Welcome to the Osteogenesis Imperfecta section of the Endocrine Society's fellow training series. The objectives are for you to identify and treat this connective tissue disorder that causes bone fragility and low bone mass. Let's start with an example of a 32-year-old woman who had several dozen bone fractures in her childhood. What is your differential diagnosis? Please pause the video and come up with your answers. Conditions on my differential diagnosis included osteogenesis imperfecta, child abuse, idiopathic juvenile osteoporosis, osteoporosis from malabsorption, glucocorticoids, hormone deficiencies, acute lymphoblastic leukemia, and immobility. In this case, it turns out the patient had osteogenesis imperfecta. Osteogenesis imperfecta is an inherited connective tissue disorder most commonly related to abnormalities in type 1 collagen. There is a wide variation in phenotypes. Mild cases may present with early osteoporosis, more severe cases with multiple fractures with minimal trauma, and the condition can cause death in utero or infancy. Patients with osteogenesis imperfecta may have aortic root dilation, joint hypermobility, easy bruising, and hypercalceria. Osteogenesis imperfecta has several manifestations in the head. About 60% of patients have wormian bones in their skull, like in the x-ray on the left. Blue-gray sclera is the most famous manifestation. Macrocephaly can also occur, such as in the picture on the bottom. Head CT can show hydrocephalus. Patients can develop badular invaginations, which are infoldings of the skull. This distorts the brainstem and can cause central nerve palsies, dysphagia, quadriparesis, ataxia, and nystagmus. The treatment is occipital cervical bracing. Occipital spine kyphosis can compress the spinal cord, requiring operative decompression and fusion. About a quarter of patients have abnormal dentin, which makes their teeth smaller. About three-quarters have malocclusions and delayed tooth eruptions. About 5% of children have hearing loss, which progresses to about half of adults by age 50. Which features are most consistent with osteogenesis imperfecta? Is it A. Macrocephaly, basilar invaginations, and aortic root dilatations? B. Café au lait spots, fibrous dysplasia, and precocious puberty? Or C. Slow growth velocity, encephalopathy, and dental abscesses? Please pause the video if you need more time. The best answer is A. B. Describes McCoon-Albright syndrome, and C. Describes hereditary hypophosphatemic rickets. Osteogenesis imperfecta type 1 is the mildest form, with non-deforming fractures and blue sclera. Patients have autosomal-dominant COL1A1 mutations, resulting in insufficient collagen. Many have fractures before puberty that become less frequent later in life. Osteogenesis imperfecta type 2-4 come from COL1A1 or COL1A2 gene mutations that cause structural defects in collagen. Newborns don't typically survive with type 2. Type 3 is severe but not lethal most of the time. Type 4 is not as bad as type 3. Let's do a case to apply your learning. A 1-year-old boy is pulling to stand when the parents hear a pop. The boy fell crying in pain from a broken leg. This is his third fracture since birth. What is the likely mode of inheritance? Is it A. Autosomal-dominant, B. Autosomal-recessive, or C. X-link recessive? Please pause the video if you need more time. The best answer is A because autosomal-dominant mutations in COL1A1 or 1A2 account for 90% of osteogenesis imperfecta. Furthermore, males and females are equally affected. Question. A teenager is struggling with rehabilitation from a femur fracture that occurred last month. X-ray shows a hyperplastic callus. Which gene likely has a mutation? Is it A. COL1A, B. COL1A2, or C. IFITM5? Please pause the video if you need more time. The best answer is C because patients with IFITM mutations develop hyperplastic calluses after trauma. Callus imperfecta type 5 comes from gene mutations in coning interferon-induced transmembrane protein 5, IFITM5. About 85% have radial head dislocations. They develop hyperplastic calluses after trauma as you can see in part A of this picture. Patients get calcifications of forearm osseous membranes as you can see in part B. They also get radiodense metaphyseal bands at growth plates of long bones as you can see in part C. There are many more types of osteogenesis imperfecta that are autosomal recessive, but are much more rare. Their genetic mutations change other aspects of collagen and osteoblast function. Management of moderate to severe osteogenesis imperfecta requires sufficient dietary calcium and vitamin D. Treatment may also include physical therapy, surgery, and bisphosphonates. Telescoping rods are better for growing children. This picture shows a rod of constant length from 30 years ago. The patient has outgrown it and there is now a fracture at the end of the rod. You can see bone extending beyond the rod distally. Ideally you want a rod that can grow with the patient. This telescoping rod lengthens during growth, allowing the patient to avoid reoperations. You can see that the rod is more narrow at the distal end because that part used to be inside the thicker part, but has lengthened as the patient has grown. Question. A newborn had multiple intrauterine long bone fractures and died shortly after birth. What is likely wrong with the type 1 collagen? Is it A. Insufficient amount, B. Defective structure, or C. Defective post-translation modifications? Please pause the video if you need more time. The best choice is B because this is likely osteogenesis imperfecta type 2 because the newborn died. A is unlikely because the patient does not have type 1, the mildest form of osteogenesis imperfecta. C is unlikely because osteogenesis imperfecta types from recessive mutations occur in less than 5% of cases. Bisphosphonate therapy can increase height and bone mineral density in children. It can decrease bone pain and fracture without slowing healing. The optimal regimen and duration is unknown. Bisphosphonate therapy is also the main treatment for adults with osteogenesis imperfecta because small clinical trials suggest that they improve bone mineral density. However, their effects on fractures in adults is not known and they are not specifically approved for this population. Consider fracture risk assessment with bone mineral density and clinical factors like fracture history and family history. Peak bone mineral density is likely lower in most adults with osteogenesis imperfecta, so consider starting treatment at menopause for women. Monitoring for complications in osteogenesis imperfecta involves hearing testing to evaluate for conductive and sensory neural hearing loss, bone mineral density scanning, spirometry to assess for restrictive defects secondary to kyphosis and fracture, neurological examination and cranial assessment to evaluate for basilar invagination, as well as ECG and echocardiogram to detect aortic root dilatation and valvular dysfunction. In summary, osteogenesis imperfecta results in fractures typically from autosomal dominant mutations that impact collagen. Insufficient collagen results in milder phenotypes. Collagen structural defects cause worse phenotypes. Treatment involves diet, physical activity, telescoping rods, and bisphosphonates. Thank you for your attention.

Osteogenesis Imperfecta

connective tissue disorder

bone fragility

genetic mutations

treatment options