Osteogenesis Imperfecta Type Research Articles

Pamidronate Therapy Increases Trabecular Bone Complexity of Mandibular Condyles in Individuals with Osteogenesis Imperfecta.

Patients with Osteogenesis Imperfecta (OI) present extra-skeletal manifestations, including important orodental and craniofacial features as dentinogenesis imperfecta, dental agenesis, failure of maxilla growth and hypotonia of masticatory muscles. These features may compromise vital functions speech and mastication. Studies have demonstrated that cyclic pamidronate infusion, the standard therapy for patients with moderate to severe OI, influences the histomorphometric pattern of different body bones. The present study aimed to investigate the condyle trabecular bone pattern in OI patients. We used fractal dimension (FD) analysis on dental panoramic radiographic images to characterize the mandibular condyle trabecular bone in adolescents diagnosed with OI and treated with pamidronate. Imaging exam of 33 adolescents of both sexes, aged between 12 and 17years, were analyzed and compared with 99 age- and sex-matched healthy adolescents. FD in patients was significantly lower (1.23 ± 0.15) than in healthy controls (1.29 ± 0.11; p < 0.01). Type of OI, age at treatment onset, and the duration of therapy were variables that showed a statistically significant effect on the FD results. This study demonstrated that the bone architecture of mandibular condyles may be altered in pediatric patients with moderate and severe forms of OI. Also, pamidronate treatment seems to have a positive effect on condyle trabecular bone in these patients. This is supported by our finding that FD values were positively influenced by the length of cyclic pamidronate treatment at the time of imaging, as well as by the age of the individual at treatment onset.

Knocking out TMEM38B in human foetal osteoblasts hFOB 1.19 by CRISPR/Cas9: A model for recessive OI type XIV.

Osteogenesis imperfecta (OI) type XIV is a rare recessive bone disorder characterized by variable degree of severity associated to osteopenia. It is caused by mutations in TMEM38B encoding for the trimeric intracellular cation channel TRIC-B, specific for potassium and ubiquitously present in the endoplasmic reticulum (ER) membrane. OI type XIV molecular basis is largely unknown and, due to the rarity of the disease, the availability of patients' osteoblasts is challenging. Thus, CRISPR/Cas9 was used to knock out (KO) TMEM38B in the human Foetal Osteoblast hFOB 1.19 to obtain an OI type XIV model. CRISPR/Cas9 is a powerful technology to generate in vitro and in vivo models for heritable disorders. Its limited cost and ease of use make this technique widely applicable in most laboratories. Nevertheless, to fully take advantage of this approach, it is important to be aware of its strengths and limitations. Three gRNAs were used and several KO clones lacking the expression of TRIC-B were obtained. Few clones were validated as good models for the disease since they reproduce the altered ER calcium flux, collagen I structure and impaired secretion and osteoblastic markers expression detected in patients' cells. Impaired proliferation and mineralization in KO clones unveiled the relevance of TRIC-B in osteoblasts functionality.

