Correlation of serum DKK1 level with skeletal phenotype in children with osteogenesis imperfecta.

PURPOSE: We aim to detect serum DKK1 level of pediatric patients with OI and to analyze its relationship with the genotype and phenotype of OI patients. METHODS: A cohort of pediatric OI patients and age-matched healthy children were enrolled. Serum levels of DKK1 and bone turnover biomarkers were measured by enzyme-linked immunosorbent assay. Bone mineral density (BMD) was measured by Dual-energy X-ray absorptiometry. Pathogenic mutations of OI were detected by next-generation sequencing and confirmed by Sanger sequencing. RESULTS: A total of 62 OI children with mean age of 9.50 (4.86, 12.00) years and 29 healthy children were included in this study. The serum DKK1 concentration in OI children was significantly higher than that in healthy children [5.20 (4.54, 6.32) and 4.08 (3.59, 4.92) ng/mL, P < 0.001]. The serum DKK1 concentration in OI children was negatively correlated with height (r = - 0.282), height Z score (r = - 0.292), ALP concentration (r = - 0.304), lumbar BMD (r = - 0.276), BMD Z score of the lumbar spine and femoral neck (r = - 0.32; r = - 0.27) (all P < 0.05). No significant difference in serum DKK1 concentration was found between OI patients with and without vertebral compression fractures. In patients with spinal deformity (22/62), serum DKK1 concentration was positively correlated with SDI (r = 0.480, P < 0.05). No significant correlation was observed between serum DKK1 concentration and the annual incidence of peripheral fractures, genotype and types of collagen changes in OI children. CONCLUSION: The serum DKK1 level was not only significantly elevated in OI children, but also closely correlated to their skeletal phenotype, suggesting that DKK1 may become a new biomarker and a potential therapeutic target of OI.

An Analysis From a Tertiary Pediatric Hospital: Does Physical Activity Play a Role in the Management of Children and Young Adults With Osteogenesis Imperfecta?

INTRODUCTION: Osteogenesis imperfecta (OI) is a hereditary connective tissue disorder characterized by reduced bone density and increased proneness to fractures. It manifests across a varied clinical spectrum of expressions in children and young adults. It is crucial for children with OI to have a multidisciplinary follow-up, including orthopedics, pediatrics, and physical medicine and rehabilitation. Although exercise may have no effect on the disease itself, it might improve the autonomy, self-esteem, and fitness of these children.  Methods: Retrospective cohort analysis of children and young adults aged three or more years old followed-up in a Level III Pediatric Hospital between 1995 and 2020. Demographic and clinical data were obtained from the hospital records and from the caregivers via phone calls. To our knowledge, this is the first national case series published assessing exercise habits in children with this condition. RESULTS: Among the 21 patients studied, the median age was 14 years, with no gender predominance. Eighteen (86%) practiced regular physical activity, while the remaining three (14%), all of whom were type III OI, were totally dependent. Of the aforementioned 18 children, 12 (67%) considered practicing the same level of physical activity compared to their healthy peers, although most of them needed adaptations. The most reported extracurricular activity was swimming, in 50% of the cases. About 39% engaged in physical activity two times or less per week, and 89% practiced for one hour or less per session. DISCUSSION: Over the years, it has become clear that physical activity is an important part of OI management. While awareness of the importance of exercise already exists, proper planning, follow-up, and monitoring are essential.

Spinal Cord Ischemia After Lower Extremity Surgery in Pediatric Osteogenesis Imperfecta With Thoracic Kyphoscoliosis: Tertiary Care Center Experience in Jeddah, Saudi Arabia.

