Cryptococcoma hipofisiario: un extraño caso de hipofisitis granulomatosa secundaria / Pituitary cryptococcoma: a strange case of secondary granulomatous hypophysitis

Resumen La hipofisitis es una afección con baja incidencia y prevalencia. Asimismo, las infecciones profundas por hongos en pacientes inmunocompetentes también re presentan un fenómeno infrecuente. Más raro aún es el caso que se describe a continuación, en donde se conjugan estos dos elementos mencionados, a saber: cryptococcoma hipofisario o hipofisitis granulomatosa causado por dicho patógeno en un huésped sin altera ción de la respuesta inmune. Luego de una búsqueda realizada en PubMed, existen limitados casos en la literatura médica de hipofisitis granulomatosa por Cryptococcus spp., que simuló por manifestaciones clínicas e imagenológicas un macro adenoma hipofisario. No encontramos informes en los que no haya evidencia de afectación del tejido meníngeo. La etiología micótica está escasamente descrita en las guías de referencia para hipofisitis y creemos que Cryp tococcus spp. debe ser tenido en cuenta en el diagnóstico diferencial de las hipofisitis granulomatosas secundarias dado que es un patógeno ubicuo y el tratamiento es sustancialmente diferente a otras entidades. Cobra mayor relevancia ante la tendencia actual al uso de glucocorticoides sistémicos a altas dosis para el tratamiento de la hipofisitis, que podría haber gene rado mayor daño de no haberse hecho el diagnóstico correcto.

Abstract Hypophysitis is a pathology with low incidence and prevalence. Likewise, deep fungal infections in immuno competent patients also represent a rare phenomenon. Even rarer is the case described below, where these two mentioned elements are combined, namely: pituitary cryptococcoma or granulomatous hypophysitis caused by said pathogen in a host without altered immune response. After research in PubMed, there are limited cases in the medical literature of granulomatous hypophysitis caused by Cryptococcus spp., which simulated a pituitary macroadenoma by clinical and imaging manifestations. We did not find reports in which there is no evidence of involvement of the meningeal tissue. The fungal etiology is scarcely described in the reference guidelines for hypophysitis and we believe that Cryptococcus spp. it should be taken into account in the differential diagnosis of secondary granuloma tous hypophysitis since it is a ubiquitous pathogen and the treatment is substantially different from other entities. It becomes more relevant given the current trend towards the use of high-dose systemic glucocorticoids for the treatment of hypophysitis, which could have generated greater damage if the correct diagnosis had not been made.

[Pituitary cryptococcoma: a strange case of secondary granulomatous hypophysitis]. / Cryptococcoma hipofisiario: un extraño caso de hipofisitis granulomatosa secundaria.

Hypophysitis is a pathology with low incidence and prevalence. Likewise, deep fungal infections in immunocompetent patients also represent a rare phenomenon. Even rarer is the case described below, where these two mentioned elements are combined, namely: pituitary cryptococcoma or granulomatous hypophysitis caused by said pathogen in a host without altered immune response. After research in PubMed, there are limited cases in the medical literature of granulomatous hypophysitis caused by Cryptococcus spp., which simulated a pituitary macroadenoma by clinical and imaging manifestations. We did not find reports in which there is no evidence of involvement of the meningeal tissue. The fungal etiology is scarcely described in the reference guidelines for hypophysitis and we believe that Cryptococcus spp. it should be taken into account in the differential diagnosis of secondary granulomatous hypophysitis since it is a ubiquitous pathogen and the treatment is substantially different from other entities. It becomes more relevant given the current trend towards the use of high-dose systemic glucocorticoids for the treatment of hypophysitis, which could have generated greater damage if the correct diagnosis had not been made.

La hipofisitis es una afección con baja incidencia y prevalencia. Asimismo, las infecciones profundas por hongos en pacientes inmunocompetentes también representan un fenómeno infrecuente. Más raro aún es el caso que se describe a continuación, en donde se conjugan estos dos elementos mencionados, a saber: cryptococcoma hipofisario o hipofisitis granulomatosa causado por dicho patógeno en un huésped sin alteración de la respuesta inmune. Luego de una búsqueda realizada en PubMed, existen limitados casos en la literatura médica de hipofisitis granulomatosa por Cryptococcus spp., que simuló por manifestaciones clínicas e imagenológicas un macroadenoma hipofisario. No encontramos informes en los que no haya evidencia de afectación del tejido meníngeo. La etiología micótica está escasamente descrita en las guías de referencia para hipofisitis y creemos que Cryptococcus spp. debe ser tenido en cuenta en el diagnóstico diferencial de las hipofisitis granulomatosas secundarias dado que es un patógeno ubicuo y el tratamiento es sustancialmente diferente a otras entidades. Cobra mayor relevancia ante la tendencia actual al uso de glucocorticoides sistémicos a altas dosis para el tratamiento de la hipofisitis, que podría haber generado mayor daño de no haberse hecho el diagnóstico correcto.

