American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 169C:6–22 (2015) ARTICLE

Differential Diagnosis and Diagnostic Flow Chart of Joint Hypermobility Syndrome/Ehlers–Danlos Syndrome Hypermobility Type Compared to Other Heritable Connective Tissue Disorders

MARINA COLOMBI, CHIARA DORDONI, NICOLA CHIARELLI, AND MARCO RITELLI

Joint hypermobility syndrome/Ehlers–Danlos syndrome hypermobility type (JHS/EDS-HT) is an evolving and protean disorder mostly recognized by generalized joint hypermobility and without a defined molecular basis. JHS/EDS-HT also presents with other connective tissue features affecting a variety of structures and organs, such as skin, eye, bone, and internal organs. However, most of these signs are present in variable combinations and severity in many other heritable connective tissue disorders. Accordingly, JHS/EDS-HT is an “exclusion” diagnosis which needs the absence of any consistent feature indicative of other partially overlapping connective tissue disorders. While both Villefranche and Brighton criteria include such an exclusion as a mandatory item, a systematic approach for reaching a stringent clinical diagnosis of JHS/EDS-HT is still lacking. The absence of a consensus on the diagnostic approach to JHS/EDS-HT concerning its clinical boundaries with similar conditions contribute to limit our actual understanding of the pathologic and molecular bases of this disorder. In this review, we revise the differential diagnosis of JHS/EDS-HT with those heritable connective tissue disorders which show a significant overlap with the former and mostly include EDS classic, vascular and kyphoscoliotic types, osteogenesis imperfecta, Marfan syndrome, Loeys–Dietz syndrome, arterial tortuosity syndrome, and lateral meningocele syndrome. A diagnostic flow chart is also offered with the attempt to support the less experienced clinician in stringently recognizing JHS/EDS-HT and stimulate the debate in the scientific community for both management and research purposes. © 2015 Wiley Periodicals, Inc.

KEY WORDS: joint hypermobility syndrome; Ehlers–Danlos syndrome hypermobility type; differential diagnosis; heritable connective tissue disorders; diagnostic flow chart How to cite this article: Colombi M, Dordoni C, Chiarelli N, Ritelli M. 2015. Differential diagnosis and diagnostic flow chart of joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type compared to other heritable connective tissue disorders. Am J Med Genet Part C 169C:6–22.

Marina Colombi is full professor of Medical Genetics at the School of Medicine, University of Brescia and Director of the Division of Biology and Genetics, Department of Molecular and Translational Medicine, and of the Postgraduate School of Medical Genetics. She has various responsibilitiesat the University of Brescia with focus on clinical genetics of rare diseases and genetic laboratory testing. Her major diagnostic and research interests include heritable connective tissue disorders, genodermatoses, and their pathomechanisms. She is author of 90 papers in international journals and various book chapters. Chiara Dordoni is a M.D. resident in Medical Genetics at the School of Medicine, University of Brescia. She has a full-time involvement in the clinical and research activity of the Division of Biology and Genetics, Department of Molecular and Translational Medicine. Her interests mostly include heritable connective tissue disorders. Nicola Chiarelli is a biologist, Ph.D., and resident in Medical Genetics at the School of Medicine, University of Brescia. He has a full-time involvement in the research and diagnostic activity of the Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia. His interests mostly include the molecular characterization of patients affected with heritable connective tissue disorders and the studyofthe pathomechanisms of these rare diseases. Marco Ritelli is a biologist with residency in Medical Genetics at the School of Medicine, University of Brescia. He has a full-time involvement in diagnostic and research activity of the Division of Biology and Genetics, Department of Molecular and Translational Medicine. His interests mostly include the molecular characterization of patients affected with heritable connective tissue disorders and the study of the pathomechanisms of these rare diseases. He is author of 30 papers in international journals, most of them on Ehlers–Danlos syndrome and related disorders. Funding: No funding was active on this project. Conflict of interest: The authors have no conflicts of interest to declare. *Correspondence to: Marina Colombi, Ph.D., Division of Biology and Genetics, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Viale Europa 11, I-25123 Brescia, Italy. E-mail: [email protected] DOI 10.1002/ajmg.c.31429 Article first published online in Wiley Online Library (wileyonlinelibrary.com).

ß 2015 Wiley Periodicals, Inc. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 7

