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Unusual Presentation of Osteogenesis Imperfecta
Alankar Ambadas Ramteke*, Satish Shripad Ugrankar**
Abstract
Although Osteogenesis Imperfecta is the most common genetic cause of osteoporosis even today the diagnosis is based on classical clinical findings when present. OI should always be kept as a differential diagnosis for a child presenting with multiple repeated fractures. This is a case of OI where the classically described triad of blue sclera, deafness and dentimogenesis imperfecta was not obvious and patient presented with fractures. Various types of clinical presentation and diagnostic modalities in literature are also described.
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Introduction1
Osteogenesis Imperfecta must be
considered as a differential diagnosis in a child having multiple repeated fractures and it may be impossible to differentiate from other causes of osteoporosis in childhood in the early stages.3 Other causes of osteoporosis in childhood and resultant fractures are as follows.
1. Idiopathic juvenile osteoporosis-usually presents about two years before puberty and is a self-limiting disease. It is difficult to differentiate from OI of late onset and one can be sure of this diagnosis only in retrospect.
2. Childhood neoplasms like leukaemia may present as osteoporosis and typical blood picture may become apparent only later.
3. Cushing’s disease, thyrotoxicosis, or scurvy may be other rare causes that can be easily differentiated.
4. Battered baby syndrome.
5. Inherited disorders like hypo-phosphatasia.4
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| Fig. 1 : normal looking dentition. |
Fig. 2 : port-wine stain. |
Fig. 3 : Looser zones and micro fractures, Dec. 2003. |
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Case Report
A 14-year-old boy presented with fracture of middle third, right femur shaft in August 2003, following a trivial fall. He was appropriately investigated and operated with Ender’s nail, but the fracture failed to unite. Hence he was operated again with a K-nail, and bone grafted in March 2004, as a lot of endosteal callus around the fracture seen intra-op, made closed nailing difficult. He was followed up at regular intervals. 8 months later, he came back with opposite side fractured shaft femur, again following trivial fall. He was investigated and operated with K-nail and bone graft in September 2004. Both fractures subsequently united in 4 months post op follow up.
On detailed clinical evaluation the boy was short and thin built and was found to be below 5th percentile for his age for height and weight according to National Centre for Health Statistics, USA.2 He had normal intelligence, with no difficulty in hearing. He had normal sclerae and normal looking dentition (Fig. 1) but there was a history of delayed dentition on inquiring from parents. There were no skeletal deformities or neurocutaneous stigmata except for port wine stain over angle of mandible on one side (Fig. 2). Skin was normal with no extensive scarring over surgical incisions or otherwise. There was no joint laxity or hyper extensile joints especially over hands joints and digits and no flat feet deformity. His radiographs revealed (1) old and previously unreported fractures of femur shaft with hypertrophic callus around fresh fractures of shaft. (2) Looser zones and micro fractures in the neck of femur (Fig. 3) (3) hypertrophic callus around fracture site (4) good union over an expected period of time.
Laboratory investigations were normal with respect to haemogram, peripheral blood smear, serum calcium and phosphorus, urine calcium and phosphorus excretion; T3, T4, TSH levels were normal, a raised serum alkaline phosphatase level was observed during the fracture and even 4 months after last fracture occurred.
Pure Tone Audiometry revealed mild conductive deafness. Patient had history of left otorrhoea 2 years back. ENT examination revealed large central perforation of left eardrum.
Histopathological examination of the bone specimen obtained during surgery revealed a diagnosis of Osteogenesis Imperfecta. In March 2004 on histopathological examination there was thick cortical sclerotic bone and cancellous bone containing crowded osteoblasts. There was no chondroid tissue. Some trabeculae covered with thin layer of osteoid were seen. Marrow spaces containing plump fibroblastic tissue were also noted. This picture was reported as consistent with clinical suspicion of Osteogenesis Imperfecta. When the child underwent surgery for the other leg in September 2004, intraoperatively obtained bone tissue was again sent for histopathologic examination. Microscopic examination showed many woven bony trabeculae, separated by fibrocollagenous stroma with partially mineralized trabeculae, focally lined by osteoblasts. This appearance was again reported to be consistent with a clinical diagnosis of Osteogenesis Imperfecta. To support the impression on microscopic examination the slides were again examined under plain polarized light on request. The polarized light examination of homogenous appearance with no organized trabecular pattern was again consistent with a clinical diagnosis of Osteogenesis Imperfecta.
