ESPE Yearbook of Paediatric Endocrinology

Abstract: N Engl J Med. 2019;380(12):1150–1157. PMID: 30893535.

In brief: Homozygous deletion of the group-specific component (GC) gene that encodes for vitamin D–binding protein causes persistently low measurable 25-hydroxy Vitamin D concentrations with no clinical features of rickets or osteomalacia.

Comment: Vitamin D and its metabolites are bound to vitamin D–binding protein and are biologically inactive. Free vitamin D metabolites, which are in equilibrium with bound vitamin D metabolites, are available for cellular functions, as is the case with 1,25(OH)₂D binding the vitamin D receptor. Group-specific component (GC) gene encodes for vitamin D–binding protein and no previous study had found complete deletion or gross alterations in GC. In addition, analyses of vitamin D–binding protein and vitamin D metabolites had not identified any person in whom this protein was absent. Knockout mice lacking vitamin D–binding protein are not only viable and fertile but, when fed on a vitamin D–enriched diet, normal calcium levels and bone structure are maintained, despite having significantly lower plasma concentrations of 25(OH)D and 1,25(OH)₂D.

Here, the authors describe for the first time a patient with complete vitamin D–binding protein deficiency caused by homozygous deletion of the GC gene. They also compare the patient with her normal and heterozygous siblings. Despite a lifelong deficiency of vitamin D–binding protein, limited sun exposure, and a diet that was probably lacking sufficient vitamin D, the patient with homozygous deletion of GC did not have rickets or osteomalacia, but rather osteopenia and fragility fractures that first occurred only in her fifth decade of life. The disconnect between low plasma 25(OH)D concentration and her relatively mild bone disease highlights the controversy surrounding the use of total 25(OH)D to define vitamin D status. The patient’s clinical course and laboratory values were similar to those of mice deficient in vitamin D–binding protein. When the mice were fed a vitamin D–replete diet, they showed significant reductions in serum 25(OH)D but maintained normal calcium, phosphate, and PTH concentrations. However, when they were fed a vitamin D–deficient diet, they remained normocalcemic while developing more pronounced secondary hyperparathyroidism, hypophosphatemia, and bone histomorphometric changes than their normal littermates.

The absence of clinical manifestations of Vitamin-D binding protein deficiency parallels that of inherited thyroid hormone binding protein deficiency, due to mutations in SERPINA7, where no clinical manifestations of thyroid disease are seen.