Expanding the phenotype of PIGP deficiency to multiple congenital anomalies-hypotonia-seizures syndrome.

Glycosylphosphatidylinositol-anchored proteins are involved in multiple physiological processes and the initial stage of their biosynthesis is mediated by PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY, and DMP2 genes, which have been linked to a wide spectrum of phenotypes depending on the gene damaged. To date, the PIGP gene has only been related to Developmental and Epileptic Encephalopathy 55 (MIM#617599) in just seven patients. A detailed medical history was performed in two affected siblings with a multiple malformation syndrome. Genetic testing was performed using whole-exome sequencing. One patient presented dysmorphic features, congenital anomalies, hypotonia and epileptic encephalopathy as described in PIGA, PIGQ and PIGY deficiencies. The other one was a fetus with a severe malformation disorder at 17 weeks of gestation whose pregnancy was interrupted. Both were compound heterozygous of pathogenic variants in PIGP gene: NM_153682.3:c.2 T > C(p.?) and a 136 Kb deletion (GRCh37/hg19 21q22.13(chr21:38329939-38 466 066)×1) affecting the entire PIGP gene. Our results extend the clinical phenotype associated to PIGP gene and propose to include it as a novel cause of Multiple Congenital Anomalies-Hypotonia-Seizures syndrome.

Effect of GnRH agonist before IVF on outcomes in infertile endometriosis patients: a randomized controlled trial.

RESEARCH QUESTION: Does 3-months of gonadotrophin releasing hormone agonist (GnRHa) treatment before IVF improve clinical pregnancy rate in infertile patients with endometriosis? DESIGN: Single-blind, placebo-controlled clinical trial of 200 infertile women with endometriosis assigned to use GnRHa (study group) or placebo (control group) for 3 months before IVF. Clinical, embryological outcomes and stimulation parameters were analysed. Clinical pregnancy rate was the primary endpoint. In a subgroup of 40 patients, follicular fluid levels of oestradiol, testosterone and androstendione were measured. Gene expression profile of CYP19A1 was analysed in cumulus and mural granulosa cells. RESULTS: Implantation or clinical pregnancy rate were not significantly different between the two groups. Clinical pregnancy rates were 25.3% and 33.7% in the study and control groups, respectively (P = 0.212). Cumulative live birth rate was not significantly different: 22.0% (95% CI 13.0 to 31.0) in the study group and 33.7% (95% CI 24.0 to 44.0) in the control group (P = 0.077). Ovarian stimulation was significantly longer and total dose of gonadotrophins significantly higher in the study group (both P < 0.001). Serum oestradiol levels on the day of HCG were significantly lower in the study group (P = 0.001). Cancellation rate was significantly higher in the study group (P = 0.042), whereas cleavage embryos were significantly more numerous in the control group (P = 0.023). No significant differences in the expression of CYP19A1 gene in mural or cumulus granulosa cells or steroid levels in follicular fluid between the two groups were observed, but testosterone was significantly lower in the study group (P < 0.001). CONCLUSION: Three-months of GnRHa treatment before IVF does not improve clinical pregnancy rate in women with endometriosis.

Prenatal Genome-Wide Cell-Free DNA Screening: Three Years of Clinical Experience in a Hospital Prenatal Diagnostic Unit in Spain.

Genome-wide prenatal cell-free DNA (cfDNA) screening can be used to screen for a wide range of fetal chromosomal anomalies in pregnant patients. In this study, we describe our clinical experience with a genome-wide cfDNA assay in screening for common trisomies, sex chromosomal aneuploidies (SCAs), rare autosomal aneuploidies (RAAs), and copy-number variations (CNVs) in about 6000 patients over a three-year period at our hospital's Prenatal Diagnostic Unit in Spain. Overall, 204 (3.3%) patients had a high-risk call, which included 76 trisomy 21, 21 trisomy 18, 7 trisomy 13, 29 SCAs, 31 RAAs, 31 CNVs, and 9 cases with multiple anomalies. The diagnostic outcomes were obtained for the high-risk cases when available, allowing for the calculation of positive predictive values (PPVs). Calculated PPVs were 95.9% for trisomy 21, 77.8% for trisomy 18, 66.7% for trisomy 13, 10.7% for RAAs, and 10.7% for CNVs. Pregnancy and birth outcomes were also collected for the majority of RAA and CNV cases. Adverse perinatal outcomes for some of these cases included preeclampsia, fetal growth restriction, preterm birth, reduced birth weight, and major congenital structural abnormalities. In conclusion, our study showed strong performance for genome-wide cfDNA screening in a large cohort of pregnancy patients in Spain.

