Clinical presentation and genetics of tricho-rhino-phalangeal syndrome (TRPS) type 1: A single-center case series of 15 patients and seven novel TRPS1 variants.

Tricho-rhino-phalangeal syndrome (TRPS) is a rare malformation syndrome characterized by distinctive facial, ectodermal, and skeletal features. TRPS is divided into TRPS type I/III caused by pathogenic variants in TRPS1 and TRPS type II caused by contiguous gene deletions also spanning EXT1 and RAD21. Due to its rarity, knowledge of the clinical course of TRPS remains limited. Therefore, we collected and characterized a case series of 15 TRPS type I patients (median age at diagnosis 15 [interquartile range: 10-18] years, 11 females [73%]) seen at Aarhus University Hospital, Denmark, with a median follow-up period of 10 years. We estimated a minimum point prevalence of 0.5 in 100,000 (95% CI: 0.3-0.8 per 100,000) persons. Common craniofacial features included fine and sparse hair with a high anterior hairline, eyebrows with lateral thinning and a thicker medial part, prominent ears, a bulbous nose tip with small nasal alae, a low-hanging, and often wide columella, and a long philtrum with a thin upper vermillion. Specific skeletal features included short stature and deviating and short fingers with cone-shaped epiphyses and shortened metacarpals on radiographs. The most significant morbidity of the cohort was joint complaints, which were reported by all patients, often already before the TRPS diagnosis was established. We identified ten different TRPS1 variants including both frameshift/nonsense, missense, and splice-site variants, including seven variants not previously reported in the literature. In accordance with previous literature, no genotype-phenotype correlation was identified. The clinical trajectories were heterogeneous involving pediatrics, dermatology, orthopedic surgery, clinical genetics, and/or odontology, emphasizing that close multidisciplinary collaboration is essential for early diagnosis of TRPS and to ensure proper and timely patient care and counseling.

A perspective on muscle phenotyping in musculoskeletal research.

Musculoskeletal research should synergistically investigate bone and muscle to inform approaches for maintaining mobility and to avoid bone fractures. The relationship between sarcopenia and osteoporosis, integrated in the term 'osteosarcopenia', is underscored by the close association shown between these two conditions in many studies, whereby one entity emerges as a predictor of the other. In a recent workshop of Working Group (WG) 2 of the EU Cooperation in Science and Technology (COST) Action 'Genomics of MusculoSkeletal traits Translational Network' (GEMSTONE) consortium (CA18139), muscle characterization was highlighted as being important, but currently under-recognized in the musculoskeletal field. Here, we summarize the opinions of the Consortium and research questions around translational and clinical musculoskeletal research, discussing muscle phenotyping in human experimental research and in two animal models: zebrafish and mouse.

Craniofacial morphology in adults with osteogenesis imperfecta-A cross-sectional study.

OBJECTIVES: The aim of this study was to compare the craniofacial and neurocranial morphology of adults with osteogenesis imperfecta (OI) with controls and to elucidate whether osseous origin impacts on morphological deviations in OI. MATERIALS AND METHODS: Fifty-four adults (mean age 45.8) with OI type I, 14 adults (mean age 42.6) with OI types III/IV and 49 adult controls (mean age 41.0) were included. All participants had European ethnicity. Cranial morphology was assessed by 2D-cephalometry. Comparison between groups was made by multiple regression analyses. RESULTS: Comparison between OI groups and controls: (1) Dimension of the maxilla and mandible, respectively was reduced (P < .01), and in relation to the posterior cranial base, the maxilla was retro-positioned (P < .001), and the mandible was prognathic (P < .001). (2) The anterior face height was reduced (P < .04), and in OI types III/IV only, the maxilla was posteriorly inclined (P < .001). (3) Anterior cranial base (P < .001) and the dimension sella-frontale (P < .02) were short. (4) The sagittal dimension of the posterior cranial fossa was increased (P < .01), and the vertical dimension was reduced (P < .01). CONCLUSIONS: Adults with OI had a hypoplastic, retro-positioned and posteriorly inclined maxilla, a hypoplastic and forward-positioned mandible, and a reduced anterior face height. Deviations were seen in morphology of the posterior cranial fossa. The impact of OI on cranial morphology was generally more evident in OI type III/IV than in OI type I. OI impacts on osseous cranial structures irrespective of bony origin being intramembranous or endochondral.

Risk of eye diseases in osteogenesis imperfecta - A nationwide, register-based cohort study.

