Evert F.S. van Velsen1, Danielle C.M. van der Kaay2, Arjan Bouman3, Frank Sleutels3, A. Rebeca Hernandez-Hernandez1, Sjoerd A.A. van den Berg4, Mark Wijnen1, M. Carola Zillikens1, Bram C.J. van der Eerden1
(1) Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
(2) Department of Pediatrics, Erasmus Medical Center, Rotterdam, The Netherlands.
(3) Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
(4) Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, The Netherlands.
Background
Vitamin D is essential for normal calcium homeostasis. Severe vitamin D deficiency is associated with rickets in children and osteomalacia/osteoporosis in adults. Vitamin D obtained from both diet and skin is hydroxylated in the liver into 25-hydroxy-vitamin D (25(OH)D), and subsequently in the kidneys into its active form 1,25-dihydroxy-vitamin D ((1,25(OH)2D)). Vitamin D binding protein (VDBP) binds vitamin D metabolites with high affinity, but around 1% of 1,25(OH)2D remains free in the circulation.
Patient Case
An 18-year old female born to consanguineous parents attended our outpatient clinic because of undetectable 25(OH)D levels (<10nmol/L) since 11 years of age despite high amounts of suppletion. She sustained a right foot fracture while playing soccer at the age of 12 years. Physical examination did not reveal signs of rickets disease. Laboratory results showed normal serum calcium, phosphate and ALP levels, with undetectable 25(OH)D (<10nmol/L), normal PTH and very low 1,25(OH)2D (18.9pmol/L; reference range: 55.2-223.2pmol/L). VDBP was undetectable. Bone mineral density on a DXA-scan was normal. Genetic testing showed a novel homozygous likely pathogenic variant in the group-specific component (GC) gene (GC): NM_000583.3(GC):c.129-1G>C, p.?, and functional testing demonstrated an (almost) complete loss of VDBP expression.
Conclusions
We demonstrated the first patient in The Netherlands, and the fourth worldwide, with hereditary VDBP deficiency caused by a novel homozygous variant in the GC gene, resulting in undetectable 25(OH)D levels, but with a normal phenotype. This observation supports the “free hormone hypothesis”.