Study describes ‘unusual trilogy’ of aHUS, Fabry disease, heart disorder
New symptoms led doctors to diagnose two additional genetic conditions
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A teenage boy who was diagnosed in childhood with atypical hemolytic uremic syndrome (aHUS) was later found to also have Fabry disease and an inherited heart condition called hypertrophic cardiomyopathy — what researchers described as an “unusual trilogy” of rare diseases.
The two additional genetic conditions were identified only after new symptoms appeared during adolescence, including worsening kidney function and increasing thickening of the heart muscle. Additional testing, including genetic analysis, eventually confirmed both diagnoses.
Although targeted treatment was started, the boy’s kidney function continued to decline, and the thickening of his heart muscle did not improve. The researchers suggested this may reflect organ damage that had already progressed by the time treatment began, along with the combined effects of multiple genetic conditions.
Case underscores challenges of diagnosing overlapping rare diseases
“This case highlights the diagnostic challenges and complex management of patients with multiple rare disorders and a compounded genetic background,” the researchers wrote. They emphasized the importance of comprehensive genetic testing for patients with unusual symptoms or a family history of inherited disease.
The study, “An unusual trilogy: a case of comorbid aHUS, Fabry disease, and hypertrophic cardiomyopathy,” was published in Frontiers in Medicine.
aHUS occurs when part of the immune system called the complement system becomes overly active, causing tiny clots to form in small blood vessels throughout the body. This leads to the classic triad of aHUS symptoms: hemolytic anemia (when red blood cells are destroyed faster than they are produced), thrombocytopenia (low platelet levels that affect blood clotting), and acute kidney failure.
Fabry disease is a genetic disorder caused by mutations in the GLA gene, which reduce the production or function of the enzyme alpha-galactosidase A (alpha-GalA). Without enough of this enzyme, fatty substances build up inside cells and gradually damage organs such as the kidneys, heart, and nervous system, leading to a wide range of symptoms.
Hypertrophic cardiomyopathy is also a genetic disorder. It is usually caused by mutations in genes involved in heart muscle contraction, including the MYH7 gene. The condition leads to abnormal thickening of the heart muscle, which can interfere with blood flow and increase the risk of irregular heart rhythms and heart failure.
Case report details boy’s complex medical journey
In the report, researchers in China detailed “an unusual case” of a boy who was first diagnosed with aHUS in childhood and, after more than a decade of follow-up, was later found to also have Fabry disease and hypertrophic cardiomyopathy.
The boy was first hospitalized at age 7 with abdominal pain, vomiting, and widespread swelling (edema). Blood tests showed hemolytic anemia, thrombocytopenia, and acute kidney injury. Reduced levels of the complement protein C3 — a sign that the complement system was overactive — supported a diagnosis of aHUS. Early heart imaging also showed mild thickening of the heart muscle.
Treatment with immunosuppressive corticosteroids and other supportive medications eased his symptoms, and steroids were discontinued after about a year and a half.
At age 10, however, new symptoms appeared. He developed palpitations, shortness of breath, and joint pain. Heart imaging showed thickening of the left ventricle — the heart’s main pumping chamber — along with partial obstruction of blood flow leaving the heart. Genetic testing was recommended at the time, but the family declined because of the cost.
By age 14, he began experiencing numbness in his fingers and pain in his toes accompanied by fever. Several medications were tried at local hospitals, but they had little effect.
At 17, worsening toe pain led to another hospitalization. Tests showed declining kidney function and markedly reduced alpha-GalA enzyme activity. Genetic testing confirmed a disease-causing mutation in the GLA gene inherited from his mother, establishing a diagnosis of Fabry disease.
Further testing reveals inherited heart disease
Heart imaging at that time showed more pronounced thickening of the left ventricle and significant obstruction of blood flow leaving the heart. More advanced imaging confirmed widespread thickening of the heart muscle, indicating progressive heart involvement.
Because the boy’s father had a history of hypertrophic cardiomyopathy but did not carry the Fabry-causing mutation, doctors performed broader genetic testing. This testing identified a second disease-causing mutation in the MYH7 gene that the boy inherited from his father. No known genetic mutations associated with aHUS were found.
The boy began standard therapy for Fabry disease at age 17, along with medications to manage symptoms such as nerve pain. After two years of treatment, his toe pain eased significantly. However, his kidney function continued to worsen, progressing to stage 5 chronic kidney disease — the most severe stage — which is marked by severely reduced kidney function. His heart thickening also showed no significant improvement.
The researchers suggested the limited response to therapy may reflect organ damage that had already progressed before treatment began, along with the combined effects of two separate genetic conditions affecting the heart.
“This case highlights the challenges of diagnosing and managing patients with multiple rare genetic disorders, particularly those with overlapping clinical features,” the researchers wrote.
They added that the case “emphasizes the importance of a comprehensive diagnostic workup, including genetic testing, in patients with atypical presentations or a family history suggestive of inherited diseases,” and “underscores the challenges in managing patients with concurrent rare diseases, where treatment for one condition may not address the issues caused by another independent genetic etiology [cause].”
