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Although the most common mechanism underlying congenital hyperinsulinism is dysfunction of the pancreatic ATPsensitive potassium channel, the pathogenesis and genetic origins of this disease remains largely unexplained in more than half of all patients. UCP2 knockout mice exhibit an hyperinsulinemic hypoglycemia, suggesting an involment of UCP2 in insulin secretion. However, a possible pathogenic role for UCP2 protein in the development of human congenital hyperinsulinism or of any human disease has not yet been investigated. We studied ten children exhibiting congenital hyperinsulinism, without detectable mutations in the known congenital hyperinsulinism-causing genes. Parental-inherited heterozygous UCP2 variants encoding amino-acid changes were found in two unrelated children with congenital hyperinsulinism. Functional assays in yeast and in insulin-secreting cells revealed an impaired activity of UCP2 mutants. Therefore, we report the finding of UCP2 coding variants in human congenital hyperinsulinism, which reveals a role for this gene in the regulation of insulin secretion and glucose metabolism in humans. Our results show for the first time a direct association between UCP2 amino acid alteration and human disease and highlight a role for mitochondria in hormone secretion. [ABSTRACT FROM AUTHOR]

Congenital hyperinsulinism (CHI), characterized by profound hypoglycaemia related to inappropriate insulin secretion, may be associated histologically with either diffuse insulin hypersecretion or focal adenomatous hyperplasia, which share a similar clinical presentation, but result from different molecular mechanisms. Whereas diffuse CHI is of autosomal recessive, or less frequently of autosomal dominant, inheritance, focal CHI is sporadic. The most common mechanism underlying CHI is dysfunction of the pancreatic ATP-sensitive potassium channel (K+ATP). The two subunits of the K+ATP channel are encoded by the sulfonylurea receptor gene (SUR1 or ABCC8) and the inward-rectifying potassium channel gene (KIR6.2 or KCNJ11), both located in the 11p15.1 region. Germ-line, paternally inherited, mutations of the SUR1 or KIR6.2 genes, together with somatic maternal haplo-insufficiency for 11p15.5, were shown to result in focal CHI. Diffuse CHI results from germ-line mutations in the SUR1 or KIR6.2 genes, but also from mutations in several other genes, namely glutamate dehydrogenase (with associated hyperammonaemia), glucokinase, short-chain L-3-hydroxyacyl-CoA dehydrogenase, and insulin receptor gene. Hyperinsulinaemic hypoglycaemia may be observed in several overlapping syndromes, such as Beckwith-Wiedemann syndrome (BWS), Perlman syndrome, and, more rarely, Sotos syndrome. Mosaic genome-wide paternal isodisomy has recently been reported in patients with clinical signs of BWS and CHI. The primary causes of CHI are genetically heterogeneous and have not yet been completely unveiled. However, secondary causes of hyperinsulinism have to be considered such as fatty acid oxidation deficiency, congenital disorders of glycosylation and factitious hypoglycaemia secondary to Munchausen by proxy syndrome. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Partial absence of the sacrum is a rare congenital defect that also occurs as an autosomal-dominant trait, whereas imperforate/ectopic anus is a relatively common malformation, usually observed in multiple congenital anomalies syndromes. We report on a girl born to healthy consanguineous parents (first cousins once removed) with anal imperforation and associated rectovaginal fistula and partial sacral agenesis. Facial dysmorphism included a high forehead, epicanthic folds, downslanting palpebral fissures, hypertelorism and a depressed nasal root. Brain MRI showed a bilateral opercular dysplasia with a unilateral (right) pachygyria; MRI and X-ray imaging of the spine disclosed a tethered cord associated with partial sacral agenesis. She showed a moderate developmental delay. Ophthalmologic examination evidenced bilateral microphthalmos and relative microcornea. Cytogenetic studies in our patient disclosed a pure de novo 6q25.3 → qter deletion. By genotype analysis, we detected in our patient a maternal allele loss encompassing D6S363 and D6S446. Pure distal 6q deletion is a rare anomaly, reported in association with sacral/anorectal malformations (sacral agenesis, anal imperforation/ectopia) and never with cortical dysplasia. Pooling deletion mapping information in patients with pure terminal and interstitial 6q deletion allowed us to define a critical region spanning 0.3 Mb between the markers D6S959 and D6S437 for sacral/anal malformations. We hypothesize that haploinsufficiency for a gene within the deleted region may impair normal development of caudal structures, possibly acting on the notochordal development.European Journal of Human Genetics (2006) 14, 971–974. doi:10.1038/sj.ejhg.5201635; published online 17 May 2006 [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) rarely complicates the clinical course of systemic lupus erythematosus (SLE). AP as the initial manifestation of SLE is exceptional, but its outcome is often fatal. Corticosteroids have been suspected to play a role in the development of AP, but the therapeutic benefit seems to be far above the risk of exacerbation of pancreatic lesions. We report a 13-y-old girl presenting with arthralgia and malaise, followed by abdominal pain, generalized oedema and haemodynamic instability. Increased CRP (325  ng/ml), serum amylase (14 000  IU/l) and lipase (2500  IU/l) levels suggested AP. Acute anuric renal failure required haemodialysis. Multiorgan involvement suggested SLE, which was confirmed 3  d later by increased anti-ds-DNA levels. Three methylprednisolone pulses were administered promptly, followed by oral prednisone (1.5  mg/kg/d) and six pulses of cyclophosphamide (500  mg/1.73  m 2 /2  wk). Mycophenolate mofetil was introduced for long-term disease control. Amylase and lipase levels decreased over 4  wk. Renal function was normal after 3  wk and proteinuria negative after 6  wk. This case suggests that steroid pulse therapy should be promptly administered if clinical and biochemical investigations suggest SLE to be responsible for AP. Aggressive treatment may be life saving. [ABSTRACT FROM AUTHOR]

