DEPARTMENT OF PEDIATRIC CARDIOLOGY AND CARDIAC SURGERY Pediatric Cardiology and Cardiac Arrhythmia/Syncope Unit Responsible: Dr.

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1 Title of Project Heart and rhythm disorders in children with Ehlers-Danlos syndrome: Principal Investigator Information: Fabrizio Drago, MD Head of IRCCS Children Hospital and Research Institute Piazza S. Onofrio 4, Rome, Italy Phone , Fax Period of Performance: 24 months Performance Site: -, IRCCS Children Hospital and Research Institute, Rome, Italy - Unit of Clinical Genetics, San Camillo-Forlanini Hospital, Sapienza University, Rome, Italy - Division of Medical Genetics, IRCCS Casa Sollievo della Sofferenza, Foggia, Italy Budget: $ 30,000 Institution of which award should be made payable: Financial Officer: dr. Elisa Del Vecchio Department: Institution: IRCCS Children Hospital and Research Institute Mailing Address: Via Torre di Palidoro, snc - Fiumicino Rome, Italy Phone Number: Address: elisa.delvecchio@opbg.net

2 Other investigators involved: Alessandro Ferraris, MD PhD Geneticist Unit of Clinical Genetics, San Camillo-Forlanini Hospital C.ne Gianicolense 87, Rome, Italy Anwar Baban, MD PhD Cardiogeneticist Cardiology and Arrhythmology Units, Syncope Unit IRCCS Children Hospital and Research Institute Piazza S. Onofrio 4, Rome, Italy Caterina Piedimonte, MD PhD Student in Medical Genetics Department of Experimental Medicine Sapienza University of Rome Viale Regina Elena 324, Rome Marco Castori, MD PhD, Head of Medical Genetics Unit IRCCS Casa Sollievo della Sofferenza Hospital Viale dei Cappuccini, San Giovanni Rotondo (FG), Italy Silvia Morlino, MD PhD Student in Medical Genetics Sapienza University of Rome Laboratory of Medical Genetics, San Camillo-Forlanini Hospital C.ne Gianicolense 87, Rome, Italy Curricula vitae et studiorum of the involved investigators are attatched to this file.

3 Principal Investigator: Fabrizio Drago Title of Project: Heart and rhythm disorders in children with Ehlers-Danlos syndrome: Peer-Language Abstract of Research Plan: Project purpose: Cardiovascular autonomic dysregulation (CAD) is a heterogeneous clinical syndrome that has gained increasing interest over the past few decades due to its increasing prevalence and clinical impact on health-related quality of life especially in patients with hypermobility disorders. Autonomic symptoms,especially in forms of Orthostatic Intollerance (OI) and Postural Orthostatic Tachycardia Syndrome (POTS), are frequent extra-articular manifestations of hypermobile Ehlers-Danlos syndrome and contribute to the chronic fatigue that characterized this rare syndrome. This symptom can largely influence the quality of life of affected patients and be even more delicate and difficult to diagnose and handle in children. Few studies on adult patients with hypermobile Ehlers-Danlos syndrome are reported in literature deciphering this specific issue. To the best of our knowledge, cohort studies on children with EDS are not yet known. Research objectives: The aim of this study is (1) to explore the association between joint hypermobility and CA profilein children with heds, (2) to discover potential disease markers of hedsaccording to results from cardiac functional tests, (4) to investigate the reduced quality of life and the progression of CAD in heds compared to controls. Study design and methodology: After obtaining informed consent, we will enroll a group of 20 pediatric patients with heds in three Italian centers of rare diseases (Unit of Clinical Genetics, San Camillo-Forlanini Hospital, Rome- dr. Silvia Morlino; Cardiogenetics, Children Hospital and Research Institute- dr. Anwar Baban; Unit of Medical Genetics, IRCCS Casa Sollievo della Sofferenza Hospital- dr. Marco Castori). The diagnosis will be based on Beighton score and the current diagnostic criteria for EDS. This heds group will be referred to Syncope Unit of IRCCS Children Hospital and Research Institute in Rome for a cardiologic work-up Each patient will be assigned a specific cardiovascular autonomic (CA) profile (POTS, OI, OH) that will be correlated with reported symptoms and quality of life. Statistical analysis will be performed compared to data from healthy control group of 20 children, matched for age, sex and same CA profile. Anticipated outcomes: From the results of this study we expect to find answers that can address with more precision for specific managment and follow-up of patients with CAD and heds.

