Ehlers-Danlos Syndromes

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BMJ 2019;366:l4966 doi: 10.1136/bmj.l4966 (Published 18 September 2019) Page 1 of 11

Practice

PRACTICE

CLINICAL UPDATES Ehlers-Danlos syndromes

Neeti Ghali consultant clinical geneticist 1, Glenda Sobey consultant dermatologist and clinical lead 2, Nigel Burrows consultant dermatologist 3

1North West Thames Regional Genetics Service and National EDS Service, London North West University Healthcare NHS Trust, Harrow HA1 3UJ, UK; 2National EDS Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK; 3Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK

What are the Ehlers-Danlos syndromes?

What you need to know http://www.bmj.com/ Ehlers-Danlos syndromes (EDS) refer to a group of inherited • Ehlers-Danlos syndromes (EDS) are inherited connective tissue disorders with variable severity; features include skin fragility, joint connective tissue disorders that affect many organ systems. hypermobility, and rupture of blood vessels and internal organs Depending on the type of EDS, clinical signs include easy • Consider the diagnosis of an EDS subtype in patients with any bruising, poor wound healing, hyperextensible skin, joint combination of easy bruising, poor scar formation, hyperextensible skin, joint hypermobility, joint pains without evidence of arthritis, and hypermobility, and fragility of connective tissue demonstrated unexplained arterial or bowel rupture by internal organ and blood vessel fragility. The EDS group is • Joint hypermobility alone is not enough to diagnose an EDS subtype, composed of distinct conditions, with the genetic basis now and not all types of EDS have pronounced hypermobility known in 12 out of the 13 types. Inheritance may be autosomal on 18 September 2019 at Imperial College London Library. Protected by copyright. • Thirteen different types of EDS are currently recognised, with the dominant (usually a result of structural defects in molecular basis known in all except for hypermobile EDS collagen-encoding genes) or autosomal recessive (often • Genetic testing is recommended for EDS types with a known molecular cause to confirm the diagnosis. involving genes encoding collagen-modifying enzymes) (fig 1). The advent of next generation sequencing has resulted in the identification of novel genes in the rarer types of EDS, such Awareness of the Ehlers-Danlos syndromes (EDS) in the UK as genes involved in the structure and function of the myomatrix has risen over the past decade, in part due to high profile of EDS or glycosaminoglycan biosynthesis. Establishing the correct patient organisations and the EDS National Diagnostic Service clinical and molecular diagnosis has important implications for commissioned in 2009. Significant advances in genetic testing management as well as accurate genetic counselling. have culminated in the publication of a new international Most patients will present to their primary care physician with classification in 2017 with 13 types identified.1 Clinicians will joint symptoms or issues relating to skin or tissue fragility, such see an increasing number of patients, some of whom will suspect as easy bruising. Traumatic wounds often result in repeated a diagnosis of EDS themselves. attendances to an emergency department. Symptoms may have This article is intended to support non-specialist clinicians to been present for some time and from a young age, and a delay consider the diagnosis of this group of conditions in appropriate in diagnosis is not uncommon. patients. It discusses the features of the different types of EDS and explains how clinicians can expect their patients to be managed in secondary care. How common are the Ehlers-Danlos syndromes? How this article was created The age of presentation is highly variable. The true prevalence The authors are members of the International Consortium on Ehlers-Danlos of the different rare types is unknown, and future research is Syndromes and Related Disorders and participated in literature searches used 2 for the basis of the articles written on the new classification of EDS published needed. No type is known to be more common in a particular in 2017. The authors have more than 10 years’ experience of EDS patient group of people. Previous estimates report EDS at 1 in 5000 consultations and data collection in the highly specialised EDS service. births, with classical and hypermobile EDS accounting for approximately 90% of cases.3 However these estimates predate the newer diagnostic criteria, which would reduce the prevalence of hypermobile EDS considerably since that term is now

Correspondence to: N Ghali [email protected], G Sobey [email protected]

