Rare Case of Homozygosity for CYB5R3 Variant c.235C > T p.(Arg79Trp) Causing Type II Methemoglobinemia

Type II methemoglobinemia is a rare genetic condition in which deficiency of the enzyme NADH-cytochrome b5 reductase 3 encoded by the gene CYB5R3 causes neurological symptoms in addition to elevated blood methemoglobin levels. The clinical presentation of Type II methemoglobinemia extends beyond hematological symptoms and include developmental delays, intellectual disability, and severe neurological symptoms. Here we present a case of a young male of Turkish origin diagnosed with type II hereditary methemoglobinemia at age 28. The proband has congenital hearing loss and was diagnosed with infantile autism in adolescence. After several hospital admissions with dyspnea, low oxygen saturation, methemoglobin levels at 4-19%, and normal p50 of 27.0 mmHg, he was evaluated for congenital methemoglobinemia. Genetic testing using targeted next generation sequencing identified the rare pathogenic CYB5R3 c.235C > T p.(Arg79Trp) missense variant (NM_001171660.2, NP_001165131.1). Enzymatic testing of NADH-cytochrome b5 reductase 3 of the patient and the mother showed decreased activities of 0.6 U/g Hb and 6.7 U/g Hb, respectively, compared to a normal group with a mean of 12 U/g Hb (standard deviation 1.7 U/g Hb). The patient had hemoglobin levels within normal and osmotic gradient ektacytometry was performed and found normal. To our knowledge, this constitutes the first report of a CYB5R3 c.235C > T homozygous. This case report emphasizes the importance of considering rare genetic disorders in patients with unexplained neurological and auditory deficits. The patient consented to publication of this case story.