Neurofibromatosis 1 and osseous fibrous dysplasia in a family.

We report on the cosegregation of neurofibromatosis 1 (NF 1) and osseous fibrous dysplasia in a family. The father and 3 children by 2 women are affected. A fourth child had neither NF 1 nor osseous fibrous dysplasia. All 4 affected individuals had NF 1, i.e., café-au-lait spots in 4, neurofibromata in 4, Lisch nodules in 3, macrocrania in 3, scoliosis in 2, and curvature of the long bones in 2. Each demonstrated various fibroosseous lesions of the skeleton including non-ossifying fibromas in 3 and both non-ossifying fibromas and fibrous dysplasia in one. This pattern suggests that the fibrous bony lesions are a component of NF 1 in this family. Alternatively, a mutant gene resulting in the fibrous changes in bone could be linked to the gene for NF 1. Another possibility is the coincidence of the 2 non-linked traits segregating in the same family.     

Heterozygous FGFR1 mutation may be responsible for an incomplete form of osteoglophonic dysplasia,characterized only by radiolucent bone lesions and teeth retentions

Non-ossifying fibromas are seen in different disorders recognizable by specific features. Indeed, osteoglophonic dysplasia (OD) is characterized by radiolucent bone lesions associated with severe short stature, dysmorphism and failure of dental eruption. This syndrome is caused by heterozygous activating mutations in the immunoglobulin-like D3 domain of the FGFR1 gene, encoding a tyrosine kinase. Here, we report three patients from the same family presenting with radiolucent bone lesions and teeth retentions. Exome sequencing allowed identification of a novel mutation c.917C > T, p. Pro306Leu in exon 7 of the FGFR1 gene. Our patients present with normal stature and no severe dysmorphism. This report describes a mild form of OD and expands the phenotype related to FGFR1 mutations. These findings emphasize the need to consider FGFR1 variants in the case of multiple non-ossifying bone lesions associated with dental eruption anomalies.     

Fine needle aspiration cytology in a case of fibrous dysplasia of jaw

Fibro‐osseous lesions of the jaw comprise of a spectrum of diseases which include osseous dysplasia, fibrous dysplasia, and ossifying fibroma. The differentiation amongst these individual pathological lesions is difficult and a combined clinico‐radiological and histological correlation is essential for exact categorization. Fine needle aspiration cytology (FNAC) is frequently carried out to distinguish between benign and malignant lesions of the jaw as is a quick and reliable modality of investigation which guides in further management. We report, a case of a jaw swelling in a young male, diagnosed as fibrous dysplasia on FNAC. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Confocal Laser Scanning Microscopy Analysis of 10 Cases of Craniofacial Fibrous Dysplasia

Fibro-osseous lesions (FOL) represent a heterogeneous group of lesions that exhibit a variety of clinic-pathological features. Recently, based on the new World Health Organization classification system, these lesions were reclassified as follows: (1) fibrous dysplasia (FD), (2) osseous dysplasia, and (3) ossifying fibroma. Nevertheless, the nosologic placement of FOL may be problematic because of substantial overlap in the histopathological findings. In this study, we analyzed 10 cases of FD by both optical and confocal laser scanning microscopy, a research technique based on the laser light microscopic analysis of stained biological samples that allows improved tissue imaging and bidimensional pictures with high resolution at the cellular level to provide a better understanding of the diagnosis of this disease.     

Is osseous dysplasia a primary feature of neurofibromatosis 1 (NF1)?

Characteristic skeletal lesions are a cardinal feature of the autosomal dominant condition, neurofibromatosis 1 (NF1). The most frequently involved skeletal sites are the sphenoid wing, vertebrae, and tibia. Osseous lesions may range in severity in NF1 but are often progressive. They may lead to serious clinical consequences and be resistant to treatment. The skeletal lesions of NF1 are usually considered to be 'dysplasias', i.e. primary defects of bone, although there is no direct evidence supporting this interpretation. Moreover, it is difficult to understand why a generalized dysplasia of bone would produce focal lesions that show such a striking predisposition to only a few bones. We review the clinical and pathological features of NF1 skeletal lesions and propose that they result from an abnormal response of NF1 halpoinsufficient bone to abnormal mechanical forces rather than from a primary osseous dysplasia.     

