Arterial aneurysm and dissection: toward the evolving phenotype of Tatton-Brown-Rahman syndrome.

BACKGROUND: Tatton-Brown-Rahman syndrome (TBRS) is a rare disorder, caused by DNMT3A heterozygous pathogenic variants, and first described in 2014. TBRS is characterised by overgrowth, intellectual disability, facial dysmorphism, hypotonia and musculoskeletal features, as well as neurological and psychiatric features. Cardiac manifestations have also been reported, mainly congenital malformations such as atrial septal defect, ventricular septal defect and cardiac valvular disease. Aortic dilatation has rarely been described. METHODS: Here we have undertaken a detailed clinical and molecular description of eight previously unreported individuals, who had TBRS and arterial dilatation and/or dissection, mainly thoracic aortic aneurysm (TAA). We have also reviewed the seven previously published cases of TAA in individuals with TBRS to try to better delineate the vascular phenotype and to determine specific follow-up for this condition. RESULTS: We include eight new patients with TBRS who presented with arterial aneurysms mainly involving aorta. Three of these patients presented with dissection that required critical surgery. CONCLUSIONS: Arterial aneurysms and dissections are a potentially lethal, age-dependent manifestation. The prevalence of aortic disease in individuals with TBRS is far in excess of that expected in the general population. This cohort, together with individuals previously published, illustrates the importance to consider dilatation/dissection, mainly in aorta but also in other arteries. Arterial vascular weakness may therefore also be a cardinal feature of TBRS and vascular surveillance is recommended.

Experience using singleton exome sequencing of probands as an approach to preconception carrier screening in consanguineous couples.

BACKGROUND: Consanguineous couples have an increased risk of severe diseases in offspring due to autosomal recessive disorders. Exome sequencing (ES) offers the possibility of extensive preconception carrier screening (PCS) in consanguineous couples who may be at risk of rare genetic disorders. METHODS: We retrospectively analysed ES data from 65 probands affected with rare genetic disorders born from consanguineous couples. We explored diagnostic yield and carrier status for recessive disorders. RESULTS: The overall diagnostic yield in a singleton approach was 53.8%, mostly recessive variants. In a hypothetical exome-based PCS, only 11.7% of these causative rare variants would have been missed in the filtering process. Carrier screening for recessive conditions allowed the identification of at least one additional pathogenic or likely pathogenic variant in 85.7% of the probands, being the majority with a gene carrier frequency <1 in 200. In addition, considering only clinically actionable conditions, we estimated that 12.3% of our close consanguineous couples may be at risk for an additional recessive disease. CONCLUSIONS: Our results demonstrate that ES outperforms panel-based screening in a PCS context in consanguineous couples and could potentially increase their reproductive autonomy and facilitate informed decision-making.

A systematic study and literature review of parental somatic mosaicism of FBN1 pathogenic variants in Marfan syndrome.

BACKGROUND: A proportion of de novo variants in patients affected by genetic disorders, particularly those with autosomal dominant (AD) inheritance, could be the consequence of somatic mosaicism in one of the progenitors. There is growing evidence that germline and somatic mosaicism are more common and play a greater role in genetic disorders than previously acknowledged. In Marfan syndrome (MFS), caused by pathogenic variants in the fibrillin-1 gene (FBN1) gene, approximately 25% of the disease-causing variants are reported as de novo. Only a few cases of parental mosaicism have been reported in MFS. METHODS: Employing an amplicon-based deep sequencing (ADS) method, we carried out a systematic analysis of 60 parents of 30 FBN1 positive, consecutive patients with MFS with an apparently de novo pathogenic variant. RESULTS: Out of the 60 parents studied (30 families), the majority (n=51, 85%) had a systemic score of 0, seven had a score of 1 and two a score of 2, all due to minor criteria common in the normal population. We detected two families with somatic mosaicism in one of the progenitors, with a rate of 6.6% (2/30) of apparently de novo cases. CONCLUSIONS: The search for parental somatic mosaicism should be routinely implemented in de novo cases of MFS, to offer appropriate genetic and reproductive counselling as well as to reveal masked, isolated clinical signs of MFS in progenitors that may require specific follow-up.

Preliminary experience of the use of self-expanding nititol stent in refractory variceal bleeding: a real-world study.

