Genetics

Ehlers-Danlos Syndrome: Key Points for Clinicians

SUMMARY:

The Ehlers-Danlos Syndromes (EDS) are a group of connective tissue disorders characterized by joint hypermobility. There are 13 defined subtypes of EDS, which are often able to be distinguished clinically based on key clinical features. Genetic testing can be useful to distinguish certain subtypes when clinical features and family history are nonspecific. Most diagnoses of EDS are based on strict clinical diagnostic criteria, which help to distinguish EDS from the many other disorders that include joint hypermobility. There are special considerations for the care of pregnant women with EDS, depending on their specific diagnosis and medical history.

EDS Subtypes and Main Clinical Features

Classical EDS (cEDS, formerly types I and II)
- Skin laxity and fragility
- Joint hypermobility and frequent dislocations
- Tissue fragility can lead to hernias and recurrent rectal prolapse in childhood
- Wide, atrophic scarring (papyraceous and/or hemosideric scars)
Hypermobility EDS (hEDS, formerly type III)
- Generalized joint hypermobility, determined by Beighton scoring
- Recurrent joint dislocations and subluxations
- Mild aortic root dilation usually remains stable without risk of dissection
- Lack of skin fragility seen in other types of EDS
- Chronic pain, psychosocial disturbance, and sleep disorders are common
- Diagnoses requires exclusion of other heritable connective tissue and neuromuscular disorders
Vascular EDS (vEDS, formerly type IV)
- Joint hypermobility
- Thin, translucent skin with easy bruising, visible veins, and acrogeria
- Risk for arterial rupture, spontaneous colon perforation, and other organ rupture
- Tendon or muscle rupture
Additional rare types of EDS have distinguishing features such as kyphoscoliosis, myopathy, dental anomalies, joint contractures, or eye abnormalities, which can often guide a diagnosis

Genetics

The majority of EDS cases are autosomal dominant, including cEDS and vEDS
- The etiology of hEDS remains unknown, there is likely significant genetic heterogeneity
Many families with hEDS exhibit autosomal dominant inheritance
Many rare forms of EDS are autosomal recessive
Genetic testing with an NGS-based panel of relevant genes is often useful, to include testing for various EDS subtypes and other heritable disorders of connective tissue with overlapping clinical features (eg. Marfan syndrome, familial thoracic aortic dissection)

Pregnancy and EDS

General considerations
- Referral to maternal fetal medicine for management of pregnancy-related risks
- May require planned cesarean delivery
- Use of longer acting suture material for wound repairs given tissue fragility, scarring, and delayed wound healing
Vascular EDS
- Complications occur in up to half of pregnancies in women with vEDS
- Premature rupture of membranes | Severe perineal tears | Uterine rupture | antepartum and postpartum hemorrhage | Aterial rupture
- Mortality rate in pregnant women with vEDS is 5%
Classical EDS
- May experience cervical insufficiency during pregnancy due to tissue fragility
- Affected mothers have a higher risk of premature rupture of membranes and prematurity
Hypermobile EDS
- Rapid labor and delivery occur in about 1/3 of women with hEDS
- Pregnant women with known aortic root dilation should have an echocardiogram in each trimester
- No evidence to support prophylactic cervical cerclage
Counsel about recurrence risk to offspring
- Most cases of EDS are autosomal dominant, risk is 50% for each offspring
- There are no fetal ultrasound findings related to EDS
- Prenatal diagnosis is available if a causative variant has been identified in the family | Genetic counseling is recommended

NOTE: Because medical interventions can prevent severe morbidity and mortality, vascular EDS is on the ACMG list of secondary findings. The ACMG document on reportable incidental secondary findings makes the following recommendations:

In the course of genetic testing for research or clinical care, the laboratory may identify variants in genes unrelated to the initial indication for testing, but nevertheless may have important health implications
Results of secondary findings should be communicated to the individuals who may benefit from this knowledge
An individual can ‘opt out’ of receiving secondary findings

KEY POINTS:

The various subtypes of EDS each have their own detailed clinical diagnostic criteria (see ‘Learn More – Primary Sources’ below)
- Not all cases of joint hypermobility will meet diagnostic criteria for EDS
- Given the range and type of conditions associated with joint hypermobility, a clinical genetics consultation is indicated
- Genetic testing may be useful to distinguish between subtypes, given overlapping common clinical features
Risks for pregnant patients vary depending on the EDS subtype
Congenital hip and shoulder dislocation may occur in affected neonates