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

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

Date RX Calcitriol (ng/day) RX CaCO3 (mg/day) Blood Calcium (RR mg/dL) N/A Treatment History Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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): Koren R. “Vitamin D Receptor Defects: The Story of Hereditary Resistance to Vitamin D.” Pediatric Endocrinology Review Supp. 3 (2006): 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): 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): Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only