4 Principal Investigator: Fabrizio Drago Title of Project: Heart and rhythm disorders in children with Ehlers-Danlos syndrome: Layperson summary: Cardiovascular autonomic dysregulation (CAD) is a heterogeneous clinical syndrome that has gained increasing interest over the past few decades due to its increasing prevalence and clinical impact on health-related quality of life especially in patients with hypermobility disorders. Autonomic symptoms,especially in forms of Orthostatic Intollerance (OI) and Postural Orthostatic Tachycardia Syndrome (POTS), are frequent extra-articular manifestations of hypermobile Ehlers- Danlos syndrome and contribute to the chronic fatigue that characterized this rare syndrome. This symptom can largely influence the quality of life of affected patients and be even more delicate and difficult to diagnose and handle in children. Few studies on adult patients with hypermobile Ehlers-Danlos syndrome are reported in literature deciphering this specific issue. To the best of our knowledge, cohort studies on children with EDS are not yet known. This project is divided in: - a diagnostic phase in which children will select for heds in three Italian centers of rare diseases (Unit of Clinical Genetics, San Camillo-Forlanini Hospital, Rome- dr. Silvia Morlino; Cardiogenetics, Children Hospital and Research Institute- dr. Anwar Baban; Unit of Medical Genetics, IRCCS Casa Sollievo della Sofferenza Hospitaldr. Marco Castori), - a second phase of cardiological study through cardiac functional tests performed at Syncope Unit of IRCCS Bambino Gesù Children Hospital and Research Institute in Rome, - a third phase of statistical analysis of the results on heds children compared to data from healthy control group of 20 children, matched for age, sex and the same CA profile. This project can help understand the basis, causes, and potential treatment strategies (pharmacological, conservative and potential interventional) of CAD in EDS.

5 Principal Investigator: Fabrizio Drago Title of Project: Heart and rhythm disorders in children with Ehlers-Danlos syndrome: Budget justification Personnel Costs: $ 25,000 for medical staff (selection and evaluation of patients, data collection and analysis/two years) Travel: $ 1,500 Other Direct Costs: $ 2,000 for publication fees, presentation of scientific data related to the project. Total amount $ 28,500 Indirect costs: $ 1,500 (not to exceed 5% of direct costs). Total amount $ 1,500 Total cost of project (including indirect costs): $ 30,000 The following costs are not included: consumable supplies and materials, consultant costs, patient costs, equipment and other fixed assets. For this project no financial support was received, no applications or proposal pending review for the proposed project were requied, no applications and proposals similar to the present projects are being planned for submission, no other financial support is active.

