Ehlers-Danlos Syndrome Update 2014

Clair A. Francomano, M.D.

Harvey Institute for Human Genetics

Baltimore, Maryland

Outline

• EDNF Center for Clinical Care and Research

• Review of articles from the literature over the past year

EDNF Center for Clinical Care and Research at the Harvey Institute for

Human Genetics

• Virtual Center in the Baltimore-Washington area

• Diagnosis and management of Ehlers-Danlos syndrome

• Expansion of existing knowledge regarding cause, pathogesis, treatment

Center Staff

• Clair Francomano, MD – Director

• Antonie Kline, MD – Pediatric Genetics

• Christy Haakonsen, CGC – Genetic Counselor

• Linda Wiley – Administrative assistant

• Pat Williams – Administrative assistant

• Nurse Practitioner – to be named

Ongoing Research Collaborations

• National Institute on Aging study – Nazli McDonnell

• Whole exome sequencing – Joel Hirschhorn – Andrew Dauber – Hal Dietz – Brendan Lee

• Hereditary connective tissue findings in children with autism – Dr. Fraser Henderson

Goals

Provide comprehensive, compassionate care for persons with Ehlers-Danlos syndrome and their families Contribute to the growing body of knowledge about the causes and management of EDS Develop educational materials for patients and providers - Physician conference in September - Monthly educational conferences in Baltimore-Washington area - Webinars for patient education

New Reports from the Literature 2013-2014

• Reviews – Hypermobile EDS/JHS – EDS – showcase of matrix biology – OB/GYN – Effectiveness of therapeutic exercise

• Expanding the phenotype of hypermobile EDS – Autonomic dysfunction – Pain – Headache – Gastro-intestinal issues, including eosinophilic esophagitis – Cardiology – Quality of life – Epilepsy – Obsessive-compulsive disorder – Diagnostic challenges

New Reports from the Literature 2013-2014

• FKBP14-related Ehlers-Danlos syndrome

• Congenital adrenal hyperplasia and EDS

• Natural history of vascular EDS

– relationship between specific mutations and prognosis

– Pregnancy outcomes

Byers and Murray, 2014. Matrix Biology

Byers and Murray, 2014. Matrix Biology

1,225 women completed a survey on the EDNF website All reported a typed diagnosis of EDS Stratification to the three most common types and reproductive age women Overall: • Preterm births in 25.2% • Spontaneous abortion 57.2% • Ectopic pregnancy 5.1% • Infertility 44.1% • Normal menstrual cycles 32.8% • Dysmenorrhea 92.5% • Dyspareunia 77&

Objective: To establish the effectiveness of therapeutic exercise for JHS Study design: Systematic literature review Study eligibility criteria: People diagnosed with JHS, therapeutic exercise as intervention Results: 2001 titles were identified and four articles met inclusion criteria. These Included one controlled trial, one comparative trial and two cohort studies. All studies found clinical improvement over time. No convincing evidence that exercise was better than control. No convincing evidence that joint-specific and generalized exercise differed in efficacy.

Palmer et al, 2014. Physiotherapy

• Literature review of Ehlers-Danlos syndrome/JHS by complication

Pain Fatigue Headache • Discussion of the authors’ clinical experience • Description of three phases of disease – “Re-writing the

National History”

Castori et al. 2013. Am J. Med. Genet.

Types of Pain in Joint Hypermobility

Castori et al. 2013. Am J. Med. Genet.

Origins of Fatigue in Joint Hypermobility

Study population: 80 patients with hEDS 11 patients with cEDS 07 patients with vEDS 38 patients with fibromyalgia 43 healthy control persons

Study tools: Autonomic symptom profile SF-36 Quality of life questionnaire Questionnaires related to Hypermobility Pain Fatigue Affective distress Physical activity

Autonomic Symptoms Hypermobile EDS

• Autonomic symptoms contribute to the disease burden in hypermobile EDS – Orthostatic

– Gastrointestinal

• These symptoms are related to a lower quality of life and to increased pain and fatigue severity

• Lack of association with affective distress and deconditioning

De Wandele et al., 2014, Sem Arth Rheum

Questions: Is dysautonomia common in hEDS? If so, what is its severity and distribution? What are possible mechanisms? Results: Dysautonomia is more common in hEDS than in control populations Dysautonomia is not limited to the cardiovascular system Mainly characterized by sympathetic deregulation

Evoked sweat volume lower in all areas – diminished sympathetic response

Bigger BP drop during valsalva suggests insufficient sympathetic vasoconstriction

74% of participants with EDS demonstrated orthostatic Intolerance 41% had POTS

De Wendele et al, 2014. Sem Arthr Rheum.

De Wendele et al, 2014. Sem Arthr Rheum.

• Retrospective review of medical records • 109 patients presenting with autonomic dysfunction evaluated for presence of EDS • Percentage of patients with EDS in POTS and non-POTS groups was calculated

• Prevalence of EDS in the POTS group was 19% • Prevalence of EDS in the non-POTS group was 4% • General population prevalence of EDS used for comparison was 0.02%

Patients with hypermobile EDS exhibited significantly lower pain pressure thresholds than controls, both in areas in which they reported pain and those areas which were reported as pain-free On average, patients reported pain over 31% of their body surface area. 40% presented with a predominantly nociceptive pain pattern 50% presented with predominantly neuropathic pain

Goals: Literature review of papers describing increased frequency of joint hypermobility among patients with certain types of headaches Postulate mechanisms whereby connective tissue disorders may predispose to headache Results: Case reports and case-control studies confirm association between CTD’s and certain types of headaches, including migraine. Also associated with CTD’s were carotid arterial dissection, intracrnaila hypotension, Chiari I malformation, cervical spine disorders and temporo-manidibular joint disorders

Martin and Neilson, 2014. Headache Currents.