TCF4 haploinsufficiency by deletions, truncating variants or loss‐of‐function missense variants within the DNA‐binding and protein interacting bHLH domain causes Pitt‐Hopkins syndrome (PTHS). This neurodevelopmental disorder (NDD) is characterized by severe intellectual disability (ID), epilepsy, hyperbreathing and a typical facial gestalt. Only few aberrations of the N‐terminus of TCF4 were associated with milder or atypical phenotypes. By personal communication and searching databases we assembled six cases with the novel, recurrent, de novo missense variant c.1165C > T, p.(Arg389Cys) in TCF4. This variant was identified by diagnostic exome or panel sequencing and is located upstream of the bHLH domain. All six individuals presented with moderate to severe ID with language impairment. Microcephaly occurred in two individuals, epilepsy only in one, and no breathing anomalies or myopia were reported. Facial gestalt showed some aspects of PTHS but was rather non‐specific in most individuals. Interestingly, the variant is located within the AD2 activation domain next to a highly conserved coactivator‐recruitment motif and might alter interaction with coactivator proteins independently from the bHLH domain. Our findings of a recurrent missense variant outside the bHLH domain in six individuals with an ID phenotype overlapping with but not typical for PTHS delineate a novel genotype–phenotype correlation for TCF4‐related NDDs. [ABSTRACT FROM AUTHOR]

Congenital disorders of glycosylation-Ia are the most frequent type of congenital disorders of glycosylation. This condition affects the nervous system as well as other organs. The estimated incidence of congenital disorders of glycosylation-Ia is higher than the number of identified cases, therefore underdiagnosis of this heterogeneous disorder is probable. Neurologic and biologic signs are hallmarks for the identification of patients with congenital disorders of glycosylation-Ia. This report describes two children with congenital disorders of glycosylation-Ia syndrome confirmed by phosphomannomutase gene mutations with normal development and absence of biologic anomalies such as elevated transaminases and altered hemostasis. In conclusion, congenital disorders of glycosylation should be considered in cases of unexplained behavioral symptoms such as hyperactivity and concentration difficulties and mild neurologic signs. Intellectual retardation is often overestimated because of dysarthria and motor difficulties. Psychomotor reeducation might improve quality of life. [Copyright &y& Elsevier]