6 Principal Investigator: Fabrizio Drago Title of Project: Heart and rhythm disorders in children with Ehlers-Danlos syndrome: Background Cardiovascular autonomic dysregulation (CAD), especially in forms of Orthostatic Intollerance (OI) and Postural Orthostatic Tachycardia Syndrome (POTS) is a worldwide problem that is increasingly identified and less understood in pediatric population (1). Autonomic symptoms are frequent extra-articular manifestations of hypermobile Ehlers-Danlos syndrome (heds) as well as developmental coordination disorder (2, 3) and contribute to poorer quality of life and chronic fatigue (4, 5). The mechanism underlying CAD in heds seems to be an increased sympathetic activity at rest and reduced sympathetic reactivity to stimuli. Moreover, connective tissue laxity was identified as important aggravating factor, although some authors have not found a significant difference in arterial stiffness and cardiac profiles between heds patients and age and sex-matched controls (6, 7). Recently, Celletti et al. (8) studied with specific functional tests (Heart rate, blood pressure variability, deep breathing, Valsalva maneuver, 30/15 ratio, handgrip test, Head-up tilt test) 35 adult heds patients. Results identified POTS (48.6%), OI (31.4%), orthostatic hypotension (OH, 3%) and significant higher baroreflex sensitivity values at rest compared to healthy controls. While CAD has been repeatedly examined in adult patients with heds, no studies have explored CAD in children with heds. In the last two years 8.4% of patients, who were referred to the Syncope Unit of IRCCS Children Hospital and Research Institute, resulted positive for POTS. This unit (9), is part of the Pediatric Cardiology and Arrhythmology Units of IRCCS Children Hospital in Rome (Italy), and recognized health care provider of the ERN GUARD HEART network. The diagnosis of heds will be carried out at three referral centers of Rare Diseases: Cardiogenetics service of IRCCS Children Hospital of Rome, Medical Genetics of IRCCS Casa Sollievo della Sofferenza Hospital of San Giovanni Rotondo and Clinical Genetics of San Camillo-Forlanini Hospital of Rome. The latter with significant experience in EDS makes part of the ERN Re-Connect. Project description This is an exploratory observational prospective study that will be divided into three phases during a period of two years. FIRST PHASE (diagnostic phase I - heds diagnosis): 5 months After obtaining informed consent from parents or legal guardians, we shall enroll a group of 20 pediatric patients with heds referred from the three Italian centers of rare diseases (Cardiogenetics, Children Hospital and Research Institute- dr. Anwar Baban; Unit of Medical Genetics, IRCCS Casa Sollievo della Sofferenza Hospital- dr. Marco Castori; Unit of Clinical Genetics, San Camillo-Forlanini Hospital, Rome- dr. Alessandro Ferraris and Silvia Morlino). The diagnosis will be based on the Beighton score and the current diagnostic criteria for EDS (10, 11). SECOND PHASE (diagnostic phase II cardiovascular work-up): 14 months heds pediatric patients (heds group) will be referred to Syncope Unit of IRCCS Children Hospital and Research Institue - Rome for general assessment including cardiac evaluation, ECG baseline, screening for thyroid function test, CBC, blood electrolytes and psychometric tests. Cardiac functional tests (heart rate, blood pressure variability, baroreflex sensitivity index, head-up tilt test). If positive for CAD, a specific cardiovascular autonomic (CA) profile (POTS, OI, OH) will be assigned to each heds pediatric patient who will be evaluated in four serial evaluations at 3 months interval (during 2 years). Whenever indicated, Holter ECG 24hours monitoring, echocardiography and cardiac MRI might be performed. Moreover, blood investigations and other multispecialistic evaluations can be offered on the basis of specific indications. Each heds pediatric patient will be evaluated with psychometric tests for the screening of quality of life, symptoms of anxiety and depression, pain and fatigue (dr. Silvia Morlino and Caterina Piedimonte). The age group established to trace homogeneous neuropsychological profiles is 8-18 years. The chosen psychometric tests are:

