Classical Ehlers-Danlos Syndrome

A rare inherited connective tissue disorder characterized by skin hyperextensibility, widened atrophic scars, and generalized joint hypermobility.

Epidemiology

Worldwide prevalence is estimated at 1/20,000.

Clinical description

Skin hyperextensilibity, atrophic scarring, and generalized joint hypermobility are the hallmarks of classical Ehlers-Danlos syndrome (cEDS). However, the clinical picture variably involves multiple organ systems, and clinical presentation may occur anywhere between birth and childhood. In childhood, bruising, skin fragility, and abnormal scarring are common signs. Primary muscular hypotonia may occur and, alongside hypermobility, may delay motor development. Fatigue and muscle cramps are relatively frequent. Atrophic scarring is typically extensive, although a minority are more mildly affected. The skin is smooth and doughy. Other dermatologic features are molluscoid pseudotumors, subcutaneous spheroids, piezogenic papules, and defective wound healing. Inguinal/umbilical hernia, mitral valve prolapse, anal prolapse in childhood, cervical insufficiency, rectal and uterine prolapse are other signs of tissue fragility. Joint hypermobility may lead to joint instability, subluxation, dislocation temporomandibular joint dysfunction, joint effusions, foot deformities, osteoarthritis, and pain. In addition to scars, typical facial characteristics are blepharochalasis and epicanthal folds. Pregnancy bears risk for the newborn (prematurity and breech where the infant is affected) and for the mother (extensive episiotomy, tearing of the perineal skin, and prolapse of the uterus and/or the bladder after delivery). In patients with a COL1A1 mutation, there might be an increased at risk for vascular events (spontaneous dissection or rupture of medium-sized arteries).

Etiology

The disease is typically caused by mutations in COL5A1 or COL5A2 encoding type V collagen. In rare cases, cEDS is caused by p.(Arg312Cys) mutation in COL1A1, encoding type I collagen.

Diagnostic methods

The minimal criteria suggestive of cEDS are skin hyperextensibility plus atrophic scarring together with either generalized joint hypermobility and/or at least three of the following minor criteria: easy bruising, soft/doughy skin, skin fragility, molluscoid pseudotumors, subcutaneous spheroids, hernia, epicanthal folds, complications of joint hypermobility, family history of a first degree relative who meets clinical criteria. Definitive diagnosis is reached by genetic testing that can include single-gene testing or use of a multigene panel.

Differential diagnosis

Differential diagnosis is extensive but primarily includes other EDS types (i.e., hypermobile, cardiac-valvular, classical-like type 1, classical-like type 2, spondylodysplastic, vascular, arthrocalasia, kyphoscoliotic, dermatosparaxis EDS), Loeys-Dietz syndromes, Marfan syndrome, cutis laxa, and other inherited connective tissue disorders.

Antenatal diagnosis

Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Genetic counseling

The pattern of inheritance is autosomal dominant and genetic counseling should be offered to affected families. The risk of disease transmission to offspring from an affected parent is 50%, intrafamilial phenotypic variability is observed.

Management and treatment

Treatment and management is symptomatic and preventative. Prevention includes avoidance of undue trauma and excessive stretching. Wounds should be expertly closed via sutures and patients should be known to their local plastic surgeons. A physiotherapeutic program is important in those with hypotonia and delayed motor development. Anti-inflammatory drugs may help with joint pain. Cardiac assessment including echocardiography to look for aortic root dilation and mitral valve prolapse is recommended. Emotional support and behavioral and psychological therapy may be indicated. Surveillance during pregnancy is warranted.

Prognosis

Life expectancy can be shortened due to the possibility of vessel rupture, but is otherwise not affected. Quality of life depends on the range of severity.