Vosoritide, a biotechnological therapy designed to increase growth in children with achondroplasia, has introduced new pressures and bodily possibilities for families navigating this rare genetic condition. While debates around its use often centre on its efficacy as a non-surgical growth treatment for the most common form of non-lethal human dwarfism, far less attention has been paid to how the medication (re)shapes the temporal landscape of maternal decision-making, children's bodily autonomy, and community dynamics. Drawing on qualitative interviews with mothers from UK dwarfism communities, comprising both average-statured and dwarf mothers, this research locates maternal decision-making within broader regimes of health governance, biosocial communities, and concepts of 'good' mothering. Conceptually, the article foregrounds how Vosoritide functions as a future-oriented health technology and a site of anticipatory biopolitics; governing decision-making through overlapping and complex regimes of temporality, maternal responsibilisation, and biosociality. Vosoritide emerges not only as a site of biomedical possibility, but also as a biopolitical discourse, shaping how mothers of children with dwarfism (re)imagine and manage their child's body, future, and identity. In doing so, this research advances sociological scholarship by exposing the temporal and anticipatory 'logics' through which biopower operates in the governance of dwarfism.

Osteogenesis imperfecta (OI) is mostly caused by pathogenic variants in COL1A1/COL1A2; while single nucleotide variants predominate, multiexon copy number variants (CNVs) remain under-recognised contributors with incompletely defined phenotypic impacts. We investigated a fetus presenting severe skeletal dysplasia using NGS with CNV calling and MLPA, clinical and radiologic assessments, and transcript analysis of maternal fibroblasts. We also reviewed the literature and curated databases for reported multiexon COL1A2 deletions. The fetus exhibited lethal OI type II features, including progressive long bone shortening and bowing, multiple fractures, diffuse hypomineralisation, and a bell-shaped thorax. Genetic analysis revealed a heterozygous in-frame COL1A2 exons 4-17 deletion. Maternal testing identified low-level mosaicism for this large deletion alongside a germline in-frame deletion of exons 12-17. Detailed breakpoint analysis of the exon 12-17 deletion revealed a complex rearrangement characterised by the insertion of an inverted duplicated segment of exon 3 and intron 3 at the deletion junction. Despite these findings, the mother showed only joint hypermobility and a family history of osteoporosis, without overt features of OI. N-terminal in-frame COL1A2 deletions show variable expressivity, including perinatal lethality. We report a novel, complex and likely unstable genomic rearrangement which probably predisposed to a secondary, larger deletion. Integrated CNV analysis and parental studies are crucial to ensure accurate recurrence risk counselling.

The clinical hallmarks of osteogenesis imperfecta (OI), often referred to as 'brittle-bone disease', are bone fragility and skeletal deformities that are usually accompanied by extra skeletal manifestations. OI is a family of collagen I-related disorders, currently classified into 23 distinct types and 5 OI-like forms, with variable phenotypic severity ranging from mild to lethal. At the molecular level, the pathophysiology of OI is driven by alterations in collagen I structure, primarily caused by dominant mutations in collagen genes (affecting approximately 85% of patients). It can also result from dominant, recessive, or X-linked defects in proteins involved in collagen biosynthesis, extracellular matrix organization, mineralization, or bone forming cell differentiation and/or activity. This review illustrates the different OI forms from a collagen I perspective, its complex biosynthetic process is first described, followed by a classification of the OI and OI-like causative mutations grouped based on whether the resulting collagen molecule is overmodified, undermodified, or unaltered. The underlying molecular mechanisms and the consequences at cellular and extracellular levels leading to the OI phenotype are discussed. An overview is provided on how newly discovered molecular pathways altered in OI can guide the development of innovative therapies aiming at increasing bone mass and improving bone quality in OI patients.

Ciliopathies are rare genetic diseases marked by considerable phenotypic heterogeneity and overlap. Among the key mechanisms of cilium biology, its compartmentalization is achieved through gating complexes and active transport such as intraflagellar transport (IFT). Among the IFT components, IFT27 plays a role in BBSome-mediated transport of ciliary membrane proteins required for ciliary signaling. While this gene was first linked to Bardet-Biedl syndrome, we next expanded its phenotypic spectrum to a fetal lethal ciliopathy. Here, we identified a second fetal case with short ribs, polydactyly, hypodysplastic kidneys, imperforate anus, and situs inversus. Genome sequencing identified novel biallelic variants in IFT27. Functional analysis of tissues from both fetal cases revealed that all the identified variants lead to mRNA decay. Immunohistochemistry on fetal kidney sections showed that those variants are associated with altered ciliogenesis. Overall, we showed that complete loss of IFT27 function leads to a severe phenotypic spectrum overlapping with short ribs polydactyly and Pallister-Hall syndromes. In addition, our results argue for a role of IFT27 in ciliogenesis in humans.

In Europe, approximately 85-90% of individuals with Osteogenesis Imperfecta (OI) have dominant pathogenic variants in the Col1a1 or Col1a2 genes whilst for Asian, especially Indian and Chinese cohorts, this ratio is much lower. This leads to decreased or abnormal Collagen type I production. Subsequently, bone formation is strongly reduced, causing bone fragility and liability to fractures throughout life. OI is clinically heterogeneous, with the severity ranging from mild to lethal depending on the gene and the type and location of the OI-causative variant and the subsequent effect on (pro) collagen type I synthesis. However, the specific effects on the phenotype and function of osteoblasts are not fully understood. To investigate this, one of the OI murine models was used, i.e. the oim/oim (OIM) mice, which closest resembling severely deforming OI in humans. We showed that in OIM, the Col1a2 mutation results in a multifactorial inhibition of the osteogenic differentiation and maturation as well as inhibition of osteoclastogenesis. The phenotype of differentiated OIM osteoblasts also differs from that of wild type mature osteoblasts, with upregulated oxidative cell stress and autophagy pathways. The extracellular accumulation of defective type I collagen fibres contributes to activation of the TGF-β signalling pathway and activates the inflammatory pathway. These effects combine to destabilise the balance of bone turnover, increasing bone fragility. Together, these findings identify the complex mechanisms underlying OI bone fragility in the OIM model of severe OI and can potentially enable identification of clinically relevant endpoints to assess the efficacy of innovative pro-osteogenic treatment for patients with OI.