PMC9289150_01
The patient presents short stature and systemic skeletal deformities. (A) At admittance, the patient was 145 cm tall with normal intelligence with multiple skeletal deformities, including (B) elbow and (C) knee and ankle valgus, and (E) 4th metatarsal shortening. (D) Scoliosis and kyphosis were not present.
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F1
Whole-body skeletal radiographs were obtained and found mild dysostosis multiplex (Figures 1, 2). Extremity deformities involve small irregular carpal bones, the ulnar deviation of the distal portion of the radius, mild genu valgum, ankle valgus, and 4th metatarsal shortening (Figures 1, 2).
X-ray, CT of the pelvis, and cervical MRI examination. (A,B) Whole-body X-ray found multiple skeletal deformities, including vertebral wedging (pink arrows), small irregular carpal bones (red arrows), the distal portion of the radius being tilted toward the ulna (blue arrows), mild genu valgum (green arrows), and ankle valgus (orange arrows). (A,F) Pelvis X-ray and (E) CT collectively show bilateral acetabular dysplasia, and femoral heads collapse (yellow arrows). (C,D) MRI excluded cervical stenosis.
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F2
Additionally, she had shallow acetabuli and flattened femoral heads (Figure 2). Whole-body skeletal radiographs were obtained and found mild dysostosis multiplex (Figures 1, 2). Extremity deformities involve small irregular carpal bones, the ulnar deviation of the distal portion of the radius, mild genu valgum, ankle valgus, and 4th metatarsal shortening (Figures 1, 2). Cervical stenosis was excluded by MRI (Figures 2C,D).
Laboratory tests, the pedigree of the patient, and sequencing information. (A) Proband is a 17-year-old woman with a major complaint of progressive walking pain in bilateral hips which gradually disabled her from any motion of lower extremities since the clinical manifestation debuted at her age of 8. We discovered compound heterozygous variants at exon 11 (c.1156C>T; blue arrows) and exon 12 (c.1288C>G; red arrows) of the GALNS gene, respectively. The sequencing results indicate both parents are respective carriers and each donated a different heterozygous allele. (B) Urinary GAG/Creatinine (mg/mmol) was measured using samples collected from MPS IVA patient and their family members during hospital visits.
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Targeted capture high-throughput WES revealed two heterozygous variants, Exon 11 (NM_000512.5:c.1156C>T) and Exon 12 (NM_000512.5:c.1288C>G) of the GALNS gene, respectively, in this patient (Figure 3A). Parental testing confirmed that variants are in trans (Figure 3A). The uGAG content was significantly higher in the patient's urine when normalized to urine creatinine, while the patient's family members exhibited normal levels (Figure 3B).
Micro-computed tomography and histology analysis of femoral heads from a 17-year-old woman with MPS IVA (Patient). (A,B) Femoral heads were collected from a 17-year-old woman with MPS IVA, showing saddle-shaped and collapsed articular surface. (C) Areas of articular cartilage from the weight-bearing area (WBA, blue square) and non-weight-bearing area (NWBA, red square) were collected for histology staining. (D-F) Areas of subchondral bone from WBA (blue square) and NWBA (red square) were collected for muCT scans. (G) Bone volume fraction (BV/TV,%), (H) trabecular number (Tb.N, mm-1), (I) trabecular thickness (Tb.Th, mm), and (J) trabecular separation (Tb.Sp, mm) of subchondral bone from WBA and NWBA were calculated using CTAn software, respectively. (K-P) Sections from WBA and NWBA were stained with H&E staining, Safranin O and Masson. "*" represents P-value < 0.05.
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F4
Bilateral femoral heads were preserved after THAs for muCT analysis (Figures 4A-F). Percentage bone volume (BV/TV, P = 0.005) and trabecular thickness (Tb.Th, P < 0.001) were significantly lower in the non-weight-bearing area (NWBA) when compared to the weight-bearing area (WBA), while the trabecular number and separation were indistinguishable (Figures 4G-J). IVA patient. In the WBA of the femoral head, the articular cartilage was abnormally thick and divided into two layers (Figures 4K-M). Both layers of WBA were strongly stained by Safranin-O, indicating GAG accumulation (Figures 4L,O). In the NWBA, the thickness of the articular chondrocytes appeared near-normal and chondrocytes cluster formation was found throughout the cartilage layer, while the subchondral bone in the NWBA was discontinuous (Figures 4N-P).