Diagnostic and mutational spectrum of progressive osseous heteroplasia (POH) and other forms of GNAS-based heterotopic ossification

Abstract

Progressive osseous heteroplasia (POH) is a rare, disabling disease of heterotopic ossification (HO) that progresses from skin and subcutaneous tissues into deep skeletal muscle. POH occurs in the absence of multiple developmental features of Albright hereditary osteodystrophy (AHO) or hormone resistance, clinical manifestations that are also associated with GNAS inactivation. However, occasional patients with AHO and pseudohypoparathyroidism 1a/c (PHP1a/c; AHO features plus hormone resistance) have also been described who have progressive HO. This study was undertaken to define the diagnostic and mutational spectrum of POH and progressive disorders of HO, and to distinguish them from related disorders in which HO remains confined to the skin and subcutaneous tissues. We reviewed the charts of 111 individuals who had cutaneous and subcutaneous ossification. All patients were assessed for eight characteristics: age of onset of HO, presence and location of HO, depth of HO, type of HO, progression of HO, features of AHO, PTH resistance, and GNAS mutation analysis. We found, based on clinical criteria, that POH and progressive HO syndromes are at the severe end of a phenotypic spectrum of GNAS-inactivating conditions associated with extra-skeletal ossification. While most individuals with superficial or progressive ossification had mutations in GNAS, there were no specific genotype-phenotype correlations that distinguished the more progressive forms of HO (e.g., POH) from the non-progressive forms (osteoma cutis, AHO, and PHP1a/c).

Fig. 1

Distribution of GNAS mutations in POH and other conditions of progressive HO. Exons for the GNAS gene (Gsα mRNA) are identified by numbers and are approximately drawn to scale. Intronic sequences are represented by straight solid lines between exons. Information presented is from this study; recent reports of GNAS mutations in AHO and PHP1a/1c also show a wide distribution throughout the GNAS exons (e.g., Jan De Beur et al. [2003]; Linglart et al. [2002]; Aldred et al. [2000]). Symbols represent patients within each diagnostic group whose GNAS sequence analysis revealed specific mutations at the indicated approximate locations. A “hot spot” (4 base pair deletion) causing a frameshift mutation at c.565-568 occurs in exon 7.

Fig. 2

Family pedigrees showing phenotypic variability of POH. A and B, Phenotypic variability of POH in affected individuals with the same exon 7 4 bp deletion. All affected individuals in families A and B have POH and the same 4 bp deletion in exon 7 (as does the non-penetrant carrier in family B). Despite having the same GNAS mutation, the affected individuals express different clinical/phenotypic characteristics. In family A, affected individuals have brachdactyly (denoted by the letter B inside the filled symbol), a typical feature of AHO, whereas affected members of family B do not posses any AHO features. Furthermore, the affected offspring in family B is a late-onset POH variant (+/−; diagonally-shaded square) and his male sibling was a non-penetrant carrier (+/−; square with filled circle) at the time of presentation. C, Family pedigree showing non-penetrance and variability of severity of the POH phenotype. The father is a non-penetrant carrier of a mutant allele (c.725 del C in codon 242) which was inherited by three of his daughters. Each affected offspring clinically exhibits different degrees of severity, as represented by intensity of shading (dark to light represent more to less severe). These families were originally reported in Shore et al. [2002] and are shown here with respect to phenotypic variation. Unaffected (+/+; unfilled symbol); Affected heterozygote (+/−; filled symbol).

Fig. 3

Algorithmic approach to the differential diagnosis of GNAS-based disorders of superficial heterotopic ossification. HR, hormone (PTH) resistance; other abbreviations are as defined in the text.

Fig. 4

Spectrum of POH and other GNAS-based conditions of superficial HO. Conditions that are associated with heterozygous inactivating GNAS mutations are depicted along axes of heterotopic ossification and hormone resistance. PHP1b and PHP1a/1c are associated with hormone resistance and no or variable/occasional superficial heterotopic ossification (HO), respectively. AHO (PPHP) and POH display no hormone resistance. Superficial HO is a variable feature of AHO (PPHP) while progressive HO is characteristic of POH. Overlapping syndromes (POH/AHO and POH/PHP1a/1c) are also indicated.