Ehlers-Danlos Syndromes

History

• Clinical hallmarks of disease are symptoms of joint hypermobility, skin hyperextensibility, and tissue fragility ^r7c1c2c3
  • Phenotypic expression is highly variable across subtypes and within a given subtype ^r4
• Joint hypermobility
  • May be generalized, involving both proximal and distal joints
    • Vascular subtype is typically limited to small joint involvement
  • Frequent complications from joint hypermobility (eg, dislocations, subluxations) may be presenting manifestation ^{c4c5c6c7c8c9c10c11c12c13c14c15}
    • May occur in the absence of trauma or with minor trauma
    • May resolve spontaneously or patient may self-reduce
    • Common in patients with classical and hypermobile subtypes
    • Often involve shoulder, patella, digits, hip, radius, and clavicle
  • Tendon and muscle rupture can occur, particularly in patients with vascular subtype ^c16c17c18
• Skin hyperextensibility ^c19
  • May be severe in classical subtype and less severe in hypermobile subtype; not reported in vascular subtype
• Tissue fragility
  • Open wounds or skin lacerations resulting from minor trauma ^c20c21
    • Often occurs over pressure points (eg, knees, elbows)
    • Common among patients with classical subtype; may occur among patients with vascular subtype
    • Not typical for patients with hypermobile subtype
  • Delayed wound healing and excessive scarring may be present, depending on subtype ^c22c23
    • Often much more severe in classical subtype than in hypermobile subtype
  • Easy bruising ^c24
    • Commonly reported in all subtypes; may be severe in classical and vascular subtypes
  • Vascular subtype
    • May present with life-threatening symptoms attributable to the following:
      • Arterial aneurysm, dissection, and rupture at a young age ^r11c25c26c27
      • Spontaneous rupture of bowel ^c28
      • Spontaneous uterine rupture during pregnancy or severe peripartum perineal tears ^c29c30
      • Recurrent pneumothorax ^c31
    • May present with more subtle symptoms, such as the following:
      • Excessive bleeding from circumcision site in males ^c32
      • Gingival fragility (eg, bleeding gums) and recession ^c33c34
      • Early-onset varicose veins (younger than 30 years and nulliparous if female) ^c35
• Pain
  • Generalized, neurologic, and musculoskeletal pain are common among patients with hypermobile subtype; less common among patients with classical subtype ^c36c37c38
• Family history
  • Primary presenting complaint may be a positive family history of a particular disease subtype ^c39
• Other associated systemic symptoms
  • Frequent and severe in patients with hypermobile subtype; reported less often and with diminished severity in some patients with classical subtype and may include:
    • Fatigue and muscle cramping ^c40c41
    • Functional gastrointestinal complaints ^c42
    • Sleep disturbance ^c43
    • Dysautonomic symptoms (eg, postural orthostatic tachycardia, orthostatic hypotension) ^c44c45c46
    • Psychiatric issues (eg, depression, anxiety) ^c47c48c49

Physical examination

• Joint hypermobility ^c50
  • Objectively measured by Beighton score
  • In general, a Beighton score of 5 or greater defines generalized joint hypermobility ^r7
  • May be diffuse or involve only a few joints
  • More commonly isolated to smaller joints (eg, digits, wrist) in vascular subtype ^r4
• Skin extensibility ^c51
  • Skin easily extends and characteristically snaps back into original position after release of tension ^r12
  • Measure by pinching and lifting the cutaneous and subcutaneous layers of the skin; stretch over the standard cutoff point in 3 areas defines hyperextensibility
    • 1 cm on the volar surface of the hand (palm) ^r1
    • 1.5 cm for the distal part of the forearms and the dorsum of the hands ^r7
    • 3 cm for neck, elbow, and knees ^r7
  • Hyperextensibility of skin is most prominent with classical subtype, slightly less pronounced with hypermobile subtype (compared with classical subtype), and absent in vascular subtype ^r8
• Abnormal scarring
  • Can range in severity depending on subtype
    • Classical subtype
      • Most have extensive atrophic scarring at multiple sites ^c52
      • Associated with formation of papyraceous scars (cigarette paper–like appearance) ^c53
      • Molluscoid pseudotumors ^c54
        • Thickened, fleshy, skin lesions associated with scars located over pressure points (eg, knees, elbows, fingers)
    • Hypermobile subtype
      • Atrophic scarring is less severe than in classical subtype
      • Extensive hemosiderin staining and true papyraceous scar formation is absent
• Easy bruising ^c55c56
  • Can range in severity depending on subtype
    • Classical subtype
      • Hallmark finding can occur anywhere on body, including unusual sites ^r1
      • Hemosiderin staining of pretibial area from previous bruising is common
    • Hypermobile subtype
      • Common but poorly defined ^r2r13
    • Vascular subtype
      • Common and can occur in unusual sites (eg, cheeks, back) and without associated preceding trauma
• Skin texture and appearance
  • Classical subtype (subjectively assessed by touch)
    • Extremely soft, doughy, velvety, smooth skin is characteristic ^c57
  • Hypermobile subtype
    • May be unusually soft, silky, or velvety ^r2
  • Vascular subtype
    • Thin, translucent skin with increased venous visibility is characteristic ^c58c59
• Other associations and manifestations based on subtype
  • Classical subtype
    • Subcutaneous spheroids
      • Nodules that are small, spherical, hard (sometimes calcified), mobile, and frequently located on forearms and shins ^c60
    • Epicanthal folds ^c61
      • More often noted in childhood, but may be apparent in some adults
    • Mild hypotonia with associated delayed motor development (eg, late walking) ^c62c63c64
    • Skeletal alterations may include scoliosis, pectus deformities, and valgus deformities of elbows, knees, and great toes ^c65c66c67c68
  • Hypermobile subtype
    • Piezogenic papules ^c69
      • Herniation of subcutaneous fat often noted on heel while bearing weight; often bilateral
    • Unexplained striae ^c70
    • Recurrent or multiple abdominal hernias ^c71
    • Unexplained uterine, rectal, or pelvic floor prolapse ^c72c73c74
    • Dental crowding and high or narrow arched palate ^c75c76c77
    • Arachnodactyly as evidenced by 1 of the following: ^c78
      • Positive bilateral Walker wrist sign ^c79
        • Positive when thumb and fifth finger overlap with each other when patient grips wrist with opposite hand
      • Positive bilateral thumb sign (Steinberg sign) ^c80
        • Positive when thumb tip extends beyond palm of hand when thumb is folded into closed fist
    • Arm span to height ratio of 1.05 or greater
    • Mitral valve prolapse (midsystolic click followed by apical high-pitched murmur) ^c81
    • Absence of inferior labial and lingual frenula is reported ^c82
  • Vascular subtype
    • Presenting manifestations are variable and may include:
      • Spontaneous rupture of bowel
        • Signs of acute abdomen may be attributable to spontaneous bowel rupture; location is characteristically the sigmoid colon ^c83
      • Spontaneous dissection or rupture of arterial tree
        • Signs of arteriovascular rupture or dissection depend on artery involved and end-organ supplied; common arteries involved are medium-sized abdominal vessels including renal, iliac, femoral, mesenteric, and hepatic ^r8r11
        • Sudden death in the third or fourth decade may be presenting feature ^r5c84
      • Sudden-onset ocular symptoms due to direct carotid-cavernous sinus fistula formation ^r3r14c85
        • Manifestations may include sudden-onset swishing sound and bruit in temporal region, ocular pain and chemosis, ophthalmoplegia, engorged episcleral veins, blurred vision, and proptosis ^{c86c87c88c89c90c91c92}
        • Usually occurs as a consequence of spontaneous rupture of internal carotid artery within the cavernous sinus ^r15
      • Pregnancy-related presentations may include signs attributable to uterine rupture, typically in the third trimester, and severe perineal tearing after vaginal delivery ^c93c94
      • Spontaneous pneumothorax ^c95
        • Signs attributable to spontaneous pneumothorax; may be recurrent
      • Characteristic facial appearance in patients with vascular subtype
        • Epicanthal folds, excess skin on eyelids, prominent eyes, thin face and nose, small lips, lobeless ears, prematurely aged appearance, scars on forehead and chin, and absence of subcutaneous fat ^{c96c97c98c99c100c101c102}
      • Keratoconus (ie, bilateral protrusion of the cornea with the apex being displaced downward and nasally) may occur in patients with vascular subtype ^c103
      • Acrogeria (prematurely aged appearance) may occur; often most striking on hands and feet ^r5c104