Discussion
OI is the most common genetic cause of osteoporosis.3 In all forms of OI, bone mineral density in unfractured bones is decreased. However, the degree of osteopenia may be difficult to evaluate because repeated fractures limit exercise and thereby worsen the decrease in bone mass. Surprisingly, fractures appear to heal normally.4 It is a generalized disorder of connective tissue caused by structural or quantitative defects in type 1 collagen with a generalized decrease in bone mass (osteopenia). Bone matrix in particular contains abnormal type 1 collagen and increased levels of type 3 and type 5 collagen.3
Clinical manifestations4 of a typical OI consist of fragile bones, blue sclerae, progressive hearing loss, dentinogenesis imperfecta, and a positive family history. Colour of sclerae can be normal or blue. Dentinogenesis imperfecta is not invariably present. Teeth may be normal, moderately discoloured or grossly abnormal. Underneath normal looking enamel there may be abnormal underlying dentin. The defect in dentin is directly attributable to the fact that normal dentin is rich in type 1 collagen. Hearing loss usually begins during the second decade of life, occurs in more than 50% subjects over the age of 30.4 It may be sensory, conductive or mixed.5 General examination may reveal mild short stature as compared to family members, easy bruisability, joint laxity, flat feet deformities, low longitudinal arches of feet and excessive mobility in digits.3,6
Biochemistry may not reveal any abnormalities6 except elevated serum alkaline phosphatase. Some patients may have elevated thyroxine levels.7
Literature review reveals that OI cannot be characterized by one histologic pattern. Neither the morphology of the cells or the matrix is consistent throughout the spectrum of the disease. By histometric analysis, the severe forms of Osteogenesis Imperfecta exhibit a significantly greater proportion of primitive osseous tissue with a woven or irregular collagenous matrix. However, all patients with OI have increased amount of woven bone as compared to normal controls.8 One of the most characteristic histological features of OI is the abundance of osteocytes. In other words, the quantity of extra cellular matrix separating the cells is reduced; as a consequence the cells are much closer together. Polarized light or silver methanamine staining can demonstrate abnormal orientation of bone collagen.9
This patient presented at adolescence without grossly deformed bones or multiple fractures in childhood. Although he had multiple repeated fractures and deafness, he did not have the other characteristic clinical features like blue sclerae and dentinogenesis imperfecta. However his histological picture was consistent with OI. His radiographs revealed osteoporosis and looser zones with fractures following history of trivial trauma with hypertrophic callus around previously unreported fractures. Therefore we present this case as one of Osteogenesis Imperfecta-“A Rare Presentation” even in absence of the characteristic clinical features as this adolescent patient has a history of fractures following trivial trauma, radiological changes of osteoporosis, biochemical changes and more importantly a histopathological appearance consistent with a clinical diagnosis of Osteogenesis Imperfecta.
Diagnosis
The diagnosis of OI is usually made on the basis of clinical criteria. There is no consensus as to whether the diagnosis of OI can be made by microscopy of bone.4 Diagnostic procedures may include a skin biopsy to evaluate the amount and structure of collagen.10 Skin fibroblasts are incubated with radioactive amino acids and analyzed for molecular defect in type 1 procollagen. However, this test is complicated and not many qualified centres are available to perform the procedure. It is not unusual for the results of the biopsy to take up to 6 months and in spite of all this molecular diagnosis is possible in only half of the patients.4,10
References
1. Wynne-Davies R, Gormley J. Clinical and Genetic Patterns in Osteogenesis Imperfecta. Clinical Orthopaedics and Related Research 1981: 159 ; 26-35.
2. Ghai OP, Gupta P, Paul VK. Ghai Essential Paediatrics. 5th ed. Interprint. New Delhi. 2000.
3. Marini JC. Osteogenesis Imperfecta. In: Behrman RE, Kliegman RM, Jenson HB, eds Nelson Textbook of Pediatrics, 17th ed. WB Saunders Company. 2004; 698 : 2336-38.
4. Prockop DJ, Ala-Kokko L. Inherited Disorders of connective Tissue. In: Kasper DL, Braunwald E, Fauci AS, Longo DL, Hauser SL, Jameson J, eds Harrison’s Principles of Internal Medicine. 16th ed. Mc Graw Hill. 2005; 342 : 2324-28.
5. Bergstrom LV. Fragile Bones and Fragile Ears. Clinical Orthopaedics and Related Research 1981: 159 : 58-63.
6. Bauze RJ, Smith R, Francis MJO. A New Look At Osteogenesis Imperfecta. J Bone and Joint Surgery 1975; 57 B (1) : 2-12.
7. Brown DM. Biochemical Abnormalities in Osteogenesis Imperfecta. Clinical Orthopaedics and Related Research 1981; 159 : 75-79.
8. Bullough PG, Davidson DD, Lorenzo JC. The Morbid Anatomy of the Skeleton in Osteogenesis Imperfecta. Clinical Orthopaedics and Related Research 1981; 159 : 42-57.
9. Sillence D. Osteogenesis Imperfecta: An Expanding Panorama of Variants. Clinical Orthopaedics and Related Research 1981; 159 : 11-25.
10. William Beaumont Hospital 2004. Available at http://www.beaumonthospitals.com/pls/portal, William Beaumont Hospitals. Accessed April 10, 2004.
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XDR-TB - A GLOBAL THREAT
‘Extensively (or extremely) drug-resistant tuberculosis (XDR-TB). Multidrug-resistant TB (MDR TB), defined as resistant to at least isoniazid and rifampicin, requires the use of second-line drugs that are less effective, more expensive, and more toxic than first-line regimens based on isoniazid and rifampicin. Recognised earlier this year, XDR-TB is MDR-TB that is also resistant to three or more of the six classes of second-line drugs. Of 17690 TB isolates taken between 2000 and 2004, 20% were MDR and 2% were XDR.
Since WHO guidelines recommend the use of at least four drugs for those with MDR-TB, XDR-TB is untreatable to international standards. Most of XDR-TB cases were coinfected with HIV; 52 of these 53 patients have died.
Failure to act now to contain the threat posed by XDR-TB will have devastating consequences for patients with TB, particularly those co-infected with HIV/AIDS.
The Lancet, 2006; 368 : 964.
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