INTRODUCTION 2015], skeletal [Castori, 2012], cardi- ably reflects the natural history within a ovascular [Camerota et al., 2014], single condition, which may have differ- Joint Hypermobility Syndrome gastrointestinal [Zarate et al., 2010; ent clinical presentations at various ages and Ehlers-Danlos Syndrome Danese et al., 2011], gynecological [Tinkle et al., 2009; Castori et al., 2014]. Hypermobility Type [Castori et al., 2012a], neurological Indeed, the diagnostic criteria for JHS/ (JHS/EDS-HT) [Voermans et al., 2009; Garcia Cam- EDS-HT reported by the Villefranche payo et al., 2011; De Wandele et al., nosology [Beighton et al., 1998] are Joint hypermobility syndrome (JHS) 2014], and psychiatric manifestations adequate for children and young adults and Ehlers–Danlos syndrome hyper- [Pasquini et al., 2014] (Table III). evaluation, whereas the Brighton cri- mobility type (EDS-HT) (OMIM teria, considering the natural progressive #130020) are two markedly overlap- loss of joint mobility by age, are more Joint Hypermobility (JHM) ping heritable connective tissue disor- suitable to assess adults [Grahame et al., ders (HCTDs), which are recently JHM is still the most clinically relevant 2000; Tinkle et al., 2009; Castori, considered as the same nosologic entity feature of JHS/EDS-HT. It refers to the 2013a]. [Beighton et al., 1998; Grahame et al., ability to actively and/or passively move 2000;Tinkleetal.,2009;Castorietal., the joints beyond normal limits Diagnosis and Differential 2014]. EDS-HT (estimated prevalence [Beighton et al., 1973]. JHM may affect Diagnosis of JHS/EDS-HT 1:5,000–15,000) reported in the last a few joints (i.e., monoarticular or EDS classification, i.e., the Villefranche localized JHM) or several joints in To date, the diagnosis of JHS/EDS-HT nosology (Table I), shows an autosomal multiple body sites (i.e., generalized is clinical and based on the agreement of dominant inheritance, and it is defined JHM). JHM can be directly assessed largely accepted diagnostic criteria to- by the association of two major criteria, using the Beighton score (BS), a nine- gether with the exclusion of other i.e., generalized joint hypermobility point evaluation (Beighton et al., 1973; partially overlapping HCTDs. No in- (JHM), and smooth, velvety, poorly Fig. 1). In patients without JHM strumental, histopathologic/ultrastruc- hyperextensible skin. Recurring joint according to the BS, a 5-point ques- tural, and molecular finding is dislocations, chronic joint/limb pain, tionnaire is available to investigate considered pathognomonic of this dis- and positive family history are minor historical JHM [Grahame et al., 2000; order. Assessment of JHS/EDS-HT lays diagnostic criteria (Table I) [Beighton Hakim and Grahame, 2003; Tinkle on accurate clinical history taking and et al., 1998]. EDS-HT is the most et al., 2009] (Table II). JHM is a sign, extensive physical examination, includ- common disorder belonging to the not a disease, and its occurrence varies by ing dermatologic, oral cavity, orthope- expanding group of EDS, and together age, sex, and ethnicity. In fact, the dic, and neurologic evaluations [Castori, with Marfan syndrome (MFS) is the majority of hypermobile individuals 2013a]. most frequent HCTD known so far. are asymptomatic, and loose joints are The wide clinical variability of Nevertheless, in contrast to the other more common among females and JHS/EDS-HT identifies a great number EDS variants, its molecular basis re- children than males and older people of partially overlapping acquired and mains unknown [Castori et al., 2014; [Beighton et al., 1973]; lastly, even some genetic disorders showing the variable Malfait and De Paepe, 2014]. JHS, occupational and sport activities may association of mucocutaneous fragility, originally considered a condition dis- naturally improve JHM [Castori, 2012]. JHM, chronic musculoskeletal pain, and tinct from EDS-HT, is assessed by In JHS/EDS-HT generalized JHM fatigue. Among them, there are other Brighton criteria [Grahame et al., contributes to generate various ortho- HCTDs with JHM, the “battered child” 2000], which consider JHM and its pedic complications, which include syndrome, bleeding disorders, develop- complications (pain, dislocations) and increased tendency to recurrent gener- mental coordination disorder, and var- other skin, ocular, soft tissue signs of alized dislocations, widespread chronic ious rheumatologic conditions with connective tissue involvement pain, soft-tissue lesions (i.e., bursitis, chronic musculoskeletal pain, such as (Table II). The further set of diagnostic tenosynovitis) and pes planus [Castori ankylosing spondylitis, rheumatoid ar- criteria proposed by Levy [2004] et al., 2010a; Castori, 2012]. thritis, and fibromyalgia. Some neuro- includes additional features not previ- logic disorders, including multiple ously considered, i.e., functional bowel sclerosis, amyotrophic lateral sclerosis, JHS/EDS-HT Natural History disorders, neurally mediated hypoten- hereditary and acquired sensory-motor sion or postural orthostatic tachycardia, The natural history of JHS/EDS-HT is and/or autonomic polyneuropathies, high narrow palate and dental crowd- characterized by a progressive worsening and chronic fatigue syndrome, as well ing. In the last years JHS/EDS-HT has of the phenotype, usually mild in the as myopathies featuring JHM have to be emerged as a multisystemic disease infancy and more severe in the adult- considered [Castori, 2012, 2013a]. associated with a wide inter- and hood [Castori et al., 2010a, 2013]. The Among the various HCTDs sharing intrafamilial variability with mucocu- existence of two distinct sets of diag- some musculoskeletal features with taneous [Castori, 2012 Castori et al., nostic criteria for JHS/EDS-HT prob- JHS/EDS-HT, there is the growing MRCNJUNLO EIA EEISPR SMNR NMDCLGNTC)ARTICLE GENETICS) MEDICAL IN (SEMINARS C PART GENETICS MEDICAL OF JOURNAL AMERICAN 8

TABLE I. The Villefranche Criteria for the Historical EDS Types [Beighton et al., 1998] and the Underlying Molecular Defect

EDS type Major criteria Minor criteria Gene(s) Classic Skin hyperextensibilitya Smooth, velvety skin COL5A1 AD Widened atrophic scars Molluscoid pseudotumors COL5A2 OMIM #130000, JHM Subcutaneous spheroids #130010 Complications of JHM (e.g., sprains, dislocations/subluxations, pes planus) Muscle hypotonia, delayed gross motor development Easy bruising Manifestations of tissue fragility (e.g., hiatal hernia, anal prolapse in childhood, cervical insufficiency) Surgical complications (postoperative hernias) Positive family history

Hypermobility Skin involvement (hyperextensibility and/or Recurring joint dislocations ? AD smooth, velvety skin) Chronic joint/limb pain OMIM #130020 Generalized JHM Positive family history

Vascular Thin, translucent skin Acrogeria COL3A1 AD Arterial/intestinal/uterine fragility or rupture Hypermobility of small joints OMIM #130050 Extensive bruising Tendon and muscle rupture Characteristic facial appearance Talipes equinovarus (clubfoot) Early-onset varicose veins Arteriovenous, carotid-cavernous sinus fistula Pneumothorax/pneumohemothorax Gingival recession Positive family history, sudden death in (a) close relative(s)

Kyphoscoliotic Generalized JHM Tissue fragility, including atrophic scars PLOD1 AR Severe muscle hypotonia at birth Easy bruising OMIM #225400 Scoliosis at birth, progressive Arterial rupture Scleral fragility and rupture of the ocular globe Marfanoid habitus Microcornea Radiologically considerable osteopenia Family history, i.e., affected sibs

Arthrochalasia Severe generalized JHM, with recurrent subluxations Skin hyperextensibility COL1A1 AD Congenital bilateral hip dislocation Tissue fragility, including atrophic scars COL1A2 OMIM #130060 Easy bruising Muscle hypotonia Kyphoscoliosis Radiologically mild osteopenia ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 9

group of the other EDSs, MFS, Loeys– 2014]. Although EDS variants show an Dietz syndrome (LDS), arterial tortuos- extensive clinical overlap, the Ville- ity syndrome (ATS), milder forms of franche nosology identifies distinctive osteogenesis imperfecta (OI), and lateral features for the six historical forms, ADAMTS2 meningocele syndrome (LMS) [Calle- considered as major or minor clinical waert et al., 2008a,b; Castori et al., criteria for inclusion (Table I). The 2013b; Malfait and De Paepe, 2014; Van major specific criteria can be all present Dijk and Sillence, 2014; Van Laer et al., or not and their combination with 2014]. The clinical overlap of JHS/ minor features suggests the diagnosis in EDS-HTwith these HCTDs, its evolv- a large majority of the cases. For the ing and variable phenotype, and the recently characterized EDS forms absence of the causal gene(s) make the (Table IV) established diagnostic criteria diagnostic process difficult. This diffi- are not available, also due to the rarity of culty is hampered in pediatric patients the patients. For all of the EDS variants without a complete manifestation of the the connective tissue signs are increasing specific disorder by which they are as far as new patients are investigated and affected [Tofts et al., 2009]. JHS/EDS- reported, and nowadays the clinical HT often becomes the “default” diag- picture of EDSs is more puzzling than nosis either of a hypermobile child or an depicted by the Villefranche nosology. adult who does not meet the criteria for JHS/EDS-HT is a clear example of this diagnosis of one of the other HCTDs. expanding knowledge (Table III). Be- Therefore, the JHS/EDS-HT is prob- sides JHS/EDS-HT, the other more ably a heterogeneous group and partic- frequently observed EDS types are, in