• Comparison findings associated with most common subtypes of Ehlers-Danlos syndrome.

  Data from Malfait F et al: The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 175(1):8-26, 2017; and Coles W: Hypermobility in children. Paediatr Child Health (Oxford). 28(2):50-6, 2018.

  Manifestation	Classical	Hypermobile	Vascular
  Joint hypermobility	Involves both large and small joints	Involves both large and small joints	Usually isolated to small joints
  Skin hyperextensibility	Most pronounced (severe)	Less pronounced (mild)	Absent
  Abnormal scarring	Atrophic scarring is pronounced; papyraceous scars and molluscoid pseudotumors are classic; hemosiderin staining associated with scars not uncommon	Posttraumatic, atrophic, and widened scarring is less pronounced than in classical subtype; absence of true papyraceous scars and molluscoid pseudotumors	Not characteristic
  Delayed wound healing	Common	Occurs but to a less severe extent than classical	Not characteristic
  Abnormal nodules	Subcutaneous spheroids are classic	Bilateral piezogenic papules of heel are classic	Not characteristic
  Skin texture and consistency	Extremely soft, smooth, velvety, and doughy skin	Unusually soft, silky, or velvety skin	Thin and translucent or parchmentlike skin with increased venous visibility
  Other common findings	Hernias are common; epicanthal folds may be present; joint complications are frequent (eg, sprains, luxation/subluxation, pain, flexible flatfoot)	Recurrent or multiple abdominal hernias; musculoskeletal complications (eg, pain, recurrent joint dislocation) are common; other associated and systemic symptoms (eg, fatigue, sleep disturbance, dysautonomia, depression, anxiety) are frequent	Arterial rupture at young age, spontaneous colonic perforation, uterine rupture during pregnancy, nontraumatic carotid-sinus fistula formation; characteristic facial appearance; spontaneous or recurrent pneumothorax; congenital hip dislocation or club foot; tendon and muscle rupture; early-onset varicose veins; keratoconus
  Skin fragility (or traumatic splitting)	Common	Absent	Severe peripartum perineal tears are classic; gingival fragility is reported
  Easy bruising	Common and can include unusual locations; hemosiderin staining of skin is common, especially pretibial areas	Common but poorly defined	Spontaneous bruising is common and can include unusual locations
  Unexplained striae	Absent	May be present	Not characteristic

Causes

• Known pathologic variants for most subtypes involve abnormalities in collagen-encoding genes or genes encoding collagen-modifying enzymes
• Cause for most common subtypes of disease include:
  • Classical Ehlers-Danlos phenotype
    • Over 90% of patients have heterozygous pathologic variant in genes encoding type V collagen ^r7c109
      • Type V collagen is present in a small amount and contributes to structural integrity of many tissues; phenotype is primarily caused by a reduction in the amount of type V collagen
      • Most pathologic variants involve COL5A1 (locus 9q34.3) (condition: OMIM #130000^r16; gene: OMIM *120215^r17) ^r7
      • Some pathologic variants involve COL5A2 (locus 2q32.2) (condition: OMIM #130010^r18; gene: OMIM *120190^r19) ^r7
    • Rarely, a single heterozygous nucleotide substitution in COL1A1 (c.934C>T, p.[Arg312Cys]), at locus 17q21.33, is responsible for phenotype; affects type I collagen (OMIM +120150^r20) ^r7c110
  • Hypermobile Ehlers-Danlos phenotype (OMIM %130020)^r21r7
    • Molecular basis is not known; genetic heterogeneity is likely ^r13
  • Vascular Ehlers-Danlos phenotype (OMIM #130050^r22) ^r7
    • Majority of patients have heterozygous pathologic variant in genes encoding type III collagen ^r7c111
      • Type III collagen is important for the structural integrity of blood vessel walls and hollow organs
      • Pathologic variants involve COL3A1 (locus 2q32.2; OMIM *120180^r23) ^r7
    • Rarely, single heterozygous arginine to cystine nucleotide substitutions in COL1A2 (7q21.3) are responsible for cardiac valvular phenotype; affects type I collagen (OMIM +120160^r24) ^r7c112
    • Very rarely, biallelic variants in COL3A1 may be responsible for phenotype ^r7

