An adult with cystathionine beta-synthase deficiency, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, and deafness: A case report

Abstract

Massive sequencing platforms allow the identification of complex clinical phenotypes involving more than one autosomal recessive disorder. In this study, we report on an adult patient, born to a related couple (third degree cousins), referred for genetic evaluation due to ectopia lentis, deafness and previous diagnosis of juvenile idiopathic arthritis. He was biochemically diagnosed as having Classic Homocystinuria (HCU); Sanger sequencing of the CBS gene showed the genotype NM_000071.2(CBS):c.[833T>C];[833T>C], compatible with the diagnosis of pyridoxine-responsive HCU. As he also had symptoms not usually associated with HCU, exome sequencing was performed. In addition to the variants found in the Sanger sequencing, the following variants were identified: NM_001256317.1(TMPRSS3):c.[413C>A];[413C>A]; and the NM_005807.6(PRG4):c.[3756dup]:[3756dup], confirming the diagnosis of autosomal recessive nonsyndromic deafness and Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome (CACP), respectively. Genomic analysis allowed the refinement of the diagnosis of a complex case and improvement of the patient's treatment.

Figure 1 -. 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.

Figure 2 -. Bilateral hip and knee X- ray showing osteonecrosis of the left femur head and right prosthesis (A) and osteopenia (B).

Figure 3 -. Bilateral hand X- ray. Pseudocysts are seen in the styloid processes (arrows) and bilateral deformity with subluxation of proximal interphalangeal joints (arrowheads).

Figure 4 -. 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.