Osseous Heteroplasia, Progressive

A number sign (#) is used with this entry because progressive osseous heteroplasia (POH) is caused by a mutation resulting in loss of function of the Gs-alpha isoform of the GNAS gene (139320) on the paternal allele.

See also pseudopseudohypoparathyroidism (PPHP; 612463), a similar disorder that is also caused by loss-of-function mutations in the GNAS gene on the paternal allele.

Description

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.

Clinical Features

Fawcett and Marsden (1983) reported osteoma cutis in 3 generations of a family. The 3-year-old proposita developed hard nodules in the skin at age 6 months. Skin biopsies showed multiple spicules of bone in the skin, which showed normal membranous bone structures. The surrounding dermis showed no scarring or inflammatory changes. She was diagnosed with celiac disease at age 3 years. Her 6-year-old sister had skin lesions of the legs and trunk starting about the same age but at age 2 years she had a painful, swollen right ankle. Soft tissue calcifications were visualized in both the hands and feet. The father of the girls had several cutaneous osteomas on the arms. His father, deceased, was known to have had similar lesions on his shoulders for many years. Fawcett and Marsden (1983) noted that Peterson and Mandel (1963) had described an affected mother and son. The mother also had multiple pigmented nevi; the son died at 15 months of alveolar sarcoma of the cerebellum. Although Brook and Valman (1971) noted that early cases may have represented AHO, Fawcett and Marsden (1983) thought that AHO was unlikely in their family.

Gardner et al. (1988) described a family in which members in 2 generations and 3 sibships had ectopic ossification. Inheritance was autosomal dominant. Most members had childhood onset of multifocal subcutaneous ossifications, or primary osteoma cutis, which were of trivial clinical significance. One family member had extensive ectopic ossification involving the right leg, first noted at the age of 3 weeks and severely interfering with growth of the limb by age 8 years.

McKusick (1989) observed osteoma cutis in a 38-year-old man who also had unerupted teeth, severe bilateral carpal tunnel syndrome, and unusual changes in the bones of the forearms and legs that were quite different from those of pseudohypoparathyroidism.

Izraeli et al. (1992) described congenital osteoma cutis in members of 3 generations with convincing clinical and laboratory evidence of Albright hereditary osteodystrophy and with one instance of male-to-male transmission. In the propositus, small, flat, and hard subcutaneous plaques were noted on the back at birth, and biopsy at the age of 3 days confirmed the diagnosis of osteoma cutis. In a sister similar nodules were noted in the first month of life, and the mother had had a hard subcutaneous nodule on the hand from birth. No deficiency of Gs activity was detected by the assay used.

Kaplan et al. (1994) reported 2 new cases and follow-up on 3 previously reported cases, 1 of which was that reported by Gardner et al. (1988). At follow-up examination of this family, the proband was 31 years old, was married, and had a daughter who was clinically normal. This patient's family was the only one in which relatives were affected; individuals in 4 sibships in 2 generations showed minor cutaneous ossification only. A maculopapular eruption was observed in the early stages of the disorder and all of the children had ossification of the skin in infancy. None of the children developed preosseous tumor-like swellings, a nearly universal finding in fibrodysplasia ossificans progressiva (FOP; 135100). All developed progression of heterotopic ossification into deep connective tissues, including fascia and skeletal muscle, in a process of ossification that was primarily intramembranous rather than endochondral. The radiologic pattern of heterotopic ossification in POH was a cocoon-like web of heterotopic bone entangling the soft connective tissues from the dermis down through skeletal muscle without regard to tissue planes.

Athanasou et al. (1994) reported a typical case in an 18-year-old girl.

Schmidt et al. (1994) reported a 9-year-old Hispanic girl who had progressive ossification of the soft tissues on the right side of the face and body. Histologic analysis of biopsy material showed intramembranous, subcutaneous ossification.

Rosenfeld and Kaplan (1995) found reports of 8 classic cases, all in female patients, and documented typical features of progressive osseous heteroplasia in 2 boys, 1 of whom showed left-sided hemimelic heterotopic ossification.

Urtizberea et al. (1998) described male patients.

Stoll et al. (2000) reported the clinical and radiologic features of a patient with POH who was 20 years old at presentation. In addition to abnormal ossifications, she had short metacarpals at the fourth and fifth rays and short metatarsals at the second rays. Her parents were unaffected. At the time of the patient's birth, her father and mother were 48 and 36 years old, respectively.

Kaplan (2000) noted that patients with POH do not have the characteristic malformation of the great toe seen in fibrodysplasia ossificans progressiva and that patients with FOP do not have ossification of the skin in infancy. POH is also distinct from tumoral calcinosis (211900).

Eddy et al. (2000) reported 2 unrelated girls with typical clinical, radiographic, and histologic features of POH who also had findings of Albright hereditary osteodystrophy. One child had mild brachydactyly but no endocrinopathy, whereas the other manifested brachydactyly, obesity, and target tissue resistance to thyrotropin and parathyroid hormone. Erythrocyte membranes from both girls showed decreased levels of the Gs-alpha, suggesting that the 2 conditions share a similar molecular basis and pathogenesis.

Faust et al. (2003) described an 8-year-old Albanian girl with POH of the face. Biopsy showed osteoma cutis superficially with ectopic bone formation in the deeper tissues, including skeletal muscle.

Adegbite et al. (2008) reviewed the charts of 111 individuals with cutaneous and subcutaneous ossification. All patients were assessed for 8 characteristics: age of onset of heterotopic ossification (HO), presence and location of HO, depth of HO, progression of HO, features of Albright hereditary osteodystrophy, parathyroid hormone resistance, and GNAS mutation analysis. Based on clinical criteria, they concluded that POH and progressive HO syndromes are at the severe end of a phenotypic spectrum of GNAS-inactivating conditions associated with extraskeletal ossification and that they can be distinguished from other GNAS-based disorders by a single clinical parameter, i.e., the extension of HO from superficial to deep tissue.

Inheritance

Urtizberea et al. (1998) noted that POH has been observed in sporadic cases and in an autosomal dominant pedigree pattern with widely variable expression.

Molecular Genetics

Shore et al. (2002) identified heterozygous inactivating mutations in the GNAS1 gene (e.g., 139320.0024) in 13 of 18 probands with POH. The defective allele in POH was inherited exclusively from fathers, a result consistent with a model of imprinting for GNAS1. Direct evidence that the same mutation can cause either POH or AHO features was observed in a single family, in which the phenotype correlated with the parental origin of the mutant allele.

In an Albanian girl with POH of the face, Faust et al. (2003) identified a heterozygous germline mutation in the GNAS1 gene (139320.0027).

Genotype/Phenotype Correlations

Adegbite et al. (2008) reviewed the charts of 111 individuals with cutaneous and subcutaneous 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, such as POH, from the nonprogressive forms, such as PPHP and pseudohypoparathyroidism types Ia (103580) and Ic (612462).

History

Maclean et al. (1966) described a mother and daughter with multifocal connective tissue ossification. The daughter was a 7-year-old mentally retarded girl of normal stature. These cases may have represented pseudopseudohypoparathyroidism (PPHP; 612463).