Case Of Progressive Osseous Heteroplasia Research Articles

MON-512 A De Novo Frameshift Mutation of FAM111B Gene Resulting in Progressive Osseous Heteroplasia in an African American Boy: First Case Report

Introduction: Progressive osseous heteroplasia (POH) is a rare bone disorder characterized by heterotopic ossification in the skin and muscles, resulting in contractures of the joints and progressive loss of function. Whereas 60-70% of the POH patients have paternally inherited inactivating mutations in GNAS gene, the remaining 30-40% harbor no specific etiologies. FAM111B gene mutations, located on chromosome 11q12.1, cause POIKTMP (hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis), a rare autosomal dominant disorder with high frequency of de novo missense mutations, which are believed to cause extensive fibrosis and adiposis of many tissues, though the exact mechanism is unknown. To our knowledge there are no reports of FAM111B associated with POH. Case: We describe a 15-year-old African American boy who presented with generalized calcific nodules, contractures, and muscle weakness leading to immobility, beginning at the age of 6 years. Cutaneous exam showed generalized hard nodules varying from small to plaque-like ulcerated erupted skin lesions. Biochemical evaluation revealed 25(OH) vitamin D insufficiency (20 ng/mL), and normal levels of parathyroid hormone, FGF-23, alkaline phosphatase, calcium, and phosphorus. Skeletal survey radiographs showed extensive heterotopic ossification involving soft tissues and muscles surrounding the bilateral humeri, ulnae, femurs, and bilateral tibias/fibulas. Computed tomography of the chest, abdomen, and pelvis showed extensive muscle ossifications involving right latissimus dorsi, left scalene, bilateral pectoralis and external oblique abdominal, right iliacus, bilateral gluteal, left adductor, and left hamstring. There was also an involvement of the subcutaneous tissues of the right upper back and left lower quadrant of the abdomen, left posterior sacral region, bilateral hips, and the fascia superficial to the erector spinae muscles with no abnormal ossifications in the bones. The clinical and radiographic findings were consistent with POH. Whole Exome Sequencing revealed a de novo heterozygous frameshift mutation in FAM111B (OMIM # 615584) of c.1462delT (p.Cys488Valfs*21) variant, causing replacement of C-terminal region with 21 alternative amino acids. Multiple previously reported disease-associated variants appear to localize within the same domain, supporting the functional importance of this region, though none have been previously associated with POH. Thus, we consider this variant to be pathogenic. Conclusion: This is the first case of POH caused by a mutation in FAM111B gene. Whether POH phenotype could be explained by mutations in FAM111B gene traditionally reserved for POIKTMP remains unclear. Further evaluations are necessary to fully elucidate this finding and potential mechanism by which the FAM111B gene mutation contributes to POH.

Progressive osseous heteroplasia: three case reports

Objective To investigate clinicopathological features, diagnosis and treatment of progressive osseous heteroplasia (POH) . Methods Clinicopathological data were collected from 3 cases of POH, and analyzed retrospectively. Related literature was also reviewed. Results All the 3 patients were female, and developed POH within a few days to months after birth. POH clinically manifested as light pink or skin-colored indurated papules, nodules or plaques scattered over the scalp, trunk and extremities without subjective symptoms. Histopathological examination showed that there were flaky bone or bone-like tissues in the middle and lower dermis. Serum levels of calcium, phosphate and parathyroid hormone were normal in the 3 children. Case 1 was treated with oral sodium bicarbonate tablets and surgical resection of skin lesions on the right lower abdomen. During the follow-up for about 7 months, the skin lesions on the right lower abdomen did not recur, while other skin lesions became more bulging, larger and harder, and new skin lesions occurred. Case 2 was treated with topical adapalene gel, and these skin lesions did not increase in number, but became larger and harder. Case 3 received no treatment, and was lost to follow-up. Conclusion POH clinically manifests as indurated maculopapules and plaques progressively affecting deeper skin tissues, and there are no effective therapies or prevention approaches at present. Key words: Bone diseases, developmental; Skin manifestations; Pathologic processes; Diagnosis; Therapy; Progressive osseous heteroplasia

Progressive osseous heteroplasia: diagnosis, treatment, and prognosis

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.

Screening for GNAS genetic and epigenetic alterations in progressive osseous heteroplasia: First Italian series

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.

Patterns of renal distal tubule PTH sensitivity in subtypes of pseudohypoparathyroidim

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.

Progressive osseous heteroplasia in a 10-year-old male child

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.