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restricted to a more tightly defined phenotype (with others now kyphoscoliotic EDS. Aneurysms and arterial complications are classified as hypermobility spectrum disorders). The prevalence more prominent in vascular EDS and in some rarer types of of vascular EDS is estimated to be 1 in 90 000,4 and the EDS. Many of the features listed in box 1 are non-specific prevalence of classical EDS is 1 in 20 000.5 manifestations of connective tissue impairment, but the Joint hypermobility is common and is thought to occur in constellation of features aids in the diagnosis. 10-30% of the population worldwide.6 Joint hypermobility is Box 1: History, examination, and investigations of suspected not necessarily symptomatic and in isolation does not indicate Ehlers-Danlos syndrome a diagnosis of hypermobile EDS or a hypermobility spectrum disorder. History Family history—Inherited or de novo; inheritance pattern History—Vascular events, pneumothorax, organ rupture, bruising, skin What are the different types of fragility, joint pain, hypermobility, congenital hip dislocation, congenital talipes, repeated other dislocations, autonomic dysfunction, gastrointestinal Ehlers-Danlos syndromes? problems, easy fatigue. 7 The Berlin classification of 1988 used Roman numerals for the Examination different types recognised clinically. This was replaced with the Villefranche classification8 in 1997, which recognised six Vascular—Visible veins, varicose veins, bruising 1 Skin—Hyperextensible skin, atrophic scarring, piezogenic pedal papules, types of EDS. The latest international classification recognises presence or absence of stretch marks, elastosis perforans serpiginosa, 13 types with pathogenic (disease-causing) variants in 19 molluscoid pseudotumours, subcutaneous spheroids, haemosiderin different genes (table 1), and it is likely that novel genes such deposition as AEBP19 and types will continue to be identified. The Berlin Musculoskeletal—Joint hypermobility, hypotonia, permanent dislocations, kyphoscoliosis, contractures, pectus deformities, skeletal abnormalities, and Villefranche classifications are no longer used. talipes, arm span:height ratio Other—Blue sclera, inspection for high arched palate, hernias Initial assessment of suspected Investigations

Ehlers-Danlos syndrome Primary care • Exclude clotting disorder as a cause for bruising—Check full blood What should I ask when taking a history? count, clotting studies http://www.bmj.com/ Take a full medical history. Ask about: • Consider non-accidental injury if bruises are in non-traumatic sites or •Joint problems such as pain, dislocations or subluxations, of unusual appearance and hypermobility (increased flexibility). How often does Secondary care joint pain occur? How many joints are affected? • Molecular genetic testing • To consider neuromuscular work-up, such as electromyography and •Skin problems such as fragility demonstrated by easy nerve conduction studies if hypotonia present bruising and poor wound healing. Do wounds take a long • Depending on which subtype is suspected, skin biopsy for electron time to heal? Do surgical scars break down in the absence microscopy or urine testing for cross linking of collagens (kyphoscoliotic

EDS) may be appropriate on 18 September 2019 at Imperial College London Library. Protected by copyright. of infection? • Echocardiography and possibly vascular imaging (computed tomography •Other connective tissue features such as hernia, angiography, magnetic resonance angiography) if history of vascular pneumothorax, chest wall or spinal deformities, and organ event rupture (see below). •Is there a history of documented vascular events—including vessel rupture, aneurysm, and dissection—in the patient What investigations are helpful in patients or a first degree relative? with a possible diagnosis of EDS? •Easily fatigued In general practice: •If easy bruising is the presenting symptom, it is important •Gastrointestinal problems such as structural issues relating to take a full bleeding history. Ask about epistaxis, to hiatus hernia, prolapse, or functional problems with menorrhagia, and bleeding from minor cuts and operations, altered gastrointestinal motility. and exclude other causes of a bleeding tendency. Perform •Autonomic dysfunction such as postural orthostatic a full blood count and clotting screen initially and refer to tachycardia syndrome (POTS) can be a feature. Ask about haematology if appropriate. Consider non-accidental injury light headedness on standing. if the pattern of bruising is unusual. •Family history. Are there other similarly affected family •Presence of specific musculoskeletal findings may guide members? If so, drawing a clinical pedigree may reveal a towards certain investigations, such as x rays in the specific inheritance pattern. presence of spinal or chest deformities or contractures. Perform serological tests to exclude inflammatory What should I look for on examination? rheumatological conditions. Perform a full examination of the skin and musculoskeletal In a specialist setting: system. Joint hypermobility is the most common feature of •To determine the exact subtype of EDS, molecular genetic Ehlers-Danlos syndromes, but the absence of joint hypermobility testing is essential. does not exclude them. The Beighton score is the accepted •Skin biopsy may prove helpful in individual cases, mainly standard for recording joint hypermobility (fig 2). A score of 5 in the context of identifying a genetic variant of uncertain 10 or more in adults indicates a generalised joint hypermobility. significance and occasionally in diagnosis. Skin features such as hyperextensible skin are more prominent •In the paediatric population, if hypotonia is identified, a in classical EDS, kyphoscoliotic EDS, and classical-like EDS. full neuromuscular work-up is recommended. Extensive scarring is seen more in classical EDS and