BACKGROUND: Osteogenesis imperfecta (OI) is a hereditary disease caused by affected collagen type 1. Collagen type 1 is an important structural component of the eye. Ocular manifestations in OI are described in literature, but little is known about the risk of eye diseases in OI. OBJECTIVE: To investigate the risk of eye diseases in OI. DESIGN: A Danish nationwide register-based cohort study based on data from the Danish National Patient Register. PARTICIPANTS: All patients registered with an OI diagnosis between January 1977 and December 2018 matched 1:5 with a reference population on gender and birth month and birth year. MEASUREMENTS: Incidence rates (IR) per 1000 patient years and sub-hazard ratio (SHR) for any eye disease, corneal diseases, cataract, refraction disorders, vitreous haemorrhage, retinal detachment, retinopathy, angiopathy, retinal haemorrhage, retinal degeneration, retinal changes, optic nerve disorders, and traumatic eye lesions. RESULTS: We identified 907 OI patients (493 women) and 4535 persons (2465 women) in the reference population. The IR for any eye disease was 4.07 [95% CI 3.41-4.85] in the OI cohort and 1.96 [95% CI 1.89-2.12] in the reference cohort. The two diseases with highest incidence was cataract (2.41 [95%CI 1.93-3.03] vs 1.29 [95% CI 1.12-1.47], SHR 1.76 [95% CI 1.34-2.33]) and glaucoma (1.08 [95% CI 0.77-1.51] vs 0.42 [95% CI 0.33-0.54], SHR 2.33 [95% CI 1.55-3.53]). The absolute risk of most other eye diseases was low, but the SHR indicated a higher risk in the OI cohort compared to the reference group showing statistically increased risk of refractive disorders, vitreous haemorrhage, retinal detachment or ruptures, other retinal diseases (i.e., retinopathy, angiopathy, retinal haemorrhage, degeneration, retinal changes), and optic nerve disorders. Corneal diseases and traumatic eye lesions were not statistically significantly increased in OI-patients. CONCLUSION: Patients with OI have a higher risk of cataract, refractive disorders, glaucoma, vitreous haemorrhages, retinal detachment/ruptures, retinal diseases, and optic nerve disorders.

Osteoarthritis in osteogenesis imperfecta: A nationwide register-based cohort study.

BACKGROUND: Osteogenesis Imperfecta (OI) is a genetic disease characterized by skeletal fragility. Collagen type 1 is found in many tissues and collagen abnormalities may result in organ specific symptomatology. Musculoskeletal pain is a known issue for patients with OI, osteoarthritis (OA) can be a likely cause. Only few studies have investigated the relationship between OI and OA but demonstrated a greater propensity in OI patients to develop rapidly progressing OA. Therefore, we wanted to investigate if OA is more frequent in patients with OI compared to the general population. OBJECTIVE: To evaluate the risk of osteoarthritis in patients with OI. DESIGN: A Danish nationwide, population-based and register-based longitudinal open cohort study. PARTICIPANTS: From 1977 to 2019, all patients registered with an OI diagnosis and a reference population matched on age and sex 5:1. MEASUREMENTS: Sub-hazard ratios for any, hip, and knee osteoarthritis comparing the OI cohort to the reference population. RESULTS: We identified 907 patients with OI (493 women) and included 4535 patients in the reference population (2465 women). The Sub Hazard Ratio was 2.20 [95% CI 1.73-2.79] for any osteoarthritis with 11.4% of the OI population and 5.4% of the reference population being registered. We found lower incidences of upper extremity joint OA compared to lower joint OA, but upper extremity joint OA was significantly more frequent in the OI population 2.1% vs 0.6%, SHR 3.19 [95% CI 1.78-5.70]. CONCLUSION: Patients with OI have a higher risk of OA than the reference population. MINIABSTRACT: Osteogenesis Imperfecta (OI) is a hereditary connective tissue disorder with skeletal fragility and extraskeletal manifestations. Osteoarthritis is a frequent joint disease and the incidence increases with age. In a population-register-based study, the risk of osteoarthritis was higher in patients with OI at an earlier age compared to a reference population.

Oral health-related quality of life in X-linked hypophosphataemia and osteogenesis imperfecta.