Osteogenesis imperfecta is a rare genetic disorder of type 1 collagen which primarily affects children and leads to recurrent bone fractures. In addition, spinal abnormalities can also occur. We report a case of a 13-year-old male with osteogenesis imperfecta type III, associated with severe femur deformity and thoracic kyphoscoliosis, who developed neurological injury after lower extremity surgery. The patient was in a supine position when general anesthesia was administered. The operation lasted for approximately 250 minutes, and anesthesia for 310 minutes, with an estimated blood loss of 600 cc. Apart from a low mean arterial pressure value (45 mm Hg) intraoperatively, the procedure was uneventful. Early postoperatively, he developed spinal paralysis at the level of T4-T7, and an MRI of the spine demonstrated high signal intensity within the spinal cord from level T3 to T7. Subsequently, he was admitted to the pediatric intensive care unit for further assessment and management. Follow-up revealed recovery of paralysis after 12 months.

The role of osteocalcin in regulation of glycolipid metabolism and muscle function in children with osteogenesis imperfecta.

Objective: Osteoblasts are discovered to secrete hormones with endocrine effects on metabolism, and osteocalcin (OC) is the most abundant non-collagenous protein in bone. We investigate the relationship between serum OC levels and glycolipid metabolism and muscle function in children with osteogenesis imperfecta (OI). Methods: A total of 225 children with OI and 80 healthy controls matched in age and gender were included in this single center study. Serum levels of fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), low- and high-density lipoprotein cholesterol (LDL-C, HDL-C) were measured by automated analyzers. Serum levels of fasting insulin (FINS) were measured using an automated electrochemiluminescence system. Serum levels of OC and undercarboxylated osteocalcin (ucOC) were measured by enzyme-linked immunosorbent assay. Grip strength and timed-up-and-go (TUG) test were measured. Bone mineral density (BMD) and body composition were measured using dual-energy X-ray absorptiometry. Results: OI patients had significantly higher body mass index (BMI), FBG, and HOMA-IR, but lower HDL-C levels, lower grip strength and longer TUG than control group (all P<0.05). Serum OC, ucOC levels, and ucOC/OC in OI type III patients were significantly lower than those in OI patients with type I and IV. Serum levels of OC, ucOC, and ucOC/OC were negatively correlated to BMI, FBG, insulin levels, and HOMA-IR (all P<0.05). The ratio of ucOC/OC was positively correlated to grip strength (r=0.512, P=0.036), lean mass percentage (%LM) of the total body and limbs, and negatively correlated to fat mass percentage (%FM) of the total body, %FM and fat mass index (FMI) of the trunk (all P<0.05). Conclusions: Obesity, glucolipid metabolic abnormalities, and reduced grip strength were common in children with OI. Circulating osteocalcin and ucOC may play an important role in the regulation of glucose metabolism, as well as the muscle function of children with OI.

[The coincidence of benign non-familial infantile seizures type 2 with osteogenesis imperfecta type 1]. / Sochetanie dobrokachestvennykh nesemeinykh infantil'nykh pristupov 2-go tipa s nesovershennym osteogenezom 1-go tipa.

A clinical case of a patient with neonatal epilepsy at the age of 5 months, with impaired bone formation, early osteoporosis and frequent limb fractures is described. Panel sequencing confirmed by Sanger sequencing revealed two independent hereditary diseases - osteogenesis imperfect type 1, associated with a mutation in the COL1A1 gene (c.2010delT) and benign non-familial infantile seizures associated with a mutation in the PRRT2 gene (c.649dupC). A unique clinical case of a combination of these diseases is presented.

Genotype-Phenotype Relationship and Follow-up Analysis of a Chinese Cohort With Osteogenesis Imperfecta.

