Classical EDS, the original

In 1901, Edvard Ehlers, a Danish dermatologist, presented a young man with hyperextensible skin, joint laxity, and a tendency to bruise after minor injury. In 1908, Henri-Alexandre Danlos, a French dermatologist, presented a similar case and observed that the skin findings were the diagnostic anchor. The condition the two of them described is what is now called classical Ehlers-Danlos syndrome. Six other subtypes had been identified by 2017 and another in 2018, but cEDS is the form that gave the family of disorders its name.

The molecular biology

Classical EDS is autosomal dominant. The vast majority of cases are caused by heterozygous variants in COL5A1 or COL5A2, the genes encoding the alpha-1 and alpha-2 chains of type V collagen. A small number of cases are caused by a specific variant in COL1A1, c.934C>T (p.Arg312Cys), which produces an arginine-to-cysteine substitution in the alpha-1 chain of type I collagen. The COL1A1 mutation produces a vascular phenotype that overlaps with vEDS, and recognition of this variant in the cEDS differential is a recurring clinical question.

Type V collagen is a regulatory collagen. It does not bear the load that type I collagen bears, but it determines how type I collagen fibrils assemble. When type V collagen is reduced or abnormal, type I collagen fibrils become disorganized: larger in diameter, irregular in cross-section, with the distinctive "cauliflower" pattern visible on electron microscopy of skin biopsy. The skin, which depends on tightly organized type I collagen for tensile strength, behaves like a fabric whose threads are uneven. It stretches further than expected, tears more easily, and heals into wider scars.

Clinical features

The defining triad of cEDS is dramatically hyperextensible skin, atrophic scarring, and generalized joint hypermobility. The skin can typically be pulled away from the body by several centimeters and snaps back. Bruising is easy and dramatic, and unexplained bruises in children with cEDS have led to investigations for child abuse before the underlying condition was recognized. Wounds heal with characteristic atrophic scars that are wide, thin, and shiny, often described as cigarette-paper scars. The forehead, knees, shins, and elbows accumulate these scars from minor childhood trauma.

Joint hypermobility is generalized and present from infancy. Hip subluxations, recurrent ankle sprains, and other joint instability are common in childhood. Adults with cEDS typically have a large Beighton score, although hypermobility decreases somewhat with age.

Other features include molluscoid pseudotumors over pressure points, subcutaneous spheroids (small, hard, mobile nodules), hernia, and pelvic floor prolapse. The vascular complication rate is much lower than in vEDS but is non-zero. People with the COL1A1 c.934C>T variant carry a vascular risk closer to that of vEDS and warrant arterial surveillance.

Diagnosis

The 2017 international classification specifies major and minor criteria. Major criteria include skin hyperextensibility plus atrophic scarring, and generalized joint hypermobility. Minor criteria include easy bruising, soft and doughy skin, fragile skin, molluscoid pseudotumors, subcutaneous spheroids, hernia, epicanthal folds, and a positive family history. Genetic testing identifies a pathogenic variant in approximately 90 percent of clinically diagnosed cases.

Reported live-birth incidence is roughly 1 in 10,000 to 1 in 20,000. cEDS is the second most commonly diagnosed EDS subtype, after hypermobile EDS.

What management looks like

There is no FDA-approved disease-specific drug therapy for classical EDS. Standard of care is protective. Skin care emphasizes avoidance of trauma, careful wound closure with prolonged suturing and extended splinting after injury, and patience with healing. Wide and deep wound closure with subcuticular sutures, plus extended splinting of joints over the wound, reduces the size of the eventual scar in many cases. Topical wound care products that minimize tension on the healing skin are part of routine practice.

Joint management mirrors hypermobile EDS: physical therapy focused on muscle strengthening for joint stability, bracing for unstable joints when needed, activity modification, and management of chronic pain when present. Cardiac surveillance with periodic echocardiography is reasonable because aortic dilation and mitral valve prolapse occur at modestly elevated rates. People with the COL1A1 c.934C>T variant receive vEDS-style arterial surveillance.

Pregnancy in cEDS is generally well-tolerated relative to vEDS. Premature rupture of membranes, rapid labor, and perineal tearing are reported at elevated rates, and pelvic floor prolapse risk increases over time. Genetic counseling addresses the 50 percent transmission risk to children.

What this looks like for a family

A child with classical EDS comes home from preschool with a forehead laceration from a fall on a playground rug. The skin pulls open further than the parents expect for the size of the impact. The pediatrician closes the wound with a thoughtful subcuticular technique, splints across the eyebrow, and asks the family to come back in three weeks. The eventual scar is wide and silvery and visible. The next time, when the same kind of fall happens, the family is prepared. They know what wound closure they want, which dressings to ask for, how long to limit running and jumping, and what the result will look like.

That is what classical EDS care looks like, in practice. Knowing what is going to happen, asking for the closure that minimizes the scar, and accepting that the skin will keep doing what it is going to do.