Molecular and Clinical Characterization of the Hb Tübingen [β106(G8) Leu→ Gln, HBB: c.320 T>A] Associated With Congenital Methemoglobinemia in a Chinese Family.

BACKGROUND

Congenital methemoglobinemia caused by hemoglobin variants is a rare hematological disorder often misdiagnosed due to overlapping features with enzymatic defects. Hb Tübingen, a β-globin chain variant (βCD106), is characterized by increased autoxidation, heat instability, and cyanosis.

METHODS

A 7-year-old Chinese boy with cyanosis and recurrent neurological symptoms was evaluated using hemoglobin electrophoresis, HPLC, methemoglobin quantification, genetic sequencing, and brain imaging.

RESULTS

Genetic analysis identified the HBB: c.320 T>A mutation, confirmed by Sanger sequencing. Hemoglobin electrophoresis revealed a false elevation of Hb F (52.3%) due to co-migration of Hb Tübingen with Hb F, which was validated by HPLC showing normal γ-globin levels. Methemoglobinemia was elevated to 34.4%, accompanied by hemolytic markers (elevated LDH). Brain imaging confirmed Moyamoya disease, a rare cerebrovascular disorder, suggesting potential hypoxia-driven vascular pathology. Family screening revealed autosomal dominant inheritance, with the mutation traced to the patient's mother and maternal relatives.

CONCLUSIONS

This study underscores the diagnostic challenges of Hb Tübingen, particularly its mimicry of Hb F, necessitating further molecular diagnostic approaches. The association with Moyamoya disease highlights unexplored interactions between chronic hypoxia and cerebrovascular remodeling. Our findings expand the genetic epidemiology of Hb Tübingen and emphasize integrated hematological and neurological evaluations in unexplained cyanosis.