Diagnostic Challenges of a Unique Digenic Iron Overload Condition in a Slovak Patient

Background and Aims Iron overload causes symptoms, which can (if not treated) damage organs and systems of the body. We report a Slovakian female patient with chronic anemia and neuropathy due to iron overloading. Methods and Results Clinical workup included laboratory investigations, body imaging, and genetic study. Patients’ iron parameters showed a low serum iron, low iron saturation, elevated serum ferritin, several neurological symptoms, and later discovered abnormal liver function tests, low serum copper and extremely low ceruloplasmin (CP) levels. Initial direct genetic testing showed homozygous variant p.(His63Asp) in HFE and indicated hereditary hemochromatosis (HHC) type 1. The following whole genome sequencing (WGS) revealed the digenic origin of iron overload, since also compound heterozygous variants p.(Tyr890*) and p.(Leu273Pro) in CP were identified, responsible for aceruloplasminemia (ACP). However, clinical significance of p.(His63Asp) is difficult to evaluate due to its low penetrance. Since the patient was intolerant to phlebotomy, chelation therapy with deferasirox was started, which appeared to prevent her liver damage. Based on ACP diagnosis, she has been recently switched to treatment with deferiprone, which has better brain penetrance. Conclusions The presented case of unique digenic iron overload condition (simultaneous HHC and ACP) clarified by WGS, demonstrated multiple diagnostic and therapeutic challenges encountered in rare diseases. It highlights the limitations of targeted genetic testing, while stressing the diagnostic value of comprehensive genomic approaches in complex genotype–phenotype presentations, co-navigating the complicated patient’s and physician’s journey that necessitates multidisciplinary collaboration and use of non-trivial clinical and therapeutic strategies.