Osteogenesis Imperfecta and hearing loss in the paediatric population

BackgroundOsteogenesis Imperfecta is a genetic disorder affecting the synthesis of collagen in the body. It is also known as ‘Brittle Bone Disease’. It is heterogenous in its clinical presentation. The commonest presentation is a history of frequent fractures, joint deformities and blue sclera. Secondary deformities of the extremities, spine, skull as well short stature observed frequently.Hearing loss has been well documented to occur in Osteogenesis Imperfecta. It is most commonly seen in types I, II and III. Hearing loss forms part of the diagnostic criteria for these types. Depending on the study, the prevalence of hearing loss in children with Osteogenesis imperfecta is between 6.7% and 77.3% The estimated prevalence of Osteogenesis Imperfecta is 1 in 20000. ObjectivesIn South Africa, the commonest type of Osteogenesis Imperfecta was found to be Type III. The prevalence of OI Type III has been estimated to be between 1:125000 and 1:200000. Hearing loss is a common feature of OI Type III. MethodsThis study was a Prospective Cross-sectional study. Ethics Approval was obtained from the University of Witwatersrand Ethics committee (Ethics number M190975) Children with Osteogenesis Imperfecta attending the Metabolic Bone Clinic at Chris Hani Baragwanath Academic Hospital were the target group. The patients and their parents or guardians were recruited at the clinic after a consent and or an assent was obtained. An Otoscopy followed by tympanometry and a hearing screen based on the age of the patient was done. DPEOAEs were also done as a screening test to confirm the pure tone audiogram findings. The results were given to the patients and their parents/guardians immediately. ResultsThe paediatric patients with Osteogenesis Imperfecta who consented to take part in the study had their hearing screen done at the Audiology Department at Chris Hani Baragwanath Academic Hospital. All of the children were found to have normal hearing. On tympanometry, all except 2 were found to have type A curves in bilaterally. Two patients had a type As curve in one ear with an A curve on the other side. ConclusionHearing loss in Osteogenesis Imperfecta forms part of the diagnostic criteria for certain types of this genetic disorder. Hearing loss in the paediatric patients does not seem to be as prevalent as previously thought. All the patients involved in the study were receiving the bisphosphonate therapy (Zoledronic acid) for OI. This may possibly cause a delay in the onset of hearing loss but long term follow-up studies and bigger sample sizes will be required to prove this hypothesis.

Effects of Long-Term Pamidronate Treatment on Bone Density and Fracture Rate in 65 Osteogenesis Imperfecta Patients.

Objective:Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous disease characterized by recurrent fractures, blue sclera, and hearing loss. Bisphosphonate treatment has been reported to decrease the annual number of fractures and improve the quality of life in patients with OI. The aim of this study is to evaluate the effect of bisphosphonate treatment in the Turkish OI cohort.Methods:Sixty-five patients with OI, who were treated with pamidronate, were included in this study. The mean treatment duration was 47.1 ± 40 months (range:12-168 months). Bone mineral densitometry (BMD) and the mean number of annual fractures were compared before and after the treatment within groups, and the difference after treatment compared between the OI types.Results:After pamidronate treatment, a significant decrease in the mean annual fracture, along with an increase in BMD Z-score was detected in all patients. Treatment duration did not affect BMD Z-score. However, there was a significant decrease in the mean annual number of fractures after 5 years of treatment (P = .048). After treatment, the decrease in the number of fractures was significant in OI type 3, and the increase in BMD Z-score was significant in OI type 4 when compared with OI type 1. Besides, pamidronate treatment relieved pain, and also corrected the platyspondyly radiologically in all OI groups.Conclusion:We demonstrated that pamidronate treatment improves the quality of life by reducing the number of fractures, relieving pain, and also protecting from deformities in all patients with OI.

A RARE CASE OF OSTEOGENESIS IMPERFECTA TYPE I

A 7 year old female patient was admitted to hospital having experienced bowing of upper and lower limbs, repeated fractures over the past 4 years. Clinical ndings and radiological investigations such as recurrent fractures and deformity of bones while bearing weight, blue sclera and low bone mineral density, all led us to conclude that this child has a mild form of osteogenesis imperfecta type I. The patient was immediately started on calcium (1000mg/day), vitamin D (800mg/day) and pamidronate (60mg) was given intravenously. Following the above protocol, we found that the quality of life of the patient showed signicant improvement. This patient is a rare case of OI type I.

Craniocervical abnormalities in osteogenesis imperfecta type V.

Craniocervical abnormalities in osteogenesis imperfecta (OI) can cause severe neurological morbidity. Although radiological cranial base abnormalities in OI have been well described in the literature, there are limited data on these abnormalities in OI type V and their association with clinical sequelae. A retrospective case series on patients with craniocervical abnormalities in OI type V at our institution. Craniocervical abnormalities were present in 7 of 37 patients with OI type V (19%). For 5 patients (age at last follow-up: 5 to 26years; 2 females), sufficient information was available for inclusion in the case series. All had genetically confirmed OI type V. Age range at diagnosis of the craniocervical abnormality was 1day to 18years. Basilar invagination was present in 3 patients; 2 had cervical kyphosis. Dysplasia of upper cervical vertebrae or base of skull was seen in 3 patients. The severity of the craniocervical abnormality did not clearly correlate with the severity of the OI phenotype. Three patients required surgical intervention (ages 7, 11, and 26years) due to compression of the spinal cord or brainstem. Craniocervical abnormalities were detected incidentally or on screening in 3 patients, and only 2 had significant positive findings on neurological examination. A variety of craniocervical abnormalities are seen in OI type V including dysplasia of the cervical vertebrae. These cases highlight the importance of screening patients with OI type V with lateral skull and cervical spine x-rays throughout childhood and after skeletal maturity.

