Recombinant Human Growth Hormone Combined With Pamidronate Disodium Can Improve The Growth And Bone Fragility Of Children With Osteogenesis Imperfecta

BackgroundOsteogenesis imperfecta,also known as brittle bone disease,porcelain doll,is a relatively rare genetic bone disease among genetic bone dysplasia diseases.The main cause of the disease is the mutation of type I collagen protein encoding gene or its metabolism-related regulation gene,resulting in bone abnormality and increased bone fragility.Osteogenesis imperfecta often starts at an early age,and children are very prone to fractures,even minor collisions can cause serious fractures.And the disease is not limited to the skeletal system,but often involves other connective tissues such as eyes,ears,teeth,skin,etc.Most children with osteogenesis imperfecta have short stature.In severe cases,it can be fatal.It brings a lot of distress and pain to patients and their families.At present,there is no unified standard treatment for osteogenesis imperfecta.Generally,it is symptomatic treatment for fractures,correction of deformities and conservative medications such as recombinant human growth hormone and bisphosphonates such as pamidronate disodium were also used off-label Osteogenesis imperfecta-related genetic testing can confirm the diagnosis of osteogenesis imperfecta.Early identification,along with genetic testing,laboratory tests and imaging tests to make an early diagnosis.This is of great significance for the treatment,improvement of prognosis and quality of life of children.Objectives1.Through the analysis of the pathogenic genes related to osteogenesis imperfection carried by 27 children diagnosed with osteogenesis imperfecta by genetic testing,and the main family members of the proband carrying osteogenesis imperfecta related pathogenic genes were tested and analyzed.Combined with the pedigree data,the influence of the disease on the progeny in the progenitor’s family was analyzed,so as to achieve early diagnosis and good birth and upbringing.2.27 patients with osteogenesis imperfecta were the observation group,and 27 healthy children of the same age and sex were the control group.The differences of serum alkaline phosphatase,serum calcium,serum magnesium and serum phosphorus levels between the two groups were analyzed.3.To observe the improvement of short stature and fracture in children with osteogenesis imperfecta treated with recombinant human growth hormone combined with pamidronate disodium during non-fracture period and the possible adverse reactions during treatment.MethodsThe medical records of 27 children diagnosed with osteogenesis imperfecta by genetic testing were retrospectively analyzed.Fulgent Genetics Biotechnology Co.,Ltd.was commissioned to extract genomic DNA from the peripheral blood of the children and entrusted to conduct the detection of human orthopedic genetic disease-related pathogenic gene mutation on the extracted peripheral blood genomic DNA of the children.The parents or relatives of the probs with osteogenesis imperfecta related pathogenic genes were tested to determine the genetic mode of the pathogenic genes.The 27 children with osteogenesis imperfecta related pathogenic genes confirmed by genetic testing were selected as the observation group.The birth of the children in the observation group was investigated,and the general characteristics of the children at first diagnosis,time of fracture,fracture location and fracture frequency,bone X-ray examination results,bone mineral density analysis results.serum alkaline phosphatase,serum calcium,serum magnesium,serum phosphorus and other levels,treatment methods and drug treatment effects were recorded.The same number of healthy children of the same age and sex were selected as the control group.Analyze the differences between the observation group and the control group in the results of various laboratory tests.The fracture frequency,the change of examination results and the change of growth rate were compared before and after treatment with pamidronate disodium and recombinant human growth hormone.Results1.In 27 cases,17 male children and 10 female children were found to be related to osteogenesis imperfecta-related pathogenic genes.One male child had mutations in SERPINF1.a gene associated with osteogenesis imperfecta,and both of his parents carried heterozygous variants of the gene.One male child had a heterozygous mutation in the osteogenesis imperfecta-related gene LRP5,which was derived from his mother.In addition,there was one heterozygous mutation in TRPV4 gene and one heterozygous mutation in COL2A1 gene,both of which originated from the father.Two male children had a heterozygous variant of the osteogenesis imperfecta gene COLIA2.One child’s mother had a heterozygous variant of COL1A2,and the other child’s father had a heterozygous mutation of COL1A2.Twenty-three of the children had COL1A1 gene mutation,including 2 male children and 2 female children whose mothers heterozygous carried COL1A1,and 2 male children and 2 female children whose fathers carried COL1A1.Before genetic testing,the mother of 1 male child was diagnosed with osteogenesis imperfecta,and the grandmother and father of 1 male child were diagnosed with osteogenesis imperfecta,but no genetic testing was performed to identify the mutated gene in either case.2.The observation group consisted of 27 children with osteogenesis imperfecta related pathogenic genes,including 17 males and 10 females.The age of initial diagnosis ranged from 5 months old to 13 years old,with a median age of 3 years and 2 months.The age of first fracture was 0 to 8 years,and the median age was 1 years.The height of the children was significantly lower than that of healthy children of the same age and gender.and the height standard deviation score(Ht SDS)was-2.50±2.49.All children had reduced bone density,sparse trabeculae,and thinning cortical bone,but normal muscle tone.Among them,22 had blue sclera,14 had lesions involving teeth,and 14 had limb deformities of varying degrees,mostly lower limb deformities.3.The levels of serum alkaline phosphatase,serum calcium,serum phosphorus and serum magnesium in the observation group were compared with those in the control group.and there were statistically significant differences in the levels of serum magnesium between the two groups(P<0.05),while there were no statistically significant differences in the levels of serum alkaline phosphatase,serum calcium and serum phosphorus between the two groups(P>0.05).No fractures occurred in 4 children treated with pamidronate disodium,recombinant human growth hormone and oral calcium supplementation during the non-fracture period.The growth rate of the children was faster than before.Other children were treated periodically with pamidronate disodium and occasionally suffered post-traumatic fractures,then surgery or external fixation was performed.The incidence of fracture was significantly lower than before(P<0.05).Conclusions1.Osteogenesis imperfecta is mainly caused by COL1A1 gene mutation,a few are caused by other gene mutation,and autosomal dominant inheritance is more common.Most of the children have a family history,and some sporadic cases may be neonatal mutations.2.Genetic testing can identify the pathogenic genes and their genetic patterns carried by the children and provide guidance for the protestor’s family to have a good birth and nurture.3.The levels of serum magnesium in osteogenesis imperfecta were different from those in healthy children,while the levels of serum alkaline phosphatase,serum calcium and serum phosphorus were basically norrmal.4.Treatment with recombinant human growth hormone and pamidronate disodium can improve the growth and bone fragility,and reduce the number of fractures in children with osteogenesis imperfecta.