X-linked hypophosphataemia (XLH) and osteogenesis imperfecta (OI) are rare congenital disorders characterised by skeletal dysplasia. The two disorders may include dental anomalies potentially affecting individual well-being. The aims of study were (a) to assess the oral health-related quality of life (OHRQoL) in Danish adults with XLH or OI, and (b) to compare the results of the groups. A cross-sectional study including 35 adults with XLH, 56 adults with OI type I and 17 adults with OI types III-IV was conducted. The OHRQoL was assessed by the 49-item version of the questionnaire Oral Health Impact Profile (OHIP). Summed domain scores (seven) were compared between XLH and OI groups. Prevalence of severe impact on OHRQoL (scores 3-4) was compared between groups. The median scores in XLH group exceeded the medians in OI (P < .05) in the domains functional limitation (XLH:6.5; OI:4.0), pain (XLH:9.5; OI:5.0), psychological discomfort (XLH:5.5; OI:2.0), psychological disability (XLH:2.0; OI:0.0), handicap (XLH:2.0; OI:0.0) and total OHIP (XLH:35.0; OI:14.0). Differences in domains physical disability (XLH: 4.0; OI: 1.0) and social disability (XLH: 0.0; OI: 0.0) were not significant. Prevalence of severe impact on OHRQoL in the XLH group significantly exceeded the level in OI group in the domains functional limitation (XLH: 59%; OI: 35%), psychological discomfort (XLH: 38%; OI: 20%) and physical disability (XLH: 32%; OI: 13%). In conclusion, adults with XLH experience a higher negative impact on their OHRQoL than adults with OI. Only to a minor degree, individuals with OI types III-IV experience a higher impact on OHRQoL than individuals with OI type I.

The dental perspective on osteogenesis imperfecta in a Danish adult population.

BACKGROUND: To report on dental characteristics and treatment load in Danish adult patients with osteogenesis imperfecta (OI). METHODS: Oral examination of 73 patients with OI was performed and OI type I, III, and IV were represented by 75.3%, 8.2%, and 16.4%, respectively. Patients were diagnosed as having dentinogenesis imperfecta (DI) if they had clinical and radiological signs of DI. In the data analysis, mild OI (type I) was compared to moderate-severe OI (type III and IV). RESULTS: Discoloration of teeth was prevalent in patients with moderate-severe compared to mild OI (83.3% vs. 5.5%, p < 0.001). Cervical constriction and pulpal obliteration were frequent findings in patients with moderate-severe OI (61.1% and 88.9%, respectively), whereas pulp stones and taurodontism were diagnosed in patients with mild OI only (29.1% and 9.1%, respectively). DI was found in 24.7% of OI patients and considerably more frequent in patients with moderate-severe (94.4%) compared to mild OI (1.8%) (p < 0.001). The number of teeth with artificial crowns was significantly higher in patients with moderate-severe OI than in patients with mild OI (median 1.5, range 0-23 vs. median 0, range 0-14) (p < 0.001). The number of teeth with fillings in patients with mild OI was significantly higher than in patients with moderate-severe OI (mean 9.7, SD 5.1, median 9.0, range 1-21 vs. mean 5.0, SD 4.4, median 4.0, range 0-16) (p < 0.001). CONCLUSIONS: One fourth of patients with OI had DI, and the vast majority of them had moderate-severe OI. Whereas discoloration of teeth, cervical constriction and pulp obliteration were frequent findings in patients with moderate-severe OI, pulp stones and taurodontism were found in patients with mild OI only. In patients with moderate-severe OI, the dental treatment load was dominated by prosthetic treatment, whereas restorative treatment with fillings was more prevalent in patients with mild OI.

Mutations That Alter the Carboxy-Terminal-Propeptide Cleavage Site of the Chains of Type I Procollagen Are Associated With a Unique Osteogenesis Imperfecta Phenotype.

Osteogenesis imperfecta (OI) is a genetic bone disorder characterized by fractures, low bone mass, and skeletal fragility. It most commonly arises from dominantly inherited mutations in the genes COL1A1 and COL1A2 that encode the chains of type I collagen. A number of recent reports have suggested that mutations affecting the carboxyl-terminal propeptide cleavage site in the products of either COL1A1 or COL1A2 give rise to a form of OI characterized by unusually dense bones. We have assembled clinical, biochemical, and molecular data from 29 individuals from 8 families with 7 different mutations affecting the C-propeptide cleavage site. The phenotype was generally mild: The median height was ∼33th centile. Eighty percent of subjects had their first fracture by the age of 10 years, and one-third had a femoral or tibial fracture by the age of 25 years. Fractures continued into adulthood, though rates varied considerably. Healing was normal and rarely resulted in long bone deformity. One-third of subjects older than 15 years had scoliosis. The teeth and hearing were normal in most, and blue sclerae were not observed. Other features noted included fibro-osseous dysplasia of the mandible and Achilles tendon calcification. The mean spinal bone mineral density Z-score was +2.9 (SD 2.1) compared with -2.2 (0.7) in subjects with COL1A1 haploinsufficiency mutations. Bone mineral density distribution, assessed by quantitative backscattered electron imaging in bone showed higher levels of mineralization than found in any other disorder. Bone histology showed high trabecular volume and increased cortical thickness, with hyperosteoidosis and delayed mineralization. In vitro studies with cultured skin fibroblasts suggested that these mutations interfere with processing of the chain in which the sequence alteration occurs, but the C-propeptide is eventually cleaved (and detectable in blood), suggesting there are alternative sites of cleavage. The precise mechanism of the bony pathology is not yet clear. © 2018 American Society for Bone and Mineral Research.

