13 different subtypes which are differentiated on the basis of clinical features and genetics. Some of the common clinical features include hypermobility, skin hyperextensibility and fragile skin.¹

Genetic basis and subtypes

According to the 2017 classification system, there are 13 subtypes of EDS and 5 out of these 13 subtypes are prevalent.¹ 

• Hypermobile EDS (hEDS) is the most common type of EDS. The genetic mutation behind hEDS is unknown and it can only be diagnosed clinically¹ 
• Classical EDS (cEDS) is a genetic disorder caused by a mutation in the COL5A1 and COL5A2 genes. These genes are responsible for making collagen type V. Alteration in any of these genes can cause deficiency of collagen type V which can make connective tissue less effective, especially in the skin and joints¹ 
• Classical like EDS (clEDS) is caused by the mutation of the TNXB gene. TXNB gene instructs the formation of protein tenascin-X. Tenascin-X is present in the connective tissue of the heart, skeletal muscles, tendons, ligaments, skin, and digestive tract. clEDS causes severe skin hyperextensibility, velvety skin texture, generalized joint hypermobility, and easy bruising¹ 
• Cardiac-valvular EDS is associated with mutations in the COL1A2 and/or NMD genes, which code for type I collagen. Clinical features include skin hyperextensibility, atrophic scarring, easy bruising, restricted or generalized joint hypermobility, and progressive cardiac-valvular problems¹ 
• Vascular EDS is caused by the mutations in the COL3A1 and/or COL1A1 genes, which code for type III and type I collagen, respectively. Major clinical symptoms include arterial rupture at a young age, uterine rupture, the formation of a carotid-cavernous sinus fistula without trauma¹

Importance of early recognition in children and adolescents

Early recognition of EDS in children and adolescents can improve quality of life, prevent financial burden, slow the progression of symptoms and disabilities, and ensure timely investigations and treatment.^2,3 Continuous pain, unstable joints and dysautonomia can lead to conditions like kinesiophobia (fear of movement) and therefore reduction of physical activity. Early diagnosis can help children and their parents focus on management. 

Early signs and clinical presentation in children

EDS causes problems in protein collagen formation and functioning. The connective tissue lacks strength and stability. Early symptoms of pediatric EDS can be from mild to severe. EDS can develop in infants. EDS in children show signs like easy bruising, extra folds of skin, or joint hypermobility. There can also be a risk of gastrointestinal and autonomic nervous system issues, early-onset osteoarthritis, or osteoporosis. Babies with EDS can struggle with early mobility like sitting, standing, crawling, or walking. EDS presents with signs and symptoms like frequent neck pain, easily dislocated joints, slow-healing injuries, and joints that make clicking noises in childhood. EDS may also cause children to struggle with concentration or sitting still, and bladder issues.⁴

Diagnostic approach in pediatric and adolescent patients

A clinical diagnostic classification system was launched in 2017 for the diagnosis of EDS in adults. Many clinical features arise over time and may not be present during childhood and adolescence. Diagnosis of EDS is characterized by the presence of joint hypermobility, tissue fragility and skin hyperextensibility. Adolescents who are biologically mature can be diagnosed based on these criteria but it's difficult to use them on chindren and biologically immature adolescents. 

• Children should not be assessed based on the 2017 criteria until they have reached biological maturity. A pediatric specific framework should be developed. This framework can support targeted genetic testing
• Adolescents with symptomatic joint hypermobility can be diagnosed using the clinical diagnostic classification developed by Tofts et al5

Diagnosis of EDS starts with a thorough medical and family history, followed by a physical exam that assesses joint hypermobility (using the Beighton Scale), skin texture, elasticity, and scarring, as well as other common signs like easy bruising or chronic pain.⁶ There is no genetic test available for the diagnosis of hypermobility EDS (hEDS). Other subtypes of EDS can be diagnosed using molecular and genetic testing methods like next generation sequencing by identifying the mutation causing genes. 

There can be challenges in diagnosis due to symptom overlap with other conditions like heritable connective tissue disorders (HCTDs), such as Marfan syndrome, Loeys-Dietz syndrome, and osteogenesis imperfecta. 

Pediatric care and management strategies

Treatment and management strategies depend on the signs and symptoms which can change over the child’s lifetime. Education and empowerment of patients and families is essential for self-management strategies. 

Physiotherapy

• Consult physiotherapists for targeted exercises for symptomatic joints. Guidance on appropriate physical activity and suitable sports
• Work with physiotherapists and occupational therapists for support with taping, bracing, judicious stretching of tight muscles, pain education, pacing strategies, home modifications and ergonomics, and activities of daily living (e.g. handwriting, dressing, using cutlery, school work)

Symptom management

• Develop coping strategies for times when symptoms are manageable (e.g. have a medication plan for controlling pain before central sensitivity increases)
• Plan physically or mentally challenging activities around the child when they are the most alert

Nutrition

• Seek advice from a dietitian if nutrition is suboptimal (e.g., food intolerances,
  under or overweight, excessive fatigue, gastrointestinal upset)

Pain management

• Access to education and resources for managing pain⁷

Long-term monitoring and transition to adolescence

Patients with EDS require monitoring for cardiovascular risks like arterial and valvular heart disease.⁸ Routine evaluation is required for joint pain, skin texture and joint mobility along with education of patient and family for self-management. 

Future perspectives in EDS care of children and adolescents

The future for Ehlers-Danlos Syndrome looks to include accelerated research for new treatments, improved diagnostic pathways, and more comprehensive, multidisciplinary care, with ongoing clinical trials.⁹ Early diagnosis and treatment can be crucial for the management of EDS to facilitate surveillance. Educating patients, families, and healthcare providers is a key component of management, enabling proper identification and care of the condition.¹⁰ Patients should be encouraged to engage in supportive interventions like physical and occupational therapies which are vital for strengthening muscles around joints, improving stability, and enhancing overall function and quality of life.¹¹ Genetic counseling can provide information on inheritance patterns and family planning for families affected by EDS. 

Summary

Ehlers-Danlos Syndrome (EDS) is a group of heritable connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Hypermobile, classical, classical-like, cardiac-valvular, and vascular types are the most prevalent out of the 13 subtypes of EDS. The mutation underlying hypermobile EDS remains unidentified and therefore it can be difficult to diagnose. The genetic causes of other EDS subtypes is often known. 

Early recognition of EDS is vital to improve quality of life, prevent complications, and enable timely interventions in children and adolescents. Early signs may include easy bruising, delayed motor milestones, frequent joint dislocations, gastrointestinal or autonomic issues, and chronic pain. Diagnosis in pediatric patients can be challenging because many features develop with age. 

Management of EDS in children and adolescents requires a multidisciplinary approach, focusing on physiotherapy, occupational therapy, pain education, lifestyle modifications, nutrition tracking, and family support. Long-term monitoring for cardiovascular disease is essential. Future perspectives emphasize improved diagnostic frameworks, advances in genetic research, multidisciplinary care, and genetic counseling for family planning.