Form Of Osteogenesis Imperfecta Research Articles

Altered Sox9 and FGF signaling gene expression in Aga2 OI mice negatively affects linear growth.

Osteogenesis imperfecta (OI), or brittle bone disease, is a disorder characterized by bone fragility and increased fracture incidence. All forms of OI also feature short stature, implying an effect on endochondral ossification. Using the Aga2+/- mouse, which has a mutation in type I collagen, we show an affected growth plate primarily due to a shortened proliferative zone. We used single-cell RNA-Seq analysis of tibial and femoral growth plate tissues to understand transcriptional consequences on growth plate cell types. We show that perichondrial cells, which express abundant type I procollagen, and growth plate chondrocytes, which were found to express low amounts of type I procollagen, had ER stress and dysregulation of the same unfolded protein response pathway as previously demonstrated in osteoblasts. Aga2+/- proliferating chondrocytes showed increased FGF and MAPK signaling, findings consistent with accelerated differentiation. There was also increased Sox9 expression throughout the growth plate, which is expected to accelerate early chondrocyte differentiation but reduce late hypertrophic differentiation. These data reveal that mutant type I collagen expression in OI has an impact on the cartilage growth plate. These effects on endochondral ossification indicate that OI is a biologically complex phenotype going beyond its known impacts on bone to negatively affect linear growth.

RF30 | PSAT178 Severe Hyperparathyroidism in a Newborn: Response to Cinacalcet

Abstract Background Neonatal severe hyperparathyroidism (NSHPT) is a rare potentially lethal disorder caused by inactivating mutations in the calcium sensing receptor (CASR) gene. In newborns it presents with multiple bone fractures often confused with forms of osteogenesis imperfecta. Diagnostic and therapeutic experience with this condition is limited, hence here we describe a term baby we identified and treated with this disorder. Case Description A 39-week-old Hispanic female, born small for gestational age (BW 2.38 kg) via vaginal delivery to a 33-year-old G3P2 healthy mother was noted to have relative asymmetry of the thighs/hips. X-rays revealed bone demineralization and multiple fractures including distal femur and proximal tibia bilaterally and rib fractures in various stages of healing. Initially, osteogenesis imperfecta was thought likely and Endocrinology was consulted. Laboratories showed hypercalcemia (calcium 12.1 mg/dL (normal 8.5-11.2), elevated serum PTH 439 pg/mL (12-72). Serum phosphorus (4.2 mg/dL), 25-OH Vitamin D (44 ng/mL) and alkaline phosphatase (232 IU/L) were normal; urine calcium/creatinine ratio was low (0.006 mg/mg). EKG showed non-specific T wave abnormalities and echocardiogram mild pulmonary hypertension. Neck ultrasound and sestamibi scan showed no parathyroid mass. She was placed on oxygen due to desaturations and had poor tone and suck. Father had documented hypercalcemia (calcium 12.6 mg/dL, PTH 53 pg/mL). Paternal aunt and grandmother also had history of hypercalcemia. Serum levels of calcium and PTH remained elevated for 2 weeks despite treatment with IV fluids and furosemide and a low calcium/vitamin D formula. On day 12 we began a trial of cinacalcet, a type 2 calcimimetic, at starting doses of 0.4 mg/kg/day divided BID orally. Over 4 days the patient showed a dramatic reduction in serum levels of calcium and PTH to 8.6 mg/dL and 24 pg/mL, respectively. Over time her clinical course improved with better tone and suck and normal oxygenation. Cinacalcet was titrated up to 2.3 mg/kg/day (2mg PO tid) and baby discharged on day 20. Gene sequencing revealed a known heterozygous pathogenic variant in an exon 4 hotspot of the CASR gene, c.658C>T (p.Arg220Trp), consistent with familial hypocalciuric hypercalcemia. Father was confirmed to have the same pathogenic variant as the child. She has now been followed for 6 months, all fractures are healing with persistently normal PTH and calcium levels. She is thriving, her development appears to be normal, able to eat orally, sit, track and smile. Conclusion Neonatal severe hyperparathyroidism can occur in infants who are heterozygous for a CASR mutation and can manifest as multiple congenital fractures. A family history of asymptomatic parental hypercalcemia/hyperparathyroidism and targeted gene sequencing can be diagnostic of NSHPT. Activators of the CASR are a promising therapy for heterozygous CASR loss-of-function pathogenic variants and can lead to reversal of skeletal demineralization and markedly improved clinical status. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 1:18 p.m. - 1:23 p.m.