) ularly in pediatric patients the evaluation decreasing order, the classic, vascular, of parents and relatives should be and kyphoscoliotic types. The arthro- considered, as well as the opportunity calasia and the dermatosparaxis types are of genetic testing for other HCTDs with infrequently observed entities. Derma- Continued ( known molecular basis, which might tosparaxis is clearly distinguishable from address, by exclusion or confirmation, a JHS/EDS-HT (Table I) and is not correct diagnosis. In this review, we will considered in the differential diagnosis. Easy bruising Premature rupture of fetalLarge membranes hernias (umbilical, inguinal)

Soft, doughy skin texture focus on the differential diagnosis of JHS/EDS-HTwith the other EDS types TABLE I. EDS Classic Type and with HCTDs with JHM, cutane- ous, skeletal, vascular, and internal JHS/EDS-HT has a great clinical overlap organs overlapping manifestations and with EDS classic type (cEDS) since they will delineate a flow chart for a clinical both share cutaneous and articular signs diagnostic approach to JHS/EDS-HT and their complications (Table I). How- patients. ever, the high skin hyperextensibility together with widened atrophic/papyra- ceous scars, and, more rarely, molluscoid DIFFERENTIAL DIAGNOSIS pseudotumors, are more remarkable and WITH OTHER EDS TYPES distinctive of cEDS [Ritelli et al., 2013] INCLUDED IN THE (Table I). In fact, in JHS/EDS-HT skin is VILLEFRANCHE usually poorly hyperextensible and pap- NOSOLOGY yraceous scars and molluscoid pseudo- EDS needs to be considered when, in tumors are absent. Small atrophic scars the absence of another explanation, one are observed in 1/4 of JHS/EDS-HT Sagging, redundant skin or more of the following manifestations cases and orthopedic post-surgical atro- Severe skin fragility occurs: (i) late walking with joint phic scars are also present in 1/4 of the hypermobility, (ii) abnormal bruising subjects, generally adults [Castori et al., and bleeding, (iii) tissue fragility, atro- 2015]. In a few cases, cEDS and JHS/ phic scarring or skin hyperextensibility, EDS-HT may share similar cutaneous (iv) symptomatic joint hypermobility presentations and cEDS patients without with or without dislocations, (v) un- atrophic scars (5% of the cases), or with AR OMIM #225410 Items in bold are distinguishing features of the particular EDS type.

EDS typeDermatosparaxis Major criteriaa explained vessel Minor criteria rupture or dissection, small atrophic scars [Ritelli et al., 2013], Gene(s) (vi) internal organ rupture [Sobey, as well as JHS/EDS-HT patients with 10 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

TABLE II. Brighton Criteria for Assessing JHS and 5-Point Questionnaire for Historical JHM

Brighton criteria for JHS 5-point questionnaire for JHM Major criteria 1. Could you ever place your hands flat on the floor Beighton score 4/9 without bending your knees? Arthralgia for >3 months in >4 joints 2. Could you ever bend your thumb to touch your Minor criteria forearm? Beighton score 1–3 3. As a child did you amuse your friends by Arthralgia in 1–3 joints contorting your body into strange shapes OR History of joint dislocations could you do the splits? Soft tissue lesions >3 4. As a child or teenager did your shoulder or Marfan-like habitus kneecap dislocate on more than one occasion? Skin striae, hyperextensibility, or scarring 5. As a child or teenager did you consider yourself Downslanting palpebral fissures, lid laxity, myopia double-jointed? History of varicose veins, hernia, visceral prolapse Agreement: both major, or 1 major and 2 minor, or Agreement: affirmative answer for two or more 4 minor criteria. Criteria major 1 and minor 1 are questions. mutually exclusive as/are major 2 and minor 2. Source: Grahame et al., [2000] and subsequent Source: modified from Hakim and Grahame [2003]. modifications (see, for example, Tinkle et al., [2009]). marked hyperextensible skin are re- (Table I) for the vascular, skin, and may be present (TableII) [Dordoni et al., ported. In these patients, the careful internal organs fragility, and for the 2013]. The fragility of the capillaries and investigation of affected family members, characteristic facial appearance, i.e., of the perivascular connective tissues can possibly showing cEDS-like scars, and triangular face with sunken and large lead to easy bruising with ecchymosis for the molecular analysis of the cEDS causal eyes, thin lips and philtrum, small chin, minimal traumas both in vEDS and genes, i.e., COL5A1 and COL5A2, and thin nose present in some patients. JHS/EDS-HT patients, though these allows for the distinction of cEDS from Generalized vascular fragility largely features are more prominent in vEDS JHS/EDS-HT patients [Ritelli et al., dominates the clinical picture of this [De Paepe and Malfait, 2004]. In fact, in 2013]. JHS/EDS-HT remains an exclu- life-threatening condition, indeed the childhood vEDS patients are usually sion diagnosis for the absence of known majority of vEDS patients (80% referred to pediatricians for the presence causal gene(s). Concerning articular within 40 years) experienced a major of frequent ecchymosis and “battered involvement, cEDS patients suffer from vascular events (i.e., spontaneous aortic child” syndrome can be considered as chronic and/or generalized joint pain; dissection or dissection of a previously differential. Concerning cutaneous however, in the majority of the cases it aneurysmatic aorta), potentially result- signs, in vEDS skin is not hyperexten- does not need chronic pharmacological ing in sudden death. Hence, in adult- sible but rather thin, transparent/trans- treatment [Ritelli et al., 2013]. In cEDS hood vEDS patients commonly receive lucent, sometimes showing a visible and in the other EDS forms chronic pain a diagnosis after referral to emergency venous pattern over the chest, abdomen might be underestimated. In a very few surgeons for vascular dissection/rupture and extremities, and fragile with mild patients with hyperextensible skin, atro- [Pepin et al., 2000; Oderich et al., 2005]. atrophic scarring. Acrogeria can be phic scarring, easy bruising, and JHM, In JHS/EDS-HT aortic dissections are observed in patients harboring specific propensity for arterial rupture at adult age extremely rare, and aortic root ectasia is mutations in COL3A1 [Drera et al., is present [Malfait et al., 2007; Ritelli observed with an overall incidence of 2011]. JHM in vEDS generally involves et al., 2013] (Table IV). These patients, approximatively 12% without an in- small joints, but can be generalized in defined as vascular-like cEDS individu- creased risk of dissection [Atzinger et al., some patients. The few vEDS patients als, typically carry arginine to cysteine 2011]. In vEDS visceral rupture (i.e., with generalized JHM and without substitution in the pro-a1(1) collagen bowel, lungs, liver, spleen, uterus during major vascular events or internal organ chain. pregnancy, heart) may also occur for rupture may partially overlap with the internal organs fragility [Drera et al., JHS/EDS-HT phenotype; in these 2011; Murray et al., 2014]; in JHS/ cases, the presence of thin skin, visible EDS Vascular Type EDS-HT internal organs rupture is not venous network, acrogeria, vascular JHS/EDS-HT is clearly distinguishable reported, whereas visceroptosis due to imaging diagnostic for arterial aneur- from the EDS vascular type (vEDS) ligaments hypoplasia and deterioration ysm, and positive family history for ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 11

