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Progressive osseous heteroplasia(POH)

MedGen UID:
137714
•Concept ID:
C0334041
•
Disease or Syndrome
Synonyms: ECTOPIC OSSIFICATION, FAMILIAL; Osseus Heteroplasia, Progressive; POH; Progressive Osseus Heteroplasia (POH)
SNOMED CT: Osteoma cutis (71304002); Cutaneous ossification (71304002); Osteosis cutis (71304002); Osteodermia (71304002); Osteoma cutis (404074003); Progressive osseous heteroplasia (719271000); Familial ectopic ossification (719271000)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
•Concept ID:
C0443147
•
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (Orphanet)
 
Gene (location): GNAS (20q13.32)
 
HPO: HP:0025027
Monarch Initiative: MONDO:0008153
OMIM®: 166350
Orphanet: ORPHA2762

Disease characteristics

Excerpted from the GeneReview: Disorders of GNAS Inactivation
Disorders of GNAS inactivation include the phenotypes pseudohypoparathyroidism Ia, Ib, and Ic (PHP-Ia, -Ib, -Ic), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). PHP-Ia and PHP-Ic are characterized by: End-organ resistance to endocrine hormones including parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), gonadotropins (LH and FSH), growth hormone-releasing hormone (GHRH), and CNS neurotransmitters (leading to obesity and variable degrees of intellectual disability and developmental delay); and The Albright hereditary osteodystrophy (AHO) phenotype (short stature, round facies, and subcutaneous ossifications) and brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb). Although PHP-Ib is characterized principally by PTH resistance, some individuals also have partial TSH resistance and mild features of AHO (e.g., brachydactyly). PPHP, a more limited form of PHP-Ia, is characterized by various manifestations of the AHO phenotype without the hormone resistance or obesity. POH and OC are even more restricted variants of PPHP: POH consists of dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia. OC consists of extra-skeletal ossification that is limited to the dermis and subcutaneous tissues. [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  GeneReview Scope  |  Diagnosis  |  Clinical Characteristics  |  Genetically Related (Allelic) Disorders  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  Chapter Notes  |  References
Authors:
Chad R Haldeman-Englert  |  Anna CE Hurst  |  Michael A Levine   view full author information

Additional descriptions

From OMIM
Progressive osseous heteroplasia is a rare autosomal dominant disorder characterized by dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia (Kaplan et al., 1994). The molecular defect causing POH is the same as that causing PPHP: an inactivating GNAS mutation caused only by paternal inheritance of the mutant allele. However, patients with PPHP have a constellation of physical findings referred to as Albright hereditary osteodystrophy (AHO; see 103580) that is often not seen in patients with POH. Bastepe and Juppner (2005) suggested that POH may be an extreme end of the spectrum of the AHO features seen in PPHP.  http://www.omim.org/entry/166350
From MedlinePlus Genetics
Progressive osseous heteroplasia is a disorder in which bone forms within skin and muscle tissue. Bone that forms outside the skeleton is called heterotopic or ectopic bone. In progressive osseous heteroplasia, ectopic bone formation begins in the deep layers of the skin (dermis and subcutaneous fat) and gradually moves into other tissues such as skeletal muscle and tendons. The bony lesions within the skin may be painful and may develop into open sores (ulcers). Over time, joints can become involved, resulting in impaired mobility.

Signs and symptoms of progressive osseous heteroplasia usually become noticeable during infancy. In some affected individuals, however, the disorder may not become evident until later in childhood or in early adulthood.  https://medlineplus.gov/genetics/condition/progressive-osseous-heteroplasia

