Concurrent CobalaminC and plasminogen deficiencies in a patient with chronic thrombotic microangiopathy.

BACKGROUND: Although most patients with atypical hemolytic uremic syndrome (aHUS) are related to variants in alternative complement pathway genes, rare variants in non-complement-related genes, including DGKE, INF2, MMACHC, PLG, and THBD, have also been described.

CASE PRESENTATION: We report an 18-year-old male patient with renal biopsy-proven chronic thrombotic microangiopathy that raised a suspicion of aHUS. Whole exome sequencing revealed a novel pathogenic homozygous MMACHC c.484G>T (p.Gly162Trp) variant. Subsequently, clinical and laboratory findings confirmed Cobalamin C (Cbl C) deficiency. Additionally, a homozygous missense c.1112C>T PLG (p.Thr371Ile) variant, which was reported as a variant of unknown significance, was detected. However, the low serum plasminogen (PLG) activity proved the pathogenicity of c.1112C>T. Hence, the patient was diagnosed with concurrent Cbl C and PLG deficiencies. Segregation analysis revealed that the mother and father had the same heterozygous PLG and MMACHC variants. PLG variants have generally been described in aHUS patients concomitant with complement gene variants in the literature; therefore, the association between aHUS and PLG variants is controversial. The possible contribution of PLG deficiency to thrombotic microangiopathy was also discussed in this case.

CONCLUSION: Non-complement-mediated aHUS is an exceptional disorder. A limited number of genes are involved in this entity. To our knowledge, this is the first aHUS patient diagnosed with both Cbl C and PLG deficiencies in the literature.