Aftosis oral y laringitis, ¿otra forma de presentación de la enfermedad relacionada con IgG4? / Aphthous stomatitis and laryngitis, another form of presentation of an IgG4-related disease?

La enfermedad relacionada con IgG4 (ER-IgG4) se caracteriza por un infiltrado linfoplasmocítico rico en células plasmáticas IgG4 positivas, fibrosis estoriforme y flebitis obliterativa. Se puede presentar como seudotumor orbitario, parotidomegalia, nefritis túbulo intersticial, fibrosis retroperitoneal o pancreatitis, aunque prácticamente cualquier órgano puede verse afectado. Presentamos el caso de una mujer de 37 años, que presenta un cuadro de disfonía severa y aftosis oral dolorosa recurrente, con unos hallazgos histopatológicos a nivel laríngeo que muestran infiltrado linfoplasmocítico y positividad para IgG4, así como amplios estudios descartando otras etiologías, por lo que se confirma una laringitis por ER-IgG4, cuya descripción en la literatura es excepcional

IgG4-related disease is characterized by a lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis and obliterative phlebitis. It can present as parotid gland enlargement, tubulointerstitial nephritis, retroperitoneal fibrosis or pancreatitis, although nearly any organ can be affected. We report the case of a 37-year-old woman who presented with severe dysphonia and recurrent painful aphthous ulcers, with histopathological findings at the level of the larynx that revealed a lymphoplasmacytic infiltrate and IgG4 positivity. In addition, extensive studies were performed to rule out other diseases. Thus the diagnosis was IgG4-related laryngitis, an exceptional finding in the literature

Aphthous Stomatitis and Laryngitis, Another Form of Presentation of an IgG4-Related Disease? / Aftosis oral y laringitis, ¿otra forma de presentación de la enfermedad relacionada con IgG4?

IgG4-related disease is characterized by a lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis and obliterative phlebitis. It can present as parotid gland enlargement, tubulointerstitial nephritis, retroperitoneal fibrosis or pancreatitis, although nearly any organ can be affected. We report the case of a 37-year-old woman who presented with severe dysphonia and recurrent painful aphthous ulcers, with histopathological findings at the level of the larynx that revealed a lymphoplasmacytic infiltrate and IgG4 positivity. In addition, extensive studies were performed to rule out other diseases. Thus the diagnosis was IgG4-related laryngitis, an exceptional finding in the literature.

Bone metastases as initial presentation of hepatocellular carcinoma.

Extra-hepatic spread is present in 5% to 15% of patients with hepatocellular carcinoma (HCC) at the time of diagnosis. The most frequent sites are lung and regional lymph nodes. Here, we report 3 cases of unsuspected HCC with symptoms due to bone lesions as initial presentation. Morphological characteristics and immunohistochemistry from the examined bone were the key data for diagnosis. None of the patients had an already known chronic liver disease. Differential diagnoses with HCC upon ectopic liver disease or hepatoid adenocarcinoma were shown. Therapy with the orally active multikinase inhibitor sorafenib plus symptomatic treatment was indicated.

Androgen receptor dysfunction as a prevalent manifestation in young male carriers of a FLNA gene mutation.

Androgenic actions require the proper signal transmission by the androgen receptor (AR), a nuclear transcription factor. This is initially located in the cell cytoplasm and should translocates to the nucleus to interact with DNA. AR functional impairment causes diverse blockage degrees of androgenic steroid action, known as androgen insensitivity syndromes. Filamin A, a protein coded by the FLNA gene, is a co-activator of various cytoplasmic factors, including AR. The mutational inactivation of the FLNA gene induces insufficiency of translocation and activation of AR. Consequently, it causes a developmental disorder of the male gonad and hypogonadism, similar to those observed in partial androgen insensitivity. We report two brothers carrying a loss-of-function mutation of FNLA with gonadal differentiation disorder and hypospadias. Specific staining for AR shows almost an absolute absence of these receptors in the testicular tissue. This association recommends investigating a possible mutational inactivation of the FLNA gene in patients with cryptorchidism and epididymo-testicular dissociation. The study is especially indicated when the family history, more often that of the mother, is suggestive. Likewise, growth and gonadal development of all male patients carrying this genetic trait should be monitored since childhood.