Clinical features

From HPO
Limb undergrowth
MedGen UID:
116086
•Concept ID:
C0239399
•
Finding
Limb shortening because of underdevelopment of one or more bones of the extremities.
See: Feature record | Search on this feature
Ankylosis
MedGen UID:
8101
•Concept ID:
C0003090
•
Pathologic Function
A reduction of joint mobility resulting from changes involving the articular surfaces.
See: Feature record | Search on this feature
Ectopic ossification in muscle tissue
MedGen UID:
868693
•Concept ID:
C4023096
•
Pathologic Function
Formation of abnormal bony tissue within muscle tissue.
See: Feature record | Search on this feature
Progressive osseous heteroplasia
MedGen UID:
137714
•Concept ID:
C0334041
•
Disease or Syndrome
Disorders of GNAS inactivation include the phenotypes pseudohypoparathyroidism Ia, Ib, and Ic (PHP-Ia, -Ib, -Ic), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). PHP-Ia and PHP-Ic are characterized by: End-organ resistance to endocrine hormones including parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), gonadotropins (LH and FSH), growth hormone-releasing hormone (GHRH), and CNS neurotransmitters (leading to obesity and variable degrees of intellectual disability and developmental delay); and The Albright hereditary osteodystrophy (AHO) phenotype (short stature, round facies, and subcutaneous ossifications) and brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb). Although PHP-Ib is characterized principally by PTH resistance, some individuals also have partial TSH resistance and mild features of AHO (e.g., brachydactyly). PPHP, a more limited form of PHP-Ia, is characterized by various manifestations of the AHO phenotype without the hormone resistance or obesity. POH and OC are even more restricted variants of PPHP: POH consists of dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia. OC consists of extra-skeletal ossification that is limited to the dermis and subcutaneous tissues.
See: Feature record | Search on this feature
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Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVProgressive osseous heteroplasia
Follow this link to review classifications for Progressive osseous heteroplasia in Orphanet.

Conditions with this feature

Progressive osseous heteroplasia
MedGen UID:
137714
•Concept ID:
C0334041
•
Disease or Syndrome
Disorders of GNAS inactivation include the phenotypes pseudohypoparathyroidism Ia, Ib, and Ic (PHP-Ia, -Ib, -Ic), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). PHP-Ia and PHP-Ic are characterized by: End-organ resistance to endocrine hormones including parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), gonadotropins (LH and FSH), growth hormone-releasing hormone (GHRH), and CNS neurotransmitters (leading to obesity and variable degrees of intellectual disability and developmental delay); and The Albright hereditary osteodystrophy (AHO) phenotype (short stature, round facies, and subcutaneous ossifications) and brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb). Although PHP-Ib is characterized principally by PTH resistance, some individuals also have partial TSH resistance and mild features of AHO (e.g., brachydactyly). PPHP, a more limited form of PHP-Ia, is characterized by various manifestations of the AHO phenotype without the hormone resistance or obesity. POH and OC are even more restricted variants of PPHP: POH consists of dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia. OC consists of extra-skeletal ossification that is limited to the dermis and subcutaneous tissues.
See: Condition Record
Progressive osseous heteroplasia

Professional guidelines

PubMed

Screening for GNAS genetic and epigenetic alterations in progressive osseous heteroplasia: first Italian series.
Elli FM, Barbieri AM, Bordogna P, Ferrari P, Bufo R, Ferrante E, Giardino E, Beck-Peccoz P, Spada A, Mantovani G
Bone 2013 Oct;56(2):276-80. Epub 2013 Jun 21 doi: 10.1016/j.bone.2013.06.015. PMID: 23796510
Clinical review: Pseudohypoparathyroidism: diagnosis and treatment.
Mantovani G
J Clin Endocrinol Metab 2011 Oct;96(10):3020-30. Epub 2011 Aug 3 doi: 10.1210/jc.2011-1048. PMID: 21816789

Recent clinical studies

Etiology

Pseudohypoparathyroidism, acrodysostosis, progressive osseous heteroplasia: different names for the same spectrum of diseases?
Elli FM, Mantovani G
Endocrine 2021 Jun;72(3):611-618. Epub 2020 Nov 11 doi: 10.1007/s12020-020-02533-9. PMID: 33179219Free PMC Article
Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement.
Mantovani G, Bastepe M, Monk D, de Sanctis L, Thiele S, Usardi A, Ahmed SF, Bufo R, Choplin T, De Filippo G, Devernois G, Eggermann T, Elli FM, Freson K, García Ramirez A, Germain-Lee EL, Groussin L, Hamdy N, Hanna P, Hiort O, Jüppner H, Kamenický P, Knight N, Kottler ML, Le Norcy E, Lecumberri B, Levine MA, Mäkitie O, Martin R, Martos-Moreno GÁ, Minagawa M, Murray P, Pereda A, Pignolo R, Rejnmark L, Rodado R, Rothenbuhler A, Saraff V, Shoemaker AH, Shore EM, Silve C, Turan S, Woods P, Zillikens MC, Perez de Nanclares G, Linglart A
Nat Rev Endocrinol 2018 Aug;14(8):476-500. doi: 10.1038/s41574-018-0042-0. PMID: 29959430Free PMC Article
Inherited ossifying diseases.
Job-Deslandre C
Joint Bone Spine 2004 Mar;71(2):98-101. doi: 10.1016/s1297-319x(03)00130-1. PMID: 15116703
Heterotopic ossification.
Kaplan FS, Glaser DL, Hebela N, Shore EM
J Am Acad Orthop Surg 2004 Mar-Apr;12(2):116-25. doi: 10.5435/00124635-200403000-00007. PMID: 15089085
Progressive osseous heteroplasia.
Kaplan FS, Shore EM
J Bone Miner Res 2000 Nov;15(11):2084-94. doi: 10.1359/jbmr.2000.15.11.2084. PMID: 11092391