Familial occurrence of periapical cemental dysplasia

A family with periapical cemental dysplasia is reported. The affected individuals displayed classical features of periapical cemental dysplasia on radiographic examination. The lesions consisted chiefly of radiolucent areas; however, some had central areas of radiodensity. Histopathological examination of one of the lesions revealed fibrous elements containing fused dense sclerotic cemental masses. Familial incidence of florid cementoosseous dysplasia with an autosomal mode of inheritance has been reported previously. The condition described in this report appears to be different. However, the two conditions may be part of a spectrum occurring in a single genetic entity with the diversity possibly resulting from variable expressivity of a single gene.     

Ultrastructure of Fibrous Dysplasia of Bone: A Study of Its Fibrous, Osseous, and Cartilaginous Components

Eight cases of fibrous dysplasia were evaluated by electron microscopy and the findings were correlated with the light microscopy. Fibroblasts and myofibroblasts were the cells seen in the fibrous component. The osseous component consisted of immature woven bone trabeculae lined by abnormal osteoblasts with a fibroblastlike appearance. The cartilaginous component resembled hyaline cartilage. The process of mineralization of both osseous and cartilaginous tissues appeared similar to normal bone and cartilage. In fibrous dysplasia there is a slow turnover of bone, and this correlates well with the flattened shape of the bone-lining cells. When compared with normal ossification, the process of bone formation appears to be arrested after an early stage resembling membranous ossification. It is possible that the abnormal osteoblastic maturation of the bone-forming mesenchyme is one of the most important alterations of this condition.     

A comparative study of fibrous dysplasia and osteofibrous dysplasia with regard to expressions of c-fos and c-jun products and bone matrix proteins: A clinicopathologic review and immunohistochemical study of c-fos, c-jun, type I collagen, osteonectin, osteopontin, and osteocalcin

Fibrous dysplasia and osteofibrous dysplasia are both benign fibro-osseous lesions of the bone and are generally seen during childhood or adolescence. Histologically, the features of these bone lesions sometimes look quite similar, but their precise nature remains controversial. We retrospectively studied clinicopathologic findings in 62 cases of fibrous dysplasia and 20 cases of osteofibrous dysplasia with regard to their anatomic location and histological appearance. From among these cases, the immunohistochemical expressions of c-fos and c-jun proto-oncogene products and bone matrix proteins of type I collagen, osteonectin, osteopontin, and osteocalcin were evaluated in 20 typical fibrous dysplasias and 17 osteofibrous dysplasias using paraffin sections, and these expressions were then assessed semiqnantitatively. Microscopically, fibrous dysplasia showed various secondary changes, such as hyalinization, hemorrhage, xanthomatous reaction, and cystic change in 22 of the 62 cases (35%). This was a higher incidence than in osteofibrous dysplasia, in which only 2 of the 20 cases (10%) showed such changes. In the elderly fibrous dysplasia cases, the cellularity of fibroblast-like cells was rather low, and those cases were hyalinized. Almost all of the cases of fibrous dysplasia and osteofibrous dysplasia showed positive expressions of c-fos and c-jun products. The expressions of type I collagen and osteopontin showed no difference between fibrous dysplasia and osteofibrous dysplasia. Immunoreactivity for osteonectin in bone matrix was detected in only 1 case of fibrous dysplasia (1 of 20), whereas it was recognized in 14 of the 17 cases of osteofibrous dysplasia. Furthermore, the immunoreactivity for osteocalcin in bone matrix and fibroblast-like cells was higher in fibrous dysplasia than it was in osteofibrous dysplasia, semiquantitatively. Our immunohistochemical results regarding osteonectin and osteocalcin suggest that the bone matrix of fibrous dysplasia is somewhat more mature than that of osteofibrous dysplasia, and that the fibroblast-like cells in fibrous dysplasia share some phenotypic features with osteoprogenitor ceils of normal osteogenic tissues. Fibrous dysplasia and osteofibrous dysplasia share Some similar histological features, including c-fos and c-jun expressions, although different clinicohistologic features and immunohistochemical expressions of osteonectin and osteocalcin were observed. These features suggest that the mechanisms behind the development of fibrous dysplasia and osteofibrous dysplasia are similar, but this is not necessarily indicative of a closer relationship between the 2 diseases.     

