There is currently no laboratory test available to diagnose hEDS. The diagnosis of hEDS is given to adults who meet the clinical diagnostic criteria for hEDS. Children and adolescents with generalized joint hypermobility can be assessed using the pediatric diagnostic framework.

To meet the diagnostic criteria for hEDS, a person must meet all three criteria (1 and 2 and 3).

Criterion 1: Generalized joint hypermobility

Criterion 2: Two or more of the following features (A, B, and C) must be presentFeature A: Manifestations of a connective tissue disorder (must have five or more of the following):

1. Unusually soft or velvety skin
2. Mild skin hyperextensibility
3. Unexplained striae such as striae distensae or rubrae at the back, groins, thighs, breasts, and/or abdomen in adolescents, men, or pre-pubertal women without a history of significant gain or loss of body fat or weight
4. Bilateral piezogenic papules of the heel
5. Recurrent or multiple abdominal hernia(s) (e.g., umbilical, inguinal, crural)
6. Atrophic scarring involving at least two (2) sites and without the formation of truly papyraceous and/or hemosideric scars as seen in classical EDS
7. Pelvic floor, rectal, and/or uterine prolapse in children, men or nulliparous women without a history of morbid obesity or other known predisposing medical condition
8. Dental crowding and high or narrow palate
9. Arachnodactyly, as defined in one or more of the following:
   1. positive wrist sign (Steinberg sign) on both sides
   2. positive thumb sign (Walker sign) on both sides
10. Arm span-to-height ratio ≥ 1.05
11. Mitral valve prolapse (MVP) mild or greater based on strict echocardiographic criteria
12. Aortic root dilatation with Z-score >+2

Feature B: Positive family history (one or more first-degree relatives independently meet the current diagnostic criteria for hEDS)

Feature C: Musculoskeletal complications (must have at least one of the following):

1. Musculoskeletal pain in two or more limbs, recurring daily for at least three (3) months
2. Chronic, widespread pain for at least three (3) months
3. Recurrent joint dislocations or frank joint instability, in the absence of trauma (a or b)
   1. Three (3) or more atraumatic dislocations in the same joint or two (2) or more atraumatic dislocations in two (2) different joints occurring at different times
      OR
   2. Medical confirmation of joint instability at two (2) or more sites not related to trauma

Criterion 3: ALL of the following prerequisites must be met:

1. Absence of unusual skin fragility, which should prompt consideration of other types of EDS
2. Exclusion of other heritable and acquired connective tissue disorders, including autoimmune rheumatologic conditions
   • In patients with an acquired connective tissue disorder (e.g., lupus, rheumatoid arthritis, etc.), additional diagnosis of hEDS requires meeting both Features A and B of Criterion 2. Feature C of Criterion 2 (chronic pain and/or instability) cannot be counted towards a diagnosis of hEDS in this situation.
3. Exclusion of alternative diagnoses that may also include joint hypermobility by means of hypotonia and/or connective tissue laxity. Alternative diagnoses and diagnostic categories include, but are not limited to:
   • Neuromuscular disorders (such as myopathic EDS and Bethlem myopathy)
   • Other heritable connective tissue disorders (such as other types of EDS, Loeys–Dietz syndrome, Marfan syndrome)
   • Skeletal dysplasias (such as osteogenesis imperfecta)

HSD in Adults

Adults are diagnosed with HSD if they have symptomatic joint hypermobility that cannot be explained by other conditions. There are four types of HSD in adults based on the type of joint hypermobility present:

HSD in Children and Adolescents

Children and adolescents with generalized joint hypermobility can be assessed using the 2023 Diagnostic Framework for Pediatric Joint Hypermobility. Children with generalized joint hypermobility may fit into one of eight categories based on their symptoms.

Children and adolescents may also be diagnosed with localized HSD (L-HSD) or peripheral HSD (P-HSD) if they have joint hypermobility in specific areas rather than throughout the body. Once a child reaches biological maturity, they can be assessed using the diagnostic criteria for hEDS.

If a person meets the diagnostic criteria for cEDS, genetic testing should be done to confirm the diagnosis. Genetic testing is used to see if a person has a genetic variant that causes cEDS.