Risk factors and/or associations

Primary diagnostic tools

• Diagnosis of Ehlers-Danlos and specific subtype can be challenging; consider referral to a specialized clinician with expertise in diagnosing and managing condition (eg, clinical geneticist) ^r25
  • Checklists to assist in diagnosis are available for clinicians ^r26
• Suspect diagnosis based on clinical presentation ^r7c121
  • Common presenting patterns for classical subtype include easy bruising in childhood, skin fragility with atrophic scarring and poor wound healing, and frequent joint subluxations and dislocations ^r1
  • Presenting patterns for hypermobile subtype are highly variable; often a constellation of symptoms in association with frequent joint subluxations and dislocations lead to suspicion of disease
  • Common clinical presentations for vascular subtype include:
    • Neonate: club foot and/or congenital hip dislocation ^r14
    • Child: easy bruising, recurrent joint subluxation/dislocation, pneumothorax, or inguinal hernia ^r14
    • Adult: sudden arterial, bowel, or uterine rupture ^r14
• Apply clinical diagnostic criteria for specific subtype to help assign provisional clinical diagnosis and guide molecular testing ^r7
  • Evidence of hypermobility is based on Beighton score and/or Grahame and Hakim 5-point questionnaire
• Definitive diagnosis
  • Molecular confirmation of pathologic variant associated with disease is required for definitive diagnosis for all subtypes except hypermobile Ehlers-Danlos syndrome ^r7
    • Genetic confirmation is important for counseling regarding inheritance pattern and recurrence risk, as well as prognosis, and may guide management
  • Definitive diagnosis of hypermobile Ehlers-Danlos syndrome is based on strict clinical criteria ^r7
    • No biochemical or genetic tests are available to confirm or exclude hypermobile subtype ^r13
  • Consultation with a clinical geneticist may aid in focused diagnostic approach to molecular testing, particularly to aid in exclusion of alternate diagnosis when diagnostic uncertainty exists ^r13c122
• Provisional diagnosis ^r7
  • Provisional diagnosis can be assigned based on fulfillment of minimal set of clinical requirements for a specific subtype without molecular confirmation when:
    • There is no access to molecular confirmation
    • Variants of uncertain significance are identified in a subtype-specific gene
    • No causative pathologic variants are identified in any of the subtype-specific genes
  • Consider expanded molecular testing and alternate diagnosis in patients with provisional diagnosis when causative pathologic variant cannot be defined by usual molecular testing strategy
• Supporting studies
  • Transmission electron microscopy may be used to support classical subtype diagnosis but cannot confirm clinical diagnosis ^r7
  • Biochemical analysis of collagen production may be used to support vascular subtype diagnosis when genetic testing is inconclusive ^r27c123

Laboratory

• Molecular testing ^c124
  • Verifies clinical diagnosis
  • Overall diagnostic strategy
    • Relies on next-generation sequencing technology with parallel sequencing of multiple genes ^r7c125
    • First step is targeted resequencing of gene panel that includes suspected genes of interest ^r7c126
    • If no pathologic variant is identified (or only 1 in an autosomal recessive disorder), second-tier expanded molecular testing strategy may include: ^r7
      • Search for large deletions or duplications with a copy number variant detection strategy (eg, Multiplex Ligation–dependent Probe Amplification, quantitative polymerase chain reaction, targeted array analysis) ^c127c128c129
      • Whole-exome sequencing, whole-genome sequencing, and RNA sequencing analysis with focus on genes of interest for a given clinical subtype ^c130c131c132
    • If no pathologic variant is identified (or only 1 in an autosomal recessive disorder) after second-tier expanded molecular testing, consider alternate diagnosis ^r7
    • Absence of confirmatory pathologic variant does not exclude diagnosis because some specific mutations (eg, deep intronic mutations) may not be detectable with standard diagnostic molecular testing strategies ^r7
  • Classical Ehlers-Danlos syndrome
    • Genes of interest include COL5A1, COL5A2, and COL1A1 ^r7
    • Acceptable techniques include targeted resequencing of gene panel, whole-exome sequencing, or whole-genome sequencing ^r7
  • Vascular Ehlers-Danlos syndrome
    • Genes of interest include COL3A1 and COL1A1^r7
    • Acceptable techniques for verifying diagnosis include Sanger sequencing of COL3A1, or targeted resequencing of a gene panel that includes COL3A1 and COL1A1
• Transmission electron microscopy ^c133
  • May be used to support diagnosis of classical subtype when genetic testing is not available ^r7
  • Skin biopsy is used for analysis ^c134
  • Finding of collagen flowers supports diagnosis but cannot confirm diagnosis ^r7
    • Collagen flowers are nonspecific and noted in other diseases (eg, some types of osteogenesis imperfecta, muscular dystrophy) ^r1
  • Absence of collagen flowers supports alternate diagnosis; no reports exist of disease affecting type V collagen without associated finding of collagen flowers on electron microscopy ^r1
• Biochemical analysis of collagen production
  • Cultured dermal fibroblasts obtained from skin biopsy may be used for testing in patients in whom a causative pathologic variant is not identified ^r14
  • Abnormalities in type III procollagen synthesis and mobility in cells can help establish the diagnosis of vascular subtype when diagnosis is suspected but not confirmed by genetic testing ^r14c135
  • Testing may help to exclude some subtypes including vascular, kyphoscoliotic, arthrochalasia, and dermatosparaxis subtypes when clinical and genetic differentiation is inconclusive ^r28

Imaging

• Echocardiography ^c136
  • Not routinely required for patients with hypermobile or classic Ehlers-Danlos syndrome ^r29
  • May be indicated in patients with hypermobile or classic Ehlers-Danlos syndrome who have a family history of aneurysms or abnormalities on cardiac auscultation, particularly when pain is not a primary symptom ^r30
  • May have a role in vascular Ehlers-Danlos syndrome as surveillance for aortic root dilation; however, alone is not sufficient for surveillance of the arterial vasculature ^r30