The Osteogenesis Imperfecta Type V Mutant BRIL/IFITM5 Promotes Transcriptional Activation of MEF2, NFATc, and NR4A in Osteoblasts.

BRIL (bone restricted ifitm-like; also known as IFITM5) is a transmembrane protein expressed in osteoblasts. Although its role in skeletal development and homeostasis is unknown, mutations in BRIL result in rare dominant forms of osteogenesis imperfecta. The pathogenic mechanism has been proposed to be a gain-of or neomorphic function. To understand the function of BRIL and its OI type V mutant (MALEP BRIL) and whether they could activate signaling pathways in osteoblasts, we performed a luciferase reporter assay screen based on the activity of 26 transcription factors. When overexpressed in MC3T3-E1 and MLO-A5 cells, the MALEP BRIL activated the reporters dependent on MEF2, NFATc, and NR4A significantly more. Additional co-transfection experiments with MEF2C and NFATc1 and a number of their modulators (HDAC4, calcineurin, RCAN, FK506) confirmed the additive or synergistic activation of the pathways by MALEP, and suggested a coordinated regulation involving calcineurin. Endogenous levels of Nr4a members, as well as Ptgs2, were upregulated by MALEP BRIL. Y2H and co-immunoprecipitation indicated that BRIL interacted with CAML, but its contribution as the most upstream stimulator of the Ca2+-calcineurin-MEF2/NFATc cascade was not confirmed convincingly. Altogether the data presented provide the first ever readout to monitor for BRIL activity and suggest a potential gain-of-function causative effect for MALEP BRIL in OI type V, leading to perturbed signaling events and gene expression.

A Novel IFITM5 Variant Associated with Phenotype of Osteoporosis with Calvarial Doughnut Lesions: A Case Report

Osteogenesis imperfecta (OI) and other decreased bone density disorders comprise a heterogeneous group of heritable diseases with skeletal fragility. Recently, it was discovered that mutations in SGMS2, encoding sphingomyelin synthetase 2, result in aberrant sphingomyelin metabolism and lead to a novel form of OI termed osteoporosis with calvarial doughnut lesions (OP-CDL) with moderate to severe skeletal fragility and variable cranial hyperostotic lesions. This study describes a Japanese family with the skeletal phenotype of OP-CDL. The affected individuals have moderately severe, childhood-onset skeletal fragility with multiple long-bone fractures, scoliosis and bone deformities. In addition, they exhibit multiple CDLs or calvarial bumps with central radiolucency and peripheral radiopacity. However, SGMS2 sequencing was normal. Instead, whole-exome sequencing identified a novel IFITM5 missense mutation c.143A>G (p.N48S) (classified as a VUS by ACMG). IFITM5 encodes an osteoblast-restricted protein BRIL and a recurrent c.-14C>T mutation in its 5' UTR region results in OI type V, a distinctive subtype of OI associated with hyperplastic callus formation and ossification of the interosseous membranes. The patients described here have a phenotype clearly different from OI type V and with hyperostotic cranial lesions, feature previously unreported in association with IFITM5. Our findings expand the genetic spectrum of OP-CDL, indicate diverse phenotypic consequences of pathogenic IFITM5 variants, and imply an important role for BRIL in cranial skeletogenesis.

Bone properties in osteogenesis imperfecta: what can we learn from abone biopsy beyond histology?

Transiliac bone biopsy samples are used to evaluate histology and bone cell activity in unclear pathological conditions. However, much additional information can be obtained from such bone samples. Using the example of osteogenesis imperfecta (OI), the current article describes how biopsy samples can be further used to study bone material characteristics including the degree of matrix mineralization, organic matrix properties, mineral particle size and bone nanoporosity. OI is aheritable collagen-related disorder that is phenotypically and genetically extremely heterogeneous. One essential finding was that OI bone is hypermineralized independently of clinical severity. Moreover, mineral particles in OI bone are of normal size or even smaller, but more densely packed than normally. Another recent finding was that in some forms of OI, collagen orientation is highly disorganized, indicating that the collagen-mineral particle network is profoundly altered in OI. These findings have contributed to the understanding of impaired bone strength in OI.

