1) J Clin Endocrinol Metab. 2010 Jun;95(6):3028-3038. Epub 2010 Apr 28.
Progressive Osseous Heteroplasia: A Model for the Imprinting Effects of GNAS Inactivating Mutations in Humans.
Lebrun M, Richard N, Abeguilé G, David A, Dieux AC, Journel H, Lacombe D, Pinto G, Odent S, Salles JP, Taieb A, Gandon-Laloum S, Kottler ML.
Centre Hospitalier Universitaire Clemenceau, Département Génétique et Reproduction, Génétique Moléculaire, 14033 Caen cedex, France. firstname.lastname@example.org .
Context: Heterozygous GNAS inactivating mutations are known to induce pseudohypoparathyroidism type 1a when maternally inherited and pseudopseudohypoparathyroidism when paternally inherited. Progressive osseous heteroplasia (POH) is a rare disease of ectopic bone formation, and studies in different families have shown that POH is also caused by paternally inherited GNAS mutations. Objective: Our purpose was to characterize parental origin of the mutated allele in de novo cases of POH and to draw phenotype/genotype correlations according to maternal or paternal transmission of a same GNAS mutation. Design and Setting: We conducted a retrospective study on patients addressed to our referral center for the rare diseases of calcium and phosphorus metabolism. Patients and Methods: We matched 10 cases of POH with cases of pseudohypoparathyroidism type 1a carrying the same GNAS mutations. Main Outcome Measures: The parental origin of the mutated allele was studied using informative intragenic polymorphisms and subcloning of PCR products. Results: Paternal origin of GNAS mutations was clearly demonstrated in eight POH cases including one patient with mutation in exon 1. Genotype/phenotype analyses suggest that there is no direct correlation between the ossifying process and the position of the inactivating GNAS mutation. It is, however, more severe in patients in whom origin of the mutation is paternal. Severe intrauterine growth retardation was clearly evidenced in paternally inherited mutations. Conclusions: Clinical heterogeneity makes genetic counseling a delicate matter, especially in which paternal inheritance is concerned because it can lead to either a mild expression of pseudopseudohypoparathyroidism or a severe expression of POH.
2) J Pediatr Endocrinol Metab. 2010 Mar;23(3):303-9.
Progressive osseous heteroplasia caused by a novel nonsense mutation in the GNAS1 gene.
Goto M, Mabe H, Nishimura G, Katsumata N.
Department of Pediatrics, Tokyo Metropolitan Hachioji Children’s Hospital, Hachioji, Japan. email@example.com
Progressive osseous heteroplasia (POH), characterized by progressive heterotopic ossifications of the dermis, skeletal muscle and deep connective tissues, is caused by inactivating mutations of GNAS1 of a paternally transmitted allele. We report a novel GNAS1 mutation in a patient with POH. The patient is a 6-year-old boy, whose short stature came to medical attention in infancy. He was diagnosed with growth hormone (GH) deficiency, and subsequent GH therapy resulted in catch-up growth. He developed soft tissue masses in the right heel and right elbow that were calcified or ossified on plain radiographs. MR imaging raised a suspicion of heterotopic ossification; thus, GNAS1 was analyzed. A novel nonsense mutation p.R342X was observed in the patient, but not in his parents. Single nucleotide polymorphism analysis revealed paternal transmission of the mutant allele. RT-PCR analysis demonstrated expression of both normal and mutant GNAS1 transcripts in the patient. Thus, the patient is considered to have developed POH because of the non-functioning truncated Gs(alpha) protein.
3) J Bone Joint Surg Br. 1998 Sep;80(5):768-71.
Progressive osseous heteroplasia. Report of a family.
We report a case of progressive osseous heteroplasia in a female infant who had progressive ossification of the skin and deep connective tissues. Isolated dermal ossification is present in her father and younger sister suggesting an autosomal dominant mode of inheritance with variable expressivity or possible somatic mosaicism. This report of a family with progressive osseous heteroplasia contributes to the understanding of this uncommon genetic disorder, which must be distinguished from fibrodysplasia ossificans progressiva and Albright’s hereditary osteodystrophy. The paucity of familial cases of progressive osseous heteroplasia currently limits the use of a genome-wide linkage analysis, but linkage exclusion analysis with promising candidate genes is a possibility.
4) Arch Dermatol. 1996 Jul;132(7):787-91.
Progressive osseous heteroplasia.
Primary heterotopic ossification beginning in childhood is quite rare but occurs in several well-described conditions, such as Albright hereditary osteodystrophy, fibrodysplasia ossificans progressiva, and platelike osteoma cutis. Recently, a new disorder called progressive osseous heteroplasia (POH) has been described in the orthopedic literature. Primary cutaneous calcification and ossification beginning in infancy are presenting signs of this progressive and potentially debilitating disorder.
We describe 2 children with POH who were recently seen at Children’s Hospital of Wisconsin. Both children were female and developed cutaneous calcification and ossification within the first 6 months of life. Both girls had progression of the lesions to involve ossification of the deeper tissues. No abnormalities in calcium, phosphorus, vitamin D, or parathyroid hormone levels were identified in these patients. No associated anomalies were detected. Biopsy results from the lesions showed calcinosis cutis superficially, with both endochondral and intramembranous bone formation in the deeper tissues.
Progressive osseous heteroplasia must now be included in the differential diagnosis of primary cutaneous ossification beginning in childhood. Because the first clinical manifestations of POH appear in the skin. It is important for dermatologists to be aware of this newly described condition.
Comment in : Skin and bones. [Arch Dermatol. 1996]
5) Pediatr Pathol Lab Med. 1995 Sep-Oct;15(5):813-27.
Progressive osseous heteroplasia, uncommon cause of soft tissue ossification: a case report and review of the literature.
We report a case of an uncommon, recently described disease manifesting shortly after birth, characterized by extensive soft tissue calcification with ossification, progressive osseous heteroplasia. We describe the complex histopathologic patterns present in this case, discuss the main differential diagnoses that the surgical pathologist must consider when confronted by soft tissue ossification, and review the pertinent literature. We conclude that although the morphologic patterns of ossification in progressive osseous heteroplasia are complex and the involvement is extensive, the morphology of the lesions lacks diagnostic specificity. The diagnosis must be based on a consideration of the combined clinical data and radiologic and pathologic findings. This approach alone makes it possible to exclude a number of clinicopathologic entities that manifest with so-called osteoma cutis but whose associated lesions and genetic implications are different.
6) Clin Orthop Relat Res. 1995 Aug;(317):243-5.
Progressive osseous heteroplasia in male patients. Two new case reports.
Progressive osseous heteroplasia is a rare developmental disorder of mesenchymal differentiation characterized by cutaneous osteomas in infancy and by progressive heterotopic intramembranous ossification of skin and deep connective tissue. To date, typical features of the disorder have been reported only in 8 female patients. This report documents progressive osseous heteroplasia in 2 boys and has important implications for the clinical detection and pathogenetic understanding of this rare disorder.
7) J Am Acad Orthop Surg. 1994 Oct;2(5):288-296.
Heterotopic Ossification: Two Rare Forms and What They Can Teach Us.
Heterotopic ossification is characterized by the formation of normal bone at ectopic soft-tissue locations. Regardless of the etiology of heterotopic ossification, requisite pathogenetic conditions include an inductive signal capable of stimulating morphogenesis, a population of inducible osteoprogenitor cells, and a heterotopic environment conducive to osteogenesis. Two rare heritable and developmental forms of heterotopic ossification, fibrodysplasia ossificans progressiva and progressive osseous heteroplasia, provide valuable clinical and pathogenetic insights into heterotopic ossification in humans. A fundamental understanding of the developmental and molecular pathology of these disorders may lead to more effective strategies for preventing and treating heterotopic ossification in humans.
8) Bone. 1994 Sep-Oct;15(5):471-5.
Progressive osseous heteroplasia: a case report.
We report the case of a young female who, from infancy, suffered extensive, progressive, heterotopic ossification of her left lower limb. Heterotopic ossification, which was largely but not exclusively intramembranous in type, was most marked in subcutaneous fat but was also noted in muscle and deep connective tissue. The spectrum of changes noted suggests that this congenital disorder of soft tissues is similar to that recently described as progressive osseous heteroplasia.
9) J Bone Joint Surg Am. 1994 Mar;76(3):425-36.
Progressive osseous heteroplasia: a distinct developmental disorder of heterotopic ossification. Two new case reports and follow-up of three previously reported cases.
Kaplan FS1, Craver R, MacEwen GD, Gannon FH, Finkel G, Hahn G, Tabas AJ, Gardner RJ, Zasloff MA
Ectopic bone formation or “heterotopic ossification” can follow surgery, trauma, or neurologic injury, but the process is usually self-limited, localized to the site of injury, and responds to surgical treatment when necessary. Aggressive, systemic forms of heterotopic ossification exist that generate lesions that often resist surgical treatment and produce a high rate of recurrence. These entities typically manifest during infancy as genetic syndromes such as fibrodysplasia ossificans progressiva or progressive osseous heteroplasia. The authors describe a case of aggressive, systemic heterotopic ossification in an adult that followed a motor vehicle accident and multiple surgeries. The patient developed a large nonhealing wound around a focus of ectopic bone. Skin grafts failed as a result of the recurrence of ectopic bone, and the patient eventually required aggressive debridement and delayed rotational flap closure. A brief review of the clinical features and surgical treatment of heterotopic ossification is outlined.
11) Joint Bone Spine. 2004 Mar;71(2):98-101.
Inherited ossifying diseases.
