SAT-080 SLC29A3 Pathogenic Variant As a Causal for Dysosteosclerosis, a Poor Osteoclast Form of Osteopetrosis

Abstract Background: Dysosteosclerosis (DSS) is a rare autosomal recessive form of osteopetrosis characterized by metaphyseal osteosclerosis and platyspondyly. At the histopathological level, a paucity of osteoclasts has been described when the disease presents genetic heterogeneity. SLC29A3 encodes a nucleoside transporter, that colocalizes intracellularly on the lysosomal membrane, is essential for lysosomal function and which is expressed in osteoclasts. Clinical case: We present a female patient from a nonconsanguineous camerunense family with DSS. Her first fracture at the age of 1 year occurred in the proximal right humerus following a very mild trauma. Subsequently she was referred to our clinic at the age of 1.8 months. At the last evaluation in our clinic at the age of 5.6 years she had suffered 5 femur fractures, 2 humerus fractures and a tibia/fibula fracture. XRays shown cortical thickening and widening of the diaphysis of the long bones, cranial base sclerosis, broad ribs with sclerosis and platyspondyly. Bone marrow biopsies and bone biopsy were not performed. The subject did not have any neurological symptoms, dental anomalies or present any dermatological issues. Dual-energy X-ray absorptiometry of the individual showed a lumbar spine BMD Z-score of +8 at 20 months of age, +7.1 at 3 years 5 months, +6.4 at 4 years 6 months and +5.1 at 5 years 6 months of age. TRACP 5 B 4.7 U/L is low in concordance with an osteoclast poor osteopetrosis, and the RANKL>>2.1 ipMol/L is high. On the other hand, CTX 1.298 ng/mL is normal. We identified and confirmed the homozygous pathogenic variant p.Arg386Gln in SLC29A3 using whole exome sequencing and sanger capillary electrophoresis.Conclusion: In summary, we show that a homozygous change in exon 6 of SCL29A3 (NM_00074; c.1157G>A; pArg386Gln) results in a phenotype of Dysosteosclerosis, adding a case to the small group of patients were pathogenic variants in this gene have been described causing sclerosing bone dysplasias with hallmarks of dysosteosclerosis. Interestingly, the other DSS cases and H syndrome cases confirms the clinical heterogeneity of disorders caused by mutations in SLC29A3 and the lack of a clear genotype-phenotype correlation. Phenotypically is also interesting to show that in our patient the bone mineral density has been decreasing over the time, with the concording increasing of TRAB5b. More mutations and functional investigations are needed to get a clearer picture for SCLC29A3 and how is involve in the process of osteoclast differentiation and activity.