PMC10196838_01
Clinical, molecular, histological, ultrastructural, and biochemical findings of the 11th patient identified with classical-like Ehlers-Danlos syndrome type 2 (clEDS2). (A) Clinical photographs of the current patient (Patient 11). Translucent skin on the upper chest at the age of 36 years (a). At age 45, the patient exhibited hyperextensible skin (b); a small atrophic scar (black arrow) and mild keloid formation (arrowhead) (c); an umbilical hernia (d); pes planus and edematous lower legs (e); and acrogeria-like skin on the hands, with hypermobile phalangeal joints (f). (B) Sanger sequencing electropherogram of variants in the adipocyte enhancer binding protein 1 gene (AEBP1). (C) Integrative Genomics Viewer visualization of the variants. The nonsense variant c.2296G>T and the frameshift variant c.2383dup are observed in trans. (D) Light microscopic images of a biopsy skin specimen (age 36) at two magnifications: low- (x20) and higher-power (x400, inset) magnifications. Hematoxylin and eosin staining showing increased spacing and disorganization of collagen fibers (b) compared with an age- and sex-matched control (a), Masson's trichrome staining showing decreased collagen fibers (blue) (d) compared with control (c), and Elastica van Gieson staining showing collagen fibers (red) and elastic fibers (black) (f) compared with control (e). (E) Transmission electron microscopic images of the dermal collagen fibrils, showing irregular contours (flower-like appearance, red arrows) and small-sized fibrils (yellow arrows). (F) Type I and type III procollagen produced by cultured skin fibroblasts obtained from the patient and an age- and sex-matched control. (G) Schematic representation of the distribution of AEBP1 variants in 11 patients from nine families with clEDS2 illustrated on AEBP1 mRNA; "1" and "3477" indicate the first and the last nucleotide positions of the coding region of the mRNA, respectively. Domains of the aortic carboxypeptidase-like protein (ACLP) are shown at the corresponding exons. hom: homozygote; P1-P11: Patients 1-11; KPE-rich: lysine, proline and glutamic acid-rich.
fgene-14-1102101-g001.jpg
PMC10196838_01_fgene-14-1102101-g001.jpg
F1
Thin translucent skin was noted (Figure 1A-a). When the patient was referred to us at the age of 45 years, she exhibited the following characteristics: hair with a kinky texture and generalized thinning; a high palate and multiple dental caries; hyperextensible and translucent skin (Figure 1A-a, b); skin striae in the lower extremities, with atrophic scars (Figure 1A-c); soft soles; an umbilical hernia (Figure 1A-d); pes planus (Figure 1A-e); and generalized joint hypermobility (Beighton score 8/9) (Figure 1A-f). The NGS panel-based analysis revealed a non-sense variant c.2296G>T,p.(Glu766*) and a frameshift variant c.2383dup,p.(Glu795Glyfs*3) in AEBP1 (NM_001129.5), which were confirmed by Sanger sequencing (Figure 1B). The IGV revealed that the two variants were observed in trans (Figure 1C). Hematoxylin and eosin staining of a skin specimen obtained by a biopsy performed at the age of 36 years showed increased spaces between collagen fibers and disorganized orientations of these fibers in the lower and middle layer of the dermis (Figure 1D-b) compared with control (Figure 1D-a). Masson's trichrome staining revealed decreased collagen fibers (Figure 1D-d) compared with control (Figure 1D-c). Elastica van Gieson staining showed prominent elastic fibers due to the decreased numbers of collagen fibers (Figure 1D-f) compared with control (Figure 1D-e). An ultrastructural analysis using transmission electron microscopy of the skin specimen revealed the presence of collagen fibrils with irregular contours (flower-like appearance) and small size under the cross-sectional view (Figure 1E). Amounts of type I and type III procollagen were both reduced compared with an age- and sex-matched individual who served as a control (Figure 1F).