The Braddock Lab in the Department of Pathology at Yale School of Medicine has found that a common disease of aging, which induces spinal stiffness and rigidity, is associated with haploinsufficiency of ENPP1 (heterozygous ENPP1 deficiency). The research was published in the Journal of Bone and Mineral Research on March 22, 2022, and the study was conducted by Demetrios Braddock, MD, PhD, Associate Professor of Pathology at Yale in collaboration with Dr. Nobuaki Ito in the Department of Endocrinology and Nephrology at the University of Tokyo.
The recent study noted that homozygous ENPP1 mutations are linked to autosomal recessive hypophosphatemic rickets type 2, severe ossification of the spinal ligaments, and generalized arterial calcification of infancy type 1. But there are a limited number of reports on phenotypes associated with heterozygous ENPP1 mutations.
The investigators reported a series of three probands and their families with heterozygous and compound heterozygous ENPP1 mutations. The first case was a 47-year-old male, diagnosed with early-onset osteoporosis and low-normal serum phosphate levels, which invoked suspicion for hypophosphatemic rickets. The second and third cases were 77- and 54-year-old females who presented with severe spinal ligament ossification and the presumptive diagnosis of diffuse idiopathic skeletal hyperostosis (DISH).
Our findings suggest that ENPP1 mutational status should be evaluated in patients presenting with the diagnosis of idiopathic DISH, ossification of the posterior longitudinal ligament (OPLL), and early-onset osteoporosis.
Dr. Demetrios Braddock
Upon workup, fibroblast growth factor 23 was noted to be relatively high in case 2 and serum phosphorous was low-normal in case 3, and the diagnoses of X-linked hypophosphatemic rickets and ARHR2 were considered. Genetic testing for genes related to congenital hypophosphatemic rickets was therefore performed, revealing heterozygous ENPP1 variants in cases 1 and 2, and compound heterozygous ENPP1 variants in case 3 constituting the same variants present in cases 1 and 2. Importantly, the ENPP1 variants discovered in the patients occur in Japanese patients at rates of about 30 times greater than in all other populations, suggesting that the variant may account for the greater rates of spinal dysplasia present in the Japanese population.
“Our findings suggest that ENPP1 mutational status should be evaluated in patients presenting with the diagnosis of idiopathic DISH, ossification of the posterior longitudinal ligament (OPLL), and early-onset osteoporosis,” the authors noted.