Functional testing

• Joint hypermobility assessments ^c137
  • Beighton screening score
    • Total possible score is 9 points: 1 point each for 4 (bilateral) joint assessments and 1 point for spine
    • In general, a score 5 or higher defines generalized joint hypermobility ^r7
    • Joint laxity often decreases with age, injury, surgery, and effects of arthritis;^r5 Beighton score of less than 5 (out of 9) may be considered positive in some cases (particularly in older patients) when patient's historical recollection supports past presence of criteria ^r7
    • Proposed cutoff values used to define joint hypermobility by specific age group for patients when considering diagnosis of hypermobility subtype ^r7
      • Prepubertal children: Beighton score 6 or higher
      • Pubertal males and females 50 years or younger: Beighton score 5 or higher
      • Older than 50 years: Beighton score 4 or higher
    • Scoring system maneuvers and points ^r7
      • Fifth finger hyperextension
        • Positive scoring (1 point for each side): metacarpal-phalangeal joint of the fifth finger can be hyperextended more than 90° with respect to the dorsum of the hand with the palm and forearm resting on a flat surface with the elbow flexed at 90°
      • Thumb hyperextension
        • Positive scoring (1 point for each side): the thumb can be passively moved to touch the ipsilateral forearm with arms outstretched forward with hand in pronation
      • Elbow hyperextension
        • Positive scoring (1 point for each side): elbow extends more than 10° with the arms outstretched to the side and hand supine
      • Knee hyperextension
        • Positive scoring (1 point for each side): the knee extends more than 10° while standing with knees locked in genu recurvatum
      • Forward bending with palms to floor
        • Positive scoring (1 point): patient can bend forward to place the total palm of both hands flat on the floor just in front of the feet with knees locked straight and feet together
    • Videos depicting Beighton score maneuvers are available ^r31
  • Grahame and Hakim 5-point questionnaire
    • May be used for patients with acquired joint limitations (eg, previous surgery, wheelchair, amputation) affecting Beighton score calculation ^r7
    • Questions include: ^r7
      • Can you now (or could you ever) place your hands flat on the floor without bending your knees?
      • Can you now (or could you ever) bend your thumb to touch your forearm?
      • As a child, did you amuse your friends by contorting your body into strange shapes, or could you do the splits?
      • As a child or teenager, did your shoulder or kneecap dislocate on more than 1 occasion?
      • Do you consider yourself “double-jointed”?
    • An affirmative answer to 2 or more questions suggests joint hypermobility with 80% to 85% sensitivity and 80% to 90% specificity ^r7
    • Score is not validated in children ^r7
  • If the Beighton score is 1 point below the age-specific cutoff threshold defining joint hypermobility and the Grahame and Hakim 5-point questionnaire is positive, then fulfillment of generalized joint hypermobility criteria can be assigned
• Skin extensibility assessment ^r7c138
  • Measure by pinching and lifting the cutaneous and subcutaneous layers of the skin
    • Forearm measurement
      • Consider extensibility of greater than 1.5 cm of the volar surface at the middle of the nondominant forearm as abnormal (positive) ^r7
      • If extensibility exceeds 2 cm then strongly consider classical subtype, especially when other cutaneous findings are supportive (ie, papyraceous scars, molluscoid pseudotumors, and/or subcutaneous spheroids) ^r7
    • Neck, elbow, and knee measurements
      • Consider extensibility of greater than 3 cm abnormal (positive) ^r7
    • Volar surface of the hand (palm)
      • Consider extensibility of greater than 1 cm abnormal (positive) ^r1

