Displasia fibrosa ósea / Fibrous dysplasia of bone

La displasia fibrosa ósea es un trastorno no hereditario del desarrollo esquelético caracterizado por una proliferación anormal de fibroblastos y diferenciación deficiente de osteoblastos que conduce a un reemplazo del tejido óseo esponjoso por tejido conectivo fibroso. Es producida por una mutación somática activadora del gen GNAS1 que induce una activación y proliferación de células mesenquimales indiferenciadas con formación de tejido fibroso y trabéculas óseas anómalas. Existen formas monostóticas, poliostóticas y craneofaciales con diversos grados de dolor, deformidades y fracturas óseas, aunque muchos casos son asintomáticos. En ocasiones se producen quistes óseos aneurismáticos, hemorragias, compromisos neurológicos y raramente osteosarcomas. Algunos casos se asocian a síndrome de McCune-Albright, síndrome de Mazabraud y a osteomalacia por hipofosfatemia por pérdida tubular renal inducida por el FGF23 producido por el tejido displásico. Los hallazgos en las radiografías convencionales son característicos, aunque variables y de carácter evolutivo. La gammagrafía ósea es la técnica de imagen con mayor sensibilidad para determinar la extensión de la enfermedad. El diagnóstico diferencial incluye múltiples lesiones óseas de características similares y en raras ocasiones se requiere biopsia ósea o estudio genético para confirmarlo. No existe un consenso unánime acerca del abordaje terapéutico de estos pacientes, razón por la cual es necesario un enfoque multidisciplinario. La conducta puede ser expectante o quirúrgica según el tipo de lesiones y es importante el manejo del dolor y de las endocrinopatías asociadas. La mayor experiencia publicada se refiere al uso de bifosfonatos y, más recientemente, denosumab. Los tratamientos actuales son insuficientes para modificar el curso de la enfermedad y es necesario el desarrollo de nuevas moléculas que actúen específicamente en el gen GNAS1 o sobre las células mesenquimales afectadas. (AU)

Fibrous dysplasia of bone is a noninherited developmental anomaly of bone characterized by abnormal proliferation of fibroblasts and differentiation of osteoblasts that cause a replacement of trabeculous bone by fibrous connective tissue. It is caused by a somatic mutation in the GNAS1 gene, which induces an undifferentiated mesenquimal cells activation and proliferation with formation of fibrous tissue and abnormal osseous trabeculae. There are monostotic, polyostotic and craniofacial variants with different grades of bone pain, deformities and fractures, although many cases remain asymptomatic. Aneurysmal bone cysts, bleeding, neurological compromise and infrequently osteosarcoma are possible complications. Some cases are associated to McCune-Albright syndrome, Mazabraud syndrome or hypophosphatemia and osteomalacia due to to renal tubular loss induced by FGF23 produced by dysplastic tissue. The findings on conventional radiography are characteristic although variable and evlolve with time. Bone scintigraphy is the most sensitive technique to evaluate the extent of disease. Differential diagnosis include several osseous lesions of similar appearance and, in some cases, bone biopsy or genetic testing may be necessary. Today, there is no consensus regarding the therapeutic approach for these patients and it is necessary a multidisciplinary medical team. Watchful waiting or surgical interventions can be indicated, depending on the type of bone lesions. Bone pain and associated endocrinopathies management are very important. Most published experience refers to the use of bisphosphonates and, more recently, denosumab. Current treatments are insufficient to modify the natural curse of the disease and therefore, new molecules with specific action on GNAS1 gene or affected mesenchymal cells are necessary. (AU)

Might Trauma Be a Triggering Factor for Craniofacial Fibrous Dysplasia?

