Novel pathogenic variants in SPARC as cause of osteogenesis imperfecta: Two case reports.

Pathogenic variants in SPARC cause a rare autosomal recessive form of osteogenesis imperfecta (OI), classified as OI type XVII, which was first reported in 2015. Only six patient cases with this specific form of OI have been reported to date. The SPARC protein plays a crucial role in the calcification of collagen in bone, synthesis of the extracellular matrix, and the regulation of cell shape. In this case report, we describe the phenotype of two patients with SPARC-related OI, including a patient with two novel pathogenic variants in the SPARC gene. Targeted Next Generation Sequencing revealed new compound heterozygous variants (c.484G > A p.(Glu162Lys)) and c.496C > T p.(Arg166Cys)) in one patient and a homozygous nonsense pathogenic variant (c.145C > T p.(Gln49*)) in the other. In line with previously reported cases, the two OI patients presented delayed motor development, muscular weakness, scoliosis, and multiple fractures. Interestingly, our study reports for the first time the occurrence of dentinogenesis imperfecta. The study also reports the effectiveness of bisphosphonate treatment for OI type XVII. This article enhances the genetic, clinical, therapeutic, and radiological understanding of SPARC-related OI.

Polyostotic Fibrous Dysplasia Mimicking Bone Involvement in Hodgkin Lymphoma: A Pediatric Case and Literature Review.

Bone involvement in Hodgkin lymphoma (HL) is rare. The differential diagnosis between HL bone localization and other malignant or benign skeletal diseases is challenging. We report the case of a girl affected by classic HL, initially staged IVA because of supradiaphragmatic lymph nodes and skeletal involvement. After 6 ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) cycles, positron emission tomography (PET) showed a complete metabolic response of the nodal localizations and a persistent, high metabolic activity of bone lesions. Salvage treatment followed by autologous stem cell transplant was carried out. After the transplant, the bone lesions maintained a high metabolic activity at PET. A targeted bone biopsy led to the diagnosis of a fibrous dysplasia excluding the presence of HL. To our knowledge, the concomitant presence of HL and fibrous dysplasia has not been previously reported. An in-depth evaluation of disease response to frontline treatment with a biopsy of the PET-hypercaptant bone lesions could have avoided overtreatment in this patient.

New 3D Cone Beam CT Imaging Parameters to Assist the Dentist in Treating Patients with Osteogenesis Imperfecta.

(1) Background: The aim of the work is to identify some imaging parameters in osteogenesis imperfecta to assist the dentist in the diagnosis, planning, and orthodontic treatment of Osteogenesis Imperfecta (OI) using 3D cone beam Computed Tomography (CBCT) and the Double Energy X-ray Absorptiometry (DEXA) technique. (2) Methods: 14 patients (9 males and 5 females; aged mean ± SD 15 ± 1.5) with a clinical-radiological diagnosis of OI were analyzed and divided into mild and moderate to severe forms. The patients' samples were compared with a control group of 14 patients (8 males and 6 females; aged mean ± SD 15 ± 1.7), free from osteoporotic pathologies. (3) Results: The statistical analysis allowed us to collect four datasets: in the first dataset (C1 sick population vs. C1 healthy population), the t-test showed a p-value < 0.0001; in the second dataset (C2 sick population vs. C2 healthy population), the t-test showed a p-value < 0.0001; in the third dataset (parameter X of the sick population vs. parameter X of the healthy population), the t-test showed a p-value < 0.0001; in the fourth dataset the bone mineralometry (BMD) value detected by the DEXA technique compared to the C2 value of the OI affected population only) the Welch-Satterthwaite test showed a p-value < 0.0001. (4) Conclusions: The research has produced specific imaging parameters that assist the dentist in making diagnostic decisions in OI patients. This study shows that patients with OI have a characteristic chin-bearing symphysis, thinned, and narrowed towards the center, configuring it with a constant "hourglass" appearance, not reported so far in the literature by any author.

Elastic intramedullary nailing of the femur fracture in patients affected by osteogenesis imperfecta type 3: Indications, limits and pitfalls.