Diagnosis

Pseudohypoparathyroidism, acrodysostosis, progressive osseous heteroplasia: different names for the same spectrum of diseases?
Elli FM, Mantovani G
Endocrine 2021 Jun;72(3):611-618. Epub 2020 Nov 11 doi: 10.1007/s12020-020-02533-9. PMID: 33179219Free PMC Article
Recommendations for Diagnosis and Treatment of Pseudohypoparathyroidism and Related Disorders: An Updated Practical Tool for Physicians and Patients.
Mantovani G, Bastepe M, Monk D, de Sanctis L, Thiele S, Ahmed SF, Bufo R, Choplin T, De Filippo G, Devernois G, Eggermann T, Elli FM, Garcia Ramirez A, Germain-Lee EL, Groussin L, Hamdy NAT, Hanna P, Hiort O, Jüppner H, Kamenický P, Knight N, Le Norcy E, Lecumberri B, Levine MA, Mäkitie O, Martin R, Martos-Moreno GÁ, Minagawa M, Murray P, Pereda A, Pignolo R, Rejnmark L, Rodado R, Rothenbuhler A, Saraff V, Shoemaker AH, Shore EM, Silve C, Turan S, Woods P, Zillikens MC, Perez de Nanclares G, Linglart A
Horm Res Paediatr 2020;93(3):182-196. Epub 2020 Aug 5 doi: 10.1159/000508985. PMID: 32756064Free PMC Article
Inactivating PTH/PTHrP Signaling Disorders.
Mantovani G, Elli FM
Front Horm Res 2019;51:147-159. Epub 2018 Nov 19 doi: 10.1159/000491045. PMID: 30641531
Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement.
Mantovani G, Bastepe M, Monk D, de Sanctis L, Thiele S, Usardi A, Ahmed SF, Bufo R, Choplin T, De Filippo G, Devernois G, Eggermann T, Elli FM, Freson K, García Ramirez A, Germain-Lee EL, Groussin L, Hamdy N, Hanna P, Hiort O, Jüppner H, Kamenický P, Knight N, Kottler ML, Le Norcy E, Lecumberri B, Levine MA, Mäkitie O, Martin R, Martos-Moreno GÁ, Minagawa M, Murray P, Pereda A, Pignolo R, Rejnmark L, Rodado R, Rothenbuhler A, Saraff V, Shoemaker AH, Shore EM, Silve C, Turan S, Woods P, Zillikens MC, Perez de Nanclares G, Linglart A
Nat Rev Endocrinol 2018 Aug;14(8):476-500. doi: 10.1038/s41574-018-0042-0. PMID: 29959430Free PMC Article
Pseudohypoparathyroidism.
Cianferotti L, Brandi ML
Minerva Endocrinol 2018 Jun;43(2):156-167. Epub 2017 Nov 10 doi: 10.23736/S0391-1977.17.02768-7. PMID: 29125274

Therapy

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement.
Mantovani G, Bastepe M, Monk D, de Sanctis L, Thiele S, Usardi A, Ahmed SF, Bufo R, Choplin T, De Filippo G, Devernois G, Eggermann T, Elli FM, Freson K, García Ramirez A, Germain-Lee EL, Groussin L, Hamdy N, Hanna P, Hiort O, Jüppner H, Kamenický P, Knight N, Kottler ML, Le Norcy E, Lecumberri B, Levine MA, Mäkitie O, Martin R, Martos-Moreno GÁ, Minagawa M, Murray P, Pereda A, Pignolo R, Rejnmark L, Rodado R, Rothenbuhler A, Saraff V, Shoemaker AH, Shore EM, Silve C, Turan S, Woods P, Zillikens MC, Perez de Nanclares G, Linglart A
Nat Rev Endocrinol 2018 Aug;14(8):476-500. doi: 10.1038/s41574-018-0042-0. PMID: 29959430Free PMC Article
Acquired and congenital forms of heterotopic ossification: new pathogenic insights and therapeutic opportunities.
Pacifici M
Curr Opin Pharmacol 2018 Jun;40:51-58. Epub 2018 Mar 31 doi: 10.1016/j.coph.2018.03.007. PMID: 29614433Free PMC Article

