Expanding the Clinical and Mutational Spectrum of Recessive AEBP1-Related Classical-Like Ehlers-Danlos Syndrome

Abstract

Ehlers-Danlos syndrome (EDS) comprises clinically heterogeneous connective tissue disorders with diverse molecular etiologies. The 2017 International Classification for EDS recognized 13 distinct subtypes caused by pathogenic variants in 19 genes mainly encoding fibrillar collagens and collagen-modifying or processing proteins. Recently, a new EDS subtype, i.e., classical-like EDS type 2, was defined after the identification, in six patients with clinical findings reminiscent of EDS, of recessive alterations in AEBP1, which encodes the aortic carboxypeptidase–like protein associating with collagens in the extracellular matrix. Herein, we report on a 53-year-old patient, born from healthy second-cousins, who fitted the diagnostic criteria for classical EDS (cEDS) for the presence of hyperextensible skin with multiple atrophic scars, generalized joint hypermobility, and other minor criteria. Molecular analyses of cEDS genes did not identify any causal variant. Therefore, AEBP1 sequencing was performed that revealed homozygosity for the rare c.1925T>C p.(Leu642Pro) variant classified as likely pathogenetic (class 4) according to the American College of Medical Genetics and Genomics (ACMG) guidelines. The comparison of the patient’s features with those of the other patients reported up to now and the identification of the first missense variant likely associated with the condition offer future perspectives for EDS nosology and research in this field.

Multisystemic manifestations in a cohort of 75 classical Ehlers-Danlos syndrome patients: natural history and nosological perspectives

“…Our results partly support the still controversial impression that bone quality might be impaired in cEDS [74][75][76][77][78], although undoubtfully less significant compared to other EDS subtypes (e.g. spondylodysplastic, arthrochalasia, kyphoscoliotic, and classical-like type 2 EDS) [9,43,44,48,49,52,59,65,68] or skeletal dysplasia [39], and suggests a potential involvement of skeletal fragility in determining a poorer quality of life (QoL) in adult patients. Our findings emphasize a milder phenotype and disease course in cEDS compared to hEDS [50,69] and other EDS subtypes (e.g.…”

“…This case highpoints that while molecular diagnosis in patients with a full-blown phenotype is mainly confirmatory, in those with an incomplete presentation it turns out to be fundamental, since these individuals might not be diagnosed or even be misdiagnosed. Indeed, considering the clinical overlap not only between the different EDS subtypes but also with other HCTDs [1,9,28,30,32,[35][36][37][38][39][40][41][42][43][44][45][46][47][48][49], differential diagnosis is not always forthright. Differential diagnosis includes the molecularly unsolved hEDS that shares with cEDS gJHM and more than a few (muco) cutaneous signs; however, hEDS patients usually show a lower degree of scarring and skin hyperextensibility and much more striking gJHM complications [1,7,28,29,50].…”

“…TNXB deficiency [51], and the recently defined clEDS type 2 caused by biallelic variants in AEBP1 [52]. The clEDS type 1 is generally distinguishable from cEDS for the absence of atrophic scarring [28,45,[53][54][55][56][57], whereas a more severe multisystemic presentation in clEDS type 2 should assist the differential diagnosis with cEDS [43,52,[58][59][60]. The dermatosparaxis (ADAMTS2) [61], cardiac-valvular (COL1A2) [62][63][64], kyphoscoliotic (PLOD1, FKBP14) [65,66], and arthrochalasia (COL1A1, COL1A2) [67,68] EDS subtypes, also sharing with cEDS several cutaneous and articular issues, are mostly distinguishable for the presence of specific hallmarks [1,9,16].…”

Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes

“…The classical (cEDS), vascular (vEDS) and the molecularly unsolved hypermobile (hEDS) EDS forms account for more than 90% of patients. Recently, a new and very rare EDS variant has been identified that is caused by biallelic mutations in the AEBP1 gene (Table 1) [33,34,35,36].…”

Novel TNXB Variants in Two Italian Patients with Classical-Like Ehlers-Danlos Syndrome

“…The 2017 international classification identifies 13 EDS types due to deleterious variants in 19 different genes [1]. More recently, a 14th type of EDS with features overlapping classical type and due to recessive variants in the AEBP1 gene was added to this nosology [2,3]. Among them, classical, vascular, and hypermobile EDS are the most common, while the others are rarer and their frequency in the general population remains mostly unknown.…”