INTRODUCTION: Patients with Osteogenesis Imperfecta (OI) Type 3 may exhibit both primitive deformities and secondary fracture malunions on a femoral level. The orthopaedic surgeon's objective is to cure the deformities in order to prevent fractures and to treat the fractures in order to prevent deformities, by using telescopic nails as the gold standard method of fixation. However, the titanium elastic nail (TEN) is indicated as a possible alternative in certain selected cases. MATERIALS AND METHODS: The Centre for Congenital Osteodystrophy of the Sapienza University of Rome follows 485 patients with osteogenesis imperfecta. For the purpose of this study, we selected 36 patients with OI type 3 (15 females and 21 males), aged between 2 and 10 years old, who were surgically treated for femur fractures with Titanium Elastic Nail (TEN) from January 2007 to December 2009. In 12 cases a single TEN was implanted, while 24 of the cases were treated by implanting 2 TENs with the Sliding Nail (SN) technique. A retrospective evaluation was carried out by analysing the data from the medical charts and dossiers related to pain symptoms, knee and hip Range of Motion (ROM), any possible complications that could cause implant revisions (infections, nail slide failure, nail migration, traumatic events following surgery, delayed consolidation, epiphysiodesis). RESULTS: At the 60th post-surgical month, the revision rate was 75%, mostly due to migration, osteolysis, nail slide failure and nail fracture. The Kaplan-Meier's survival curve analysis showed a coefficient of 0.25-60 months (confidence interval -0.31 and 0.81). DISCUSSION: The percentage of complications and the high rate of revisions recorded in our sample confirm that telescopic nail is the gold standard in the treatment of femoral fractures in patients with OI type 3. CONCLUSIONS: In patients under the age of 4, with narrow medullary canals, low life expectancy, few to nil rehabilitative prospectives or severe comorbidities, the use of TEN may be considered as a less invasive approach compared to telescopic nail surgery, however only temporarily, as it will still most probably require a surgical revision a few years down the line.

Genotype-phenotype correlation study in 364 osteogenesis imperfecta Italian patients.

Osteogenesis imperfecta (OI) is a rare genetic disorder of the connective tissue and 90% of cases are due to dominant mutations in COL1A1 and COL1A2 genes. To increase OI disease knowledge and contribute to patient follow-up management, a homogeneous Italian cohort of 364 subjects affected by OI types I-IV was evaluated. The study population was composed of 262 OI type I, 24 type II, 39 type III, and 39 type IV patients. Three hundred and nine subjects had a type I collagen affecting function mutations (230 in α1(I) and 79 in α2(I)); no disease-causing changes were noticed in 55 patients. Compared with previous genotype-phenotype OI correlation studies, additional observations arose: a new effect for α1- and α2-serine substitutions has been pointed out and heart defects, never considered before, resulted associated to quantitative mutations (P = 0.043). Moreover, some different findings emerged if compared with previous literature; especially, focusing the attention on the lethal form, no association with specific collagen regions was found and most of variants localized in the previously reported "lethal clusters" were causative of OI types I-IV. Some discrepancies have been highlighted also considering the "50-55 nucleotides rule," as well as the relationship between specific collagen I mutated region and the presence of dentinogenesis imperfecta and/or blue sclera. Despite difficulties still present in defining clear rules to predict the clinical outcome in OI patients, this study provides new pieces for completing the puzzle, also thanks to the inclusion of clinical signs never considered before and to the large number of OI Italian patients.

Treatment of tibial deformities with the Fassier-Duval telescopic nail and minimally invasive percutaneous osteotomies in patients with osteogenesis imperfecta type III.