Health-Related Quality of Life in Adults with Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a systemic connective tissue disorder most often caused by mutations in collagen type 1 related genes. Patients with OI suffer from multiple fractures and various degrees of growth deficiency and bone deformity. It is unknown whether the systemic effect of defect collagen type 1 influences the quality of life in patients with OI. We therefore aimed to investigate health-related quality of life (HRQoL) in a well-characterized cohort of adult patients with OI. We included 85 adult patients with mild to severe OI (types I, III, and IV) and obtained information about skeletal- and non-skeletal phenotypes and patient demographics. We investigated physical and mental HRQoL using a validated questionnaire, SF-36, and compared the data to values obtained in a population without OI. Patients with mild, moderate, and severe OI all had lower mean scores on domains describing physical HRQoL and a lower mean physical component score compared to the general population, p < 0.001. Patients with severe OI had lower mean scores on physical HRQoL, p < 0.05. The scores on domains reflecting mental HRQoL were more inhomogenously affected, but did not differ significantly from the general population. OI has an impact on physical and some aspects of mental HRQoL. The scores on physical health were correlated to severity of the OI disease. The mental component score in the OI patients was unaffected and comparable with the general population.

Fracture Rates and Fracture Sites in Patients With Osteogenesis Imperfecta: A Nationwide Register-Based Cohort Study.

Osteogenesis imperfecta (OI) is a hereditary, clinically heterogeneous, connective tissue disorder. The population prevalence of OI in Denmark is 10.6 in 100,000. A hallmark of the disease is frequent fractures that are often precipitated by minimal trauma. The aim of the current study was to compare the fracture rates across the lifespan of patients with OI with that of a reference population from the general population. The present study was a Danish nationwide, population-based, cohort study using register data. We identified 644 (55.6% females) patients in the OI cohort through the Danish National Patient Register and 3361 (55.2% females) persons, randomly selected from the Civil Registry System. A total of 416 patients with OI experienced a total of 1566 fractures during the observation period of median 17.9 years (interquartile range [IQR], 12.4 to 18.0 years), summing to 10137 person years. In comparison, 709 persons in the reference population experienced a total of 1018 fractures during follow-up. Both male and female patients with OI had an increased fracture rate throughout their life. The fracture rate ratio for participants aged 0 to 19 years was 10.7, for participants aged 20 to 54 years 17.2, and for participants aged 55 years and over 4.1 when compared to the reference population. The highest fracture rate was seen in males with OI aged 0 to 19 years (257 fractures per 1000 person-years). The fractures appear to follow the same pattern as in the general population, with a peak during the toddler and adolescent years (incidence rate [IR] 233.9 per 1000 person years), fewer fractures during adulthood (IR 84.5 per 1000 person years), and increased fracture rates in older women (IR 111.9 per 1000 person years). This is the largest register-based nationwide study on the fracture epidemiology of patients with OI. The risk of fractures seems largest in the childhood and adolescent years, and the relative risk of fracture declines with age in patients with OI compared to the general population. © 2016 American Society for Bone and Mineral Research.

Cardiovascular disease in patients with osteogenesis imperfecta - a nationwide, register-based cohort study.

