Classical-like Ehlers-Danlos Syndrome, Type 2 · clEDS2

Description

Classical-like Ehlers-Danlos Syndrome Type 2 (clEDS2) is an autosomal recessive connective tissue disorder caused by biallelic loss-of-function variants in AEBP1, the gene encoding aortic carboxypeptidase-like protein. AEBP1 participates in collagen fibril assembly through interaction with type I and type III collagen, and complete loss disrupts dermal and vascular matrix integrity. The disorder was first reported by Blackburn and colleagues in the American Journal of Human Genetics in 2018, who described two unrelated families with skin hyperextensibility, generalized joint hypermobility, and atrophic scarring resembling classical EDS, plus features outside the cEDS phenotype.

The 2017 international EDS classification published by Malfait and colleagues in the American Journal of Medical Genetics Part C predates the AEBP1 discovery, so clEDS2 sits alongside the formally named subtypes as a recognized entity rather than a numbered category in that document. Clinical features that distinguish it from cEDS include early-onset osteoporosis, dental abnormalities including delayed eruption and tooth loss, foot deformities, inguinal and umbilical hernias, and reported vascular complications. Superior mesenteric artery rupture has been documented in the published cohort, and aneurysms at other arterial sites have appeared in subsequent case reports. Approximately 15 families had been described in the medical literature as of 2023, making clEDS2 ultra-rare even within the EDS taxonomy.

Diagnosis is genetic. The 2017 framework lists major clinical features for cEDS-like presentation, including skin hyperextensibility with atrophic scarring and generalized joint hypermobility, alongside minor features such as easy bruising, soft doughy skin, skin fragility, and molluscoid pseudotumors. When the clinical picture overlaps cEDS but COL5A1, COL5A2, and COL1A1 sequencing return negative, AEBP1 sequencing is the next step. Confirmatory testing is biallelic pathogenic AEBP1 variants on a multigene connective tissue panel or exome.

Treatments to date

Management is supportive and follows the same scaffold as classical EDS, with added attention to bone density and vascular surveillance given the documented expanded phenotype. There is no approved disease-modifying therapy.

Skin care focuses on wound protection. Lacerations are closed with care to avoid further dermal tearing, and adhesive removal uses gentle technique. Joint protection through physical therapy supports stability without forcing the hypermobile joint through extreme range. Orthotics address foot deformity when present.

Bone density screening with DXA is recommended given the early osteoporosis seen in the reported cohort, with calcium and vitamin D repletion as first-line measures and bisphosphonates considered when fracture risk warrants. Dental care follows the elevated risk of periodontal disease and early tooth loss in the published families.

Vascular surveillance has emerged as a priority since the original Blackburn report described superior mesenteric artery rupture and subsequent series have added other arterial events. Baseline imaging of the thoracic and abdominal aorta and visceral arteries through MR angiography or CT angiography is reasonable at diagnosis, with surveillance intervals tailored to findings. Acute abdominal or chest pain warrants prompt vascular imaging given the described complication profile. Pregnancy management draws on connective tissue disorder protocols, with multidisciplinary planning given the limited natural-history data.

No clinical trials specific to clEDS2 are active. The cohort size has not yet supported registry-scale outcome research, and most published evidence remains at the case-series level.