ESPE Abstracts

Dysosteosclerosis (DOS) is a rare form of dense bone disease and, short stature, recurrent fractures, optic atrophy, cranial nerve palsy, developmental delay, flattened fingernails, skin related complications, and failure of tooth eruption are the characteristic features of the disease (MIM %224300). Irregular osteosclerosis, flattened diffusely dense vertebral bodies, sclerotic skull, radiolucent sub-metaphyseal portions of the long tubular bones with sclerotic diaphysis are radiological features of DOS [1]. Moreover, metaphyseal osteosclerosis and platyspondyly are the characteristic and important guiding findings in differentiating DOS from other types of sclerosing bone dysplasia [2]. DOS is inherited in an autosomal recessive manner and is genetically and clinically heterogeneous. Various genetic causes associated with DOS disease have been described to date (1-3). SLC29A3 (solute carrier family 29 member 3) was the first identified causative gene for DOS, followed by TNSFR11A (tumor necrosis factor receptor superfamily member 11a), TCIRG1 (T cell immune regulator 1) and CSF1R (Colony stimulating factor 1 receptor), respectively [1-6]. It is well known that RANK (receptor activator of nuclear factor kappa B, also known as TNSFR11A), RANK ligand (RANKl, also known as TNFSF11) and osteoproteogerin, members of the TNF and TNF-receptor superfamily, play a crucial role in stimulating osteoclastic formation and differentiation [7]. To date, four individuals with DOS have been reported with five different mutations in TNFRSF11A (2 missense/nonsense, 2 splice-site, 1 deletion) [1,4-6]. According to the previous hypothesis, aberrant mutant RANK proteins (missense or truncated) cause DOS, while null mutations lead to osteopetrosis, autosomal recessive 7 (OPTB7) (1,4-6). Herein, we present the fifth case of TNFRSF11A-associated DOS in a 19-month-old boy, in whom we identified a novel homozygous variation in TNFRSF11A (c.19_31del; p.[Arg7CysfsTer172]). Unlike previously reported variants [1,4-6], the variant is predicted to cause nonsense mutation-mediated mRNA decay (NMD) in all RANK isoform transcripts, which enabled us to re-consider the phenotype and genotype characteristics of the TNFRSF11A-associated DOS.