Neurofibromatosis 1 and osseous fibrous dysplasia in a family

We report on the consegregation 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., caféau-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. © 1992 Wiley-Liss, Inc.     

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.     

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.     

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.     

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.     

Matrix vesicles in bone tumors. Ultrastructural analysis and their significance in neoplastic bone formation.

Bone tumors were categorized into alkaline phosphatase (ALPase)-positive (2 ossifying fibromas, 1 benign osteoblastoma and 16 osteosarcomas) and negative (2 chondromas, 2 chondrosarcomas, 3 non-ossifying fibromas, 2 malignant fibrous histiocytomas and 6 giant cell tumors of bone) groups. Production and distribution of matrix vesicles (MVs) in the tumor tissues were examined to clarify their role in neoplastic bone formation. Four distinct types of MV were isolated primarily in ALPase positive bone tumors: empty, amorphous, crystalline and ruptured MVs. They were formed by budding off from the cytoplasmic projections of the osteoblastic tumor cells. The significance of differences in the production rate of MVs between ALPase-positive and negative bone tumors was investigated in view of the predominantly high production of MVs in ALPase-positive bone tumors. Many more mature MVs (crystalline and ruptured) were observed in the osteoblastic lesions of osteosarcoma than in the fibroblastic and MFH-like lesions, suggesting an intimate relationship with maturation and differentiation of the osteoblastic tumor cells. The above findings indicate that production of MVs is one of the diagnostic parameters for osteoblast-derived bone tumors, as well as ALPase activity, and that vesicle-induced mineralization is a major mineralization mechanism in neoplastic bone formation.     

Ossifying fibroma of long bone: its distinction from fibrous dysplasia and its association with adamantinoma of long bone.

Two cases of ossifying fibroma of long bones are presented. This tumor is confused with monostotic fibrous dysplasia, but can be distinguished by its intracortical location, as demonstrated radiographically, and by its histologic pattern. Distinction from fibrous dysplasia is important since ossifying fibroma of long bone is a more aggressive lesion with different therapeutic implications. It appears that ossifying fibroma and adamantinoma of long bones are somehow related, and that lesions resembling fibrous dysplasia in association with adamantinomas of long bones are actually ossifying fibromas.     

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.     

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.     

Prenatal diagnosis of a trisomy 7/maternal uniparental heterodisomy 7 mosaic fetus

This article describes four patients with non-ossifying fibromas (NOFs) and multiple café-au-lait spots. Two of the patients were diagnosed with NOFs when they presented with a femur fracture. The other two patients were diagnosed with NOFs because of complaints of leg problems. In addition, axillary freckles and Lisch nodules were present in all four patients and multiple cutaneous neurofibromas in two patients. These four patients fulfilled the diagnostic criteria for neurofibromatosis type 1 (NF1) and also have been diagnosed with Jaffe-Campanacci syndrome. We propose that Jaffe-Campanacci syndrome is a manifestation of NF1 and suggest that patients with NF1 should have more rigorous radiographic screening of the long bones during early adolescence or adulthood to determine the presence or absence of NOFs. Appropriate intervention (exercise restriction, bracing, and/or surgery) might decrease the long-term disability associated with Jaffe-Campanacci syndrome.     

Juvenile ossifying fibroma diagnosed on fine needle aspiration cytology: A diagnostic challenge

Preoperative diagnosis of jaw lesions is not always possible on the basis of clinico‐radiological findings alone and needs to be confirmed before attempting any surgical intervention. Fibro‐osseous lesions of the jaw comprise a spectrum of diseases which include cement‐osseous dysplasia, fibrous dysplasia, and ossifying fibroma. The cytomorphological distinction between these individual entities is difficult. We present a case of maxillary fibro‐osseous lesion in an adolescent girl diagnosed and categorized as juvenile ossifying fibroma preoperatively on cytology and confirmed on histopathology. Although aspirates are usually paucicellular in fibro‐osseous lesions, certain cytological features if present in cellular cytosmears can offer further categorization and a definitive diagnosis may be possible in light of clinico‐radiological correlation. Diagn. Cytopathol. 2015;43:75–79. © 2014 Wiley Periodicals, Inc.     