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Which conditions can be mistaken for a subtype of EDS? •Other inherited connective tissue disorders that predispose to aneurysm formation or blood vessel fragility, such as Loeys-Dietz syndromes, Marfan syndrome, and isolated familial thoracic aortopathy conditions. •Conditions presenting with bruising, such as clotting disorders and non-accidental injury. •Conditions associated with abnormal skin, such as pseudoxanthoma elasticum and cutis laxa. •Neuromuscular conditions, such as collagen VI-related disorders (Ullrich congenital muscular dystrophy, Bethlem myopathy) and collagen XII-related disorders. •Other connective tissue disorders presenting with a degree of joint hypermobility, such as skeletal dysplasias (including osteogenesis imperfecta, chondrodysplasias, Larsen syndrome) and Stickler syndrome. •Rare genetic syndromic causes of hypermobility and hypotonia, such as chromosomal abnormalities or single gene disorders (for example, Noonan syndrome, mucopolysacharidoses).

When should patients be referred? Refer patients who have clinical features suggestive of any of http://www.bmj.com/ the EDS types with a monogenic aetiology to a clinician experienced in the diagnosis and management of that condition. The diagnosis is confirmed by molecular testing either through the mainstream specialty or through the Clinical Genetics/EDS National Diagnostic Service commissioned by NHS England. This will ensure that the clinically suspected diagnosis is correct and allow for appropriate management of the specific condition, for example, with regards to lifestyle advice, surveillance, on 18 September 2019 at Imperial College London Library. Protected by copyright. treatment, and emergency intervention, as well as accurate genetic counselling. The diagnosis of hypermobile EDS is made using a check-list produced by the International EDS society (box 2).

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Box 2: Diagnostic criteria for hypermobile • Exclusion of alternative diagnoses that may also Ehlers-Danlos syndrome* include joint hypermobility by means of hypotonia or connective tissue laxity. These include neuromuscular The clinical diagnosis of hypermobile EDS needs the disorders (such as Bethlem myopathy), other hereditary simultaneous presence of all three criteria disorders of the connective tissue (such as other types of EDS, Loeys-Dietz syndrome, Marfan syndrome), Criterion 1—Generalised joint hypermobility and skeletal dysplasias (such as osteogenesis • Beighton hypermobility score: imperfecta). Exclusion of these conditions may be based on history, physical examination, or molecular ≥6 in pre-pubertal children and adolescents genetic testing, as indicated ≥5 in pubertal men and woman to age 50 years *Adapted from Ehlers-Danlos Society. hEDS diagnostic ≥4 in men and women over the age of 50 years checklist. https://www.ehlers-danlos.com/heds-diagnostic- checklist/ • If Beighton score is one point below age- and sex-specific cut-off, two or more of the following must also be selected to meet criterion: – Can you now (or could you ever) place your hands flat on the floor without bending your knees? How would I recognise and manage the – Can you now (or could you ever) bend your thumb types of Ehlers-Danlos syndromes? to touch your forearm? – As a child, did you amuse your friends by contorting Patients with EDS tend to be followed up in specialist clinics, your body into strange shapes or could you do the but non-specialist doctors such as GPs may be involved in splits? ongoing management and monitoring in the longer term. The – As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion? commonest EDS types are classical, vascular, and hypermobile: – Do you consider yourself “double jointed”? Classical EDS Criterion 2—Two or more of the following features (A, B, or C) must be present This typically has the features of skin hyperextensibility (3 cm