OBJECTIVE: To evaluate the genotype-phenotype relationship and the effect of treatment on the clinical course of osteogenesis imperfecta (OI). METHODS: We established a Chinese hospitalized cohort with OI and followed them up for an average of 6 years. All patients were confirmed as having OI using whole-exome sequencing. We analyzed the genotype-phenotype relationship based on different types, pathogenic mechanisms, and gene inheritance patterns of OI. Additionally, we assessed whether there was a difference in treatment efficacy based on genotype. RESULTS: One hundred sixteen mutations in 6 pathogenic genes (COL1A1, COL1A2, IFITM5, SERPINF1, FKBP10, and WNT1) were identified in 116 patients with type I, III, IV, V, VI, XI, or XV OI. Compared with patients with COL1A1 mutations, patients with COL1A2 mutations were younger at the time of the first fracture, whereas other phenotypes were similar. When 3 groups (helical, haploinsufficiency, and non-collagen I gene mutations) were compared, patients with helical mutations were the shortest and most prone to dentinogenesis imperfecta. Patients with haploinsufficiency mutations were the oldest at the time of the first fracture. Moreover, patients with non-collagen I gene mutations were least susceptible to blue sclerae and had the highest fracture frequency. Furthermore, there were some minor phenotypic differences among non-collagen I gene mutations. Interestingly, pamidronate achieved excellent results in the treatment of patients with OI, and the treatment effect appeared to be unrelated to their genotypes. CONCLUSION: Our findings indicated a genotype-phenotype relationship and a similar effect of pamidronate treatment in patients with OI, which could provide a basis for guiding clinical treatment and predicting OI prognosis.

Cementless posterior spinal fusion for the treatment of OI patients with severe spine deformity-a case series.

PURPOSE: The purpose of this study is to present the outcomes all patients with osteogenesis imperfecta (OI) who underwent cementless posterior spinal fusion for the treatment of severe spine deformity in our institution. METHODS: All patients with OI who underwent surgical correction of their spine deformity in our institution between 2003 and 2020 were enrolled. The collected data included demographics, operative and follow-up findings, medical history, bisphosphonate therapy, HGT protocol, pre- and post-HGT and postoperative scoliosis and kyphosis curve measurements, hospitalization length, complications, and revision surgeries. General treatment strategies included cessation of bisphosphonate therapy around the surgery, 30-day HGT protocol, titanium rods, cementless screw technique, and a high implant density policy. RESULTS: Eleven consecutive patients with OI who underwent surgery for spine deformity in our institution were identified. The mean age at surgery was 15.6 ± 2.3. Mean follow-up period was 6.6 ± 5.8 years. The mean pre- and postoperative scoliosis curves were 85.4 ± 19.3° and 43.1 ± 12.5°, respectively, representing a 49.5% correction rate. Five patients underwent HGT and achieved a mean correction of 27.6 ± 7.1° (31.6%) preoperatively. Implant density ratio was 1.5 (screw or hook/level). Mean postoperative hospitalization length was 5.9 ± 1.6 days. One patient had deep wound infection which resolved following treatment according to our protocol for surgical site infection, and one patient had skull penetration by one of the halo pins. CONCLUSION: Surgical treatment of severe spine deformity in OI patients with cementless posterior spinal fusion is safe and effective after applying a specific preoperative strategy.

Craniocervical abnormalities in osteogenesis imperfecta type V.

Craniocervical abnormalities in osteogenesis imperfecta (OI) such as basilar invagination or cervical kyphosis can cause severe neurological morbidity. These abnormalities may be more frequent in OI type V compared with other OI subtypes of similar disease severity, underlining the importance of screening in this group. INTRODUCTION: 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. METHODS: A retrospective case series on patients with craniocervical abnormalities in OI type V at our institution. RESULTS: Craniocervical abnormalities were present in 7 of 37 patients with OI type V (19%). For 5 patients (age at last follow-up: 5 to 26 years; 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 1 day to 18 years. 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 26 years) 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. CONCLUSION: 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.

Long-term vascular access for infants with moderate to severe osteogenesis imperfecta.

