When two rare diseases meet: atypical hemolytic uremic syndrome and alkaptonuria in two siblings

Atypical hemolytic uremic syndrome (aHUS) is a rare complement-mediated thrombotic microangiopathy (TMA), whereas alkaptonuria (AKU) is an uncommon inherited metabolic disorder. Their coexistence has not previously been described. We report two siblings from a consanguineous family with CD46-associated aHUS and AKU to highlight an unusual diagnostic challenge and the importance of recognizing coexisting inherited diseases. Two brothers experienced recurrent episodes of TMA characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, while maintaining preserved long-term renal function despite persistent proteinuria. Genetic analysis identified a homozygous CD46 variant consistent with familial aHUS. During evaluation, recurrent black discoloration of urine, chronic back and knee pain, scleral pigmentation, and a history of black-stained diapers since infancy suggested an additional inherited disorder. Subsequent testing confirmed a homozygous pathogenic HGD variant, establishing the diagnosis of AKU. Both patients achieved hematologic remission following complement inhibition and remained free of dialysis throughout follow-up. To our knowledge, this is the first report of the coexistence of aHUS and AKU. These cases demonstrate that persistent or recurrent black discoloration of urine in patients with TMA should not be assumed to result solely from hemolysis. Careful assessment of atypical clinical features, supported by genetic testing when appropriate, may facilitate recognition of coexisting inherited disorders, particularly in consanguineous families, and improve diagnostic accuracy and long-term patient management.