[Toxic epidermal necrolysis: idiosyncratic reaction to drugs]. / Necrólisis epidérmica tóxica: reacción idiosincrática a neurofármacos.

Toxic epidermal necrolysis (NET) and Steven Johnson syndrome (SJS) are infrequent mucocutaneous hypersensitivity reactions with systemic involvement. They are predominantly caused by drugs. We report the case of a patient over 60 years of age who presented with extensive mucocutaneous and ophthalmic injury with hemodynamic failure, associated with the rapid onset of lamotrigine in a short period of time. Although the incidence is low, the mortality rate is high. It requires early suspicious and diagnosis in addition to an interdisciplinary therapeutic approach.

Splice variant rs72613567 prevents worst histologic outcomes in patients with nonalcoholic fatty liver disease.

Hydroxysteroid 17-ß dehydrogenase 13 (HSD17B13) is a lipid droplet-associated protein; its gene-encoding variants affect the chronic liver diseases, including nonalcoholic fatty liver disease (NAFLD). To estimate the effect of rs72613567, a splice variant with an adenine insertion (A-INS), on NAFLD susceptibility and severity, we performed a case-control study with 609 individuals. We investigated the effect of carrying the A-INS allele in 356 patients with biopsy-proven disease and explored the relationship between rs72613567 genotypes and the hepatic transcriptome. The A-INS allele protected against NAFLD [odds ratio (OR) per adenine allele = 0.667; 95% CI, 0.486-0.916; P = 0.012]; this effect was nonsignificant when logistic regression analysis included BMI. The A-INS allele protected against nonalcoholic steatohepatitis (NASH) (OR = 0.612; 95% CI, 0.388-0.964; P = 0.033), ballooning degeneration (OR = 0.474; 95% CI, 0.267-0.842; P = 0.01), lobular inflammation (OR = 0.475; 95% CI, 0.275-0.821; P = 0.007), and fibrosis (OR = 0.590; 95% CI, 0.361-0.965; P = 0.035). In patients carrying A-INS, HSD17B13 levels decreased proportionally to allele dosage. Whole-transcriptome genotype profiling showed overrepresented immune response-related pathways. Thus, the rs72613567 A-INS allele reduces the risk of NASH and progressive liver damage and may become a therapeutic target.

A Rare Nonsense Mutation in the Glucokinase Regulator Gene Is Associated With a Rapidly Progressive Clinical Form of Nonalcoholic Steatohepatitis.

We report on the presence of a rare nonsense mutation (rs149847328, p.Arg227Ter) in the glucokinase regulator (GCKR) gene in an adult patient with nonalcoholic fatty liver disease (NAFLD), morbid obesity, and type 2 diabetes; this patient developed a progressive histological form of the disease. Analysis of paired (5 years apart) liver biopsies (at baseline and follow-up) showed progression of simple steatosis to severe nonalcoholic steatohepatitis and cirrhosis. Study design involved an initial exploration that consisted of deep sequencing of 14 chromosomal regions in 96 individuals (64 of whom were patients with NAFLD who were diagnosed by liver biopsy that showed the full spectrum of histological severity). We further performed a replication study to explore the presence of rs149847328 that included a sample of 517 unrelated individuals in a case-control study (n = 390), including patients who were morbidly obese (n = 127). Exploration of sequence variation by next-generation sequencing of exons, exon-intron boundaries, and 5' and 3' untranslated regions of 14 genomic loci that encode metabolic enzymes of the tricarboxylic acid cycle revealed the presence of heterozygosity for the p.Arg227Ter mutation, the frequency of which is 0.0003963 (4:10,000; Exome Aggregation Consortium database). GCKR protein expression was markedly decreased in the liver of the affected patient compared with patients with NAFLD who carry the wild-type allele. Sequencing of the same 14 genomic loci in 95 individuals failed to reveal the rare mutation. The rarity of p.Arg227Ter was confirmed in a more extensive screening. Conclusion: While rare variants/mutations are difficult to detect in even reasonably large samples (frequency of the mutant allele of p.Arg227Ter was ~1:1,000 in our data set), the presence of this mutation should be suspected as potentially associated with NAFLD, particularly in young adults at the extreme of histological phenotypes. Hepatology Communications 2018;0:0-0).

