BACKGROUND

Osteogenesis imperfecta (OI) is a group of connective tissue disease characterized by propensity to fractures following minimal trauma. OI is a lifelong inheritable disease and currently has no definitive cure. Management goals are directed towards prevention of fractures, controlling the symptoms, maximizing independent mobility, and developing optimal bone mass and muscle strength. Bisphosphonates are the mainstay of pharmacologic fracture-prevention therapy for most forms of OI. The University of the Philippines-Philippine General Hospital Bisphosphonate Treatment Program for OI was started in 2006 by the Clinical Genetics Service. For more than a decade now, the program has been serving more than 50 OI patients. This study evaluated the clinical outcomes of the patients who were included in the program to add to the body of knowledge on Filipino patients with OI.

This study sought to determine the clinical outcomes of children with OI on intravenous pamidronate treatment at the Philippine General Hospital (PGH) from January 2010 to December 2018.

The study utilized a retrospective review of medical records of 24 patients diagnosed with OI on pamidronate therapy seen at the PGH from January 2010 to December 2018. Descriptive statistics were used to summarize the demographic and baseline clinical characteristics of the patients. Median annualized fracture rates before and during treatment were calculated and compared. The patient functional mobility before and during pamidronate infusion was classified accordingly based on the Gross Motor Function Classification System (GMFCS) and were compared.

Twenty-four patients, which include seven males and 17 females, with ages at the time of conduct of the study ranging from four years to 11 years, fulfilled the inclusion criteria. There were four patients with OI type I, six with OI type III, 11 with OI type IV and three with OI type V. The annualized long bone fracture rate decreased significantly from a median of 2.0/year (range 1-2.75) to 0.75/year (range 0-1) after more than a year on pamidronate infusion (pCONCLUSION

Cyclic intravenous pamidronate treatment in young children with moderate-severe OI is well tolerated and associated with reduced fracture frequency with a tendency to improvement of gross functional mobility.

OBJECTIVE: To explore the genetic basis of two fetuses with an osteogenesis imperfecta (OI) phenotype. METHODS: Two fetuses diagnosed at the Affiliated Hospital of Weifang Medical College respectively on June 11, 2021 and October 16, 2021 were selected as the study subjects. Clinical data of the fetuses were collected. Amniotic fluid samples of the fetuses and peripheral blood samples of their pedigree members were collected for the extraction of genomic DNA. Whole exome sequencing (WES) and Sanger sequencing were carried out to identify the candidate variants. Minigene splicing reporter analysis was used to validate the variant which may affect the pre-mRNA splicing. RESULTS: For fetus 1, ultrasonography at 17+6 weeks of gestation had revealed shortening of bilateral humerus and femurs by more than two weeks, in addition with multiple fractures and angular deformities of long bones. WES revealed that fetus 1 had harbored a heterozygous c.3949_3950insGGCATGT (p.N1317Rfs*114) variant in exon 49 of the COL1A1 gene (NM_000088.4). Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), it was classified as a pathogenic variant (PVS1+PS2+PM2_Supporting) for disrupting the downstream open reading frame resulting in premature translational termination, being de novo in origin, and lacking records in the population and disease databases.For fetus 2, ultrasonography at 23 weeks of gestation also revealed shortening of bilateral humerus and femurs by one and four weeks, respectively, in addition with bending of bilateral femurs, tibias and fibulas. Fetus 2 had harbored a heterozygous c.1557+3A>G variant in intron 26 of the COL1A2 gene (NM_000089.4). Minigene experiment showed that it has induced skipping of exon 26 from the COL1A2 mRNA transcript, resulting in an in-frame deletion (c.1504_1557del) of the COL1A2 mRNA transcript. The variant was inherited from its father and had been previously reported in a family with OI type 4. It was therefore classified as a pathogenic variant (PS3+PM1+PM2_Supporting+PP3+PP5). CONCLUSION The c.3949_3950insGGCATGT (p.N1317Rfs*114) variant in the COL1A1 gene and c.1557+3A>G variant in the COL1A2 gene probably underlay the disease in the two fetuses. Above findings not only have enriched the mutational spectrum of OI, but also shed light on the correlation between its genotype and phenotype and provided a basis for genetic counseling and prenatal diagnosis for the affected pedigrees.
Pregnancy ; Female ; Humans ; Osteogenesis Imperfecta/genetics* ; Collagen Type I, alpha 1 Chain ; Collagen Type I/genetics* ; Mutation ; Fetus