Encephalocraniocutaneous lipomatosis accompanied by the formation of bone cysts: Harboring clues to pathogenesis?

Encephalocraniocutaneous lipomatosis (ECCL) is a sporadically occurring neurocutaneous disorder characterized by ocular anomalies, mainly choristomas; by skin lesions consisting of hairless fatty tissue nevi (nevus psiloliparus), focal dermal hypoplasia, alopecia, and periocular skin tags; and by CNS anomalies, including intracranial and spinal lipomas and often mental retardation and seizures. Here, we report on three boys with ECCL with typical abnormalities of the eyes, skin and brain and, in addition, coarctation of the aorta. All three children developed multiple cystic bone lesions, which progressively spread throughout the skeleton in Patient 1 and was shown histologically to be non-ossifying fibromas in Patient 2. We hypothesize that ECCL may be caused by mosaicism for a mutated gene involved in benign mesenchymal tumors and in vasculogenesis.     

Immunoexpression of neurofibromin, S-100 protein, and leu-7 and mutation analysis of the NF1 gene at codon 1423 in osteofibrous dysplasia.

The NF1 (neurofibromatosis type 1, or von Recklinghausen disease) gene, is a tumor-suppressor gene, and its product, neurofibromin, down-regulates ras protein by its guanosine triphosphatase-activating protein (GAP)-related domain. Osteofibrous dysplasia (OFD) is characterized by fibroblast-like spindle cells and osseous tissue and is generally seen in the tibia or fibula during childhood. The precise nature of OFD remains controversial. Cosegregations of OFD and NF1 have been reported, and it has been surmised that OFD is associated with the NF1 gene. We studied the expressions of NF1 gene product (neurofibromin) and so-called Schwann cell markers (S-100 protein, Leu-7) in 17 cases of OFD immunohistochemically. Ten cases of fibrous dysplasia (FD) were also used for the purpose of comparison. Five OFD and 7 FD cases were analyzed for NF1 gene mutation at codon 1423, which is a GAP-related domain, by single-strand conformation polymorphism. Fibroblast-like cells of OFD showed the expression of neurofibromin (5 of 17), S-100 protein (9 of 17), and Leu-7 (5 of 17), and those of FD did not show these expressions, with the exception of 1 case that showed Leu-7 expression. Regarding the OFD cases, significant correspondence was found between cases showing expression of neurofibromin and S-100 protein, between cases showing expression of neurofibromin and Leu-7, and between cases showing expression of S-100 protein and Leu-7 (P < .01). NF1 gene mutation at codon 1423 was not detected in either the OFD (0 of 5) or FD (0 of 7) cases. These results seem to suggest the possible involvement of neurofibromin in the development of OFD, which is associated with the expression of Schwann cell markers (S-100 protein and Leu-7). Furthermore, NF1 gene mutation at codon 1423 did not seem to be related to OFD.     

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.     

Loss of heterozygosity for the NF2 gene in retinal and optic nerve lesions of patients with neurofibromatosis 2

Individuals affected with the neurofibromatosis 2 (NF2) cancer predisposition syndrome develop specific ocular lesions. To determine whether these lesions result from altered NF2 gene expression, microdissection and PCR were used to investigate 40 ocular lesions from seven eyes of four NF2 patients for LOH, with markers that flank the NF2 gene on chromosome 22q. NF2 protein (merlin) expression was also evaluated in these lesions, using immunohistochemistry. Retinal hamartoma was observed in all seven eyes, including one with combined pigment epithelial and retinal hamartoma (CPERH). Retinal tufts were present in four eyes (three patients), retinal dysplasia in two eyes (two patients), optic nerve neurofibroma in one eye, iris naevoid hyperplasia in two eyes (two patients) and pseudophakia in all eyes. Markers were informative in three patients (six eyes from three unrelated families). One patient was non-informative due to prolonged decalcification. All retinal and optic nerve, but not iris lesions, demonstrated consistent LOH for the NF2 gene. Merlin was not expressed in the retina, optic nerve, or iris lesions. These results suggest that inactivation of the NF2 gene is associated with the formation of a variety of retinal and optic nerve lesions in NF2 patients.     