A novel mutation combining with rs66612022 in a Chinese pedigree suggests a new pathogenesis to osteogenesis imperfecta via whole genome sequencing.

Osteogenesis imperfecta (OI) is a rare heritable disease with systemic connective tissue disorder. Most of the patients represent autosomal dominant form of OI, and are usually resulting from the mutations in type I collagen genes. However, the gene mutations reported previously only account for ∼70% of the OI cases. Here, in a Chinese OI family, we examined seven patients and nine normal individuals using the whole genome sequencing and molecular genetic analysis. The mutation of rs66612022 (COL1A2:p.Gly328Ser) related to glycine substitution was found in the seven patients. Moreover, we identified a novel missense mutation (HMMR:p.Glu2Gln). Interestingly, the individuals of this family with both the mutations were suffering from OI, while the others carried one or none of them are normal. The mutations of COL1A2 and HMMR and their combined effect on OI would further expand the genetic spectrum of OI.

Progresive-deforming form of osteogenesis imperfecta in neonates - own experience

Progresive-deforming form of osteogenesis imperfecta in neonates - own experience

Co-occurrence of heterozygous mutations in COL1A1 and SERPINF1 in a high-risk pregnancy complicated by osteogenesis imperfecta

Mutations in several genes, including SERPRINF1 and COL1A1, have been associated with the development of osteogenesis imperfecta (OI). Here, we reported the co-occurrence of a rare heterozygous variant (c.167C>G p.Ala56Gly) in SERPRINF1 and a novel heterozygous mutation (c.1634G>A p.Gly545Asp) in COL1A1 in a foetus with a severe form of OI. Bioinformatics modelling revealed that the effect of the mutation on SPERINF1 is neutral. In contrast, the mutation in COL1A1 is deleterious. It is predicted to cause distortion of the α (1) chain of the type I collagen and results in structural instability of the protein. Therefore, a novel dominant variant of COL1A1 likely underlies the severe foetal pathology observed, although we do not exclude the possibility that the heterozygous mutations in SERPINF and COL1A1 may interact and co-ordinately cause pathogenesis. This novel COL1A1 mutation is recommended to be included in the diagnostic panels for OI.

Dentinogenesis imperfecta in Osteogenesis imperfecta type XI in South Africa: a genotype\u2013phenotype correlation

BackgroundThe maxillofacial and dental manifestations of Osteogenesis imperfecta (OI) have significant implications in terms of management. Although the occurrence of abnormal dentine in some forms of OI is well documented, there is scant information on the association of abnormal dentine in the Black African persons with phenotypic OI III and genotypic OI XI in South Africa.MethodsThis was a cross-sectional analytic study. A series of 64 Black South African individuals with a confirmed phenotypic diagnosis of OI III, ages ranging from 3 months to 29 years, were assessed clinically, radiographically, and at a molecular level.ResultsA total number of 64 saliva samples were analyzed and 3 DNA variations were identified in exon 5 of the FKBP10 gene. The homozygous mutation, c.[831dupC]; [831dupC], was identified in 23 affected persons who had no clinically obvious features of DI in their primary and secondary teeth. Radiologically, mild features of DI were evident in 10 persons in whom radiographic images were obtained and were given a Clinical–radiological score of 2. A compound heterozygous mutation, c. [831delC]; [831dupC], was identified in three siblings. An intraoral examination of these affected persons revealed no clinically apparent features of DI in their primary and secondary teeth. Due to the lack of radiological facilities, the presence or absence of DI could not be confirmed or negated. A second compound heterozygous mutation, c.[831dupC]; [1400-4C>G], was identified in a female of 29 years belonging to the Xhosa linguistic group. Her teeth appeared clinically normal but it was not possible to obtain radiographs. In 37 affected individuals, no disease-causing mutations were identified.ConclusionBlack African individuals in SA with the homozygous mutation in the FKBP10 gene have clinically unaffected teeth yet exhibited radiographic features of DI to varying degrees. This characterization is suggestive of a relationship between the genetic abnormality and the clinical manifestations of DI. The authors suggest that this diagnosis must include teeth that are clinically and/or radiologically aberrant, and should not exclude the presence of other, milder, dentinal aberrations associated with OI. There was no correlation between severity of OI and DI in this cohort of individuals.