Comparative study of fibrous dysplasia and osteofibrous dysplasia: histopathological, immunohistochemical, argyrophilic nucleolar organizer region and DNA ploidy analysis

Fibrous dysplasia and osteofibrous dysplasia are both benign fibro-osseous lesions of the bone. We retrospectively studied the clinicopathological findings in 90 cases of fibrous dysplasia and 17 cases of osteofibrous dysplasia. In these cases, the expression of proliferating cell nuclear antigen (PCNA) and the presence of argyrophilic nucleolar organizer regions (AgNOR), as well as DNA ploidy, were examined. The bones affected by fibrous dysplasia were the maxilla, femur and frontal bone. Osteofibrous dysplasia occurred exclusively in the tibia or fibula. The average age of patients with fibrous dysplasia (24.0 years) was higher than that of patients with osteofibrous dysplasia (12.9 years). Fibrous dysplasias were divided into four major histological subtypes: Pagetoid, Chinese alphabet, small bone and parallel bone. Bone lining cells, which are known as resting osteoblasts, were seen in some cases of fibrous dysplasia. Cartilage differentiation was not seen in osteofibrous dysplasia. PCNA expression was strongly positive in the nuclei of osteoblasts around the bone trabeculae in osteofibrous dysplasia, but negative in the nuclei of bone lining cells around the bone trabeculae in fibrous dysplasia. The number of AgNOR in osteofibrous dysplasia was slightly higher than that in fibrous dysplasia. Both fibrous dysplasia and osteofibrous dysplasia were diploid. These features suggest that fibrous dysplasia can be differentiated from osteofibrous dysplasia by anatomical site, patient age, histological appearance, cartilage differentiation and PCNA positivity. DNA content by image cytometry is not a useful tool for differentiating these two diseases.     

Pseudotumors of bone and bone lesions mimicking tumours

We review entities that have historically been thought to be pseudotumors or mimics of bone tumours. We discuss tumifactive amyloid deposits, the brown tumours of hyperparathyroidism, the various types of cysts that can be seen in bone, Nora lesion, subungual exostosis, haemophilic pseudotumors, non-ossifying fibroma, fibrous dysplasia, osteofibrous dysplasia, Paget disease, tophaceous gout and pseudogout.     

Symmetrical fibro-osseous dysplasia of rib–post-traumatic dysplasia?

We describe two patients with a distinctive histological condition which clinically and radiologically mimics fibrous dysplasia of the rib. Both patients presented with chronic pain confined to one rib. In each case their radiographs showed a solitary, fusiform expansion of a rib with variable calcification. Histologically the lesions were characterized by a central core of xanthomatous macrophages surrounded by cancellous bone that showed symmetrical and progressive maturation centrifugally towards the cortex, a pattern which distinguishes these lesions from the irregular pattern of fibrous dysplasia.     

Clonal status of fibrous dysplasia

AIM: The purpose of this study was to elucidate the clonality of fibrous dysplasia based on X-chromosome inactivation mosaicism and polymorphism in female somatic cells at the phosphoglycerate kinase (PGK) and androgen receptor (AR) loci using microdissection technology. MATERIALS AND METHODS: Nine patients with fibrous dysplasia were examined using clonality assays based on X-chromosome inactivation mosaicism. Lesions and surrounding soft tissues were microdissected from paraffin sections, and genomic DNA was extracted, pretreated with Hpa II or Hha I, and the PGK and AR genes were amplified by nested PCR. The single nucleotide polymorphism (SNP) at the PGK locus was identified by incubation with Bst XI and agarose gel electrophoresis. The CAG repeat length polymorphism at the AR locus was revealed on denaturing polyacrylamide gels and visualised by silver staining. RESULT: Microscopically, typical histological characteristics were seen in each sample. Lesions consisted of varying proportions of fibrous tissue and immature trabecular bone. Tissue consisted of collagenous fibres and fish-hook or comma-shaped trabecular bone without rows of cuboidal appositional osteoblasts on the surface. Restriction fragment length polymorphism (RFLP) of AR was found in seven of nine cases. The results of clonality assays demonstrated that seven cases of fibrous dysplasia were monoclonal, suggesting that they are neoplastic lesions. CONCLUSION: We conclude that fibrous dysplasia may not be a hyperplastic lesion, but a neoplastic lesion. Additional studies with larger sample sizes will be needed to conclusively prove our hypothesis.     

