Progressive Osseous Heteroplasia

Disease Overview

Summary

Progressive osseous heteroplasia (POH) is an extremely rare disorder characterized by abnormal development of bone in areas of the body where bone is not normally present (heterotopic ossification). The disorder first appears as areas of patchy bone formation (ossification) in the skin during infancy; heterotopic ossification progresses to involve superficial and deep connective tissues, including areas of fat beneath the skin (subcutaneous fat), muscles, tendons, ligaments and the sheets of fibrous tissue that envelop muscle (fascia). This abnormal formation of bone may restrict the movement of affected joints and/or hinder the growth of affected limbs. The course of the disease is unpredictable; some areas of the body may become severely affected while others may remain unaffected. A diagnosis of POH is made only if the bone formation progresses to the deeper connective tissues. Otherwise, bone formation is classified as osteoma cutis.

• View Full Report Show Less
• Print / Download as PDF

• Next section >

• < Previous section
• Next section >

Synonyms

• POH

• < Previous section
• Next section >

• < Previous section
• Next section >

Signs & Symptoms

Progressive osseous heteroplasia (POH) is a rare condition where abnormal bone formation occurs outside the normal skeleton. Signs and symptoms can vary among the affected people. In addition, the progression of POH can vary much from person to person, even within the same family. Some people may experience a slow progression, while others may have a more rapid onset. 

In POH, bone formation may occur more within the membranes (intramembranously) than within cartilage (endochondrally) and there is no inflammation. Histologically, bone can be seen to arise directly within adipose stromal tissue although the exact cell(s) of origin remain unknown.  

Symptoms often appear at birth or within the first few weeks of life. Babies with POH usually show a rash with patchy areas of bone within the skin’s dermis layer. The affected skin may feel unusually rough to the touch. 

Main signs and symptoms may include:

• Extra-skeletal bone formation: The key feature of POH is the development of bone outside the usual skeleton, known as heterotopic ossification.

• Osseous nodules or plaques are small, hard areas of bone that may form within the skin and are called osteoma cutis.

• Over time, these can spread and merge to form larger areas of hardened skin (dermal ossification).

• Subcutaneous extension occurs as POH progresses, where these abnormal bone growths can extend deeper into the skin layers and into connective tissues like fascia and skeletal muscles.

Additional symptoms may include:

• Bone projections, sharp, needle-like bone projections (spicules) that can break through the skin, potentially causing irritation or superficial infections.

• Movement restriction caused by the growth of these abnormal bones that can restrict joint movement and may eventually cause joints to lock (ankylosis). This restriction can occur in any part of the body.

• Asymmetrical growth, where POH can cause one side of the body to be more affected than the other, leading to uneven growth. For example, one leg or arm may become shorter than the other.

• Scoliosis, an abnormal lateral curvature of the spine if bone growth occurs around the spinal area.

POH is a complex condition with a wide range of symptoms and severity. While there is no cure, understanding these symptoms can help in managing the condition and improving the quality of life for those affected.

In mouse models POH have been shown to alter the bone quality. However, detailed studies of skeletal bone quality in POH remain to be thoroughly investigated.

• < Previous section
• Next section >

• < Previous section
• Next section >

Causes

Progressive osseous heteroplasia (POH) is a rare genetic condition caused by changes (pathogenic variants) in the GNAS gene.  

The GNAS gene carries instructions for making a protein called Gsα, which is involved in regulating other proteins that influence bone growth and how cells develop. In about three-fourths of POH patients, there are specific changes (variants) in the GNAS gene that result in a deficiency or dysfunction of the Gsα protein. This abnormal protein function is believed to contribute to the symptoms of POH, although the exact mechanisms are still under investigation. 

POH is associated with a specific gene regulation process known as genetic imprinting. Everyone has two copies of every gene (except for genes on X and Y chromosomes) – one received from the father, and one received from the mother. In most people, both gene copies can be “turned on” and are active. However, some genes are maintained as preferentially silenced or “turned off” based upon which parent that gene came from (genetic imprinting).  

For individuals with POH, the disease-causing variant of the GNAS gene is typically inherited from the father. If the GNAS gene variant comes from the mother, it usually leads to related but different conditions known as Albright hereditary osteodystrophy (AHO) and/or pseudohypoparathyroidism type 1a (PHP1a). 

The exact way variants of the GNAS gene bring about the symptoms of POH is not yet known, however evidence implicates activation of the “hedgehog” signaling pathway in this process. The hedgehog signaling pathway is a group of proteins working together to transmit signals from a cell’s membrane to its nucleus. This pathway plays a significant role in several key biological processes such as cell growth and differentiation and others.  