Tyrosinemia type 1 and Angelman syndrome due to paternal uniparental isodisomy 15.

Uniparental isodisomy arises when an individual inherits two copies of a specific chromosome from a single parent, which can unmask a recessive mutation or cause a problem of genetic imprinting. Here we describe an exceptional case in which the patient simultaneously presents tyrosinemia type 1 and Angelman syndrome. The genetic studies showed that the patient presents paternal uniparental isodisomy of chromosome 15, with absence of the maternal homolog. As a consequence of this isodisomy, the patient is homozygous for the mutation IVS12+5G>A in the FAH gene, located in the chromosomal region 15q23-25, causing tyrosinemia type 1. The mutation was inherited from his father in double dosage, whereas the mother is not a carrier, which implies that the recurrence risk in the family is negligible. On the other hand, the lack of maternal contribution causes Angelman syndrome, a neurodevelopmental disorder associated with a loss of maternal gene expression in chromosome region 15q11-q13, and more specifically, of the UBE3A gene. This gene shows a tissue-specific imprinting, and only the maternally derived allele is expressed in certain areas of the brain. We observed through a literature review that uniparental disomy probably occurs more frequently than suspected, although it is more usually detected when the uniparental disomy implies the appearance of a disease because of the gene imprinting or by reduction to homozygosity of a recessive mutation. The conclusion is that uniparental disomy should always be considered when more than one genetic disease mapping to the same chromosome is present in a patient.

Estudio del efecto intercromosómico en portadores de anomalías cromosómicas estructurales equilibradas mediante PGT-SR / Study of the interchromosomal effect in carriers of balanced structuralchromosomal rearrangements by PGT-SR

Los portadores de anomalías estructurales cromosómicas equilibradas, a pesar de ser fe-notípicamente normales, tienen una competencia reproductiva disminuida de manera significativa conrespecto a la población general. Esto se debe a que, durante la gametogénesis, dependiendo de cómo sesegregue la alteración cromosómica en la meiosis I, se generarán gametos normales, equilibrados o des-equilibrados en mayor proporción que en portadores de cariotipos normales. Esta es la causa principalEstudio del efecto intercromosómico en portadores de anomalías cromosómicasestructurales equilibradas mediante PGT-SRStudy of the interchromosomal effect in carriers of balanced structuralchromosomal rearrangements by PGT-SR de la mayor tasa de abortos y descendencia con alteraciones que presentan los individuos portadores de inversiones ytranslocaciones recíprocas o robertsonianas. Otra posible fuente de gametos y/o embriones aneuploides, es el denominadoefecto intercromosómico (EIC), que consiste en una interferencia producida por una alteración cromosómica estructuralsobre la adecuada disyunción y segregación de otros cromosomas no involucrados en dicha alteración.Material y Métodos:Un total de 40 parejas fueron incluidas en el estudio, de las cuales 31 pertenecieron al grupo de es-tudio: catorce translocaciones robertsonianas, trece translocaciones recíprocas y cuatro de inversiones pericéntricas. Endiecinueve casos la mujer era portadora y en los doce restantes era el hombre el afecto. Nueve parejas con cariotipo normal,portadoras de una mutación responsable de enfermedad monogénica fueron incluidas en el grupo control. (AU)

Introduction: Carriers of balanced structural rearrangements, despite being phenotypically normal, they have a signifi-cantly decreased reproductive competence compared to the general population. The reason is because, during gametoge-nesis, depending on how the chromosomal alteration is segregated in meiosis I, normal, balanced, or unbalanced gameteswill be generated in greater proportion than in carriers of normal karyotypes. This is the main cause of the higher rate ofabortions and offspring with alterations that carriers of inversions, reciprocal translocations or Robertsonian translocationspresent. Another possible source of aneuploid gametes and/or embryos is the so-called interchromosomal effect (ICE),which consists of an interference produced by a structural chromosomal alteration on the proper disjunction and segregationof other chromosomes not involved in the rearrangement.Material and methods:A total of 40 couples were included in the study, of which 31 belonged to the study group: fourteenRobertsonian translocations, thirteen reciprocal translocations and four pericentric inversions. As for the affected parent,in nineteen of the cases the woman was the carrier of the chromosomal alteration and in the remaining twelve it was theman who was affected. Nine couples with a normal karyotype, carriers of a mutation responsible for monogenic disease,were included in the control group. (AU)

Fetal arthrogryposis secondary to a giant maternal uterine leiomyoma.

