Vitamin D-binding protein deficiency: an underrecognized Mendelian disorder of vitamin D metabolism.

Vitamin D-binding protein (VDBP) deficiency is a recently discovered apparently benign biochemical disorder that can masquerade as treatment-resistant vitamin D deficiency and is likely underrecognized. We present the case of a child with persistently low 25OH vitamin D levels despite replacement therapy. Exome sequencing revealed a novel homozygous nonsense variant in the GC gene, leading to undetectable levels of VDBP. Interestingly, exome sequencing also revealed a homozygous loss-of-function variant in ZNF142, which likely explains the additional clinical features of recurrent febrile convulsions and global developmental delay. Our findings corroborate the two previously reported patients with autosomal recessive VDBP deficiency caused by biallelic GC variants and emphasize the importance of measuring VDBP levels in cases of apparent vitamin D deficiency that is treatment-resistant. We also urge caution in concluding "atypical" presentations without careful investigation of a potential dual molecular diagnosis.