FIBRODYSPLASIA OSSIFICANS PROGRESSIVA Your name here Biology 423L 2006 Date Fibrodysplasia Ossificans Progressiva Abstract Fibrodysplasia ossificans progressive FOP is a rare autosomal dominant disorder of connective tissue that results in heterotopic osteogenesis in humans and results in the postnatal formation of an ectopic skeleton It affects about 1 in 2 million people Mahboubi et al 2001 FOP was first described by Patin in 1648 as the woman who turned into wood The term FOP was introduced by Bauer and Bode in 1800 and since then over 700 cases of the disorder have been reported This disorder usually arises from a spontaneous mutation in a gene that gets passed down to future generations and since reproductive fitness is low Kaplan et al 1993 the rarity of this disorder increases making traditional positional cloning and linkage analysis difficult There are very distinct clinical features for FOP One of these features is the Congenital malformation of the great toes with shortening of the first metatarsal and proximal phalanx which is the earliest phenotypic feature of FOP and is present in nearly all affected individuals at birth Meij et al 2005 Another feature is the heterotopic ossification of soft tissue Feldmen et al 2000 and the third feature is the temporal progression of osteogenesis in characteristic anatomic patterns Mahoubi et al 2001 A person afflicted with FOP has basically 2 skeletons one that was formed during embryogenesis called normatopic and a second skeleton that is formed around the first skeleton postnatally called a heterotopic skeleton Spinal deformity is a variable feature of FOP In a study researchers reviewed clinical records in order to characterize the spinal deformity in forty patients who have established diagnosis of FOP 65 had scoliosis present since childhood 88 of those who had scoliosis had unbalanced c shaped curves while 12 of them had s shaped curves Shah et al 1994 Scoliosis is seen as the result of asymmetric bars of heterotopic bone connecting the rib cage to the pelvis Mahboubi et al 2001 Figure 1 FOP patients are characterized by malformed big toes Conner et al 1982 Figure 2 On the left is a 25 year old man afflicted with FOP On the right is the skeleton of that man at the age of 40 after he died of pneumonia The picture on the right clearly shows how this man s muscles around his shoulders and throughout his arms have been turned into bone and have become a part of his skeleton Feldmen et al 2000 Figure 3 Spinal deformity is common in FOP patients This is a figure of an 8 year old girl with an unbalanced c shaped lumbar scoliosis Shah et al 1994 FOP is a Progressive disorder Although the rate of disease progression is variable most patients are confined to a wheelchair by their early twenties Mobility of the person with FOP becomes more rigid and disabled with age Any injury to soft tissue can increase the progression of its transformation into bone and is usually the case but can occur without detectable trauma Feldman et al 2000 Mahboubi and fellow researchers observed that the ossification of the affected site are recognized by the spontaneous appearance of large tumor like swellings of highly vascular fibroproliferative tissue that arises after the death of muscle cells These swelling occasionally regress but most often from bones They are first identified by soft tissue lesions A biopsy of the lesion can not be taken since the process of taking it would exacerbate the condition The lesions progress through an expected course in the first few weeks there is pain swelling warmth and tenderness but after several weeks the swelling as well as the pain starts to subside as the intermediate lesion forms Within three months the swelling disappears and the patient is left with a new bone created by heterotopic ossification The bone formed in FOP is normal but is temporally and spatially inappropriate Fiori et al 2006 Figure 4 Infant showing soft tissue nodules on the back These nodules are characteristically present in the earliest stages of FOP Kaplan et al 1993 In a study researchers Connor and Evans found the progression of disability was erratic but severe restriction of movement of the shoulder and spine was usual by the age of 10 years and the hips were affected by the age of 20 years and confined to a wheelchair by the age of 30 years Researchers have also observed that Permanent restriction of mandibular opening is seen in approximately 80 of the cases and occurs on the average age of 18 years Meij et al 2005 Figure 5 This table shows the progression of FOP in three age categories It shows the distribution and percentage frequency of severe involvement of the joints related to age With every increasing age column the frequency of the joint involvement increases Conner et al 1982 Fibrodysplasia ossificans progressiva is genetically linked In a study by Feldmen and fellow researches in 2000 they described a genome wide linkage analysis in four small families containing individuals affected with FOP and demonstrated locus homogeneity and linkage of the FOP gene at a 36 cM segment on the long arm of human chromosome 4 To identify the chromosomal location of the FOP gene they conducted a genome wide linkage analysis using four affected families with a total of 14 informative meiosis events These subjects were first genotyped The researchers obtained peripheral blood from them and a set of highly polymorphic microsatellite markers covering all human autosomes were amplifies by use of PCR They were then denatured and separated by sized markers on gel and exposed to autoradiography film A two point linkage analysis was performed and on the basis that penetrance of the FOP gene is 100 They then constructed haplotypes from the genotype data Figure 6 The pedigrees of 4 different families who have a history of FOP They all have genotypes for makers from the chromosome 4q27 31 The haplotypes for the markers that are listed on the left of the table are listed below the symbols for the family members For instance II1 in FOP1 is the afflicted male in the second generation The haplotype that represents the people with the disorder are boxed Feldmen at al 2000 Based on their results they excluded X linked inheritance since male to male transmission of the FOP phenotype was observed In each family penetrance was complete and the inheritance pattern was consistent with autosomal dominant transmission They also used radiation hybrid mapping to