TABLE III. Clinical spectrum of JHS/EDS-HT

System/apparatus Clinical finding Reference Mucocutaneous Mildly hyperextensible skin Beighton et al., [1998] Velvety/silky/soft skin texture Castori, [2012] Striae rubrae and/or distensae in young age Castori, [2013] Small or post-surgical atrophic scars (non-papyraceous) Castori et al., [2015] Keratosis pilaris Wiesmann et al., [2014] Inguinal/umbilical/incisional hernia Light blue sclerae Gingival inflammation/recessions Hypoplastic lingual frenulum Easy bruising Resistance to local anaesthetic drugs Osteoarticular Generalized joint hypermobility Beighton et al., [1998] Recurrent dislocations (mostly at hips, shoulders, Levy, [2004] temporomandibular joint, fingers, and vertebrae) Castori et al., [2010a] Recurrent soft-tissue lesions (bursitis, tendonitis, synovitis, tenosynovitis, and fasciitis) Temporomandibular joint dysfunction Chronic /recurrent not inflammatory joint pain Chronic generalized pain Muscular/myofascialneuropathic/osteoarthritic Early osteoarthritis Orthopedic High arched/narrow palate Beighton et al., [1998] Flat foot Grahame et al., [2000] Not surgical pectus excavatum Gulbahar et al., [2006] Mild scoliosis, dorsal hyperkyphosis, lumbar hyperlordosis Castori, [2012] Genua, halluces, and cubita valga Minor asymmetry at lower limbs and other body areas Non-postmenopausal reduced bone mass Marfanoid habitus (i.e., arm span/height ratio >1.03, arachnodactyly) Muscular Hypotonia of mild degree Castori, [2012] Recurrent myalgias and cramps Voemans et al., [2009] Fibromyalgia Myofascial pain Involuntary muscle contractions Reduced muscle power (rare) Gastrointestinal Dysphagia and dysphonia Castori et al., [2010] Gastroesophageal reflux Danese et al., [2011] Hiatal hernia Dordoni et al., [2013] Chronic/recurrent gastritis Zarate et al., [2010] Delayed gastric empty Defecatory dysfunction Delayed small bowel and colonic transit Unexplained abdominal pain Various food intolerances Visceroptosis Cardiovascular Valvular regurgitation with mild hemodynamic involvement Atzinger et al., [2011] Mitral valve prolapse/insufficiency Camerota et al., [2014] Varicose veins De Wandele et al., [2014] Low progressive aortic root dilatation Raynaud’s phenomenon/acrocyanosis/livedo reticularis Uro-gynecological Meno/metrorrhagias Castori et al., [2012a] Disabling dysmenorrhea (Continued) 12 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE TABLE III. (Continued)

System/apparatus Clinical finding Reference Pelvic prolapse Dyspareunia Urinary stress incontinence Neuropsychiatric Chronic fatigue (syndrome) Rombaut et al., [2010] Sleep disturbances Castori, [2012] Impaired memory and concentration Granata et al., [2013] Headache and migraine De Wandele et al., [2014] Recurrent paresthesias Neilson et al., [2014] Cardiovascular dysautonomia (e.g., postural orthostatic Pasquini et al., [2014] tachycardia syndrome, neuromediated hypontension) Somatosensory/central sensitization Clumsiness Anxiety, panic, and fears Depression Obsessive-compulsive disorder Ocular Myopia and/or strabismus Castori, [2012] Palpebral ptosis

arterial dissection in young age can EDS Arthrochalasia Type detailed phenotypes are reported for the support the diagnosis. Molecular anal- few patients so far characterized ysis of COL3A1 can confirm or exclude The arthrochalasia type of EDS (aEDS) (Table IV). The major cause of the this diagnosis. is characterized by severe generalized historical EDSs appears to be impaired JHM and bilateral congenital hip dis- biosynthesis and enzymatic modification location (CHD) (Table I). Generalized of the three main fibrillar collagens, but EDS Kyphoscoliotic Type JHM is shared as a major feature with EDSs are also associated with proteogly- JHS/EDS-HT; CHD can be also ob- JHS/EDS-HT is distinguishable from can abnormalities (the progeroid and the served in JHS/EDS-HT patients, but it the kyphoscoliotic type of EDS (kEDS) musculocontractural types of EDS), as is not a major sign and in most cases is (Table I) for the recessive inheritance, well as with alteration of an endoplasmic unilateral (our unpublished data). Other the presence of early onset progressive reticulum folding protein (EDS with signs distinguishing aEDS from JHS/ kyphoscoliosis, neonatal thoracic sco- progressive kyphoscoliosis, myopathy EDS-HTare marked hypotonia at birth, liosis, and severe muscular hypotonia and hearing loss), of transcription factors short stature, and wormian bones with delayed gross motor development, (Brittle cornea type 1 and 2), and of a zinc [Klaassens et al., 2012]. Hence, bilateral osteopenia, microcornea, and in some transporter (spondylocheirodysplastic CHD in patients with extreme JHM and patients scleral fragility with risk for EDS). This heterogeneity of causes significant hypotonia at birth suggests rupture of the globe, and occurrence of involving several systems leads to the aEDS and molecular testing for a specific life-threatening rupture of medium- variety of distinguishable phenotypes set of COL1A1 and COL1A2 muta- sized arteries [Rohrbach et al., 2011]. reported in Table IV. On the other tions, involving their exons 6 splice Features common to kEDS and JHS/ hand, since the genes involved in this junctions, can confirm the diagnosis. In EDS-HT are mainly cutaneous, i.e., growing number of EDS types encode patients without a causal mutation fragile, hyperextensible, and bruisable for components or regulators of the clinical diagnosis of JHS/EDS-HT has skin with atrophic scarring, articular, connective tissue extracellular matrix, to be considered searching for cardio- i.e., generalized JHM, and skeletal. The common features are present in the vascular, gastrointestinal, gynecological, diagnosis of kEDS relies on the dem- different variants which have to be and neurological signs (Table III), which onstration of an increased ratio of considered in differential diagnosis with at the moment are not reported in aEDS deoxypyridinoline to pyridinoline JHS/EDS-HT, especially for their artic- patients. crosslinks in urine, caused by deficient ular and cutaneous signs (Table IV) activity of lysyl hydroxylase 1, the [Malfait and De Paepe, 2014; Miyake enzyme encoded by PLOD1. Alterna- et al., 2014; Sobey, 2014]. In particular, DIFFERENTIAL DIAGNOSIS tively, an assay of lysyl hydroxylase JHS/EDS-HT shows a marked overlap WITH RARE EDS TYPES enzyme activity in skin fibroblasts is with a small subset of patients with diagnostic. Mutations in PLOD1 are Concerning the rare EDS forms not homozygous /compound heterozygous causative [Rohrbach et al., 2011]. included in the Villefranche nosology, TNXB mutations (TNX-deficient ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 13