Most cases of POH are not inherited but occur due to a new spontaneous change in the GNAS gene. This means the condition appears randomly without being passed down from a parent. 

In some instances, POH can be inherited. When this happens, it follows an autosomal dominant pattern, meaning that only one copy of the disease-causing gene variant inherited from either parent can cause the condition. 

• < Previous section
• Next section >

• < Previous section
• Next section >

Affected populations

More than 50 affected individuals with POH have been identified around the world. Although most of the reported patients have been females, the disorder appears to affect males and females in similar numbers. Because POH often goes unrecognized or misdiagnosed, determining the true frequency of the disorder in the general population is difficult. In the most severe cases, symptoms are usually apparent at birth or within the first few weeks of life. Symptoms usually progress as affected individual’s age.

POH was first described in 1994.

• < Previous section
• Next section >

• < Previous section
• Next section >

Disorders with Similar Symptoms

Symptoms of the following diseases may be similar to those of progressive osseous heteroplasia. Comparisons may be useful for differential diagnosis:

Fibrodysplasia ossificans progressiva (FOP) is a very rare inherited connective tissue disorder characterized by the abnormal development of bone in areas of the body where bone is not normally present (heterotopic ossification), such as the ligaments, tendons and muscles. Specifically, this disorder causes the body’s skeletal muscles and soft connective tissue to undergo a transformation into bone, progressively locking joints in place and making movement difficult or impossible. FOP is characterized by malformation of the big toe that is present at birth (congenital). Other skeletal malformations variably occur. As the disease progresses, there may be abnormal formation of bone in soft tissues that may lead to stiffness in affected areas and limited movement in affected joints (e.g., knees, wrists, shoulders, spine and/or neck). FOP usually begins during early childhood and progresses throughout life. Most cases of FOP occur randomly (sporadic). FOP is caused by variants of the gene (ACVR1/ALK2) in the “BMP pathway” which is associated with the formation of the skeleton in the embryo and the repair of the skeleton following birth. (For more information on this disorder, choose “FOP” as your search term in the Rare Disease Database.)

Albright hereditary osteodystrophy (AHO) is a rare disorder characterized by short stature, an unusually round face, abnormally short fingers (brachydactyly) and/or the development of bony growths (osseous plaques) on the surface of the skin but not in the deep connective tissue. These growths may spread to the lower level of the skin as well (subcutaneous ossification). Other symptoms may include mild intellectual disability, abnormally low levels of calcium in the blood (hypocalcemia) and/or the clinical features of pseudohypoparathyroidism. Pseudohypoparathyroidism type 1a (PHP1a) is caused by defective G-proteins that are needed to properly respond to parathyroid hormone and other hormones. In addition to hormone resistance, symptoms of pseudohypoparathyroidism include weakness, muscle cramps, excessive nervousness, headaches and/or abnormal sensations such as tingling, burning, and numbness of the hands. AHO and PHP1a are caused by variants of the same gene (GNAS) that causes POH. Both conditions can be inherited in an autosomal dominant pattern. While POH occurs only when the gene variant is inherited from fathers, AHO features are associated with GNAS gene variants that are inherited either from mothers or fathers. PHP1a and/or AHO-associated obesity occur when the gene variant is inherited from mothers. (For more information on this disorder, choose “AHO” as your search term in the Rare Disease Database.)

• < Previous section
• Next section >

• < Previous section
• Next section >

Diagnosis

The diagnosis of POH may be confirmed by a thorough clinical evaluation, characteristic physical findings and tests that demonstrate the presence of heterotopic ossification (e.g., x-ray or roentgenograms and CT scans) with characteristic appearance for POH in the deep connective of the fascia, muscles, tendons, muscles and/or ligaments.

• < Previous section
• Next section >

• < Previous section
• Next section >

Standard Therapies

For people affected with POH, managing symptoms and maintaining mobility are crucial aspects of care.  The management may include: 

Mobility and support aids such as:  

• Special shoes and braces: These devices can assist in walking and bearing weight, especially when POH affects the lower limbs. They help stabilize the legs and provide support, making it easier to move. 

• Occupational therapy: For people with POH affecting the upper limbs, occupational therapy can be beneficial. It involves evaluations and the use of assistive devices to aid in daily activities like eating, dressing, and personal care. 

Due to the bony growths associated with POH, it’s important that vaccines are administered in areas of the skin that are not affected by these growths to avoid complications. 

Symptomatic and supportive treatment ideally should involve a multidisciplinary team approach that is beneficial for infants and children with POH. This may include social, educational, and medical services to address the various challenges posed by the condition. 

These measures aim to improve the quality of life for those affected by POH by managing symptoms and providing necessary support. 