Other diagnostic tools

• Minimal clinical requirements for specific subtypes
  • Classical Ehlers-Danlos syndrome ^r7
    • Major diagnostic criteria
      • Skin hyperextensibility and atrophic scarring
      • Generalized joint hypermobility
        • In general, measured by Beighton score 5 or greater ^r7
    • Minor diagnostic criteria
      • Easy bruising
      • Soft, doughy skin
      • Fragile skin (or traumatic splitting)
      • Molluscoid pseudotumors
      • Subcutaneous spheroids
      • Hernia (or history thereof)
      • Epicanthal folds
      • Complications of joint hypermobility (eg, sprains, luxation or subluxation, pain, flexible flatfoot)
      • Family history of a first-degree relative who meets clinical criteria
    • Minimal criteria suggestive for classical subtype of syndrome
      • Major criterion 1 plus either major criterion 2 and/or 3 or more minor criteria ^r7
  • Hypermobile Ehlers-Danlos syndrome ^r7
    • Major diagnostic criteria
      • Criterion 1: measurement of generalized joint hypermobility
        • Based on Beighton screening score and/or Grahame and Hakim 5-point questionnaire
      • Criterion 2: 2 or more of the following constellations of features (A through C) must be present (eg, A and B; A and C; B and C; or A, B, and C)
        • A. Systemic manifestations of a generalized connective tissue disorder (must have 5 or more)
          • Unusually soft or velvety skin
          • Mild skin hyperextensibility
            • Measured by pinching and lifting the cutaneous and subcutaneous layers of the skin on the volar surface at the middle of the nondominant forearm
          • Unexplained striae, including:
            • Adolescents with back, groin, thigh, breast, and/or abdominal striae
            • Men or prepubertal girls without a history of significant gain or loss of body fat or weight
          • Bilateral piezogenic papules (ie, herniation of subcutaneous fat) of the heel
          • Recurrent or multiple abdominal hernia(s) (eg, umbilical, inguinal)
          • Atrophic scarring involving at least 2 sites and without the formation of truly papyraceous and/or hemosideric scars as seen in classical subtype
          • Pelvic floor, rectal, and/or uterine prolapse in children, males, or nulliparous females without a history of morbid obesity or other known predisposing medical condition
          • Dental crowding and high or narrow palate
          • Arachnodactyly, as defined by 1 or more of the following:
            • Positive wrist sign (Walker sign) on both sides: positive when thumb and fifth finger overlap with each other when patient grips wrist with opposite hand
            • Positive thumb sign (Steinberg sign) on both sides: positive when thumb tip extends beyond palm of hand when thumb is folded into closed fist
          • Arm span to height ratio of 1.05
          • Mitral valve prolapse mild or greater based on strict echocardiographic criteria
          • Aortic root dilation with z score greater than +2
        • B. Positive family history, with 1 or more first-degree relatives independently meeting the current diagnostic criteria for hypermobile subtype
        • C. Musculoskeletal complications (must have at least 1)
          • Musculoskeletal pain in 2 or more limbs, recurring daily for at least 3 months
          • Chronic, widespread pain for 3 months or longer
          • Recurrent joint dislocations or frank joint instability, in the absence of trauma (a or b)
            • 3 or more atraumatic dislocations in the same joint or 2 or more atraumatic dislocations in 2 different joints occurring at different times
            • Medical confirmation of joint instability at 2 or more sites not related to trauma
      • Criterion 3: all of the following prerequisites must be met
        • Absence of unusual skin fragility, which should prompt consideration of other subtypes of Ehlers-Danlos syndrome
        • Exclusion of other heritable and acquired connective tissue disorders, including autoimmune rheumatologic conditions
          • Dual diagnosis in patients with an acquired connective tissue disorder, such as lupus erythematosus or rheumatoid arthritis (eg, concurrent lupus erythematosus and hypermobile Ehlers-Danlos syndrome) requires meeting both features A and B of criterion 2
          • Feature C of criterion 2 (chronic pain and/or instability) cannot be counted toward a diagnosis of hypermobile Ehlers-Danlos Syndrome in this situation
        • Exclusion of alternative diagnoses that may also include joint hypermobility by means of hypotonia and/or connective tissue laxity
          • Such alternate diagnosis may include neuromuscular disorders, other Ehlers-Danlos subtypes, Loeys-Dietz syndrome, Marfan syndrome, and skeletal dysplasias (eg, osteogenesis imperfecta)
          • Exclusion of alternate conditions may be based on history, physical examination, and/or molecular genetic testing, as indicated
    • Clinical diagnosis may be assigned only when all 3 major criteria are simultaneously present ^r7
    • Of note, many other features commonly associated with hypermobile subtype are not included in formal diagnostic criteria owing to insufficient sensitivity and specificity for clinical subtype diagnosis at present
      • Common associated (and often debilitating) features include sleep disturbance, fatigue, orthostatic tachycardia, functional gastrointestinal disorders, dysautonomia, anxiety, and depression
      • Despite not being included in current formal diagnostic criteria, experts recommend maintaining a high index of suspicion for diagnosis of hypermobile Ehlers-Danlos syndrome in the presence of a constellation of otherwise unexplained debilitating symptoms
  • Vascular Ehlers-Danlos syndrome ^r7
    • Major diagnostic criteria
      • Family history of subtype with documented causative variant in COL3A1
      • Arterial rupture at a young age
      • Spontaneous sigmoid colon perforation in the absence of known diverticular disease or other bowel condition
      • Uterine rupture during the third trimester in the absence of previous cesarean delivery and/or severe peripartum perineum tears
      • Carotid-cavernous sinus fistula formation in the absence of trauma
    • Minor diagnostic criteria
      • Bruising unrelated to identified trauma and/or in unusual sites (eg, cheeks, back)
      • Thin, translucent skin with increased venous visibility
      • Characteristic facial appearance
      • Spontaneous pneumothorax
      • Acrogeria (ie, thin, parchmentlike skin of hands and feet)
      • Talipes equinovarus (ie, club foot)
      • Congenital hip dislocation
      • Hypermobility of small joints
      • Tendon and muscle rupture
      • Keratoconus (protrusion of the cornea with the downward and medial displacement of the apex)
      • Gingival recession and gingival fragility
      • Early-onset varicose veins (younger than 30 years and nulliparous if female)
    • Minimal criteria suggestive for syndrome ^r7
      • Accurate clinical diagnosis is difficult even for experienced clinicians; given natural history of subtype and risk of life-threatening events, confirm diagnosis by identifying pathologic variant associated with syndrome
      • Order genetic testing for vascular subtype with any of the following:
        • Family history of the disorder
        • Unexplained arterial rupture or dissection in persons younger than 40 years
        • Unexplained sigmoid colon rupture
        • Spontaneous pneumothorax in the presence of other features consistent with subtype
      • Consider genetic testing in the presence of a combination of several other minor clinical features