Lack of evidence supporting a role of TMC4-rs641738 missense variant-MBOAT7- intergenic downstream variant-in the Susceptibility to Nonalcoholic Fatty Liver Disease.

Current knowledge on the genetic basis of nonalcoholic fatty liver disease (NAFLD) suggests that variants contributing not only to the disease predisposition but histological severity as well are located in genes that regulate lipid metabolism. We explored the role of rs641738 C/T located in TMC4 (transmembrane channel-like 4) exon 1 (p.Gly17Glu) and 500 bases- downstream of MBOAT7 gene (TMC4/MBOAT7), in the genetic risk for developing NAFLD in a case-control study. Our sample included 634 individuals (372 patients with NAFLD diagnosed by liver biopsy and 262 control subjects); genotyping was performed by a Taqman assay. Genotype frequencies in controls (CC: 84, CT: 137, TT: 41) and patients (CC: 134, CT: 178, TT: 60) were in Hardy-Weinberg equilibrium; minor allele frequency 40.8%. Our sample had 84-99% power if an additive genetic model is assumed for estimated odds ratios of 1.3-1.5, respectively. We found no evidence of association between rs641738 and either NAFLD (Cochran-Armitage test for trend, p = 0.529) or the disease severity (p = 0.61). Low levels of MBOAT7 protein expression were found in the liver of patients with NAFLD, which were unrelated to the rs641738 genotypes. In conclusion, the role of rs641738 in the pathogenesis of NAFLD is inconclusive.

[Congenital hypothyroidism secondary to thyroid hypoplasia detected in adulthood]. / Hipotiroidismo congénito secundario a hipoplasia tiroidea detectado en edad adulta.

The anatomical location of the thyroid gland and its hormone byosinthesis are regulated by the expression of certain genes, whose disruption leads to the so-called thyroid dysgenesis: agenesis, ectopia and hypoplasia, and to dyshormonogenesis. We present the case of a patient with mental retardation and hypothyroidism whose diagnosis was made in adulthood. Biochemical determinations confirmed the diagnosis without evidence of thyroid autoimmunity. This patient represents the extended evolution of a thyroid hypofunction, which lasted in an unsuspected way for 53 years, with important consequences of this deficiency at diagnosis. Exogenous therapy achieved great improvement in clinical symptoms, but did not reverse the neurological damage attributable to the lack of thyroid hormone necessary for fetal development. The necropsy revealed little thyroid tissue in the neck corresponding to eutopic thyroid hypoplasia. The discovery of a remaining thyroid of less than 1 cm justified the patient survival up to old age.

Hipotiroidismo congénito secundario a hipoplasia tiroidea detectado en edad adulta / Congenital hypothyroidism secondary to thyroid hypoplasia detected in adulthood

La ubicación anatómica de la glándula tiroidea y su biosíntesis hormonal están reguladas por la expresión de ciertos genes, cuya alteración puede conducir a las denominadas disgenesias tiroideas: agenesia, ectopía e hipoplasia, así como a las variantes dishormonogenéticas. Se presenta el caso de una paciente con retraso mental y diagnóstico de hipotiroidismo realizado en la edad adulta. Las determinaciones bioquímicas confirmaron el diagnóstico de hipotiroidismo no autoinmune. Este caso representa la evolución prolongada de una hipofunción tiroidea, que cursó en forma solapada y no diagnosticada durante 53 años de vida, con secuelas relevantes de esta deficiencia al momento del diagnóstico. La terapia exógena logró mejorías evidentes en la signo sintomatología, pero no revirtió el presunto daño neurológico atribuible a la falta de hormona tiroidea necesaria durante el desarrollo fetal. En la necropsia realizada se encontró escaso tejido tiroideo cervical correspondiente a hipoplasia tiroidea eutópica. El hallazgo de un remanente tiroideo menor a 1 cm permite explicar la supervivencia de la paciente hasta una edad avanzada.

