The congenital great toe malformation of fibrodysplasia ossificans progressiva? - A close call

O. Will Towler, Eileen M. Shore, Meiqi Xu, Abbey Bamford, Ilse Anderson, Robert Pignolo, Frederick S. Kaplan

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)399-402
Number of pages4
JournalEuropean Journal of Medical Genetics
Volume60
Issue number7
DOIs
StatePublished - Jul 1 2017
Externally publishedYes

Fingerprint

Myositis Ossificans
Hallux
Type I Bone Morphogenetic Protein Receptors
Toes
Activins
Mutation
Comparative Genomic Hybridization
Single Nucleotide Polymorphism
Phosphotransferases
Brachydactyly
Activin Receptors
Bone Morphogenetic Protein Receptors
Hallux Valgus
Inborn Genetic Diseases
Medical Genetics
Genetic Testing
Osteogenesis
Genes
Embryonic Development
Joints

Keywords

  • ACVR1
  • BMP receptor IB
  • Bone morphogenetic protein (BMP) signaling
  • Brachydactyly
  • Fibrodysplasia ossificans progressiva
  • Heterotopic ossification

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

The congenital great toe malformation of fibrodysplasia ossificans progressiva? - A close call. / Towler, O. Will; Shore, Eileen M.; Xu, Meiqi; Bamford, Abbey; Anderson, Ilse; Pignolo, Robert; Kaplan, Frederick S.

In: European Journal of Medical Genetics, Vol. 60, No. 7, 01.07.2017, p. 399-402.

Research output: Contribution to journalArticle

Towler, O. Will ; Shore, Eileen M. ; Xu, Meiqi ; Bamford, Abbey ; Anderson, Ilse ; Pignolo, Robert ; Kaplan, Frederick S. / The congenital great toe malformation of fibrodysplasia ossificans progressiva? - A close call. In: European Journal of Medical Genetics. 2017 ; Vol. 60, No. 7. pp. 399-402.
@article{ec0e2f1f62984610aa6b379c77397677,
title = "The congenital great toe malformation of fibrodysplasia ossificans progressiva? - A close call",
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.",
keywords = "ACVR1, BMP receptor IB, Bone morphogenetic protein (BMP) signaling, Brachydactyly, Fibrodysplasia ossificans progressiva, Heterotopic ossification",
author = "Towler, {O. Will} and Shore, {Eileen M.} and Meiqi Xu and Abbey Bamford and Ilse Anderson and Robert Pignolo and Kaplan, {Frederick S.}",
year = "2017",
month = "7",
day = "1",
doi = "10.1016/j.ejmg.2017.04.013",
language = "English (US)",
volume = "60",
pages = "399--402",
journal = "European Journal of Medical Genetics",
issn = "1769-7212",
publisher = "Elsevier Masson SAS",
number = "7",

}

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

AU - Kaplan, Frederick S.

PY - 2017/7/1

Y1 - 2017/7/1

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.

AB - 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.

KW - ACVR1

KW - BMP receptor IB

KW - Bone morphogenetic protein (BMP) signaling

KW - Brachydactyly

KW - Fibrodysplasia ossificans progressiva

KW - Heterotopic ossification

UR - http://www.scopus.com/inward/record.url?scp=85020161576&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85020161576&partnerID=8YFLogxK

U2 - 10.1016/j.ejmg.2017.04.013

DO - 10.1016/j.ejmg.2017.04.013

M3 - Article

C2 - 28473268

AN - SCOPUS:85020161576

VL - 60

SP - 399

EP - 402

JO - European Journal of Medical Genetics

JF - European Journal of Medical Genetics

SN - 1769-7212

IS - 7

ER -