Inherited ossifying diseases are relatively uncommon diseases leading ta a great disability and life-threatening complications. Fibrodysplasia Ossificans Progressiva is characterized by the association of skeletal abnormalities mainly in great toes, and enchondral ossifications in tendons and muscles. BMP dysregulation seems to be the main underlying mechanism of the heterotopic ossifications. The genetic basis remain controversial between a mutation on chromosome 4 or 17. Progressive Osseous Heteroplasia (HOP), more recently described, shares some similarities with Albrights hereditary osteodystrophy. In HOP, the intramembranous ossifications progressively developped from the dermis to the deeper layer. The genetic abnormality involved the GNAS 1 gene leading to an inactivation of the alpha subunit of the G protein-complex. Some therapeutic approaches have been tried: angiogenesis inhibition, mast cell inhibition; others remained in project: BMP 4 inhibition; actually there is no proved efficacy of any of them.
12) J Am Acad Orthop Surg. 2004 Mar-Apr;12(2):116-25.
Heterotopic ossification, the formation of bone in soft tissue, requires inductive signaling pathways, inducible osteoprogenitor cells, and a heterotopic environment conducive to osteogenesis. Little is known about the molecular pathogenesis of this condition. Research into two rare heritable and developmental forms, fibrodysplasia ossificans progressiva and progressive osseous heteroplasia, has provided clinical, pathologic, and genetic insights. In fibrodysplasia ossificans progressiva, overexpression of bone morphogenetic protein 4 and underexpression of multiple antagonists of this protein highlight the potential role of a potent morphogenetic gradient. Research on fibrodysplasia ossificans progressiva also has led to the identification of the genetic cause of progressive osseous heteroplasia: inactivating mutations in the alpha subunit of the gene coding for the stimulatory G protein of adenylyl cyclase. Better understanding of the complex developmental and molecular pathology of these disorders may lead to more effective strategies to prevent and treat other, more common forms of heterotopic ossification.
13) Clin Exp Dermatol. 2004 Jan;29(1):77-80.
Progressive osseous heteroplasia resulting from a new mutation in the GNAS1 gene.
Progressive osseous heteroplasia (OMIM 166350) is a rare autosomal dominant condition that presents in childhood as dermal ossification and may progress deeper to involve subcutaneous fat and connective tissue. Recently, paternally inherited inactivating mutations in the GNAS1 gene on chromosome 20q13 have been implicated in the pathogenesis, although sporadic cases have also been reported. We report a 9-year-old British Chinese girl with progressive osseous heteroplasia resulting from a de novo missense mutation (W281R) in the GNAS1 gene. She is of small stature (0.4th centile) and started to develop skin lesions at the age of 9 months. These have been confirmed histologically as osteoma cutis. She is of normal intelligence and development and has no dysmorphic features. The GNAS1 gene exhibits imprinting and maternally inherited mutations have previously been shown to result in Albright’s hereditary osteodystrophy (OMIM 103580) with pseudohypothyroidism type 1a, whereas paternally inherited mutations result in progressive osseous heteroplasia or the Albright’s hereditary osteodystrophy phenotype with pseudopseudohypothyroidism (OMIM 300800). With only nine mutations of the GNAS1 gene reported so far in progressive osseous heteroplasia, this new mutation helps to extend further the genotype-phenotype correlation.
14) Am J Med Genet A. 2003 Apr 1;118A(1):71-5.
Progressive osseous heteroplasia in the face of a child.
We describe a rare case of progressive osseous heteroplasia of the face in a child. Biopsy showed osteoma cutis superficially with ectopic bone formation in the deeper tissues including skeletal muscle. Analysis of DNA from peripheral blood leukocytes showed mutations in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase (GNAS1), confirming the diagnosis of progressive osseous heteroplasia.
15) J Pediatr Orthop B. 2002 Oct;11(4):339-42.
Progressive osseous heteroplasia. A case report and review of the literature.
Progressive osseous heteroplasia is a rare childhood disorder that is characterized by ectopic progressive ossification of skin, muscle, and connective tissue. We report a 5 year-old female patient with familial transmission. She developed cutaneous calcifications and ossifications within the first 2 months of life. Her father and father’s aunt had subcutaneous nodules. At the age of 5 years, physical examination of the patient revealed ossified subcutaneous nodules and plaques on both upper limbs, the right side was predominantly affected. All the joints of the upper limbs were ankylosed except the left shoulder. Biopsy specimens of the patient and her father revealed islands of bone in the reticular dermis and deep dermis, respectively. We suggest that all family members of progressive osseous heteroplasia patients are carefully investigated for ossified nodules because of autosomal dominant inheritance.
16) N Engl J Med. 2002 Jan 10;346(2):99-106.
Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia.
Erratum in N Engl J Med 2002 May 23;346(21):1678.
Progressive osseous heteroplasia (POH), an autosomal dominant disorder, is characterized by extensive dermal ossification during childhood, followed by disabling and widespread heterotopic ossification of skeletal muscle and deep connective tissue. Occasional reports of mild heterotopic ossification in Albright’s hereditary osteodystrophy (AHO) and a recent report of two patients with AHO who had atypically extensive heterotopic ossification suggested a common genetic basis for the two disorders. AHO is caused by heterozygous inactivating mutations in the GNAS1 gene that result in decreased expression or function of the alpha subunit of the stimulatory G protein (Gsalpha) of adenylyl cyclase.
We tested the hypothesis that GNAS1 mutations cause POH, using the polymerase chain reaction to amplify GNAS1 exons and exon-intron boundaries in 18 patients with sporadic or familial POH.
Heterozygous inactivating GNAS1 mutations were identified in 13 of the 18 probands with POH. The defective allele in POH is 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 was observed within a single family, in which the phenotype correlated with the parental origin of the mutant allele.
Paternally inherited inactivating GNAS1 mutations cause POH. This finding extends the range of phenotypes derived from haplo insufficiency of GNAS1, provides evidence that imprinting is a regulatory mechanism for GNAS1 expression, and suggests that Gsalpha is a critical negative regulator of osteogenic commitment in nonosseous connective tissues.
17) J Bone Miner Res. 2000 Nov;15(11):2084-94.
Progressive osseous heteroplasia.
Progressive osseous heteroplasia (POH) is a recently described genetic disorder of mesenchymal differentiation characterized by dermal ossification during infancy and progressive heterotopic ossification of cutaneous, subcutaneous, and deep connective tissues during childhood. The disorder can be distinguished from fibrodysplasia ossificans progressiva (FOP) by the presence of cutaneous ossification, the absence of congenital malformations of the skeleton, the absence of inflammatory tumorlike swellings, the asymmetric mosaic distribution of lesions, the absence of predictable regional patterns of heterotopic ossification, and the predominance of intramembranous rather than endochondral ossification. POH can be distinguished from Albright hereditary osteodystrophy (AHO) by the progression of heterotopic ossification from skin and subcutaneous tissue into skeletal muscle, the presence of normal endocrine function, and the absence of a distinctive habitus associated with AHO. Although the genetic basis of POH is unknown, inactivating mutations of the GNAS1 gene are associated with AHO. The report in this issue of the JBMR of 2 patients with combined features of POH and AHO–one with classic AHO, severe POH-like features, and reduced levels of Gsalpha protein and one with mild AHO, severe POH-like features, reduced levels of Gsalpha protein, and a mutation in GNAS1–suggests that classic POH also could be caused by GNAS1 mutations. This possibility is further supported by the identification of a patient with atypical but severe platelike osteoma cutis (POC) and a mutation in GNAS1, indicating that inactivating mutations in GNAS1 may lead to severe progressive heterotopic ossification of skeletal muscle and deep connective tissue independently of AHO characteristics. These observations suggest that POH may lie at one end of a clinical spectrum of ossification disorders mediated by abnormalities in GNAS1 expression and impaired activation of adenylyl cyclase. Analysis of patients with classic POH (with no AHO features) is necessary to determine whether the molecular basis of POH is caused by inactivating mutations in the GNAS1 gene.
- 18) J Bone Miner Res. 2000 Nov;15(11):2074-83.Deficiency of the alpha-subunit of the stimulatory G protein and severe extraskeletal ossification.
Eddy MC1, Jan De Beur SM, Yandow SM, McAlister WH, Shore EM, Kaplan FS, Whyte MP, Levine MA.Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, Missouri 63131, USA.
Progressive osseous heteroplasia (POH) is a rare disorder characterized by dermal ossification beginning in infancy followed by increasing and extensive bone formation in deep muscle and fascia. We describe two unrelated girls with typical clinical, radiographic, and histological features of POH who also have findings of another uncommon heritable disorder, Albright hereditary osteodystrophy (AHO). One patient has mild brachydactyly but no endocrinopathy, whereas the other manifests brachydactyly, obesity, and target tissue resistance to thyrotropin and parathyroid hormone (PTH). Levels of the alpha-subunit of the G protein (Gsalpha) were reduced in erythrocyte membranes from both girls and a nonsense mutation (Q12X) in exon 1 of the GNAS1 gene was identified in genomic DNA from the mildly affected patient. Features of POH and AHO in two individuals suggest that these conditions share a similar molecular basis and pathogenesis and that isolated severe extraskeletal ossification may be another manifestation of Gsalpha deficiency.
19) J Bone Miner Res. 2000 Nov;15(11):2063-73.
GNAS1 mutation and Cbfa1 misexpression in a child with severe congenital platelike osteoma cutis.Yeh GL1, Mathur S, Wivel A, Li M, Gannon FH, Ulied A, Audi L, Olmstead EA, Kaplan FS, Shore EM.Department of Orthopaedic Surgery, University of Pennsylvania, School of Medicine, Philadelphia 19104-6081, USA.
