Fibrous dysplasia of bone: craniofacial and dental implications

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Abstract

<p class="first" id="P1">Fibrous dysplasia (FD) is a rare bone disease caused by postzygotic somatic activating mutations in the <i>GNAS</i> gene, which lead to constitutive activation of adenylyl cyclase, and elevated levels of cyclic AMP, which act on downstream signaling pathways, and cause normal bone to be replaced with fibrous tissue and abnormal (woven) bone. The bone disease may occur in one bone (monostotic), multiple bones (polyostotic), or in combination with hyperfunctioning endocrinopathies and hyperpigmented skin lesions (in the setting of McCune-Albright Syndrome). FD is common in the craniofacial skeleton, causing significant dysmorphic features, bone pain, and dental anomalies. This review summarizes the pathophysiology, clinical findings and treatment of FD, with an emphasis on the craniofacial and oral manifestations of the disease. </p>

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FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting.

Mara Riminucci, Michael T Collins, Neal Fedarko … (2003)

FGF-23, a novel member of the FGF family, is the product of the gene mutated in autosomal dominant hypophosphatemic rickets (ADHR). FGF-23 has been proposed as a circulating factor causing renal phosphate wasting not only in ADHR (as a result of inadequate degradation), but also in tumor-induced osteomalacia (as a result of excess synthesis by tumor cells). Renal phosphate wasting occurs in approximately 50% of patients with McCune-Albright syndrome (MAS) and fibrous dysplasia of bone (FD), which result from postzygotic mutations of the GNAS1 gene. We found that FGF-23 is produced by normal and FD osteoprogenitors and bone-forming cells in vivo and in vitro. In situ hybridization analysis of FGF-23 mRNA expression identified "fibrous" cells, osteogenic cells, and cells associated with microvascular walls as specific cellular sources of FGF-23 in FD. Serum levels of FGF-23 were increased in FD/MAS patients compared with normal age-matched controls and significantly higher in FD/MAS patients with renal phosphate wasting compared with those without, and correlated with disease burden bone turnover markers commonly used to assess disease activity. Production of FGF-23 by FD tissue may play an important role in the renal phosphate-wasting syndrome associated with FD/MAS.

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Denosumab treatment for fibrous dysplasia.

Alfredo Molinolo, Carol Bassim, Dan Chamberlain … (2012)

Fibrous dysplasia (FD) is a skeletal disease caused by somatic activating mutations of the cyclic adenosine monophosphate (cAMP)-regulating protein, α-subunit of the Gs stimulatory protein (G(s) α). These mutations lead to replacement of normal bone by proliferative osteogenic precursors, resulting in deformity, fracture, and pain. Medical treatment has been ineffective in altering the disease course. Receptor activator of NF-κB ligand (RANKL) is a cell-surface protein involved in many cellular processes, including osteoclastogenesis, and is reported to be overexpressed in FD-like bone cells. Denosumab is a humanized monoclonal antibody to RANKL approved for treatment of osteoporosis and prevention of skeletal-related events from bone metastases. We present the case of a 9-year-old boy with severe FD who was treated with denosumab for a rapidly expanding femoral lesion. Immunohistochemical staining on a pretreatment bone biopsy specimen revealed marked RANKL expression. He was started on monthly denosumab, with an initial starting dose of 1 mg/kg and planned 0.25 mg/kg dose escalations every 3 months. Over 7 months of treatment he showed marked reduction in pain, bone turnover markers (BTMs), and tumor growth rate. Denosumab did not appear to impair healing of a femoral fracture that occurred while on treatment. With initiation of treatment he developed hypophosphatemia and secondary hyperparathyroidism, necessitating supplementation with phosphorus, calcium, and calcitriol. BTMs showed rapid and sustained suppression. With discontinuation there was rapid and dramatic rebound of BTMs with cross-linked C-telopeptide (reflecting osteoclast activity) exceeding pretreatment levels, accompanied by severe hypercalcemia. In this child, denosumab lead to dramatic reduction of FD expansion and FD-related bone pain. Denosumab was associated with clinically significant disturbances of mineral metabolism both while on treatment and after discontinuation. Denosumab treatment of FD warrants further study to confirm efficacy and determine potential morbidity, as well as to determine the mechanism of RANKL in the pathogenesis of FD and related bone marrow stromal cell diseases. Copyright © 2012 American Society for Bone and Mineral Research.

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Minireview: GNAS: normal and abnormal functions.

Ai-min Chen, Roberto Weinstein, Akio Sakamoto … (2004)

GNAS is a complex imprinted gene that uses multiple promoters to generate several gene products, including the G protein alpha-subunit (G(s)alpha) that couples seven-transmembrane receptors to the cAMP-generating enzyme adenylyl cyclase. Somatic activating G(s)alpha mutations, which alter key residues required for the GTPase turn-off reaction, are present in various endocrine tumors and fibrous dysplasia of bone, and in a more widespread distribution in patients with McCune- Albright syndrome. Heterozygous inactivating G(s)alpha mutations lead to Albright hereditary osteodystrophy. G(s)alpha is imprinted in a tissue-specific manner, being primarily expressed from the maternal allele in renal proximal tubules, thyroid, pituitary, and ovary. Maternally inherited mutations lead to Albright hereditary osteodystrophy (AHO) plus PTH, TSH, and gonadotropin resistance (pseudohypoparathyroidism type 1A), whereas paternally inherited mutations lead to AHO alone. Pseudohypoparathyroidism type 1B, in which patients develop PTH resistance without AHO, is almost always associated with a GNAS imprinting defect in which both alleles have a paternal-specific imprinting pattern on both parental alleles. Familial forms of the disease are associated with a mutation within a closely linked gene that deletes a region that is presumably required for establishing the maternal imprint, and therefore maternal inheritance of the mutation results in the GNAS imprinting defect. Imprinting of one differentially methylated region within GNAS is virtually always lost in pseudohypoparathyroidism type 1B, and this region is probably responsible for tissue-specific G(s)alpha imprinting. Mouse knockout models show that G(s)alpha and the alternative G(s)alpha isoform XLalphas that is expressed from the paternal GNAS allele may have opposite effects on energy metabolism in mice.

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Author and article information

Journal

Title: Oral Diseases

Abbreviated Title: Oral Dis

Publisher: Wiley

ISSN: 1354523X

Publication date Created: September 2017

Publication date (Print): September 2017

Publication date (Electronic): September 01 2016

Volume: 23

Issue: 6

Pages: 697-708

Affiliations

[1 ]Section on Skeletal Disorders and Mineral Homeostasis; Craniofacial and Skeletal Diseases Branch; National Institute of Dental and Craniofacial Research; National Institutes of Health; Bethesda MD USA

[2 ]Division of Endocrinology and Diabetes; Children's National Health System; Washington D.C. USA

[3 ]Bone Health Program; Division of Orthopaedics and Sports Medicine; Children's National Health System; Washington D.C. USA