Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms.

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.

Elastography in musculoskeletal imaging: A tool or a toy?

Elastography is a novel imaging technique based on ultrasound that evaluates the deformability of tissues to help characterize lesions. It is widely used and has been validated in many tissues (e.g., liver, breast, thyroid). It is also used in the study of musculoskeletal disease. Although the use of elastography in musculoskeletal radiology is limited by the variability and heterogeneity of tissues, it is a very promising technique. In this article, we aim to review the usefulness, possible indications, limitations, and future perspectives of this technique in musculoskeletal radiology.

Elastografía en musculoesquelético. ¿Herramienta o juguete? / Elastography in musculoskeletal imaging: a tool or a toy?

La elastografía es una novedosa técnica de imagen basada en los ultrasonidos que valora la deformabilidad de los tejidos para ayudar a caracterizar las lesiones. Su uso está muy extendido y ha sido validada en muchos tejidos (hígado, mama, tiroides, etc.). También se aplica en el estudio de la patología musculoesquelética, aunque con limitaciones debido a la variabilidad y heterogeneidad de los tejidos; no obstante, es una técnica muy prometedora. En este artículo trataremos de revisar su utilidad, posibles indicaciones, limitaciones y perspectivas de futuro.(AU)

Elastography is a novel imaging technique based on ultrasound that evaluates the deformability of tissues to help characterize lesions. It is widely used and has been validated in many tissues (e.g., liver, breast, thyroid). It is also used in the study of musculoskeletal disease. Although the use of elastography in musculoskeletal radiology is limited by the variability and heterogeneity of tissues, it is a very promising technique. In this article, we aim to review the usefulness, possible indications, limitations, and future perspectives of this technique in musculoskeletal radiology.(AU)

Central adrenal insufficiency screening with morning plasma cortisol and ACTH levels in Prader-Willi syndrome.

OBJECTIVES: Prader-Willi syndrome (PWS) is a complex genetic disorder with severe hypotonia, failure to thrive, childhood obesity, hypogonadism/hypogenitalism and learning/behavioral problems with endocrine-related growth and other hormone deficiencies. The prevalence of central adrenal insufficiency (CAI) using dynamic testing ranges from rare to 60%. We compared routine morning plasma cortisol (MPC) and ACTH levels in large cohorts of PWS and control children to address CAI. METHODS: Retrospective analysis of MPC and ACTH levels was undertaken in 128 PWS growth hormone (GH)-treated children under medical care before considering dynamic testing for CAI and 128 non-syndromic control children with short stature evaluated for GH deficiency. RESULTS: The average MPC level in PWS was 9.7 ± 3.7 µg/dL with no difference in age, gender or PWS genetic subtype and 13.4 ± 5.7 µg/dL in the control group. MPC levels were significantly lower (p < 0.05) in PWS but in the normal range. The morning plasma ACTH level in the PWS group was 22.1 ± 8.0 pg/mL with one individual having an initial low plasma ACTH level (8 pg/mL), but normal upon repeat. CONCLUSIONS: MPC levels in PWS are normal and comparable with control children, without evidence or increased risk of CAI. Lower but normal MPC levels were seen in PWS and suggestive of reduced local regeneration of cortisol from cortisone in adipose tissue by the GH-IGF-I system. Hence, MPC measures alone or in combination with ACTH should be considered for initial screening for CAI in PWS but prior to dynamic testing.

What Is the most Important for Elite Control: Genetic Background of Patient, Genetic Background of Partner, both or neither? Description of Complete Natural History within a Couple of MSM.

BACKGROUND: We describe a homosexual man who strongly controlled HIV-1 for ten years despite lack of protective genetic background. METHODS: HIV-1 DNA was measured in blood and other tissues. Cell susceptibility was evaluated with various strains. HIV-1-specific (CD4 and CD8 activation markers and immune check points) and NK cells responses were assessed; KIRs haplotypes and HLA alleles were determined. FINDINGS: Two HIV-1 RNA copies/mL of plasma were detected in 2009, using an ultra-sensitive assay. HIV-DNA was detected at 1.1 and 2 copies/106 PBMCs in 2009 and 2015 respectively, at 1.2 copies/106 cells in rectal cells in 2011. WBs showed weak reactivity with antibodies to gp160, p55 and p25 from 2007 to 2014, remaining incomplete in 2017. CD4 T cells were susceptible to various strains including HIVKON, a primary isolate of his own CRF02_AG variant. CD8 T cells showed a strong poly-functional response against HIV-Gag, producing mainly IFN-γ; a robust capacity of antibody-dependant cell cytotoxicity (ADCC) was observed in NK cells. Case patient was group B KIR haplotype. Neutralizing antibodies were not detected. CD4 and CD8 blood T cells showed normal proportions without increased activation markers. Phylogenetic analyses identified the same CRF02_AG variant in his partner. The patient and his partner were heterozygous for the CCR5ΔD32 deletion and shared HLA-B*07, C*07 non-protective alleles. INTERPRETATION: This thorough description of the natural history of an individual controlling HIV-1 in various compartments for ten years despite lack of protective alleles, and of his partner, may have implications for strategies to cure HIV-1 infection.