BACKGROUND AND AIMS: The fully-covered self-expanding metal stent (SEMS) has a role in the management of refractory acute variceal haemorrhage. The aim of this study was to evaluate its effectiveness and complications in real-world practice. PATIENTS AND METHODS: An observational, descriptive, multicenter study was carried out. Eight patients with clinically significant portal hypertension who underwent a SEMS were included. RESULTS: SEMS placement controlled acute bleeding in 7 patients with technical success. Stents were removed after a median of 8 days. Rescue transjugular intrahepatic portosystemic shunt was performed around 48 hours after SEMS placement. Four patients survived after successful SEMS removal. The most common adverse event was stent loop in 2 patients. CONCLUSIONS: In our experience, SEMS was highly effective in controlling acute refractory variceal bleeding. Bleeding-related mortality rate was probably due to impossibility of TIPS implantation. Stent loop was a common limiting factor.

TCF12 haploinsufficiency causes autosomal dominant Kallmann syndrome and reveals network-level interactions between causal loci.

Dysfunction of the gonadotropin-releasing hormone (GnRH) axis causes a range of reproductive phenotypes resulting from defects in the specification, migration and/or function of GnRH neurons. To identify additional molecular components of this system, we initiated a systematic genetic interrogation of families with isolated GnRH deficiency (IGD). Here, we report 13 families (12 autosomal dominant and one autosomal recessive) with an anosmic form of IGD (Kallmann syndrome) with loss-of-function mutations in TCF12, a locus also known to cause syndromic and non-syndromic craniosynostosis. We show that loss of tcf12 in zebrafish larvae perturbs GnRH neuronal patterning with concomitant attenuation of the orthologous expression of tcf3a/b, encoding a binding partner of TCF12, and stub1, a gene that is both mutated in other syndromic forms of IGD and maps to a TCF12 affinity network. Finally, we report that restored STUB1 mRNA rescues loss of tcf12 in vivo. Our data extend the mutational landscape of IGD, highlight the genetic links between craniofacial patterning and GnRH dysfunction and begin to assemble the functional network that regulates the development of the GnRH axis.

De novo missense variants in the E3 ubiquitin ligase adaptor KLHL20 cause a developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder.

PURPOSE: KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20. METHODS: Patients were ascertained by the investigators through Matchmaker Exchange. Phenotyping of patients with de novo missense variants in KLHL20 was performed. RESULTS: We studied 14 patients with de novo missense variants in KLHL20, delineating a genetic syndrome with patients having mild to severe intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity, and subtle dysmorphic facial features. We observed a recurrent de novo missense variant in 11 patients (NM_014458.4:c.1069G>A p.[Gly357Arg]). The recurrent missense and the 3 other missense variants all clustered in the Kelch-type ß-propeller domain of the KLHL20 protein, which shapes the substrate binding surface. CONCLUSION: Our findings implicate KLHL20 in a neurodevelopmental disorder characterized by intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, and hyperactivity.

Differences between genetic dilated cardiomyopathy and myocarditis in children presenting with severe cardiac dysfunction.

Acute myocarditis is an inflammatory disease of the myocardium, and it can present as severe heart failure in children. Differential diagnosis with genetic cardiomyopathy can be difficult. The objective of this study is to identify patterns of clinical presentation and to assess invasive and non-invasive measures to differentiate patients with acute myocarditis from patients with dilated genetic cardiomyopathy. We performed a retrospective descriptive study of all paediatric patients (0-16 years old) that presented with new-onset heart failure with left ventricle ejection fraction < 35% in whom we performed an endomyocardial biopsy (EMB) during the period from April 2007 to December 2020. The patients were classified into two groups: Group 1 included 18 patients with myocarditis. Group 2 included 9 patients with genetic cardiomyopathy. Findings favouring a diagnosis of myocarditis included a fulminant or acute presentation (77.8% vs 33.3%, p = 0.01), higher degree of cardiac enzyme elevation (p = 0.011), lower left ventricular dimension z-score (2.2 vs 5.4, p = 0.03) increase of ventricular wall thickness (88.8% vs 33.3%, p = 0.03) and oedema in the EMB. Seven (77.8%) patients with genetic cardiomyopathy had inflammation in the endomyocardial biopsy fulfilling the diagnostic criteria of inflammatory cardiomyopathy.Conclusion: Differentiating patients with a myocarditis from those with genetic cardiomyopathy can be challenging, even performing an EMB. Some patients with genetic cardiomyopathy fulfil the diagnostic criteria of inflammatory cardiomyopathy. Using invasive and non-invasive measures may be useful to develop a predictive model to differentiate myocarditis from genetic cardiomyopathy. What is Known: • Acute myocarditis could present with cardiogenic shock in paediatric patients. • Parvovirus B19 is the main cause of myocarditis in this population. What is New: • Current diagnostic criteria for myocarditis have limited use in paediatric patients presenting with new-onset heart failure. • Some patients with a genetic cardiomyopathy and a new-onset heart failure fulfill the diagnostic criteria of inflammatory cardiomyopathy.

