RESEARCH UPDATES
The link below was recorded from our 2021 Patient Symposium.
https://drive.google.com/file/d/1ffZszRuW2blIU9v-NaGcGWA_eF58HzJA/view?usp=sharing
Diagnostic and Mutational Spectrum of Progressive Osseous Heteroplasia and Other Forms of GNAS-Based Heterotopic Bone.
https://drive.google.com/file/d/11eOv2SXO_5OD8UnqrYaRSTdkTraLbfH8/view?usp=sharing
The Path to a Clinical Trial
https://drive.google.com/file/d/1y18SUxCuXqcjBhiEOBGRkqG7IXsvvij-/view?usp=sharing
Progressive Osseous Heteroplasia
rarediseases.org/rare-diseases/progressive-osseous-heteroplasia/
NORD gratefully acknowledges Frederick S. Kaplan, MD, Isaac & Rose Nassau Professor of
Orthopaedic Molecular Medicine; Chief, Division of Orthopaedic Molecular Medicine and
Director, Center for Research in FOP & Related Disorders, The Perelman School of Medicine at
The University of Pennsylvania and Eileen M. Shore, PhD, Cali/Weldon Professor of FOP
Research, Departments of Orthopaedic Surgery and Genetics, and Co-Director, Center for
Research in FOP & Related Disorders, The Perelman School of Medicine at The University of
Pennsylvania, for assistance in the preparation of this report.
Synonyms of Progressive Osseous Heteroplasia
POH
General Discussion
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, the bone formation is classified as osteoma
cutis.
Signs & Symptoms
The symptoms of POH are usually present at birth (congenital) or within the first few
weeks of life, and they tend to progress slowly and asymmetrically as an affected
individual grows older. Infants with POH typically have a maculopapular rash (with
patchy areas of bone within the dermis). Initially, affected skin may feel abnormally
rough.
The major finding in infants with POH is the development of extra-skeletal bone
(heterotopic ossification). Initially, bone growth may develop within the skin (osseous
nodules or plaques called osteoma cutis). These areas may become progressively
widespread and may grow together (coalesce) to form even larger areas of hardened and
thickened skin (dermal ossification). As the disease progresses, these bony growths may
extend into the deeper layers of the skin (subcutaneous layers). Eventually, abnormal
bony growths occur in various connective tissues of the body such as fascia and skeletal
muscle.
Children with osteoma cutis or POH may also have sharp, needle-like projections of bone
(spicules) that break through the surface of the skin, causing irritation or superficial
infection.
As the abnormal development of bone progresses, it may restrict movement of joints and
eventually lock the joints (ankylosis). POH may also restrict movement in any area of the
body. Affected arms and legs may become malformed and not grow to full length. This can
occur on one side of the body and lead to unequal growth; one leg or one arm may
become shorter than the other, for example. Some areas of the body may be severely
affected, while other areas may remain unaffected. In some patients, lesion formation
occurs predominantly or exclusively on one side (either left or right) of the body
(hemimelic progressive osseous heteroplasia).
In addition, when bone growth occurs around the spine, some affected individuals may
develop an abnormal sideways curvature of the spine (scoliosis).
The progression of POH is highly variable even among members of the same family. In
some individuals, it may progress extremely slowly; in others it may progress more
rapidly. Most individuals experience a gradual progression of the condition.
Heterotopic bone formation in POH may be more intramembranous than endochondral
in nature, and no inflammatory component has been identified. Histologically, bone can
be seen to arise directly within adipose stromal tissue although the exact cell(s) of origin
remain unknown.
In addition to induction of extra-skeletal bone formation, inactivating mutations in the
GNAS gene have been associated with altered skeletal bone quality in mouse models.
Detailed studies of skeletal bone quality in POH remain to be thoroughly investigated.
Causes Some cases of POH may be caused by disruption or changes (mutations) of
the GNAS gene. About three-fourths of examined POH patients have
inactivating GNAS gene mutations.
The GNAS (guanine nucleotide-binding protein, alpha-stimulating polypeptide) gene
contains instructions for producing (encoding) a protein that researchers believe may be
involved in regulating the activity of proteins (produced by other genes) that promote
bone growth and direct cell fate decisions. In POH, mutation of the GNAS gene results in
deficiency or dysfunction of the Gsα protein. The exact manner in which mutations 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.
Most cases of POH occur randomly as the result of a spontaneous (sporadic) genetic
change (new mutation) of the GNAS gene. However, this mutation can also be inherited
from a parent and follow autosomal dominant inheritance. Dominant genetic disorders
occur when only a single copy of a non-working gene is necessary to cause a particular
disease.