• Feature A (five must be present): for neck, elbow, and knees; 1 cm on the volar surface of the – Unusually soft or velvety skin hand) (fig 3), together with skin fragility resulting in widened – Mild skin hyperextensibility atrophic scars of the skin (fig 4) and generalised joint 11 – Unexplained striae distensae or rubae at the back, hypermobility. Stretch marks are absent in classical EDS, and groins, thighs, breasts, and/or abdomen in easy bruising with staining due to haemosiderin deposition is http://www.bmj.com/ adolescents, men, or pre-pubertal girls without a commonly seen. Easy bruising and scarring can lead to suspicion history of significant change in body fat or weight of non-accidental injury. The diagnosis is confirmed by – Bilateral piezogenic papules of the heel molecular testing. – Recurrent or multiple abdominal hernia(s) – Atrophic scarring involving at least two sites and Management—Offer patients with confirmed classical EDS: without the formation of truly papyraceous or •Cardiology assessment including echocardiogram to look haemosideric scars as seen in classical EDS for valvular prolapse and aortic root dilatation particularly – Pelvic floor, rectal, and/or uterine prolapse in on 18 September 2019 at Imperial College London Library. Protected by copyright. children, men, or nulliparous women without a history •Management of musculoskeletal problems such as joint of morbid obesity or other known predisposing hypermobility as advised by a rheumatology department, condition including physiotherapy and occupational therapy – Dental crowding and high or narrow palate – Arachnodactyly, as defined by one or more of: •Advice on the use of protective garments, which are close ♦ Positive wrist sign (Walker sign) on both sides fitting with long sleeves and leggings that can be worn ♦ Positive thumb sign (Steinberg sign) on both sides under clothes to reduce skin injury in childhood. – Arm span-to-height ratio ≥1.05 Custom-made shin pads help limit damage to the lower – Mitral valve prolapse mild or greater based on strict legs in active children echocardiographic criteria •Access to plastic surgery for specialist suturing of wounds, – Aortic root dilatation with z score ≥2 which need to be sutured in layers. Use appropriate • Feature B: supportive dressings. – Positive family history; one or more first degree relatives independently meeting the current criteria for hypermobile EDS Vascular EDS • Feature C (must have at least one): – Musculoskeletal pain in two or more limbs, recurring Vascular EDS can present with vessel dissection or rupture or daily for ≥3 months hollow organ rupture.12 Up to 25% of patients have a significant – Chronic, widespread pain for ≥3 months complication by age 20 years, and more than 80% have had a 13 – Recurrent joint dislocations or frank joint instability complication by the age of 40. Bowel, splenic, and uterine in the absence of trauma rupture should raise suspicion of vascular EDS, as well as Criterion 3—All of the following required pneumothorax, if other connective tissue features are present. The clinical features on examination can be subtle, and so the • Absence of unusual skin fragility, which should prompt consideration of other types of EDS diagnosis can be easily missed, particularly in the absence of a • Exclusion of other heritable and acquired connective family history. Occasionally, easy bruising may be the only tissue disorders, including autoimmune rheumatologic presenting feature, raising the suspicion of non-accidental injury conditions in children. Obstetric complications of uterine and arterial In patients with an acquired connective tissue disease (such as lupus, rheumatoid arthritis, etc), additional rupture, postpartum haemorrhage, and severe lacerations at diagnosis of hypermobile EDS requires meeting both vaginal delivery are recognised. Feature A and Feature B of Criterion 2 (Feature C (chronic pain and/or instability) cannot be counted Specific clinical features include: toward a diagnosis of hypermobile EDS in this •Thin and translucent skin with unusually visible veins and situation) frequent easy and spontaneous bruising (fig 5)