Osteogenesis imperfecta (OI) is a rare congenital osteodystrophy. Patients with OI present with osteoporosis, extreme bone fragility and severe deformities of the lower limbs, which predispose them to frequent fractures. The aim of our study is to describe the minimally invasive osteotomy technique to correct the tibial deformities in patients with OI type III, using the Fassier-Duval (FD) intramedullary nailing, which is considered the gold standard in this kind of surgery. We analyzed the results obtained from 14 patients with OI type III, treated for tibial deformities with the minimally invasive percutaneous osteotomy technique and osteosynthesis with the FD telescopic nail. The results were compared with that of a control group composed of 18 patients with OI type III, treated for tibial deformities with open technique osteotomies and osteosynthesis with FD telescopic nail. The follow-up was set at 18 months postoperatively. The data concerning the following were collected from the two groups: duration of surgery, number of osteotomies performed, postoperative pain, time required for functional recovery, and for the formation of bone callus. To analyze the variations in the quality of life, all the patients were given the Pediatric Outcomes Data Collection Instrument questionnaire, before surgery and at the end of the follow-up. In patients who underwent corrective surgery with the percutaneous technique, the average duration of surgery was inferior, the postoperative pain was significantly lower, the recovery of 90° range of motion of knee flexion was reached at an average of 37.8 days, and they ambulated bearing full weight on the leg without auxiliary aids on average 45 days after surgery. The Pediatric Outcomes Data Collection Instrument questionnaire values were satisfactory in both groups. The osteosynthesis with the FD telescopic nail, performed with the minimally invasive surgical technique, has improved the management of deformities in OI. The minimally invasive technique, however, requires the maturation of three distinct learning curves: surgery on patients with OI, open technique with the FD nail, and percutaneous technique with the FD nail.

Intraoperative bleeding in patients with osteogenesis imperfecta type III treated by Fassier-Duval femoral rodding: analysis of risk factors.

The surgical treatment of osteogenesis imperfecta (OI) is negatively influenced by clinical features such as osteoporosis, limb deformities and bone changes caused by bisphosphonate therapy. Blood loss during femoral nailing surgeries in patients with OI is a serious problem. Platelet anomalies have been associated with an elevation of the serum pyrophosphate originating from the platelets during clotting, even if the causality with the platelet dysfunction has not yet been established. To identify predictive risk factors regarding intraoperative bleeding, a retrospective analysis was conducted on 23 patients aged between 6 and 13 years, affected by OI type III, who were treated to correct femoral deformities or to perform an osteosynthesis for femoral shaft fractures, using the Fassier-Duval telescopic nail. Osteotomies were performed in 14 cases of deformities and in two out of seven cases of fractures. A survey about the bleeding had been obtained by calculating the sum of the blood aspirated and that lost with the gauzes or present on the surgical drapes. To obtain an estimate of the intraoperative blood losses, one must resort to a calculation based on an algorithm that evaluates the ratio between the effective blood loss divided by the total blood volume expected as per age and weight (γ distribution). The average blood loss was 237.4 ml (0.12 γ). In seven cases, it was necessary to perform postoperative transfusions, owing to an average blood loss of 502.8 ml (0.27 γ). Patients aged less than 10 years had a minor blood loss. A greater number of osteotomies was associated with a significant increase of average bleeding (P=0.046). Patients who were never treated with bisphosphonates showed a significantly greater bleeding rate (P=0.048). Patients affected by OI type III have a high risk of severe blood loss during surgery, even caused by the platelet disfunction, which characterizes this OI type. In addition to this predisposing factor, there are other risk factors to consider in preoperative surgical planning. In patients who were never treated with bisphosphonates, the bleeding was higher than in the ones treated with bisphosphonates since at least 1 year. The effects of bisphosphonates on bone tissue (such as the medullar canal narrowing and the bone cortex thickening) could reduce the spongious bone amount and the bleeding. Inhibiting the farnesyl pyrophosphate synthase enzyme and reducing the prenylation of many plasma proteins, including the methylene tetrahydrofolate reductase, the bisphosphonates could lead to an alteration of the coagulation cascade. The correlation found with the intake of bisphosphonates, capable of inhibiting the action of the farnesyl pyrophosphate synthase enzyme, thus influencing coagulation, requires further prospective studies with research of the methylene tetrahydrofolate reductase mutation in patients with OI type III undergoing surgical procedures. The number of osteotomies, the patient's age and the intake of bisphosphonates for at least 1 year seem to be the best predictive factors for blood loss.