PURPOSE: Osteogenesis imperfecta (OI) is a genetic disorder that causes skeletal fragility. For the most fragile infants and young children with OI, intravenous (IV) bisphosphonate administration is essential, but IV access attempts often cause fractures. Port-a-caths help prevent these events, but some surgeons are hesitant to insert these devices in these infants due to lack of data on their safety. METHODS: Retrospective study of pediatric patients with OI who underwent port-a-cath placement from 1999 to 2018; incidence of complications such as infection and thrombosis and need for reoperation or replacement are described. RESULTS: Port-a-caths were placed in 17 patients with OI (median age, 8 mos [5-23 mos]; median weight, 5.8 kg [3.96-9.08 kg]) and remained in place for a median of 53.5 mos (10-127 mos). One port-a-cath was replaced because of thrombosis. Two port-a-caths were removed because of malfunction, one for skin erosion, and one for infection. In these five cases, replacement was not needed because patients could safely tolerate IV access. Two patients have their port-a-cath in place and the remaining ten patients had theirs removed electively as it was no longer needed. CONCLUSION: Port-a-cath placement in pediatric patients with OI is safe and efficacious for durable central access, enabling reliable IV bisphosphonate delivery and reducing iatrogenic trauma.

Incidence and treatment of adult femoral fractures with osteogenesis imperfecta: An analysis of a center of 72 patients in Taiwan.

Background: Osteogenesis imperfecta (OI) is a rare disease characterized by increased bone fragility and susceptibility for fractures. Only few studies have compared the management for femoral fractures in children with OI. Nevertheless, no cohort studies have described the treatment for femoral fractures in adults with OI in Taiwan. This study aimed to investigate and compare the incidence of union and non-union femoral fractures and the best treatment options to avoid non-union fractures. Methods: We enrolled 72 patients with OI who were older than 18 years at MacKay Memorial Hospital between January 2010 and December 2018. Femoral fracture incidence, non-union rate, and treatment modality were analyzed. Results: Of 72 patients with OI, 11 patients had femoral fractures and 4 patients of them had >1 femoral fracture. The incidence for all types of femoral fractures was 651 fractures per 100,000 person-years annually. In 15 total fractures, 4 fractures resulted in non-union, and patients with type 4 OI mostly had shaft fractures. The best outcomes for non-union shaft fracture is achieved by surgical treatment. Conclusion: Adults with OI tended to develop femoral fractures and non-unions. Adults with type 4 OI were particularly at high risk for non-unions in shaft fractures with conservative treatment.

Consanguineous-derived homozygous WNT1 mutation results in osteogenesis imperfect with congenital ptosis and exotropia.

BACKGROUND: Wnt signaling pathway plays an important role in promoting ostergenesis. WNT1 mutations have been considered as a major cause of ostergenesis imperfect (OI). We identified an OI patient with pathogenic consanguineous-derived homozygous WNT1 missense mutation. METHODS: We designed and applied a panel of known 261 genes associated with hereditary bone diseases for targeted next-generation sequencing to examine clinically diagnosed OI patients. Detected mutations were confirmed by Sanger sequencing. RESULTS: The female proband presented with severe OI with low bone density, multiple long bone fractures, short stature, and absence of dentinogenesis imperfect and brain malformation. She had congenital ptosis and exotropia with her left eye, and absence of blue sclera. The proband came from a consanguineous family and had a homozygous WNT1 missense mutation (c.677C>T, (p.S226L)). In addition, three other compound heterozygous mutations (c.1729C>T in FKBP10, c.1958A>C in FGFR3, c.760G>C in TRPV4) were also detected in her family members. CONCLUSION: We report the first identified case of consanguineous derived homozygous WNT1 mutation leading to severe osteogenesis imperfecta with congenital ptosis and exotropia.

Management of Catastrophic Proximal Junctional Failure Following Spinal Deformity Correction in an Adult with Osteogenesis Imperfecta: Case Report and Technical Note.