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•Facial features of a thin nose, prominent eyes, and lobeless Box 4: Details of 10 rare types of Ehlers-Danlos syndrome ears Classical-like EDS—This autosomal recessive condition is due to a •A prematurely aged appearance of the hands and feet, deficiency of tenascin X glycoprotein. Features include marked skin hyperextensibility, significant joint hypermobility, and easy and severe known as acrogeria bruising. Some degree of muscle weakness is common. There is no •Joint hypermobility, which is often limited to the small abnormal scarring, and this distinguishes the condition clinically from classical EDS. joints of the hands (distal hypermobility) Kyphoscoliotic EDS—This subtype includes autosomal recessive •Congenital talipes. conditions resulting from molecular defects in PLOD12 and FKBP1416 genes. Characteristic features include early onset, progressive Management—Box 3 lists the recommended management for kyphoscoliosis, hypotonia, gross motor delay, and joint hypermobility. Other features include skin hyperextensibility, easy bruising, and atrophic vascular EDS. scarring. Vascular rupture has also been reported. Hearing loss is an additional feature with pathogenic variants in FKBP14, and ocular and scleral fragility is seen with defects in PLOD1. Box 3: Recommendations for vascular Ehlers-Danlos syndrome management Periodontal EDS—Causative genes for this autosomal recessive condition have recently been identified.17 There is a wide phenotype with skin and • Regular follow-up in a multidisciplinary clinic with genetics and joints variably affected. Early onset periodontitis and dental loss are a cardiovascular experts for discussion of vascular surveillance and consistent feature and should prompt referral for investigation if there is consideration of medication no obvious cause. • Surgical and endovascular procedures are discouraged outside of Arthrochalasia EDS—This autosomal dominant condition has features of specialist centres, and conservative treatment is preferred. The tissue congenital bilateral hip dislocation, significant joint hypermobility, skin and vessel fragility of vascular EDS can result in life threatening hyperextensibility, atrophic scars, easy bruising, kyphoscoliosis, and complications during surgery osteopenia. • Patients are advised to modify their lifestyle and avoid potentially harmful Brittle cornea syndrome—The main feature of this autosomal recessive activities such as contact sports and heavy lifting as well as activities condition is a thin cornea (microcornea) with predisposition to corneal involving rapid acceleration or deceleration. High intensity interval rupture and early onset keratoconus and keratoglobus. Musculoskeletal training is contraindicated. Appropriate regular cardiovascular features including joint hypermobility are often present. conditioning exercise is recommended Dermatosparaxis EDS—This very rare autosomal recessive condition has • Obstetric management of women with vascular EDS should be features of redundant, sagging, fragile skin. Delayed closure of the undertaken in specialist centres fontanelles, blue sclerae, umbilical hernia, and short stature are also seen. • Patients should carry an emergency card with details of their condition Most patients have a severe phenotype, but some have milder features. and instructions for their care. In the UK this card (fig 6) is available Musculocontractural EDS—This condition results from molecular defects from the EDS National Diagnostic Service. Additional methods to ensure in CHST14 and DSE genes. CHST14-mediated EDS results in a severe that information is immediately available include medical emergency phenotype with progressive kyphoscoliosis, adducted thumbs in infancy, http://www.bmj.com/ necklaces or bracelets and information storage using Apps on mobile congenital talipes, arachnodactyly, joint hypermobility, hyperextensible devices. Carrying a copy of the last clinic letter can be helpful when and fragile skin, and poor wound healing. The phenotype in DSE-mediated presenting to an emergency department EDS is usually milder. • Any musculoskeletal problems should be managed as advised by Spondylodysplastic, myopathic, and cardiac valvular EDS—Diagnosis rheumatology services, physiotherapy and occupational therapy may and management of these extremely rare types are beyond the scope of be required this article. A detailed recent review is available.2 on 18 September 2019 at Imperial College London Library. Protected by copyright. Hypermobile EDS Useful resources There is still no genetic test available for this condition. After • NHS. Ehlers-Danlos syndromes. https://www.nhs.uk/conditions/ehlers- the new EDS classification, a diagnostic checklist was produced danlos-syndromes/ to aid diagnosis (box 2). The term hypermobility spectrum • Ehlers-Danlos Support UK. https://www.ehlers-danlos.org/ disorder was also introduced, encompassing the variable patterns • The Ehlers-Danlos Society (international). https://www.ehlers-danlos. com/ of hypermobility and associated symptoms.14 The Beighton • Annabelle’s Challenge (vascular EDS charity). https://www. score can be used to document the presence and extent of joint annabelleschallenge.org/ hypermobility, but this score can decrease with age, repeated • Vascular EDS emergency card (fig 6) dislocations and other injuries, surgery, and the manifestations • The National Ehlers-Danlos syndrome Service, UK. Located at London of arthritis. North West University Healthcare NHS Trust ([email protected]) and Northern General Management—Management needs to be targeted to the patient’s Hospital, Sheffield ([email protected]) symptoms. Referral to rheumatology for active rehabilitation focusing on self management can be helpful. If pain is widespread beyond affected joints and disrupts sleep or if there Recommendations for future research is significant difficulty with pain management then referral to a dedicated pain clinic may be helpful. • Establishing international databases • What is the true prevalence of the Ehlers-Danlos syndromes? Prognosis—This is highly variable and will in part depend on the severity of involvement in the patient. Hypermobility may • What is the natural disease progression in different EDS types? increase the susceptibility of joints to osteoarthritis.15 • How can we best reduce morbidity and mortality in vascular EDS? • What is the underlying molecular cause(s) for hypermobile EDS? • How do we optimally manage the joint hypermobility associated with Other types some types of EDS? The remaining types of EDS are rare and seldom encountered outside specialist units. Box 4 briefly describes them.