Isolated olecranon fractures in children affected by osteogenesis imperfecta type I treated with single screw or tension band wiring system: Outcomes and pitfalls in relation to bone mineral density.

The purpose of this study is to compare the results of 2 techniques, tension band wiring (TBW) and fixation with screws, in olecranon fractures in children affected with osteogenesis imperfecta (OI) type I. Between 2010 and 2014, 21 olecranon fractures in 18 children with OI (average age: 12 years old) were treated surgically. Ten patients were treated with the screw fixation and 11 with TBW. A total of 65% of olecranon fractures occurred as a result of a spontaneous avulsion of the olecranon during the contraction of the triceps muscle. The average follow-up was 36 months. Among the children treated with 1 screw, 5 patients needed a surgical revision with TBW due to a mobilization of the screw. In this group, the satisfactory results were 50%. In patients treated with TBW, the satisfactory results were 100% of the cases. The average Z-score, the last one recorded in the patients before the trauma, was -2.53 in patients treated with screw fixation and -2.04 in those treated with TBW. TBW represents the safest surgical treatment for patients suffering from OI type I, as it helps to prevent the rigidity of the elbow through an earlier recovery of the range of motion, and there was no loosening of the implant. In analyzing the average Z-score before any fracture, the fixation with screws has an increased risk of failure in combination with low bone mineral density.

Osteogenesis imperfecta and clubfoot-a rare combination: Case report and review of the literature.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare congenital genetic osteodystrophy, which has a prevalence of 1:20,000. OI is caused by the mutation of the COL1A1/COL1A2 genes, leading to a deficit of quality and/or quantity in the synthesis of procollagen-α type 1. Seven different forms of diverse clinical entity have been classified by Sillence and Glorieux, although, recently, up to 11 forms characterized by different genetic mutations have been recognized. Patients with OI suffer from extreme bone fragility and osteoporosis, which often predisposes them to frequent fractures. This paper presents the case of a child with OI type IV who, at birth, was also diagnosed with a severe clubfoot (congenital talipes equinovarus) grade III. Patient's mother also suffers from OI type IV. METHODS: The treatment was started by placing femoro-podalic corrective casts, according to the Ponseti method, but some unexpected problems occurred during this treatment. When the patient was 3 months of age, we decided to correct the clubfoot before the time limit planned, performing a bilateral posteromedial surgical release. RESULTS: Three weeks after surgery the casts were removed and replaced with bilateral Spica cast-like braces. On the 6th postoperative week, the patient began wearing Bebax corrective shoes, after 1 year ambidextrous orthopedic shoes. Now, he is 2 years old and has started to walk properly without any orthesis. CONCLUSION: In the presence of an orthopedic pathology associated with OI, it is recommended to manage the patient according to the underlying pathology, always considering the bone fragility associated with OI. The final surgical treatment to correct the clubfoot can be done earlier, if necessary. In our opinion, this uncommon association between OI and clubfoot is non-syndromic. This means that the two congenital diseases are not necessarily included in a singular uncommon genetic syndrome, but the clubfoot was caused by multifactorial causes, especially by both the mother's bisphosphonate drug therapy and the amniocentesis performed during her pregnancy to drain polyhydramnios. In our analysis, those environmental factors could have interacted with an already altered genetic substratum, contributing to develop this rare combination of congenital disorders.

Osteogenesis imperfecta and rapid maxillary expansion: Report of 3 patients.