BACKGROUND: Proximal junctional failure (PJF) is a major and sometimes devastating problem following adult spinal deformity (ASD) correction surgery. Common consensus still lags on guidelines for preventing and managing these complications. Surgical treatment of scoliosis in the presence of osteogenesis imperfecta (OI) in the pediatric population is well described. The complication rates are unusually higher in this special subset of patients owing to poor quality of bone. There is a paucity of literature focusing on surgical techniques, strategies, and problems involved in the management of ASD associated with OI. CASE DESCRIPTION: We report a 59-year-old female with type 1 OI and adult scoliosis who underwent T10-to-pelvis fusion for ASD according to the principles of adult deformity correction. At a 1-year follow-up, she presented with asymptomatic proximal junctional kyphosis of 45° and 2 weeks later had PJF along with spinal cord injury after a fall. On computed tomography scan, kyphosis was increased to 60° at T9-T10. She underwent decompression and revision deformity correction using quadruple rods, with extension of instrumentation to T2 with soft landing using rib bands. At a 4-year follow-up, she had a good functional outcome after revision surgery. CONCLUSIONS: This is the first report of successful management of PJF following ASD correction in the presence of OI using this technique. Suboptimal hold of implants due to poor bone quality must be at the focus of any surgical planning for these patients. All possible strategies to prevent PJF must be considered when planning the deformity correction in adults with OI.

Interpreting Osteogenesis Imperfecta Variants of Uncertain Significance in the Context of Physical Abuse: A Case Series.

Unexplained childhood fracture(s) warrant consideration of physical abuse and osteogenesis imperfecta (OI). Genetic OI testing may identify "variants of unknown significance (VUS)." Interpretation of VUS in context of potential abuse may have protective, criminal, and medical impacts. This case series explores practices regarding clinicians' interpretation of VUS during child abuse evaluations. Variability was noted regarding factors considered for interpreting clinical significance. Based on these cases, recommendations for careful and thorough evaluation are detailed, including proposed use of a limited follow-up skeletal survey in 3 months, as a consideration to assess healing of prior fractures and to look for any additional injuries.

A Newborn with Multiple Fractures in Osteogenesis Imperfecta: A Case Report.

INTRODUCTION: Multiple bone fractures in a newborn can be associated with osteogenesis imperfect (OI). OI is a rare genetic disorder that causes Type I collagen synthesis disturbance results in bone fragility. CASE REPORT: We present a female newborn which had numerous fractures of the humerus, bilateral clavicle, and bilateral femur. Her delivery was at 36 weeks gestation by spontaneous vaginal delivery. She had has not any pathological symptom at 2 weeks after birth, the patient had a fracture of the humerus, bilateral clavicle, and femur without any trauma. Genetic analysis of the patient was reported and OI diagnosed. The patient was followed up for 8 months with regularly and without any complication. CONCLUSION: Multiple fractures with OI in an infant after birth may require an accurate orthopedic plan for diagnosing and treatment.

Sleep-Disordered Breathing in Children with Rare Skeletal Disorders: A Survey of Clinical Records.

OBJECTIVE: Craniofacial disharmony in skeletal diseases is strongly associated with sleep-disordered breathing. This study was aimed at studying the sleep respiratory patterns in young children with rare skeletal disorders. DESIGN: This retrospective study included children with achondroplasia (ACH), osteogenesis imperfecta (OI) and Ellis van Creveld Syndrome. Our subjects underwent an in-laboratory overnight respiratory polygraph between January 2012 and April 2016. All medical records were reviewed and brain Magnetic Resonance Imaging was conducted on patients with ACH, nasopharynx, oropharynx and laryngopharynx spaces. PATIENTS: Twenty-four children were enrolled, 13 with ACH, 2 with spondyloepiphyseal dysplasia, 1 with odontochondrodysplasia, 6 with OI and 2 with Ellis van Creveld Syndrome. RESULTS: Children with ACH, who had adenotonsillectomy, showed fewer sleep respiratory involvement than untreated children. Among 13 patients with ACH, brain magnetic resonance imaging was available in 10 subjects and significant negative correlation was found between sleep respiratory patterns, nasopharynx and oropharynx space (p < 0.05). In 2 patients with spondyloepiphyseal dysplasia, mild-to-moderate sleep respiratory involvement was found. Both subjects had a history of adenotonsillectomy. Mild sleep respiratory involvement was also observed in 4 out of 6 patients with OI. One patient with Ellis van Creveld syndrome had mild sleep respiratory disturbance. CONCLUSIONS: Sleep respiratory disturbances were detected in children with ACH, and with less severity also in OI and Ellis van Creveld syndrome. Adenotonsillectomy was successful in ACH in reducing symptoms. In light of our findings, multicenter studies are needed to obtain further information on these rare skeletal diseases.

