AHUS in children: A severe disease with increasingly better diagnostic and treatment options

Abstract

Atypical haemolytic uraemic syndrome (aHUS) accounts for around 10% of children presenting with haemolytic uremic syndrome, a triad of thrombocytopenia, haemolytic anaemia and renal failure. As opposed to diarrhoeal causes usually associated with E. coli infection producing the toxin STEC, aHUS generally presents without diarrhoea and is frequently associated with defects in the complement pathway leading to over-activation of complement.The major cause of paediatric aHUS is due to defects in complement factor H, a regulatory protein that limits complement activation. Mutations in CFH that are both dominant and recessive have been described. There are now over 10 other genes that have been described in aHUS with around 40% of sporadic cases of aHUS without an identified genetic cause.Clinically patients often present acutely with an infectious prodrome, and may require supportive haemodialysis and transfusion. Children occasionally have extra renal manifestations involving GI and CNS. Therapy involves plasma exchange to replace complement factors and more recently the use of C5 inhibitors that have been highly effective.In those who progress to end-stage renal failure, transplantation carries a high risk of disease recurrence and this is highest with CFH mutations.Exclusion of infectious HUS and of TTP, a similar adult disease due to defects in ADAMTS13, is important. Genetic diagnosis has been significantly aided by massively parallel sequencing that can sequence the 10 known genes in one run. Further analysis using MLPA to identify rearrangements and deletions is also increasingly of use. Genetic identification assists in risk stratification and in identifying those children who will benefit from C5 inhibitors. Atypical haemolytic uraemic syndrome (aHUS) accounts for around 10% of children presenting with haemolytic uremic syndrome, a triad of thrombocytopenia, haemolytic anaemia and renal failure. As opposed to diarrhoeal causes usually associated with E. coli infection producing the toxin STEC, aHUS generally presents without diarrhoea and is frequently associated with defects in the complement pathway leading to over-activation of complement. The major cause of paediatric aHUS is due to defects in complement factor H, a regulatory protein that limits complement activation. Mutations in CFH that are both dominant and recessive have been described. There are now over 10 other genes that have been described in aHUS with around 40% of sporadic cases of aHUS without an identified genetic cause. Clinically patients often present acutely with an infectious prodrome, and may require supportive haemodialysis and transfusion. Children occasionally have extra renal manifestations involving GI and CNS. Therapy involves plasma exchange to replace complement factors and more recently the use of C5 inhibitors that have been highly effective. In those who progress to end-stage renal failure, transplantation carries a high risk of disease recurrence and this is highest with CFH mutations. Exclusion of infectious HUS and of TTP, a similar adult disease due to defects in ADAMTS13, is important. Genetic diagnosis has been significantly aided by massively parallel sequencing that can sequence the 10 known genes in one run. Further analysis using MLPA to identify rearrangements and deletions is also increasingly of use. Genetic identification assists in risk stratification and in identifying those children who will benefit from C5 inhibitors.