Case report: further delineation of AEBP1-related Ehlers–Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature

Abstract

The Ehlers–Danlos Syndromes (EDS), a group of hereditary connective tissue disorders, were classified into 13 subtypes in the 2017 International Classification. Recently, a new subtype of EDS called classical-like EDS type 2 (clEDS2), which is caused by biallelic variants in the adipocyte enhancer binding protein 1 (AEBP1) gene, was identified. We describe the 11th patient (9th family) with clEDS2, who was complicated by a critical vascular event (superior mesenteric artery aneurysm and rupture). A next-generation sequencing panel-based analysis revealed compound heterozygous variants in AEBP1: NM_001129.5:c.[2296G>T]; [2383dup], p.[(Glu766*)]; [(Glu795Glyfs*3)]. Light microscopic analyses showed increased interfibrillar spaces in the reticular dermis, a disorganized arrangement of collagen fibers, and decreased collagen content. An electron microscopic analysis showed the presence of collagen fibrils with irregular contours (flower-like appearance) and small collagen fibrils. A biochemical analysis showed reduced secretion of type I and type III procollagen. Clinical and molecular features of the current patient and all previously reported patients were reviewed comprehensively. Manifestations noted in most cases (>80%) included skin features (hyperextensibility, atrophic scars, easy bruising, excessive skin/skin folding, delayed wound healing, translucency, piezogenic papules), skeletal features (generalized joint hypermobility, dislocations/subluxations, pes planus), dental abnormalities, and neuromuscular abnormalities. Critical complications, each occurring in a single case, included superior mesenteric artery multiple aneurysm and rupture, aortic root dilation requiring surgery, and bowel rupture. Most AEBP1 variants were predicted or experimentally confirmed to lead to nonsense-mediated mRNA decay, whereas one variant resulted in a protein that was retained intracellularly and not secreted. Clinical, molecular, pathological, and biochemical features of the current patient, as well as a review of all previously reported patients, suggest the importance of the aortic carboxypeptidase-like protein encoded by AEBP1 in collagen fibrillogenesis.

Clinical and Molecular Characterization of a Novel Homozygous Frameshift Variant in AEBP1-Related Classical-like Ehlers Danlos Syndrome Type 2 with Comparison to Previously Reported Rare Cases

“…clEDS2 appears to be rare, with only 14 previously reported individuals described in the literature [3,4,6,[8][9][10][11][12]. Including our patient, this syndrome is reported in nine females and six males, and the median age at the time of diagnosis was 35 years with a range of 12-65 years old (Table S1).…”

“…Classical-like EDS (clEDS) is a rare type of autosomal recessive EDS that is further categorized based on genetic causes: classical-like EDS type 1 (clEDS1) MIM #606408 is associated with variants in the TNXB gene [1], and classical-like EDS type 2 (clEDS2) MIM #618000 is associated with variants in the AEBP1 gene [2,3]. Although there are many overlapping clinical features between clEDS1 and Genes 2024, 15, 461 2 of 7 clEDS2, clEDS2 is reported to have additional features of atrophic scarring, early onset osteopenia, and cardiovascular features [2,4].…”

“…clEDS2 is specifically linked to the expression, localization, and function of the ACLP protein [6]. To date, 14 patients from 12 families with clEDS2 have been described [3,4,6,[8][9][10][11][12].…”

A rare case of mitral valve dysplasia and left ventricular noncompaction: surgical management and genetic investigation

“…Genetic testing was conducted, and although no variants highly associated with disease were found, three loci ( FLNC , AGL , and AEBP1 ) showed insufficient evidence to exclude possible pathogenic variants. FLNC , AGL , and AEBP1 have been linked to familial hypertrophic cardiomyopathy ( 2 ), glycogen storage disease type III ( 3 ), and classic Ehlers-Danlos syndrome type 2 ( 4 ) respectively, all of which may involve MV-related issues. Previous studies have indicated there to be a link between familial hypertrophic cardiomyopathy and MV complex abnormalities ( 5 ).…”

Barriers to the Diagnosis, Care, and Management of Pediatric Patients With Ehlers-Danlos Syndrome in the United States: A Qualitative Analysis

“…3 There are currently 13 officially recognized distinct clinical subtypes, 2,4 with a 14th subtype that has been recently described but not yet officially classified. 5 -7 Each EDS subtype is defined by major and minor criteria. Patients with EDS are prone to many co-morbidities across multiple body systems, including neurologic, 8,9 cardiovascular, 10 gastrointestinal, 11 dermatologic, 12 gynecologic, 9 and musculoskeletal issues.…”