Genetic disorders with heterotopic ossificans

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Abstract

Fibrodysplasia ossificans progressiva (FOP) and progressive ossific heteroplasia (POH) are rare genetic disorders characterized by heterotopic bone formation leading to progressive loss of mobility and function. We report three cases of these rare disorders (two cases of FOP and one case of POH), which were clinically diagnosed and underwent genetic analysis. The aim of this report is to highlight the clinical features and the differences between these two conditions. We would also like to emphasize on the morbidity that can arise from unnecessary invasive investigations for diagnostic purposes.

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Most cited references 23

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Inherited human diseases of heterotopic bone formation.

F Kaplan, Roy E. Shore (2010)

Human disorders of hereditary and nonhereditary heterotopic ossification are conditions in which osteogenesis occurs outside of the skeleton, within soft tissues of the body. The resulting extraskeletal bone is normal. The aberration lies within the mechanisms that regulate cell-fate determination, directing the inappropriate formation of cartilage or bone, or both, in tissues such as skeletal muscle and adipose tissue. Specific gene mutations have been identified in two rare inherited disorders that are clinically characterized by extensive and progressive extraskeletal bone formation-fibrodysplasia ossificans progressiva and progressive osseous heteroplasia. In fibrodysplasia ossificans progressiva, activating mutations in activin receptor type-1, a bone morphogenetic protein type I receptor, induce heterotopic endochondral ossification, which results in the development of a functional bone organ system that includes skeletal-like bone and bone marrow. In progressive osseous heteroplasia, the heterotopic ossification leads to the formation of mainly intramembranous bone tissue in response to inactivating mutations in the GNAS gene. Patients with these diseases variably show malformation of normal skeletal elements, identifying the causative genes and their associated signaling pathways as key mediators of skeletal development in addition to regulating cell-fate decisions by adult stem cells.

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Fibrodysplasia Ossificans Progressiva: Clinical and Genetic Aspects

Robert J. Pignolo, Eileen Shore, Frederick Kaplan (2011)

Fibrodysplasia ossificans progressiva (FOP) is a severely disabling heritable disorder of connective tissue characterized by congenital malformations of the great toes and progressive heterotopic ossification that forms qualitatively normal bone in characteristic extraskeletal sites. The worldwide prevalence is approximately 1/2,000,000. There is no ethnic, racial, gender, or geographic predilection to FOP. Children who have FOP appear normal at birth except for congenital malformations of the great toes. During the first decade of life, sporadic episodes of painful soft tissue swellings (flare-ups) occur which are often precipitated by soft tissue injury, intramuscular injections, viral infection, muscular stretching, falls or fatigue. These flare-ups transform skeletal muscles, tendons, ligaments, fascia, and aponeuroses into heterotopic bone, rendering movement impossible. Patients with atypical forms of FOP have been described. They either present with the classic features of FOP plus one or more atypical features [FOP plus], or present with major variations in one or both of the two classic defining features of FOP [FOP variants]. Classic FOP is caused by a recurrent activating mutation (617G>A; R206H) in the gene ACVR1/ALK2 encoding Activin A receptor type I/Activin-like kinase 2, a bone morphogenetic protein (BMP) type I receptor. Atypical FOP patients also have heterozygous ACVR1 missense mutations in conserved amino acids. The diagnosis of FOP is made by clinical evaluation. Confirmatory genetic testing is available. Differential diagnosis includes progressive osseous heteroplasia, osteosarcoma, lymphedema, soft tissue sarcoma, desmoid tumors, aggressive juvenile fibromatosis, and non-hereditary (acquired) heterotopic ossification. Although most cases of FOP are sporadic (noninherited mutations), a small number of inherited FOP cases show germline transmission in an autosomal dominant pattern. At present, there is no definitive treatment, but a brief 4-day course of high-dose corticosteroids, started within the first 24 hours of a flare-up, may help reduce the intense inflammation and tissue edema seen in the early stages of the disease. Preventative management is based on prophylactic measures against falls, respiratory decline, and viral infections. The median lifespan is approximately 40 years of age. Most patients are wheelchair-bound by the end of the second decade of life and commonly die of complications of thoracic insufficiency syndrome.

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Heterotopic ossification: a review.

Sarah E. McCarthy, Gopinath Sundaram (2005)

Heterotopic ossification is the formation of bone in the soft tissues. Soft tissue bone deposition may range from the minimal and inconsequential to massive and clinically significant. In some clinical settings it is a predictable finding with an unpredictable course and in other settings it may be diagnostically confounding. Heterotopic ossification may be encountered in clinically disparate disease processes and circumstances. We review the genetic, neurogenic, post-traumatic, post-surgical and "reactive" causes of heterotopic ossification and discuss some current concepts of its pathogenesis.

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Author and article information

Journal

Journal ID (nlm-ta): Indian J Orthop

Journal ID (iso-abbrev): Indian J Orthop

Journal ID (publisher-id): IJOrtho

Title: Indian Journal of Orthopaedics

Publisher: Medknow Publications & Media Pvt Ltd (India )

ISSN (Print): 0019-5413

ISSN (Electronic): 1998-3727

Publication date (Print): May-Jun 2015

Volume: 49

Issue: 3

Pages: 361-364

Affiliations

[1]Department of Orthopedics, Kanchi Kamakoti Childs Trust Hospital, Nungambakkam, Chennai, Tamil Nadu, India

[1 ]Department of Medical Genetics, Kanchi Kamakoti Childs Trust Hospital, Nungambakkam, Chennai, Tamil Nadu, India

Author notes

Address for correspondence: Dr. Saraswati Viswanathan, Department of Orthopedics, Kanchi Kamakoti Childs Trust Hosptial, 12-A, Nageswar Road, Nungambakkam, Chennai - 600 034, Tamil Nadu, India. E-mail: saraswati.v@ 123456gmail.com

Article

Publisher ID: IJOrtho-49-361

DOI: 10.4103/0019-5413.156228

PMC ID: 4443422

PubMed ID: 26015640

SO-VID: f5721ca2-59e1-4c1a-91b0-43553973281f

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.