• Case report • 38 year old woman with Ehlers-Danlos syndrome • Chronic Headache • Elevated CSF pressure • High IGF-1 levels • Responsive to octreotide, an inhibitor of the GH-IGF1 axis

• Prospective cross-sectional study • Looked at the prevalence of JHS in newly referred

patients with gastrointestinal complaints • Compared GI symptoms in patients with and without JHS • Analyzed the factors contributing to the burden of GI

symptoms in patients with JHS chronic pain autonomic psychological medication-related

Younger Female Poorer QOL GI symptoms increased with increasing severity of JHS phenotype Autonomic factors contributed to upper GI symptoms

Questionnaire study Questionnaires were sent to 212 patients through the French EDS support group Functional bowel disorders 84% Irritable bowel syndrome 48% Gastroesophageal reflux 67.7% Functional constipation 36% Quality of life negatively impacted by the presence of Irritable bowel or functional constipation Significant correlation between functional bowel disorders and esophageal reflux

42 patients with Eosinophilic Esophagitis (EoE) and a hereditary connective tissue disorder were found on review of the electronic medical record and Eosinophilic Esophagitis Research registry This represents 0.8% of patients with CTDs and 1.3% of patients with EoE 8-fold risk of EoE in patients with CTDs

• Case-control study • 28 adults with JHS/EDS-HT and 29 healthy subjects • Resting ECG • 24 hour ECG • Resting heart ultrasound (echocardiogram) • ECG – moderate increase in PR interval and P wave interval • Increased rate of heart conduction and rate abnormalities • Increased prevalence of mitral and tricuspid valve insufficiency

• Questionnaire study • 237 questions • Completed by 466 participants with hypermobile EDS • Pain, fatigue and disability found to be highly prevalent.

METHODS: EEGs, Clinical data and Neuroimaging in 42 patients Analyzed at onset of seizures and after at least 5 years of follow-up Patients were divided into two groups, with and without structural brain changes Results: Group A – 11/26 presented with focal epilepsy, 7/26 generalized epilepsy Patients were treated with anti-epileptic drugs and all were seizure free at 2 years Only one continued to receive anti-epileptic drugs Group B – 9/16 presented with focal epilepsy; 7/16 with generalized epilepsy. More of these patients required multiple drugs for therapy All patients required continued pharmacologic treatment

• Case-control study • 47 consecutive patients with JHS/hEDS and 45 controls • Patients underwent structured interviews and completed

questionnaires • Frequency of obsessive-compulsive disorder was 10.6% (5 cases);

none in controls • Odds ratio for any psychiatric disease was 4.3

Leaves true medical issues unrecognized and untreated Presenting symptoms persist and usually worsen Diagnosis is difficult to expunge once present in the medical record Compromises chances of getting good medical care Especially to children, represents an accusation of either dishonesty or “craziness,” undermining trust in the medical system

“Clinical findings provide evidence of incompatibility between the symptom and recognized neurological or medical conditions.”

Case report and summary of interviews conducted at the EDNF conference, 2013

Considerable variation among clinicians as to -Diagnostic criteria -How to perform diagnostic tests

Editorial comment on Remvig et al. 2014

• Autosomal recessive • Joint hypermogility • Severe kyphoscoliosis • Restrictive/obstructive lung disease • Short stature, • Mild hearing loss • Decreased musclemass • Arterial tortuousity and dissection

• Similar phenotype to Kyphoscoliotic type of EDS (Formerly type VI) • Biochemistry is different (normal lysyl hydroxylation)

Goal: Characterize the natural history of vascular EDS in persons with known COL3A1 mutations Method: Reviewed clinical records for vascular, bowel and organ complications in 1231 persons (630 index cases, 601 relatives) Results: Median survival was 51 years. Lower in men, and influenced by the type of mutation.

The investigators compared outcomes in patients with patients with haploinsufficiency mutations (causing complete loss of production from one copy of the COL3A1 gene) and those producing minimal amounts of type three collagen. Patients with hapolonsufficiency mutations were: older at first vascular event more likely to have aortic complications less likely to have post-operative complications

Goal: characterize the nature and magnitude of pregnancy risk in women with vEDS Methods: Review of pedigrees of families with vEDS . Interviews with affected women or their next of kin. Results: Pregnancy related deaths occurred in 30/563 pregnancies (5.3%) 46% of deliveries were uncomplicated Most common complications – severe lacerations (20%) and preterm delivery (19%) Life-threatening complications - 14.5% Arterial dissection/rupture 9.2% Uterine rupture 2.6% Surgical complications 2.6% Pregnancy did not appear to alter the overal life-expectancy of women with vEDS

Deepest Appreciation

• Sandy Chack • Ehlers-Danlos National Foundation Board • Ehlers-Danlos National Foundation PAN • Ehlers-Danlos National Foundation members

• Bauerfeind • Hawkins family

• Elliot Clark

• My patients and their families