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6 Hakim A, Grahame R. Joint hypermobility. Best Pract Res Clin Rheumatol Education into practice 2003;17:989-1004. 10.1016/j.berh.2003.08.001 15123047 7 Beighton P, de Paepe A, Danks D, etal . International Nosology of Heritable Disorders of • Do you feel confident in assessing the skin and joints in your patients? Connective Tissue, Berlin, 1986. Am J Med Genet 1988;29:581-94. • What proportion of your patients mention a diagnosis of EDS without a 10.1002/ajmg.1320290316 3287925 specific subtype? Have they undergone molecular testing to confirm 8 Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJEhlers-Danlos National the diagnosis? Foundation (USA) and Ehlers-Danlos Support Group (UK). Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Am J Med Genet 1998;77:31-7. • Have your patients with EDS been assessed using the current 10.1002/(SICI)1096-8628(19980428)77:1<31::AID-AJMG8>3.0.CO;2-O 9557891 classification system? 9 Blackburn PR, Xu Z, Tumelty KE, etal . Bi-allelic alterations in AEBP1 lead to defective collagen assembly and connective tissue structure resulting in a variant of Ehlers-Danlos syndrome. Am J Hum Genet 2018;102:696-705. 10.1016/j.ajhg.2018.02.018 29606302 10 Beighton P, Horan F. Orthopaedic aspects of the Ehlers-Danlos syndrome. J Bone Joint How patients were involved in the creation of this article Surg Br 1969;51:444-53. 10.1302/0301-620X.51B3.444 5820785 11 Bowen JM, Sobey GJ, Burrows NP, etal . Ehlers-Danlos syndrome, classical type. Am J The Ehlers-Danlos Support Group and Annabelle’s Challenge Charity both Med Genet C Semin Med Genet 2017;175:27-39. 10.1002/ajmg.c.31548 28192633 reviewed the article and provided helpful comments, which were incorporated 12 Byers PH, Belmont J, Black J, etal . Diagnosis, natural history, and management in in to the manuscript. vascular Ehlers-Danlos syndrome. Am J Med Genet C Semin Med Genet 2017;175:40-7. 10.1002/ajmg.c.31553 28306228 13 Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med 2000;342:673-80. 10.1056/NEJM200003093421001 10706896 Competing interests: We have read and understood BMJ policy on declaration of 14 Castori M, Tinkle B, Levy H, Grahame R, Malfait F, Hakim A. A framework for the classification of joint hypermobility and related conditions. Am J Med Genet C Semin Med interests and have no relevant interests to declare. Genet 2017;175:148-57. 10.1002/ajmg.c.31539 28145606 Provenance and peer review: Commissioned; externally peer reviewed. 15 Tinkle B, Castori M, Berglund B, etal . Hypermobile Ehlers-Danlos syndrome (a.k.a. Ehlers-Danlos syndrome type III and Ehlers-Danlos syndrome hypermobility type): clinical description and natural history. Am J Med Genet C Semin Med Genet 2017;175:48-69. 1 Malfait F, Francomano C, Byers P, etal . The 2017 international classification of the 10.1002/ajmg.c.31538 28145611 Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet 2017;175:8-26. 16 Giunta C, Baumann M, Fauth C, etal . A cohort of 17 patients with kyphoscoliotic 10.1002/ajmg.c.31552 28306229 Ehlers-Danlos syndrome caused by biallelic mutations in FKBP14: expansion of the clinical 2 Brady AF, Demirdas S, Fournel-Gigleux S, etal . The Ehlers-Danlos syndromes, rare and mutational spectrum and description of the natural history. Genet Med 2018;20:42-54. types. Am J Med Genet C Semin Med Genet 2017;175:70-115. 10.1038/gim.2017.70 28617417 10.1002/ajmg.c.31550 28306225 17 Kapferer-Seebacher I, Pepin M, Werner R, etal. Molecular Basis of Periodontal EDS 3 Royce P, Superti-Furga A. The Ehlers-Danlos Syndrome. In: Royce P, Steinmann B, eds. Consortium. Periodontal Ehlers-Danlos syndrome is caused by mutations in C1R and Connective tissue and its heritable disorders. Wiley-Liss, 1993: 351-407. C1S, which encode subcomponents C1r and C1s of complement. Am J Hum Genet 4 Malfait F. Vascular aspects of the Ehlers-Danlos Syndromes. Matrix Biol 2016;99:1005-14. 10.1016/j.ajhg.2016.08.019 27745832 2018;71-72:380-95. 10.1016/j.matbio.2018.04.013. 29709596 Published by the BMJ Publishing Group Limited. For permission to use (where not already 5 Colombi M, Dordoni C, Cinquina V, Venturini M, Ritelli M. A classical Ehlers-Danlos granted under a licence) please go to http://group.bmj.com/group/rights-licensing/ http://www.bmj.com/ syndrome family with incomplete presentation diagnosed by molecular testing. Eur J Med Genet 2018;61:17-20. 10.1016/j.ejmg.2017.10.005 29024828 permissions on 18 September 2019 at Imperial College London Library. Protected by copyright.