7 - CDI (Children s Depression Inventory)(12), - MASC (Multidimensional Anxiety Scale for Children) (13), -PedsQL (Pediatric Quality of Life Inventory) (14), - PSI-SF (Parenting Stress Index Short Form) (15), Patients parents will be given the following questionnaires: - CBCL (Children Behavior Checklist) (16) -PedsQL (Pediatric Quality of Life Inventory) (14), - PSI-SF (Parenting Stress Index Short Form) (15), - MASC (Multidimensional Anxiety Scale for Children) (13). THIRD PHASE (POST-ANALYTICAL PHASE - statistical analysis): 5 months Data will be collected from heds pediatric patients in a database including history, clinical features, results of psychometric tests, blood investigations, and cardiac functional tests. These data will be compared to non-heds pediatric patients (control group) matched for number (20), age, sex and same CA profile (patients evaluated at Syncope Unit). Statistical analysis will be performed by the Unit of Biostatistics of IRCCS Casa Sollievo della Sofferenza Hospital. Expected outcomes This study will pave the road for novel global assessment of a cohort of heds patients and association to CAD in an Italian pediatric population. Moreover, it will aim at identifying any phenotypic and /or etiopathogenic subtypes of heds, based on CA profiles and psychometric tests. Such information may have personalized therapeutic consequences in the perspective of precision medicine and family-oriented rehabilitative approach to treatment. In summary, the aims of this study is: 1) to explore the association between joint hypermobility and CA profile in Italian children with heds, 2) to discover potential disease markers of heds according to results from cardiac functional tests, 3) to investigate the reduced quality of life and other markers of co-morbidities through psychometric tests and the other routine assessments. Actually, the CAD profile and progression in heds will be compared to those of non- heds controls. References 1. Benarroch EE. Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clin Proc. 2012; 87: Morlino S, Dordoni C, Sperduti I, Clark CJ, Piedimonte C, Fontana A, Colombi M, Grammatico P, Copetti M, Castori M. Italian validation of the functional difficulties questionnaire (FDQ-9) and its correlation with major determinants of quality of life in adults with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorder. Am J Med Genet B Neuropsychiatr Genet. 2019; 180: Piedimonte C, Penge R, Morlino S, Sperduti I, Terzani A, Giannini MT, Colombi M, Grammatico P, Cardona F, Castori M. Exploring relationships between joint hypermobility and neurodevelopment in children (4-13 years) with hereditary connective tissue disorders and developmental coordination disorder. Am J Med Genet B Neuropsychiatr Genet. 2018;177: Roma M, Marden CL, De Wandele I, Francomano CA, Rowe PC. Postural tachicardia syndrome and other forms of orthostatic intolerance in Ehlers-Danlos syndrome. Auton Neurosci. 2018; 215: De Wandele I, Rombaut L, De Backer T, Peersman W, Da Silva H, De Mits S, De Paepe A, Calders P, Malfait F. Orthostatic intolerance and fatigue in the hypermobility type of Ehlers-Danlos Syndrome. Rheumatology (Oxford). 2016; 55: Cheng JL, Au JS, Guzman JC, Morillo CA, MacDonald MJ. Cardiovascular profile in postural orthostatic tachycardia syndrome and Ehlers-Danlos syndrome type III. Clin Auton Res Apr;27(2): Miglis MG, Schultz B, Muppidi S. Postural tachycardia in hypermobile Ehlers-Danlos syndrome: A distinct subtype? Auton Neurosci Dec;208:

8 8. Celletti C, Camerota F, Castori M, Censi F, Gioffrè L, Calcagnini G, Strano S. Orthostatic Intolerance and Postural Orthostatic Tachycardia Syndrome in Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome, Hypermobility Type: Neurovegetative Dysregulation or Autonomic Failure? Biomed Res Int.2017; 2017: Drago F, Calvieri C, Placidi S, Righi D, Paglia S, Del Vecchio E, Silvetti MS, Gimigliano F, Di Mambro C, Unolt M, Giordano U, Raucci U, Raponi M. Use of a Pediatric Syncope Unit Improves Diagnosis and Lowers Costs: A Hospital- Based Experience. J Pediatr. 2018; 201: Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology, Villefranche, Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet. 1998; 77: Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L, Bowen JM, Brady AF, Burrows NP, Castori M, Cohen H, Colombi M, Demirdas S, De Backer J, De Paepe A, Fournel-Gigleux S, Frank M, Ghali N, Giunta C, Grahame R, Hakim A, Jeunemaitre X, Johnson D, Juul-Kristensen B, Kapferer-Seebacher I, Kazkaz H, Kosho T, Lavallee ME, Levy H, Mendoza-Londono R, Pepin M, Pope FM, Reinstein E, Robert L, Rohrbach M, Sanders L, Sobey GJ, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Wheeldon N, Zschocke J, Tinkle B. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017; 175: Kovacs M. The Children's Depression, Inventory (CDI). Psychopharmacol Bull. 1985;21: Multidimensional Anxiety Scale for Children- Second Edition, Italian version. Paloscia C, Giangregorio R, Guerini R, Melchiori FM. Hogrefe Editore, Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of life inventory. Med Care Feb;37: Abidin RR. Parenting Stress Index - short form, Italian version. Guarino A, Di Blasio P, D Alessio M, Camisasca E, Serantoni G. Giunti Editore, Achenbach TM, Howell CT, Quay HC, Conners CK. National survey of problems and competencies among four- to sixteen-year-olds: parents' reports for normative and clinical samples. Monogr Soc Res Child Dev. 1991;56:1-131.