Síndrome de Haglund con espolón calcáneo posterosuperior asociado: a propósito de un caso / Haglund's syndrome with associated posterior-superior heel spur: a propros of a case

La deformidad de Haglund, el espolón calcáneo posterosuperior y el espolón plantar son las exostosis más frecuentes a nivel del talón, siendo importante estar familiarizado con ellas porque, en ocasiones, pueden asociarse a tendinopatía aquílea o a fascitis plantar, siendo estas las principales causas de dolor en el retropié. No obstante, estas exostosis pueden estar presentes en pacientes asintomáticos y, en ocasiones, coexistir simultáneamente, tendiendo que tener muy claros todos estos conceptos cuando nos encontremos con un paciente con dolor en el talón. Presentamos el caso de una mujer de 58 años con dolor en el retropié izquierdo de 3 meses de evolución, sin antecedentes de traumatismo previo, que presentaba una tumoración palpable a nivel del talón izquierdo y que fue diagnosticada de síndrome de Haglund con espolón calcáneo posterosuperior asociado (AU)

Haglund's deformity, posterior-superior heel spur and plantar spur are the most common exostosis in the rearfoot. It is very important to be familiar with these entities, because they can sometimes be associated with Achilles tendinopathy or plantar fasciitis, which are the main causes of heel pain. Nevertheless, these exostoses may be present in asymptomatic patients and can sometimes coexist simultaneously. All these concepts need to be taken into consideration in patients with heel pain. We report the case of a 58-year-old woman with a 3 month history of left rearfoot pain, with no history of previous trauma, who presented with a palpable tumor in the left heel and was finally diagnosed with Haglund's syndrome associated with posterior-superior heel spur (AU)

Aluminum and iron can be deposited in the calcified matrix of bone exostoses.

Exostosis (or osteochondroma) is the most common benign bone tumor encountered in children and adults. Exostoses may occur as solitary or multiple tumors (in the autosomal syndromes of hereditary multiple exostoses). Exostoses are composed of cortical and medullary bone covered by an overlying hyaline cartilage cap. We have searched iron (Fe) and aluminum (Al) in the matrix of cortical and trabecular bone of 30 patients with exostosis. Al(3+) and Fe(3+) are two cations which can substitute calcium in the hydroxyapatite crystals of the bone matrix. The bone samples were removed surgically and were studied undecalcified. Perls' Prussian blue staining (for Fe) and solochrome azurine B (for Al) were used on the histological sections of the tumors. Al(3+) was detected histochemically in 21/30 patients as linear bands deposited by the osteoblasts. Fe(3+) was detected in 10 out of these 21 patients as linear bands in the same locations. Fe(3+) and Al(3+) were not identified in the bone matrix of a control group of 20 osteoporotic patients. Energy X-ray Dispersive Spectrometry failed to identify Fe and Al in bone of these tumors due to the low sensitivity of the method. Wavelength Dispersive Spectrometry identified them but the concentrations were very low. Histochemistry appears a very sensitive method for Fe(3+) and Al(3+) in bone.The presence of these two metals in the exostoses advocates for a disturbed metabolism of osteoblasts which can deposit these metals into the bone matrix, similar to which is observed in case of hemochromatosis with Fe(3+).

The ratio 1660/1690 cm(-1) measured by infrared microspectroscopy is not specific of enzymatic collagen cross-links in bone tissue.

In postmenopausal osteoporosis, an impairment in enzymatic cross-links (ECL) occurs, leading in part to a decline in bone biomechanical properties. Biochemical methods by high performance liquid chromatography (HPLC) are currently used to measure ECL. Another method has been proposed, by Fourier Transform InfraRed Imaging (FTIRI), to measure a mature PYD/immature DHLNL cross-links ratio, using the 1660/1690 cm(-1) area ratio in the amide I band. However, in bone, the amide I band composition is complex (collagens, non-collagenous proteins, water vibrations) and the 1660/1690 cm(-1) by FTIRI has never been directly correlated with the PYD/DHLNL by HPLC. A study design using lathyritic rats, characterized by a decrease in the formation of ECL due to the inhibition of lysyl oxidase, was used in order to determine the evolution of 1660/1690 cm(-1) by FTIR Microspectroscopy in bone tissue and compare to the ECL quantified by HPLC. The actual amount of ECL was quantified by HPLC on cortical bone from control and lathyritic rats. The lathyritic group exhibited a decrease of 78% of pyridinoline content compared to the control group. The 1660/1690 cm(-1) area ratio was increased within center bone compared to inner bone, and this was also correlated with an increase in both mineral maturity and mineralization index. However, no difference in the 1660/1690 cm(-1) ratio was found between control and lathyritic rats. Those results were confirmed by principal component analysis performed on multispectral infrared images. In bovine bone, in which PYD was physically destructed by UV-photolysis, the PYD/DHLNL (measured by HPLC) was strongly decreased, whereas the 1660/1690 cm(-1) was unmodified. In conclusion, the 1660/1690 cm(-1) is not related to the PYD/DHLNL ratio, but increased with age of bone mineral, suggesting that a modification of this ratio could be mainly due to a modification of the collagen secondary structure related to the mineralization process.