Несовершенный остеогенез: современные аспекты этиологии, патогенеза, классификации (систематический обзор)

The constantly changing information about the genetic nature of osteogenesis imperfecta (OI), new approaches to classification and diagnosis, and the growing interest in this pathology require careful analysis and generalization of the available data in the recent literature. Purpose Analysis of recent literature on epidemiology, pathogenesis, etiology, classification of osteogenesis imperfecta. Materials and methods The literature search was carried out in the scientific literature databases of PubMed, Web of Science, Scopus, eLIBRARY, RSCI, and references of the key works. The following inclusion criteria were used: literature reviews, review articles, multicenter studies, cohort studies of patients with osteogenesis imperfecta. Results This systematic review included 18 publications that met the inclusion criteria. All selected publications were published within the period from 2012 to 2020. The study designs were review articles or literature reviews. Discussion Osteogenesis imperfecta is one of the most common types of skeletal dysplasia, a phenotypically and genetically heterogeneous group of hereditary bone diseases. OI is characterized by high variability of manifestations, even within the same type and one family. The results of the analysis of the prevalence of this disease in different population groups remain not fully covered. The degree of genetic heterogeneity of the disease has not yet been determined. Research is ongoing to identify new genes involved in the pathogenesis of OI. The introduction of modern methods for determining mutations in genes contributed to the progress of research into the molecular pathogenesis of osteogenesis imperfecta, and identification of new genes, mutations in which lead to OI. The large number of causative genes complicates the process of creating an optimal classification of OI. The difficulty of creating a comprehensive classification of OI subtypes is the fact that there is no clear phenotype-genotype relationship; based on the mutation, conclusions about its clinical severity cannot be drawn. Conclusion The classification of various types of osteogenesis imperfecta is still the subject of ongoing debate and research.

Несовершенный остеогенез: роль и место ортопедической хирургии нижних конечностей

Introduction Surgical correction of orthopedic problems in children and adults with severe osteogenesis imperfecta is of interest to the medical community. The aim of this study was to review the current relevant literature on the role of orthopedic surgery in the treatment of children and adults with osteogenesis imperfecta and the integration of surgery into a multidisciplinary approach to the treatment of patients with osteogenesis imperfecta. The review is based on the material of the report presented at the first educational conference of the European Pediatric Orthopedic Society which was held in Russia at the Ilizarov Center in 2021. Material and methods To prepare the review, we searched for information sources at the scientific platforms such as PubMed, Scopus, ResearchGate, RSCI, as well as published products (Elsevier, Springer). Results and discussion The review includes a discussion of the classification, indications, features of the surgical technique and the early postoperative period, the role of early functional loading, the features of long-term treatment results of using telescopic transphyseal constructs in the correction of deformities of lower limb long bones as well as issues of the combination of orthopedic surgery and bisphosphonate therapy. Conclusion Orthopedic support of children and adults with severe and moderate types of osteogenesis imperfecta requires construction of a multifactorial strategy that takes into account the requirements of physical therapy and medication treatment, as well as the use of specialized implants, instrumentation and methods of surgical intervention, while an optimal solution has been still sought.

Genotypic and Phenotypic Characteristics of 29 Patients With Rare Types of Osteogenesis Imperfecta: Average 5 Years of Follow-Up.

Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by bone fragility and abnormal connective tissue. Ninety percent of OI patients are caused by two mutations of COL1A1 and COL1A2, and more investigation was needed to better understand the rare types of OI. We followed up 29 patients with rare types of OI for an average of 5.4 years, and genotype, height, bone mineral density (BMD), blood biochemical indexes, misdiagnosis, and fracture were recorded. IFITM5 gene mutation was found in 18 patients (62.1%), which represents the most common pathogenic gene of rare types of OI in Chinese population. Thirteen cases had once been misdiagnosed, and the initial misdiagnosis rate was 44.8% (13/29). The higher misdiagnosis rate should be paid attention to by clinicians and healthcare providers, and we also give corresponding suggestions. Compared with the non-bisphosphonate treatment group, patients treated with bisphosphonates had higher lumbar spine BMD, fewer fractures, and lower levels of β-CTX and osteocalcin. However, there was no significant difference between OI type V patients and non-type V patients. Our study enriched the knowledge of genotype and phenotype characteristics of OI patients with rare types and bisphosphonate therapy.

Long-Term Follow-Up Outcomes of 19 Patients with Osteogenesis Imperfecta Type XI and Bruck Syndrome Type I Caused by FKBP10 Variants.

Osteogenesis imperfecta type XI (OI-XI) and Bruck syndrome type I (BS1) are two rare disorders caused by biallelic variants in the FKBP10, characterized by early-onset bone fractures and progressive skeletal deformities. The patients with OI-XI, also co-segregated with autosomal-recessive epidermolysis bullosa simplex caused by KRT14 variant, have been reported. In this study, the follow-up clinical features of the patients with OI-XI and BS1 phenotypes due to biallelic FKBP10 variants are compared. The aim of this study is to investigate the follow-up findings of OI-XI and BS1 phenotypes in patients with the FKBP10 variants. A total of 19 children, ten males and nine females, from 16 unrelated families were included in the study. FKBP10 variants were investigated by next-generation sequencing (NGS) based panel gene test or Sanger sequencing. Seventeen patients were followed between 1.5 and 16.8years, and the last follow-up age was between 2 and 24.6years (median 10.7years). They received intravenous bisphosphonate infusions once every 3months in follow-up period. We identified four different biallelic FKBP10 variants, two of which are novel (c.890_897dup TGATGGAC, p.Gly300Ter and c.1256 + 1G > A) in 16 families. Five of these patients also had findings of epidermolysis bullosa simplex, and the same biallelic c.612T > A (p.Tyr204Ter) variant in KRT14, as well as FKBP10, were identified. Twelve patients were diagnosed with OI-XI; whereas, seven were diagnosed with BS1. The BS1 phenotype was late-onset and the annual fracture number was lower. After bisphosphonate treatment, bone mineral densitometry Z score at L1-L4 increased (p = 0.005) and the number of annual fractures decreased (p = 0.036) in patients with OI-XI. However, no significant effect of bisphosphonate treatment was found on these values in BS1 patients. Despite the treatment, the rate of scoliosis and long bone deformity had increased in both groups at the last examination; and, only two patients could take a few steps with the aid of a walker, while others were not ambulatory, and they used wheelchairs for mobility. We identified two novel variants in FKBP10. Families originating from the same geographic region and having the same variant suggest founder effects. Although the number of fractures decreased with bisphosphonate treatment, none of our patients were able to walk during the follow-up. This study is valuable in terms of showing the follow-up findings of patients with FKBP10 variants for the first time.

The Stimulating Effect of Rosmarinic Acid and Extracts from Rosemary and Lemon Balm on Collagen Type I Biosynthesis in Osteogenesis Imperfecta Type I Skin Fibroblasts.

Rosemary extract (RE) and lemon balm extract (LBE) attract particular attention of pharmacists due to their high therapeutic potential. Osteogenesis imperfecta (OI) type I is a heritable disease caused by mutations in type I collagen and characterized by its reduced amount. The aim of the study was to evaluate the effect of the extracts and rosmarinic acid (RA) on collagen type I level in OI skin fibroblasts. Phytochemical analysis of RE and LBE was carried out by liquid chromatography–photodiode array detection–mass spectrometry. The expression of collagen type I at transcript and protein levels was analyzed by qPCR, ELISA, SDS-urea PAGE, and Western blot. In OI patient’s fibroblasts the exposure to the extracts (0.1–100 µg/mL) and RA (0.1–100 µM) significantly increased collagen type I and the best results were obtained with 0.1–10 µM RA and 0.1–10 µg/mL of the extracts. LBE showed a greater stimulating effect than RE, likely due to a higher RA content. Moreover, collagen type III expression and matrix metalloproteinase (MMP-1, -2, -9) activity remained unchanged or decreased. The obtained data support the clinical potential of RA-rich extracts and RA itself in modulating the quantitative defect of type I collagen in type I OI.