A single-copy Sleeping Beauty transposon mutagenesis screen identifies new PTEN-cooperating tumor suppressor genes.

The overwhelming number of genetic alterations identified through cancer genome sequencing requires complementary approaches to interpret their significance and interactions. Here we developed a novel whole-body insertional mutagenesis screen in mice, which was designed for the discovery of Pten-cooperating tumor suppressors. Toward this aim, we coupled mobilization of a single-copy inactivating Sleeping Beauty transposon to Pten disruption within the same genome. The analysis of 278 transposition-induced prostate, breast and skin tumors detected tissue-specific and shared data sets of known and candidate genes involved in cancer. We validated ZBTB20, CELF2, PARD3, AKAP13 and WAC, which were identified by our screens in multiple cancer types, as new tumor suppressor genes in prostate cancer. We demonstrated their synergy with PTEN in preventing invasion in vitro and confirmed their clinical relevance. Further characterization of Wac in vivo showed obligate haploinsufficiency for this gene (which encodes an autophagy-regulating factor) in a Pten-deficient context. Our study identified complex PTEN-cooperating tumor suppressor networks in different cancer types, with potential clinical implications.

Síndrome sarcoidosis-linfoma / Sarcoidosis-lymphoma syndrome

Mujer de 65 años de edad con antecedentes de sarcoidosis, con afectación pulmonar y articular, que tras 5 años del diagnóstico comienza con afectación del sistema nervioso central, manifestándose como diplopía. Presenta analíticas normales. En las pruebas de imagen se identifica masa intraconal derecha dependiente del nervio óptico derecho, así como múltiple afectación adenopática. Se realizó biopsia con diagnóstico de linfoma B de células grandes, forma atípica de tumor asociado a sarcoidosis (AU)

A 65 year-old female with a history of sarcoidosis with pulmonary and joint involvement, who after 5 years of diagnosis begins with central nervous system involvement manifesting as diplopia. She presents normal analysis results. In imaging results, a mass is identified in the right intraconal space; it depends of right optic nerve, and shows multiple lymph node involvement. Biopsy was performed diagnosed with large B-cell lymphoma, an atypical form of tumor associated with sarcoidosis (AU)

Sarcoidosis-lymphoma syndrome. / Síndrome sarcoidosis-linfoma.

A 65 year-old female with a history of sarcoidosis with pulmonary and joint involvement, who after 5 years of diagnosis begins with central nervous system involvement manifesting as diplopia. She presents normal analysis results. In imaging results, a mass is identified in the right intraconal space; it depends of right optic nerve, and shows multiple lymph node involvement. Biopsy was performed diagnosed with large B-cell lymphoma, an atypical form of tumor associated with sarcoidosis.

Loss of MT1-MMP causes cell senescence and nuclear defects which can be reversed by retinoic acid.

MT1-MMP (MMP14) is a collagenolytic enzyme located at the cell surface and implicated in extracellular matrix (ECM) remodeling. Mmp14(-/-) mice present dwarfism, bone abnormalities, and premature death. We demonstrate herein that the loss of MT1-MMP also causes cardiac defects and severe metabolic changes, and alters the cytoskeleton and the nuclear lamina structure. Moreover, the absence of MT1-MMP induces a senescent phenotype characterized by up-regulation of p16(INK4a) and p21(CIP1/WAF) (1), increased activity of senescence-associated ß-galactosidase, generation of a senescence-associated secretory phenotype, and somatotroph axis alterations. Consistent with the role of retinoic acid signaling in nuclear lamina stabilization, treatment of Mmp14(-/-) mice with all-trans retinoic acid reversed the nuclear lamina alterations, partially rescued the cell senescence phenotypes, ameliorated the pathological defects in bone, skin, and heart, and extended their life span. These results demonstrate that nuclear architecture and cell senescence can be modulated by a membrane protease, in a process involving the ECM as a key regulator of nuclear stiffness under cell stress conditions.

MMP-8 deficiency increases TLR/RAGE ligands S100A8 and S100A9 and exacerbates lung inflammation during endotoxemia.