Jaffe–Campanacci syndrome,revisited: detailed clinical and molecular analyses determine whether patients have neurofibromatosis type 1, coincidental manifestations,or a distinct disorder

Purpose“Jaffe–Campanacci syndrome” describes the complex of multiple nonossifying fibromas of the long bones, mandibular giant cell lesions, and café-au-lait macules in individuals without neurofibromas. We sought to determine whether Jaffe–Campanacci syndrome is a distinct genetic entity or a variant of neurofibromatosis type 1.MethodsWe performed germline NF1, SPRED1, and GNAS1 (exon 8) mutation testing on patients with Jaffe–Campanacci syndrome or Jaffe–Campanacci syndrome–related features. We also performed somatic NF1 mutation testing on nonossifying fibromas and giant cell lesions.ResultsPathogenic germline NF1 mutations were identified in 13 of 14 patients with multiple café-au-lait macules and multiple nonossifying fibromas or giant cell lesions (“classical” Jaffe–Campanacci syndrome); all 13 also fulfilled the National Institutes of Health diagnostic criteria for neurofibromatosis type 1. Somatic NF1 mutations were detected in two giant cell lesions but not in two nonossifying fibromas. No SPRED1 or GNAS1 (exon 8) mutations were detected in the seven NF1-negative patients with Jaffe–Campanacci syndrome, nonossifying fibromas, or giant cell lesions.ConclusionIn this study, the majority of patients with café-au-lait macules and nonossifying fibromas or giant cell lesions harbored a pathogenic germline NF1 mutation, suggesting that many Jaffe–Campanacci syndrome cases may actually have neurofibromatosis type 1. We provide the first proof of specific somatic second-hit mutations affecting NF1 in two giant cell lesions from two unrelated patients, establishing these as neurofibromatosis type 1–associated tumors.Genet Med16 6, 448–459.     

Juvenile trabecular ossifying fibroma: an update

Fibro-osseous lesions are characterized by the presence of bone marrow that has changed into fibrous tissue and that contains mineralized material of varying appearances. Because of overlapping clinical, radiological, and histopathological features, their classification has evoked much discussion. The current classification recognizes fibrous dysplasia, ossifying fibroma, and osseous dysplasia. Juvenile trabecular ossifying fibroma is a rare variant of ossifying fibroma that is clinically characterized by rapid growth that may suggest malignancy. A series of 15 cases is reported with emphasis on a hitherto unnoticed histological feature that may be helpful in recognizing this lesion.     

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.     

一个Ⅱ型神经纤维瘤病家系的临床表现和NF2基因突变分析

目的 报告1个Ⅱ型神经纤维瘤病家系NF2基因的剪接突变(IVS3+3A＞C),并探讨基因型与表型的关系.方法 先证者有听神经瘤家族史,2年前因听神经瘤已经伽玛刀治疗.提取该家系所有患者、疑似患者、正常成员和150个无血缘关系健康人的血样本基因组DNA.选择与NF2基因连锁的短串联重复(short tandem repeat,STR)位点(D22S1150、D22S268)对家系成员进行多态性分析,并计算2点连锁的LOD值.对先证者NF2基因的启动子、17个外显子和外显子内含子剪接处进行 PCR,对其产物进行测序.对家系另外3例患者,1例疑似患者和有血缘关系的9名健康者及150名无血缘的健康对照者进行第3外显子-第3内含子剪接处PCR和测序.结果 两点连锁分析显示NF2基因为疾病的候选基因(Zmax=2.109,θ=0.00,D22S1150位点).PCR产物测序发现先证者NF2基因IVS3+3A＞C,呈杂合突变.3例患者和1例疑似患者均带有与先证者相同的突变,但9名健康成员和150名无血缘关系的健康对照者均无此改变.结论 NF2基因的INS3+3A＞C突变是该家系疾病的分子原因.