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Between 1975 and 1977, my collaborators and I conducted a whole-of-population study in Victoria, Australia, examining the various presentations and clinical manifestations of osteogenesis imperfecta (OI) and familial forms of bone fragility. In 1975, the prevailing view was that all presentations of OI reflected variable expression of pathogenic genomic variants at a single gene locus—possibly involving the recently identified protein, type I collagen. We concluded that OI was in fact genetically heterogeneous, setting the scene for future biochemical and genomic discoveries. Currently, OI is recognised to result from pathological variants in >20 genes, with variants in many further loci resulting in related forms of familial osteoporosis or special syndromes characterised by bone fragility. A dyadic nosology has been adopted to help clinicians, researchers and affected individuals in accessing OI diagnosis, treatment and research with a focus on precision medicine.

A paper published in Orphanet Journal of Rare Diseases proposes a new classification of osteogenesis imperfecta (OI) based upon underlying pathological mechanisms. The proposed numbering of OI types conflicts with the currently used numbering and is likely to lead to confusion. In addition, classification of OI according to underlying pathogenic mechanisms is not novel.

Children with osteogenesis imperfecta are often treated with intravenous bisphosphonates. We aimed to assess the safety and efficacy of risedronate, an orally administered third-generation bisphosphonate, in children with the disease. In this multicentre, randomised, parallel, double-blind, placebo-controlled trial, children aged 4–15 years with osteogenesis imperfecta and increased fracture risk were randomly assigned by telephone randomisation system in a 2:1 ratio to receive either daily risedronate (2·5 or 5 mg) or placebo for 1 year. Study treatment was masked from patients, investigators, and study centre personnel. Thereafter, all children received risedronate for 2 additional years in an open-label extension. The primary efficacy endpoint was percentage change in lumbar spine areal bone mineral density (BMD) at 1 year. The primary efficacy analysis was done by ANCOVA, with treatment, age group, and pooled centre as fixed effects, and baseline as covariate. Analyses were based on the intention-to-treat population, which included all patients who were randomly assigned and took at least one dose of assigned study treatment. The trial is registered with ClinicalTrials.gov, number NCT00106028. Of 147 patients, 97 were randomly assigned to the risedronate group and 50 to the placebo group. Three patients from the risedronate group and one from the placebo group did not receive study treatment, leaving 94 and 49 in the intention-to-treat population, respectively. The mean increase in lumbar spine areal BMD after 1 year was 16·3% in the risedronate group and 7·6% in the placebo group (difference 8·7%, 95% CI 5·7–11·7; p<0·0001). After 1 year, clinical fractures had occurred in 29 (31%) of 94 patients in the risedronate group and 24 (49%) of 49 patients in the placebo group (p=0·0446). During years 2 and 3 (open-label phase), clinical fractures were reported in 46 (53%) of 87 patients in the group that had received risedronate since the start of the study, and 32 (65%) of 49 patients in the group that had been given placebo during the first year. Adverse event profiles were otherwise similar between the two groups, including frequencies of reported upper-gastrointestinal and selected musculoskeletal adverse events. Oral risedronate increased areal BMD and reduced the risk of first and recurrent clinical fractures in children with osteogenesis imperfecta, and the drug was generally well tolerated. Risedronate should be regarded as a treatment option for children with osteogenesis imperfecta. Alliance for Better Bone Health (Warner Chilcott and Sanofi).

In 2023 following extensive consultation with key stakeholders, the expert Nosology Working Group of the International Skeletal Dysplasia Society (ISDS) published the new Dyadic Nosology for Genetic Disorders of the Skeleton. Some 770 entities were delineated associated with 552 genes. From these entities, over 40 genes resulting in distinct forms of Osteogenesis Imperfecta (OI) and Bone Fragility and/or Familial Osteoporosis were identified. To assist clinicians and lay stake holders and bring the considerable body of knowledge of the matrix biology and genomics to people with OI as well as to clinicians and scientists, a dyadic nosology has been recommended. This combines a genomic co-descriptor with a phenotypic naming based on the widely used Sillence nosology for the OI syndromes and the many other syndromes characterized in part by bone fragility.This review recapitulates and explains the evolution from the simple Congenita and Tarda subclassification of OI in the 1970 nosology, which was replaced by the Sillence types I–IV nosology which was again replaced in 2009 with 5 clinical groups, type 1 to 5. Qualitative and quantitative defects in type I collagen polypeptides were postulated to account for the genetic heterogeneity in OI for nearly 30 years, when OI type 5, a non-collagen disorder was recognized. Advances in matrix biology and genomics since that time have confirmed a surprising complexity both in transcriptional as well as post-translational mechanisms of collagens as well as in the many mechanisms of calcified tissue homeostasis and integrity.

