Update on classification of EDS 2017 ILC foundation meeting Hanna Faghfoury, MDCM, FRCPC, FCCMG November 4, 2017

Disclosure I have no financial or other conflicts of interest to disclose

Outline At the end of this talk you should be able to: Describe the rationale for updating the classification of EDS syndromes Outline the differences between old and new classification of EDS Summarize areas for future EDS research

Reference American Journal of Medical Genetics Part C: Seminars in Medical Genetics March 2017 “The Ehlers-Danlos Syndromes: Reports from the International Consortium on the Ehlers-Danlos Syndromes”

History EDS classification In 1988 “Berlin nosology” established when molecular diagnostics was not yet discovered Update in 1998 “Villefranche criteria” when biochemical and genetic aspects were increasingly known 9 subtypes of EDS “Major” and “Minor” criteria Need identified for an update as the knowledge of clinical and molecular subtypes of EDS had expanded over past 2 decades The subjective interpretation of several semi-quantitative clinical signs, such as joint hypermobility, skin hyperextensibility,tissue fragility and bruising, however, led to clinical uncertainty, diagnostic confusion regarding the type of EDS and the inclusion of phenotypically similar conditions under the broad diagnosis of EDS. Furthermore, in the persistent lack of a genetic defect, there is a dire need for a better clinical definition of the hypermobile type of EDS and its delineation from other hypermobility disorders.

Villefranche criteria

Brighton criteria JHS

THE 2017 INTERNATIONAL CLASSIFICATION 13 subtypes All types have in common: Joint hypermobility, skin hyperextensibility and tissue fragility Aims to regroup EDS subtypes based on genes and pathway function with the exception of hypermobile EDS Aims to provide a standardized framework for management and homogeneity for future genetic research

Hypermobile EDS (hEDS) Replaces EDS III, hypermobility type EDS, hypermobility syndrome hEDS remains a clinical diagnosis Genetic heterogeneity likely at play (with contributions of age, sex, environmental factors) Aim of new criteria is to reduce heterogeneity of the patient population and facilitate efforts to discover the genetic cause of the syndrome Which may help clinical management ultimately for not only patients who meet criteria for hEDS but those with overlapping features of joint hypermobility syndrome

Attempt to determine genetic basis of hEDS Largely unsuccessful despite multiple attempts by multiple international groups Only a few case reports have pointed to a specific genetic factor in hEDS: one case report of a COL3A1 variant (Narcisi et al, 1994) a variant of LZTS1 gene in 4 Belgian families (Syx et al, 2015)

Clinical diagnosis of hEDS needs simultaneous presence of criterion 1, 2 AND 3

Criterion 1: Generalized joint hypermobility (GJH) Criterion met with Beighton score: ≥6 pre-pubertal children and adolescents ≥5 pubertal adults up to 50 yo ≥4 adults over 50 yo Used to be more than or equal to 5 which was likely underdiagnosing adults who may have lost hypermobility with time, and overdiagnosing children who are naturally flexible With those patients with lower Beighton scores below cutoff assessment of other joints not included in Beighton is considered but felt that inclusion is too subjective at this time in determination of GJH.

Criterion 1: Generalized joint hypermobility (GJH) If patient has acquired joint limitations AND is 1 point below Beighton score cutoff, GJH diagnosed if patient answers “yes” to 2/5 questions on a 5 point questionnaire

Criterion 2: Two or more of the following features (A, B or C) Systemic manifestations of a more generalized connective tissue disorder (min 5/12): unusually soft/velvety skin, mild skin hyperextensibility, unexplained striae, bilateral piezogenic heel papules, recurrent or multiple herniae, atrophic scarring, organ prolapse, dental crowding and high/narrow palate, arachnodactyly, arm span to height ≥1.05, Mild mitral valve prolapse, and aortic root dilatation Positive family history of 1+ first degree relatives independently meeting the current diagnostic criteria for hEDS Musculoskeletal complications (min 1/3): pain in two or more limbs recurring daily for at least 3 months, chronic widespread pain for ≥3 months, recurrent joint dislocations in the absence of trauma

Criterion 3: All the following prerequisites must be met Absence of unusual skin fragility Exclusion of other heritable and acquired connective tissue disorders including autoimmune disorders (RA, Lupus) Exclusion of alternative diagnoses that may cause joint hypermobility (eg. Osteogenesis imperfecta)

But what about all the other features? Many other features are described in hEDS but at the current time are not sufficiently specific/sensitive to be included in the formal diagnostic criteria: Sleep disturbances Fatigue POTS Functional GI disorders Dyautonomia Anxiety/Depression

Clinical spectrum of joint hypermobility Symptomatic JH Other conditions/genetic syndromes Asymptomatic JH hEDS HSDs HSDs hypermobility spectrum disorders: Gneralized joint HSD (many patients not fulfiling full diagnostic criteria fall here), peripheral HSD, Localized HSD, Historical HSD (5 pt questionnaire)

Clinical spectrum of joint hypermobility The new terminology within this spectrum updates terms used to define patients (different types of HSDs, hEDS) Clinical diagnostic criteria without a known molecular cause will, by definition, be imperfect Definition of hEDS may change over time with increasing knowledge of the underlying pathophysiology of symptomatic joint hypermobility Imperfect and at worse, many feel, arbitrary

Future directions Stringent application of criteria will allow for more standardized classification and phenotyping of patients with EDS Creation of patient registries may become more useful in delineating risk factors for EDS co-morbidities and set the groundwork for evidence-based treatment modalities Molecular studies can be more efficiently completed on more homogeneous sub-groups of patients Discovery of other subtypes of EDS may lead to a better understanding of common pathologic features

Studying efficacy of interventions: ++Need for randomized control trials Pain management: Utility of earlier diagnosis and preventative measures for pain, research on use of NSAIDs in the context of increased bleeding, Oxygen therapy, Studies into proprioceptive impairment and treatment, low dose naltrexone Psychiatric: Efficacy of psychiatric and psychological approaches (CBT dealing with dysfunctional coping, pharmacologic treatment) Gastrointestinal: aetiology of GI symptoms in hEDS require further clarification, elucidating precipitating factors for GI problems in EDS Orthopedic: Efficacy of surgical interventions vs. conservative mgt IIH idiopathic intercranial hypertension, AAI, atlantoaxial instability

Studying efficacy of interventions: Need for randomized control trials Physical Therapy: Use of strengthening programs, orthotics, exercises of proprioception/balance, taping, hydrotherapy Cardiovascular: Prevalence of autonomic dysfunction, efficacy of treatments Neurosurgical: Studies in risks of shunting, stenting for IIH, prospective studies on outcomes for chiari malformation treatment, utility of dynamic imaging studies to dx AAI, long term studies on surgical outcomes for treatment of instability, determine clinical criteria for TCS in hEDS, incidence of TCS, surgical outcomes, investigations on treatment of tarlov cysts IIH idiopathic intercranial hypertension, AAI, atlantoaxial instability

Other areas of research Prevalence and treatment of Gynecological/Obstetric issues in EDS Determine evidence for best practice in medical surveillance and surgical intervention in vascular EDS Improvement in patient outcomes given educational interventions to health care practitioners

In summary 2017 update in classification of EDS has not fully addressed ongoing questions regarding pathophysiology and management of hEDS and HSDs Aim is for increased homogeneity of groups leading to a possible molecular diagnosis and better studies to elucidate treatments Revision of current criteria may be necessary once molecular pathophysiology further elucidated and natural history of HSDs and hEDS examined over time