Matrix metalloproteinase-8, released mainly from neutrophils, is a critical regulator of the inflammatory response by its ability to cleave multiple mediators. Herein, we report the results of a model of endotoxemia after intraperitoneal LPS injection in mice lacking MMP-8 and their wildtype counterparts. Control, saline-treated animals showed no differences between genotypes. However, there was an increased lung inflammatory response, with a prominent neutrophilic infiltration in mutant animals after LPS treatment. Using a proteomic approach, we identify alarmins S100A8 and S100A9 as two of the main differences between genotypes. Mice lacking MMP-8 showed a significant increase in these two molecules in lung homogenates, but not in spleen and serum. Mice lacking MMP-8 also showed an increase in MIP-1α levels and a marked activation of the non-canonical NF-κB pathway, with no differences in CXC-chemokines such as MIP-2 or LIX. These results show that MMP-8 can modulate the levels of S100A8 and S100A9 and its absence promotes the lung inflammatory response during endotoxemia.

Loss of mitochondrial protease OMA1 alters processing of the GTPase OPA1 and causes obesity and defective thermogenesis in mice.

Mitochondria are dynamic subcellular organelles that convert nutrient intermediates into readily available energy equivalents. Optimal mitochondrial function is ensured by a highly evolved quality control system, coordinated by protein machinery that regulates a process of continual fusion and fission. In this work, we provide in vivo evidence that the ATP-independent metalloprotease OMA1 plays an essential role in the proteolytic inactivation of the dynamin-related GTPase OPA1 (optic atrophy 1). We also show that OMA1 deficiency causes a profound perturbation of the mitochondrial fusion-fission equilibrium that has important implications for metabolic homeostasis. Thus, ablation of OMA1 in mice results in marked transcriptional changes in genes of lipid and glucose metabolic pathways and substantial alterations in circulating blood parameters. Additionally, Oma1-mutant mice exhibit an increase in body weight due to increased adipose mass, hepatic steatosis, decreased energy expenditure and impaired thermogenenesis. These alterations are especially significant under metabolic stress conditions, indicating that an intact OMA1-OPA1 system is essential for developing the appropriate adaptive response to different metabolic stressors such as a high-fat diet or cold-shock. This study provides the first description of an unexpected role in energy metabolism for the metalloprotease OMA1 and reinforces the importance of mitochondrial quality control for normal metabolic function.

Inflammation and matrix remodeling during repair of ventilator-induced lung injury.

High-pressure ventilation triggers different inflammatory and matrix remodeling responses within the lung. Although some of them may cause injury, the involvement of these mediators in repair is largely unknown. To identify mechanisms of repair after ventilator-induced lung injury (VILI), mice were randomly assigned to baseline conditions (no ventilation), injury [90 min of high-pressure ventilation without positive end-expiratory pressure (PEEP)], repair (injury followed by 4 h of low-pressure ventilation with PEEP), and ventilated controls (low-pressure ventilation with PEEP for 90 and 330 min). Histological injury and lung permeability increased during injury, but were partially reverted in the repair group. This was accompanied by a proinflammatory response, together with increases in TNF-α and IFN-γ, which returned to baseline during repair, and a decrease in IL-10. However, macrophage inflammatory protein-2 (MIP-2) and matrix metalloproteinases (MMP)-2 and -9 increased after injury and persisted in being elevated during repair. Mortality in the repair phase was 50%. Survivors showed increased cell proliferation, lower levels of collagen, and higher levels of MIP-2 and MMP-2. Pan-MMP or specific MMP-2 inhibition (but not MIP-2, TNF-α, or IL-4 inhibition) delayed epithelial repair in an in vitro wound model using murine or human alveolar cells cultured in the presence of bronchoalveolar lavage fluid from mice during the repair phase or from patients with acute respiratory distress syndrome, respectively. Similarly, MMP inhibition with doxycycline impaired lung repair after VILI in vivo. In conclusion, VILI can be reverted by normalizing ventilation pressures. An adequate inflammatory response and extracellular matrix remodeling are essential for recovery. MMP-2 could play a key role in epithelial repair after VILI and acute respiratory distress syndrome.

Kaposi's sarcoma: an opportunistic infection by human herpesvirus-8 in ulcerative colitis.

