Expanding the Autosomal Recessive Hypophosphatemic Rickets Type I Carrier Phenotype and Adult Treatment with Burosumab.

Autosomal recessive hypophosphatemic rickets type 1 (ARHR1) is a rare, inherited cause of fibroblast growth factor 23 (FGF23)-mediated renal phosphate-wasting that results from homozygous inactivating pathogenic variants in the dentin matrix acidic phosphoprotein-1 (DMP1) gene. A variable clinical spectrum has been described in this condition, including features of rickets (in children), hyperostotic osteomalacia (in children and adults), bone pain, short stature, lower limb deformities, recurrent dental abscesses, and hearing defects. The purpose of this report is to describe the clinical evolution in an adult with a bi-allelic, loss of function pathogenic variant in DMP1 who developed an unusual feature of the condition—osteonecrosis of the jaw—as well as her clinical response to conventional therapy (phosphate supplementation and active vitamin D) followed by burosumab. In addition, we describe deep phenotyping in ARHR1 carriers from two unrelated kindreds who had normal clinical and serum biochemical profiles but lumbar spine bone mineral density (BMD) Z-scores that, while attenuated relative to fully affected family members, were considerably higher than a family member with two normal alleles. A trans-iliac bone biopsy from one of the ARHR1 carriers showed histomorphometric signs of a mild mineralization defect despite euphosphatemia, plus distinct osteocyte dysmorphology. These data expand the description of the clinical phenotype in fully affected individuals with ARHR1 and provide further evidence of a subclinical phenotype in the ARHR1 carrier state.