Genetic variants causing loss of function in the synthesis of nicotinamide adenine dinucleotide were shown to cause congenital malformations that comprise the VACTERL association. Niacin supplementation during gestation prevented similar defects in mouse models.

Purpose We report aspects of sleep-disordered breathing in a cohort of achondroplastic children who attended our hospital. Methods A retrospective chart review was conducted for a 15-year period to further evaluate the diagnosis and treatment of sleep-disordered breathing in children with achondroplasia. Results A review of the medical records was undertaken for 46 children (63%, mean age 3.9 years) with achondroplasia that had overnight polysomnography. Among them, 25 (54.3%) had obstructive sleep apnea (OSA). For 19 out of 46 patients (follow-up rate, 41.3%) with a mean follow-up of 31.3 months (range, 3 month to 11 years), 13 had undergone adenotonsillectomy, while nine were treated with continuous positive airway pressure. Conclusions Prospective evaluation of our clinic population confirms a high incidence of SDB in achondroplastic children. OSA has been linked to raise intracranial pressure as well as neurocognitive deficits in children and we hypothesize that associations between neurological and respiratory abnormalities in this disorder are a consequence of the early onset of associated respiratory, rather than the neurological complications.

Infantile cortical hyperostosis (Caffey disease) is characterized by spontaneous episodes of subperiosteal new bone formation along 1 or more bones commencing within the first 5 months of life. A genome-wide screen for genetic linkage in a large family with an autosomal dominant form of Caffey disease (ADC) revealed a locus on chromosome 17q21 (LOD score, 6.78). Affected individuals and obligate carriers were heterozygous for a missense mutation (3040Ctwo head right arrowT) in exon 41 of the gene encoding the alpha1(I) chain of type I collagen (COL1A1), altering residue 836 (R836C) in the triple-helical domain of this chain. The same mutation was identified in affected members of 2 unrelated, smaller families with ADC, but not in 2 prenatal cases and not in more than 300 chromosomes from healthy individuals. Fibroblast cultures from an affected individual produced abnormal disulfide-bonded dimeric alpha1(I) chains. Dermal collagen fibrils of the same individual were larger, more variable in shape and size, and less densely packed than those in control samples. Individuals bearing the mutation, whether they had experienced an episode of cortical hyperostosis or not, had joint hyperlaxity, hyperextensible skin, and inguinal hernias resembling symptoms of a mild form of Ehlers-Danlos syndrome type III. These findings extend the spectrum of COL1A1-related diseases to include a hyperostotic disorder.

Alpha‐mannosidosis is a rare inherited metabolic disorder (OMIM #248500) caused by mutations in the enzyme α‐mannosidase encoded by the gene MAN2B1. Patients have distinct physical and developmental features, but only limited information regarding standardized cognitive functioning of patients has been published. Here we contribute intellectual ability scores (IQ) on 12 patients with alpha‐mannosidosis (ages 8‐59 years, 10 males, 2 females). In addition, a pooled analysis was performed with data collected from this investigation and 31 cases obtained from the literature, allowing a comprehensive analysis of intellectual functioning in this rare disease. The initial and pooled analyses show that patients with alpha‐mannosidosis have variable degrees of intellectual disability but show decline in IQ with age, particularly during the first decade of life. Patients treated with hematopoietic stem cell transplantation tend to show stabilized cognitive abilities.

Background In this study we aimed to identify and review publications relating to the diagnosis of joint hypermobility and instability and develop an evidence based approach to the diagnosis of children presenting with joint hypermobility and related symptoms. Methods We searched Medline for papers with an emphasis on the diagnosis of joint hypermobility, including Heritable Disorders of Connective Tissue (HDCT). Results 3330 papers were identified: 1534 pertained to instability of a particular joint; 1666 related to the diagnosis of Ehlers Danlos syndromes and 330 related to joint hypermobility. There are inconsistencies in the literature on joint hypermobility and how it relates to and overlaps with milder forms of HDCT. There is no reliable method of differentiating between Joint Hypermobility Syndrome, familial articular hypermobility and Ehlers-Danlos syndrome (hypermobile type), suggesting these three disorders may be different manifestations of the same spectrum of disorders. We describe our approach to children presenting with joint hypermobility and the published evidence and expert opinion on which this is based. Conclusion There is value in identifying both the underlying genetic cause of joint hypermobility in an individual child and those hypermobile children who have symptoms such as pain and fatigue and might benefit from multidisciplinary rehabilitation management. Every effort should be made to diagnose the underlying disorder responsible for joint hypermobility which may only become apparent over time. We recommend that the term \"Joint Hypermobility Syndrome\" is used for children with symptomatic joint hypermobility resulting from any underlying HDCT and that these children are best described using both the term Joint Hypermobility Syndrome and their HDCT diagnosis.