Arthrogryposis multiplex congenital is a rare condition defined as contractures in multiple joints at birth due to disorders starting in fetal life. Its etiology is associated with many different conditions and in many instances remains unknown. The final common pathway to all of them is decreased fetal movement (fetal akinesia) due to an abnormal intrauterine environment. Causes of decreased fetal movements may be neuropathic abnormalities, abnormalities of connective tissue or muscle, intrauterine vascular compromise, maternal diseases, and space limitations within the uterus. When the cause of arthrogryposis is space limitations in uterus, the most common etiology is oligohydramnios. The same can result from intrauterine tumours as fibroids, although to our knowledge there are only two papers reporting cases of fetal deformities related to uterine leiomyomas. We describe a well-documented exceptional case of arthrogryposis associated with the presence of a large uterine fibroid. It could illustrate the importance of a careful and appropriate assessment of uterine fibroids before and in the course of a pregnancy considering that they can cause both serious maternal and fetal complications.

Aplicación del diagnóstico genético preimplantacional en la distrofia miotónica tipo 1 o enfermedad de Steinert / Application of pre-implantation genetic diagnosis in Myotonic dystrophy type 1 - Steinert's disease

La distrofia miotónica tipo 1 (DM1) es la forma más común de distrofia muscular en adultos causada por la expansión de una repetición de trinucleótidos CTG en el gen DMPK (Distrofia miotónica proteína quinasa) y su herencia es autosómica dominante. Hasta el momento, la técnica de Diagnóstico Genético Preimplantacional parece ser la aproximación reproductiva más eficaz para aquellas parejas en las que alguno de sus progenitores es afecto de DM1. En este estudio se evaluó la técnica de Diagnóstico Genético Preimplantacional en función del sexo del progenitor afecto y el número de repeticiones CTG y su influencia sobre el resultado reproductivo de la misma. Un total de 13 parejas, del programa de Diagnóstico Genético Preimplantacional de la Unidad de Reproducción Asistida del Hospital Universitari i Politècnic La Fe, fueron incluidas en el estudio. En 8 de éstas la afecta es la mujer, mientras que en las 5 restantes es el hombre el portador de la enfermedad. En todas ellas se llevaron a cabo todos los pasos del programa. Los embriones fueron analizados mediante mTP-PCR y PCR multiplex. El efecto de ambas variables se analizó mediante análisis bivariado (prueba T, Chi-cuadrado, regresión lineal y test Anova) y análisis multivariante utilizando análisis de correlación (Rho de Spearman). Los resultados obtenidos revelaron una transmisión preferencial de los alelos expandidos en DM1, independiente del sexo del progenitor afecto. A pesar de ello, no mostraron ninguna relación estadísticamente significativa entre el sexo del progenitor afecto ni el número de repeticiones CTG y el resultado reproductivo de la técnica. De modo que, atendiendo a nuestros resultados, el Diagnóstico Genético Preimplantacional sería una buena aproximación reproductiva en casos de DM1 con una tasa de gestación de 53,8 % y de nacidos sanos de 38,5 %, independientemente del sexo del progenitor afecto y del número de repeticiones CTG

Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults caused by the expansion of a CTG trinucleotide repeat in the DMPK gene (dystrophia myotonica-protein kinase gene) and its inheritance is autosomal dominant. So far, the technique of Preimplantation Genetic Diagnosis (PGD) seems to be the most effective reproductive approach for those couples in which one of their parents is affected by DM1. In this study, the Preimplantation Genetic Diagnosis technique was evaluated according to the sex of the affected progenitor and the number of CTG repetitions and their influence on the reproductive result of itself. A total of 13 couples from the Preimplantation Genetic Diagnosis program of the Assisted Reproduction Unit of the Hospital Universitario i Politècnic La Fe were included in the study were included in the study. In 8 of them the affected parent is the woman, whereas the 5 remaining is the man who is the disease carrier. In all of them, all the steps of the program were followed. The embryos were analyzed by mTP-PCR and multiplex PCR. The variables effect was analyzed by bivariate analysis (T-test, Chi-square, linear regression and Anova test) and multivariate analysis using correlation analysis (Spearman's rho). The results obtained revealed a preferential transmission of the expanded alleles in DM1, regardless of the sex of the affected parent. In spite of, the results obtained do not show any statistically significant relation between the sex of the progenitor and the number of repetitions and the reproductive result of the technique. Thus, according to our results, Preimplantation Genetic Diagnosis would be a good reproductive approach in cases of DM1 with a gestation rate of 53.8% and healthy births of 38.5%, regardless of the sex of the affected parent and the number of CTG repetitions