GIST. Duodenopancreatectomía. Tumor neuroendocrino no funcionante.

Zollinger Ellison syndrome is an unusual entity. This termn is used to describe the clinical manifestations of a gastrin-synthesizing neoplasm. Gastrinomas occur mainly in the duodenum and pancreas. Primary gastrinomas are rarely found in other intra-abdominal sites, such as the ovary, bile ducts, spleen or kidney, or even more unusual in extra-abdominal locations. Several studies provide strong evidence that gastrinomas can also occur in the lymph nodes. However, the existence of primary lymph node gastrinomas is controversial.

Randomized, double-blind, placebo-controlled clinical trial on the usefulness of probiotic Lactobacillus reuteri in bismuth-containing quadruple eradication therapy for infection with Helicobacter pylori.

INTRODUCTION: the primary goal of this study was to compare gastrointestinal symptom reduction in patients on bismuth-containing quadruple eradication therapy supplemented with Lactobacillus reuteri strains (DSM 17938 and ATCC PTA 6475) or placebo. MATERIALS AND METHODS: this was a randomized, double-blind, parallel-arm, placebo-controlled clinical trial. Patients received a first-line eradication regimen based on bismuth subcitrate potassium, metronidazole, tetracycline hydrochloride (three-in-one capsules) and omeprazole 40 mg twice a day for ten days, plus a probiotic or placebo tablet for 30 days. During follow-up, gastrointestinal symptoms were assessed using an evaluation scale (GSRS), and adverse events were collected at 0, 14, 28 and 56 days. RESULTS: a total of 80 patients were included from February 2018 to May 2019 at a single site. Eradication therapy was effective in 85 % of patients, with no differences between treatment arms. In the group receiving the probiotic, abdominal pain decreased in 42 % of patients, compared with 19 % in the control group (OR: 0.27; CI, 0.13-0.58; p < 0.001), and abdominal distension decreased in 25 % versus 17 % in the control group (OR: 0.24; IC, 0.19-0.84; p < 0.001); Conclusions: treatment with L. reuteri only reduced abdominal pain and distension. Further studies are needed to establish the role of probiotics as adjuvant therapy in H. pylori eradication.

Switch to subcutaneous infliximab during the SARS-CoV-2 pandemic: preliminary results.

A new subcutaneous formulation of the infliximab biosimilar CT-P13 has recently been developed for the treatment of inflammatory bowel disease (IBD), providing response rates similar to intravenous treatment. The use of this new formulation was requested, in an effort to limit patient attendance at intravenous infusion centers and to maintain biological treatment during the COVID-19 pandemic. The objective of this observational, retrospective and descriptive study was to assess CT-P13 efficacy and safety after switching from intravenous to a subcutaneous formulation in patients with IBD receiving maintenance therapy. This article shows preliminary results after six months of follow-up.

An extremely uncommon complication of acute pancreatitis: spontaneous pancreatic cutaneous fistula.

We report the case of a 67-year-old male who was referred to our hospital due to severe abdominal pain and fever. His past medical history included a total gastrectomy surgery for stomach cancer. Abdominal examination showed intense pain on deep palpation in the epigastric region. Laboratory test revealed elevated C-reactive protein (235 mg/l) and amylase (1,789 U/l). Computerized tomography reported a pancreatic collection with the presence of air bubbles inside and areas of necrotic pancreatic parenchyma.

Views of patients with inflammatory bowel disease during the COVID-19 pandemic: ACCU survey results.