Síndrome de Kearns-Sayre / Kearns-Sayre syndrome

No disponible

Psychiatric adverse effects of rimonobant in adults with Prader Willi syndrome.

BACKGROUND: Prader Willi syndrome (PWS) without strict environmental modifications can lead to obesity associated with significant morbidity and mortality. In addition to increased appetite, these individuals have decreased energy expenditure with lower insulin like growth factor 1 (IGF1), which contributes to adiposity. No effective treatment is available for this condition. Endocannabinoid receptor CB1 antagonist, rimonobant, has been effective for treatment of obesity in adult subjects. Rimonabant promotes weight loss by multiple proposed mechanisms, including decreased appetite and lipogenesis, and increased energy expenditure. Therefore, we conducted this pilot study to evaluate the effect of rimonabant on body weight and composition of adults with PWS. METHOD: This was a double blind placebo controlled study. Body weight, total fat mass, fasting ghrelin, leptin, IGF1 and insulin like growth factor binding protein (IGFBP-3) were collected at baseline, and after 90 and 180 days of treatment with placebo or 20 mg of rimonabant. RESULTS: Due to psychiatric adverse effects, 50% of subjects in the rimonabant group withdrew, and the study was terminated early (N=10) for safety concerns. There was a trend for weight loss, lower fat mass and higher IGF1 level at the end of study in this group. Leptin followed the fat mass and decreased with rimonabant treatment. CONCLUSION: Rimonabant administration may be efficacious for weight loss in adults with PWS; unfortunately it is associated with an unacceptably high risk of psychiatric side effects. Future CB1 antagonists will need a better psychiatric profile before considered in the treatment of obesity in this genetic condition.

Lesión quística congénita en la pelvis: un caso de útero didelfo con doble vagina, hematocolpos y agenesia renal ipsilateral: papel de la resonancia magnética / The role of MRI in congenital cystic lesions in the pelvis: A case of uterus didelphys with double vagina, hematocolpos, and ipsilateral renal agenesis

Se presenta un caso de útero didelfo con hemivagina ciega y agenesia renal ipsilateral. Es una anomalía infrecuente del desarrollo de los conductos de Müller. El defecto en uno de los conductos de Wolf condiciona un fallo en la inducción de la formación renal y en la fusión de los conductos de Müller. La resonancia magnética desempeña un papel decisivo en el diagnóstico y caracterización de la malformación (AU)

We report a case of uterus didelphys with blind hemivagina and ipsilateral renal agenesis. This is an uncommon anomaly of the development of the Mullerian ducts in which a defect in one of the Wolffian ducts leads to failed induction in kidney formation and in the fusion of the Mullerian ducts. MRI plays a decisive role in the diagnosis and characterization of the malformation (AU)

[The role of MRI in congenital cystic lesions in the pelvis: a case of uterus didelphys with double vagina, hematocolpos, and ipsilateral renal agenesis.]. / Lesión quística congénita en la pelvis: un caso de útero didelfo con doble vagina, hematocolpos y agenesia renal ipsilateral: papel de la resonancia magnética.

We report a case of uterus didelphys with blind hemivagina and ipsilateral renal agenesis. This is an uncommon anomaly of the development of the Mullerian ducts in which a defect in one of the Wolffian ducts leads to failed induction in kidney formation and in the fusion of the Mullerian ducts. MRI plays a decisive role in the diagnosis and characterization of the malformation.

Hemangioendotelioma hepático infantil / Infantile hemangioendothelioma of the liver

El hemangionedotelioma hepático infantil es un tumor benigno compuesto de canales vasculares anastomosados. Lo más frecuente es que se produzcan síntomas en los 6 primeros meses de vida, que en ocasiones pueden ser graves, sobre todo en casos de fallo cardiaco congestivo o coagulopatía. En muchos casos se puede obtener con técnicas de imagen (ultrasonidos, tomografía computarizada y resonancia magnética) suficiente información para el diagnóstico y planificación del tratamiento adecuado. Presentamos el caso de un neonato con fallo cardiaco congestivo y hepatomegalia debido a hemangioendotelioma hepático. Se revisa la presentación, diagnóstico y tratamiento del mismo así como los principales diagnósticos diferenciales a tener en cuenta ante una neoplasia hepática neonatal (AU)

Infantile hemangioendothelioma of the liver is a benign tumor composed of anastomosed vascular channels. Usually they cause symptoms during the first 6 months of life which occasionally may be serious, above all in cases of congestive heart failure or coagulopathy. In many cases it may be provided by imaging techniques (ultrasound, computed tomography and magnetic resonance imaging) sufficient information to diagnose and to plan for adequate treatment. We present a case of a newborn with congestive heart failure and hepatomegaly due to hemangioendothelioma of the liver. We review the presentation, diagnostic and treatment of it, as soon as the principal differential diagnoses to take into account in the presence of aneounatal hepatic neoplasm (AU)

Final adult height in children with Prader-Willi syndrome with and without human growth hormone treatment.

