Progressive osseous heteroplasia

GNAS is one of the most complex gene loci in the human genome and encodes multiple gene products including Gsα, XLαs, NESP55, A/B, and AS transcripts. XLαs, the extra-large G protein ɑ-subunit, is paternally expressed. XLɑs and Gsɑ share the common 2-13 exons with different promoters and first exons. Therefore, XLɑs contains most of the functional domains of Gsα including receptor and effector binding sites. In vitro studies suggest a "Gsɑ"-like function of XLɑs regarding the stimulation of cAMP generation in response to receptor activation with different cellular actions...

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Primary osteoma cutis is a rare condition belonging to a spectrum of related genetic disorders, including progressive osseous heteroplasia, plate-like osteoma cutis, and Albright hereditary osteodystrophy, which share identical histologies with cutaneous intramembranous ossification and mutations in GNAS. We report a case of a 15-week-old girl who presented with an enlarging, indurated subcutaneous lesion on her right flank. CT scan showed an extensive subcutaneous sheet of calcification. Histologic evaluation revealed heterotopic calcification and intramembranous ossification within the dermis and mature bone largely replacing the subcutaneous fat compatible with osteoma cutis...

BACKGROUND: The GNAS gene on chromosome 20q13.3 is a complex, imprinted locus regulated in a tissue-specific manner. GNAS inactivation disorders are a heterogeneous group of rare disorders caused by mutations and methylation defects. These are divided into pseudohypoparathyroidism (PHP) types 1A and 1B, pseudo-pseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH), depending on the presence or absence of hormone resistance, Albright's hereditary osteodystrophy (AHO), and ectopic ossification...

Introduction. Nonhereditary heterotopic ossification (NHO) is a common complication of trauma. Progressive osseous heteroplasia (POH) and fibrodysplasia ossificans progressiva (FOP) are rare genetic causes of heterotopic bone. In this article, we detail the vascular patterning associated with genetic versus NHO. Methods. Vascular histomorphometric analysis was performed on patient samples from POH, FOP, and NHO. Endpoints for analysis included blood vessel (BV) number, area, density, size, and wall thickness...

Metabolic disorders caused by impairments of the Gsα/cAMP/PKA pathway affecting the signaling of PTH/PTHrP lead to features caused by non-responsiveness of target organs, in turn leading to manifestations similar to the deficiency of the hormone itself. Pseudohypoparathyroidism (PHP) and related disorders derive from a defect of the α subunit of the stimulatory G protein (Gsα) or of downstream effectors of the same pathway, such as the PKA regulatory subunit 1A and the phosphodiesterase type 4D. The increasing knowledge on these diseases made the actual classification of PHP outdated as it does not include related conditions such as acrodysostosis (ACRDYS) or progressive osseous heteroplasia (POH), so that a new nomenclature and classification has been recently proposed grouping these disorders under the term "inactivating PTH/PTHrP signaling disorder" (iPPSD)...

Pseudohypoparathyroidism (PHP), pseudo-PHP, acrodysostosis, and progressive osseous heteroplasia are heterogeneous disorders characterized by physical findings, differently associated in each subtype, including short bones, short stature, a stocky build, ectopic ossifications (features associated with Albright's hereditary osteodystrophy), as well as laboratory abnormalities consistent with hormone resistance, such as hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) and thyroid-stimulating hormone levels...

How osteoblast cells are induced is a central question for understanding skeletal formation. Abnormal osteoblast differentiation leads to a broad range of devastating craniofacial diseases. Here we have investigated intramembranous ossification during cranial bone development in mouse models of skeletal genetic diseases that exhibit craniofacial bone defects. The GNAS gene encodes Gαs that transduces GPCR signaling. GNAS activation or loss-of-function mutations in humans cause fibrous dysplasia (FD) or progressive osseous heteroplasia (POH) that shows craniofacial hyperostosis or craniosynostosis, respectively...

