Page 19 - Delaware Medical Journal - June 2016
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SCIENTIFIC ARTICLE
different mutation from the COL1A1 and COL1A2 (IFITM5) and
hypertrophic callus development after fracture.6-8 The mutation associated with Type VI is a loss of function of SERPINF1
and patients present with reduced bone mass, increased bone brittleness, increased levels of alkaline phosphatase, high levels of other signs of OI such as DI and blue sclera.8,9
PATHOPHYSIOLOGY
Before elaborating on the diagnosis and treatment of OI, it is important to understand what happens at the molecular level with respect to the biosynthesis of type I collagen. Procollagen is formed in the rough endoplasmic reticulum as triple helix from two a1(I) collagen chains and one a2(I) collagen chain which
are encoded by the COL1A1 and COL1A2 genes, respectively. Each of these chains contains C and N terminal propeptides
as well as a domain with a repetitive amino acid arrangement and folding, the procollagen molecule is transported to the extracellular matrix by the Golgi apparatus where cleavage of
the terminal propeptides occurs and the collagen molecules form 10
While more than 90 percent of OI can be attributed to mutations in the COL1A1 and COL1A2 genes, over 1,350 different autosomal dominant and over 150 autosomal broad heterogeneity in clinical manifestations.11,12 Milder forms of OI occur with quantitative disorders of type I collagen while more severe forms of the disease occur with qualitative disorders. OI type I is the result of a 50 percent reduction
in type I collagen from variants in a single allele of the COL1A1 gene or absence of an allele resulting in instability
of mRNA. OI types II thru IV result from a qualitative defect in type I collagen and intermixing of normal and abnormal procollagen chains as a result of glycine substitutions and
other less common mutations.13 Autosomal recessive variants
of the disease occur in around 10 percent of cases as a
result of mutations in genes that involve post-translational 12
DIAGNOSIS
Prenatal diagnosis of OI is possible in types II and III and sometimes type IV. Increased nuchal translucency is the earliest 14 include less fetal bone echogenicity, evidence of fractures
in varied stages of healing, and gross skeletal deformity.15 Manifestations of type III and IV include bowing of long bones without evidence of fracture and typically can be seen at 18 and 20 weeks gestation, respectively.13 Shortened femur length has also been shown in OI type III.16 by chorionic villus sampling and either electrophoresis or amniocentesis.17
Unfortunately, there is no test with 100 percent sensitivity for
OI. The traditional way to establish a diagnosis was by studying identify approximately 90 percent of individuals.17 False negative rates have been reported to be up to 15 percent.18
recent best practice guidelines have been established with direct genomic analysis of COL1A1/2 genes as the starting point in
of individuals, has a shorter time to diagnosis, and is associated with reduced costs. If clinical suspicion remains high with no aberrations may be done.17
Special consideration should be given to differentiating OI from child abuse. Both conditions may present with multiple fractures in various stages of healing as well as fractures involving the skull, ribs and metaphysis of bones. The distinction between the two can be further clouded as the two entities are not necessarily mutually exclusive.20 Between these two diagnoses, one should note that OI is exceedingly rare. One study of the work-up of
39 patients presenting with rib fractures revealed a diagnosis of child abuse in 82 percent, accidental injury in 8 percent, birth trauma in one patient, and a metabolic bone disease in 8 percent. Within this metabolic subset, only one patient had a diagnosis
of OI.21 Further, a prospective study by Metz et al on 2,890 children undergoing evaluation for abuse found a 0.001 percent incidence of OI.22
Dual energy X-ray absorptiometry (DEXA) scanning may have an adjunct role in diagnosis as Bone Mineral Density (BMD) either remains the same or decreases in OI patients with time. Normal children will have increases in BMD with time. Some
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