OBJECTIVE: To identify the pathogenic variant for a husband with osteogenesis imperfecta and provide preimplantation genetic testing (PGT) for the couple. METHODS: High-throughput sequencing and Sanger sequencing were carried out to identify the pathologic variant in the husband patients. PGT of embryos was performed through direct detection of the mutation site. Meanwhile, chromosome aneuploidy of the blastocysts was screened. Following transplantation, cytogenetic and genetic testing of fetal amniotic fluid sample was carried out during mid-pregnancy. Chromosome copy number variant (CNV) was detected at multiple sites of the placenta after delivery. RESULTS: The husband was found to harbor heterozygous c.544-2A>G variant of the COL1A1 gene. The same variant was not detected in either of his parents. PGT revealed that out of three embryos of the couple, one was wild-type for the c.544-2A site but mosaicism for duplication of 16p13.3.11.2. The other two embryos were both heterozygous for the c.544-2A>G variant. Following adequate genetic counseling, the wild-type embryo was transplanted. Amniotic fluid testing confirmed that the fetus had normal chromosomes and did not carry the c.544-2A>G variant. The copy number of chromosomes at different parts of placenta was normal after birth. CONCLUSION For couples affected with monogenic disorders, e.g., osteogenesis imperfecta, direct detection of the mutation site may be used for PGT after identifying the pathogenic variant. After adequate genetic counseling, prenatal diagnosis must be carried out to ensure the result.
Aneuploidy ; China ; Female ; Genetic Testing ; Humans ; Osteogenesis Imperfecta/genetics* ; Pregnancy ; Preimplantation Diagnosis

OBJECTIVE: To explore the genetic basis for a Chinese pedigree with two individuals suffering from congenital blindness. METHODS: Clinical data and peripheral blood samples of the pedigree were collected. Whole exome sequencing was carried out. Suspected variants were verified by Sanger sequencing. Pathogenicity of candidate variants was validated through searching of PubMed and related databases, and analyzed with bioinformatics software. RESULTS: Both patients had congenital blindness and a history of multiple fractures. Other features have included microphthalmia and cornea opacity. One patient had normal intelligence, whilst the other had a language deficit. Both patients were found to harbor compound heterozygous variants of the LRP5 gene, namely c.1007_1015delGTAAGGCAG (p.C336X), c.4400G>A (p.R1467Q) and c.4600C>T (p.R1534X). The first one was derived from their mother, whilst the latter two were derived from their father. None of the three variants was detected in their elder sister. CONCLUSION The compound heterozygous variants of c.1007_1015delGTAAGGCAG (p.C336X) and c.4600C>T (p.R1534X) of the LRP5 gene probably underlay the pathogenesis of the Osteoporosis-pseudoglioma syndrome in this pedigree. The clinical significance of the c.4400G>A (p.R1467Q) variant has remained uncertain. Above finding has enriched the mutational spectrum of Osteoporosis-pseudoglioma syndrome.
Aged ; China ; Humans ; Language ; Low Density Lipoprotein Receptor-Related Protein-5/genetics* ; Mutation ; Osteogenesis Imperfecta/genetics* ; Pedigree

Humans ; Osteogenesis Imperfecta/diagnosis*

OBJECTIVE: To carry out preimplantation genetic testing (PGT) for a couple where the husband was affected by osteogenesis imperfecta combined with balanced translocation using the karyomapping technique. METHODS: Blastocysts were detected using karyomapping, the carrier status of COL1A1 c.760G>A (p.Gly254Arg) variant and the carrier status of the translocated chromosome were analyzed simultaneously. RESULTS: For a total of 10 blastocysts, two euploid blastocysts were found to not carry the COL1A1 c.760G>A (p.Gly254Arg) variant but a balanced translocation. After transplanting one of the blastocysts, clinical pregnancy was achieved. Amniocentesis at 18th gestational week and prenatal genetic testing was in keeping with the result of PGT.A healthy female was born at 40+4 weeks gestation. CONCLUSION For patients simultaneously carrying genetic variant and balanced chromosomal translocation, PGT can be performed with efficiency by the use of karyomapping method.
Blastocyst ; Female ; Fertilization in Vitro ; Genetic Testing ; Humans ; Osteogenesis Imperfecta/genetics* ; Pregnancy ; Preimplantation Diagnosis ; Spouses ; Translocation, Genetic