Most common

• Nonaccidental trauma (child abuse) ^r32r33c139
  • Similar to classical, hypermobile, or vascular subtype of Ehlers-Danlos syndrome, may present in children as abnormal and unexplained bruising
  • Historical features concerning for abuse include prior involvement with Child Protective Services for suspicion of abuse, injuries inconsistent with developmental capabilities of child, changing account of injury, and delay in seeking medical care
    • Children with special health care needs, disability, or chronic illness are at increased risk
  • Suggestive findings for abuse include patterned bruising (eg, slap marks, loop marks), bruising in unusual locations (eg, cheeks, ears, torso, neck), bruising in nonambulatory children, patterned burns, adult human bites, unexplained fractures, multiple fractures at various stages of healing, certain fracture types (eg, metaphyseal bucket-handle fracture, posterior rib fracture), subdural hemorrhages, and retinal hemorrhages
  • Diagnosis of nonaccidental trauma can be challenging and depends on age of child; diagnosis often rests on results of formal social services evaluation, supportive findings on imaging (skeletal series, bone scan, head CT), and opinion of expert child abuse team
  • Differentiation may require additional evaluation to assess for genetic cause of Ehlers-Danlos and other mimicking conditions in a presentation with isolated bruising, no other concerns for abuse after an extensive initial work-up; positive family history of Ehlers-Danlos may help guide specific evaluation
• Fibromyalgia ^r34c140d1
  • Common disorder of unknown cause characterized by chronic widespread pain and fatigue associated with a spectrum of additional manifestations (eg, nonrestorative sleep, restless legs, headaches, temporomandibular disorders, irritable bowel, interstitial cystitis, anxiety, depression, cognitive disturbance [foggy sensorium])
  • May present similarly to hypermobile subtype with chronic pain, fatigue, and similar additional associated and systemic manifestations
  • Point tenderness may be elicited at certain predictable locations
  • Differentiate from hypermobile subtype of Ehlers-Danlos by absence of other features characteristic of Ehlers-Danlos (eg, skin hyperextensibility, skin fragility, abnormal scarring, generalized joint instability)
  • Diagnosis is based on clinical diagnostic criteria;^r35 diagnosis does not exclude comorbid conditions
• Marfan syndrome ^r36c141d2
  • Autosomal dominant, systemic disorder of connective tissue caused by pathologic variants in FBN1 encoding for extracellular matrix protein fibrillin-1; cardinal manifestations involve the ocular, skeletal, and cardiovascular systems
  • May present similarly to hypermobile and classical subtypes of Ehlers-Danlos syndrome because of the following:
    • Joint hypermobility is common in many patients with Marfan syndrome
    • Some patients with hypermobile-type Ehlers-Danlos syndrome have a Marfanoid build ^r13
    • Several subtle manifestations of these syndromes overlap (eg, myopia, mitral valve prolapse, spontaneous pneumothorax, striae, predisposition to hernias, high arched palate)
  • Clinical differentiation can be difficult; several clinical manifestations that suggest Marfan syndrome over Ehlers-Danlos include:
    • Ocular: ectopia lentis is a hallmark feature; severe myopia, retinal detachment, glaucoma, and early cataracts may also occur
    • Skeletal: bone overgrowth (eg, dolichostenomelia, pectus excavatum, pectus carinatum, scoliosis) and tall build
    • Facial features: long and narrow face with enophthalmos, malar hypoplasia, downward slanting of the palpebral fissures, high arched palate, dental crowding, micrognathia, and retrognathia
    • Cardiovascular
      • Progressive aortic root dilation predisposing to aortic tear and rupture, and enlargement of the proximal pulmonary artery
      • Mitral valve prolapse with or without regurgitation, and tricuspid valve prolapse
      • Symptomatic mitral and/or aortic valve regurgitation predisposing to left ventricular dysfunction
  • Skin findings characteristic of Ehlers-Danlos syndromes are not typical for patients with Marfan syndrome
  • Diagnosis of Marfan syndrome rests on established clinical criteria (revised Ghent nosology) and/or demonstration of pathologic variant in FBN1^r8
• Cutis laxa ^r37c142
  • Group of inherited (and rarely acquired) disorders affecting elastic tissue that result from loss or fragmentation of elastic fiber networks; modes of inheritance include autosomal-dominant, autosomal-recessive, and X-linked forms
  • Characteristically presents with cutaneous finding of redundant skin that hangs in loose folds, often most appreciable on the neck, hands, groin, and face
  • Variable systemic manifestations may be present depending on type of cutis laxa (and underlying cause) ^r37
  • Subtle cutaneous findings may help to differentiate; as opposed to Ehlers-Danlos, in cutis laxa
    • Skin is more redundant in nature and does not snap back into position after release of tension when stretched ^r28
    • Skin does not show easy bruising or abnormal scarring
  • Definitive diagnosis of cutis laxa depends on specific type but often rests on clinical presentation in conjunction with characteristic histopathologic and electron microscopy findings on skin biopsy; identification of pathologic variant associated with disease can confirm diagnosis for inherited forms ^r38
• Loeys-Dietz syndrome ^r39c143
  • Autosomal-dominant systemic disorder of connective tissue caused by a heterozygous pathologic variant in 1 of 6 genes (ie, SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, TGFBR2) encoding for components of transforming growth factor-β signaling pathway ^r8
  • Cardinal manifestations involve vascular, skeletal, and cutaneous systems; however, this syndrome presents with high phenotypic variability and can mimic vascular, hypermobile, or classic subtypes of Ehlers-Danlos syndrome
  • May present similarly with skin changes (eg, translucent or velvety skin), easy bruising, dystrophic scarring, joint laxity, vascular accidents, predisposition to uterine rupture during pregnancy, and strong association with gastrointestinal disorders
  • Differentiate by the presence of diffuse arteriovascular abnormalities (eg, tortuosity, aneurysms, dissections) and dysmorphic features (eg, Marfanoid facies, cleft palate, blue sclerae, craniosynostosis, pectus deformity, arachnodactyly) along with other typical associated manifestations (eg, cervical spine instability, atopic disease)
  • Diagnosis is based on characteristic clinical findings and confirmed by identification of pathologic variant associated with syndrome ^r39
• Osteogenesis imperfecta ^r40c144d3
  • Collection of inherited connective tissue disorders characterized by increased bone fragility and low bone mass; most cases are caused by autosomal dominant pathologic variants involving COL1A1 and COL1A2, resulting in abnormal type I collagen ^r41
  • May present similarly to hypermobile and classical subtypes of Ehlers-Danlos syndrome with skin hyperelasticity, easy bruising, and joint hypermobility associated with frequent dislocation/subluxation; aortic valve dilation and mitral valve prolapse are not uncommon
  • May differentiate clinically by presence of frequent fractures (with minimal or absent trauma), bone deformities, short stature, blue sclera, progressive hearing loss, dental abnormalities (eg, dentinogenesis imperfecta, delayed tooth eruption, gray-brown teeth), triangular face, hypercalciuria, macrocephaly, and hydrocephalus
  • Diagnosis is based on biochemical abnormalities detected in structure and quantity of type I collagen in cultured dermal fibroblasts and confirmed by identification of pathologic variants associated with disease ^r40

Recommendations for specialist referral

• Manage in consultation with treatment team with expertise and experience managing Ehlers-Danlos syndrome
  • All patients need a primary care physician to coordinate specialist and ancillary care
  • Many patients can benefit from care by a mental health professional to address psychosocial impact of disease
  • Treatment team for patients with classical subtype may also include:
    • Specialists with experience managing joint manifestations (eg, rheumatologist, orthopedist, sports medicine specialist, physiotherapist, occupational and physical therapist)
    • Clinical geneticist for diagnostic and genetic consultation for patient and family members
    • Consider plastic surgeon for management of wounds requiring repair ^r5
  • Treatment team for patients with hypermobile subtype may also include:
    • Specialists with experience managing joint manifestations (eg, rheumatologist, orthopedist, sports medicine specialist, physiotherapist, occupational and physical therapist)
    • Pain medicine specialist
    • Gastroenterologist for recalcitrant functional gastrointestinal manifestations
  • Treatment team for patients with vascular subtype may also include: ^r3
    • Specialists capable of managing major manifestations and complications (eg, general surgeon, vascular surgeon, high-risk obstetrician)
    • Clinical geneticist for diagnostic and genetic consultation for patient and family members

