10 1136@bmj l4966

BMJ: first published as 10.1136/bmj.l4966 on 18 September 2019. Downloaded from http://www.bmj.com/ on 21 September 2019 at Linkopings Universitets Bibliotek.
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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
1 2
Neeti Ghali consultant clinical geneticist , Glenda Sobey consultant dermatologist and clinical lead ,
3
Nigel Burrows consultant dermatologist
1
North 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
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
• 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
Syndromes and Related Disorders and participated in literature searches used
of the different rare types is unknown, and future research is
for the basis of the articles written on the new classification of EDS published needed.2 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 neeti.ghali@nhs.net, G Sobey Glenda.sobey@nhs.net
For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe
PRACTICE
BMJ: first published as 10.1136/bmj.l4966 on 18 September 2019. Downloaded from http://www.bmj.com/ on 21 September 2019 at Linkopings Universitets Bibliotek. Protected by copyright.
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
History
disorder.
Family history—Inherited or de novo; inheritance pattern
What are the different types of History—Vascular events, pneumothorax, organ rupture, bruising, skin
fragility, joint pain, hypermobility, congenital hip dislocation, congenital
Ehlers-Danlos syndromes? talipes, repeated other dislocations, autonomic dysfunction, gastrointestinal
problems, easy fatigue.
The Berlin classification7 of 1988 used Roman numerals for the Examination
different types recognised clinically. This was replaced with
Vascular—Visible veins, varicose veins, bruising
the Villefranche classification8 in 1997, which recognised six
Skin—Hyperextensible skin, atrophic scarring, piezogenic pedal papules,
types of EDS. The latest international classification1 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
Take a full medical history. Ask about: • Consider non-accidental injury if bruises are in non-traumatic sites or
of unusual appearance
• Joint problems such as pain, dislocations or subluxations,
and hypermobility (increased flexibility). How often does Secondary care
• Molecular genetic testing
joint pain occur? How many joints are affected?
• 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
of infection?
• Echocardiography and possibly vascular imaging (computed tomography
• Other connective tissue features such as hernia, angiography, magnetic resonance angiography) if history of vascular
event
pneumothorax, chest wall or spinal deformities, and organ
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
or more in adults indicates a generalised joint hypermobility.10 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
PRACTICE
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
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,
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).
PRACTICE
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
to touch your forearm?
types of Ehlers-Danlos syndromes?
– 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
– Unexplained striae distensae or rubae at the back, hypermobility.11 Stretch marks are absent in classical EDS, and
groins, thighs, breasts, and/or abdomen in easy bruising with staining due to haemosiderin deposition is
adolescents, men, or pre-pubertal girls without a
history of significant change in body fat or weight
commonly seen. Easy bruising and scarring can lead to suspicion
– Bilateral piezogenic papules of the heel
of non-accidental injury. The diagnosis is confirmed by
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
children, men, or nulliparous women without a history • Management of musculoskeletal problems such as joint
of morbid obesity or other known predisposing
condition
hypermobility as advised by a rheumatology department,
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
– Recurrent joint dislocations or frank joint instability complication by the age of 40.13 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)
PRACTICE
• 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
abnormal scarring, and this distinguishes the condition clinically from
• Joint hypermobility, which is often limited to the small 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,
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
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-
danlos-syndromes/
the new EDS classification, a diagnostic checklist was produced
• Ehlers-Danlos Support UK. https://www.ehlers-danlos.org/
to aid diagnosis (box 2). The term hypermobility spectrum
• The Ehlers-Danlos Society (international). https://www.ehlers-danlos.
disorder was also introduced, encompassing the variable patterns 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
(LNWH-tr.EDSLONDONOFFICE@nhs.net) and Northern General
Management—Management needs to be targeted to the patient’s Hospital, Sheffield (eds@sch.nhs.uk)
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
• Establishing international databases
a dedicated pain clinic may be helpful.
• What is the true prevalence of the Ehlers-Danlos syndromes?
Prognosis—This is highly variable and will in part depend on
• What is the natural disease progression in different EDS types?
the severity of involvement in the patient. Hypermobility may
• How can we best reduce morbidity and mortality in vascular EDS?
increase the susceptibility of joints to osteoarthritis.15
• 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.
PRACTICE
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
Surg Br 1969;51:444-53. 10.1302/0301-620X.51B3.444 5820785
How patients were involved in the creation of this article 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
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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/
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
PRACTICE
Table
1
Table 1| Current international classification of Ehlers-Danlos syndromes (EDS)
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
PRACTICE
Figures
Fig 1 Autosomal dominant and recessive inheritance patterns
PRACTICE
Fig 2 Beighton score for measuring joint hypermobility (adapted from Beighton et al 196910)
PRACTICE
Fig 3 Skin hyperextensibility seem in classical EDS
Fig 4 Atrophic scarring seem in classical EDS
Fig 5 Thin, translucent skin seen in vascular EDS
PRACTICE
Fig 6 Emergency card for patients with vascular EDS

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BMJ: first published as 10.1136/bmj.l4966 on 18 September 2019. Downloaded from http://www.bmj.com/ on 21 September 2019 at Linkopings Universitets Bibliotek.

What are the Ehlers-Danlos syndromes?

Correspondence to: N Ghali neeti.ghali@nhs.net, G Sobey Glenda.sobey@nhs.net

When should patients be referred?

Hypermobile EDS Useful resources

EDS type Inheritance pattern Genetic basis

AR=autosomal recessive, AD=autosomal dominant

Fig 1 Autosomal dominant and recessive inheritance patterns

Fig 4 Atrophic scarring seem in classical EDS

Fig 5 Thin, translucent skin seen in vascular EDS

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