Profound vitamin D deficiency in four siblings with Imerslund‐Grasbeck syndrome with homozygous CUBN mutation

Imerslund‐Grasbeck syndrome (IGS, OMIM 261100) is a rare autosomal recessive disease characterized by vitamin B12 malabsorption resulting in megaloblastic anemia and asymptomatic proteinuria. IGS is caused by bi‐allelic mutations in either CUBN or AMN that respectively encode the cubilin and amnionless subunits of the cobalamin‐intrinsic factor receptor. We report four siblings (three boys, one girl) of non‐consanguineous parents of Jewish background, aged 10 months to 12 years, with homozygous CUBN frameshift c.2614_2615deIGA p.(Asp872LeufisTer3) mutation and typical features of IGS. The two older brothers presented in early infancy with lethargy, mouth ulcerations, eosinophilic enterocolitis, megaloblastic anemia and failure to thrive. Investigations revealed low serum cobalamin levels. Intramuscular hydroxycobalamin supplementation resulted in dramatic resolution of all symptoms including lethargy. A positive impact on their growth curve was seen. Prospective early treatment in the younger siblings prevented these manifestations. Proteinuria with proximal tubulopathy was seen in all patients, plasma protein level and renal function were normal. All children had pronounced vitamin D deficiency and required high doses of oral supplementation. Vitamin B12 treatment could be individually adjusted; requirement decreased with age. Tubulopathy showed improvement over time. Low vitamin D could be explained by cubilin being involved in reabsorption of vitamin carriers.