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.

Facial morphology analysis in osteogenesis imperfecta types I, III and IV using computer vision

AbstractObjectiveOsteogenesis imperfecta (OI) is an autosomal dominant genetic disease that mainly affects the COL1A1/A2 genes. Individuals affected by OI types I, III, and IV have been reported to demonstrate characteristic facial manifestations of the disease. This study aimed to quantitatively assess OI patients’ morphological characteristics.Materials and MethodsThis retrospective case‐control study involved 306 individuals (145 male and 161 female). It used automatic facial annotation and statistical shape analysis to compare facial photographs of individuals affected by OI types I, III, and IV with a normocephalic control group. Four facial ratios were used to compare facial proportions. Additionally, we proposed a novel approach to facial analysis using 68 landmarks and statistical shape analysis to compare morphological features. A predictive model (PCALog) was trained to detect whether a subject was affected by OI, based on facial landmarks.ResultsOur findings correlate with previous reports of OI type III patients’ facial characteristics being the most severely affected among the three types studied. Our novel approach facilitated an interpretation and comparison of morphological changes. Moreover, we successfully trained our PCALog model to automatically detect OI based on landmark features.ConclusionWe found patients’ facial manifestations of OI to be more pronounced at the level of the eyes and temples. Our morphological approach facilitates the comparison of various groups and should be considered for future craniofacial analysis studies. Machine learning models can be trained using facial landmarks to detect the presence of conditions that affect facial morphology.

Lethal and life-limiting skeletal dysplasias: Selected prenatal issues.

Skeletal dysplasias are a heterogeneous group of congenital bone and cartilage disorders with a genetic etiology. The current classification of skeletal dysplasias distinguishes 461 diseases in 42 groups. The incidence of all skeletal dysplasias is more than 1 in every 5000 newborns. The type of dysplasia and associated abnormalities affect the lethality, survival and long-term prognosis of skeletal dysplasias. It is crucial to distinguish skeletal dysplasias and correctly diagnose the disease to establish the prognosis and achieve better management. It is possible to use prenatal ultrasonography to observe predictors of lethality, such as a bell-shaped thorax, short ribs, severe femoral shortening, and decreased lung volume. Individual lethal or life-limiting dysplasias may have more or less specific features on prenatal ultrasound. The prenatal features of the most common skeletal dysplasias, such as thanatophoric dysplasia, osteogenesis imperfecta type II, achondrogenesis, and campomelic dysplasia, are discussed in this article. Less frequent dysplasias, such as asphyxiating thoracic dystrophy, fibrochondrogenesis, atelosteogenesis, and homozygous achondroplasia, are also discussed.

Pectus excavatum in osteogenesis imperfecta type I treated with Nuss procedure after pamidronate therapy

Osteogenesis imperfecta is a genetic disorder caused by mutations in genes affecting type I collagen that is mostly found in bone, skin and tendons. In addition to bone fragility and increased risk of fractures, patients with osteogenesis imperfecta can have chest wall deformities including pectus excavatum and pectus carinatum. Cardiorespiratory problems caused by these deformities is the major cause of morbidity and mortality in these patients. Outcomes of surgical correction of pectus excavatum in patients with osteogenesis imperfecta have not been described in the literature. It is important to establish definitive treatment options for these patients to improve their respiratory capacity and reduce mortality. In this case series we present the case of two pre-pubertal pediatric patients with osteogenesis imperfecta type I who underwent surgical correction of pectus excavatum with the Nuss procedure after pamidronate therapy. Both patients had successful correction of the chest wall deformity with significant improvement in their quality of life. • Osteogenesis imperfecta is a rare genetic disorder that causes bone fragility. • Pectus excavatum can be associated with this disease, however the number of cases is limited. • Bisphosphonate therapy can be given prior to undergoing Nuss procedure in patients with osteogenesis imperfecta type I.