Pitt‐Hopkins syndrome (PTHS) is a neurodevelopmental disorder characterized by intellectual disability, specific facial features, and marked autonomic nervous system dysfunction, especially with disturbances of regulating respiration and intestinal mobility. It is caused by variants in the transcription factor TCF4. Heterogeneity in the clinical and molecular diagnostic criteria and care practices has prompted a group of international experts to establish guidelines for diagnostics and care. For issues, for which there was limited information available in international literature, we collaborated with national support groups and the participants of a syndrome specific international conference to obtain further information. Here, we discuss the resultant consensus, including the clinical definition of PTHS and a molecular diagnostic pathway. Recommendations for managing particular health problems such as dysregulated respiration are provided. We emphasize the need for integration of care for physical and behavioral issues. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimization of diagnostics and care. [ABSTRACT FROM AUTHOR]

[Display omitted] Osteogenesis imperfecta (OI) is a genetically heterogeneous connective tissue disorder characterized by bone fragility and different extra-skeletal manifestations. The severity of these manifestations makes it possible to classify OI into different subtypes based on the main clinical features. This review aims to outline and describe the current pharmacological alternatives for treating OI, grounded on clinical and preclinical reports, such as antiresorptive agents, anabolic agents, growth hormone, and anti-TGFβ antibody, among other less used agents. The different options and their pharmacokinetic and pharmacodynamic properties will be reviewed and discussed, focusing on the variability of their response and the molecular mechanisms involved to attain the main clinical goals, which include decreasing fracture incidence, improving pain, and promoting growth, mobility, and functional independence. [ABSTRACT FROM AUTHOR]

A20 haploinsufficiency (HA20) is an autoinflammatory disease caused by heterozygous loss- of- function variations in TNFAIP3, the gene encoding the A20 protein. Diagnosis of HA20 is challenging due to its heterogeneous clinical presentation and the lack of pathognomonic symp- toms. While the pathogenic effect of TNFAIP3 truncating variations is clearly established, that of missense variations is difficult to determine. Herein, we identified a novel TNFAIP3 variation, p.(Le- u236Pro), located in the A20 ovarian tumor (OTU) domain and demonstrated its pathogenicity. In the patients' primary cells, we observed reduced A20 levels. Protein destabilization was predicted in silico for A20_Leu236Pro and enhanced proteasomal degradation was confirmed in vitro through a flow cytometry- based functional assay. By applying this approach to the study of another missense variant, A20_Leu275Pro, for which no functional characterization has been performed to date, we showed that this variant also undergoes enhanced proteasomal degradation. Moreover, we showed a disrupted ability of A20_Leu236Pro to inhibit the NF-kB pathway and to deubiquitinate its substrate TRAF6. Structural modeling revealed that two residues involved in OTU pathogenic missense variations (i.e. Glu192Lys and Cys243Tyr) establish common interactions with Leu236. Interpretation of newly identified missense variations is challenging, requiring, as illustrated here, functional demonstration of their pathogenicity. Together with functional studies, in silico structure analysis is a valuable approach that allowed us (i) to provide a mechanistic explanation for the haplo-insufficiency resulting from missense variations and (ii) to unveil a region within the OTU domain critical for A20 function. [ABSTRACT FROM AUTHOR]

Objective: To identify the molecular basis of a severe systemic autoinflammatory disorder (SAID) and define its main phenotypic features, and to functionally assess the sequence variations identified in LYN, a gene encoding a nonreceptor tyrosine kinase. Methods: We used targeted next‐generation sequencing and in vitro functional studies of Lyn phosphorylation state and Lyn‐dependent NF‐κB activity after expression of recombinant Lyn isoforms carrying different sequence variations. Results: We identified a de novo LYN variation (p.Tyr508His) in a patient presenting since birth with recurrent fever, chronic urticaria, atopic dermatitis, arthralgia, increased inflammatory biomarkers, and elevated plasma cytokine levels. We studied the consequences on Lyn phosphorylation state of the p.Tyr508His variation and of the 2 LYN variations reported so far (p.Tyr508Phe and p.Tyr508*), and found that all 3 variations prevent phosphorylation of residue 508 and lead to autophosphorylation of Tyr397. Additionally, these 3 LYN variations activate the NF‐κB pathway. These results show a gain‐of‐function effect of the variations involving Tyr508 on Lyn activity. Conclusion: This study demonstrates the pathogenicity of the first 3 LYN variations identified in SAID patients and delineates the phenotypic spectrum of a disease entity characterized by severe, early‐onset, systemic inflammatory disease affecting neonates with no family history of SAID. All 3 LYN variations affect the same tyrosine residue located in the C‐terminus of Lyn, thereby demonstrating the critical role of this residue in the proper regulation of Lyn activity in humans. [ABSTRACT FROM AUTHOR]