Objective: To investigate the clinical phenotype, treatment and prevention of Van der Hoeve syndrome, and analyze the variation characteristics of its related gene COL1A1. Methods: Hearing and sequencing data of syndromic deafness patients who had undergone genetic testing for deafness at the Chinese People's Liberation Army General Hospital since January 2008 to October 2020 were retrospectively reviewed. The variation of the COL1A1 gene and return visits to traceable patients and families were summarized, the disease progress and clinical treatment effects were analyzed, and the prevention strategies were discussed. Results: A total of 7 patients with COL1A1 gene mutation underwent clinical intervention. The mutation sites were c.1342A>T (p.Lys448*), c.124C>T (p.Gln42*), c.249insG(p.Ala84*), c.668insC(p.Gly224*), c.2829+1G>C, c.1081C>T (p.Arg361*), c.1792C>T (p.Arg598*), of which c.1081C>T and c.1792C>T had been previously reported, and the remaining 5 were novo mutations that have not been reported. All the 7 probands underwent stapes implantation and received genetic counseling and prevention guidance. Conclusions: Van der Hoeve syndrome belongs to osteogenesis imperfecta type Ⅰ. The disease has high penetrance. Timely surgical intervention for hearing loss can improve the life quality in patients. Accurate genetic counseling and preimplantation genetic diagnosis can achieve the primary prevention for the disease.
Hearing ; Hearing Tests ; Humans ; Osteogenesis Imperfecta ; Retrospective Studies ; Stapes

OBJECTIVE: To explore the genetic basis for a couple with normal phenotype but repeated pregnancies with fetuses affected by osteogenesis imperfecta. METHODS: Whole exome sequencing (WES) was carried out on fetal specimens and parental DNA to detect potential pathologic variants. Suspected variants were verified by Sanger sequencing. Semen sample of the husband was collected for the extraction of genome DNA, and whole genome amplification (WGA) was performed for single sperms isolated from the sample. RESULTS: WES has identified a heterozygous c.1378G>A (p.G460S) variant of the COL1A2 gene in the fetus, which was predicted to be pathogenic but not detected in peripheral blood samples of both husband and wife. The heterozygotic variant was detected in semen DNA from the husband. Among 15 spermatozoa, 4 were found to harbor the variant. CONCLUSION The fetus was diagnosed with osteogenesis imperfecta, and the gonadal mosaicism probably accounted for the repeated abnormal pregnancies. Possibility of gonadal mosaicism should be considered when counseling couples with normal phenotype and genotype but recurrent abnormal pregnancies and/or births of children with similar phenotypes and genetic variants.
Adult ; Child ; Collagen Type I ; genetics ; Female ; Fetus ; Gonadal Disorders ; genetics ; Humans ; Male ; Mosaicism ; Mutation ; Osteogenesis Imperfecta ; diagnosis ; genetics ; Pregnancy ; Prenatal Diagnosis ; Whole Exome Sequencing

OBJECTIVE: To analyze the clinical phenotype of six pedigrees affected with osteogenesis imperfecta and their genetic basis. METHODS: Peripheral blood or abortic tissues of the six pedigrees were collected for the extraction of genomic DNA. Next generation sequencing (NGS) was carried out to detect pathological variants in the genome. Sanger sequencing was used for validating suspected variant among the six pedigrees and 100 healthy controls. RESULTS: In pedigree 1, the proband and his daughter both carried a heterozygous c.1976G>C variant of COL1A1. The probands in pedigrees 2 to 6 respectively carried heterozygous variants of c.2224G>A of COL1A2, c.2533G>A of COL1A1, c.2845G>A of COL1A2, c.2532_2540del of COL1A1, and c.1847G>A of COL1A2. The same variants were not detected in their parents and the 100 healthy controls. CONCLUSION Variants of COL1A1/2 gene probably underlie the pathogenesis for osteogenesis imperfecta in these pedigrees. Discovery of the nevol variants has enriched the spectrum of COL1A1/2 gene variants and facilitated genetic counseling and prenatal diagnosis for the affected pedigrees.
Collagen Type I ; genetics ; Female ; Genetic Variation ; Genotype ; Humans ; Male ; Mutation ; Osteogenesis Imperfecta ; genetics ; Pedigree ; Phenotype ; Pregnancy

Osteogenesis imperfecta is a heterogeneous group of connective tissue diseases that is predominantly characterized by bone fragility and skeletal deformity. Two siblings with undiagnosed type I osteogenesis imperfecta underwent orthognathic surgery for the treatment of facial asymmetry and mandibular prognathism. The authors report two cases of combined orthodontics and orthognathic surgery in patients with type I osteogenesis imperfecta, mandibular prognathism, and facial asymmetry.
Congenital Abnormalities ; Connective Tissue Diseases ; Facial Asymmetry ; Humans ; Orthodontics ; Orthognathic Surgery ; Osteogenesis Imperfecta ; Osteogenesis ; Prognathism ; Siblings