Progressive osseous heteroplasia (POH)

(OMIM phenotype number #166350)

Progressive osseous heteroplasia (POH) is a very rare genetic disease characterized by progressive ectopic ossification. This disease is generally caused by a mutation resulting in loss of function of the Gs-alpha isoform of the GNAS gene on the paternal allele. GNAS gene encodes the alpha subunit of the G-stimulatory protein of adenylyl cyclase. Cutaneous ossification usually presents in early life, and involves subcutaneous and then subsequently deep connective tissues (muscle and fascia). Other diseases, such as Albright hereditary dystrophy, pseudohypoparathyroidism, and primary osteoma cutis are caused by inactivating mutations of GNAS, and share common features of superficial heterotopic ossification. POH is distinguished clinically from these other related diseases by the deep and progressive nature of the heterotopic bone. The degree of morbidity depends on the location and extent of heterotopic ossification, resulting, in some cases, in severe disability. Few data exist about prognosis.

Treatment: Currently, there are no effective treatments or prevention for POH. Surgical resection of diffuse lesions usually leads to recurrences or complications, but in some cases, areas of circumscribed heterotopic ossification can be removed by surgery, with successful long-term outcomes.


GNAS (paternal) gene, 20q13.32 (OMIM gene/locus number *139320).


Heterotopic ossifications in the dermis (osteoma cutis) with possible extension to deep tissues, intramembranous ossification, and growth retardation of affected limbs due to heterotopic bone formation.

Main biochemical alterations

Normal Ca, normal Pi, normal PTH.


Fig. Appearance of heterotopic ossification in POH. (a-b) Early clinical appearance of heterotopic ossification in POH. Note the maculopapular lesions that correspond to extensive dermal and subcutaneous ossification.

Reproduced from Appl Clin Genet. 2015 Jan 30;8:37-48 under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported (CC BY-NC 3.0) License.

Other resources


  1. Pignolo RJ, Ramaswamy G, Fong JT et al. Progressive osseous heteroplasia: diagnosis, treatment, and prognosis. Appl Clin Genet. 2015 Jan 30;8:37-48.
  2. Kaplan FS, Shore EM. Progressive osseous heteroplasia. J Bone Miner Res. 2000 Nov;15(11):2084-94. Review.
  3. Adegbite NS, Xu M, Kaplan FS, et al. Diagnostic and mutational spectrum of progressive osseous heteroplasia (POH) and other forms of GNAS-based heterotopic ossification. Am J Med Genet A. 2008 Jul 15;146A(14):1788-96.
  4. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.