Drug therapy

• Vasopressin analog
  • Desmopressin acetate
    • for treatment of bleeding, including epistaxis and gingival bleeding ^c145
      • Desmopressin Acetate Nasal spray, solution; Children and Adolescents weighing less than 50 kg: 150 mcg into 1 nostril for a total dose of 150 mcg once daily as needed for up to 2 consecutive days.
      • Desmopressin Acetate Nasal spray, solution; Children and Adolescents weighing 50 kg or more: 150 mcg into each nostril for a total dose of 300 mcg once daily as needed for up to 2 consecutive days.
      • Desmopressin Acetate Nasal spray, solution; Adults weighing less than 50 kg: 150 mcg into 1 nostril for a total dose of 150 mcg once daily as needed for up to 2 consecutive days.
      • Desmopressin Acetate Nasal spray, solution; Adults weighing 50 kg or more: 150 mcg into each nostril for a total dose of 300 mcg once daily as needed for up to 2 consecutive days.
    • for surgical bleeding prophylaxis
      • Intranasal
        • Desmopressin Acetate Nasal spray, solution; Children and Adolescents weighing less than 50 kg: 150 mcg into 1 nostril once for a total dose of 150 mcg. May repeat dose if needed based on laboratory response and clinical condition.
        • Desmopressin Acetate Nasal spray, solution; Children and Adolescents weighing 50 kg or more: 150 mcg into each nostril once for a total dose of 300 mcg. May repeat dose if needed based on laboratory response and clinical condition.o each nostril for a total dose of 300 mcg prior to the procedure.
        • Desmopressin Acetate Nasal spray, solution; Adults weighing less than 50 kg: 150 mcg into 1 nostril once for a total dose of 150 mcg. May repeat dose if needed based on laboratory response and clinical condition.
        • Desmopressin Acetate Nasal spray, solution; Adults weighing 50 kg or more: 150 mcg into each nostril once for a total dose of 300 mcg. May repeat dose if needed based on laboratory response and clinical condition.
      • Intravenous ^r49c146c147
        • Desmopressin Acetate Solution for injection; Infants, Children, and Adolescents: 0.3 mcg/kg/dose IV once. May repeat dose once daily for 2 days postoperatively if needed based on laboratory response and clinical condition.
        • Desmopressin Acetate Solution for injection; Adults: 0.3 mcg/kg/dose IV once. May repeat dose once daily for 2 days postoperatively if needed based on laboratory response and clinical condition.
• Nutritional supplementation
  • Ascorbic acid ^c148
    • Vitamin C (Ascorbic Acid) Oral tablet; Adults: 750 to 4,000 mg/day PO.
  • Calcium ^c149
    • Calcium Oral suspension; Neonates: 200 mg/day elemental calcium (500 mg/day calcium carbonate) PO.
    • Calcium Oral suspension; Infants 1 to 6 months: 200 mg/day elemental calcium (500 mg/day calcium carbonate) PO.
    • Calcium Oral suspension; Infants 7 to 11 months: 260 mg/day elemental calcium (650 mg/day calcium carbonate) PO.
    • Calcium Oral suspension; Children 1 to 3 years: 700 mg/day elemental calcium (1,750 mg/day calcium carbonate) PO.
    • Calcium Oral suspension; Children 4 to 8 years: 1,000 mg/day elemental calcium (2,500 mg/day calcium carbonate) PO.
    • Calcium Oral tablet; Children and Adolescents 9 to 17 years: 1,300 mg/day elemental calcium (3,250 mg/day calcium carbonate) PO.
    • Calcium Oral tablet; Adults 18 years: 1,300 mg/day elemental calcium (3,250 mg/day calcium carbonate) PO.
    • Calcium Oral tablet; Adult Females 19 to 50 years: 1,000 mg/day elemental calcium (2,500 mg/day calcium carbonate) PO.
    • Calcium Oral tablet; Adult Males 19 to 70 years: 1,000 mg/day elemental calcium (2,500 mg/day calcium carbonate) PO.
    • Calcium Oral tablet; Adult Females 51 to 70 years: 1,200 mg/day elemental calcium (3,000 mg/day calcium carbonate) PO.
    • Calcium Oral tablet; Adults older than 70 years: 1,200 mg/day elemental calcium (3,000 mg/day calcium carbonate) PO.
  • Vitamin D ^c150
    • Vitamin D (Cholecalciferol) Oral solution; Neonates: 10 mcg/day (400 International Units/day) PO.
    • Vitamin D (Cholecalciferol) Oral solution; Infants: 10 mcg/day (400 International Units/day) PO.
    • Vitamin D (Cholecalciferol) Oral solution; Children and Adolescents: 15 mcg/day (600 International Units/day) PO.
    • Vitamin D (Cholecalciferol) Oral tablet; Adults 18 to 70 years: 15 mcg/day (600 International Units/day) PO.
    • Vitamin D (Cholecalciferol) Oral tablet; Adults older than 70 years: 20 mcg/day (800 International Units/day) PO.
• Anti-hypertensive
  • β₁ antagonist and β₂ agonist
    • Celiprolol ^c151
      • Currently being studied in the United States
      • Received orphan drug status from FDA in 2015 ^r50
      • Celiprolol Hydrochloride Oral tablet; Adults: 50 mg PO twice daily, initially. Adjust dose by 100 mg every 6 months based on tolerability. Max: 400 mg/day ^r47