A case of progressive osseous heteroplasia: a first case in Japan

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.

Fibrodysplasia Ossificans Progressiva and Progressive Osseous Heteroplasia: <I>Two Genetic Disorders of Heterotopic Ossification</I>

Heterotopic ossification (HO) as a primary clinical finding is uncommon, but it occurs in two human genetic disorders: fibrodysplasia ossific, ans progressiva (FOP) and progressive osseous heteroplasia (POH). In these disorders, the progression and stages of the ectopic bone formation appear normal, but disregulation of cell differentiation leads to improper induction of bone formation—in other words, normal bone forms in the wrong place at the wrong time. Cases of POH were initially recognized following misdiagnosis as FOP. However, POH can be distinguished from FOP by several criteria: the presence of cutaneous ossification, the absence of congenital malformations of the skeleton, the absence of inflammatory tumor-like swellings, the asymmetric mosaic distribution of lesions, the absence of predictable regional patterns of HO, and the predominance of intramembranous rather than endochondral ossification. Both FOP and POH are rare conditions, with most cases apparently the result of a de novo (spontaneous) mutation: however, when inherited, both are transmitted through an autosomal-dominant inheritance pattern. Although FOP can be inherited from either a mother or a father, POH is only inheried paternally. Consistent with this parental inheritance pattern, POH patients carry inactivating mutations of the GNAS gene, a gene that is regulated through genomic imprinting and allele-specific gene expression. The genetic cause of FOP remains undetermined. A combination of clinical and genetic evaluations can identify FOP and POH, two distinct disorders of extensive HO.

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.

Progressive osseous heteroplasia

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.

Progressive osseous heteroplasia

The Journal of Bone and Joint Surgery. British volumeVol. 80-B, No. 5 PaediatricFree AccessProgressive osseous heteroplasiaREPORT OF A FAMILYJ. A. Urtizberea, H. Testart, F. Cartault, L. Boccon-Gibod, M. Le Merrer, F. S. KaplanJ. A. UrtizbereaConsultation MyogèneService de Génétique Médicale, Hôpital Necker, 149 rue de Sèvres, 75015 Paris, France.Search for more papers by this author, H. TestartHôpital d’Enfants, 60 rue Bertin, 97400 St Denis de la Réunion, France.Search for more papers by this author, F. CartaultLaboratoire de Génétique, CHD Felix Guyon, 97400 St Denis de la Réunion, France.Search for more papers by this author, L. Boccon-GibodLaboratoire d’Anatomie Pathologique, Hôpital Trousseau, 75012 Paris, France.Search for more papers by this author, M. Le MerrerService de Génétique Médicale, Hôpital Necker, 149 rue de Sèvres, 75015 Paris, France.Search for more papers by this author, F. S. KaplanUniversity of Pennsylvania Medical Centre, 3400 Spruce Street, Silver-stein Two, Philadelphia, Pennsylvania 19104-4283, USA.Search for more papers by this authorPublished Online:1 Sep 1998https://doi.org/10.1302/0301-620X.80B5.0800768AboutSectionsPDF/EPUB ToolsAdd to FavouritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InRedditEmail AbstractWe 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.FiguresReferencesRelatedDetailsCited ByCase Report: Two Monochorionic Twins With a Critically Different Course of Progressive Osseous Heteroplasia23 June 2021 | Frontiers in Pediatrics, Vol. 9Genetic and Acquired Heterotopic Ossification: A Translational Tale of Mice and Men14 December 2020 | Biomedicines, Vol. 8, No. 12Fibrodysplasie ossifiante progressive et hétéroplasie ossifiante progressiveRevue du Rhumatisme Monographies, Vol. 86, No. 1Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement29 June 2018 | Nature Reviews Endocrinology, Vol. 14, No. 8Progressive osseous heteroplasia, as an isolated entity or overlapping with Albright hereditary osteodystrophyJournal of Pediatric Endocrinology and Metabolism, Vol. 28, No. 7-8Progressive Osseous Heteroplasia: A Model for the Imprinting Effects of GNAS Inactivating Mutations in HumansThe Journal of Clinical Endocrinology & Metabolism, Vol. 95, No. 6PProgressive Osseous Heteroplasia. A Case Report and Review of the LiteratureJournal of Pediatric Orthopaedics, Part B, Vol. 11, No. 4 Vol. 80-B, No. 5 Metrics History Published online 1 September 1998 Published in print 1 September 1998 InformationCopyright © 1998, The British Editorial Society of Bone and Joint Surgery: All rights reservedPDF download