INTRODUCTION: The aim of this study was to analyze the effects of orthopedic therapy with rapid maxillary expansion (RME) in growing patients affected by osteogenesis imperfecta and treated with bisphosphonates. METHODS: Three boys with osteogenesis imperfecta (mean age, 10.6 years) were treated with RME. They all had treatment with quarterly intravenous infusions of bisphosphonates. They were in either the early or the late mixed dentition and had indications for RME. The expansion screw was activated twice daily until correction of the transverse relationships was achieved. The retention period with the expander in place was 6 months. In 2 Class III patients, RME was associated with the use of a facemask. In all patients, occlusal radiographs were taken at the end of active RME therapy to assess the opening of the midpalatal suture and 1 year after the end of active expansion therapy to evaluate the reossification and reorganization of the midpalatal suture. RESULTS: In all patients, the opening of the midpalatal suture and the healing with reorganization of the midpalatal suture were documented with the occlusal radiographs. No complications were found after a 1-year follow-up. CONCLUSIONS: In growing patients affected by osteogenesis imperfecta and treated with bisphosphonates, it is possible to perform RME with a standard protocol with no complications after a 1-year follow-up.

Osteochondritis dissecans of the lateral femoral condyle in a patient affected by osteogenesis imperfecta: a case report.

Osteochondritis dissecans is a very uncommon phenomenon in osteogenesis imperfecta (OI). A 14-year-old boy, affected by OI and followed in our Center for Congenital Osteodystrophies, had a knee trauma and MRI indicated a hollowed area of 2.5×1.5 cm in the lateral femoral condyle, which was classified as grade III. The patient underwent surgery, performed as a one-step surgical treatment: the osteochondral fragment was removed, curettage of lesion's bottom was performed, and a biphasic scaffold was used to fill the defect, implanted with a press-fit technique. MRI at 12 and 24 months after surgery showed scaffold integration. At the final follow-up, the patient did not feel any pain or articular limitations. It is difficult to provide a guideline on osteochondritis dissecans in patients affected by OI because of the lack of literature reports on this rare disorder in a rare disease. According to our experience, in these patients, osteosynthesis of the bone fragment and the use of autograft are not recommended because of the patient's bone weakness and osteoporosis. Moreover, compared with two-step surgery, one-step surgery is preferred to reduce the risk related to anesthesia, often observed to be higher in these patients.

Serum brain-type creatine kinase increases in children with osteogenesis imperfecta during neridronate treatment.

BACKGROUND: Creatine kinase (Ck) catalyzes the reversible transfer of high-energy phosphate groups between adenosine triphosphate and phosphocreatine. The brain isoform (Ckbb) is greatly induced in mature osteoclasts, playing an important role in bone-resorbing function during osteoclastogenesis. High Ckbb serum level has been found in patients with osteopetrosis and in patients with bisphosphonate (BP)-induced osteopetrosis. BPs are considered the treatment of choice for children with osteogenesis imperfecta (OI), acting as potent inhibitors of bone resorption by suppressing the activity of osteoclasts. METHODS: We determined total serum Ck and isoform activity in 18 prepubertal children with type I OI, before and during treatment with the BP neridronate infusions. RESULTS: Basal serum Ckbb levels were slightly elevated with respect to controls (mean ± SD = 3.0 ± 2.7 vs. 2.0 ± 2.2) and progressively increased after neridronate treatment (t0 vs. t4: mean ± SD = 3.0 ± 2.7 to 10.8 ± 8.1), with significant increment after first, second, and fourth infusions (P < 0.01). An inverse correlation was found between serum Ckbb and serum CTx at basal level. CONCLUSION: Our results support previous observations that increased serum Ckbb reflects failure of osteoclasts or, at least, suppression of osteoclasts. Upon considering that BPs are long acting, this information could be useful to prevent the risk of overtreatment after long-term BP exposure in pediatric patients with OI.

Child abuse and osteogenesis imperfecta: how can they be still misdiagnosed? A case report.

