Assessment Item No. 2 (Research Paper) Description: You are presented with a case of a specific molecular condition. You will critically research the literature, describe the clinical, molecular and...

Osteogenesis Imperfecta
Osteogenesis imperfect is also identified by many different terms such as as ‘Brittle bone’ disease, Fragilitis Ossium, Osteopsathyrosis, Lobstein’s disease. Osteogenesis imperfecta is a genetic disorder affecting the bone and leading to reduced bone fragility and surge in the bone mass. This condition relates from the abnormality in type 1 collagen, which then presents itself as fragility of bones. It is primarily considered to be a hereditary autosomal dominant disorder, while autosomal recessive and non hereditary types also prevail. Most of the cases of osteogenesis imperfecta presents with mutation in one of the two genes (COL1A1 and COL1A2) that encrypt for synthesis of collagen type 1 chains. It can have a wide range of exhibition from change in color of sclera, dentinogenesis imperfecta, flaxity of ligaments and skin, deficiency of hearing abilities , to occurrence of wormian bones on skull radiographs. It can be very severe so as to cause the intra uterine fractures or can be mild enough to cause no fracture (Shapiro et al., 1992).
The chief clinical presentation of osteogenesis Imperfecta are the extreme fragility and porosity of the bones leading to increased susceptibility to fractures. Even after the healing of the fracture that is quite fast, the newly bone formed bone is porous and not of good quality. Bluish discoloration of sclera is another common manifestation of osteogenesis imperecta. These discolorations are readily visible due to the minute thickness of sclera. Otosclerosis causes by this disease may lead to deafness. It also leads to abnormal electrical reactions of muscles, laxity of ligaments and a characteristic skull shape with frontal and temporal bossing. It creates dentinogenesis imperfecta like conditions in mouth, crossbites, open bites, impacted and ectopic teeth are also seen in osteogenesis imperfecta.
Classification of osteogenesis imperfecta
Initially Osteigenesis Imperfecta was categorized into four different forms- Type I, Type II, Type III and Type IV (Sillence et al, 1979). After further researches four more types- Type V, Type VI, Type VIIand type VII were added.
Type I Osteogenesis Imperfecta- the Ostegenesis Imperfecta tarda or Lobstein’s Osteogenesis Imperfecta, it is mild, non deforming type characterized by regular height or slight short stature, with blue sclera and absence of associated Dentinogenesis Imperfecta caused due toe the untimely stop codon in COL1A1.
Type II Osteogenesis Imperfecta- osteogenesis imperfecta congenital is neonathal, described by the fracture of long bones and ribs during birth, noticeable deformities, broad long bones, radiographs showing little density of skull bones and a dark colored sclera. This is typically caused be the susbtitutions of Glycine in COL1A1 and COL1A2.
Type III Osteogenesis Imperfecta- it is a progressively deforming type which presents as greyisg discoloration of sclera, development of dentinogenesis imperfecta, and the individual has a short stature with characteristic triangular face and there is severe sclerosis present. It also results from glycine substitution in COL1A1 and COL1A2.
Type IV Osteogenesis Imperfecta- moderately deforming type with chief characteristic features such as discreetly small stature, slight to modest scoliosis. The color of sclera is greyish or white sclera. dentinogenesis imperfecta is seen in this type. It also occurs due to Glycine substitutions in COL1A1 and COL1A2.
Type V Osteogenesis Imperfecta- it is moderately to severe deforming type with characteristic features such as mild to moderate short stature. The sclera is white in color and dentinogenesis imperfecta is absent. There is a dislocation of radial head, occurrence of hyperplastic callus and mineralization of the interosseous membrane.
Type VI Osteogenesis Imperfecta- it is moderately to severely deforming. The patient has a moderately short stature with marked scoliosis. There is deposition of osteoid in bone tissue and fish-scale pattern of bone lamellation. The sclera is white and there is absence of dentinogenesis imperfecta.
Type VII Osteogenesis Imperfecta- it is discreetly deforming characterized by slight small stature, white colored sclera, tiny humeri and femora, coxa vara and absence of dentinogenesis imperfecta.
The associated mutation with Type V, VI and VII are unknown.
Other genes responsible for Osteogenesis Imperfecta involve-
X-linked recessive genes- CRTAP, LEPRE1, PPIB, BMP1, FKBP10, SERPINH1, SERINF1, WNT1, SP7, SERPINF1, TMEM38B, SPARC, MBTPS2 and TENT5A .
Autosomal-dominant inherited genes- COL1A1 and COL1A2.
COL1A1/2 osteogenesis imperfecta manifests as fractures with negligible or no injury, inconstant dentinogenesis imperfecta (DI), and hearing impairment in adults.
Diagnosis/testing
The diagnosis can be made by a proband by identifying a heterozygous pathogen or likely the pathogenic variant in COL1A1/2 by the help of molecular genetic testing.
Genetic research
Osteogenesis imperfecta type COL1A1 and COL1A2 is autosomal dominant in behavior. The percentage of individuals that were affected by it depended upon the severity of disease. About the 60% of probands with slight Osteogenesis Imperfecta represents the simplest of cases. Whereas on virtual bases a 100% of probands with increasing deforming or perinatally lethal Osteogenesis Imperfecta represent simplex cases and the pathogenic variant that is received from parent somatic or through germline mosaicism is present in up to 16% of families.
If an individual is having autosomal dominant COL1A1 or COL1A2 type of Osteogenesis Imperfecta then there is 50% probability of inheriting the causative agent and chances og having manifestations of Osteogenesis Imperfecta. for eg. If a family relataive is infected by Osteogenesis Imperfecta then Prenatal testing in at-risk pregnancies can be achieved by molecular genetic examination..
Other then molecular genetic testing, Ultrasound examination can be valuable in the prenatal identification of the lethal form of Osteogenesis Imperfecta, other most severe forms can be detected prior to 20 weeks of gestation and if fractures or other deformities occur of milder forms they may be detected later in pregnancy.
Radiographic features
The radiographic features of osteogenesis imperfecta are dependent on age and change accordingly.
1. Fractures of different types and different stages involving the long bones, ribs and skull. Sometimes metaphyseal fractures are seen in children with Ostegenesis Imperfecta.
2. Spinal cord fracture that usually occurs in adults presents "Codfish"vertebrae, appearance on radiograph.
3. Wormian bones- when the sutural bones of diameter 6 mm /4 mm or larger up to 10 in numbers, arrange themselves in a mosaic pattern.
4. Protrusio acetabuli, prsesentation where the hip joint socket is very...