To meet the diagnostic criteria for cEDS, a person must meet:

• Major criterion 1 AND major criterion 2
  OR
• Major criterion 1 AND three or more minor criteria

Major Criteria

1. Skin hyperextensibility and atrophic scarring
2. Generalized joint hypermobility

Minor Criteria

1. Easy bruising
2. Soft, doughy skin
3. Skin fragility (or traumatic splitting)
4. Molluscoid pseudotumors
5. Subcutaneous spheroids
6. Hernia (or history thereof)
7. Epicanthal folds
8. Complications of joint hypermobility (e.g., sprains, dislocations/subluxations, pain, flexible flatfoot)
9. Family history of a first-degree relative who meets clinical criteria

Genetic testing is used to see if a person has a genetic variant that causes vEDS. Genetic testing should be considered if a person has any of the major criteria or several minor criteria, particularly in people under the age of 40.

Major Criteria

1. Family history of vEDS with a documented causative variant in COL3A1
2. Arterial rupture at a young age
3. Spontaneous sigmoid colon perforation in the absence of known diverticular disease or other bowel pathology
4. Uterine rupture during the third trimester in the absence of previous C-section and/or severe peripartum perineum tears
5. Carotid-cavernous sinus fistula (CCSF) formation in the absence of trauma

Minor Criteria

1. Bruising unrelated to identified trauma and/or in unusual sites such as the cheeks and back
2. Thin, translucent skin with increased venous visibility
3. Characteristic facial appearance
4. Spontaneous pneumothorax
5. Acrogeria
6. Talipes equinovarus
7. Congenital hip dislocation
8. Hypermobility of small joints
9. Tendon and muscle rupture
10. Keratoconus
11. Gingival recession and gingival fragility
12. Early-onset varicose veins (under age 30 and starting before pregnancy if female)

If a person meets the diagnostic criteria for aEDS, genetic testing should be done to confirm the diagnosis. Genetic testing is used to see if a person has the genetic variants that cause aEDS.   

To meet the diagnostic criteria for aEDS, a person must meet: 

• Major criterion 1 AND major criterion 3
  OR 
• Major criterion 1 AND major criterion 2 and at least two minor criteria 

Major Criteria 

1. Congenital bilateral hip dislocation 
2. Severe generalized joint hypermobility, with multiple dislocations/subluxations 
3. Skin hyperextensibility 

Minor Criteria 

1. Muscle hypotonia 
2. Kyphoscoliosis 
3. Radiologically mild osteopenia 
4. Tissue fragility, including atrophic scars 
5. Easily bruisable skin 

Diagnostic Criteria

To meet the diagnostic criteria for BCS, a person must meet:

Major criterion 1 AND at least one other major criterion
OR

Major criterion 1 AND at least three minor criteria

Major Criteria

1. Thin cornea, with or without rupture (central corneal thickness often <400µm)
2. Early onset progressive keratoconus
3. Early onset progressive keratoglobus
4. Blue sclerae

Minor Criteria

1. Enucleation or corneal scarring as a result of previous rupture
2. Progressive loss of corneal stromal depth, especially in central cornea
3. High myopia, with normal or moderately increased axial length
4. Retinal detachment
5. Deafness, often with mixed conductive and sensorineural components, progressive, higher frequencies often more severely affected (“sloping” pure tone audiogram)
6. Hypercompliant tympanic membranes
7. Developmental dysplasia of the hip
8. Hypotonia in infancy, usually mild if present
9. Scoliosis
10. Arachnodactyly
11. Hypermobility of distal joints
12. Pes planus, hallux valgus
13. Mild contractures of fingers (especially 5th)
14. Soft, velvety skin, translucent skin

Genetic Testing

If a person meets the diagnostic criteria for BCS, genetic testing should be done to confirm the diagnosis. Genetic testing is used to see if a person has the genetic variants that cause BCS. BCS is caused by having two pathogenic variants in these genes:

• ZNF469
• PRDM5

If a person meets the diagnostic criteria for cvEDS, genetic testing should be done to confirm the diagnosis. Genetic testing is used to see if a person has the genetic variants that cause cvEDS.

To meet the diagnostic criteria for cvEDS, a person must meet:

• Major criterion 1 AND family history compatible with autosomal recessive inheritance AND at least one other major criterion
  OR
• Major criterion 1 AND family history compatible with autosomal recessive inheritance AND at least two minor criteria

Major Criteria

1. Severe progressive cardiac-valvular problems (aortic valve, mitral valve)
2. Skin involvement: skin hyperextensibility, atrophic scars, thin skin, easy bruising
3. Joint hypermobility (generalized or restricted to small joints)

Minor criteria

1. Inguinal hernia
2. Pectus deformity (especially excavatum)
3. Joint dislocations
4. Foot deformities: pes planus, pes planovalgus, hallux valgus

If a person meets the diagnostic criteria for clEDS, genetic testing should be done to confirm the diagnosis. Genetic testing is used to see if a person has the genetic variants that cause clEDS.   