Osteogenesis imperfecta (OI) is a rare hereditary disease caused by mutations in genes coding for type I collagen, resulting in bone fragility. In literature are described forms lethal in perinatal period, forms which are moderate and slight forms where the only sign of disease is osteopenia. Child abuse is an important social and medical problem. Fractures are the second most common presentation after skin lesions and may present specific patterns.The differential diagnosis between slight-moderate forms of OI and child abuse could be very challenging especially when other signs typical of abuse are absent, since both could present with multiple fractures without reasonable explanations. We report a 20 months-old female with a history of 4 fractures occurred between the age of three and eighteen months, brought to authorities' attention as a suspected child abuse.However when she came to our department physical examination, biochemical tests, total body X-ray and a molecular analysis of DNA led the diagnosis of OI.Thus, a treatment with bisphosphonate and a physical rehabilitation process, according to Vojta method, were started with improvement in bony mineralization, gross motor skills and absence of new fracture.In conclusion our case demonstrates how in any child presenting fractures efforts should be made to consider, besides child abuse, all the other hypothesis even the rarest as OI.

Celiac disease and lamellar ichthyosis. Case study analysis and review of the literature.

We describe a 5-year-old female affected by lamellar ichthyosis, diagnosed in the first month of life, who attended our pediatric clinic for Mycoplasma pneumoniae pneumonia. The evidence of severe osteoporosis with hyperparathyroidism secondary to malabsorption suggested the occurrence of celiac disease. Endoscopy with multiple duodenal biopsies revealed total villous atrophy. The child started a gluten-free diet, supported by oral calcium and vitamin D. After 1-year follow-up, the girl showed complete normalization of bone mineral density. The introduction of the gluten-free diet did not lead to lesion repair, but the child reported significant improvement of her quality of life.

Ebstein's anomaly in a child with osteogenesis imperfecta type I.

Cardiovascular involvement is relatively rare in osteogenesis imperfecta and has a predilection for left-sided cardiac valves. We report a 5 years old female child affected by osteogenesis imperfecta type I in which an asymptomatic mild form of Ebstein's anomaly, a congenital tricuspid malformation, was diagnosed during routinely investigation. The association of these two relatively rare entities could provide new insight to better understand the pathogenesis of cardiac involvement in osteogenesis imperfecta.

Impairment of diastolic function in adult patients affected by osteogenesis imperfecta clinically asymptomatic for cardiac disease: casuality or causality?

Osteogenesis imperfecta (OI) is a rare inherited connective disorder causing increased bone fragility and low bone mass. OI includes severe bone fragility, impaired dentinogenesis, with less common alterations in the joints, blood vessels, heart valves, skin. Interestingly, description of left ventricular rupture, aortic dissection and heart valves incompetence has been previously described. Death may occur in OI patients for cardiac disease in asyntomatic subjects. Aim of our study has been to evaluate the presence of potential subclinical cardiac disorders and to characterize cardiac functional parameters by echocardiography in adults with OI in absence of cardiac symptoms. Forty patients (21 females and 19 males) affected by type I, III, IV OI and 40 control subjects (20 females and 20 males) were evaluated in the study. Patients and controls underwent clinical examination, screening for endocrine and metabolic disorders, 12-lead electrocardiogram and echocardiogram. In particular, all subjects were evaluated by two-dimensional echocardiography with continuous- and pulse-wave Doppler. Patients and controls belonged to NYHA class I and no significant electrocardiographic alteration was documented in both groups. Thirty-eight patients (95%) showed valvular regurgitation compared to one control subject (2.5%; P<0.001). As regards the diastolic function parameters, in OI patients E wave velocity was reduced by 23% (95% CI: 9% to 29%; P<0.001), E/A ratio was reduced by 17% (95% CI: 15% to 26%; P<0.001) while isovolumetric relaxation time (IRT) was increased by 47% (95% CI: 26% to 53%; P<0.001) and E wave deceleration time (DT) was increased by 18% (95% CI: 13% to 26%; P<0.001) compared to controls. In conclusion, our data indicate that adult patients affected by OI have an altered diastolic function in absence of other metabolic alterations. These diastolic echocardiographic parameters might worsen over time, especially if other cardiovascular risk factors (e.g., smoking, hypertension, metabolic and endocrine alterations) are not carefully checked, monitored and treated. In the context of a multidisciplinary evaluation of OI patients, our data suggest that a careful cardiological evaluation of these patients is indicated beside skeletal evaluation and therapeutical skeletal options.