Splicing defect in FKBP10 gene causes autosomal recessive osteogenesis imperfecta disease: a case report.

BACKGROUND: Osteogenesis imperfecta (OI) is a group of connective tissue disorder caused by mutations of genes involved in the production of collagen and its supporting proteins. Although the majority of reported OI variants are in COL1A1 and COL1A2 genes, recent reports have shown problems in other non-collagenous genes involved in the post translational modifications, folding and transport, transcription and proliferation of osteoblasts, bone mineralization, and cell signaling. Up to now, 17 types of OI have been reported in which types I to IV are the most frequent cases with autosomal dominant pattern of inheritance. CASE PRESENTATION: Here we report an 8- year- old boy with OI who has had multiple fractures since birth and now he is wheelchair-dependent. To identify genetic cause of OI in our patient, whole exome sequencing (WES) was carried out and it revealed a novel deleterious homozygote splice acceptor site mutation (c.1257-2A > G, IVS7-2A > G) in FKBP10 gene in the patient. Then, the identified mutation was confirmed using Sanger sequencing in the proband as homozygous and in his parents as heterozygous, indicating its autosomal recessive pattern of inheritance. In addition, we performed RT-PCR on RNA transcripts originated from skin fibroblast of the proband to analyze the functional effect of the mutation on splicing pattern of FKBP10 gene and it showed skipping of the exon 8 of this gene. Moreover, Real-Time PCR was carried out to quantify the expression level of FKBP10 in the proband and his family members in which it revealed nearly the full decrease in the level of FKBP10 expression in the proband and around 75% decrease in its level in the carriers of the mutation, strongly suggesting the pathogenicity of the mutation. CONCLUSIONS: Our study identified, for the first time, a private pathogenic splice site mutation in FKBP10 gene and further prove the involvement of this gene in the rare cases of autosomal recessive OI type XI with distinguished clinical manifestations.

Hemiarthroplasty of the Hip in a 52-Year-old Patient with Osteogenesis Imperfecta-Related Femoral Neck Fracture: A Case Report.

INTRODUCTION: Osteogenesis imperfecta (OI)-related femoral neck fractures are rare. This is rarely described in the literature. This article presents a way to surgically treat such a fracture. CASE REPORT: We describe the case of a 52-year-old patient with OI Type III with a displaced femoral neck fracture with varus deformity. We performed a hemiarthroplasty of the hip with valgus and shortening osteotomy of the proximal femoral shaft. CONCLUSION: The incidence of OI is 1 in 10,000-,000 births. People suffering from OI are known to be at more risk of fractures. Due to the bone deformity and weakness, treatment of fractures in patients with OI is a big challenge for orthopedic surgeons. Combined osteotomy and hemiarthroplasty is a reliable technique to treat a femoral neck fracture in a patient with typical OI-related varus deformity of the femora.

Pedigree analysis of a osteogenesis imperfect and prolactinoma family caused by a newly found gene mutation in COL1A1 / 中华内分泌代谢杂志

Objective To explore the collagen, typeⅠ, α 1 chain ( COL1A1) gene mutation in a family with type 1 osteogenesis imperfect. Methods The medical records and DNA samples of an osteogenesis imperfect patient and her family members were collected, and their DNA sequencing were performed and compared with 50 non-relative healthy control from the same area. Results The proband and her three family members ( father, younger brother, and younger nephew) with clinical features of osteogenesis imperfect as well as prolactinoma were confirmed of COL1A1 gene mutation at the 24th intron with a shear mutation of c. 1669-1 G＞A which was not reported previously. Other family members were genetically normal compared with the normal. Conclusions We found a new COL1A1 gene mutation family and mutation site, but the relationship between osteogenesis imperfect and prolactinoma was unknown.