Currently there are no specific treatments for abnormal bone growth.  

• While surgery might be considered to remove ectopic bone (bone growing outside the normal skeleton), it is typically not recommended for POH. This is because surgical removal often worsens the condition, leading to more extensive and rapid regrowth of abnormal bone. Radiation therapy does not seem to be effective. Various drugs have been explored to treat heterotopic ossification, but they have not shown effectiveness for POH.  

The unique nature of bone growth in POH, which is different from other forms of heterotopic ossification, poses a significant challenge. A careful, research-driven approach is necessary to develop appropriate therapies for those affected by this rare and challenging condition. 

Genetic counseling is recommended for individuals with POH and their families. This can help them understand the genetic aspects of the disorder, including the risks of recurrence in future pregnancies and the implications for other family members. 

 

• < Previous section
• Next section >

• < Previous section
• Next section >

Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

Contacts for additional information about progressive osseous heteroplasia:

For basic research questions:
Eileen M. Shore, PhD
Professor, Departments of Orthopaedic Surgery and Genetics
Perelman School of Medicine
University of Pennsylvania
309A Stemmler Hall
3450 Hamilton Walk
Philadelphia, PA 19104-6081
phone: 215-898-2330
fax: 215-573-2133
email: [email protected]

For clinical questions:
Frederick S. Kaplan, MD
Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine
Chief, Division of Orthopaedic Molecular Medicine
Perelman School of Medicine
The University of Pennsylvania
c/o Department of Orthopaedic Surgery
Penn Musculoskeletal Center – Suite 600
3737 Market Street
Philadelphia, PA 19104
tel: 215-294-9145
fax: 215-222-8854
email: [email protected]

• < Previous section
• Next section >

• < Previous section
• Next section >

References

TEXTBOOKS
Kaplan FS, Pignolo RJ, Al Mukaddam M, and Shore EM. Genetic Disorders of Heterotopic Ossification: Fibrodysplasia Ossificans Progressiva and Progressive Osseous Heteroplasia. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Ninth Edition. John Bilezikian, Editor. ASBMR, Washington, DC. 2019;Chapter 112:1719-1729.

Shore, EM and Kaplan FS. Extraskeletal Bone Formation. Pediatric Bone, Second Edition. F.H. Glorieux, J.M. Pettifor, H. Juppner, Editors, Academic Press. 2011; Chapter 30; 821-840.

Shore EM, Kaplan FS. Progressive Osseous Heteroplasia. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003; 203-204.

REVIEW ARTICLES
Kaplan FS, Shore EM. Progressive osseous heteroplasia. J Bone Miner Res. 2000; 15: 2084-2094.

Pignolo R, Ramaswamy G, Fong J, Shore E, Kaplan F. Progressive osseous heteroplasia: diagnosis, treatment, and prognosis. Appl Clin Genet. 2015; 8: 37-48.

Shore EM, Kaplan FS. Inherited human diseases of heterotopic bone formation. Nat Rev Rheumatol. 2010;6: 518-527.

Shore EM, Kaplan FS. Insights from a rare genetic disorder of extra-skeletal bone formation, fibrodysplasia ossificans progressiva (FOP). Bone. 2008;43(3):427-433. doi:10.1016/j.bone.2008.05.013

Shore EM and Kaplan FS. FOP and POH: two genetic disorders of heterotopic ossification. Clinical Reviews in Bone and Mineral Metabolism. 2005: 3, 257-260.

Stoll C, Javier MR, Bellocq JP. Progressive osseous heteroplasia: an uncommon cause of ossification of soft tissues. Ann Genet. 2000; 43: 75-80.

JOURNAL ARTICLES
Adegbite, NS, Xu M, Kaplan FS, Shore EM, Pignolo RJ. Clinical features, GNAS mutational analysis, and diagnostic criteria for progressive osseous heteroplasia (POH) and POH-like syndromes. Amer J Med. Genet. 2008; 146A: 1788-1796.

Athanasou NA, Benson MK, Brenton BP, Smith R. Progressive osseous heteroplasia: a case report. Bone. 1994; 15: 471-475.

Cairns DM, Pignolo RJ, Uchimura T, et al. Somitic disruption of GNAS in chick embryos mimics progressive osseous heteroplasia [published correction appears in J Clin Invest. 2013 Nov;123(11):4981]. J Clin Invest. 2013;123(8):3624-3633. doi:10.1172/JCI69746

Faust, RA, Shore EM, Stevens CE, Xu M, Shah S, Phillips CD, and Kaplan FS. Progressive osseous heteroplasia in the face of a child. Amer. J. Med. Genet. 2003; 118A: 71-75.