Fibrous dysplasia (FD) is a rare, benign disease of unclear etiology where normal bone is replaced with abnormal fibrous and weak osseous tissue. Any bone of the skeleton might be involved but skull is one of the most commonly affected sites. Fibrous dysplasia is known to be caused by a genetic mutation leading to inappropriate proliferation and differentiation of osteoblastic cells. However; it is not known whether any triggering factor exists which might contribute to this genetic mutation. The authors postulated that trauma might be a triggering factor for this disease. Trauma, as a triggering factor, has not been reported to be clearly linked to FD in the literature so far. Through this perspective; the authors report a patient of fronto-orbital fibrous dysplasia developing 6 years after a fronto-orbital skull fracture, at the same localization of the fracture line.

Displasia fibrosa poliostótica: revisión de la literatura y reporte de caso / Polyostotic fibrous dysplasia: literature review and case report

La displasia fibrosa (DF) es una enfermedad rara causada por una mutación genética esporádica y congénita donde existe un trastorno en la maduración del mesénquima óseo. Se presenta un paciente de sexo masculino de 27 años, con antecedentes de fractura de tabique nasal y dolor en la región frontal asociada a náuseas e imposibilidad para caminar desde hace ocho años. Al examen físico se encuentra asimetría craneofacial, disminución de la agudeza visual e hipoacusia bilateral. La resonancia magnética cerebral revela hiperostosis y disminución de volumen del cerebro, cerebelo y senos paranasales. La exploración radiológica revela aumento difuso del volumen del componente medular óseo con compromiso poliostótico. Se diagnostica displasia fibrosa ósea poliostótica sobre la base de los datos clínicos y de imágenes. El diagnóstico de este paciente fue tardío. Se ha reportado que, en pacientes jóvenes, el diagnóstico de displasia fibrosa es radiológico y que, en raras ocasiones se requiere biopsia ósea. (AU)

Fibrous dysplasia (FD) is a rare disease caused by a sporadic genetic mutation that generates a disruption in the maturation of bone mesenchyme. We report a 27 year old male patient, with a history of nasal septum fracture and frontal region pain associated with nausea, and walking disability for eight years. At the physical examination we found craniofacial asymmetry, decreased visual acuity, and bilateral deafness. Brain magnetic resonance imaging revealed hyperostosis and decreased volume of brain volume, cerebellum, and sinuses. Skeletal survey revealed diffuse enlargement of the bone marrow component and polyostotic involvement. Diagnosis of polyostotic fibrous dysplasia bone was based on clinical and imaging data. The diagnosis of this patient was late. It has been reported that in young patients FD is diagnosed by radiological methods, rarely requiring bone biopsy. (AU)

Total knee arthroplasty for massive joint destruction in a patient with rheumatoid arthritis complicated with fibrous dysplasia.

We report the case of a patient requiring total knee arthroplasty (TKA) due to massive knee bone deformities caused by rheumatoid arthritis (RA) complicated with polyostotic fibrous dysplasia. Reconstruction of the knee with large osseous defect was achieved with conventional TKA by impaction bone grafting. Benign tumor-like conditions such as fibrous dysplasia may be treated with conventional TKA instead of endoprosthesis, custom-made knee prosthesis, or osteoarticular allografting.

Transsphenoidal surgery in a patient with acromegaly and McCune-Albright syndrome: application of neuronavigation.

The McCune-Albright syndrome (MAS) is characterized by a clinical triad of polyostotic fibrous dysplasia, café-au-lait hyperpigmented macules, and hypersecretory endocrinopathies. Acromegaly is an uncommon manifestation of the endocrine disturbance associated with MAS, and the role of surgery in managing these cases has been a topic of debate. The authors present the case of a 35-year-old man with MAS who was also diagnosed with acromegaly, hyperprolactinemia, and pituitary macroadenoma. The patient had an 18-year history of fibrous dysplasia involving the right frontal bone and ribs as well as multiple endocrinopathies, but no cutaneous hyperpigmented macules. An oral glucose tolerance test demonstrated partial suppression of plasma levels of growth hormone (GH). The patient underwent transsphenoidal resection of the pituitary tumor, performed with assistance of neuronavigation, and tolerated the procedure well. After the surgery, both prolactin and GH levels returned to normal. These results suggest that neuronavigation-assisted transsphenoidal surgery can safely remove pituitary adenomas associated with MAS and successfully treat the underlying endocrine abnormalities.