We evaluated a 7-year-old girl with severe platelike osteoma cutis (POC), a variant of progressive osseous heteroplasia (POH). The child had congenital heterotopic ossification of dermis and subcutaneous fat that progressed to involve deep skeletal muscles of the face, scalp, and eyes. Although involvement of skeletal muscle is a prominent feature of POH, heterotopic ossification has not been observed in the head, face, or extraocular muscles. The cutaneous ossification in this patient was suggestive of Albright hereditary osteodystrophy (AHO); however, none of the other characteristic features of AHO were expressed. Inactivating mutations of the GNAS1 gene, which encodes the alpha-subunit of the stimulatory G protein of adenylyl cyclase, is the cause of AHO. Mutational analysis of GNAS1 using genomic DNA of peripheral blood and of lesional and nonlesional tissue from our patient revealed a heterozygous 4-base pair (bp) deletion in exon 7, identical to mutations that have been found in some AHO patients. This 4-bp deletion in GNAS1 predicts a protein reading frameshift leading to 13 incorrect amino acids followed by a premature stop codon. To investigate pathways of osteogenesis by which GNAS1 may mediate its effects, we examined the expression of the obligate osteogenic transcription factor Cbfa1/RUNX2 in lesional and uninvolved dermal fibroblasts from our patient and discovered expression of bone-specific Cbfa1 messenger RNA (mRNA) in both cell types. These findings document severe heterotopic ossification in the absence of AHO features caused by an inactivating GNAS1 mutation and establish the GNAS1 gene as the leading candidate gene for POH.
20) Ann Genet. 2000 Apr-Jun;43(2):75-80.
Progressive osseous heteroplasia: an uncommon cause of ossification of soft tissues.Stoll C1, Javier MR, Bellocq JP.Service de génétique médicale, hôpital de Hautepierre, avenue Molière, 67098 cedex, Strasbourg, France. firstname.lastname@example.org
Whereas the deposition of calcium within soft tissues is not infrequent, the development of highly structured, mineralized tissue histologically identifiable as true bone is uncommon and can cause a variety of clinical features. This article reports the clinical and radiological features in a patient with progressive osseous heteroplasia (POH), a recently identified disorder characterized by heterotopic ossification. The patient, a female, was 20 years of age 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. Until the results of Rosenfeld and Kaplan in 1995 reporting POH in two boys, typical features had only been reported in females (n=8). POH is usually sporadic; however, familial associations and atypical phenotypes have been reported.
21) Stem Cells. 2012 Jul;30(7):1477-85. doi: 10.1002/stem.1109.
Paternally inherited gsα mutation impairs adipogenesis and potentiates a lean phenotype in vivo.Liu JJ1, Russell E, Zhang D, Kaplan FS, Pignolo RJ, Shore EM.Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Paternally inherited inactivating mutations of the GNAS gene have been associated with a rare and disabling genetic disorder, progressive osseous heteroplasia, in which heterotopic ossification occurs within extraskeletal soft tissues, such as skin, subcutaneous fat, and skeletal muscle. This ectopic bone formation is hypothesized to be caused by dysregulated mesenchymal progenitor cell differentiation that affects a bipotential osteogenic-adipogenic lineage cell fate switch. Interestingly, patients with paternally inherited inactivating mutations of GNAS are uniformly lean. Using a mouse model of Gsα-specific exon 1 disruption, we examined whether heterozygous inactivation of Gnas affects adipogenic differentiation of mesenchymal precursor cells from subcutaneous adipose tissues (fat pad). We found that paternally inherited Gsα inactivation (Gsα(+/p-) ) impairs adipogenic differentiation of adipose-derived stromal cells (ASCs). The Gsα(+/p-) mutation in ASCs also decreased expression of the adipogenic factors CCAAT-enhancer-binding protein (C/EBP)β, C/EBPα, peroxisome proliferator-activated receptor gamma, and adipocyte protein 2. Impaired adipocyte differentiation was rescued by an adenylyl cyclase activator, forskolin, and provided evidence that Gsα-cAMP signals are necessary in early stages of this process. Supporting a role for Gnas in adipogenesis in vivo, fat tissue weight and expression of adipogenic genes from multiple types of adipose tissues from Gsα(+/p-) mice were significantly decreased. Interestingly, the inhibition of adipogenesis by paternally inherited Gsα mutation also enhances expression of the osteogenic factors, msh homeobox 2, runt-related transcription factor 2, and osteocalcin. These data support the hypothesis that Gsα plays a critical role in regulating the balance between fat and bone determination in soft tissues, a finding that has important implications for a wide variety of disorders of osteogenesis and adipogenesis.
22) Zhonghua Er Ke Za Zhi. 2012 Jan;50(1):10-4.
[Clinical features, mutation of the GNAS1 and pathogenesis of progressive osseous heteroplasia].[Article in Chinese]Wu FQ1, Wang L, Zou JZ, Huang XL, Yuan XY.Department of Rheumatology and Immunology, Capital Institute of Pediatrics, Beijing, China.
To investigate the clinical features, mutation of the GNAS1 and pathogenesis of progressive osseous heteroplasia (POH).
The typical clinical, pathological and radiographic features of a boy with POH were collected and summarized following family survey. The GNAS1 gene sequence of all family members were amplified by polymerase chain reaction (PCR) and the products were sequenced directly to identify the mutations. A literature review and long-term follow up were also conducted.
The patient was an 11-year-old boy who had the onset in infancy, which indicates a chronic progressive cause of disease. The clinical features include the unsmooth local skin of the right shank where spread many rigid rice-like or irregular slabby uplifts, slabby bone-like sclerosis on the left lower mandible, left masticatory muscles, in lateral subcutaneous site of left hip joint and deep tissue, accompanied by gradually progressive difficulty in opening mouth. Histopathology showed that there were loosened hyperplasia of fibroblast and interstitial edema with punctiformed ossification. Radiographs showed flocculence hyperdense image in the subcutaneous tissues and muscles around left lower mandible, and the left masticatory muscles were obviously involved. The 3-dimensional computed tomography showed dislocations of the left temporomandibular joint. Sheeted hyperdense image with inequable density could be noted in lateral muscles of the left hip. And lamellar hyperdense image parallel to the long axis of the bone could be seen in the subcutaneous dorsum of the left foot and achilles tendon. Macro-thumb and of brachydactylia of the hands and feet were not present. The level of calcium, phosphorus and alkaline phosphatase in the blood were normal. Brother of same father but different mothers was free of the disease and no patient of the same disease was found in maternal line and paternal lines. A mutated allele in exon 7 and a polymorphism in exon 5 were found in GNAS1 gene in both of the patient and his father.
There is possibility/likelihood/probability that Chinese children could develop POH. Translocated dermal ossification began in infancy and shows a progressive cause in childhood. The disease is characterized by the heterotopic ossification of the skin, deep tissue, muscles and facial surface tissues. The location of the mutation in this study was different from that reported in abroad studies although exist in the same exons.
23) J Bone Miner Res. 2011 Nov;26(11):2647-55. doi: 10.1002/jbmr.481.
Heterozygous inactivation of Gnas in adipose-derived mesenchymal progenitor cells enhances osteoblast differentiation and promotes heterotopic ossification.Pignolo RJ1, Xu M, Russell E, Richardson A, Kaplan J, Billings PC, Kaplan FS, Shore EM.Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. email@example.com
Human genetic disorders sharing the common feature of subcutaneous heterotopic ossification (HO) are caused by heterozygous inactivating mutations in GNAS, a gene encoding multiple transcripts including two stimulatory G proteins, the α subunit of the stimulatory G protein (G(s)α) of adenylyl cyclase, and the extralong form of G(s)α, XLαs. In one such disorder, progressive osseous heteroplasia (POH), bone formation initiates within subcutaneous fat before progressing to deeper tissues, suggesting that osteogenesis may involve abnormal differentiation of mesenchymal precursors that are present in adipose tissues. We determined by immunohistochemical analysis that GNAS protein expression is limited to G(s)α in bone-lining cells and to G(s)α and XLαs in osteocytes. By contrast, the GNAS proteins G(s)α, XLαs, and NESP55 are detected in adipocytes and in adipose stroma. Although Gnas transcripts, as assessed by quantitative RT-PCR, show no significant changes on osteoblast differentiation of bone-derived precursor cells, the abundance of these transcripts is enhanced by osteoblast differentiation of adipose-derived mesenchymal progenitors. Using a mouse knockout model, we determined that heterozygous inactivation of Gnas (by disruption of the G(s)α-specific exon 1) abrogates upregulation of multiple Gnas transcripts that normally occurs with osteoblast differentiation in wild-type adipose stromal cells. These transcriptional changes in Gnas(+/-) mice are accompanied by accelerated osteoblast differentiation of adipose stromal cells in vitro. In vivo, altered osteoblast differentiation in Gnas(+/-) mice manifests as subcutaneous HO by an intramembranous process. Taken together, these data suggest that Gnas is a key regulator of fate decisions in adipose-derived mesenchymal progenitor cells, specifically those which are involved in bone formation.
24) Indian J Orthop. 2011 May;45(3):280-2. doi: 10.4103/0019-5413.80050.
Progressive osseous heteroplasia in a 10-year-old male child.Singh GK1, Verma V.Department of Orthopaedics, CSM Medical University, Lucknow, Uttar Pradesh, India.
We report a sporadic case of progressive osseous heteroplasia (POH) in a 10-year-old male child who developed progressive ossification of the skin and deep connective tissue. The condition needs to be distinguished from other causes of childhood heterotopic ossification, such as fibrodysplasia ossificans progressiva, pseudohypoparathyroidism, and pseudopseudohypoparathyroidism. The cause of POH is an inactivating GNAS1 (guanine nucleotide-binding protein alpha-stimulating activity polypeptide 1) mutation caused only by paternal inheritance of the mutant allele. Most cases are sporadic and only 2 instances of familial transmission have been documented, suggesting an autosomal dominant mode of inheritance with possible somatic mosaicism. The condition is associated with progressive superficial to deep ossification, progressive restriction of range of motion, bleak prognosis, and recurrence if excised.