Associations of osseous abnormalities in Neurofibromatosis 1

The characteristic sites of Neurofibromatosis 1-associated osseous manifestations are the long bones (usually the tibia and fibula), vertebrae and sphenoid wing. Although these focal bony lesions may cause profound clinical consequences, a minority of people with NF1 are affected. However, most people with NF1 are shorter than expected for their age, gender and family. The pathogenesis of NF1 focal osteopathy and its relationship, if any, to short stature are unknown. We examined associations between the occurrence of various osseous lesions in 3377 NF1 probands from the Children's Tumor Foundation NF International Database. Using logistic regression analysis among 260 NF1 probands who had undergone radiological examination of both the spine and skull, we found associations between the occurrence of sphenoid wing and long bone osteopathy (conditional odds ratio [OR] = 6.1; 95% confidence interval [CI] = 1.7-22.3; P = 0.006) and between sphenoid wing and vertebral osteopathy (OR = 16.9; 95% CI = 5.3-53.3; P < 0.001) after adjusting for age and gender. Similar findings were observed from all 3377 NF1 probands using a multivariate probit regression model. In a separate analysis, we found lower age- and gender-standardized height in patients who had characteristic vertebral or sphenoid wing lesions than in people who did not (P < 0.05). We found no relationship between height and tibial osteopathy. We conclude that some people with NF1 are more likely to develop osseous manifestations than others and speculate that there may be a common pathogenetic mechanism responsible for the development of osseous abnormalities and that of the vertebrae and long bones.     

Expansile bone lesions in a three‐generation family

We report on a three‐generation family with “expansile” bone lesions of the distal radius and ulna, cortical thickening of the proximal long bones, and pathologic fractures. The differential diagnosis of expansile bone lesions includes isolated bone cysts and tumors, such as enchondromas and fibrous dysplasia; familial expansile osteolysis; and the genochondromatoses. Our patients have findings most similar to the genochondromatoses; however, the distribution of the lesions and the accompanying manifestations may be evidence for a unique genetic condition in this family. Am. J. Med. Genet. 82:1–5, 1999. © 1999 Wiley‐Liss, Inc.     

Omani-type spondyloepiphyseal dysplasia with cardiac involvement caused by a missense mutation in CHST3

We describe a family with progressive skeletal dysplasia and severe spinal involvement, short stature, premature arthrosis and joint contractures diagnosed as spondyloepiphyseal dysplasia Omani type. Mutation analysis in CHST3 , the gene encoding for the chondroitin 6- O -sulfotransferase-1 (C6ST-1), revealed a homozygous missense mutation (T141M) in exon 3 in all three affected members of the family. Using recombinant C6ST-1, we showed that the identified missense mutation results in a reduction of C6ST-1 activity to 24–29% of the wild type protein. In addition to the previously noted skeletal features, affected members of this family also had cardiac involvement including mitral, tricuspid and/or aortic regurgitations and type E brachydactyly.     

Liposclerosing myxofibrous tumour: a traumatized variant of fibrous dysplasia? Report of four cases and review of the literature

