Mutation of TCIRG1 gene may arise from deletion or gene splicing defects, leading to frame-shifts of the nucleotides of the gene.TCIRG1 mutations illustrate the heterogeneity of DSS through a case study where DSS occurred due to a frameshift mutation, in conjunction with a mutation at an intron located in the gene in one of the alleles of chromosome 11 resulting in a splice site mutation. Despite a frameshift mutation altering the C-terminal of the proton pump, due to increased remnant expression of the wild type transcript, it only resulted in intermediate autosomal recessive DSS due to the partial retainment of vacuolar proton pump function. TNFRSF11A mutation
The TNFRSF11A gene is present in chromosome locus 18q21.33, which encodes for the receptor activator of NF-κB (RANK). RANK is expressed in immature osteoclasts, which facilitates osteoclasts maturation upon binding of RANK ligand (RANKL). Binding of RANK ligand mediates the RANK/RANKL/OPG signalling pathway. The pathway mediates osteoclast differentiation and activation by promoting differentiation of precursors into multinucleated osteoclasts, and activating osteoclasts, thereby contributing to bone resorption and remodelling. Health conditions related to genetic changes in TNFRSF11A includes osteopetrosis, osteolysis, and Pagets disease of bone.Multiple reports of gene mutations exists underlining the mutation of the exons and introns leading to aberrant splicing. There are five variants to the TNFRSF11A gene which produces five unique protein iso-forms. The effects of alternative splicing on each variants are unclear. However, it is suggested that such changes lead to different expression patterns of the gene in both space and time.
Other spinal abnormalities associated with DSS include widened intervertebral disks, small, dense vertebral bodies, irregular vertebral endplates, hypoplastic vertebral bodies, and pronounced vertebral anterior notches.More than 80% of patients also reported abnormalities of the skull. Common symptoms include craniofacial hyperostosis, which is the excessive growth of bone in the skull and face. Skull base sclerosis, periorbital sclerosis, hypoplastic mandibular condyle, and absent paranasal or frontal sinuses are present in rare cases.It is also reported that individuals may also have pelvic abnormalities. This includes the development of narrow iliac wings, as well as widened femoral necks. However, incidence of both symptoms are rare in patients with DSS, occurring in less than 30% of cases.The occurrence of DSS also leads to deformities of the limbs. 80% of patients reported with abnormalities of the metaphysis such as metaphyseal flaring, radiolucent metaphyses, abnormal metaphyseal trabeculation, which is abnormal trabecula patterns in the metaphyseal region, and epimetaphyseal sclerosis. Other limbic abnormalities include progressive bowing of long bones, which is present in rare cases. Physical abnormalities
In general, patients appear to be short statured. In addition, as a result of sclerosis of the frontal and parietal region of the calvarium, macrocephaly and square shaped heads are reported in more than 80% of patients.Abnormal skin conditions of red-violet macular mottled skins over the entire body are occasionally observed in patients. However it is unclear whether this clinical feature is relevant to diagnosis of DSS. Neurological abnormalities
Visual problems are often found in people with DSS.