Kaposi's sarcoma is a vascular tumor caused by human herpesvirus-8 infection. Iatrogenic Kaposi's sarcoma often occurs in patients receiving immunosuppressive therapy. To date, a few cases of colonic Kaposi's sarcoma have been reported in ulcerative colitis patients treated with immunomodulators. We describe a 65-year-old male diagnosed with left-sided ulcerative colitis who was treated with methotrexate and low-dose steroids for greater than 6 years. He presented with several papular, violet lesions on both legs. Colonoscopy revealed the presence of multiple reddish, elevated lesions in the sigmoid colon and rectum. Histological evaluation of skin and colonic biopsies showed findings suggestive of Kaposi's sarcoma; immunohistochemistry for human herpesvirus-8 was positive in the colonic lesions. To avoid the need for further immunosuppressive treatment, the patient underwent a colectomy. Following immunomodulator discontinuation, the patient experienced spontaneous regression of his skin lesions. With the present case, we wish to stress the important interaction of immunosuppressive therapy (mainly corticosteroids) used in ulcerative colitis patients in relation to the development of colonic Kaposi's sarcoma. Human herpesvirus-8 infection should be recognized as a possible opportunistic infection in patients with inflammatory bowel disease.

Malignant triton tumor of the infratemporal fossa.

Malignant triton tumor is a very aggressive type of sarcoma that comprises rhabdomyoblasts and malignant Schwann cells. It is a different entity from malignant schwannoma, characterized by their aggressiveness and poor prognosis. Head and neck location is frequent, and early diagnosis and complete resection followed by radiation therapy is important for long-term survival. However, the therapeutic plan should be individualized, taking into account the location and size of the primary tumor. The use of adjuvant chemotherapy and molecular therapies should be considered in the treatment of these tumors. We report an unusual presentation of a malignant triton tumor located in the infratemporal fossa, describing its clinical and pathologic features, and we try to update the knowledge in the management of these tumors, including the use of molecular therapies.

[Luetic hepatitis. An emerging entity]. / Hepatitis luética. Una entidad emergente.

Liver involvement is unusual in the course of syphilitic infection. We present four cases of luetic hepatitis diagnosed at our hospital in the last 5 years. One patient was coinfected with hepatitis B virus and another patient was coinfected with hepatitis C virus and HIV. The presence of maculopapular skin lesions in palmoplantar distribution, as well as serological confirmation, were decisive for the diagnosis of syphilitic hepatitis, allowing early antibiotic therapy to be established, with clinical and analytical improvement in all patients. Luetic hepatitis should be considered in patients with risky sexual behavior, skin lesions and altered liver function tests with a predominance of cholestasis, despite the finding of other, more frequent, liver diseases, given that these entities may be concurrent. Early diagnosis of syphilis leads to effective treatment of the patient and to epidemiological control of the infection.

Hepatitis luética. Una entidad emergente / Luetic hepatitis. An emerging entity

La afectación hepática por sífilis es infrecuente. Se exponen 4 casos de hepatitis luética diagnosticados en los últimos 5 años. Uno presentaba coinfección por virus de la inmunodeficiencia humana y virus de la hepatitis C, y otro por virus de la hepatitis B. Las lesiones cutáneas maculopapulosas de extensión palmoplantar y la confirmación serológica fueron determinantes para llegar al diagnóstico. Ante el aumento de incidencia de las enfermedades de transmisión sexual, entre ellas la sífilis, es importante tener en cuenta el diagnóstico de hepatitis luética en aquellos pacientes que presentan hábitos sexuales de riesgo y alteración de pruebas de función hepática con predominio de colestasis, y no conviene descartarla a pesar del hallazgo de otras enfermedades hepáticas más frecuentes, dado que pueden coexistir. El diagnóstico precoz de la sífilis conduce a un tratamiento eficaz para el individuo y para el control epidemiológico de la infección(AU)

Liver involvement is unusual in the course of syphilitic infection. We present four cases of luetic hepatitis diagnosed at our hospital in the last 5 years. One patient was coinfected with hepatitis B virus and another patient was coinfected with hepatitis C virus and HIV. The presence of maculopapular skin lesions in palmoplantar distribution, as well as serological confirmation, were decisive for the diagnosis of syphilitic hepatitis, allowing early antibiotic therapy to be established, with clinical and analytical improvement in all patients. Luetic hepatitis should be considered in patients with risky sexual behavior, skin lesions and altered liver function tests with a predominance of cholestasis, despite the finding of other, more frequent, liver diseases, given that these entities may be concurrent. Early diagnosis of syphilis leads to effective treatment of the patient and to epidemiological control of the infection(AU)