Fibrodysplasia Ossificans Progressiva: Three Indian Patients with Mutation in the ACVR1 Gene

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by ectopic bone formation involving the connective tissues leading to severe skeletal manifestations. The genetic defect in this disorder has not been characterized in Indian patients till date. The authors report three cases of FOP along with the molecular defects identified in them. Exon 4 of the ACVR1 gene was amplified and analysed by sequencing. All three cases revealed common heterozygous mutation i.e., c.617(G>A). Identification of this mutation would lead to decrease in misdiagnosis and subsequent iatrogenic harm caused to these children by unnecessary surgical procedures. Also, mutation detection would provide an opportunity for prenatal diagnosis.

Classical and Atypical Fibrodysplasia Ossificans Progressiva in India

“…This allele has also been identified in several countries including South Africa, Korea, Spain, Italy, and Turkey (Bocciardi et al, 2009;Lee et al, 2009;Dandara et al, 2012;Morales-Piga et al, 2012;Eresen Yazıcıoglu et al, 2013). Our identification of the c.617G>A; p.Arg206His allele in 12 individuals, combined with the previous report of three Indian patients (Shukla et al, 2013), suggests that in India most cases of FOP result from this allelic variant. A summary of ACVR1 variants found worldwide is provided in Table 2.…”

“…Hence, when FOP is clinically suspected in the absence of heterotopic ossification or great toe abnormality, molecular diagnosis is most helpful as biopsy is nondiagnostic and is contraindicated (Kaplan et al, 2008b). Genotyping is a valuable technique which will help to avoid medical diagnostic and therapeutic procedure error (Shukla et al, 2013). Our diagnosis of one child in early infancy prior to manifestation of the heterotopic ossification phenotype shows the importance of diagnosing this disease at the earliest opportunity and highlights the value of the genetic diagnosis.…”

“…Korea, France, Italy, Brazil, Spain, South, Africa, India, Mexico, Egypt, Turkish, China, Germany (Lin et al, 2006), (Nakajima et al, 2007), , (Lucotte et al, 2008), (Bocciardi et al, 2009), (Carvalho et al, 2010), (Morales-Piga et al, 2012), (Dandara et al, 2012), (Shukla et al, 2013), (Herrera-Esparza et al, 2013), (Al-Haggar et al, 2013), (Eresen Yazıcıoglu et al, 2013), (Zhang et al, 2013), (Stefanova et al, 2012) (Connor & Evans, 1982), (Stefanova et al, 2012), (Carvalho et al, 2010) Exons 8 and 9 c.1067 G>A p.Gly356Asp Present Japan, Germany, China (Kaplan et al, 2009), 3 (Furuya et al, 2008), (Stefanova et al, 2012), (Zhang et al, 2013) Exon 9 c.1124 G>C p.Arg375Pro Absent Unspecified (Kaplan et al, 2009) …”

ACVR1 Function in Health and Disease

“…This mutation is localised in the intracellular GS-rich domain of the ACVR1 receptor, and it is present in the majority of FOP patients, usually showing the typical clinical features detailed above [20,24]. The R206H mutation has been extensively analysed in multiple studies, different populations, and geographical groups worldwide, and it has been invariably linked to FOP [24,28,29,30,31,32,33,34,35,36,37,38,39,40]. To date, up to 14 different mutations have been identified to cause FOP, and all of them are localised in the ACVR1 gene (Figure 1).…”