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The congenital great toe malformation of fibrodysplasia ossificans progressiva? - A close call.
Eur J Med Genet. 2017 Jul; 60(7):399-402.EJ

Abstract

BACKGROUND

Congenital bilateral hallux valgus with associated absence or fusion of the interphalangeal joint is a classic diagnostic feature of fibrodysplasia ossificans progressiva (FOP), a human genetic disease of extra-skeletal bone formation caused in nearly all cases by a gain-of-function mutation in Activin A Receptor I/Activin-like Kinase 2 (ACVR1/ALK2), which encodes a bone morphogenetic protein (BMP) Type 1 receptor. This toe malformation prompts the suspicion of FOP even before the appearance of extra-skeletal bone. Here we report the case of a four-month-old child who was suspected of having FOP on the basis of a great toe malformation identical to that seen in children with the disease.

METHODS

The patient's genomic DNA of the coding region of ACVR1 was sequenced and analyzed for mutations known to cause FOP and novel mutations. Subsequent comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) analyses were performed to detect mutations elsewhere in the genome.

RESULTS

Genetic testing exonerated ACVR1 as culpable for the patient's toe malformation. CGH and SNP analyses identified a large intragenic deletion in a different BMP Type 1 receptor gene, BMP Receptor 1B/Activin-like kinase 6 (BMPR1B/ALK6), a gene associated with a variable spectrum of autosomal dominant brachydactyly phenotypes.

CONCLUSIONS

This report illustrates that while toe morphology remains the earliest indicator of FOP, toe morphology alone is not an unequivocal clinical diagnostic feature of FOP, and supports that embryonic development of the great toe is highly sensitive to dysregulated signaling from at least two BMP type I receptors.

Authors+Show Affiliations

Department of Orthopaedic Surgery, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104, USA; The Center for Research in FOP & Related Disorders, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104, USA.Department of Orthopaedic Surgery, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104, USA; The Center for Research in FOP & Related Disorders, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104, USA.Department of Orthopaedic Surgery, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104, USA; The Center for Research in FOP & Related Disorders, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104, USA.The University of Tennessee Genetics Center, Knoxville, TN 37920, USA.The University of Tennessee Genetics Center, Knoxville, TN 37920, USA.Department of Orthopaedic Surgery, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104, USA; The Center for Research in FOP & Related Disorders, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104, USA.Department of Orthopaedic Surgery, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104, USA; The Center for Research in FOP & Related Disorders, The Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: frederick.kaplan@uphs.upenn.edu.

Pub Type(s)

Case Reports
Journal Article

Language

eng

PubMed ID

28473268

Citation

Towler, O Will, et al. "The Congenital Great Toe Malformation of Fibrodysplasia Ossificans Progressiva? - a Close Call." European Journal of Medical Genetics, vol. 60, no. 7, 2017, pp. 399-402.
Towler OW, Shore EM, Xu M, et al. The congenital great toe malformation of fibrodysplasia ossificans progressiva? - A close call. Eur J Med Genet. 2017;60(7):399-402.
Towler, O. W., Shore, E. M., Xu, M., Bamford, A., Anderson, I., Pignolo, R. J., & Kaplan, F. S. (2017). The congenital great toe malformation of fibrodysplasia ossificans progressiva? - A close call. European Journal of Medical Genetics, 60(7), 399-402. https://doi.org/10.1016/j.ejmg.2017.04.013
Towler OW, et al. The Congenital Great Toe Malformation of Fibrodysplasia Ossificans Progressiva? - a Close Call. Eur J Med Genet. 2017;60(7):399-402. PubMed PMID: 28473268.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The congenital great toe malformation of fibrodysplasia ossificans progressiva? - A close call. AU - Towler,O Will, AU - Shore,Eileen M, AU - Xu,Meiqi, AU - Bamford,Abbey, AU - Anderson,Ilse, AU - Pignolo,Robert J, AU - Kaplan,Frederick S, Y1 - 2017/05/01/ PY - 2017/01/20/received PY - 2017/03/03/revised PY - 2017/04/29/accepted PY - 2017/5/6/pubmed PY - 2017/9/29/medline PY - 2017/5/6/entrez KW - ACVR1 KW - BMP receptor IB KW - Bone morphogenetic protein (BMP) signaling KW - Brachydactyly KW - Fibrodysplasia ossificans progressiva KW - Heterotopic ossification SP - 399 EP - 402 JF - European journal of medical genetics JO - Eur J Med Genet VL - 60 IS - 7 N2 - BACKGROUND: Congenital bilateral hallux valgus with associated absence or fusion of the interphalangeal joint is a classic diagnostic feature of fibrodysplasia ossificans progressiva (FOP), a human genetic disease of extra-skeletal bone formation caused in nearly all cases by a gain-of-function mutation in Activin A Receptor I/Activin-like Kinase 2 (ACVR1/ALK2), which encodes a bone morphogenetic protein (BMP) Type 1 receptor. This toe malformation prompts the suspicion of FOP even before the appearance of extra-skeletal bone. Here we report the case of a four-month-old child who was suspected of having FOP on the basis of a great toe malformation identical to that seen in children with the disease. METHODS: The patient's genomic DNA of the coding region of ACVR1 was sequenced and analyzed for mutations known to cause FOP and novel mutations. Subsequent comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) analyses were performed to detect mutations elsewhere in the genome. RESULTS: Genetic testing exonerated ACVR1 as culpable for the patient's toe malformation. CGH and SNP analyses identified a large intragenic deletion in a different BMP Type 1 receptor gene, BMP Receptor 1B/Activin-like kinase 6 (BMPR1B/ALK6), a gene associated with a variable spectrum of autosomal dominant brachydactyly phenotypes. CONCLUSIONS: This report illustrates that while toe morphology remains the earliest indicator of FOP, toe morphology alone is not an unequivocal clinical diagnostic feature of FOP, and supports that embryonic development of the great toe is highly sensitive to dysregulated signaling from at least two BMP type I receptors. SN - 1878-0849 UR - https://www.unboundmedicine.com/medline/citation/28473268/The_congenital_great_toe_malformation_of_fibrodysplasia_ossificans_progressiva___A_close_call_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1769-7212(17)30043-5 DB - PRIME DP - Unbound Medicine ER -