A Case With Adult GH Deficiency Complicated With Osteogenesis Imperfecta: Effect of GH Replacement on Bone Mineral Density

Background: Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with many phenotypic presentations. Bisphosphonates are the mainstay of pharmacologic fracture prevention therapy, although they aren’t officially approved for the treatment of OI. Clinical Case: The patient was born by breech delivery. After he had multiple fractures at the age of two years, he was diagnosed with osteogenesis imperfecta (OI) type I by genetic analysis (c.1299 + 1G> A mutation in the COL1A1 gene). On the growth curve, his height fell below -2SD at the age of six years. When he was 12 years old, he visited another hospital because of short stature (Hight 119 cm: -2.7SD). Pituitary MRI revealed pituitary stalk disruption and pituitary atrophy. Endocrinological examinations (ITT, TRH, LHRH, arginine stimulation tests) showed severe GH deficiency. Growth hormone replacement therapy was started. At the age of 16 years, he was diagnosed to have central hypothyroidism and central diabetes insipidus, and levothyroxine and DDAVP were started. His bone mineral density of the lumbar spine was 0.546 g/cm2, and alendronate was started. At the age of 17, central hypogonadism was diagnosed by LHRH stimulation test, and HCG injections were initiated. His bone mineral density continued to increase by GH replacement, HCG injections and bisphosphonate and reached 0.820 g/cm2 (Z-score: -0.27) by the age of 18 years. GH replacement was discontinued (final height 180 cm). At that age, his bone mineral density declined to 0.717 g/cm2 at the age of 25 years, although he stayed on an alendronate and HCG injections. At that time, total testosterone 890 ng/dL (142<n<923 ng/dL) was within normal range, but IGF-1 level was below the lower limit (44 ng/mL; -4.6SD, 225<n<337 ng/mL). He was referred to our hospital for transition to adult endocrine care. Endocrinologic evaluation revealed low serum cortisol level in the early morning (2.26 µg/dL, 7.07<n<19.6 μg/dL). GH-releasing peptide-2 stimulation test revealed severe GH deficiency (peak GH 0.18 ng/mL, n> 15 ng/mL (1)) and replacements with GH and hydrocortisone were initiated. After the GH replacement, the bone mineral density started to increase to 0.954 g/cm2 (Z-score: -0.5). Conclusion: So far as we know, this is the first case report of OI with panhypopituitarism treated with GH and bisphosphonate. This case suggests that bisphosphonate alone is not sufficient to maintain bone mineral density complicated with both OI and severe GHD. GH replacement therapy was inevitable to increase bone mineral density in this patient. Reference: (1) Kazuo Chihara et al. A simple diagnostic test using GH-releasing peptide-2 in adult GH deficiency. Eur J Endocrinol.2007;157;19-27.

Increased Osteocyte Lacunae Density in the Hypermineralized Bone Matrix of Children with Osteogenesis Imperfecta Type I.

Osteocytes are terminally differentiated osteoblasts embedded within the bone matrix and key orchestrators of bone metabolism. However, they are generally not characterized by conventional bone histomorphometry because of their location and the limited resolution of light microscopy. OI is characterized by disturbed bone homeostasis, matrix abnormalities and elevated bone matrix mineralization density. To gain further insights into osteocyte characteristics and bone metabolism in OI, we evaluated 2D osteocyte lacunae sections (OLS) based on quantitative backscattered electron imaging in transiliac bone biopsy samples from children with OI type I (n = 19) and age-matched controls (n = 24). The OLS characteristics were related to previously obtained, re-visited histomorphometric parameters. Moreover, we present pediatric bone mineralization density distribution reference data in OI type I (n = 19) and controls (n = 50) obtained with a field emission scanning electron microscope. Compared to controls, OI has highly increased OLS density in cortical and trabecular bone (+50.66%, +61.73%; both p < 0.001), whereas OLS area is slightly decreased in trabecular bone (−10.28%; p = 0.015). Correlation analyses show a low to moderate, positive association of OLS density with surface-based bone formation parameters and negative association with indices of osteoblast function. In conclusion, hyperosteocytosis of the hypermineralized OI bone matrix associates with abnormal bone cell metabolism and might further impact the mechanical competence of the bone tissue.