A specific gene regulation process associated with POH is 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 cases, 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). Genetic imprinting is controlled by chemical regulation through a
process called DNA methylation. Proper genetic imprinting is necessary for normal
development. Defective imprinting has been associated with several human diseases
including POH. In individuals with POH, the defective copy of the GNAS gene is inherited
from the father. If a defective GNAS gene is inherited from the mother, individuals
typically develop related, yet clinically distinct, disorders known as Albright hereditary
osteodystrophy (AHO) and/or pseudohypoparathyrodism type 1a (PHP1a).
Affected Populations
More than 50 affected individuals with POH have been identified around the world.
Although the majority of the cases initially reported occurred in 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.
Related Disorders 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). The genetic mutation that results in this disorder has been
identified. FOP is caused by the mutation of a 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 mutations of the same gene (GNAS) that causes
POH. Both conditions can be inherited in an autosomal dominant pattern. While POH
occurs only when the mutant gene is inherited from fathers, AHO features are associated
with GNAS gene mutations that are inherited either from mothers or fathers. PHP1a
and/or AHO-associated obesity occur when the mutant gene is inherited from mothers.
(For more information on this disorder, choose “AHO” as your search term in the Rare
Disease Database.)
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.
Standard Therapies
Treatment
Special shoes, braces, and other devices to assist in walking and weight-bearing have been
used to help people with POH involving the lower limbs. Occupational therapy
evaluations and appropriate assistive devices for activities of daily living may be helpful
for those in whom POH involves the upper limbs. Immunizations should be given on
areas of the skin that are unaffected by the bony growths that are prevalent with this
disorder. Other treatment is symptomatic and supportive. A team approach for infants
with this disorder will be of benefit and may include special social, educational, and
medical services.
Genetic counseling is recommended for affected individuals and their families.
Investigational Therapies
Surgery, radiation therapy, and several different types of drugs have been used to treat
disorders involving the abnormal development of bone (heterotopic ossification) but are
ineffective in POH. Surgery to remove heterotopic bone characteristically exacerbates
POH. Surgical removal of ectopic bone has provided only temporary relief in some cases;
in other cases, the improper bone growth has recurred massively after the surgery.
Extreme caution should be used in considering surgery for individuals affected by POH. It
is rarely indicated. More research must be conducted to determine the effectiveness of
radiation and various drug therapies when used to treat POH.
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]
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/for-patients-and-families/information-resources/news-patient-
recruitment/
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/
Supporting Organizations
Genetic and Rare Diseases (GARD) Information Center
PO Box 8126
Gaithersburg, MD 20898-8126
Phone: (301) 251-4925
Toll-free: (888) 205-2311
Website: http://rarediseases.info.nih.gov/GARD/
NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases
Information Clearinghouse
One AMS Circle
Bethesda, MD 20892-3675 USA
Phone: (301) 495-4484
Toll-free: (877) 226-4267
Email: [email protected]
Website: http://www.niams.nih.gov/
Progressive Osseous Heteroplasia Association
1460 Bolingbrook Drive
Columbus, OH 43228 USA
Phone: (614) 887-7642
Email: [email protected]
Website: http://www.pohdisease.org
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
Pignolo R, Ramaswamy G, Fong J, Shore E, Kaplan F. Progresssive 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, E.M. and F.S. Kaplan. Insights from a rare genetic disorder of extra-skeletal bone
formation, fibrodysplasia ossificans progressiva (FOP). Bone. 2008; 43: 427-433.
Shore E.M. and F. S. Kaplan.FOP and POH: Two Genetic Disorders of Heterotopic
Ossification. Clinical Reviews in Bone and Mineral Metabolism.2005: 3, 257-260.
Kaplan FS, Shore EM. Progressive osseous heteroplasia. J Bone Miner Res. 2000; 15:
2084-2094.
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
Ware, A.D., N. Brewer, E. McCarthy, E.M. Shore, and A.W. James. Differential vascularity
in genetic and non-genetic heterotopic ossification. International J. Surg. Pathology 2019;
27: 859-867.
Ramaswamy, G., J. Fong, N. Brewer, H. Kim, D. Zhang, Y. Choi, F.S. Kaplan, and E.M.
Shore. Ablation of Gsa signaling in osteoclast progenitor cells adversely affects skeletal
bone maintenance. Bone 2018; 109: 86-90.
Ramaswamy, G., H. Kim, D. Zhang, V. Lounev, J.Y. Wu, Y. Choi, F.S. Kaplan, R.J.
Pignolo, and E.M. Shore. Gsα Controls Cortical Bone Quality by Regulating Osteoclast
Differentiation via cAMP/PKA and β-Catenin Pathways. Scientific Reports 2017; 7:
45140; doi:10.1038/srep45140.
