Congenital Defects in a Patient Carrying a Novel Homozygous AEBP1 Variant: Further Expansion of the Phenotypic Spectrum of Ehlers–Danlos Syndrome Classical-like Type 2?

Abstract

In 2018, a new clinical subtype, caused by biallelic variants in the AEBP1 gene, encoding the ACLP protein, was added to the current nosological classification of the Ehlers–Danlos Syndromes (EDS). This new phenotype, provisionally termed EDS classical-like type 2 (clEDS2), has not yet been fully characterized, as only nine cases have been reported to date. Here we describe a patient, homozygous for a novel AEBP1 pathogenic variant (NM_001129.5 c.2123_2124delTG (p.Val708AlafsTer5)), whose phenotype is reminiscent of classical EDS but also includes previously unreported multiple congenital malformations. Furthermore, we briefly summarize the current principal clinical manifestations of clEDS2 and the molecular evidence surrounding the role of AEBP1 in the context of extracellular matrix homeostasis and connective tissue development. Although a different coexisting etiology for the multiple congenital malformations of our patient cannot be formally excluded, the emerging role of ACLP in TGF-β and WNT pathways may explain their occurrence and the phenotypical variability of clEDS2.

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).…”

“…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].…”

Ehlers-Danlos syndrome: From bedside to bench

“…identified biallelic variants in the adipocyte enhancer binding protein 1 (AEBP1) gene in patients displaying EDS-like features that were considered to represent a new subtype of EDS and were tentatively named classical-like type 2 (clEDS2; MIM #618000) . To date, 10 patients from eight families have been described (Alazami et al, 2016;Hebebrand et al, 2019;Syx et al, 2019;Maddirevula et al, 2020;Vishwanath et al, 2020;Di Giosaffatte et al, 2022).…”

The Language of Pain in the Hypermobile Ehlers-Danlos Syndrome: Metaphors as a Key to Understand the Experience of Pain and a Rehabilitation Tool

“…Ehlers-Danlos syndromes (EDS) are a heterogeneous group of rare hereditary disorders of connective tissue (HCTDs), with common features including joint hypermobility, skin hyperextensibility, and tissue fragility [1]. The most recent clinical classification, introduced in 2017, and subsequent updates, now recognize 14 different subtypes of EDS [1][2][3][4]. The hypermobile type (hEDS) is generally considered to be the most frequent in the general population, followed by the classical (cEDS) and vascular (vEDS) types, while others appear mostly ultrarare.…”