Mice deficient in Ext2 lack heparan sulfate and develop exostoses.

Hereditary multiple exostoses (HME) is a genetically heterogeneous human disease characterized by the development of bony outgrowths near the ends of long bones. HME results from mutations in EXT1 and EXT2, genes that encode glycosyltransferases that synthesize heparan sulfate chains. To study the relationship of the disease to mutations in these genes, we generated Ext2-null mice by gene targeting. Homozygous mutant embryos developed normally until embryonic day 6.0, when they became growth arrested and failed to gastrulate, pointing to the early essential role for heparan sulfate in developing embryos. Heterozygotes had a normal lifespan and were fertile; however, analysis of their skeletons showed that about one-third of the animals formed one or more ectopic bone growths (exostoses). Significantly, all of the mice showed multiple abnormalities in cartilage differentiation, including disorganization of chondrocytes in long bones and premature hypertrophy in costochondral cartilage. These changes were not attributable to a defect in hedgehog signaling, suggesting that they arise from deficiencies in other heparan sulfate-dependent pathways. The finding that haploinsufficiency triggers abnormal cartilage differentiation gives insight into the complex molecular mechanisms underlying the development of exostoses.

Differentiation-induced loss of heparan sulfate in human exostosis derived chondrocytes.

An exostosis or osteochondroma is an aberrant bony growth occurring next to the growth plate either as an isolated growth abnormality or as part of the Hereditary Multiple Exostosis (HME) syndrome. Mutations in either exostosin 1 (EXT1) or exostosin 2 (EXT2) gene cause the HME syndrome and also some isolated osteochondromas. The EXT1 and EXT2 genes are glycosyltransferases that function as hetero-oligomers in the Golgi to add repeating glycosaminoglycans (GAGs) to heparan sulfate (HS) chains. Previously, we demonstrated that HS is markedly diminished in the exostosis cartilage cap and that the HS proteoglycan, perlecan, has an abnormal distribution in these caps. The present studies were undertaken to evaluate which chondrocyte-specific functions are associated with diminished HS synthesis in human chondrocytes harboring either EXT1 or EXT2 mutations. Systematic evaluation of exostosis cartilage caps and chondrocytes, both in vitro and in vivo, suggests that chondrocyte-specific cell functions account for diminished HS levels. In addition, we provide evidence that perichondrial cells give rise to chondrocytes that clonally expand and develop into an exostosis. Undifferentiated EXT chondrocytes synthesized amounts of HS similar to control chondrocytes; however, EXT chondrocytes displayed very poor survival in vitro under conditions that promote normal chondrocyte differentiation with high efficiency. Collectively, these observations suggest that loss of one copy of either the EXT1 or EXT2 gene product compromises the perichondrial chondrocytes' ability to differentiate normally and to survive in a differentiated state in vitro. In vivo, these compromised responses may lead to abnormal chondrocyte growth, perhaps from a perichondrial stem cell reserve.

Potential cellular receptors involved in hepatitis C virus entry into cells.

Hepatitis C virus (HCV) infects hepatocytes and leads to permanent, severe liver damage. Since the genomic sequence of HCV was determined, progress has been made towards understanding the functions of the HCV-encoded proteins and identifying the cellular receptor(s) responsible for adsorption and penetration of the virus particle into the target cells. Several cellular receptors for HCV have been proposed, all of which are associated with lipid and lipoprotein metabolism. This article reviews the cellular receptors for HCV and suggests a general model for HCV entry into cells, in which lipoproteins play a crucial role.

Heparan sulfate abnormalities in exostosis growth plates.

