Case report identifies likely pathogenic COL1A1 variant in pediatric bone fragility

A 13-year-old boy with congenital blue sclerae and recurrent fractures after minor trauma was diagnosed with osteogenesis imperfecta type 1 after targeted genetic testing identified a previously unreported frameshift variant in COL1A1. The 2026 multigenerational case report found the same heterozygous variant in his mother, while his father was wild-type for it. During six months of follow-up after sequential denosumab and zoledronic acid treatment, the patient experienced no new fragility fracture, and the investigators reported improved bone mineral density, substantially reduced joint pain and no adverse drug events. These findings describe one treated patient and provide limited observational evidence rather than proof that the treatment sequence prevents fractures.

Osteogenesis imperfecta, also called brittle bone disease, is a group of inherited connective-tissue disorders characterized by increased bone fragility and recurrent fractures. The report notes that it can also involve the eyes, ears, teeth and skin, with findings that may include blue sclerae, short stature, dental abnormalities, hearing impairment and laxity of skin, tendons and ligaments. COL1A1 and COL1A2 encode chains of type I collagen and account for about 90% of cases in the report. Type 1 is described as the mildest major clinical form, commonly associated with low bone mass, blue sclerae and fractures after minor trauma, while major skeletal deformity and growth retardation are usually absent.

The patient first fractured his right shoulder and clavicle at age 3 after falling from playground equipment. The report states that he then sustained nine additional fractures between June 2019 and 2024 following collisions, falls or landings after exercise. The enumerated sites included the left second metacarpal, right distal radius, right distal ulna, left clavicle, left distal radius and left knee joint, with some sites recorded more than once. All fractures were managed conservatively, and follow-up showed good healing. Persistent joint pain after the repeated injuries prompted referral to the endocrinology department in 2024 for evaluation of osteoporosis, bone fragility, inherited skeletal disorders and long-term bone-health management.

At admission, the boy was 159 centimeters tall and weighed 55 kilograms, giving him a body mass index of 21.8 kilograms per square meter. Physical examination showed blue sclerae and mild left-sided scoliosis but no limb deformity, tenderness or restriction of movement. He had no significant hearing impairment, recurrent dental caries, loose teeth or vision loss. His developmental milestones had been normal. The family history revealed blue sclerae and a history of fractures in his mother, maternal grandmother, maternal great-grandfather, maternal great-aunt, maternal cousin and older maternal cousin. The investigators interpreted this maternal-line pattern as consistent with autosomal-dominant inheritance.

Because OI can present through overlapping clinical and genetic features, the diagnosis combined the patient’s phenotype, family history, imaging, bone-density measurements and molecular results rather than relying on one test alone. The report is explicitly a narrative case report with a pedigree and literature review, not a PRISMA-based systematic review. The family pattern, recurrent low-trauma fractures, congenital blue sclerae and reduced bone mass supported suspicion of OI, while the target-panel sequencing result supplied a molecular basis for the diagnosis. The authors retained the clinical designation of type 1 because the proband and affected relatives exhibited a phenotype consistent with that form, despite recommendations to distinguish clinical severity from numbered genetic subtypes.

Bone-density measurements showed low bone mass for age. An external regional scan produced Z-scores of −1.7 for the lumbar spine, −2.7 for the femoral neck and −2.3 for the total hip. A total-body dual-energy X-ray absorptiometry scan excluding the head yielded a Z-score of −2.2 and a bone mineral density of 0.614 grams per square centimeter. Radiographs showed diffusely reduced bone radiodensity, leftward spinal curvature with kyphosis, and mild flattening of the T8 and T9 vertebral bodies suggestive of possible low-trauma microfractures. His measured bone age was 12 years and 10 months. These findings, together with the fracture history, indicated impaired bone strength.

Targeted-panel sequencing tested COL1A1 and COL1A2, which the authors prioritized because of their reported contribution to approximately 90% of OI cases and the boy’s typical clinical phenotype. The panel identified the heterozygous duplication NM_000088.4:c.358dup, p.(Arg120ProfsTer49), in the proband and his mother; the father was wild-type. The frameshift introduces a premature termination codon and was classified as likely pathogenic under the 2015 ACMG/AMP criteria. The authors state that it is expected to cause COL1A1 haploinsufficiency through premature translation termination, reducing production of the affected type I collagen chain. Searches of gnomAD version 4.1.2, ClinVar, LOVD-COL1A1, ClinGen and published OI literature returned no entry for the exact variant.

The variant was reported as absent from the queried public databases and previously undescribed in the published literature, although the investigators noted that other truncating variants affecting codon 120 of COL1A1 had been associated with mild type 1 OI. Its apparent relationship to the family phenotype was supported by complete clinical co-segregation across the pedigree, with the carrier mother also showing characteristic features. Frameshift variants can reduce collagen synthesis and are commonly associated with type 1 OI, while missense variants affecting the collagen triple helix may produce more severe phenotypes. The pedigree and six-month follow-up cannot establish the variant’s effects in all carriers or determine the independent contributions of the two drugs to the observed improvement.

After diagnosis, the patient received oral elemental calcium at 600 milligrams once daily and calcitriol at 0.25 micrograms every other day. He then received one 60-milligram subcutaneous dose of denosumab, followed by annual intravenous zoledronic acid at 5 milligrams, a regimen specified for patients weighing more than 25 kilograms. The sequence was predefined at the treatment center rather than initiated in response to adverse effects, inadequate response or limited availability. Denosumab was intended to suppress high bone turnover rapidly, while zoledronic acid was selected for longer-term suppression and to mitigate the risk of rebound hypercalcemia associated with repeated denosumab exposure in children. He tolerated the treatment without hypocalcemia or other bisphosphonate-related adverse events.

During the six-month observation period, no new fragility fracture occurred, pre-existing joint pain was substantially relieved and bone mineral density improved relative to baseline. The patient returned to his school routine with improved quality of life, according to the report. Management also included avoiding strenuous exercise and trauma, rehabilitation through activities such as swimming and walking, and monitoring of bone mineral density, bone-metabolism markers and liver and kidney function. The accompanying narrative review describes bisphosphonates as commonly used anti-resorptive treatments for pediatric OI and identifies surgery for selected severe long-bone deformity, recurrent fracture instability or severe scoliosis. It describes rehabilitation as a central component of long-term care and gene therapy as a research direction rather than an established intervention in this case.

Subject of Research: Pediatric pedigree case report of a likely pathogenic COL1A1 variant associated with osteogenesis imperfecta type 1

Article Title: Case Report: Pediatric osteogenesis imperfecta type 1: a pedigree report and literature review

Article References: Rong, R., Li, X., & Liu, X. (2026). Case Report: Pediatric osteogenesis imperfecta type 1: a pedigree report and literature review. Frontiers in Pediatrics, 14, Article 1944269. https://doi.org/10.3389/fped.2026.1944269

Image Credits: AI Generated

DOI: 10.3389/fped.2026.1944269

Keywords: osteogenesis imperfecta, COL1A1, pediatric bone fragility, recurrent fractures, genetic variant, blue sclerae, bone mineral density, denosumab, zoledronic acid, case report, Case, Report