A 17-year-old (y/o) woman presented with progressive pain in her bilateral hips. The patient was a wheelchair user and was previously diagnosed with developmental dysplasia of the hip (DDH), seeking hip replacement surgery. Additionally, she had shallow acetabuli and flattened femoral heads (Figure 2). Radiology noticed spondyloepiphyseal dysplasia, suggestive of a genetic cause. The urinary sample was collected for the GAG level test, and a blood sample was collected for genotyping via whole-exome sequencing (WES).
WES discovered compound heterozygous variants of GALNS (NM_000512.5). Together with clinical manifestations, radiographic and laboratory tests, MPS IVA was diagnosed. The patient received bilateral total hip arthroplasties (THAs) sequentially and regained mobility. The patient is now under supportive therapy elsewhere. Femoral heads were preserved after surgeries. In this case, we will review the epiphyseal parameters via micro-CT (muCT) and histology analysis in the MPS IVA femoral heads with the patient/guardian's consent.
We studied a 17 y/o woman with a 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. At admittance, the patient was 145 cm tall with normal intelligence. 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).
WES was performed due to the radiographic findings of systemic skeletal anomalies which suggested a genetic cause. 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).
To confirm the phase of variants, WES was performed on the patient's parents and maternal grandmother who are free of the clinical phenotype. Parental testing confirmed that variants are in trans (Figure 3A). Sanger sequencing confirmed the occurrence of the compound heterozygous GALNS variants in the patient.
The first morning void urine was collected from the patient, mother, and maternal grandmother. The urinary excretion of GAG (uGAG) was measured by the Dimethylmethylene Blue (DMMB) method and was normalized with urinary creatinine. 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).
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).
Sections of the articular surface from both WBA and NWBA of the preserved femoral heads were stained with hematoxylin & eosin (H&E), Safranin O/Fast green, or Masson to evaluate the morphological change of cartilage and subchondral bone in the femoral heads of MPS IVA patient. In the WBA of the femoral head, the articular cartilage was abnormally thick and divided into two layers (Figures 4K-M). The superficial layer exhibited fibrous change, while the chondrocytes in the middle zone appeared to be hypertrophic. The disorganized chondrocytes were accompanied by clusters formation. In the deeper layer, the subchondral bone was filled with metaplastic tissue composed of irregular fibrous-like structure with no mature chondrocytes seen. 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).