Figure 1. Assessment of joint hypermobility with the Beighton score: (a) passive dorsiflexion of the fifth metacarpophalangeal joint to 90°, (b) opposition of the thumb to the volar aspect of the ipsilateral forearm, (c) hyperextension of the elbow to 10°, and hyperextension of the knee to 10°, d) placement of hands flat on the floor without bending the knees (Figure drawn by L. Manenti). The Beighton score is incorporated into the diagnostic criteria for EDSs, MFS, LDS, ATS, and OI. patients), but also with the heterozygous results in JHS/EDS-HT phenotype (periodontal ligament, alveolar bone, carriers of mutations leading to TNXB [Zweers et al., 2003; Mercke et al., and connective tissue) leading to pre- haploinsufficiency, including a recurrent 2013]. Recently, it is emerging that mature loss of teeth, associated with JHM 30 kb deletion involving TNXB and TNX-deficient patients also suffer from and atrophic scars [Reinstein et al., CYP21A2 [Schalkwijk et al., 2001; myopathy, generalized muscle weakness, 2013]. For this heterogeneous disorder Zweers et al., 2003], therefore suggesting and possible distal contractures in adult the molecular basis is still unknown. that the EDS phenotype associated with age [Pénisson-Besnier et al., 2013; Voer- Periodontal disease is common also in TNX-deficiency is a dose-dependent mans et al., 2014]. Myopathic pattern at JHS/EDS-HT patients, but true paro- phenomenon. The patients with the electromyography is observed also in dontopathy with early tooth loss is rarely 30 kb deletion in homozygosity [Burch some JHS/EDS-HT patients who com- observed, whereas gingival fragility and et al., 1997], or in compound hetero- plain of neuromuscular symptoms, i.e., inflammation causing bleeding, retrac- zygosity with a second CYP21A2 muta- muscle cramps and myalgia, and in other tion, and impaired oral cleansiness are tion [Mercke et al., 2013], also present EDS variants, i.e., musculocontractural common [Castori, 2012]. Otherwise, with congenital adrenal hyperplasia type 1 and type 2 EDS, progressive gingival mucosal fragility is not a specific (CAH). In patients with CAH and kyphoscoliosis, myopathy and hearing sign of JHS/EDS-HT, as it is found in TNXB haploinsufficiency (CAH-X syn- loss EDS, and progeroid type 1 and type 2 about 74% of the EDS population drome), mainly due to the recurrent EDS (Tables I, III, and IV) [Voermans without any significant difference be- 30 kb deletion, JHM is the predominant et al., 2009; Baumann et al., 2012]. Since tween the most prevalent subtypes, i.e., clinical feature, in addition to variable JHM secondary to muscle hypotonia in cEDS, JHS/EDS-HT, and vEDS [De findings including joint dislocations, combination with cutaneous features is Coster et al., 2005]. Instead, dentin chronic joint pain, and soft tissue lesions also observed in Ullrich congenital defects, i.e., abnormal pulp shape and [Mercke et al., 2013]. Therefore, in muscular dystrophy, and in the allelic pulp stones, appear to be more specific of patients with JHM and CAH the Bethlem myopathy [Voermans et al., cEDS or vEDS, and it was never presence of the 30 kb TNXB deletion 2008], also these myopathies have to be described in JHS/EDS-HT [De Coster should be investigated. Patients with considered in the differential with JHS/ et al., 2005; Ferrè et al., 2012]. Gingival complete TNX-deficiency show a EDS-HT,especially in pediatric patients. regression was considered a minor marked cEDS overlapping phenotype The periodontitis EDS type is Villefranche criterion for vEDS; how- without atrophic scarring [Schalkwijk distinguished for the severe periodontal ever, recent evidences suggested that it is et al., 2001], whereas TNXB haploin- disease characterized by irreversible de- inappropriate for its low frequency sufficiency, without concomitant CAH, struction of the periodontal tissues among vEDS patients [Ferrè et al., 2012]. 14 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

TABLE IV. EDS Forms Not Included in the Villefranche Nosology with the Clinical Features and the Involved Genes

EDS variant Feature Gene(s) Reference Classic vascular-like Hyperextensible skin COL1A1 Malfait et AD Atrophic scarring al., [2007] Easy bruising Ritelli et JHM al., [2013] Propensity for arterial rupture at adult agea Cardiac valvular Severe mitral valve regurgitation/insufficiency COL1A2 Schwarze AR Arrhythmia, atrial fibrillation and septal defect, left et al., OMIM #225320 ventriculum enlargement [2004] JHM Skin hyperextensibility Tenascin-X deficiency Marked skin hyperextensibility TNXB Schalkwijk AR Normal scarring et al., OMIM #606408 Generalized JHM [2001] Severe easy bruising Pénisson- Besnier et al., [2014] Voermans et al., [2014] EDS/OI overlap Short stature COL1A1 Malfait AD Blue sclerae COL1A2 and De Mild signs of bone fragility Paepe, Osteopenia [2014] Infrequent fractures Generalized JHM Skin hyperextensibility Atrophic/hypertrophic scars Easy bruising Signs of vascular fragility Valvular regurgitation Periodontitis Gingival recessions Locus Reinstein AD Periodontitis heterogeneity et al., OMIM #130080 Premature loss of permanent teeth Unknown [2013b] Alveolar bone resorption by the IIIrd decade genes Atrophic scars JHM Umbilical hernia Arachnodactyly Musculocontractural Congenital contractures of thumbs and fingers CHST14 Malfait et type 1/ Craniofacial dysmorphisms al., [2010] D4ST1 deficiency Blue sclerae AR Microcornea OMIM #601776 Clubfoot Arachnodactyly Severe kyphoscoliosis Muscle hypotonia JHM Hyperextensible skin Atrophic scars Easy bruising Wrinkled palms Musculocontractural Joint dislocations and deformity DSE Müller et ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 15 TABLE IV. (Continued)