Enrichment of ultraconserved elements among genomic imbalances causing mental delay and congenital anomalies.

BACKGROUND: The ultraconserved elements (UCEs) are defined as stretches of at least 200 base pairs of human DNA that match identically with corresponding regions in the mouse and rat genomes, albeit their real significance remains an intriguing issue. These elements are most often located either overlapping exons in genes involved in RNA processing or in introns or nearby genes involved in the regulation of transcription and development. Interestingly, human UCEs have been reported to be strongly depleted among segmental duplications and benign copy number variants (CNVs). However no comprehensive survey of a putative enrichment of these elements among pathogenic dose variants has yet been reported. RESULTS: A survey for UCEs was performed among the 26 cryptic genomic rearrangements detected in our series of 200 patients with idiopathic neurodevelopmental disorders associated to congenital anomalies. A total of 29 elements, out of the 481 described UCEs, were contained in 13 of the 26 pathogenic gains or losses detected in our series, what represents a highly significant enrichment of ultraconserved elements. In addition, here we show that these elements are preferentially found in pathogenic deletions (enrichment ratio 3.6 vs. 0.5 in duplications), and that this association is not related with a higher content of genes. In contrast, pathogenic CNVs lacking UCEs showed almost a threefold higher content in genes. CONCLUSIONS: We propose that these elements may be interpreted as hallmarks for dose-sensitive genes, particularly for those genes whose gain or loss may be directly implied in neurodevelopmental disorders. Therefore, their presence in genomic imbalances of unknown effect might be suggestive of a clinically relevant condition.

Prenatal study of common submicroscopic "genomic disorders" using MLPA with subtelomeric/microdeletion syndrome probe mixes, among gestations with ultrasound abnormalities in the first trimester.

PURPOSE: The present study aims to investigate the presence of common submicroscopic chromosomal rearrangements in fetuses with ultrasound abnormalities or positive screening in the first trimester and normal karyotype. We used the multiplex ligation-dependent probe amplification (MLPA) technique with subtelomeric (SALSA P036B) and microdeletion syndrome (SALSA P064B/P096) probe mixes as a screening method to measure copy number changes on the tested probes in chorionic villus sampling. MLPA with P036B and P064/P096 probe mixes was performed on 49 chorionic villi DNA samples obtained between the 11th and 13th week of gestation. RESULTS: The MLPA analyses did not detect any diminished or increased intensity for all the tested probes in the samples. CONCLUSIONS: Our results suggest that the common submicroscopic "genomic disorders" (microdeletion and microduplication syndromes) would not be frequently detected in the first trimester anomalies screening.

Duplication of the Williams-Beuren critical region: case report and further delineation of the phenotypic spectrum.

Only 12 patients with a duplication of the Williams-Beuren critical region (WBCR) have been reported to date, with variable developmental, psychomotor and language delay, in the absence of marked dysmorphic features. In this paper we present a new WBCR microduplication case, which supports the wide variability displayed by this duplication in the phenotype. The WBCR microduplication may be associated with autistic spectrum disorder, but most reported cases do not show this behavioral disorder, or may even show a hypersociable personality, as with our patient. From the present case and a review of the 12 previously described,1(-)6 we conclude that the phenotype associated with duplication of WBCR can affect the same domains as WBCR deletion, but that they cluster near the polar ends of social relationship (autism-like v hypersociability), language (expressive language impairment v "cocktail party" speech), visuospatial (severe v normal), mental retardation (severe v mild) and dysmorphic (severe v mild) features.