Prognosis

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement.
Mantovani G, Bastepe M, Monk D, de Sanctis L, Thiele S, Usardi A, Ahmed SF, Bufo R, Choplin T, De Filippo G, Devernois G, Eggermann T, Elli FM, Freson K, García Ramirez A, Germain-Lee EL, Groussin L, Hamdy N, Hanna P, Hiort O, Jüppner H, Kamenický P, Knight N, Kottler ML, Le Norcy E, Lecumberri B, Levine MA, Mäkitie O, Martin R, Martos-Moreno GÁ, Minagawa M, Murray P, Pereda A, Pignolo R, Rejnmark L, Rodado R, Rothenbuhler A, Saraff V, Shoemaker AH, Shore EM, Silve C, Turan S, Woods P, Zillikens MC, Perez de Nanclares G, Linglart A
Nat Rev Endocrinol 2018 Aug;14(8):476-500. doi: 10.1038/s41574-018-0042-0. PMID: 29959430Free PMC Article
Inherited ossifying diseases.
Job-Deslandre C
Joint Bone Spine 2004 Mar;71(2):98-101. doi: 10.1016/s1297-319x(03)00130-1. PMID: 15116703
Heterotopic ossification.
Kaplan FS, Glaser DL, Hebela N, Shore EM
J Am Acad Orthop Surg 2004 Mar-Apr;12(2):116-25. doi: 10.5435/00124635-200403000-00007. PMID: 15089085
Progressive osseous heteroplasia. A case report and review of the literature.
Aynaci O, Müjgan Aynaci F, Cobanoğlu U, Alpay K
J Pediatr Orthop B 2002 Oct;11(4):339-42. PMID: 12370587
Progressive osseous heteroplasia.
Kaplan FS, Shore EM
J Bone Miner Res 2000 Nov;15(11):2084-94. doi: 10.1359/jbmr.2000.15.11.2084. PMID: 11092391

Clinical prediction guides

A Novel De Novo Frameshift Pathogenic Variant in the FAM111B Resulting in Progressive Osseous Heteroplasia Phenotype.
Ryabets-Lienhard A, Panjawatanan P, Vogt K, Ji J, Georgia S, Pitukcheewanont P
Calcif Tissue Int 2023 Apr;112(4):518-523. Epub 2022 Dec 27 doi: 10.1007/s00223-022-01053-0. PMID: 36575358
Clinical and Molecular Characteristics of GNAS Inactivation Disorders Observed in 18 Korean Patients.
Han SR, Lee YA, Shin CH, Yang SW, Lim BC, Cho TJ, Ko JM
Exp Clin Endocrinol Diabetes 2021 Feb;129(2):118-125. Epub 2019 Sep 23 doi: 10.1055/a-1001-3575. PMID: 31546270
Unilateral progressive osseous heteroplasia.
Santiago F, Vieira R, Cordeiro M, Tellechea O, Figueiredo A
Eur J Dermatol 2009 May-Jun;19(3):214-5. Epub 2009 Feb 12 doi: 10.1684/ejd.2009.0634. PMID: 19213659
Progressive osseous heteroplasia.
Kaplan FS, Shore EM
J Bone Miner Res 2000 Nov;15(11):2084-94. doi: 10.1359/jbmr.2000.15.11.2084. PMID: 11092391
Progressive osseous heteroplasia.
Miller ES, Esterly NB, Fairley JA
Arch Dermatol 1996 Jul;132(7):787-91. PMID: 8678571

Recent systematic reviews

Progressive osseous heteroplasia in a 5-year-old boy with a novel mutation in exon 2 of GNAS: a case presentation and literature review.
Ma J, Mo W, Sun J, Li Y, Han T, Mao H
BMC Musculoskelet Disord 2023 Mar 31;24(1):247. doi: 10.1186/s12891-023-06371-4. PMID: 37003989Free PMC Article

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