WNT1-associated osteogenesis imperfecta with atrophic frontal lobes and arachnoid cysts.

A rare form of osteogenesis imperfecta (OI) caused by Wingless-type MMTV integration site family 1 (WNT1) mutations combines central nervous system (CNS) anomalies with the characteristic increased susceptibility to fractures. We report an additional case where arachnoid cysts extend the phenotype, and that also confirms the association of intellectual disabilities with asymmetric cerebellar hypoplasia here. Interestingly, if the cerebellum is normal in this disorder, intelligence is as well, analogous to an association with similar delays in a subset of patients with sporadic unilateral cerebellar hypoplasia. Those cases typically appear to represent vascular disruptions, and we suggest that most brain anomalies in WNT1-associated OI have vascular origins related to a role for WNT1 in CNS angiogenesis. This unusual combination of benign cerebellar findings with effects on higher functions in these two situations raises the possibility that WNT1 is involved in the pathogenesis of the associated sporadic cases as well. Finally, our patient reacted poorly to pamidronate, which appears ineffective with this form of OI, so that a lack of improvement is an indication for molecular testing that includes WNT1.

Wnt1 is an Lrp5-independent bone-anabolic Wnt ligand.

WNT1 mutations in humans are associated with a new form of osteogenesis imperfecta and with early-onset osteoporosis, suggesting a key role of WNT1 in bone mass regulation. However, the general mode of action and the therapeutic potential of Wnt1 in clinically relevant situations such as aging remain to be established. Here, we report the high prevalence of heterozygous WNT1 mutations in patients with early-onset osteoporosis. We show that inactivation of Wnt1 in osteoblasts causes severe osteoporosis and spontaneous bone fractures in mice. In contrast, conditional Wnt1 expression in osteoblasts promoted rapid bone mass increase in developing young, adult, and aged mice by rapidly increasing osteoblast numbers and function. Contrary to current mechanistic models, loss of Lrp5, the co-receptor thought to transmit extracellular WNT signals during bone mass regulation, did not reduce the bone-anabolic effect of Wnt1, providing direct evidence that Wnt1 function does not require the LRP5 co-receptor. The identification of Wnt1 as a regulator of bone formation and remodeling provides the basis for development of Wnt1-targeting drugs for the treatment of osteoporosis.

Whole exome sequencing analysis identifies a missense variant in COL1A2 gene which causes osteogenesis imperfecta Type IV in a family from Saudi Arabia

Objectives: Molecular diagnosis of a large Saudi family presenting an autosomal dominant form of osteogenesis imperfecta (OI). Methods: Genetic analysis of the index patient was performed through 100× paired end whole exome sequencing (WES) covering 24,000 coding genes of the human genome. The causative variant was filtered out among the previously known 23 genes' panel reported for 17 subtypes of OI. The dominant segregation of the causative variant with the disease phenotype was confirmed by Sanger sequencing. Pathogenicity of the altered protein was predicted through SIFT, PolyPhen, and MutationTaster software. Results: A heterozygous variant (c.1801G>A; p. Gly601Ser) in exon 31 of collagen 1α2 was identified. In this study, WES was successfully applied to identify the molecular basis of OI in the proband. The rest of family members were confirmed through Sanger validation confirming the autosomal dominant mode of inheritance in large Saudi family. Conclusion: OI is a rare heterogeneous disorder of connective tissues with 17 overlapping subtypes, for which 23 genes are known. Our work adds to the growing list of disease-causing variants in COL1A2. Reporting the disease-causing variants is one of the best ways to share data for better and accurate variants interpretation. We tested that WES can be used as an efficient tool for the molecular diagnosis of this rare phenotype.

