case_images: PMC11003653_01
case_images: Family History. The family pedigree representing six generations. Subject IV-4 died of acute myeloid leukemia. Subject V-2 died at 5 months (skin lesions/meningitis/hospitalized for 3 months). No other family member presents clinical manifestations of Classic Homocystinuria or Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome or autosomal recessive nonsyndromic deafness.
case_images: 1415-4757-GMB-47-01-e20220335-gf1.jpg
case_images: PMC11003653_01_1415-4757-GMB-47-01-e20220335-gf1.jpg
case_images: f1
case_images: He was the first-born of a related couple (the parents were third cousins), with no family history of genetic diseases (Figure 1). 
case_images: Bilateral hip and knee X- ray showing osteonecrosis of the left femur head and right prosthesis (A) and osteopenia (B).
case_images: 1415-4757-GMB-47-01-e20220335-gf2.jpg
case_images: PMC11003653_01_1415-4757-GMB-47-01-e20220335-gf2.jpg
case_images: f2
case_images: No acetabular cyst was detected (Figure 2).
case_images: Bilateral hand X- ray. Pseudocysts are seen in the styloid processes (arrows) and bilateral deformity with subluxation of proximal interphalangeal joints (arrowheads).
case_images: 1415-4757-GMB-47-01-e20220335-gf3.jpg
case_images: PMC11003653_01_1415-4757-GMB-47-01-e20220335-gf3.jpg
case_images: f3
case_images: A hand X-ray was performed at age 37 and showed periarticular osteopenia, deformity with subluxation of the bilateral proximal interphalangeal joints, bone proliferations along the bilateral ulnar radio articulations, pseudocysts in the styloid processes, and tenuous images with calcic attenuation projected laterally in the region of the triangular fibrous cartilage (Figure 3).
case_images: Genetic analyses of CBS, PRG4 and TMPRSS3 genes. A) electropherogram of patient showing the pathogenic variant NM_000071.2(CBS):c.833T>C (p.Ile278Thr) in homozygosis in CBS gene. The red arrow indicates the position of variant. Below, pathogenic variants identified through exome sequencing in CBS (B), PRG4 (C), and TMPRSS3 (D) genes.
case_images: 1415-4757-GMB-47-01-e20220335-gf4.jpg
case_images: PMC11003653_01_1415-4757-GMB-47-01-e20220335-gf4.jpg
case_images: f4
case_images: Targeted genetic analysis (Sanger sequencing of the CBS gene) confirmed a homozygous pathogenic variant in CBS NM_000071.2:c.[833T>C]:[833T>C] (p.(Ile278Thr)), which is located at exon 8, and associated with pyridoxine responsiveness (Figure 4a ). Illumina HiSeq, using the GRCh37 version of the human genome as reference). In addition to the pathogenic variant in CBS, the exome sequencing revealed a homozygous pathogenic variant in TMPRSS3 NM_001256317.1:c.[413C>A]:[413C>A] (p.(Ala138Glu)), which is located at exon 5, that has been associated with nonsyndromic autosomal recessive deafness (OMIM 605511), as well as a homozygous likely pathogenic variant in PRG4 NM_005807.6:c.[3756dup]:[3756dup] (p.(Lys1253Ter)), which is located at exon 10, related to Camptodactyly-Arthropathy-Coxa Vara-Pericarditis (CACP) Syndrome (OMIM 208250; Figure 4b  -d).