EDS variant Feature Gene(s) Reference type 2 Hyperextensible fragile skin al., [2013] AR Atrophic scarring OMIM #615539 Easy bruising Muscle hypoplasia Gross motor development delay Facial dysmorphisms Arachnodactyly Adducted thumbs Clubfoot Inguinal hernia Generalized mild cerebral atrophy With progressive Severe hypotonia and weakness at birth FKBP14 Baumann kyphoscoliosis, Hyperextensible skin et al., myopathy and hearing JHM [2012] loss Severe progressive scoliosis AR Sensorineural hearing impairment OMIM #614557 Myopathy Vascular dissection Brittle cornea syndrome Blue sclerae ZNF469 Burkitt type 1 Corneal rupture Wright et AR Keratoconus/keratoglobus al., [2013] OMIM #229200 Skin hyperextensibility JHM Brittle cornea syndrome Corneal rupture PRDM5 Burkitt type 2 Microcornea Wright et AR Cornea plana al., [2011, OMIM #614170 Keratoconus/keratoglobus 2013] Myopia Hyperextensible skin Easy bruising JHM (localized) Pectus excavatum Scoliosis Mitral valve prolapse Hearing loss (conductive and sensorineural deafness) Spondylocheirodysplasia Short stature SLC39A13 Giunta et EDS-like Protuberant eyes al., [2008] AR Blue sclerae OMIM #612350 Hyperextensible skin Easy bruising JHM Hands with wrinkled palms Tenar muscles atrophy Tapering fingers Spondyloepiphyseal dysplasia Progeroid type 1 Aged appearance B4GALT7 Guo et AR Short stature al., [2013] OMIM Forearm bones and elbow anomalies, radioulnar #130070 synostoses Bowing of the extremities Facial dysmorphisms Hyperextensible skin 16 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE TABLE IV. (Continued)

EDS variant Feature Gene(s) Reference Atrophic/papyraceous scars JHM Pes planus Developmental delay Muscle hypotonia Progeroid type 2/ Aged appearance B3GALT6 Nakajima Spondyloepimetaphyseal Developmental delay et al., dysplasia with joint Disproportionate short stature [2013] Malfait laxity type 1 Craniofacial disproportion et AR Generalized severe osteopenia al., [2013] OMIM #615349 Defective wound healing Ritelli et OMIM #271640 Hyperextensible skin al., [2015] JHM Muscle hypotonia Spondyloepimetaphyseal dysplasia

AD, autosomal dominant; AR, autosomal recessive. aItems in bold are distinguishing features of the particular EDS type.