KEYWORDS: GNAS1 mutation; heterotopic ossification; subcutaneous ossification
25) Nat Rev Rheumatol. 2010 Sep;6(9):518-27. doi: 10.1038/nrrheum.2010.122. Epub 2010 Aug 10.
Inherited human diseases of heterotopic bone formation.Shore EM1, Kaplan FS.Department of Orthopedic Surgery, University of Pennsylvania School of Medicine, 424 Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104-6081, USA. firstname.lastname@example.org
Human disorders of hereditary and nonhereditary heterotopic ossification are conditions in which osteogenesis occurs outside of the skeleton, within soft tissues of the body. The resulting extraskeletal bone is normal. The aberration lies within the mechanisms that regulate cell-fate determination, directing the inappropriate formation of cartilage or bone, or both, in tissues such as skeletal muscle and adipose tissue. Specific gene mutations have been identified in two rare inherited disorders that are clinically characterized by extensive and progressive extraskeletal bone formation-fibrodysplasia ossificans progressiva and progressive osseous heteroplasia. In fibrodysplasia ossificans progressiva, activating mutations in activin receptor type-1, a bone morphogenetic protein type I receptor, induce heterotopic endochondral ossification, which results in the development of a functional bone organ system that includes skeletal-like bone and bone marrow. In progressive osseous heteroplasia, the heterotopic ossification leads to the formation of mainly intramembranous bone tissue in response to inactivating mutations in the GNAS gene. Patients with these diseases variably show malformation of normal skeletal elements, identifying the causative genes and their associated signaling pathways as key mediators of skeletal development in addition to regulating cell-fate decisions by adult stem cells.
26) Bone. 2010 Mar;46(3):868-72. doi: 10.1016/j.bone.2009.11.001. Epub 2009 Nov 10.
GNAS-associated disorders of cutaneous ossification: two different clinical presentations.Schimmel RJ1, Pasmans SG, Xu M, Stadhouders-Keet SA, Shore EM, Kaplan FS, Wulffraat NM.Department of Paediatric Dermatology and Allergology, Wilhelmina’s Children Hospital, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands.
Progressive osseous heteroplasia (POH) is a rare genetic disorder characterized by dermal ossification during infancy and progressive ossification into deep connective tissue during childhood. POH is at the severe end of a spectrum of GNAS-associated ossification disorders that include osteoma cutis and Albright Hereditary Osteodystrophy (AHO). Here we describe two girls who have different clinical presentations that reflect the variable expression of GNAS-associated disorders of cutaneous ossification. Each girl had a novel heterozygous inactivating mutation in the GNAS gene. One girl had POH limited to the left arm with severe contractures and growth retardation resulting from progressive heterotopic ossification in the deep connective tissues. The other girl had AHO with widespread, superficial heterotopic ossification but with little functional impairment. While there is presently no treatment or prevention for GNAS-associated ossification disorders, early diagnosis is important for genetic counselling and for prevention of iatrogenic harm.
27) Eur J Dermatol. 2009 May-Jun;19(3):214-5. doi: 10.1684/ejd.2009.0634. Epub 2009 Feb 12.
Unilateral progressive osseous heteroplasia.Santiago F1, Vieira R, Cordeiro M, Tellechea O, Figueiredo A.Dermatology Department, Hospitais da Universidade de Coimbra, Praceta Mota Pinto, 3000-075 Coimbra, Portugal. email@example.com
A 50-year-old male patient presented with firm subcutaneous nodules and plaques with a gritty texture, unilaterally affecting the left side of the trunk and the left limbs. These lesions had had a progressive course since early childhood and caused functional impairment. There was no family history of similar disorders. No phospho-calcium metabolism abnormalities were observed. Biopsies of the affected areas demonstrated osteoma cutis. Analysis of DNA showed no mutation of the GNAS gene. The clinical features were consistent with progressive osseous heteroplasia, atypically presented in a unilateral form, probably revealing a mosaic distribution.
28) Am J Med Genet A. 2008 Jul 15;146A(14):1788-96. doi: 10.1002/ajmg.a.32346.
Diagnostic and mutational spectrum of progressive osseous heteroplasia (POH) and other forms of GNAS-based heterotopic ossification.Adegbite NS1, Xu M, Kaplan FS, Shore EM, Pignolo RJ.Department of Orthopaedic Surgery, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104, USA.
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).
29) Skeletal Radiol. 2008 Jun;37(6):563-7. doi: 10.1007/s00256-008-0469-9.
A case of progressive osseous heteroplasia: a first case in Japan.Kumagai K1, Motomura K, Egashira M, Tomita M, Suzuki M, Uetani M, Shindo H.Department of Orthopedic Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki City, Japan. firstname.lastname@example.org
Progressive osseous heteroplasia (POH) is a rare, hereditary, disorder (number 166350 in Mendelian Inheritance in Man), which was first identified in 1994 and is characterized by dermal ossification beginning in infancy as a result of increasing and extensive bone formation in deep muscle and fascia. We describe a boy with typical clinical, radiographic, and genetic features of POH. A nonsense mutation in exon 7 of the GNAS1 gene was identified in genomic DNA from the patient. No such case has been reported in East Asia or Japan before this patient.
30) Bone. 2007 May;40(5):1425-8. Epub 2006 Dec 28.
Progressive osseous heteroplasia-like heterotopic ossification in a male infant with pseudohypoparathyroidism type Ia: a case report.Gelfand IM1, Hub RS, Shore EM, Kaplan FS, Dimeglio LA.Department of Pediatrics, Division of Pediatric Endocrinology and Diabetology, Indiana University School of Medicine, James Whitcomb Riley Hospital for Children, Indianapolis, IN, USA. email@example.com
Pseudohypoparathyroidism (PHP) Ia is a rare condition associated with multiple hormone resistance and the Albright Hereditary Osteodystrophy (AHO) phenotype. Progressive osseous heteroplasia (POH) is characterized by progressive ossifications of dermal, skeletal muscle and deep connective tissue during childhood. Both PHP Ia and POH are caused by heterozygous inactivating mutations in the GNAS gene. Maternal inheritance of a GNAS mutation leads to an AHO phenotype with hormonal resistance (PHP Ia), whereas paternal inheritance leads to an AHO phenotype without the hormonal resistance (pseudopseudo-hypoparathyroidism). Pure POH (no other AHO features) is also caused by a paternal inheritance of GNAS mutations. Mutations that cause PHP Ia when maternally inherited can cause POH when paternally inherited. We present an unusual case of a boy with clinical features of both POH and PHP Ia, and a GNAS inactivating mutation.
The patient was referred at 1 month of age with a “knot on his leg”. Plain radiographs revealed subcutaneous ossifications. PE at age 4 months included: length and weight >95%, a round face, short 4th metacarpals, and extensive subcutaneous ossifications of the lower limbs, buttocks, and back. Studies at age 4 months included an elevated TSH 12.4 mIU/l, free T4 0.86 ng/dl (0.8-2.3), PTH 61 pg/ml (10-65), calcium 9. 8 mg/dl (9.0-11.0), and phosphorus 6. 4 mg/dl (3.8-6.5). By age 16 months, the PTH was elevated at 126 pg/ml. Biopsies of the skin lesions demonstrated osteoma cutis consistent with POH. GNAS analysis revealed a heterozygous deletion in exon 7. The mutation was not detected in either parent.
POH and PHP Ia are rare genetic disorders caused by loss of function mutations of the GNAS gene. POH and PHP Ia do not commonly occur in the same individual as they are associated with paternal versus maternal inheritance (imprinting) of an affected GNAS gene. Our patient has evidence of both severe POH and PHP Ia, apparently due to a de novo mutation in GNAS.
31) J Pediatr Orthop B. 2014 Sep;23(5):477-84. doi: 10.1097/BPB.0000000000000045.
Endochondral ossification in a case of progressive osseous heteroplasia in a young female child.Schrander DE1, Welting TJ, Caron MM, Schrander JJ, van Rhijn LW, Körver-Keularts I, Schrander-Stumpel CT.Departments of aOrthopedics bPediatrics cClinical Genetics, Maastricht Universitair Medisch Centrum+, Maastricht University dGROW School for Oncology and Developmental Biology, Maastricht University eCAPHRI School for Public Health and Primary Care, Maastricht University Medical Center, Maastricht, The Netherlands.
Progressive osseous heteroplasia (POH) (OMIM 166350) is a rare autosomal dominant condition, characterized by heterotopic ossification of the skin, subcutaneous fat, and deep connective tissue. This condition is distinct from Albright’s hereditary osteodystrophy or McCune Albright syndrome (OMIM 103580) and fibrodysplasia ossificans progressiva (OMIM 135100). We present an unusual presentation of POH in a 7-year-old female child. The clinical features included a painful swelling on the left foot, with mechanical complaints. There was no congenital hallux valgus. Family anamnesis was positive in the father. There were subcutaneous ossifications of his left upper arm, right-sided thorax, and lateral side of the right ankle. The father did not allow any radiographs or further examinations. Radiographic examination of the patient revealed ossified subcutaneous plaques on the left foot, lumbar spine, and left scapulae. Additional blood samples were analyzed, revealing no pseudohypoparathyroidism. Sequence analysis of the gene associated with POH, the GNAS1 gene, revealed the heterozygote mutation c.565_568del, previously found in Albright’s hereditary osteodystrophy. Histopathological examination of the subcutaneous ossification showed presence of chondrocyte clusters, a feature usually found in fibrodysplasia ossificans progressiva. The combination of the clinical features, the absence of pseudohypoparathyroidism, histology revealing chondrocyte clusters, and the specific GNAS mutation in this patient makes this a truly unusual presentation of POH. The findings in the described case might denote subdivisions of POH. The condition is associated with progressive superficial to deep ossification, progressive restriction of range of motion, and recurrence if excised. We hope to inform pediatricians and orthopedic surgeons to create more awareness of this disorder so that unnecessary treatments can be avoided and proper counseling offered.