Síndrome de Berdon: diagnóstico intrauterino y evolución posnatal / Berdon syndrome: intrauterine diagnosis and postnatal outcome

El síndrome de Berdon es un síndrome muy poco frecuente de carácter congénito, caracterizado por megavejiga, microcolon e hipoperistalsis intestinal, cuyo pronóstico es infausto en la mayoría de las ocasiones y cuyo manejo supone un reto que requiere un abordaje multidisciplinar. Revisamos una serie de casos diagnosticados en nuestro centro entre 1997 y 2010, comentando el diagnóstico, manejo y evolución de estos pacientes(AU)

Berdon syndrome is a rare congenital syndrome characterized by megacystis, microcolon and intestinal hypoperistalsis. It has an ominous prognosis in most cases, and its management requires a multidisciplinary approach. We review a series of cases diagnosed in our center between 1997 and 2010, and discuss the diagnosis, management and outcomes of these patients(AU)

Eosinofilia en enfermos de uveitis anterior aguda / Eosinophilia in patients presenting with acute anterior uveitis

Se realizo un estudio prospectivo en 50 enfermos de uveitis anterior aguda con el proposito de describir en los mismos la eosinofilia ocular y en sangre. En el estudio se corrobora que en la totalidad de los casos con sensibilidad alergica demostrada, aparece eosinofilia ocular y en sangre. Sin embargo, en aquellos en que la etiologia fue una colecistopatia con giardiasis cronica asociada, aparece eosinofilia ocular en el 79,0 por ciento. Es destacable que en los pacientes cuya causa fue un poco septico,toxoplasmosis o enfermedad autoinmune, no se contato eosinofilia. En dicha investigacion se valora la importancia del eosinofilo en los pacientes con uveitis anterior aguda, cuya causa probable es alergica, infecciosa o autoinmunitaria

Eosinofilia en enfermos de uveítis anterior aguda / Eosinophilia in patients presenting with acute anterior uveitis

Se realizó un estudio prospectivo en 50 enfermos de uveítis anterior aguda con el propósito de describir en los mismos la eosinofilia ocular y en sangre. En el estudio se corrobora que en la totalidad de los casos con sensibilidad alérgica demostrada, aparece eosinofilia ocular y en sangre. Sin embargo, en aquellos en que la etiología fue una colecistopatía con giardiasis crónica asociada, aparece eosinofilia ocular en el 79,0 por ciento. Es destacable que en los pacientes cuya causa fue un poco séptico,toxoplasmosis o enfermedad autoinmune, no se contató eosinofilia. En dicha investigación se valora la importancia del eosinófilo en los pacientes con uveítis anterior aguda, cuya causa probable es alérgica, infecciosa o autoinmunitaria

Crisis hipertensiva secundaria al consumo de queso durante el tratamiento con isocarboxacida / Hipertensive crisis secondary to the consuption of chesse during a treatment with isocarboxacid

Una paciente de 31 años, normotensa, bajo tratamiento con isocarboxacida y que simultáneamente ingería queso y yogourt, presentó una crisis hipertensiva con cefalea temporal pulsátil y déficit motor del hemicuerpo izquierdo, a predominio braquial, que regresó sin dejar secuelas, en pocas semanas. La tiramina presente en alimentos como el queso, yogourt, etcétera, es responsable de las crisis hipertensivas que se observan en pacientes que reciben inhibidores de la monoamina oxidasa, ya que libera los depósitos aumentados de catecolaminas de las terminaciones nerviosas simpáticas posganglionares. Las manifestaciones deficitarias del hemicuerpo izquierdo se originaron por el edema cerebral secundario a la crisis hipertensiva, y cesaron con ésta

Crisis hipertensiva secundaria al consumo de queso durante el tratamiento con isocarboxacida / Hipertensive crisis secondary to the consumption of chesse during a treatment with isocarboxacid

Una paciente de 31 años, normotensa, bajo tratamiento con isocarboxacida y que simultáneamente ingería queso y yogourt, presentó una crisis hipertensiva con cefalea temporal pulsátil y déficit motor del hemicuerpo izquierdo, a predominio braquial, que regresó sin dejar secuelas, en pocas semanas. La tiramina presente en alimentos como el queso, yogourt, etcétera, es responsable de las crisis hipertensivas que se observan en pacientes que reciben inhibidores de la monoamina oxidasa, ya que libera los depósitos aumentados de catecolaminas de las terminaciones nerviosas simpáticas posganglionares. Las manifestaciones deficitarias del hemicuerpo izquierdo se originaron por el edema cerebral secundario a la crisis hipertensiva, y cesaron con ésta