Objective To identify the molecular basis of a systemic autoinflammatory disorder (SAID) evocative of TNF receptor-associated periodic syndrome (TRAPS). Methods (i) Deep next generation sequencing (NGS) through a SAID gene panel; (ii) variant allele distribution in peripheral blood subpopulations; (iii) in silico analyses of mosaic variants using TNF receptor superfamily 1A (TNFRSF1A) crystal structure; (iv) review of the very rare TNFRSF1A mosaic variants reported previously. Results In a 36-year-old man suffering from recurrent fever for 12 years, high-depth NGS revealed a TNFRSF1A mosaic variant, c.176G>A p.(Cys59Tyr), which Sanger sequencing failed to detect. This mosaic variant displayed a variant allele fraction of 14% in whole blood; it affects both myeloid and lymphoid lineages. p.(Cys59Tyr), a recurrent germline pathogenic variant, affects a crucial cysteine located in the first cysteine-rich domain (CRD1) and involved in a disulphide bridge. Introduction of a tyrosine at this position is expected to disrupt the CRD1 structure. Review of the three previously reported TNFRSF1A mosaic variants revealed that they are all located in a small region of CRD2 and that germinal cells can be affected. Conclusion This study expands the localization of TNFRSF1A mosaic variants to the CRD1 domain. Noticeably, residues involved in germline TNFRSF1A mutational hot spots can also be involved in post-zygotic mutational events. Including our study, only four patients have been thus far reported with TNFRSF1A mosaicism, highlighting the need for a high-depth NGS-based approach to avoid the misdiagnosis of TRAPS. Genetic counselling has to consider the potential occurrence of TNFRSF1A mosaic variants in germinal cells. [ABSTRACT FROM AUTHOR]

Objective Cryopyrin-associated periodic syndrome (CAPS) is a rare but treatable inherited autoinflammatory condition including familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS) and chronic infantile neurologic cutaneous articular syndrome (CINCA). Our objective was to describe the main features of CAPS AA amyloidosis (AA-CAPS) associated and the efficacy of IL-1 inhibitors in this indication. Methods Retrospective study in France associated with a systematic literature review. Results Eighty-six patients were identified: 23 new French cases and 63 from the literature, with a median age at amyloidosis diagnosis of 39 years old. CAPS subtypes were MWS (n  = 62), FCAS (n  = 9), frontier forms between MWS and FCAS (n  = 12) and between CINCA and MWS (n  = 3). NLRP3 had been sequenced in 60 patients (70%) and the most frequent mutation was R260W (60%). Three AA-CAPS patients displayed somatic NLRP3 mutations. Death occurred in 35 patients (41%), none of whom having ever received IL-1 inhibitors. Twenty-eight patients (33%) received IL-1 inhibitors, with a >50% decrease in proteinuria in 89% of cases. Conclusion AA amyloidosis can occur in nearly all CAPS subtypes. IL-1 inhibitors are effective, underlining the necessity of an early diagnosis of CAPS in order to start this treatment as soon as possible among AA-CAPS patients. [ABSTRACT FROM AUTHOR]

Familial Mediterranean fever (FMF) patients may have hepatic cytolysis, although its origin is not formally elucidated. We aimed to evaluate liver involvement in familial Mediterranean fever (FMF) using non-invasive methods. All adult FMF patients harboring two non-ambiguous mutations of the MEFV gene with hepatic cytolysis were identified in a French tertiary adult center for FMF. Liver impairment was explored with FibroMax (a non-invasive method to estimate hepatic steatosis, necrosis, inflammation and fibrosis) and liver ultrasound. Among 520 FMF adult patients, 43 had persistent hepatic cytolysis and 20 patients were included (11 women, median age at inclusion: 49.5 years). According to the FibroMax results, patients were classified as having steatosis, fibrosis, and possible or definite nonalcoholic steato-hepatitis in 10 (50%), 9 (45%) and 7 (35%) of cases, respectively. The score of steatosis did not seem associated with the usual metabolic risk factors. No significant association was found between the cumulated dose of colchicine and any of the scores included in FibroMax. In adult FMF patients with persistent hepatic cytolysis, steatosis is the first cause to consider even in the absence of usual metabolic risk factors, suggesting other mechanisms. Colchicine did not seem to be involved in this toxicity. [ABSTRACT FROM AUTHOR]