To meet the diagnostic criteria for clEDS, a person must meet all three major criteria AND have a family history compatible with autosomal recessive inheritance. 

Major Criteria

1. Skin hyperextensibility, with velvety skin texture and absence of atrophic scarring 
2. Generalized joint hypermobility, with or without recurrent dislocations (most commonly shoulder and ankle) 
3. Easily bruisable skin/spontaneous ecchymoses 

Minor Criteria

1. Foot deformities (broad/plump forefoot; brachydactyly with excessive skin; pes planus; hallux valgus; piezogenic papules) 
2. Edema in the legs in the absence of cardiac failure 
3. Mild proximal and distal muscle weakness 
4. Axonal polyneuropathy 
5. Atrophy of muscles in hands and feet 
6. Acrogeric hands, mallet finger(s), clinodactyly, brachydactyly 
7. Vaginal/uterus/rectal prolapse 

If a person meets the diagnostic criteria for dEDS, genetic testing should be done to confirm the diagnosis. Genetic testing is used to see if a person has the genetic variants that cause dEDS.  

To meet the diagnostic criteria for dEDS, a person must meet: 

• Major criterion 1 AND major criterion 2 AND at least one other major criterion

OR

•  Major criterion 1 AND major criterion 2 AND at least three minor criteria 

Major Criteria  

1. Extreme skin fragility with congenital or postnatal skin tears 
2. Characteristic craniofacial features, which are evident at birth or early infancy or evolve later in childhood 
3. Redundant, almost lax skin, with excessive skin folds at the wrists and ankles 
4. Increased palmar wrinkling 
5. Severe bruisability with a risk of subcutaneous hematomas and hemorrhage 
6. Umbilical hernia 
7. Postnatal growth retardation 
8. Short limbs, hands, and feet 
9. Perinatal complications due to connective tissue fragility 

 Minor Criteria 

1. Soft and doughy skin texture 
2. Skin hyperextensibility 
3. Atrophic scars  
4. Generalized joint hypermobility 
5. Complications of visceral fragility (e.g., bladder rupture, diaphragmatic rupture, rectal prolapse) 
6. Delayed motor development 
7. Osteopenia 
8. Hirsutism 
9. Tooth abnormalities 
10. Refractive errors (myopia, astigmatism) 
11. Strabismus 

If a person meets the diagnostic criteria for kEDS, genetic testing should be done to confirm the diagnosis. Genetic testing is used to see if a person has the genetic variants that cause kEDS.

To meet the diagnostic criteria for kEDS, a person must meet:

• Major criterion 1 AND major criterion 2 AND major criterion 3
  OR
• Major criterion 1 AND major criterion 2 AND three minor criteria (general or gene-specific)

Major Criteria

1. Congenital muscle hypotonia
2. Congenital or early onset kyphoscoliosis (progressive or non-progressive)
3. Generalized joint hypermobility with dislocations/subluxations (shoulders, hips, and knees in particular)

Minor Criteria

1. Skin hyperextensibility
2. Easily bruisable skin
3. Rupture/aneurysm of a medium-sized artery
4. Osteopenia/osteoporosis
5. Blue sclerae
6. Hernia (umbilical or inguinal)
7. Pectus deformity
8. Marfanoid habitus
9. Talipes equinovarus
10. Refractive errors (myopia, hypermetropia)

Gene-Specific Minor Criteria

PLOD1

1. Skin fragility (easy bruising, friable skin, poor wound healing, widened atrophic scarring)
2. Scleral and ocular fragility/rupture
3. Microcornea
4. Facial dysmorphology

FKBP14

1. Congenital hearing impairment (sensorineural, conductive, or mixed)
2. Follicular hyperkeratosis
3. Muscle atrophy
4. Bladder diverticula

If a person meets the diagnostic criteria for mcEDS, genetic testing should be done to confirm the diagnosis. Genetic testing is used to see if a person has the genetic variants that cause mcEDS.

To meet the diagnostic criteria for mcEDS at birth or in early childhood, a person must meet major criterion 1 AND major criterion 2.

To meet the diagnostic criteria for mcEDS in adolescence and adulthood, a person must meet major criterion 1 AND major criterion 3.

