Progressive osseous heteroplasia: diagnosis, treatment, and prognosis

Abstract

Progressive osseous heteroplasia (POH) is an ultrarare genetic condition of progressive ectopic ossification. Most cases of POH are caused by heterozygous inactivating mutations of GNAS, the gene encoding the alpha subunit of the G-stimulatory protein of adenylyl cyclase. POH is part of a spectrum of related genetic disorders, including Albright hereditary osteodystrophy, pseudohypoparathyroidism, and primary osteoma cutis, that share common features of superficial ossification and association with inactivating mutations of GNAS. The genetics, diagnostic criteria, supporting clinical features, current management, and prognosis of POH are reviewed here, and emerging therapeutic strategies are discussed.

Keywords: GNAS; heterotopic ossification; progressive osseous heteroplasia.

Figure 1

Schematic diagram of multiple transcripts from the GNAS locus. Notes: Gsα, XLαs, and NESP55 are the primary transcripts that produce proteins from the GNAS locus. GNAS-AS1 is transcribed in the antisense direction. All transcripts have distinct first exons that splice to common exons 2–13. Gsα is biallelic in most tissues. XLαs, A/B, and GNAS-AS1 are restricted to expression from the paternal allele, whereas NESP55 is only expressed maternally. Imprinting is regulated by differentially methylated regions (DMR) in the promoters. Alternative splicing leads to neuronal-specific transcripts Gsα-N1 and XLαs-N1, whereas a second open reading frame of XLαs leads to a protein called ALEX. Transcripts from maternal and paternal alleles are shown above and below, respectively. Bold lines indicate exons, and dashed lines indicate introns.

Figure 2

Appearance of heterotopic ossification in POH. Notes: (A and B) Early clinical appearance of heterotopic ossification in POH. Note the maculopapular lesions that correspond to extensive dermal and subcutaneous ossification. (C) Advanced heterotopic ossification in POH results in large coalesced bony plaques. Note the distinct lateralization of lesions that is observed in some patients, as well as contracture and ankyloses of the left lower extremity. Abbreviation: POH, progressive osseous heteroplasia.

Figure 3

Radiographic appearance of severe heterotopic ossification in POH. Notes: (A) Anterior view roentgenogram of the lower extremities of a child with POH shows progressive heterotopic ossification on the left side. Note the web-like pattern of ossification. (B) Cross-sectional, midfemur view by computerized tomography demonstrates extensive ossification of soft tissues in the superficial and deep posterior compartments of the leg. Abbreviation: POH, progressive osseous heteroplasia.

Figure 4

Photomicrograph of a POH lesional section shows intramembranous ossification. Notes: Note that deposits of bone are surrounded by adipose tissue (inset). Hematoxylin and eosin staining; original magnification, 200×. Abbreviation: A, adipose tissue; B, bone; POH, progressive osseous heteroplasia.

Figure 5

Diagnostic algorithm for distinguishing among GNAS-based conditions of heterotopic ossification. Abbreviations: HO, heterotopic ossification; OC, osteoma cutis; POH, progressive osseous heteroplasia; AHO, Albright hereditary dystrophy; HR, hormone resistance; PPHP, pseudopseudo-hypoparathyroidism; PHP, pseudohypoparathyroidism.