32) Nat Med. 2013 Nov;19(11):1505-12. doi: 10.1038/nm.3314. Epub 2013 Sep 29.
Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification.Regard JB1, Malhotra D, Gvozdenovic-Jeremic J, Josey M, Chen M, Weinstein LS, Lu J, Shore EM, Kaplan FS, Yang Y.1] National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. .
Heterotopic ossification, the pathologic formation of extraskeletal bone, occurs as a common complication of trauma or in genetic disorders and can be disabling and lethal. However, the underlying molecular mechanisms are largely unknown. Here we demonstrate that Gαs restricts bone formation to the skeleton by inhibiting Hedgehog signaling in mesenchymal progenitor cells. In progressive osseous heteroplasia, a human disease caused by null mutations in GNAS, which encodes Gαs, Hedgehog signaling is upregulated in ectopic osteoblasts and progenitor cells. In animal models, we show that genetically-mediated ectopic Hedgehog signaling is sufficient to induce heterotopic ossification, whereas inhibition of this signaling pathway by genetic or pharmacological means strongly reduces the severity of this condition. As our previous work has shown that GNAS gain-of-function mutations upregulate WNT-β-catenin signaling in osteoblast progenitor cells, resulting in their defective differentiation and fibrous dysplasia, we identify Gαs as a key regulator of proper osteoblast differentiation through its maintenance of a balance between the Wnt-β-catenin and Hedgehog pathways. Also, given the results here of the pharmacological studies in our mouse model, we propose that Hedgehog inhibitors currently used in the clinic for other conditions, such as cancer, may possibly be repurposed for treating heterotopic ossification and other diseases caused by GNAS inactivation.
Comment in: Bone: Hedgehog signalling linked to heterotopic ossification in POH. [Nat Rev Rheumatol. 2013]
33) J Clin Endocrinol Metab. 2013 Sep;98(9):E1549-56. doi: 10.1210/jc.2013-1667. Epub 2013 Jul 24.
Paternal GNAS mutations lead to severe intrauterine growth retardation (IUGR) and provide evidence for a role of XLαs in fetal development.Richard N1, Molin A, Coudray N, Rault-Guillaume P, Jüppner H, Kottler ML.Centre Hospitalier Universitaire de Caen, Department of Genetics, Reference Centre for Rare Disorders of Calcium and Phosphorus Metabolism, F-14000 Caen, France.
Heterozygous GNAS inactivating mutations cause pseudohypoparathyroidism type Ia (PHP-Ia) when maternally inherited and pseudopseudohypoparathyroidism (PPHP)/progressive osseous heteroplasia (POH) when paternally inherited. Recent studies have suggested that mutations on the paternal, but not the maternal, GNAS allele could be associated with intrauterine growth retardation (IUGR) and thus small size for gestational age.
The aim of the study was to confirm and expand these findings in a large number of patients presenting with either PHP-Ia or PPHP/POH.
PATIENTS AND METHODS:
We collected birth parameters (ie, gestational age, weight, length, and head circumference) of patients with either PHP-Ia (n = 29) or PPHP/POH (n = 26) with verified GNAS mutations. The parental allele carrying the mutation was assessed by investigating the parents or, when a de novo mutation was identified, through informative intragenic polymorphisms.
Heterozygous GNAS mutations on either parental allele were associated with IUGR. However, when these mutations are located on the paternal GNAS allele, IUGR was considerably more pronounced than with mutations on the maternal allele. Moreover, birth weights were lower with paternal GNAS mutations affecting exons 2-13 than with exon 1/intron 1 mutations.
These data indicate that a paternally derived GNAS transcript, possibly XLαs, is required for normal fetal growth and development and that this transcript affects placental functions. Thus, similar to other imprinted genes, GNAS controls growth and/or fetal development.
34) J Clin Invest. 2013 Aug;123(8):3624-33. doi: 10.1172/JCI69746. Epub 2013 Jul 25.
Somitic disruption of GNAS in chick embryos mimics progressive osseous heteroplasia.Cairns DM1, Pignolo RJ, Uchimura T, Brennan TA, Lindborg CM, Xu M, Kaplan FS, Shore EM, Zeng L.
Program in Cellular, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts 02111, USA.
Erratum in: J Clin Invest. 2013 Nov;123(11):4981.
Progressive osseous heteroplasia (POH) is a rare developmental disorder of heterotopic ossification (HO) caused by heterozygous inactivating germline mutations in the paternal allele of the GNAS gene. Interestingly, POH lesions have a bewildering mosaic distribution. Using clinical, radiographic, and photographic documentation, we found that most of the 12 individuals studied had a lesional bias toward one side or the other, even showing exclusive sidedness. Most strikingly, all had a dermomyotomal distribution of HO lesions. We hypothesized that somatic mutations in a progenitor cell of somitic origin may act on a background of germline haploinsufficiency to cause loss of heterozygosity at the GNAS locus and lead to the unilateral distribution of POH lesions. Taking advantage of the chick system, we examined our hypothesis by mimicking loss of heterozygosity of GNAS expression using dominant-negative GNAS that was introduced into a subset of chick somites, the progenitors that give rise to dermis and muscle. We observed rapid ectopic cartilage and bone induction at the axial and lateral positions in a unilateral distribution corresponding to the injected somites, which suggests that blocking GNAS activity in a targeted population of progenitor cells can lead to mosaic ectopic ossification reminiscent of that seen in POH.
35) Bone. 2013 Oct;56(2):276-80. doi: 10.1016/j.bone.2013.06.015. Epub 2013 Jun 21.
Screening for GNAS genetic and epigenetic alterations in progressive osseous heteroplasia: first Italian series.Elli FM1, Barbieri AM, Bordogna P, Ferrari P, Bufo R, Ferrante E, Giardino E, Beck-Peccoz P, Spada A, Mantovani G.Department of Clinical Sciences and Community Health, University of Milan, Endocrinology and Diabetology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, via F. Sforza 35, 20122 Milano, Italy.
Progressive osseous heteroplasia (POH) is a rare autosomal dominant disorder of mesenchymal differentiation characterized by progressive heterotopic ossification (HO) of dermis, deep connective tissues and skeletal muscle. Usually, initial bone formation occurs during infancy as primary osteoma cutis (OC) then progressively extending into deep connective tissues and skeletal muscle over childhood. Most cases of POH are caused by paternally inherited inactivating mutations of GNAS gene. Maternally inherited mutations as well as epigenetic defects of the same gene lead to pseudohypoparathyroidism (PHP) and Albright’s hereditary osteodystrophy (AHO). During the last decade, some reports documented the existence of patients with POH showing additional features characteristic of AHO such as short stature and brachydactyly, previously thought to occur only in other GNAS-associated disorders. Thus, POH can now be considered as part of a wide spectrum of ectopic bone formation disorders caused by inactivating GNAS mutations. Here, we report genetic and epigenetic analyses of GNAS locus in 10 patients affected with POH or primary OC, further expanding the spectrum of mutations associated with this rare disease and indicating that, unlike PHP, methylation alterations at the same locus are absent or uncommon in this disorder.
KEYWORDS: GNAS; Heterotopic ossification (HO); Osteoma cutis (OC); Progressive osseous heteroplasia (POH)
36) Horm Metab Res. 2012 Sep;44(10):724-31. doi: 10.1055/s-0032-1321845. Epub 2012 Aug 17.
Different roles of GNAS and cAMP signaling during early and late stages of osteogenic differentiation.Zhang S1, Kaplan FS, Shore EM.Department of Orthopaedic Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-6081, USA.
Progressive osseous heteroplasia (POH) and fibrous dysplasia (FD) are genetic diseases of bone formation at opposite ends of the osteogenic spectrum: imperfect osteogenesis of the skeleton occurs in FD, while heterotopic ossification in skin, subcutaneous fat, and skeletal muscle forms in POH. POH is caused by heterozygous inactivating germline mutations in GNAS, which encodes G-protein subunits regulating the cAMP pathway, while FD is caused by GNAS somatic activating mutations. We used pluripotent mouse ES cells to examine the effects of Gnas dysregulation on osteoblast differentiation. At the earliest stages of osteogenesis, Gnas transcripts Gsα, XLαs and 1A are expressed at low levels and cAMP levels are also low. Inhibition of cAMP signaling (as in POH) by 2′,5′-dideoxyadenosine enhanced osteoblast differentiation while conversely, increased cAMP signaling (as in FD), induced by forskolin, inhibited osteoblast differentiation. Notably, increased cAMP was inhibitory for osteogenesis only at early stages after osteogenic induction. Expression of osteogenic and adipogenic markers showed that increased cAMP enhanced adipogenesis and impaired osteoblast differentiation even in the presence of osteogenic factors, supporting cAMP as a critical regulator of osteoblast and adipocyte lineage commitment. Furthermore, increased cAMP signaling decreased BMP pathway signaling, indicating that G protein-cAMP pathway activation (as in FD) inhibits osteoblast differentiation, at least in part by blocking the BMP-Smad pathway, and suggesting that GNAS inactivation as occurs in POH enhances osteoblast differentiation, at least in part by stimulating BMP signaling. These data support that differences in cAMP levels during early stages of cell differentiation regulate cell fate decisions. Supporting information available online at http:/www.thieme-connect.de/ejournals/toc/hmr.
37) Eur J Med Genet. 2016 May;59(5):290-4. doi: 10.1016/j.ejmg.2016.04.001. Epub 2016 Apr 4.
Progressive osseous heteroplasia is not a Mendelian trait but a type 2 segmental manifestation of GNAS inactivation disorders: A hypothesis.Happle R1.Department of Dermatology, Freiburg University Medical Center, Freiburg, Germany. Electronic address: firstname.lastname@example.org.