Heterotopic ossification (HO) involves the formation and accumulation of extraskeletal bone tissue at the expense of local tissues including muscles and connective tissues. There are common forms of HO that are triggered by extensive trauma, burns and other bodily insults, and there are also rare congenital severe forms of HO that occur in children with Fibrodysplasia Ossificans Progressiva or Progressive Osseous Heteroplasia. Given that HO is often preceded by inflammation, current treatments usually involve anti-inflammatory drugs alone or in combination with local irradiation, but are not very effective...

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Mesenteric heterotopic ossification (MHO) is very rare and occurs in mid- to late-adulthood, usually in the context of prior abdominal surgery. The mechanisms of MHO are unknown. Here we describe the case of a 72-year-old man with MHO. Standard histological staining revealed that MHO occurred through an endochondral process. By comparison to known mutations in genetic conditions of HO such as fibrodysplasia ossificans progressiva (FOP) and progressive osseous heteroplasia (POH), DNA sequencing analysis demonstrated the presence of a commonly occurring heterozygous synonymous polymorphism (c...

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The term pseudohypoparathyroidism (PHP) refers to a spectrum of rare disorders of mineral metabolism, characterized by features due to end-organ resistance to PTH. The phenotypes of Albright hereditary osteodystrophy (AHO), originally described as associated to the disease, and progressive osseous heteroplasia, can be associated to the endocrine manifestations of hormonal resistance. Genetic or epigenetic alterations in the complex imprinted GNAS locus, encoding the alpha-subunit of the stimulatory G protein (GSα) and several other transcripts, give rise to the different forms oh PHP, which can be differentiated according to the phenotype, the response to PTH infusion and in vitro assays testing Gsα activity...

GNAS is a complex imprinted gene encoding the alpha-subunit of the stimulatory heterotrimeric G protein (Gsα). GNAS gives rise to additional gene products that exhibit exclusively maternal or paternal expression, such as XLαs, a large variant of Gsα that shows exclusively paternal expression and is partly identical to the latter. Gsα itself is expressed biallelically in most tissues, although the expression occurs predominantly from the maternal allele in a small set of tissues, such as renal proximal tubules...

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Progressive osseous heteroplasia is a rare inherited disease that begins with skin ossification and proceeds into the deeper connective tissues. The disease should be distinguished from other genetic disorders of heterotopic ossification including fibrodysplasia ossificans progressiva (FOP) and Albright hereditary osteodystrophy (AHO). We report a case of progressive osseous heteroplasia in a twenty four years old male with a complaint of ankylosis of the entire upper left limb and digital cutaneous lesions and sparing of the other limbs and the axial skeleton...

CONTEXT: The term pseudohypoparathyroidism (PHP) was coined to describe the clinical condition resulting from end-organ resistance to parathormone (rPTH), caused by genetic and/or epigenetic alterations within or upstream of GNAS. Although knowledge about PHP is growing, there are few data on the prevalence of underlying molecular defects. OBJECTIVE: The purpose of our study was to ascertain the relative prevalence of PHP-associated molecular defects. DESIGN: With a specially designed questionnaire, we collected data from all patients (n = 407) clinically and molecularly characterized to date by expert referral centers in France, Italy, and Spain...

OBJECTIVE: Disorders caused by impairments in the parathyroid hormone (PTH) signalling pathway are historically classified under the term pseudohypoparathyroidism (PHP), which encompasses rare, related and highly heterogeneous diseases with demonstrated (epi)genetic causes. The actual classification is based on the presence or absence of specific clinical and biochemical signs together with an in vivo response to exogenous PTH and the results of an in vitro assay to measure Gsa protein activity...

Progressive osseous heteroplasia (POH) is a segmental disorder characterized by progressive heterotopic ossification that extends from dermal and subcutaneous tissues to deeper structures. So far, it has been taken as a rarely occurring bone disease with autosomal dominant inheritance. Here, arguments are presented in favor of the alternative concept that the disorder is merely a type 2 segmental manifestation of autosomal dominant GNAS inactivation disorders. Type 2 segmental mosaicism arises, in a heterozygous embryo, from a somatic mutational event that occurs at an early developmental stage, resulting in loss of the corresponding wild-type allele and giving rise to a homozygous or hemizygous cell clone...

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