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Table

Table 1| Current international classification of Ehlers-Danlos syndromes (EDS)1

EDS type Inheritance pattern Genetic basis Hypermobile EDS Presumed AD Unknown Vascular EDS AD COL3A1, specific variants in COL1A1 Classical EDS AD COL5A1, COL5A2, specific variants in COL1A1 Classical-like EDS AR TNXB Kyphoscoliotic EDS AR PLOD1, FKBP14 Brittle cornea syndrome AR ZNF469, PRDM5 Periodontal EDS AD C1R, C1S Arthrochalasia EDS AD Specific variants in COL1A1, COL1A2 Musculocontractural EDS AR CHST14, DSE Myopathic EDS AD/AR COL12A1 Cardiac-valvular EDS AR COL1A2 Spondylodysplastic EDS AR B4GALT7, B3GALT6, SLC39A13 Dermatosparaxis EDS AR ADAMTS2

AR=autosomal recessive, AD=autosomal dominant http://www.bmj.com/ on 18 September 2019 at Imperial College London Library. Protected by copyright.

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Figures http://www.bmj.com/ on 18 September 2019 at Imperial College London Library. Protected by copyright.

Fig 1 Autosomal dominant and recessive inheritance patterns

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Fig 2 Beighton score for measuring joint hypermobility (adapted from Beighton et al 196910)

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Fig 3 Skin hyperextensibility seem in classical EDS http://www.bmj.com/

Fig 4 Atrophic scarring seem in classical EDS on 18 September 2019 at Imperial College London Library. Protected by copyright.

Fig 5 Thin, translucent skin seen in vascular EDS

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Fig 6 Emergency card for patients with vascular EDS http://www.bmj.com/ on 18 September 2019 at Imperial College London Library. Protected by copyright.

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