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. As a characteristic feature, such type 2 segmental involvement is far more pronounced than the type 1 segmental mosaicism as noted in otherwise healthy individuals. The concept of type 2 segmental mosaicism has been proven at the molecular level in six human traits including neurofibromatosis 1, Hailey-Hailey disease, and Gorlin syndrome. In POH, molecular proof of principle is so far lacking. The following lines of reasoning, however, support the hypothesis that POH can be explained by a similar mechanism. Firstly, POH has been found to be associated with different phenotypes caused by inactivating GNAS mutations, which is why it cannot be categorized as one distinct Mendelian trait. Secondly, POH occurs as a rather rare complication of these autosomal dominant traits, which is not compatible with the assumption of a separate Mendelian disorder. Thirdly, in a case of plate-like osteoma that represents a more superficial variant of POH, molecular proof of the concept of type 2 segmental manifestation has already been provided, and the available literature suggests that POH can be best explained by a similar mechanism. Moreover, findings obtained in animal experiments support the assumption that human POH represents such superimposed segmental manifestation of GNAS inactivation disorders.
KEYWORDS: Albright hereditary osteodystrophy; Osteoma cutis; Progressive osseous heteroplasia; Pseudohypoparathyroidism; Type 2 segmental manifestation of autosomal dominant disorders
38) Ann Endocrinol (Paris). 2015 May;76(2):105-9. doi: 10.1016/j.ando.2015.03.010. Epub 2015 May 4.
[Paternal GNAS mutations: Which phenotypes? What genetic counseling?].[Article in French]Kottler ML1.Department of Genetics, Reference centre for rare disease of calcium and phosphorus metabolism, Caen University Hospital, 14033 Caen, France. Electronic address: Kottleremail@example.com.
Parental imprinting and the type of the genetic alteration play a determinant role in the phenotype expression of GNAS locus associated to pseudohypoparathyroidism (PHP). GNAS locus gives rise to several different messenger RNA transcripts that are derived from the paternal allele, the maternal allele, or both and can be either coding or non-coding. As a consequence, GNAS mutations lead to a wide spectrum of phenotypes. An alteration in the coding sequence of the gene leads to a haplo-insufficiency and a dysmorphic phenotype (Albright’s syndrome or AHO). AHO is a clinical syndrome defined by specific physical features including short stature, obesity, round-shaped face, subcutaneous ossifications, brachymetarcapy (mainly of the 4th and 5th ray). If the alteration is on the maternal allele, there is a hormonal resistance to the PTH at the kidney level and to the TSH at the thyroid level. The phenotype is known as pseudohypoparathyroidism type 1a (PHP1a). If the alteration is on the paternal allele, there are few clinical signs with no hormonal resistance and the phenotype is known as pseudopseudo hypoparathyroidism (pseudo-PPHP). Heterozygous GNAS mutations on the paternal GNAS allele were associated with intra uterin growth retardation (IUGR). Moreover, birth weights were lower with paternal GNAS mutations affecting exon 2-13 than with exon 1/intron 1 mutations suggesting a role for loss of function XLαs. Progressive osseous heteroplasia (POH) is a rare disease of ectopic bone formation, characterized by cutaneous and subcutaneous ossifications progressing towards deep connective and muscular tissues. POH is caused by a heterozygous GNAS inactivating mutation and has been associated with paternal inheritance. However, genotype/phenotype correlations suggest that there is no direct correlation between the ossifying process and parental origin, as there is high variability in heterotopic ossification. Clinical heterogeneity makes genetic counseling a very delicate matter, specifically where paternal inheritance is concerned as it can lead either to a mild expression of pseudo-PHP or to a severe one of POH.
KEYWORDS: Albright hereditary osteodystrophy; Empreinte parentale; Hétéroplasie progressive osseuse; Imprinting; Intra uterin growth retardation; Ostéodystrophie héréditaire d’Albright; Progressive osseous heteroplasia; Pseudo-pseudohypoparathyroidism; Pseudo-pseudohypoparathyroïdie; Pseudohypoparathyroidism 1a; Pseudohypoparathyroïdie 1a; Retard de croissance intra-utérin.
39) J Pediatr Endocrinol Metab. 2015 Jul;28(7-8):911-8. doi: 10.1515/jpem-2014-0435.
Progressive osseous heteroplasia, as an isolated entity or overlapping with Albright hereditary osteodystrophy.Lin MH, Numbenjapon N, Germain-Lee EL, Pitukcheewanont P.
Progressive osseous heteroplasia (POH) is a condition of invasive heterotopic ossification. Reports of patients with mild POH with Albright hereditary osteodystrophy (AHO), specifically pseudohypoparathyroidism type Ia (PHP Ia) with hormonal resistance, suggest the possibility of a common molecular basis. GNAS has been implicated to account for overlapping features of POH and PHP Ia. Case 1: A 4-year-old boy with obesity, speech delay, and expanding subcutaneous masses on buttock/forearm. Physical exam revealed round facies and brachydactyly. Blood tests showed normal Ca, P, Mg, 25-OH vitamin D levels but elevated parathyroid hormone (PTH) and thyroid-stimulating hormone (TSH). Abdominal computed tomography (CT) showed areas with calcifications in the subcutaneous tissue, fat, and muscle. Pathology of excised tissue revealed ossifications. Genomic study revealed no GNAS mutation. He had POH and PHP Ia. Case 2: A 3-year-old boy with painful ossifications in the left lower extremity. Lab tests were notable for elevated PTH and high-normal TSH. The CT-scan showed subcutaneous/intramuscular calcifications. Genetic testing showed GNAS mutation in exon 12 [c.1024C>T (R342X)]. Patient had POH and PHP Ia. Case 3: A 9-year-old boy with knee pain and subcutaneous ossifications in back and upper/lower extremity, causing significantly limited joint mobility. Lab tests were normal. The CT-scan showed areas corresponding to subcutaneous/intramuscular ossifications throughout torso and extremities, consistent with POH. There was no GNAS mutation.
Patients with heterotopic ossifications present with a wide spectrum of disease. Although GNAS-based mutations have been postulated to account for overlapping features of AHO and POH, normal DNA studies in certain patients with POH/AHO suggest that there may exist other molecular/epigenetic mechanisms explaining their overlapping features.
40) Appl Clin Genet. 2015 Jan 30;8:37-48. doi: 10.2147/TACG.S51064. eCollection 2015.
Progressive osseous heteroplasia: diagnosis, treatment, and prognosis.Pignolo RJ1, Ramaswamy G2, Fong JT2, Shore EM3, Kaplan FS1.1-Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA ; Department of Orthopaedic Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA ; The Center for Research in FOP and Related Disorders, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
- 2-Department of Orthopaedic Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA ; The Center for Research in FOP and Related Disorders, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
- 3-Department of Orthopaedic Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA ; The Center for Research in FOP and Related Disorders, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA ; Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
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.
41) Hum Mutat. 2015 Jan;36(1):11-9. doi: 10.1002/humu.22696. Epub 2014 Nov 28.
GNAS mutations in Pseudohypoparathyroidism type 1a and related disorders.Lemos MC1, Thakker RV.CICS-UBI, Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Covilhã 6200-506, Portugal.
Pseudohypoparathyroidism type 1a (PHP1a) is characterized by hypocalcaemia and hyperphosphatemia due to parathyroid hormone resistance, in association with the features of Albright’s hereditary osteodystrophy (AHO). PHP1a is caused by maternally inherited inactivating mutations of Gs-alpha, which is encoded by a complex imprinted locus termed GNAS. Paternally inherited mutations can lead either to pseudopseudohypoparathyroidism (PPHP) characterized by AHO alone, or to progressive osseous heteroplasia (POH), characterized by severe heterotopic ossification. The clinical aspects and molecular genetics of PHP1a and its related disorders are reviewed together with the 343 kindreds with Gs-alpha germline mutations reported so far in the literature. These 343 (176 different) mutations are scattered throughout the 13 exons that encode Gs-alpha and consist of 44.9% frameshift, 28.0% missense, 14.0% nonsense, and 9.0% splice-site mutations, 3.2% in-frame deletions or insertions, and 0.9% whole or partial gene deletions. Frameshift and other highly disruptive mutations were more frequent in the reported 37 POH kindreds than in PHP1a/PPHP kindreds (97.3% vs. 68.7%, P < 0.0001). This mutation update and respective genotype-phenotype data may be of use for diagnostic and research purposes and contribute to a better understanding of these complex disorders.
42) Orthopedics. 2014 May;37(5):329-40. doi: 10.3928/01477447-20140430-07.
Evaluation of the cellular origins of heterotopic ossification.Kan L, Kessler JA.
Heterotopic ossification (HO), acquired or hereditary, is featured by the formation of bone outside of the normal skeleton. Typical acquired HO is a common, debilitating condition associated with traumatic events. Cardiovascular calcification, an atypical form of acquired HO, is prevalent and associated with high rates of cardiovascular mortality. Hereditary HO syndromes, such as fibrodysplasia ossificans progressiva and progressive osseous heteroplasia, are rare, progressive, life-threatening disorders. The cellular origins of HO remain elusive. Some bona fide contributing cell populations have been found through genetic lineage tracing and other experiments in vivo, and various other candidate populations have been proposed. Nevertheless, because of the difficulties in establishing cellular phenotypes in vivo and other confounding factors, the true identities of these populations are still uncertain. This review critically evaluates the accumulating data in the field. The major focus is on the candidate populations that may give rise to osteochondrogenic lineage cells directly, not the populations that may contribute to HO indirectly. This issue is important not solely because of the clinical implications, but also because it highlights the basic biological processes that govern bone formation.
43) Disorders of GNAS Inactivation.
Haldeman-Englert CR1, Hurst ACE2, Levine MA3.