Investigating the blue sclera in osteogenesis imperfecta by in vivo confocal microscopy

PurposeThe blue sclera appearance is a distinctive clinical sign for osteogenesis imperfecta (OI), a connective tissue disorder caused by an abnormality of type I collagen. It is a challenging diagnosis because multiple bone fractures, occurring in early childhood, can be the only sign of the non‐lethal forms of OI. In these situations, child abuse is a major concern for Paediatricians.AimTo investigate the in vivo confocal microscopy (IVCM) of the sclera and its characteristics as a diagnostic test for OI.MethodsA father and his daughter suffering from OI gave informed consent for non‐invasive ocular examination. The cornea and sclera were examined with a handheld dermatological IVCM (VivaScope 3000, MAVIG GmbH/Lucid), which we pioneered for ophthalmological examination. The examination of two age matched healthy volunteers and corneoscleral donor tissues served as a control.ResultsThe IVCM in OI shows a very specific and reproducible pattern where the collagen fibres have a well organised parallel alignment as would be expected within the clear corneal stroma. Collagen fibres were cross striated in the control.ConclusionsThese findings were consistent with the electron‐microscopic features previously described. The blue appearance results from the visualisation of the underlying choroid through the translucent sclera, which displays a specific parallel orientation of the collagen fibres. To the best of our knowledge, this is the first report of IVCM of the blue sclera. This rapid and non‐invasive imaging technique is an interesting diagnostic tool for challenging cases, especially in children, with multiple bone fractures.GRANT: GIRCI RAA

Are Changes in Composition in Response to Treatment of a Mouse Model of Osteogenesis Imperfecta Sex-dependent?

Osteogenesis imperfecta (OI) is a genetic disease characterized by skeletal fragility and deformity. There is extensive debate regarding treatment options in adults with OI. Antiresorptive treatment reduces the number of fractures in growing oim/oim mice, an animal model that reproducibly mimics the moderate-to-severe form of OI in humans. Effects of long-term treatments with antiresorptive agents, considered for treatment of older patients with OI with similar presentation (moderate-to-severe OI) are, to date, unknown. Fourier transform infrared (FTIR) imaging, which produces a map of the spatial variation in chemical composition in thin sections of bone, was used to address the following questions: (1) do oim/oim mice show a sex dependence in compositional properties at 6.5 months of age; (2) is there a sex-dependent response to treatment with antiresorptive agents used in the treatment of OI in humans; and (3) are any compositional parameters in oim/oim mice corrected to wild-type (WT) values after treatment? FTIR imaging data were collected from femurs from four to five mice per sex per genotype per treatment. Treatments were 24 weeks of saline, alendronate, or RANK-Fc; and 12 weeks of saline+12 weeks RANK-Fc and 12 weeks of alendronate+RANK-Fc. FTIR imaging compositional parameters measured in cortical and cancellous bones were mineral-to-matrix ratio, carbonate-to-mineral ratio, crystal size/perfection, acid phosphate substitution, collagen maturity, and their respective distributions (heterogeneities). Because of the small sample size, nonparametric statistics (Mann-Whitney U- and Kruskal-Wallis tests with Bonferroni correction) were used to compare saline-treated male and female mice of different genotypes and treatment effects by sex and genotype, respectively. Statistical significance was defined as p<0.05. At 6.5 months, saline-treated male cortical oim/oim bone had increased mineral-to-matrix ratio (p=0.016), increased acid phosphate substitution (p=0.032), and decreased carbonate-to-mineral ratio (p=0.016) relative to WT. Cancellous bone in male oim/oim also had increased mineral-to-matrix ratio (p=0.016) relative to male WT. Female oim/oim mouse bone composition for all cortical and cancellous bone parameters was comparable to WT (p>0.05). Only the female WT mice showed a response of mean compositional properties to treatment, increasing mineral-to-matrix after RANK-Fc treatment in cancellous bone (p=0.036) compared with saline-treated mice. Male oim/oim increased mineral-to-matrix cortical and cancellous bone heterogeneity in response to all long-term treatments except for saline+RANK-Fc (p<0.04); female oim/oim cortical mineral-to-matrix bone heterogeneity increased with ALN+RANK-Fc and all treatments increased cancellous female oim/oim bone acid phosphate substitution heterogeneity (p<0.04). Both oim/oim and WT mice, which demonstrate sex-dependent differences in composition with saline treatment, showed few responses to long-term treatment with antiresorptive agents. Female WT mice appeared to be more responsive; male oim/oim mice showed more changes in compositional heterogeneity. Changes in bone composition caused by these agents may contribute to improved bone quality in oim/oim mice, because the treatments are known to reduce fracture incidence. The optimal drug therapy for long-term treatment of patients with moderate-to-severe OI is unknown. Based on bone compositional changes in mice, antiresorptive treatments are useful for continued treatment in OI. There is a reported sexual dimorphism in fracture incidence in adults with OI, but to date, no one has reported differences in response to pharmaceutical intervention. This study suggests that such an investigation is warranted.