Early manifestation of obesity and calcinosis cutis in infantile pseudohypoparathyroidism.

Pseudohypoparathyroidism is a parathyroid hormone resistance condition, characterised by biochemical findings of hypocalcaemia or normocalcaemia with inappropriately elevated parathyroid hormone level and usually with a typical osteodystrophy feature. We report an infant with pseudohypoparathyroidism type Ia, who presented with obesity and calcinosis cutis as a clue to diagnosis. A 1-year-old female infant presented with suspected Cushing syndrome. She had round face, flushed cheeks, short nose and low nasal bridge. The infant was normotensive and not virilised. Investigations for Cushing syndrome were all negative. Calcinosis cutis was detected over both legs and the abdominal wall. Parathyroid hormone level was inappropriately elevated with a slightly high calcium level. Her mother was also noted to have Albright's hereditary osteodystrophy features with normal calcium and parathyroid hormone levels. Therefore, the diagnoses of infantile pseudohypoparathyroidism type Ia and maternal pseudopseudohypoparathyroidism were made. This infant presented with an early manifestation of Albright's hereditary osteodystrophy. Diagnosis of pseudohypoparathyroidism should be considered as an unusual cause of obesity in infants, particularly in the differential diagnosis of Cushing syndrome when tall stature rather than growth failure is present.

[McCune-Albright syndrome: a difficult and complicated case study].

McCune-Albright syndrome is a rare G proteins alpha disorder. The disorder is characterized by polyostotic fibrous dysplasia, sexual precocity and hyperpigmented macules. It is caused due to mutations in the gene Gsalpha that incodes the alpha subunit of the trimeric guanosine triphate-binding protein. There is no specific treatment for this syndrome. Treatment is generally symptomatic. This paper reported three cases of McCune-Albright syndrome and reviewed the relevant literatures regarding to the pathogenesis, pathological features, diagnosis and treatment. All three cases presented with a characteristic triad: polyostotic fibrous dysplasia, sexual precocity and hyperpigmented macules and were thus definitely diagnosed with McCune-Albright syndrome.

Single burr hole surgery for the spheno-orbital fibrous dysplasia using intraoperative computed tomography.

Total removal of spheno-orbital fibrous dysplasia was achieved through intraoperative CT-assisted surgery via a burr hole. A 32-year-old man had persistent headache. Radiological studies demonstrated a small osteolytic lesion in the sphenoidal bone underneath the superior orbital fissure. Intraoperative serial CT scans showed the depth and width of the tumor within the complicated structure of the skull base. The lesion was successfully removed by CT-guided minimally invasive surgery.

Paediatric management of endocrine complications in McCune-Albright syndrome.

McCune-Albright syndrome was diagnosed at 2.5 years in a male, with a lower limb fracture and café-au-lait markings. Polyostotic fibrous dysplasia was treated with pamidronate for 4 years, with control of bone pain, improved quality of life, normal growth and visual fields monitored 4-6 monthly. Gonadotrophin independent precocious puberty occurred between ages 5-7 years but was slowly progressive, requiring no treatment. Bone age was 9 years at 7.5 years. From age 8-8.5 years, growth velocity increased further, with widening of spaces between teeth, acral enlargement, sweating and facial acne but no change in pubertal status (testes 6 ml, pubic hair Tanner stage I). Binasal field loss occurred. MRI demonstrated a bulging pituitary gland typical of adolescence, with no discrete tumour, with a markedly thickened calvarium and sphenoid. Bone age advanced from 9 to 12 years in 1 year. Basal growth hormone (GH) was 78 mIU/l, rising to 100 mIU/l with glucose tolerance test, basal IGF-I 2.4 IU/l, FSH <0.1 mIU/l, LH 0.1 mIU/l, testosterone 1.4 nmol/l. Treatment with octreotide LAR, flutamide and testolactone resulted in control of GH (12 mIU/l) and precocious puberty, slowing of growth, return to normal jaw size and tooth spacing, sweating, acne, facial appearance and restoration of full visual fields. Response demonstrated short-term efficacy of medical treatment and a remarkable capacity for facial remodelling in a child with acromegaly. Visual field change is attributed to reduction in soft tissue swelling around the optic foramina. Management issues concern long-term control of GH secretion, the impracticability of surgery in this patient and radiotherapy concerns in a young child.