In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors.
GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.
2017 Oct 26.
1 Fullerton Genetics Center, Asheville, North Carolina
2 Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama
- 3 Department of Pediatrics, Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
Disorders of GNAS inactivation include the phenotypes pseudohypoparathyroidism Ia, Ib, and Ic (PHP-Ia, -Ib, -Ic), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). PHP-Ia and PHP-Ic are characterized by: End-organ resistance to endocrine hormones including parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), gonadotropins (LH and FSH), growth hormone-releasing hormone (GHRH), and CNS neurotransmitters (leading to obesity and variable degrees of intellectual disability and developmental delay); and The Albright hereditary osteodystrophy (AHO) phenotype (short stature, round facies, and subcutaneous ossifications) and brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb). Although PHP-Ib is characterized principally by PTH resistance, some individuals also have partial TSH resistance and mild features of AHO (e.g., brachydactyly). PPHP, a more limited form of PHP-Ia, is characterized by various manifestations of the AHO phenotype without the hormone resistance or obesity. POH and OC are even more restricted variants of PPHP: POH consists of dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia. OC consists of extra-skeletal ossification that is limited to the dermis and subcutaneous tissues.
The diagnosis of a disorder of GNAS inactivation is established in a proband with all or some of the characteristic clinical and endocrine findings and evidence on molecular genetic testing of a genetic or epigenetic alteration resulting in lack of expression/function of the GNAS complex locus. PHP-Ia,.-Ib, and -Ic are associated with reduced or absent expression/function of the protein Gsα (encoded by the maternal GNAS complex locus) due to one of the following: An inactivating GNAS pathogenic variant. A genetic alteration in the imprinting regulatory elements in the GNAS complex locus or the nearby gene, STX16, that prevents proper maternal imprint of the GNAS complex locus. Isolated epimutations. Paternal 20q disomy. PPHP and POH/OC phenotypes are associated with lack of expression/function of Gsα encoded by the paternal GNAS allele due to an inactivating GNAS pathogenic variant; the POH/OC phenotypes are also associated with lack of expression/function of Gsα (encoded by the maternal GNAS allele) as a result of an inactivating GNAS pathogenic variant.
Treatment of manifestations: Deficiencies of parathyroid hormone, thyroid hormone, and gonadotropins due to hormone resistance are treated in a standard manner. Growth hormone replacement therapy should be considered if screening for growth hormone deficiency with appropriate provocative testing is abnormal. Subcutaneous ossifications that are superficial and well circumscribed may be surgically removed when they are large or cause local irritation, although they may recur. Obesity tends to be the most difficult manifestation to treat as individuals with PHP-Ia and PHP-Ic have decreased resting energy expenditure and hyperphagia; thus, the usual recommendation of reduced caloric intake and increased physical activity may be less successful than in persons with obesity from other causes. Surveillance: Routine monitoring of: Endocrine function: measurement of serum concentration of PTH, calcium and phosphate, TSH and free T4, and urinary calcium excretion; Growth velocity and growth hormone status (serum IGF1 and/or stimulated growth hormone testing); New and/or enlarging ectopic ossifications; Development of and/or progression of cataracts; and Psychoeducational needs regarding school assistance / educational support and developmental therapies (e.g., physical, occupational, and speech therapy). Agents/circumstances to avoid: Limit dietary intake of phosphorus (dairy products and meats) in persons with persistently elevated serum levels of phosphate. Evaluation of relatives at risk: It is appropriate to evaluate apparently asymptomatic first-degree relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment. Pregnancy management: For women with a disorder of GNAS inactivation that affects the maternal allele: Monitoring of serum concentration of calcium and thyroid studies (TSH, free T4) throughout pregnancy, labor, and the postpartum period and supplementation of calcium, vitamin D, and thyroid hormone as needed.
Disorders of GNAS inactivation are inherited in an autosomal dominant manner with the specific phenotype determined by the parental origin of the defective allele. Of individuals with a disorder of GNAS inactivation, approximately 38% have an affected parent and 38% have a de novo GNAS pathogenic variant; in the remaining approximately 25% the cause is unknown. Each child of an individual with a disorder of GNAS inactivation has a 50% chance of inheriting the parent’s genetic alteration (except for simplex cases with PHP-1b for whom the mode of inheritance is not well established). If the maternal GNAS complex locus is affected, her offspring are at risk for PHP-Ia, PHP-Ib (when associated with deletions at the imprinting regulatory elements), or PHP-Ic; if the paternal allele has an inactivating GNAS pathogenic variant, his offspring are at risk for PPHP or POH/OC. If the genetic alteration in the GNAS complex locus or the GNAS pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are technically possible.
44) Bone. 2018 Apr;109:80-85. doi: 10.1016/j.bone.2017.09.002. Epub 2017 Sep 6.
GNAS mutations and heterotopic ossification.Bastepe M1.Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, United States. Electronic address: firstname.lastname@example.org.
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. Inactivating mutations in Gsα-coding GNAS exons are responsible for Albright’s hereditary osteodystrophy (AHO), which refers to a constellation of physical and developmental disorders including obesity, short stature, brachydactyly, cognitive impairment, and heterotopic ossification. Patients with Gsα mutations can present with AHO in the presence or absence of end-organ resistance to multiple hormones including parathyroid hormone. Maternal Gsα mutations lead to AHO with hormone resistance (i.e. pseudohypoparathyroidism type-Ia), whereas paternal mutations cause AHO alone (i.e. pseudo-pseudohypoparathyroidism). Heterotopic ossification associated with AHO develops through intramembranous bone formation and is limited to dermis and subcutis. In rare cases carrying Gsα mutations, however, ossifications progress into deep connective tissue and skeletal muscle, a disorder termed progressive osseous heteroplasia (POH). Here I briefly review the genetic, clinical, and molecular aspects of these disorders caused by inactivating GNAS mutations, with particular emphasis on heterotopic ossification.
45) Arch Bone Jt Surg. 2016 Jun;4(3):285-8.
Total Ankylosis of the Upper Left Limb: A Case of Progressive Osseous Heteroplasia.Birjandinejad A1, Taraz-Jamshidi MH1, Hosseinian SH1.Orthopedic Research Center, Shahid Kamyab Hospital, Nakhrisi Junc, Fadaeian Islam St, Mashhad, Iran.
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. Absence of great toe malformation, presence of cutaneous ossification, dermal bone spicules extruding in fingers, and involvement of just left upper limb were unique findings in contrast with FOP diagnosis in this case. There is no effective treatment or prevention for POH. Awareness of diagnostic features is necessary in early diagnosis of POH.
46) Exp Clin Endocrinol Diabetes. 2019 Sep 23. doi: 10.1055/a-1001-3575. [Epub ahead of print]
Clinical and Molecular Characteristics of GNAS Inactivation Disorders Observed in 18 Korean Patients.Han SR1, Lee YA1, Shin CH1, Yang SW1, Lim BC1, Cho TJ2, Ko JM1.
1 Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children’s Hospital, Seoul, Korea.
2 Department of Orthopaedics, Seoul National University College of Medicine, Seoul National University Children’s Hospital, Seoul, Korea.
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.
This study analyzed the clinical characteristics and molecular genetic backgrounds of 18 Korean patients from 16 families with a genetically confirmed GNAS defect. Auxological parameters, AHO phenotypes, types of hormonal resistance, family history, and molecular genetic disturbances were reviewed retrospectively.
Nine (90%) patients with PHP1A showed resistance to parathyroid hormone (PTH) and all patients showed elevated thyroid-stimulating hormone (TSH) levels at diagnosis. Eight (80%) patients were managed with levothyroxine supplementation. Three of six patients with PHP1B had elevated TSH levels, but none of whom needed levothyroxine medication. AHO features were absent in PHP1B. Patients with PPHP and POH did not show any hormone resistance, and both of them were born as small for gestational age. Among the 11 families with PHP1A, PPHP, and POH, eight different (three novel) mutations in the GNAS gene were identified. Among the six patients with PHP1B, two were sporadic cases and four showed isolated loss of methylation at GNAS A/B:TSS-DMR.
Clinical and molecular characteristics of Korean patients with GNAS inactivation disorders were described in this study. Also, we reaffirmed heterogeneity of PHP, contributing to further accumulation and expansion of current knowledge of this complex disease.
47) Int J Surg Pathol. 2019 Jun 28:1066896919857135. doi: 10.1177/1066896919857135. [Epub ahead of print]
Differential Vascularity in Genetic and Nonhereditary Heterotopic Ossification.Ware AD1, Brewer N2, Meyers C1, Morris C1, McCarthy E1, Shore EM2, James AW1.
1 Johns Hopkins University, Baltimore, MD, USA.
2 University of Pennsylvania, Philadelphia, PA, USA.
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. Results. Results demonstrated conserved temporal dynamic changes in vascularity across all heterotopic ossification lesions. Immature areas had the highest BV number, while the more mature foci had the highest BV area. Most vascular parameters were significantly increased in genetic as compared with NHO. Discussion. In sum, both genetic and NHO show temporospatial variation in vascularity. These findings suggest that angiogenic pathways are potential therapeutic targets in both genetic and nonhereditary forms of heterotopic ossification.
KEYWORDS: angiogenesis; fibrodysplasia ossificans progressive; heterotopic bone; heterotopic ossification; progressive heterotopic ossification.
48) Best Pract Res Clin Endocrinol Metab. 2018 Dec;32(6):941-954. doi: 10.1016/j.beem.2018.09.008. Epub 2018 Sep 28.
Parathyroid hormone resistance syndromes – Inactivating PTH/PTHrP signaling disorders (iPPSDs).Elli FM1, Pereda A2, Linglart A3, Perez de Nanclares G4, Mantovani G5.
1 Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. Electronic address: email@example.com.