Nondrug and supportive care

• For patients with classical subtype
  • Skin precautions
    • Provide specialized wound care, including: ^r1c152
      • Expert closure of wounds using sutures without tension
      • Generous application of sutures in multiple layers
      • Leaving sutures in place for twice as long as with typical patient
      • Application of tape to prevent scar stretching and ensure gentle tape removal in effort to avoid added trauma
    • Recommend use of protective gear, including: ^r28c153
      • Pads or bandages over forehead, shins, and knees to avoid skin tears, particularly in young children
      • Soccer shin guards or ski stockings during sports or recreational activities may prevent skin tears in older children
  • Musculoskeletal management
    • Physical therapy for children with hypotonia or delayed motor development ^r1c154
    • Light, non–weight-bearing, muscle-strengthening exercise (eg, isometric training, swimming) ^{r1c155c156c157}
    • Manage joint hypermobility in consultation with rheumatologist, physiatrist, sports medicine specialist, and occupational and physical therapist ^{r1c158c159c160c161c162}
      • Ring splints, individualized bracing, and orthotics may be beneficial ^c163c164c165
    • Maximize bone density with appropriate daily intake of calcium and vitamin D
  • Pain management
    • Encourage regular and appropriate exercise ^r1c166
    • Suggest relaxation techniques ^r1c167
    • Use cognitive behavioral therapy and counseling with focus on acceptance and coping skills ^r1c168
    • Use nonnarcotic pain medications and anti-inflammatory drugs preferentially; use narcotics sparingly and only as last resort ^{r1c169c170c171}
  • Discouraged activities and avoidance measures
    • Patient should avoid the following:
      • Competitive activities and sports associated with heavy joint strain (eg, gymnastics, repetitive heavy lifting, contact sports, running) ^{r1r28c172c173c174c175}
      • Excessive hyperextension and stretching of joints ^r1c176c177
      • Excessive sun exposure to reduce risk of premature skin aging ^r1c178
      • Elective surgery unless benefits greatly outweigh risks ^r1c179
        • Recurrence of original problem is not uncommon owing to extreme tissue fragility
      • Accidental trauma with use of protective pads ^r1
    • Perform endoscopy and colonoscopy only with extreme care owing to increased risk of bleeding and mucosal fragility ^r1
    • Some experts advise against use of aspirin owing to increased risk for bruising ^c180
• For patients with hypermobile subtype
  • Musculoskeletal management
    • Physical therapy tailored to the patient; may include a number of modalities, such as myofascial release, heat or cold application, ultrasonography, electrical stimulation, acupuncture, acupressure, biofeedback, and conscious relaxation ^{r13c181c182c183c184c185c186c187}
    • Low-resistance muscle toning exercises as opposed to muscle-strengthening exercises (more repetitions, less voluntary force exerted) ^r13c188
      • May include walking, biking, swimming, low-impact aerobics, range-of-motion exercises, and core-toning exercises ^{c189c190c191c192c193}
      • Recommend avoidance of high-impact activity owing to increased risk for subluxation/dislocation, chronic pain, and osteoarthritis ^r13c194
    • Ambulatory assistive devices (eg, wheelchair, scooter) to off-load lower-extremity joint stress ^r13c195c196
    • Braces intended to improve joint stability ^r13c197
    • Supplementation with appropriate daily intake of calcium and vitamin D to maximize bone density ^c198c199
    • Various orthopedic procedures may be attempted in an effort to control pain and joint instability (eg, joint debridement, tendon relocations, capsulorrhaphy, arthroplasty) ^{r13c200c201c202c203}
      • When feasible, medical management is preferred over surgical management; anticipate some improvement in symptoms, but results are often less than optimal ^r13
• For patients with vascular subtype
  • Action plan for vascular emergencies should include patient education and centralized information regarding individual nature of disease and protocol for emergency treatment to be archived in local emergency departments ^r3
    • Immediate and expedited medical and/or surgical evaluation for sudden, unexplained pain ^r14
  • Discouraged activities and avoidance measures include:
    • Collision sports and isometric activities (eg, football, weight lifting, weight training) ^r3c204c205
    • Running on hard surfaces for long distances ^r3c206
    • Activities associated with rapid acceleration and deceleration ^r3
    • Arteriography with high-pressure injection ^r3c207
    • Vein stripping ^r3c208
    • Colonoscopy in the absence of clinical concern or strong positive family history of colon cancer ^r14c209
    • Elective surgery unless benefits are projected to greatly outweigh risks ^r14
• Provide all families with support group and resource information; some organizations include: ^c210
  • Ehlers-Danlos Society ^r51
  • Ehlers-Danlos Network CARES Foundation ^r52
• Offer genetic counseling for affected patients and families to assist with reproductive planning and discussion of risk to offspring ^c211

Special populations

• Pregnant patients with vascular and classical subtypes
  • Preferred mode of delivery has not been established ^r14
  • Individualized high-risk obstetric monitoring is suggested ^r14

At-risk populations

• Patients with family history of disease

Screening tests

• Prenatal testing ^c332
  • Genetic testing is available for patients with known pathologic variant responsible for classical and vascular subtype disease ^r14c333
  • Chorionic villus sampling cells may be used for culture and biochemical analysis if familial pathologic variant is not identified or known ^r14c334
• Asymptomatic relatives of patients with vascular subtype
  • Offer genetic testing to at-risk relatives ^c335
  • Knowledge of diagnosis allows for monitoring for vascular complications, awareness of need for immediate evaluation for unexplained symptoms, and appropriate restriction from high-risk activities

Screening for associated congenital anomalies

• Additional evaluations following initial diagnosis include:
  • Classical subtype
    • Evaluation for hypotonia and motor development for infants and children ^r12c336
    • Prothrombin time and partial thromboplastin time if severe or easy bruising is part of phenotype ^r28c337
    • Baseline echocardiography with aortic diameter measurement ^r5r28c338
  • Hypermobile subtype
    • Echocardiography ^r13c339
      • Obtain baseline study in all patients to evaluate aortic root diameter
      • Consider alternate diagnosis if significant aortic root enlargement and/or additional significant cardiac abnormalities are identified
    • Consider the following studies when indicated based on individualized clinical concerns:
      • Tilt table testing in patients with significant orthostatic intolerance ^r13c340
      • Gastroenterology consultation for possible endoscopy when significant gastrointestinal symptoms are reported ^r13c341
      • DXA in patients with signs or symptoms suggestive of osteopenia (eg, height loss greater than 1 inch, suggestive radiograph findings) ^r13c342
      • Hematologic evaluation to assess for concurrent bleeding disorder (eg, von Willebrand disease, thrombocytopenia) in patients with severe or prolonged bleeding ^r13c343
      • Screening evaluation for potential cause or exacerbating factors associated with chronic fatigue and pain (eg, deficiency in vitamin D, B₁₂, folate, iron, celiac disease, hypothyroidism)₁₂ ^r13
      • Brain MRI when associated Chiari I malformation is clinically suspected ^r13c344
  • Vascular subtype
    • Consensus is lacking regarding extent of evaluation at time of initial diagnosis; approach varies by region and treatment team ^r14
    • Evaluation is individualized based on age of patient and circumstances of presentation; often includes targeted and diffuse noninvasive vascular tree imaging (eg, Doppler ultrasonography, low-radiation CT angiography, magnetic resonance angiography) ^{r14c345c346c347}
  • All patients should have a complete ophthalmology examination (including slitlamp and dilated funduscopic examinations) at time of diagnosis ^c348c349c350