Hereditary multiple exostoses (HME), a condition associated with development and growth of bony exostoses at the ends of the long bones, is caused by germline mutations in the EXT genes. EXT1 and EXT2 function as glycosyltransferases that participate in the biosynthesis of heparan sulfate (HS) to modify proteoglycans. HS proteoglycans, synthesized by chondrocytes and secreted to the extracellular matrix of the growth plate, play critical roles in growth plate signaling and remodeling. As part of studies to delineate the mechanism(s) by which an exostosis develops, we have systematically evaluated four growth plates from two HME and two solitary exostoses. Mutational events were correlated with the presence/absence and distribution of HS and the normally abundant proteoglycan, perlecan (PLN). DNA from the HME exostoses demonstrated heterozygous germline EXT1 or EXT2 mutations, and DNA from one solitary exostosis demonstrated a somatic EXT1 mutation. No loss of heterozygosity was observed in any of these samples. The chondrocyte zones of four exostosis growth plates showed absence of HS, as well as diminished and abnormal distribution of PLN. These results indicate that, although multiple mutational events do not occur in the EXT1 or EXT2 genes, a complete loss of HS was found in the exostosis growth plates. This functional knockout of the exostosis chondrocytes' ability to synthesize HS chains further supports the observations of cytoskeletal abnormalities and chondrocyte disorganization associated with abnormal cell signaling.

Periosteal hyperostosis (exostosis) in DBA/1 male mice.

Periosteal hyperostosis (exostosis) was identified in 5.9% (11/188) of DBA/1 male mice 10-14 weeks old used for collagen-induced arthritis (CIA) efficacy testing of immunomodulatory biologics. Mice with and without CIA in the affected limb, and also control and treated groups, were involved, with bilateral lesions in one mouse. Hyperostosis was characterized by circumferential and raised masses of variable location, length, and laterality, generally external to but occasionally breaching the periosteum of the metatarsals, metacarpals, tibia, femur, and humerus. Proportionally, the hyperostotic foci consisted of cancellous and woven bone, followed by osteoid, cartilage, and fibrous connective tissue and rarely inflammatory cells. A displaced, presumably pathological fracture with callus formation was a concurrent lesion in only one case. Tartrate-resistant acid phosphatase-positive cells were frequent at bony interfaces, indicating an active resorptive process. Periosteal hyperostosis is an incidental and potentially common finding in DBA/1 mice. Underreporting may occur due to the male bias in disease expression of this CIA model, sampling bias (generally paws only), tissue obliteration in the presence of CIA, and lack of comprehensive historical data on the background and aging lesions in this strain of mouse. Identification of such confounding bony lesions is important to the interpretation of efficacy studies, and suggests the need to further examine the biology of bone development in this strain of mouse.

Differential expression of collagen types I, II, III, and X in human osteophytes.

BACKGROUND: Osteophytes are neoplastic cartilaginous and osseous protrusions growing at the margins of osteoarthritic joints. Their formation involves complex patterns of cellular proliferation, differentiation, as well as matrix synthesis and turnover that are poorly understood. EXPERIMENTAL DESIGN: Here we report on an experimental approach using in situ hybridization and immunohistology to elucidate pathways of chrondrocyte differentiation in human osteophytes. Ab and cDNA probes for collagen types were used as specific parameters for chondrocyte phenotypes. RESULTS: In early precartilaginous mesenchymal tissue, cytoplasmic mRNA for alpha 1(I) and alpha 1(III) collagen genes (Col1A1 and Col3A1) were found by in situ hybridization, correlating with the distribution of type I and III collagen as revealed by Ab staining. Strong expression of type II collagen both at mRNA and protein levels was the hallmark of chondrogenic differentiation in the cartilaginous zone of osteophytes. Type II collagen expression increased in all cartilaginous and fibrocartilaginous areas with growth and maturation of osteophytes. The signal intensity obtained after in situ hybridization with a COL2A1 probe was high and corresponded to that obtained in fetal cartilage, whereas normal adult articular cartilage usually did not show measurable type II collagen expression. In fibrocartilaginous areas, the most abundant, but heterogeneous tissue type seen in osteophytes, type II and III collagen mRNA expression overlapped considerably. Type III collagen was scattered, both pericellularly and interterritorially, over the whole osteophyte, excluding bone and chondrocytic cells of the deep zone. The strongest type I collagen expression was seen in bone and in the superficial fibrous layer. In areas of endochondral ossification, large chondrocytes were found expressing type X collagen, a specific marker for hypertrophic chondrocytes. CONCLUSIONS: These results show that discrete stages of cartilage differentiation can be precisely followed in osteophytes using collagen type-specific cDNA probes and Ab as markers. In addition, a fibrocartilaginous chondrocyte phenotype was identified that expresses type II and III, but not type I collagen.