Major Criteria

1. Congenital multiple contractures, characteristically adduction-flexion contractures and/or talipes equinovarus (clubfoot)
2. Characteristic craniofacial features, which are evident at birth or in early infancy
3. Characteristic cutaneous features including skin hyperextensibility, easy bruisability, skin fragility with atrophic scars, increased palmar wrinkling

Minor Criteria

1. Recurrent/chronic dislocations
2. Pectus deformities (flat, excavated)
3. Spinal deformities (scoliosis, kyphoscoliosis)
4. Peculiar fingers (tapering, slender, cylindrical)
5. Progressive talipes deformities (valgus, planus, cavum)
6. Large subcutaneous hematomas
7. Chronic constipation
8. Colonic diverticula
9. Pneumothorax/ pneumohemothorax
10. Nephrolithiasis/cystolithiasis
11. Hydronephrosis
12. Cryptorchidism in males
13. Strabismus
14. Refractive errors (myopia, astigmatism)
15. Glaucoma/elevated intraocular pressure

If a person meets the diagnostic criteria for mEDS, genetic testing should be done to confirm the diagnosis. Genetic testing is used to see if a person has the genetic variants that cause mEDS.  

To meet the diagnostic criteria for mEDS, a person must meet: 

• Major criterion 1 AND at least one other major criterion
  OR 
• Major criterion 1 AND at least three minor criteria 

Major Criteria

1. Congenital muscle hypotonia and/or muscle atrophy that improves with age 
2. Proximal joint contractures (knee, hip, and elbow) 
3. Hypermobility of distal joints 

Minor Criteria

1. Soft, doughy skin 
2. Atrophic scarring 
3. Motor developmental delay 
4. Myopathy on muscle biopsy 

If a person meets the diagnostic criteria for pEDS, genetic testing should be done to confirm the diagnosis. Genetic testing is used to see if a person has the genetic variants that cause pEDS.

To meet the diagnostic criteria for pEDS, a person must meet:

• Major criterion 1 AND two other major criteria AND one minor criterion
  OR
• Major criterion 2 AND two other major criteria AND one minor criterion

Major Criteria

1. Severe and intractable periodontitis of early onset (childhood or adolescence)
2. Lack of attached gingiva
3. Pretibial plaques
4. Family history of a first-degree relative who meets the clinical diagnostic criteria for pEDS

Minor Criteria

1. Easy bruising
2. Joint hypermobility, mostly distal joints
3. Skin hyperextensibility and fragility, abnormal scarring (wide or atrophic)
4. Increased rate of infections
5. Hernias
6. Marfanoid facial features
7. Acrogeria
8. Prominent vasculature

If a person meets the diagnostic criteria for spEDS, genetic testing should be done to confirm the diagnosis. Genetic testing is used to see if a person has the genetic variants that cause spEDS.

To meet the diagnostic criteria for spEDS, a person must meet major criterion 1 AND major criterion 2 AND have characteristic radiographic abnormalities AND at least two other minor criteria (general or gene-specific).

Major Criteria

1. Short stature (progressive in childhood)
2. Muscle hypotonia (ranging from severe congenital to mild later onset)
3. Bowing of limbs

Minor Criteria

1. Skin hyperextensibility, soft, doughy skin, thin, translucent skin
2. Pes planus
3. Delayed motor development
4. Osteopenia
5. Delayed cognitive development

Gene-Specific Minor Criteria

B4GALT7

1. Radioulnar synostosis
2. Bilateral elbow contractures or limited elbow movement
3. Generalized joint hypermobility
4. Single transverse palmar crease
5. Characteristic craniofacial features
6. Characteristic radiographic findings
7. Severe hypermetropia
8. Clouded cornea

B3GALT6

1. Kyphoscoliosis (congenital or early onset, progressive)
2. Joint hypermobility (generalized or restricted to distal joints, with joint dislocations)
3. Joint contractures (congenital or progressive, especially hands)
4. Peculiar fingers (slender, tapered, arachnodactyly, spatulate, with broad distal phalanges)
5. Talipes equinovarus
6. Characteristic craniofacial features
7. Tooth discoloration, dysplastic teeth
8. Characteristic radiographic findings
9. Osteoporosis with multiple spontaneous fractures
10. Ascending aortic aneurysm
11. Lung hypoplasia, restrictive lung disease

SLC39A13

1. Protuberant eyes with bluish sclerae
2. Hands with finely wrinkled palms
3. Atrophy of the thenar muscles and tapering fingers
4. Hypermobility of distal joints
5. Characteristic radiologic findings