Lethal osteogenesis imperfecta type XX caused by compound heterozygous frameshift mutations in MESD

Lethal osteogenesis imperfecta type XX caused by compound heterozygous frameshift mutations in MESD

Detection of a Recurrent TMEM38B Gene Deletion Associated with Recessive Osteogenesis Imperfecta.

Osteogenesis imperfecta is a clinically and genetically group of heterogeneous disorders associated with decreased bone density, brittle bones, bone deformity, recurrent fractures, and growth retardation. Osteogenesis imperfecta is commonly associated with mutations of the genes encoding for type I collagen (COL1A1/COL1A2). Mutations in other genes, some associated with type I collagen post-translational processing, have also been identified as the cause of osteogenesis imperfecta. Mutations in the transmembrane protein 38B (TMEM38B) gene have been reported in a rare autosomal recessive form of osteogenesis imperfecta. TMEM38B encodes TRIC-B - a trimeric intracellular cation channel type B which is essential to modulate intracellular calcium signaling. In this study, we are reporting a case of osteogenesis imperfecta type XIV from a Saudi consanguineous family. Our patient was an eight-month-old child with short limbs, club feet, and lower limb deformities with developmental delay. Radiological findings were consistent with the evidence of osteogenesis imperfecta. There was no evidence of impaired hearing or blue sclera and based on the clinical assessment, we classified our patient as a non-syndromic osteogenesis imperfecta. A pathogenic deletion in the chromosome 9q31.2 region, partially encompassing the TMEM38B gene, was detected using chromosomal microarray analysis. This study expands our knowledge about the rare type of osteogenesis imperfecta in our consanguineous population. Besides, it emphasizes the use of genomic medicine in clinical practices to formulate early interventions to clinically improve the patient’s condition.

Osteogenesis imperfecta tooth level phenotype analysis: Cross-sectional study.

Dental anomalies in Osteogenesis imperfecta (OI), such as tooth discoloration, pulp obliteration (calcified dental pulp space), and taurodontism (enlarged dental pulp space) vary between and within patients. To better understand the associations and variations in these anomalies, a cross-sectional study was designed to analyze the dental phenotype in OI patients at the individual tooth type. A cohort of 171 individuals with OI type I, III and IV, aged 3-55 years, were recruited and evaluated for tooth discoloration, pulp obliteration, and taurodontism at the individual tooth level, using intraoral photographs and panoramic radiographs. Genetic variants were identified in 154 of the participants. Patients with Helical α1 and α2 glycine substitutions presented the highest prevalence of tooth discoloration, while those with α1 Haploinsufficiency had the lowest (<10%). C-propeptide variants did not cause discoloration but resulted in the highest pulp obliteration prevalence (~%20). The prevalence of tooth discoloration and pulp obliteration was higher in OI types III and IV and increased with age. Tooth discoloration was mainly observed in teeth known to have thinner enamel (i.e. lower anterior), while pulp obliteration was most prevalent in the first molars. A significant association was observed between pulp obliteration and tooth discoloration, and both were associated with a lack of occlusal contact. Taurodontism was only found in permanent teeth and affected mostly first molars, and its prevalence decreased with age. The dental phenotype evaluation at the tooth level revealed that different genetic variants and associated clinical phenotypes affect each tooth type differently, and genetic variants are better predictors of the dental phenotype than the type of OI. Our results also suggest that tooth discoloration is most likely an optical phenomenon inversely proportional to enamel thickness, and highly associated with pulp obliteration. In turn, pulp obliteration is proportional to patient age, it is associated with malocclusion and likely related to immature progressive dentin deposition. Taurodontism is an isolated phenomenon that is probably associated with delayed pulpal maturation.