AIMS: To describe the pathological and radiological features of four cases of liposclerosing myxofibrous tumour (LSMFT). LSMFT is a benign fibro-osseous lesion of bone with a marked predilection for the intertrochanteric region of the proximal femur. It is characterized by a complex mixture of histological elements including fibrous dysplasia-like bony trabeculae, myxofibrous tissue, lipomatous areas, xanthoma cells and pseudo-Paget's bone. This lesion is not a universally accepted pathological entity and often appears in the literature under variants of fibrous dysplasia or other benign lytic bone lesions. METHODS AND RESULTS: All lesions exhibited histological and/or radiological overlap with fibrous dysplasia. A relationship to trauma was noted in three of the cases. The hypothesis that these lesions represent a traumatized variant of fibrous dysplasia was explored. After reviewing the biomechanics of the proximal femur, a possible relationship between predilection of LSFMT for this anatomical region and increased susceptibility to fracture was noted. CONCLUSIONS: We hypothesize that when fibrous dysplasia involves the proximal femur, it makes the bone more susceptible to fatigue fracture, thereby altering its histological appearance. The wide variety of histological patterns in LSMFT could represent the end result of repeated reaction to fatigue stresses.     

A probable monogenic form of polyostotic fibrous dysplasia

A 37 year-old female patient with polyostotic fibrous dysplasia (PFD) is described. She presented the typical "café au lait" spots and severe bone involvement including a maxillary osteosarcoma. The father, four sibs, two nephews, two paternal aunts and two paternal first cousins were clinically examined, and seven of them also radiologically evaluated. "Café au lait" spots were found in the father, three sibs, one nephew, one aunt and one first cousin. Although no definite PFD bone lesions, mild radiological abnormalities were found in the father, three sibs and one nephew. These findings were interpreted as the variable expression of a pleiotropic gene. The present observation and three previous familial cases of this entity strongly suggest the existence of a form of PFD determined by an autosomal dominant gene.     

Ossifying fibroma vs fibrous dysplasia of the jaw: molecular and immunological characterization.

Ossifying fibroma and fibrous dysplasia of the jaw are maxillofacial fibro-osseous lesions that should be distinguished each other by a pathologist because they show distinct patterns of disease progression. However, both lesions often show similar histological and radiological features, making distinction between the two a diagnostic dilemma. In this study, we performed immunological and molecular analyses of five ossifying fibromas, four cases of extragnathic fibrous dysplasia, and five cases of gnathic fibrous dysplasia with typical histological and radiographic features. First, we examined the difference between fibrous dysplasia and ossifying fibroma in the expression of Runx2 (which determined osteogenic differentiation from mesenchymal stem cells) and other osteogenic markers. Fibroblastic cells in fibrous dysplasia and ossifying fibroma showed strong Runx2 expression in the nucleus. The bone matrices of both lesions showed similar expression patterns for all markers tested except for osteocalcin. Immunoreactivity for osteocalcin was strong throughout calcified regions in fibrous dysplasia, but weak in ossifying fibroma lesions. Second, we performed PCR analysis with peptide nucleic acid (PNA) for mutations at the Arg(201) codon of the alpha subunit of the stimulatory G protein gene (GNAS), which has reported to be a marker for extragnathic fibrous dysplasia. All nine cases of extragnathic or gnathic fibrous dysplasia were positive for this mutation. On the other hand, none of the five cases of ossifying fibroma showed the mutation. These findings indicate that although fibrous dysplasia and ossifying fibroma are similar disease entities, especially in the demonstration of the osteogenic lineage in stromal fibroblast-like cells, they show distinct differences that can be revealed by immunohistochemical detection of osteocalcin expression. Furthermore, PCR analysis with PNA for GNAS mutations at the Arg(201) codon is a useful method to differentiate between fibrous dysplasia and ossifying fibroma.     

Encephalocraniocutaneous lipomatosis (ECCL): neuroradiological findings in three patients and a new association with fibrous dysplasia

Encephalocraniocutaneous lipomatosis (ECCL) is a rare neurocutaneous syndrome characterized by involvement of tissues of ectodermal and mesodermal origin such as skin, eye, adipose tissue, and brain. Since 1970, when Haberland and Perou had described the first patient, 54 cases of ECCL have been reported in literature. We report on three new boys with ECCL. In addition to their typical dermal, ocular and central nervous system anomalies, one of them had a spheno-ethmoidal osseous lesion. Histopathological evaluation confirmed the benign nature of the lesion and was consistent with fibrous dysplasia. The aim of our study is to review clinical records and brain imaging studies of these three new patients with ECCL and compare these findings with those reported in literature to better define the phenotypic spectrum and radiological findings in ECCL.