BACKGROUND: Osteogenesis imperfecta (OI) is a hereditary connective tissue disease often due to mutations in genes coding for type 1 collagen. Collagen type 1 is important in the development of the heart and vasculature. Little is known about the risk of cardiovascular disease (CVD) in OI. OBJECTIVE: To investigate the risk of symptomatic CVD in OI. DESIGN: A Danish nationwide, population-based and register-based longitudinal open cohort study. PARTICIPANTS: All patients registered with the diagnosis of OI from 1977 to 2013 and a reference population matched 5:1 to the OI cohort. MEASUREMENTS: Sub-hazard ratios for mitral and aortic valve regurgitation, atrial fibrillation and flutter, heart failure and vascular aneurisms and dissections comparing the OI cohort to the reference population. RESULTS: We identified 687 cases with OI (379 women) and included 3435 reference persons (1895 women). The SHR was 6.3 [95% CI: 2.5-15.5] for mitral valve regurgitation, 4.5 [95% CI: 1.4-13.9] for aortic valve regurgitation, 1.7 [95% CI: 1.1-2.8] for atrial fibrillation/flutter, and 2.3 [95% CI: 1.4-3.7] for heart failure. The SHRs were not increased arterial aneurisms or dissections. LIMITATION: Our results were limited by lacking clinical information about phenotype and genotype of the included patients. CONCLUSION: We confirm that patients with OI have an increased risk of CVD compared to the general population. This held true even when adjusting for factors that are known to contribute to development of these diseases. Our results suggest that the collagenopathy seen in OI may be part of the pathogenesis of CVD in OI.

Mortality and Causes of Death in Patients With Osteogenesis Imperfecta: A Register-Based Nationwide Cohort Study.

Osteogenesis imperfecta (OI) is a hereditary connective tissue disease that causes frequent fractures. Little is known about causes of death and length of survival in OI. The objective of this work was to calculate the risk and cause of death, and the median survival time in patients with OI. This study was a Danish nationwide, population-based and register-based cohort study. We used National Patient Register data from 1977 until 2013 with complete long-term follow-up. Participants comprised all patients registered with the diagnosis of OI from 1977 until 2013, and a reference population matched five to one to the OI cohort. We calculated hazard ratios for all-cause mortality and subhazard ratios for cause-specific mortality in a comparison of the OI cohort and the reference population. We also calculated all-cause mortality hazard ratios for males, females, and age groups (0 to 17.99 years, 18.00 to 34.99 years, 35.00 to 54.99 years, 55.00 to 74.99 years, and >75 years). We identified 687 cases of OI (379 women) and included 3435 reference persons (1895 women). A total of 112 patients with OI and 257 persons in the reference population died during the observation period. The all-cause mortality hazard ratio between the OI cohort and the reference population was 2.90. The median survival time for males with OI was 72.4 years, compared to 81.9 in the reference population. The median survival time for females with OI was 77.4 years, compared to 84.5 years in the reference population. Patients with OI had a higher risk of death from respiratory diseases, gastrointestinal diseases, and trauma. We were limited by the lack of clinical information about phenotype and genotype of the included patients. Patients with OI had a higher mortality rate throughout their life compared to the general population. © 2016 American Society for Bone and Mineral Research.

Bone geometry, density, and microarchitecture in the distal radius and tibia in adults with osteogenesis imperfecta type I assessed by high-resolution pQCT.

Osteogenesis imperfecta (OI) is a hereditary disorder characterized by decreased biosynthesis or impaired morphology of type I collagen that leads to decreased bone mass and increased bone fragility. We hypothesized that patients with OI have altered bone microstructure and bone geometry. In this cross-sectional study we compared patients with type I OI to age- and gender-matched healthy controls. A total of 39 (13 men and 26 women) patients with OI, aged 53 (range, 21-77) years, and 39 controls, aged 53 (range, 21-77) years, were included in the study. Twenty-seven of the patients had been treated with bisphosphonates. High-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius and distal tibia and dual-energy X-ray absorptiometry of total hip, femoral neck, trochanteric region, and the lumbar spine (L1-L4) were performed. The patients were shorter than the controls (159 ± 10 cm versus 170 ± 9 cm, p < 0.001), but had similar body weight. In OI, areal bone mineral density (aBMD) was 8% lower at the hip (p < 0.05) and 13% lower at the spine (p < 0.001) compared with controls. The trabecular volumetric bone mineral density (vBMD) was 28% lower in radius (p < 0.001) and 38% lower in tibia (p < 0.001) in OI compared with controls. At radius, total bone area was 5% lower in OI than in controls (p < 0.05). In the tibia, cortical bone area was 18% lower in OI (p < 0.001). In both radius and tibia the number of trabeculae was lower in patients compared to the controls (35% and 38%, respectively, p < 0.001 at both sites). Furthermore, trabecular spacing was 55% higher in OI in both tibia and radius (p < 0.001 at both sites) when compared with controls. We conclude that patients with type I OI have lower aBMD, vBMD, bone area, and trabecular number when compared with healthy age- and gender-matched controls.