Short stature is characteristic of children with Prader-Willi syndrome (PWS). While previous studies have demonstrated acceleration of linear height velocity with growth hormone (GH) treatment, the long-term benefit on final adult height (AH) has not been reported. The objective of this study was to compare AH attained in PWS subjects with and without GH treatment. We reviewed the records of 21 children (aged 8.3 +/- 2.7 years) with PWS and confirmed GH deficiency that attained AH after receiving human GH treatment (0.25 +/- 0.06 mg/kg/week) for a period of 7.9 +/- 1.7 years. A group of 39 non-GH-treated adults with matched initial height standard deviation score (SDS) at age 6.8 +/- 1.3 years was used as control. In the GH-treated group the mean initial height and AH-SDS was -1.9 +/- 1.7 and -0.3 +/- 1.2 respectively (P < 0.0001), whereas the mean initial and AH-SDS in the control group was -1.9 +/- 1.3 and -3.1 +/- 1 respectively (P < 0.0001). Scoliosis was seen in 43% and 39% in the GH-treated and control group respectively. Premature adrenarche (PA) was noticed in 57% of GH-treated group. Six subjects in the control group but none of the GH-treated subjects developed type 2 diabetes mellitus. Our data show that administration of GH to children with PWS restores linear growth and final AH without significant adverse effects other than PA. Further studies will be necessary to determine related morbidity and mortality in individuals with PWS that reached final AH with or without GH treatment.

[Optic nerve hypoplasia associated to ectopic neurohypophysis]. / Hipoplasia del nervio optico asociada a neurohipófisis ectópica.

Hypoplasia of the optic nerve is a rare congenital anomaly of unknown etiology that is a frequent cause of blindness in children. It can present in isolation or associated to other malformations of the central nervous system. Magnetic resonance is the technique of choice for the study of this condition; it enables both the hypoplasia of the nerve and the possible associated malformations to be demonstrated. We present a case of optic nerve hypoplasia associated to ectopic neurohypophysis.

High frequency of human cytomegalovirus (HCMV)-specific CD8+ T cells detected in a healthy CMV-seropositive donor.

Human cytomegalovirus (HCMV) persists after infection but is controlled by cellular immune responses, particularly by CD8+ T cells. If infected individuals are immunosuppressed, HCMV can be reactivated. Upon testing the blood of healthy donors with human lymphocyte antigen tetramers, we found one individual with about 50% of his CD8+ T cells being specific for the immunodominant pp65 epitope NLVPMVATV Over a period of 2 years the high level of HCMV-specific T cells was maintained, and no HCMV DNA could be detected. At one timepoint, however, HCMV-specific DNA was detected, while 65% of CD8+ T cells were specific for HCMV. When virus was detectable, a lower percentage of HCMV-specific CD8+ T cells showed interferon gamma (IFN-gamma) production after peptide stimulation in vitro. These data suggest that HCMV reactivation may also occur in immunocompetent persons, accompanied by the presence of HCMV-specific CD8+ T cells which are not producing IFNy, and therefore potentially anergic or in vivo exhausted.

HLA-A2 restricted, melanocyte-specific CD8(+) T lymphocytes detected in vitiligo patients are related to disease activity and are predominantly directed against MelanA/MART1.

Vitiligo is a skin and hair disorder characterized by circumscribed depigmented lesions due to lack of melanocytes in the respective areas. It has been suggested that vitiligo is caused by an autoimmune-mediated destruction of melanocytes. Recently, the presence of a high frequency of skin-homing melanocyte-specific cytotoxic T lymphocytes in the peripheral blood of patients with vitiligo was reported. Our study examines the frequency of melanocyte-specific cytotoxic T lymphocytes in vitiligo patients and its relationship to disease activity. Thirty-two patients with moderate to active vitiligo and 17 control subjects were included. Melanocyte specific reactive CD8(+) T cells were identified by enzyme-linked immunospot assay after stimulation with five peptides from gp100, four peptides from MelanA/MART1, and two peptides from tyrosinase. In selected patients, intracellular interferon-gamma staining for the detection of specific reactive CD8(+) T cells was additionally performed. In seven of 10 patients (70%) with actively progressive disease CD8(+) T cells directed against melanocyte epitopes were detected, whereas only in four of 22 patients (18%) with moderate disease activity such specific reactivity was found. MelanA/MART1 peptides were immunodominant in nine patients reacting against EAAGIGILTV and three patients reacting against ILTVILGVL. Intracellular interferon-gamma staining confirmed the findings obtained by the enzyme-linked immunospot technique. The present study supports the hypothesis that vitiligo is a cytotoxic T lymphocyte-mediated autoimmune disease. The presence of melanocyte-specific reactive CD8(+) T cells seems to be closely related to disease activity.