Cellular and molecular basis of fibrous dysplasia.

Recent advances have been made in the cellular and molecular mechanisms involved in monostotic and polyostotic fibrous dysplasia, a rare nonmalignant disease causing bone deformations and fractures. The molecular basis of fibrous dysplasia has been clarified when mutations affecting the stimulatory alpha subunit of G protein (Gs) have been found in dysplastic bone lesions. The histological analysis of dysplastic lesions revealed that the mutations in Gsalpha caused abnormalities in cells of the osteoblastic lineage and therefore in the bone matrix. Further in vitro analyses of bone cells from mutant dysplastic bone lesions revealed that the abnormal deposition of immature bone matrix in fibrous dysplasia results from decreased differentiation and increased proliferation of osteoblastic cells. Finally, the signaling pathway involved in these osteoblastic abnormalities has been identified. It is now apparent that the constitutive elevation in cAMP level induced by the Gsalpha mutations leads to alterations in the expression of several target genes whose promoters contain cAMP-responsive elements, such as c-fos, c-jun, Il-6 and Il-11. This in turn affects the transcription and expression of downstream genes and results in the alterations of osteoblast recruitment and function in dysplastic bone lesions. These mechanisms provide a cellular and molecular basis for the alterations in bone cells and bone matrix in fibrous dysplasia.

Parathyroid hormone-related protein in the aetiology of fibrous dysplasia of bone in the McCune Albright syndrome.

OBJECTIVE: Fibrous dysplasia, observed in bone lesions in the McCune Albright syndrome (MAS), is thought to result from abnormalities in cells of the osteogenic lineage associated with over-activation of the cAMP signalling pathway in affected cells. The aim of this study was to investigate the role of parathyroid hormone-related protein (PTHrP) in the aetiology of MAS, and to determine a possible therapeutic role for 1,25-dihydroxy vitamin D(3) (1,25(OH)(2)D(3)). DESIGN: The effects of 1,25(OH)(2)D(3) on PTHrP production and mRNA expression were determined in vitro. 1,25(OH)(2)D(3) therapy was administered to three patients with MAS. PATIENTS: Clinical data from four MAS patients (MAS1, 2, 3 and 4), and in vitro studies using bone from three MAS patients (MAS1, 2, and 3), are presented. MEASUREMENTS: Immunoradiometric assay and low-cycle number reverse transcriptase-linked PCR were used to determine PTHrP production and mRNA expression in vitro. Standard clinical biochemistry was recorded pre and post commencement of 1,25(OH)(2)D(3) treatment. RESULTS: We report the elevated secretion of PTHrP, and a concomitant rise in PTHrP mRNA expression, in cultured osteoblasts from three MAS patients. Treatment with 1,25(OH)(2)D(3) produced a dose-dependent decrease in PTHrP protein secretion and mRNA expression. Marked improvement in bone biochemistry in MAS1, 2 and 3 post treatment with 1,25(OH)(2)D(3) is documented. CONCLUSION: This study provides the first evidence suggesting that PTHrP may contribute to the aetiology of fibrous dysplasia in MAS. In addition, the therapeutic administration of 1,25(OH)92)D(3) may provide clinicians with an important new regime for symptomatic relief of bone pain and fracture in some patients with MAS.

GNAS1 mutation and Cbfa1 misexpression in a child with severe congenital platelike osteoma cutis.

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.

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.