Objectives TNF receptor-1-associated periodic syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder associated with mutations in the TNF receptor super family 1 A (TNFRSF1A) gene. AA amyloidosis (AA) is the most severe complication of TRAPS. To study the occurrence and prognosis of AA in TRAPS, we conducted a retrospective study of all French cases and a systematic literature review. Methods This case series includes TRAPS patients followed by our centre from 2000 to 2020 presenting with histologically confirmed AA. We conducted a systematic literature review on the PubMed and EMBASE databases for articles published up to February 2021 following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and using the keywords: amyloidoisis, amyloid, TNF receptor-associated periodic syndrome, TNF receptor-associated periodic syndrome, tumor necrosis factor receptor-associated periodic syndrome, TRAPS, TNFRSF1A , familial hibernian fever and hibernian familial fever. Results A total of 41 TRAPS with AA were studied: three new patients and 38 cases from the literature. AA diagnosis preceded that of TRAPS in 96% of cases, and 17/36 (47%) required renal replacement therapy. Death occurred in 5/36 (14%) with a median follow-up of 23 months. Effect of biologics on AA were available for 21 regimens in 19 patients: 10 improved renal function, seven stabilized and four worsened. Four patients (36% of transplanted patients) relapse AA on kidney graft (only one under etanercept). Conclusion TRAPS is revealed by AA in most cases. Therefore, clinical features of TRAPS should be screened for in AA patients. IL-1 antagonist can help to normalize inflammation and to preserve renal function. [ABSTRACT FROM AUTHOR]

Background: Terminal deletions of the long arm of chromosome 7 are well known and frequently associated with syndromic holoprosencephaly due to the involvement of the SHH (aliases HHG1, SMMCI, TPT, TPTPS, and MCOPCB5) gene region. However, interstitial deletions including CNTNAP2 (aliases Caspr2, KIAA0868, and NRXN4) and excluding the SHH region are less common. Methods: We report the clinical and molecular characterization associated with pure 7q35 and 7q35q36.1 deletion in two unrelated patients as detected by oligonucleotide‐based array‐CGH analysis. Results: The common clinical features were abnormal maternal serum screening during first‐trimester pregnancy, low occipitofrontal circumference at birth, hypotonia, abnormal feet, developmental delay, impaired language development, generalized seizures, hyperactive behavior, friendly personality, and cranio‐facial dysmorphism. Both deletions occurred de novo and sequencing of CNTNAP2, a candidate gene for epilepsy and autism showed absence of mutation on the contralateral allele. Conclusion: Combined haploinsufficiency of GALNTL5 (alias GalNAc‐T5L), CUL1, SSPO (aliases SCO‐spondin, KIAA0543, and FLJ36112), AOC1(alias DAO), RHEB, and especially KMT2C (alias KIAA1506 and HALR) with monoallelic disruption of CNTNAP2 may explain neurologic abnormalities, hypotonia, and exostoses. Haploinsufficiency of PRKAG2 (aliases AAKG, AAKG2, H91620p, WPWS, and CMH6) and KCNH2 (aliases Kv11.1, HERG, and erg1) genes may be responsible of long QT syndrome observed for one patient. [ABSTRACT FROM AUTHOR]