The anatomical location of the thyroid gland and its hormone byosinthesis are regulated by the expression of certain genes, whose disruption leads to the so-called thyroid dysgenesis: agenesis, ectopia and hypoplasia, and to dyshormonogenesis. We present the case of a patient with mental retardation and hypothyroidism whose diagnosis was made in adulthood. Biochemical determinations confirmed the diagnosis without evidence of thyroid autoimmunity. This patient represents the extended evolution of a thyroid hypofunction, which lasted in an unsuspected way for 53 years, with important consequences of this deficiency at diagnosis. Exogenous therapy achieved great improvement in clinical symptoms, but did not reverse the neurological damage attributable to the lack of thyroid hormone necessary for fetal development. The necropsy revealed little thyroid tissue in the neck corresponding to eutopic thyroid hypoplasia. The discovery of a remaining thyroid of less than 1 cm justified the patient survival up to old age.

Hipotiroidismo congénito secundario a hipoplasia tiroidea detectado en edad adulta / Congenital hypothyroidism secondary to thyroid hypoplasia detected in adulthood

La ubicación anatómica de la glándula tiroidea y su biosíntesis hormonal están reguladas por la expresión de ciertos genes, cuya alteración puede conducir a las denominadas disgenesias tiroideas: agenesia, ectopía e hipoplasia, así como a las variantes dishormonogenéticas. Se presenta el caso de una paciente con retraso mental y diagnóstico de hipotiroidismo realizado en la edad adulta. Las determinaciones bioquímicas confirmaron el diagnóstico de hipotiroidismo no autoinmune. Este caso representa la evolución prolongada de una hipofunción tiroidea, que cursó en forma solapada y no diagnosticada durante 53 años de vida, con secuelas relevantes de esta deficiencia al momento del diagnóstico. La terapia exógena logró mejorías evidentes en la signo sintomatología, pero no revirtió el presunto daño neurológico atribuible a la falta de hormona tiroidea necesaria durante el desarrollo fetal. En la necropsia realizada se encontró escaso tejido tiroideo cervical correspondiente a hipoplasia tiroidea eutópica. El hallazgo de un remanente tiroideo menor a 1 cm permite explicar la supervivencia de la paciente hasta una edad avanzada.(AU)

The anatomical location of the thyroid gland and its hormone byosinthesis are regulated by the expression of certain genes, whose disruption leads to the so-called thyroid dysgenesis: agenesis, ectopia and hypoplasia, and to dyshormonogenesis. We present the case of a patient with mental retardation and hypothyroidism whose diagnosis was made in adulthood. Biochemical determinations confirmed the diagnosis without evidence of thyroid autoimmunity. This patient represents the extended evolution of a thyroid hypofunction, which lasted in an unsuspected way for 53 years, with important consequences of this deficiency at diagnosis. Exogenous therapy achieved great improvement in clinical symptoms, but did not reverse the neurological damage attributable to the lack of thyroid hormone necessary for fetal development. The necropsy revealed little thyroid tissue in the neck corresponding to eutopic thyroid hypoplasia. The discovery of a remaining thyroid of less than 1 cm justified the patient survival up to old age.(AU)

Hipotiroidismo congénito secundario a hipoplasia tiroidea detectado en edad adulta. / [Congenital hypothyroidism secondary to thyroid hypoplasia detected in adulthood].

The anatomical location of the thyroid gland and its hormone byosinthesis are regulated by the expression of certain genes, whose disruption leads to the so-called thyroid dysgenesis: agenesis, ectopia and hypoplasia, and to dyshormonogenesis. We present the case of a patient with mental retardation and hypothyroidism whose diagnosis was made in adulthood. Biochemical determinations confirmed the diagnosis without evidence of thyroid autoimmunity. This patient represents the extended evolution of a thyroid hypofunction, which lasted in an unsuspected way for 53 years, with important consequences of this deficiency at diagnosis. Exogenous therapy achieved great improvement in clinical symptoms, but did not reverse the neurological damage attributable to the lack of thyroid hormone necessary for fetal development. The necropsy revealed little thyroid tissue in the neck corresponding to eutopic thyroid hypoplasia. The discovery of a remaining thyroid of less than 1 cm justified the patient survival up to old age.