Two mutations in IFITM5 causing distinct forms of osteogenesis imperfecta

The IFITM5 gene has recently been found to be mutated in patients with autosomal dominant osteogenesis imperfecta (OI) type V. This form of OI is characterized by distinctive clinical manifestations, including hyperplastic callus formation at the site of fractures, calcification of the interosseous membrane of the forearm, and dislocation of the head of the radius. Notably, in spite of the fact that a considerable number of patients with IFITM5 mutations have been identified, to date all of them have been shown to have the same heterozygous mutation (c.-14C>T). Herein, we describe one patient with a de novo c.119C>T heterozygous mutation in IFITM5, which predicts p.Ser40Leu, and another with the recurrent c.-14C>T transition that was also apparently de novo. While the patient with the p.Ser40Leu mutation had none of the typical signs of OI type V and was diagnosed with limb shortening at prenatal stages, the patient with the c.-14C>T mutation developed hyperplastic calluses and had calcification of the forearm interosseous membrane. This study challenges the lack of allelic and clinical heterogeneity in IFITM5 mutations.

What's New in Osteogenesis Imperfecta?

This article discusses the pathophysiology of osteogenesis imperfecta (OI), in particular in relation to some rare, recessive forms of the condition. Although historically considered a collagen-related condition, predominantly due to mutations in genes that encode the alpha chains of collagen type I, mutations in various noncollagenous genes have also more recently been discovered to cause some forms of OI.

Challenges in managing osteogenesis imperfecta patients in H. Adam Malik hospital, North Sumatera, Indonesia

Background Osteogenesis imperfecta (OI) is a genetic disorder with increased bone fragility and low bone mass, the incidence has been estimated at 1 in per 10000-20000 births, however milder forms of OI are probably under recognized. Cyclical intravenous therapy with the biphosphonate pamidronate has been reported to be beneficial in children and adolescents with moderate to severe forms of OI.

Osteogenesis imperfecta in children: Indosesian experiences

Medical management of osteogenesis imperfecta (OI), a genetic disorder of connective tissue characterized by reduced bone mass and frequent fractures, is focused on maximizing patients’ mobility and function. Many methods of pharmacological treatment have been introduced for the severe forms of OI, including calcium, anabolic steroids, growth hormone, and calcitonin, without consistent benefit. Recent studies reported beneficial effect of intravenous and oral bisphosphonates on moderate to severe form of OI in children. This report is to review OI cases in Indonesian children and to know the effect of bisphosphonate treatment for them. Data on age, gender, age at diagnosis, availability of bisphosphonate treatment, and its effects were collected from Indonesian OI children registry, which documented from April to June 2012. Fourteen centers which have members of pediatric endocrinology chapter, Indonesian Pediatric society, were involved in obtaining data for the registry. Forty-six OI cases (17 female), who were diagnosed at the age of 7 days-11 years old and mostly categorized as type 3 of OI, were recorded. Two patients were died before commencing treatment. There were twenty-seven (27/46) patients received bisphosphonates, which were administered to moderate to severe cases. Two patients,who were treated, were died due to hyperthermia after the first day of pamidronate infusion, and pneumonia aspiration. Twenty-five patients received intravenous pamidronate and 3 oral alendronate. Liver and renal function test, and serum electrolyte were evaluated before and after treatment. Most patients reported decreased irritability, increased muscle tone and mobility. In addition, despite hyperthermia in one case, no serious adverse effects documented. Although some patients had government health insurance for the poor, unfortunately, the medicine, which is considered expensive for the patients, is not yet included in the drug list of government insurance. Most of registered OI cases in Indonesian children were type 3. More than half of the cases underwent treatment with bisphosphonates with beneficial effects, although long-term follow up and well-documented data are required.

Novel splicing mutation in FKBP10 gene in a patient with moderate/severe form of osteogenesis imperfecta

Novel splicing mutation in FKBP10 gene in a patient with moderate/severe form of osteogenesis imperfecta

Phenotype-genotype correlation and role of ancillary investigations in atypical and rare forms of osteogenesis imperfecta

Phenotype-genotype correlation and role of ancillary investigations in atypical and rare forms of osteogenesis imperfecta