Poster Presentation 33rd ASM of the Australian & New Zealand Bone & Mineral Society 2023

Three cases of vitamin D deficient osteomalacia probably associated with mild dysfunctional variants in the causative genes for vitamin D-dependent rickets (#227)

Soichiro Kimura 1 2 , Takashi Sunouchi 1 2 , Yoshitomo Hoshino 1 2 , Naoko Hidaka 1 2 , Hajime Kato 1 2 , Taku Saito 2 3 , Nobuaki Ito 1 2
  1. Division of Nephrology and Endocrinology, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
  2. Osteoporosis Center, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan
  3. Department of Orthopedic Surgery and Spinal Surgery, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan

【Objective】

Although severe vitamin D deficiency is considered to cause rickets and osteomalacia, these cases are extremely rare in the clinical setting. In the present study, whole genome sequencing (WGS) was performed in 3 patients with osteomalacia with severe dietary restriction and scarce sun exposure in adulthood, to explore the involvement of mild dysfunction in causative genes for vitamin D-dependent rickets (VDDR).

【Case1】

At age 25, she started strict diet therapy and UV protection for her dermatitis and 11 years later, general bone pain developed. Low serum Pi, Ca, 25OHD, and 1,25OH2D, high BAP and iPTH were observed. Bone scintigraphy revealed pseudofractures in the rib. WGS identified a heterozygous CYP3A4  variant (c.554C>G; p.Thr185Ser). After cholecalciferol supplementation, blood Pi, Ca, BAP, and iPTH were normalized and pseudofractures disappeared.

【Case2】

A 24-year-old woman with eating disorder noticed stiffness and numbness in the fingers. Low Ca, 25OHD, and relatively low 1,25OH2D, high ALP and iPTH were identified. WGS disclosed a homozygous CYP3A4 intronic variant (c.218+544 del(CA)4). Low Ca and high ALP were improved by cholecalciferol supplementation.

【Case3】

She has avoided meat and milk from childhood, then, pain in the hip and knee appeared after adulthood. Low Ca, 25OHD, and high 1,25OH2D, ALP, and iPTH were presented. Bone scintigraphy revealed multiple pseudofractures. Some homozygous VDR large intronic variants were detected. Cholecalciferol supplementation resulted in normalization of Ca, ALP, and iPTH.

【Discussion】

Although functional analysis was not conducted, yet, the involvement of mild CYP3A4 gain-of-function and VDR loss-of-function variants were suspected in 3 cases of vitamin D deficient osteomalacia. With these results, we hypothesize that the majority of patients with vitamin D deficient osteomalacia might harbor mild pathogenic variants in the causative genes for VDDR.