In the rare spondylocheirodysplasia-like topia EDS variant (OMIM #300537), V); severe progressively deforming OI and progeroid type 1 and 2 EDS in addition to bilateral nodular hetero- (type III), and perinatally lethal OI (type variants, JHM and hyperextensible topia on brain MRI, aortic dilatation II) [Van Dijk and Sillence, 2014]. skin are associated with skeletal dyspla- and dissection in early adulthood, ex- JHM is reported in non-deforming sia, including moderate to severe dis- cessive bleeding and bruisability, and OI with blue sclerae (OI type I, OMIM proportionate short stature, skeletal abnormalities. This X-linked #166200); these patients are distin- pathognomonic bone deformities, disorder, due to dominant mutations in guishable for the presence of blue sclerae and/or severe kyphoscoliosis with pla- filamin A gene (FLNA), is lethal in males and wormian bones; dentinogenesis im- tyspondyly. Since short stature and and presents with epilepsy in hetero- perfecta (i.e., opalescent dentine) and evident bone deformities are absent in zygous females. Since some patients can sensorineural deafness may be present in JHS-EDS-HT, differential diagnosis be- primarily present with JHM, screening a subset of the patients [Steiner et al., tween these conditions is straightfor- for cardiovascular manifestations should 2005]. Reduction in the synthesis of ward; skeletal and spine radiography can be offered when there are associated type I procollagen and the presence of classify bone and vertebral alterations, seizures or an X-linked pattern of mutations in COL1A1 confirm the reinforcing clinical diagnosis of these inheritance [Reinstein et al., 2013]. diagnosis of OI type I with normal EDS types with skeletal dysplasia. In teeth, whereas COL1A2 mutations are JHS/EDS-HT skeletal alterations in- present in OI type I patients with DIFFERENTIAL DIAGNOSIS clude moderate scoliosis and platyspon- opalescent dentine. The other OI sub- WITH OTHER HCTDs dyly, leg length discrepancy, genua valga, types are not considered in the differ- hallux valgus, as well as early onset ential with JHS/EDS-HT for: (i) the Osteogenesis Imperfecta osteopenia [Castori, 2012; our unpub- perinatal lethality (type II), (ii) the lished data]. These skeletal signs, ob- Osteogenesis imperfecta (OI) comprises a presence of respiratory and swallowing served also in other EDS, f.e., cEDS heterogeneous group of diseases char- problems in newborns, and multiple [Ritelli et al., 2013], are not specific of acterized by susceptibility to bone long-bone fractures at birth with pro- JHS/EDS-HT and are not useful in fractures with variable severity. The gressive deformity (type III), (iii) short differential diagnosis. last available classification identifies OI stature, basilar impression, and long JHM with recurrent dislocations with mild to moderate severity, i.e., bones bowing (type IV), (iv) calcifica- and soft/fragile/hyperextensible skin are non-deforming OI with blue sclerae (type tion of the interosseous membranes also found in a disorder with combined I), common variable OI with normal and/or hypertrophic callus (type V) connective tissue and neurological fea- sclerae (type IV), and OI with calcifica- [Van Dijk and Sillence, 2014]. Occa- tures, i.e., the periventricular hetero- tion and interosseous membranes (type sionally, patients are encountered who ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 17 display a phenotype that combines EDS-HTyoung patients, unlike in MFS, organ systems was also recognized and clinical manifestations of both OI and does not show any progression in include craniofacial (e.g., craniosynos- EDS. These OI/EDS patients present adulthood [Castori, 2012; Atzinger tosis), musculoskeletal (JHM, marfanoid relevant bone fragility with repeated et al., 2011]. JHS-EDS-HT patients habitus with arachnodactyly, dolichoste- fractures and overt blue sclerae together presenting with marfanoid habitus and nomelia, pectus deformities and joint with marked joint hypermobility and aortic root ectasia are comparable but contractures), integumental (e.g. skin instability, skin hyperextensibility and/ distinguishable from MFS patients for hyperextensibility, dural ectasia), and or translucency, and signs of peripheral ectopia lentis, which is not reported in ocular findings (e.g., strabismus) [Loeys vascular fragility (Table IV). The ma- JHS/EDS-HT. In most cases of MFS, et al., 2005; Loeys and Dietz, 2008]. A jority of OI/EDS patients harbor a JHM spares the elbows and pectus group of LDS patients, previously dominant mutation in the most N- deformities are common and generally defined as LDSII, presents with severe terminal part of the type I collagen more impressive than in JHS/EDS-HT. vascular involvement together with helical region in either the a1- or a2- MASS syndrome (Mitral valve, thin, translucent skin, atrophic scars, chain, which affects to some extent Aorta, Skeleton, and Skin syndrome; and marked easy bruising, and without processing of the N-propeptide [Malfait OMIM #604308) is a MFS-related craniosynostosis and/or marfanoid hab- and De Paepe, 2014]. phenotype sharing skeletal features, itus, thus resembling vEDS [Loeys and i.e., scoliosis, marfanoid habitus, and Dietz, 2008; Drera et al., 2008, 2009; JHM, and cutaneous signs, i.e., striae Fattori et al., 2012]. LDS3 can show Marfan Syndrome rubrae/distensae, and is distinguishable for osteoarthritis in young age [Van de Laar Marfan syndrome (MFS) (OMIM mitral valve prolapse (MVP), aortic root et al., 2011; Regalado et al., 2011; #154700) is a relatively common auto- ectasia without progression to aneurysm Wischmeijer et al., 2013]. LDS4 somal dominant multisystem HCTD or dissection, and absence of ectopia lentis presents a lower rate of life-threatening that exhibits marked inter- and intra- [Glesby and Pyeritz, 1989; Dietz et al., aortic dissection compared to the other familial variability with predominant 1993]. JHS/EDS-HT patients with a LDS types, a high rate of MVP, JHM, manifestations in the cardiovascular, marfanoid habitus may show a great and skeletal signs common to MFS skeletal, and ocular systems; additionally, overlap with MASS phenotype when [Lindsay et al., 2012; Boileau et al., the skin, fascia, lung, skeletal muscle, MVP is present. The rate of MVP in 2012; Ritelli et al., 2014a]. LDS and adipose tissue may be involved JHS/EDS-HT is not well delineated. clinically overlaps with MFS also for [Pyeritz, 2000]. The clinical diagnosis Contrasting data exist as in some reports aortic root aneurysm and for skeletal is based on the revised Ghent nosology, its incidence does not seem significantly deformities and can be distinguished for which can include the presence of a higher than in controls [Atzinger et al., the absence of ectopia lentis and for the mutation in FBN1 encoding fibrillin 1 2011], while others found a clearly presence of craniosynostosis, hyperte- [Loeys et al., 2010]. When moderate increase in rate [Camerota et al., lorism, bifid uvula, severe vascular JHM is associated with a marfanoid 2014]. Hence, in the small subset of involvement, and early osteoarthritis. habitus (tall and slender build, arachno- JHS/EDS-HT patients with marfanoid JHS/EDS-HT with marfanoid habitus dactyly and/or true dolichostenomelia, habitus and MVP FBN1 molecular may partially overlap with LDS with i.e., arm span/height ratio 1.05) analysis should be considered. mild vascular involvement and without coupled with a history of ectopia lentis craniosynostosis as LDS4; in these cases and/or aortic dilatation or aneurysm, familial investigation and arterial evalu- Loeys–Dietz Syndrome MFS should be strongly suspected. In ation are mandatory [Ritelli et al., about one-third of JHS/EDS-HT pa- Loeys–Dietz syndrome (LDS1–4, 2014a]. Molecular analysis of the genes tients a marfanoid habitus is recognizable OMIM #609192, #610168, #613795, involved in LDS, i.e., TGFBR1, and includes arachnodactyly, dolichos- #614816) is an autosomal dominant TGFBR2, SMAD3, and TGFB2, en- tenomelia with an arm span:height ratio aortic aneurysm syndrome with multi- coding for components of the trans- 1.03 (which is significantly different system involvement and inter- and forming growth factor beta (TGFb) from the cut-off of the revised Ghent intrafamilial variability. LDS is charac- signaling pathway, conclude the diag- criteria which is 1.05), long hands and terized by a clinical triad including nosis of LDS. feet, increased skin stretches in young hypertelorism, bifid uvula or cleft palate, Recently also TGFB3 mutations age, JHM and characteristic changes in and aortic aneurysm with arterial tor- were reported to be associated with the pectus physiology [Hakim and Gra- tuosity. Natural history is significant for abnormal development of several mes- hame, 2003; Grahame and Hakim, life-threatening aortic dissection that enchymal-derived tissues, including 2013]. Aortic root ectasia, another occur at smaller aortic diameter and muscle and craniopalatofacial structures, distinctive feature of MFS, is reported younger age compared to MFS. Aortic accompanied by low muscle mass, in a subset (about 12%) of JHS/EDS- aneurysms can be detected throughout growth retardation, distal arthrogrypo- HT patients [Atzinger et al., 2011]. the whole arterial tree. Furthermore, a sis, and other secondary changes However, aortic root ectasia in JHS- widespread involvement of different (Rienhoff syndrome). The syndrome 18 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE shares some clinical features with the belonging to nine families, is charac- When specific signs of the different MFS and LDS, including arachnodac- terized by widespread spinal lateral EDSs or HCTDs are found, the initial tyly, pectus excavatum, pes planus, and meningoceles (meningeal diverticula) diagnosis is addressed accordingly. hyperextensible large joints, as well as protruding through the intervertebral When the presence of other EDSs, hypertelorism and bifid uvula without spaces, in association with facial dys- OI, MFS, LDS, ATS, or LMS is evidence of vascular disease [Rienhoff morphisms and variable signs of con- suspected, additional investigations for et al., 2013; Matyas et al., 2014; nective tissue involvement, including the assessment of vascular, skeletal, Rienhoff, 2014] and is distinguishable JHM, present in about 74% of reported ophthalmologic, and bone health should from JHS/EDS-HT for the absence of patients, and chronic musculoskeletal be performed. In particular, when the mucocutaneous features, and the pres- pain, found in about 64,3% of the cases suspicion of a vascular disorder (i.e., ence of growth retardation, hypertelor- [Castori et al., 2013b]. Cutaneous signs, vEDS, LDS, ATS) persists, extensive ism, distal arthrogryposis, and positive i.e., hyperextensible and soft skin, are vascular imaging (i.e., whole body TGFB3 genetic testing. rarely disclosed (21% of the patients). angio-MRI, or brain angio-MRI plus Multiple meningeal diverticula have thoracic and abdominal angio-CT, or never been reported in JHS/EDS-HT heart, abdominal aorta, epiaortic and Arterial Tortuosity Syndrome patients or in cEDS, kEDS, MFS, and limb vessels Doppler ultrasound) is Arterial tortuosity syndrome (ATS, LDS, hence the presence of this clinical mandatory. When MFS is suspected OMIM #208050) is a rare, autosomal sign can distinguish LMS. heart ultrasound for MVP and aortic recessive HCTD chiefly characterized root ectasia, ocular evaluation for ectopia by tortuosity and elongation of the lentis and/or myopia, and spine MRI for DIAGNOSTIC FLOW CHART large- and medium-sized arteries and a dural ectasia must be performed. In OF JHS/EDS-HT propensity towards aneurysm formation patients with an OI type I resembling and vascular dissection. Additional car- When a patient presents with JHM and phenotype, bone densitometry for early diovascular features include aberrant variable cutaneous signs, including soft, osteoporosis/osteopenia, skull radiogra- origin of aortic branches, arterial and velvety, thin, hyperextensible skin, striae phy for wormian bones, orthodontic pulmonary valve stenosis, and vaso- rubraeordistensae, and abnormal scar- evaluation for dentinogenesis imperfecta are motor instability. ATS also shares with ring, a clinical evaluation is mandatory required. In LMS patients spine MRI is other HCTDs soft/velvety/hyperexten- in order to identify other possible signs needed. sible skin, cutis laxa, mildly dysmorphic of connective tissue fragility, and his/her In EDSs ultrastructural examina- facial features (i.e., elongated face, family history must be investigated. In tion of the skin usually reveals abnor- hypertelorism, cleft palate and/or bifid particular, clinical signs indicative of the malities of collagen fibrils which include uvula, and micro/retrognathia), kerato- different forms of EDS and of the partly irregular, disrupted fibrils (“collagen conus, abdominal hernias, joint hyper- overlapped HCTDs (MFS, LDS, ATS, flowers”), and variability within their mobility and instability, and other OI, and LMS) should be sought. A diameter. However, these abnormalities skeletal anomalies. Systemic symptoms synthetic flow chart with the main are common to several EDS variants and and sudden death due to acute respira- clinical signs present in JHS/EDS-HT usually not specific enough to discrim- tory insufficiency and/or cardiac failure and in the most frequently observed inate between individual EDS types, can occur in the pediatric age [Call- EDSs and HCTDs that have to be with the exception of the pathogno- ewaert et al., 2008b; Ritelli et al., considered in the differential with JHS/ monic hieroglyphic fibers observed in 2014b]. ATS is caused by mutations in EDS-HT is reported in Figure 2. This the dermatosparaxis type of EDS [Mal- SLC2A10 [Coucke et al., 2006; Ritelli flow chart will address the diagnostic fait and De Paepe, 2014]. At the et al., 2014b], encoding for the facili- suspicion of physicians or specialists in moment, ultrastructural abnormalities tative glucose transporter 10, GLUT10. one of the different clinical fields of are only occasionally identified in JHS/ For patients without cardiovascular interest for JHS/EDS-HT. In a speci- EDS-HT and no finding is specific of complications, EDS can be suspected alized center, the careful clinical evalua- this condition. Therefore, skin biopsy and particularly JHS/EDS-HT for the tion and the assessment of the reported ultrastructure is not included in the cutaneous, articular and skeletal signs; in findings is sufficient to confirm the JHS/ standard diagnostic schedule of JHS/ these cases, cardiovascular evaluation EDS-HT diagnosis in the majority of EDS-HT [Castori, 2013]. This is also and SLC2A10 molecular analysis allow the cases (about 90% - Colombi, the case of biochemical analyses, none is the distinction between these disorders unpublished data). Only in pediatric available for JHS/EDS-HT, whereas [Castori et al., 2012b]. patients and in patients without a some have been developed for other complete or with a borderline pheno- EDSs. In particular, the biochemical type the diagnosis is doubtful and evaluation of urinary pyridinoline con- Lateral Meningocele Syndrome requires a second evaluation in older firms the kEDS diagnosis and distin- Lateral meningocele syndrome (LMS), a age or targeted molecular testing for the guishes this form from EDS with rare HCTD described in 14 patients exclusion of overlapping disorders. progressive kyphoscoliosis, myopathy ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 19

