Diagnosis of Osteogenesis Imperfecta in Children

Study Overview
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Brief Summary
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The study will be conducted at Assiut university children hospital and it will include patients with history of repeated fractures due to mild or irrelevant trauma. Diagnosis will be established by biochemical tests, bone survey to exclude secondary causes followed by Dual Energy absorbiometry scan to detect bone density of selected cases then confirm our diagnosis by detection of gene mutations of Osteogenesis imperfecta during one and half year duration with starting zoledronic acid therapy during this duration.

Detailed Description
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Osteogenesis imperfecta is a genetic disorder of the connective tissue matrix caused by abnormal collagen microﬁbril assembly, .Several clinical subtypes of Osteogenesis imperfecta have been described based on the clinical, biochemical, and molecular nature of the disorder . New research is emphasizing the structural interaction within the microﬁbril and identifying regions within the collagen, which play greater or lesser roles in the structural properties of the triple helix, .In taking this information into account, clinical phenotypes resulting from certain mutations can be predicted because of this pathogenetic correlation. The clinical manifestations vary considerably, ranging from a severe perinatal lethal form to a mild disorder which only becomes evident in adulthood, manifesting as premature osteoporosis, .Most commonly, however, Osteogenesis imperfecta presents in childhood with multiple fractures and related complications, .The precise incidence of Osteogenesis imperfecta is unknown and reports vary from approximately 1/100,000 to 1/25,000 dependent on the criterion used to deﬁne Osteogenesis imperfecta. Severe forms and milder disease occur with approximately similar incidence. Severe and mild forms share the cardinal feature of bone fragility, which is characterized by bone fractures often after little or no trauma, .Several ﬁndings in Osteogenesis imperfecta are common to other disorders of connective tissues; hyper-mobile joints and a blue sclera are among these features frequently described, The incorporation of abnormal type 1 collagen in teeth results in brittle opalescent teeth, the hallmark of Dentinogenesis Imperfecta, often seen in Osteogenesis imperfecta, .Progressive conductive hearing loss in early adulthood is the result of damage to the ossicles in the middle ear; over time, hearing loss typically progresses and combined conductive and sensorineural hearing loss may be seen in adults, similar to that of otosclerosis. Short stature and bone deformity are common features of the disorder The mainstay of treatment is orthopedic management along with physiotherapy, Bisphosphonates are being evaluated for efﬁcacy and clinical trials have shown improvement at least in bone mineral density Disorders associated with fragility fractures in children: A) Primary conditions Genetic disorders :- Osteogenesis imperfecta - Ehlers-Danlos syndrome - Marfan syndrome Homocystinuria - Osteoporosis - Hypophosphatasia Polyostotic fibrous dysplasia - Rickets (genetic forms) Idiopathic juvenile osteoporosis B) Secondary conditions 1- Chronic inflammatory conditions Systemic lupus erythematosus - Inflammatory bowel disease - Nephrotic syndrome 2- Reduced mobility Cerebral palsy - Duchenne muscular dystrophy - Posttraumatic 3- Infiltrative Leukemia - Thalassemia 4- Endocrine Hypogonadism - Growth hormone deficiency - Cushing syndrome Hyperthyroidism - Diabetes mellitus 5- Nutritional/malabsorptive Vitamin D deficiency - Celiac disease - Biliary atresia Cystic fibrosis - Anorexia nervosa 6- Renal Chronic kidney disease - Secondary hyperparathyroidism 7- Iatrogenic Glucocorticoids - Anticonvulsants - Methotrexate - Radiation therapy

Official Title
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Molecular Genetic Study of Suspected Cases of Osteogenesis Imperfecta Attending Assiut University Children Hospital

Conditions
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Bone Disease, Metabolic

Intervention / Treatment
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* Drug: Zoledronic Acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Positive family history of fractures or stillbirths. Results of biochemical tests correlate with osteogenesis imperfecta. Low bone density. Exclusion Criteria: Presence of secondary causes of fractures. Abnormalities of biochemical tests or hormonal profile. Negative family history. Fractures in same site each time.

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Repeated fractures group<br>detection of gene mutations of osteogenesis imperfecta in single group of patients with repeated fractures then start treatment with zoledronic acid in doses children less than 5 years ( 0.025 milligram for each kilogram every 3 months for 18 months duration) children more than 5 years ( 0.05 milligram for each kilogram every 6 months for 18 months duration) | Drug: Zoledronic Acid<br>* intravenous injections once every 3 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of children diagnosed as osteogenesis imperfecta | diagnosis based on molecular genetic study | 1 month |