Diagnosis and treatment of the Ehlers-Danlos syndromes in China: synopsis of the first guidelines

The challenges in diagnosis and management of EDS have long been recognized. Patients suspected or diagnosed with EDS have reported a significant, unmet medical need during both the diagnosis and management processes [8‐10]. The average diagnostic delay from first symptom is around 14 years, which is likely to be consequential [11]. It not only delays appropriate treatment, but also places considerable psychological stress on the patients and families [12]. After receiving the diagnosis, patients see multiple doctors across specialties at different clinics, and report desires for multi-disciplinary care and support from patient community [8, 10, 13]. The uncoordinated care leads to worsened health outcomes and a significant decline in the quality of life, posing challenges to patients and families, as well as healthcare professionals.

The barriers are partially caused by the complex nature of EDS, limited awareness, and lack of practical guidelines. Despites the prominent features, the entire clinical presentation of EDS varies significantly across subtypes and among individuals. Some patients may present with recurrent multiple joint dislocations with widespread pain since childhood, which lead to diminished quality of life and disabilities. Others may remain unaware of the disorder until a sudden onset of life-threatening arterial dissection in their 20s. The manifestations of EDS also overlap with a number of disorders, such as Hypermobility spectrum disorders, Marfan syndrome, Loeys-dietz syndrome, Cutis laxa and Osteogenesis imperfecta [14, 15]. Therefore, the diagnosis and management of EDS typically requires coordinated multi-disciplinary team (MDT) approaches, which remain scant [16, 17]. In addition, limited knowledge and awareness among healthcare professionals further complicates the overall situation [16‐18]. Efforts have been made to address the unmet clinical need, such as the free on-line program Ehlers-Danlos Society Extension for Community Health Care Outcomes (EDS ECHO), the outpatient EDS clinic at Mayo Clinic, USA, and the Ehlers-Danlos Syndrome Expert Panel and GoodHope EDS clinic at the Toronto General Hospital, Canada [16, 18, 19].

However, even at a multi-disciplinary clinic with experienced practitioners, the lack of clinical practice guidelines results in physician-dependent management plans that rely on theoretical and limited research evidence [20]. A recently published study conducted in the United States has reported an urgent need among medical providers for accessible consensus guidelines for care and management of patients with EDS [21]. However, creating high quality guidelines for rare disorders like EDS is challenging, largely due to the difficulties in gathering convincing evidence and gaining clinical experience [22].

The current focus of MDT approaches primarily centers on the management stage after diagnosis. But equal attention should be given to an MDT collaboration between geneticists and physicians from different departments during the diagnostic phase. Performing a comprehensive evaluation at individual level rather than organ level offers a broader understanding of the condition and markedly expedites timely diagnosis.

An MDT approach is recommended for the medical assessment of patients clinically suspected to have EDS. The clinical diagnostic criteria for each subtype of EDS were published in the 2017 International Classification and the extended 2020 version [5, 6]. It largely relies on physician’s personal experience and medical judgement since there is no test with high sensitivity or specificity. Patients suspected with EDS, however, usually present with a myriad of symptoms. Many of the symptoms, such like joint hypermobility, scoliosis, hypotonia, mitral valve prolapses and retinal detachment, may not be EDS-specific. Additionally, symptoms like wide-spread chronic pain may have both physical and psychological bases. The considerable overlapping features between subtypes and with other disorders further exacerbate the diagnostic intricacies. The Guidelines recommend physicians, especially dermatologists, pediatrician, or other physicians working in “Initial Consultation Departments”, to be aware of features that may not related to primary complaints but are indicative of a diagnosis of EDS. The features include joint hypermobility, skin hyperextensibility and fragility, characteristic facial features, and organ or vessel fragility. And then, an MDT approach is recommended for further assessment, differentiation of similar conditions, and identification of patients for genetic testing. As for hEDS, the only subtype without known genetic basis, the diagnosis relies solely on clinical evaluation. An MDT approach is particularly crucial for this group of patients to prevent misdiagnosis, as well as overdiagnosis, which may lead to unnecessary medical interventions and psychological burden.

The Guidelines also emphasize an MDT collaboration during the genetic testing stage to improve outcomes. The confirmation of the diagnosis in most of the subtypes requires genetic testing, but discrepancies between the clinical and molecular diagnosis have been observed [24, 25]. Besides, receiving a negative or inconclusive genetic test result is not uncommon. Deep phenotyping has been demonstrated an important role in improving diagnostic yield [26‐30]. Physicians specialized in relevant field are recommended to participate in the pre-testing phenotyping, collaborating and communicating under an MDT framework, to provide accurate phenotypic description. During data analysis, geneticists may need support from clinicians to further evaluate and classify the pathogenicity of specific variants through methods such as reverse phenotyping. This MDT approach is critical in reducing the rate of false-negative results and the numbers of the variants of unknown significance.

After arriving at a diagnosis, the announcement is usually difficult for both the patients and their families. Psychologists hold a key position helping the patients and families in coping with their emotions, coming to terms with the diagnosis and transition into the management stage.

The collective integration of nursing care, rehabilitation, psychology, and nutrition within an MDT approach is increasingly acknowledged as crucial for optimizing patient care, especially in complex disorders requiring holistic and multidisciplinary interventions. Undoubtedly, the collective expertise of professionals from these departments develops specialized and individualized plans, significantly expediting the recovery process within the hospital setting. Moreover, the Guidelines emphasize its key role in assisting patients and families effectively manage EDS on a day-to-day basis at home and live life to the fullest.

Some patients with EDS may often encounter joint instability, hypotonia, or postural tachycardia syndrome (PoTS), placing them at an increased risk of falls. It is recommended to implement home adaptations and various preventive strategies, including gradual postural changes, to minimize the risk of falls at home. Frequently, family caregivers feel unprepared and lack knowledge. Nurses can provide education about the disorder, assist in developing caregiving skills, and design individualized home care plan.

Rehabilitation for patients with EDS typically involves long-term participation. Rehabilitation professionals develop personalized clinic- or home- based rehabilitation plans to address various challenges such as joint instabilities, hypotonia, joint pain, reduced bone mineral density, shortness of breath, writing difficulties, and PoTS-related symptoms. Patient-centered self-management rehabilitation interventions aim to restore and improve daily functioning, eventually promoting independence in daily living activities.

Psychological interventions help manage chronic pain, a frequently reported challenge impacting daily lives. Moreover, chronic conditions like EDS may cause tremendous life changes, interfere with physical and social function, and shape the feelings. But it’s crucial to understand that the life is not solely defined by the diseases. Psychosocial adjustments address the fear and anxiety associated with uncertainties, such as the potential decline in abilities and sudden death. Additionally, EDS impacts the wellbeing of the families. Coping strategies not only help alleviate stress and tension for caregivers, but also provide support to healthy siblings who may feel overlooked.

Underweight and overweight are both frequently observed in patients with EDS. The complexity necessitates individualized nutritional care plans created by nutrition experts. From dietary supplements and modifications to eternal and total parenteral nutrition, home nutritional support serves as the foundation for treating symptoms and maintaining daily function.

One of the limitations of the Guidelines is that because EDS is a rare disease and there are few studies on relevant populations, it is difficult to form high-quality evidence for the research questions raised in the Guidelines. Therefore, the recommendations in the Guidelines are mainly recommendations given by multidisciplinary experts based on limited research evidence and their own clinical experience.