Gelfand IM, Hub RS, Shore EM, Kaplan FS, Dimeglio LA. Progressive osseous heteroplasia-like heterotopic ossification in a male infant with pseudohypoparathyroidism type Ia: a case report. Bone. 2007;40(5):1425-1428. doi:10.1016/j.bone.2006.12.058

Kaplan FS, Craver R, MacEwen GD, et al. Progressive osseous heteroplasia: a distinct developmental disorder of heterotopic ossification. Two new case reports and follow-up of three previously reported cases. J Bone Joint Surg Am. 1994; 76: 425-436.

Kaplan FS, Glaser DL, Hebela N, Shore EM. Heterotopic ossification. J Am Acad Ortho Surg. 2004; 12: 116-125.

Kaplan FS, Hahn JV, Zasloff MA. Heterotopic ossification: two rare forms and what they can teach us. J Am Acad Orthop Surg. 1994; 2: 288-296.

Liu J, Russell E, Zhang D, Kaplan FS, Pignolo RJ and Shore EM. Paternally inherited Gsa mutation impairs adipogenesis and potentiates a lean phenotype in vivo. Stem Cells. 2012; 30: 1477-1485

Pignolo RJ, Xu M, Russell E, et al. Heterozygous inactivation of Gnas in adipose-derived mesenchymal progenitor cells enhances osteoblast differentiation and promotes heterotopic ossification. J Bone Miner Res. 2011; 26: 2647-2655.

Ramaswamy G, Fong J, Brewer N, et al. Ablation of Gsα signaling in osteoclast progenitor cells adversely affects skeletal bone maintenance. Bone. 2018;109:86-90. doi:10.1016/j.bone.2017.11.019

Ramaswamy G, Kim H, Zhang D, et al. Gsα Controls Cortical Bone Quality by Regulating Osteoclast Differentiation via cAMP/PKA and β-Catenin Pathways. Sci Rep. 2017;7:45140. Published 2017 Mar 24. doi:10.1038/srep45140

Regard JB, Malhotra D, Gvozdenovic-Jeremic J, et al. Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification. Nat Med. 2013;19(11):1505-1512. doi:10.1038/nm.3314

Rosenfeld SR, Kaplan FS. Progressive osseous heteroplasia in male patients: Two new case reports. Clin Orthop. 1995; 317: 243-245.

Schimmel RJ, Pasmans SG, Xu M, Stadhouders-Keet SA, Shore EM, Kaplan FS, Wulfraat NM. GNAS-associated disorders of cutaneous ossification: two different clinical presentations. Bone. 2010; 46: 868-872.

Schmidt AH, Vincent KA, Aiona MD. Hemimelic progressive osseous heteroplasia: a case report. J Bone Joint Surg Am. 1994; 76: 907-912.

Shore EM, Ahn J, Jan de Beur S, et al. Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N Engl J Med. 2002; 346: 99-106.

Ware AD, Brewer N, Meyers C, et al. Differential Vascularity in Genetic and Nonhereditary Heterotopic Ossification. Int J Surg Pathol. 2019;27(8):859-867. doi:10.1177/1066896919857135

Zhang S, Kaplan FS, Shore EM. Different roles of GNAS and cAMP signaling during early and late stages of osteogenic differentiation. Horm Metab Res. 2012;44(10):724-731. doi:10.1055/s-0032-1321845

INTERNET
Osseous Heteroplasia, Progressive. Online Mendelian Inheritance in Man (OMIM). Entry No: 166350. Last Edit: 10/1/13. Available at http://omim.org/entry/166350 Accessed May 14, 2024.

• < Previous section
• Next section >

• < Previous section

Programs & Resources

• Assistance Programs
• Patient Organizations
• More Information

RareCare^® Assistance Programs

NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.

Additional Assistance Programs

MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/

Rare Caregiver Respite Program

This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.

Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/

Learn more about Patient Assistance Programs >

---

Patient Organizations

NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases

Phone: 301-495-4484 Email: [email protected] Fax: 301-718-6366

Related Rare Diseases: Chanarin-Dorfman Syndrome, Congenital Myasthenic Syndromes, Arterial Tortuosity Syndrome, ...

https://rarediseases.org/organizations/nih-national-institute-of-arthritis-and-musculoskeletal-and-skin-diseases/

View Profile >

Progressive Osseous Heteroplasia Association

Email: [email protected]

Related Rare Diseases: Progressive Osseous Heteroplasia, Fibrodysplasia Ossificans Progressiva

https://rarediseases.org/organizations/progressive-osseous-heteroplasia-association/

View Profile >

Learn more about Patient Organization & Membership >

---

More Information

The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.

• < Previous section