Regard, J.B., D. Malhotra, J. Gvozdenovic-Jeremic, M. Josey, M. Chen, L.S. Weinstein,
E.M. Shore, F.S. Kaplan, and Y. Yang. Activation of Hedgehog signaling by loss of GNAS
causes heterotopic ossification. Nature Medicine. 2013; 19: 1505-1512.
Cairns, D.M., R.J. Pignolo, T. Uchimura, T.A. Brennan, C.M. Lindborg, M. Xu, F.S.
Kaplan, E.M. Shore, and L. Zeng. Somitic disruption of GNAS in chick embryos mimics
progressive osseous heteroplasia. J. Clinical Invest. 2013; 123: 3624-3633.
Zhang, S. F.S. Kaplan, E.M. Shore. Different roles of Gnas and cAMP signaling during
early and late stages of osteogenic differentiation. Hormone Metab. Res. 2012; 44: 724-
731.
Liu, J., E. Russell, D. Zhang, F.S. Kaplan, R.J. Pignolo, and E.M. Shore. 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.
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.
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.
Gelfand, I., 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: 1425-1428.
Kaplan FS, Glaser DL, Hebela N, Shore EM. Heterotopic ossification. J Am Acad Ortho
Surg. 2004; 12: 116-125.
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.
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.
Rosenfeld SR, Kaplan FS. Progressive osseous heteroplasia in male patients: Two new
case reports. Clin Orthop. 1995; 317: 243-245.
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.
Schmidt AH, Vincent KA, Aiona MD. Hemimelic progressive osseous heteroplasia: a case
report. J Bone Joint Surg Am. 1994; 76: 907-912.
Athanasou NA, Benson MK, Brenton BP, Smith R. Progressive osseous heteroplasia: a
case report. Bone. 1994; 15: 471-475.
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.
INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The
Johns Hopkins University; Entry No: 166350 available
at http://omim.org/entry/166350 Last Edit: 10/1/13. Accessed August 13, 2020.
Years Published
1996, 2002, 2008, 2009, 2011, 2014, 2017, 2020
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intended to replace the advice of a physician or other qualified medical professional.
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commercial or public purpose, without prior written authorization and approval from NORD.
Individuals may print one hard copy of an individual disease for personal use, provided that content
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The POH Collaborative Research Project
Introduction | Research Summary | POHA Annual Reports | 5-Year Report
In Search of a Cure for POH
POH research is detective work. The main goal of research was to identify the damaged gene that causes POH and to use that knowledge to establish a cure. Through individual donations and fundraising events, the POHA directly funds POH research. These contributions help support a skilled and dedicated research team at the University of Pennsylvania in Philadelphia. From here, efforts are coordinated with other physicians and scientists throughout the world (POH Collaborative Research Group) in an effort to find a cure for POH. This dedicated research team established under the guidance of Drs. Frederick S. Kaplan, Eileen M. Shore, and Michael A. Zasloff view their efforts not as a job, but as a mission.
Opening Doors for More Common Conditions
The importance and implication of POH research for affected children and their families is unquestionable. However, the importance of POH research for the general medical community is far greater than its rarity might indicate. Research on POH is relevant to all disorders of renegade bone formation. By unraveling the complex pathogenesis of POH, there is great hope that more common disorders of bone formation will become understandable and treatable.
Knowledge gained from this work has the likelihood of elucidating not only the basic molecular mechanisms of POH, but also the basic molecular mechanisms involved in disorders as diverse as congenital limb anomalies, bone cancer, osteoarthritic bone spurs, osteoporosis, and abnormal fracture repair. Recently, our laboratory (propelled by discoveries in FOP and POH has identified bone formation in heart valves as a common finding in patients who have endstage valvular heart disease. Research in POH, therefore has the possibility of elucidating mechanisms of phenotype stability in disorders as fundamental as cancer, aging and valvular heart disease.
During the past several years, great progress has been made in understanding not only the cellular and molecular mechanisms involved in normal bone formation, but also in understanding the complex mysteries of POH. The work undertaken by the collaborative research group is focused on elucidating the underlying molecular cause of POH, and using that knowledge to design medications and treatments that will be genuinely useful to the children and adults who have POH. The most significant breakthrough has been the identification of the damaged gene (GNAS1) responsible for POH.
Research Need
The POH Research Team at the University of Pennsylvania is interested in seeking additional patients and speaking with POH patients. For information please call:
Frederick Kaplan, M.D.
215-349-8726 or Frederick.Kaplan@uphs.upenn.edu.
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