1. Case No. 07-2888 Crystal L. Johnson North Carolina State University College of Veterinary Medicine Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

2. Signalment and History Seven month old intact female Pomeranian dog Weakness and muscle tremors progressing to seizures Generalized non-pruritic alopecia Short stature, bowing of forelegs Hypocalcemia Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

3. Date RX Calcitriol (ng/day) RX CaCO3 (mg/day) Blood Calcium (RR 8.9-11.4 mg/dL) 8-17-07N/A 5.6 8-25-07150100- 9-15-072002506.0 9-20-07250 5.1 10-1-073502504.9 10-20-074003005.7 Treatment History Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

4. Normal Littermate and Patient Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

5. Radiological Findings  Smooth marginated zones of increased lucency in distal radial and ulnar physes Metaphyses and epiphyses are widened with adjacent bone sclerosis Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

6. Maxilla Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

7. Costochondral Junctions Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

8. Radius Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

9. Nasal Turbinates Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

10. Normal Physis vs. Patient Physis Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

11. Irregular Cartilage Proliferation Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

12. Reduced Zone of Hypertrophy Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

13. Increased Osteoclasts and Decreased Osteoblasts Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

14. Reduction of Trabeculae, Diaphysis Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

15. T11 Compression Fracture Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

16. Damage to Spinal Cord Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

17. Diagnosis Radius: Failure of endochondral ossification (Vitamin D-resistant rickets, Type II) Patient fibroblasts were submitted to Stanford University and diagnosis was confirmed Failure of calcitriol to induce the enzyme 25- hydroxyvitamin D 3 24-hydroxylase in fibroblasts in vitro can serve as the diagnosis for vitamin D-resistant rickets (VDRR) Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

18. Vitamin D-Resistant Rickets (VDRR) Two forms are recognized Type I is inborn error in conversion of vitamin D to its active form due to deficiency of the renal 1-hydroxylase enzyme Responds to large doses of vitamin D Type II is an end organ resistance to the active form of vitamin D Does not respond to vitamin D Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

19. Vitamin D Receptor Location Cholecalciferol (skin or ingestion)  calcidiol (liver)  calcitriol (kidney) Major target tissues for vitamin D are small intestine, bone, and kidney Secondary tissues with receptors include skin, pancreas, parathyroid gland, stomach, gonads, brain, monocytes, and activated T and B lymphocytes Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

20. Decreased number of cytosolic receptors Deficient maximal hormonal binding Deficient hormone binding affinity Normal binding but undetectable nuclear localization Abnormal DNA-binding domain for the calcitriol receptor VDRR Receptor Defects Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

21. VDRR Features and Treatment Alopecia occurs in 50% of human cases and is a marker for more severe form of disease An unexplained feature of the disease is the tendency for calcium levels to normalize and for the radiographic abnormalities to improve Large continuous parenteral doses of calcium “overcome” the receptor defect and maintain bone remodeling Treatment is cost prohibitive in veterinary medicine Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

22. Acknowledgements Dr. Keith Linder Dr. Linda Kooistra Dr. Dana Levine Dr. Stuart Hunter NCSU Histology Laboratory, especially Monica Mattmuller All my resident mates Vitamin D molecule 3dchem.com Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

23. Questions? BigWorldPhoto.com Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

24. References Tanner E, Langley-Hobbs, SJ. “Vitamin D-Dependent Rickets Type 2 with Characteristic Radiographic Changes in a 4-month- old Kitten.” Journal of Feline Medicine and Surgery 7 (2005): 307-11. Koren R. “Vitamin D Receptor Defects: The Story of Hereditary Resistance to Vitamin D.” Pediatric Endocrinology Review Supp. 3 (2006): 470-5. Malloy PJ, Xu R, Peng L, Peleg S, AL-Ashwal A, Feldman D. “Hereditary 1,25-Dihydroxyvitamin D Resistant Rickets Due to a Mutation Causing Multiple Defects in Vitamin D Receptor Function.” Endocrinology 145 (2004): 5106-14. Stacy BA, Parker JM. “Lack of the Vitamin D Receptor is Associated with Reduced Epidermal Differentiation and Hair Follicle Growth.” Journal of Investigative Dermatology 118 (2002): 11-16. Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only