2 Molecular (Epi)Genetics Laboratory, BioAraba National Health Institute, OSI Araba University Hospital, Vitoria-Gasteiz, Spain. Electronic address: firstname.lastname@example.org.
3 APHP, Department of Paediatric Endocrinology and Diabetes for Children, Bicêtre Paris-Sud Hospital, Le Kremlin-Bicêtre, France; APHP, Reference Center for Rare Disorders of Calcium and Phosphate Metabolism, Filière OSCAR and Plateforme d’Expertise Maladies Rares Paris-Sud, Bicêtre Paris-Sud Hospital, Le Kremlin Bicêtre, France. Electronic address: email@example.com.
4 Molecular (Epi)Genetics Laboratory, BioAraba National Health Institute, OSI Araba University Hospital, Vitoria-Gasteiz, Spain. Electronic address: firstname.lastname@example.org.
- 5 Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. Electronic address: email@example.com.
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). This review will focus on the pathophysiology, clinical and molecular aspects of these rare, heterogeneous but closely related diseases.
KEYWORDS: GNAS; PDE3A; PDE4D; PRKAR1A; inactivating PTH/PTHrP signaling disorders (iPPSD); pseudohypoparathyroidism (PHP)
49) Bone Res. 2018 Nov 20;6:33. doi: 10.1038/s41413-018-0034-7. eCollection 2018.
Gαs signaling controls intramembranous ossification during cranial bone development by regulating both Hedgehog and Wnt/β-catenin signaling.Xu R1,2, Khan SK1, Zhou T1,3, Gao B1,4, Zhou Y1, Zhou X2, Yang Y1.
1 Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA USA.
2 State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Cariology and Endodontology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
3 Department of Orthopaedic Surgery, Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
- 4 Department of Spine Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
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. We find here that, while Hh ligand-dependent Hh signaling is essential for endochondral ossification, it is dispensable for intramembranous ossification, where Gαs regulates Hh signaling in a ligand-independent manner. We further show that Gαs controls intramembranous ossification by regulating both Hh and Wnt/β-catenin signaling. In addition, Gαs activation in the developing cranial bone leads to reduced ossification but increased cartilage presence due to reduced cartilage dissolution, not cell fate switch. Small molecule inhibitors of Hh and Wnt signaling can effectively ameliorate cranial bone phenotypes in mice caused by loss or gain of Gnas function mutations, respectively. Our work shows that studies of genetic diseases provide invaluable insights in both pathological bone defects and normal bone development, understanding both leads to better diagnosis and therapeutic treatment of bone diseases.
50) Nat Rev Endocrinol. 2018 Aug;14(8):476-500. doi: 10.1038/s41574-018-0042-0.
Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement.Mantovani G1, Bastepe M2, Monk D3, de Sanctis L4, Thiele S5, Usardi A6,7, Ahmed SF8, Bufo R9, Choplin T10, De Filippo G11, Devernois G10, Eggermann T12, Elli FM1, Freson K13, García Ramirez A14, Germain-Lee EL15,16, Groussin L17,18, Hamdy N19, Hanna P20, Hiort O5, Jüppner H2, Kamenický P6,21,22, Knight N23, Kottler ML24,25, Le Norcy E18,26, Lecumberri B27,28,29, Levine MA30, Mäkitie O31, Martin R32, Martos-Moreno GÁ33,34,35, Minagawa M36, Murray P37, Pereda A38, Pignolo R39, Rejnmark L40, Rodado R14, Rothenbuhler A6,7, Saraff V41, Shoemaker AH42, Shore EM43, Silve C44, Turan S45, Woods P23, Zillikens MC46, Perez de Nanclares G47, Linglart A48,49,50.
1 Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
- 2 Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- 3 Imprinting and Cancer Group, Cancer Epigenetic and Biology Program (PEBC), Institut d’Investigació Biomedica de Bellvitge (IDIBELL), Barcelona, Spain.
- 4 Pediatric Endocrinology Unit, Department of Public Health and Pediatric Sciences, University of Torino, Turin, Italy.
- 5 Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of Lübeck, Lübeck, Germany.
- 6 APHP, Reference Center for Rare Disorders of Calcium and Phosphate Metabolism, Platform of Expertise Paris-Sud for Rare Diseases and Filière OSCAR, Bicêtre Paris Sud Hospital (HUPS), Le Kremlin-Bicêtre, France.
- 7 APHP, Endocrinology and diabetes for children, Bicêtre Paris Sud Hospital (HUPS), Le Kremlin-Bicêtre, France.
- 8 Developmental Endocrinology Research Group, School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, UK.
- 9 IPOHA, Italian Progressive Osseous Heteroplasia Association, Cerignola, Foggia, Italy.
- 10 K20, French PHP and related disorders patient association, Jouars Pontchartrain, France.
- 11 APHP, Department of medicine for adolescents, Bicêtre Paris Sud Hospital (HUPS), Le Kremlin-Bicêtre, France.
- 12 Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany.
- 13 Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, Gasthuisberg, University of Leuven, Leuven, Belgium.
- 14 AEPHP, Spanish PHP and related disorders patient association, Huércal-Overa, Almería, Spain.
- 15 Albright Center & Center for Rare Bone Disorders, Division of Pediatric Endocrinology & Diabetes, Connecticut Children’s Medical Center, Farmington, CT, USA.
- 16 Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT, USA.
- 17 APHP, Department of Endocrinology, Cochin Hospital (HUPC), Paris, France.
- 18 University of Paris Descartes, Sorbonne Paris Cité, Paris, France.
- 19 Department of Medicine, Division of Endocrinology and Centre for Bone Quality, Leiden University Medical Center, Leiden, Netherlands.
- 20 INSERM U1169, Bicêtre Paris Sud, Paris Sud – Paris Saclay University, Le Kremlin-Bicêtre, France.
- 21 APHP, Department of Endocrinology and Reproductive Diseases, Bicêtre Paris Sud Hospital (HUPS), Le Kremlin-Bicêtre, France.
- 22 INSERM U1185, Paris Sud – Paris Saclay University, Le Kremlin-Bicêtre, France.
- 23 UK acrodysostosis patients’ group, London, UK.
- 24 Department of Genetics, Reference Centre for Rare Disorders of Calcium and Phosphate Metabolism, Caen University Hospital, Caen, France.
- 25 BIOTARGEN, UNICAEN, Normandie University, Caen, France.
- 26 APHP, Department of Odontology, Bretonneau Hospital (PNVS), Paris, France.
- 27 Department of Endocrinology and Nutrition, La Paz University Hospital, Madrid, Spain.
- 28 Department of Medicine, Autonomous University of Madrid (UAM), Madrid, Spain.
- 29 Endocrine Diseases Research Group, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain.
- 30 Division of Endocrinology and Diabetes and Center for Bone Health, Children’s Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
- 31 Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
- 32 Osteometabolic Disorders Unit, Hormone and Molecular Genetics Laboratory (LIM/42), Endocrinology Division, Hospital das Clínicas HCFMUSP, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil.
- 33 Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, CIBERobn, ISCIII, Madrid, Spain.
- 34 Department of Pediatrics, Autonomous University of Madrid (UAM), Madrid, Spain.
- 35 Endocrine Diseases Research Group, Hospital La Princesa Institute for Health Research (IIS La Princesa), Madrid, Spain.
- 36 Division of Endocrinology, Chiba Children’s Hospital, Chiba, Japan.
- 37 Department of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
- 38 Molecular (Epi)Genetics Laboratory, BioAraba National Health Institute, Hospital Universitario Araba-Txagorritxu, Vitoria-Gasteiz, Alava, Spain.
- 39 Department of Medicine, Mayo Clinic, Rochester, MN, USA.
- 40 Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
- 41 Department of Endocrinology and Diabetes, Birmingham Children’s Hospital, Birmingham, UK.
- 42 Pediatric Endocrinology and Diabetes, Vanderbilt University Medical Center, Nashville, TN, USA.
- 43 Departments of Orthopaedic Surgery and Genetics, Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- 44 APHP, Service de Biochimie et Génétique Moléculaires, Hôpital Cochin, Paris, France.
- 45 Department of Pediatrics, Division of Endocrinology and Diabetes, Marmara University, Istanbul, Turkey.
- 46 Department of Internal Medicine, Bone Center Erasmus MC – University Medical Center Rotterdam, Rotterdam, Netherlands.
- 47 Molecular (Epi)Genetics Laboratory, BioAraba National Health Institute, Hospital Universitario Araba-Txagorritxu, Vitoria-Gasteiz, Alava, Spain. firstname.lastname@example.org.
- 48 APHP, Reference Center for Rare Disorders of Calcium and Phosphate Metabolism, Platform of Expertise Paris-Sud for Rare Diseases and Filière OSCAR, Bicêtre Paris Sud Hospital (HUPS), Le Kremlin-Bicêtre, France. email@example.com.
- 49 APHP, Endocrinology and diabetes for children, Bicêtre Paris Sud Hospital (HUPS), Le Kremlin-Bicêtre, France. firstname.lastname@example.org.
- 50 INSERM U1169, Bicêtre Paris Sud, Paris Sud – Paris Saclay University, Le Kremlin-Bicêtre, France. email@example.com.
This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders.
51) Curr Opin Pharmacol. 2018 Jun;40:51-58. doi: 10.1016/j.coph.2018.03.007. Epub 2018 Mar 31.
Acquired and congenital forms of heterotopic ossification: new pathogenic insights and therapeutic opportunities.Pacifici M1.Translational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: Pacificim@email.chop.edu.
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. Recent studies have provided novel insights into the pathogenesis of acquired and genetic forms of HO and have used the information to conceive and test new and more specific therapies in animal models. In this review, I provide salient examples of these exciting and promising advances that are undoubtedly paving the way toward resolution of this debilitating and at times fatal disease.