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.

Keywords: ACLP; AEBP1; Ehlers–Danlos Syndrome; Poland anomaly; TGF-β pathway; amniotic band sequence; clEDS2; cleft palate; multiple congenital anomalies.

Figure 1

General examination of the patient. (A) mild facial dysmorphism (down-slanting palpebral fissures, epicanthus, deep set eyes, malar hypoplasia; (B) webbed neck, scoliosis; (C) thoracic asymmetry due to unilateral hypoplasia of right pectoralis major muscle; (D) lower limbs dysmetria.

Figure 2

Extremities and joints assessment: (A,B), progeroid aspect of the hands with apparently short “stubby” fingers; (C,D) right foot with hammer toes; left foot with aplasia/hypoplasia of phalanges; (E,F) joint hypermobility of the V and I finger. Beighton score was 7/9, including distal hypermobility. (H): radiogram of the hands; (I): radiogram of the feet.

Figure 3

Skin examination: (A,B) atrophic and hemosiderotic scars of the knee and elbow, the latter also showing small molluscoid pseudotumors and skin wrinkling/acquired cutis laxa.; (C) marked skin hyperextensibility; (D) hyperlinear palm with pits, callosities, and apparently aberrant keratinization.

Figure 4

Electropherograms of the homozygous patient and his heterozygous parents.