Figure 2. Diagnostic flow chart for a patient presenting with JHM and cutaneous features which considers JHS/EDS-HT, the most frequently observed EDSs, MFS, LDS, ATS, OI, and LMS.

and hearing loss and from JHS/EDS- the diagnosis of the HCTDs with other disorders either inherited or HT overlapping phenotypes. prominent vascular involvement. Rapid acquired. Careful clinical evaluation of Genetic testing is available for all of detection of such rarer HCTDs is crucial JHS/EDS-HT patients and their fami- the genes involved in the so far defined for prognosis establishment due to their lies for all the known manifestations of EDS types, except JHS/EDS-HT and high risk of vascular accidents, a com- this disorder, and the application of the the periodontitis type, and for the other plication never reported in JHS/EDS- diagnostic flow chart with the over- HCTDs, except LMS, and mutation HT. Exclusion of other overlapping lapping HCTDs, should facilitate a detection can be performed on genomic HCTDs is a crucial step in borderline correct diagnosis to the different special- DNA obtained from peripheral blood patients to confirm the clinical diagnosis ists following these patients, including sample either by Sanger sequencing or of JHS/EDS-HT, allowing the multi- clinical geneticists, rheumatologists, by targeting panel-based NGS. The disciplinary management of these pa- dermatologists, orthopedists, ophthal- molecular evaluation of COL5A1 and tients, which covers pharmacologic, mologists, cardiologists, gynecologists/ COL5A2 allows for the distinction of physical therapy, surgical, and nutra- obstetricians, neurologists, and clinical cEDS patients without scarring and ceutical aspects, as well as general life- psychologists. All these patients should generalized JHM from JHS/EDS-HT; style recommendations. refer to centers specialized in the and if no mutations in these genes are diagnosis of these disorders also offering detected TNXB analysis could be per- genetic testing to be diagnosed in a short CONCLUSIONS formed. COL1A1 and COL1A2 anal- time and to receive an appropriate ysis permits the distinction of OI type I Diagnosis of JHS/EDS-HT can be management. For JHS/EDS-HT the and OI/EDS from the overlapping JHS/ difficult due to the intrafamilial and future challenge will be the definition EDS-HT phenotypes. Molecular test- interfamilial variability, the evolving of its molecular basis; the knowledge of ing for the COL3A1, FBN1, TGFBR1, presentation, the multisystem involve- the causal gene(s) will give a powerful TGFBR2, SMAD3, TGFB2, and ment, the unknown molecular basis, and diagnostic tool and likely open novel SLC2A10 genes confirms/excludes the overlap with a wide spectrum of therapeutic perspectives. 20 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

ACKNOWLEDGMENTS Burkitt Wright, Porter EM, Spencer LF,Clayton- syndrome in a 55-year-old woman with Smith HL, Au J, Munier L, Smithson FL, symptoms of joint instability and chronic The authors want to thank all patients Suri S, Rohrbach M, Manson M, Black FD. musculoskeletal pain. Am J Med Genet Part 2013. Brittle cornea syndrome: Recogni- A 164A:528–534. and their families who taught them tion, molecular diagnosis and management. Castori M, Dordoni C, Valiante M, Sperduti I, about their disorders and chose to share Orphanet J Rare Dis 8:68. Ritelli M, Morlino S, Chiarelli N, Celletti their sufferings hoping to help future Callewaert B, Malfait F, Loeys B, De Paepe A. C, Venturini M, Calzavara-Pinton P, Ca- 2008a. Syndromes and Marfan syndrome. merota F,Grammatico P,Colombi M. 2014. generations of affected people. The Best Pract Res Clin Rheumatol 22: Nosology, inheritance pattern(s) and proce- authors also thank Dr. M. 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