INTRODUCTION AND OBJECTIVES: the SARS-COV-2 pandemic has forced a substantial change in the care of patients with digestive pathologies, especially for inflammatory bowel disease (IBD) patients taking immunosuppessive medications. In this regard, some national and international guidelines have indicated the standards to be taken into account. However, few studies have evaluated how patients have dealt with this infection. Therefore, this study was performed with the aim to determine how the SARS-COV-2 pandemic has affected our IBD patients. MATERIAL AND METHODS: an online survey was performed among the members (295) of the Association of Crohn's Disease and Ulcerative Colitis (ACCU), which consisted of 19 questions. Finally, it was completed by 168 patients. RESULTS: fifty-eight per cent of cases were female, 63.7 % had Crohn's disease (CD) and 53 % received biologic therapy. Five per cent were infected by SARS-CoV-2 and were male. The main concern of the patients was the fear of acquiring the infection (80.9 %). More than 90 % continued their treatments and half of the patients worked from home during the pandemic period. CONCLUSIONS: the perspective of the patients is necessary to achieve an adequate management and evolution of the disease. More studies are needed to assess the impact that exceptional situations, such as the COVID-19 pandemic, may have on IBD patients in order to improve adherence and control of the disease.

Skeletal abnormalities are common features in Aymé-Gripp syndrome.

Aymé-Gripp syndrome (AYGRPS) is a recognizable condition caused by a restricted spectrum of dominantly acting missense mutations affecting the transcription factor MAF. Major clinical features of AYGRPS include congenital cataracts, sensorineural hearing loss, intellectual disability, and a distinctive flat facial appearance. Skeletal abnormalities have also been observed in affected individuals, even though these features have not been assessed systematically. Expanding the series with four additional patients, here we provide a more accurate delineation of the molecular aspects and clinical phenotype, particularly focusing on the skeletal features characterizing this disorder. Apart from previously reported malar flattening and joint limitations, we document that carpal/tarsal and long bone defects, and hip dysplasia occur in affected subjects more frequently than formerly appreciated.

Expanding the phenotype of cerebellar-facial-dental syndrome: Two siblings with a novel variant in BRF1.

Cerebellofaciodental syndrome (MIM #616202) is an autosomal recessive condition characterized by intellectual disability, microcephaly, cerebellar hypoplasia, dysmorphic features, and short stature. To date, eight patients carrying biallelic BRF1 variants have been reported. Here, we describe two siblings with congenital microcephaly and corpus callosum hypoplasia, pre and postnatal growth retardation, congenital heart defect and severe global developmental delay. We also detected additional findings not previously reported in this syndrome, including bilateral sensorineural hearing impairment and inner ear malformation. Whole exome sequencing identified a novel homozygous missense variant (c.654G>C, p.[Trp218Cys]) in BRF1, predicted to affect the protein structure. Expression assessment showed extremely low BRF1 protein expression caused by the identified variant, supporting its causal involvement. The description of new patients with cerebellofaciodental syndrome is essential to better delineate the phenotypic and genotypic spectrum of the disease.

Characterization of Two Novel Variants of the Steroidogenic Acute Regulatory Protein Identified in a Girl with Classic Lipoid Congenital Adrenal Hyperplasia.

Congenital adrenal hyperplasia (CAH) consists of several autosomal recessive disorders that inhibit steroid biosynthesis. We describe a case report diagnosed with adrenal insufficiency due to low adrenal steroids and adrenocorticotropic hormone excess due to lack of cortisol negative feedback signaling to the pituary gland. Genetic work up revealed two missense variants, p.Thr204Arg and p.Leu260Arg in the STAR gene, inherited by both parents (non-consanguineous). The StAR protein supports CYP11A1 enzyme to cleave the side chain of cholesterol and synthesize pregnenolone which is metabolized to all steroid hormones. We used bioinformatics to predict the impact of the variants on StAR activity and then we performed functional tests to characterize the two novel variants. In a cell system we tested the ability of variants to support cholesterol conversion to pregnenolone and measured their mRNA and protein expression. For both variants, we observed loss of StAR function, reduced protein expression and categorized them as pathogenic variants according to guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. These results fit the phenotype of the girl during diagnosis. This study characterizes two novel variants and expands the list of missense variants that cause CAH.

Esophageal compression by a mediastinal vascular structure as a result of a dysphagia lusoria.

Dysphagia lusoria is an uncommon cause of mechanical dysphagia due to extrinsic compression. It is a congenital aortic root abnormality that occurs as a consequence of an aberrant right subclavian artery, in most cases. We report an illustrative case of dysphagia lusoria in a young female, secondary to the presence of the abnormal mediastinal vessel.

A foreign body in the small bowel: a rare entity of acute abdomen.

Acute abdomen secondary to intestinal impactation due to ingestion of foreign body is a rare entity. We report a 73-year-old male patient who presented ileal perforation due to ingestion of a fishbone.