The peptide-specific alloreactive human T cell repertoire varies largely between individuals and is not extended in HLA-A*0205--anti-HLA-A*0201 pairings.

Alloreactive T cells recognize framework or peptide-dependent determinants on foreign MHC molecules. Among the peptide-dependent alloreactive T cells a significant proportion is specific for one particular peptide presented by the allo-MHC molecule as antigen-specific T cells would do. Such alloreactive, peptide-specific T cells are referred to as 'allorestricted'. High-avidity HLA-A*02 allorestricted cytotoxic T lymphocyte (CTL) clones specific for peptide libraries can be generated from HLA-A*02(-) donors. We made use of this technique to study the role of closely related self-HLA molecules on shaping of the alloreactive T cell repertoire. Peripheral blood lymphocytes from HLA-A*0205 individuals were stimulated by HLA-A*0201 targets pulsed with an HLA-A*0201 peptide library. We did not observe a bias towards peptide-specific CTL in the HLA-A*0201-directed alloreactive repertoire of HLA-A*0205 donors as compared to HLA-A*02(-) donors. Comparison of the alloreactive T cell response between two donors having similar HLA haplotypes demonstrated that the allorestricted T cell repertoire is largely different between individuals.

Ex vivo generation of human cytomegalovirus-specific cytotoxic T cells by peptide-pulsed dendritic cells.

Adoptive transfer of donor-derived human cytomegalovirus (HCMV)-specific T-cell clones can restore protective immunity after stem cell transplantation. Ex vivo induction of HCMV-specific T cells using HCMV-infected fibroblasts as stimulator cells confines this approach to HCMV-seropositive donors and requires the presence of infectious virus during the stimulation procedure. In this study, we describe a potential alternative strategy to generate HCMV-specific T cells ex vivo for adoptive immunotherapy. Generation of HCMV-specific cytotoxic T lymphocytes (CTLs) ex vivo was investigated using peptide-pulsed dendritic cells as antigen-presenting cells. HCMV-specific T cells were generated and sufficiently expanded for adoptive immunotherapy in 6 out of 14 HCMV-seropositive and 2 out of 11 HCMV-seronegative donors. The CTLs recognized HCMV-infected autologous fibroblasts. No lysis was observed with either non-infected autologous or HLA-mismatched infected fibroblasts. Staining with tetrameric HLA/peptide complexes revealed significant enrichment for peptide-specific T cells of up to 28% and > 90% of CD8(+) T cells after three and five specific stimulations respectively. In addition, the expansion rates indicated that ex vivo generation of > 1 x 10(9) HCMV-specific T cells was possible after 6--7 weeks when cultures were initiated with 1--5 x 10(6) responder cells. Thus, the approach with peptide-pulsed DCs to generate HCMV-specific CTLs is feasible for clinical application after allogeneic stem cell transplantation.

A MAGE-A1 HLA-A A*0201 epitope identified by mass spectrometry.

Peptides presented by HLA-A*0201 molecules on the surface of the human breast carcinoma cell line KS24.22 after IFN-gamma induction were analyzed by the "Predict-Calibrate-Detect" approach, which combines epitope prediction and high-performance liquid chromatography mass spectrometry. One of the predicted epitopes, MAGE-A1(278-286) (KVLEYVIKV), was found to be presented by HLA-A*0201, with an estimated copy number of 18 molecules/cell. HLA-A*0201 transgenic mice (HHD mice) were used to generate CTL lines that stained positive with an HLA-A*0201 tetramer folded around the KVLEYVIKV peptide and killed peptide-loaded mouse target cells expressing HLA-A*0201. IFN-gamma-treated or -nontreated HLA-A*0201 expressing HeLa cells transiently transfected with a plasmid expressing the MAGE-A1 gene stimulated in vitro cytokine production by the CTL lines. Moreover, IFN-gamma-treated KS24.22 cells, but not IFN-gamma-treated HLA-A*0201(+) MAGE-A1(-) cells or IFN-gamma-treated HLA-A*0201(-) MAGE-A1(+) cells, were killed by these CTLS: Thus, the combination of HLA epitope prediction, peptide analysis, and immunological methods is a powerful approach for the identification of tumor-associated epitopes.