Background & Aims: Secondary to tumour necrosis factor‐alpha induced protein 3 (TNFAIP3) mutations, A20 haploinsufficiency (HA20) is a recently described autoinflammatory disease with clinical features similar to those of Behçet's and Crohn's diseases but with a constantly expanding clinical spectrum. Here, we describe HA20 liver involvement in three new patients from the same family. Methods: We retrospectively assessed clinical, biological and/or histological findings for eight patients over three generations of the same family with heterozygous mutations in the TNFAIP3 gene (c.259C > T, p.Arg87*). Results: The eight patients exhibited the following: aphthous ulcers (8/8, bipolar in 7), autoimmune features (6/8, including 5 with definitive autoimmune disease diagnoses, ie, type I diabetes, Hashimoto thyroiditis, pernicious anaemia, and/or 5 with antinuclear antibodies ≥320), pustulosis/folliculitis (5/8), abdominal pain (4/8), arthralgia (3/8), enlarged cervical lymph nodes (3/8) and pericarditis (1/8). In addition, three patients (twin sisters and their grandmother aged 23 and 70 years, respectively) exhibited persistent mild hepatic cytolysis associated with splenomegaly (n = 3), hepatomegaly (n = 1) and/or liver atrophy (n = 1) on echography. We could not detect any other causes of chronic liver diseases. Liver biopsies from three patients displayed hepatic fibrosis, hepatocyte injury and/or CD4+/CD8+ T lymphocyte infiltration, and patterns of inflammatory cells and NLRP3 or NF‐κB immunostaining differed from the predominant neutrophil infiltration observed in skin or some digestive tract biopsies. Conclusions: This study reinforces the dual involvement of innate and adaptive immunity in HA20 according to both acute and chronic injury and the organ involved and widens its clinical spectrum to include chronic hepatic involvement. [ABSTRACT FROM AUTHOR]

Introduction: Familial Mediterranean Fever (FMF), the most common monogenic auto‐inflammatory disease, is characterized by recurrent febrile abdominal pain. Helicobacter pylori infection (HPI), one of the most frequent infections worldwide, can mimic an FMF attack. Objectives: Identify FMF patients with HPI in a cohort of French FMF patients and the literature and identify features allowing to distinguish HPI from an FMF attack. Methods: A retrospective study of all HPI cases was performed on the cohort of FMF patients fulfilling the Livneh criteria from the French Reference Center for rare Auto‐Inflammatory Diseases and Amyloidosis (CEREMAIA). A systematic literature review of HPI in FMF patients was conducted according to the PRISMA guidelines. Results: Eight French patients developed HPI, whose symptoms of epigastralgia, diarrhea, anorexia/weight loss, and nausea/vomiting differed from their typical abdominal FMF attacks. A total of 112 FMF patients with HPI have been described in the literature, including 61 adults. Diagnosis of HPI was made by gastroscopy (n = 43), labelled urea test (n = 55) or IgG serology by ELISA (n = 12). When performed, C‐reactive protein was always elevated. Ten cases of interaction between colchicine and antibiotic therapy for HPI (clarithromycin (n = 9) and azithromycin (n = 1)) were reported. Conclusion: We described a total of 120 patients with typical FMF and HPI. When FMF patients develop atypical abdominal symptoms, upper gastrointestinal endoscopy with biopsies is essential to eliminate underlying HPI. Untreated HPI can lead to misdiagnosis of colchicine resistance with inappropriate prescription of an interleukin‐1 inhibitor at a non‐negligible cost. [ABSTRACT FROM AUTHOR]

Aim of the study: Mowat Wilson syndrome (MWS) is a complex genetic disorder due to mutation or deletion of the ZEB2 gene (ZFHX1B), including multiple clinical features. Hirschsprung disease is associated with this syndrome with a prevalence between 43 and 57%. The aim of this study was to demonstrate the severe outcomes and the high complication rates in children with MWS, focusing on their complicated follow-up. Methods: A retrospective comparative study was conducted on patients referred to Robert-Debré Children's Hospital for MWS from 2003 to 2018. Multidisciplinary follow-up was carried out by surgeons, geneticists, gastroenterologists, and neurologists. Data regarding patient characteristics, surgical management, postoperative complications, and functional outcomes were collected. Results: Over this period of 15 years, 23 patients were diagnosed with MWS. Hirschsprung disease was associated with 10 of them (43%). Of these cases, two patients had recto-sigmoïd aganglionosis (20%), three had aganglionic segment extension to the left colic angle (30%), two to the right colic angle (20%), and three to the whole colon (30%). The median follow-up was 8.5 years (2 months–15 years). All patients had seizures and intellectual disability. Six children (60%) presented with cardiac defects. At the last follow-up, three patients still had a stoma diversion and 7 (70%) were fed orally. One patient died during the first months. Eight (80%) of these children required a second surgery due to complications. At the last follow-up, three patients reported episodes of abdominal bloating (42%), one recurrent treated constipation (14.3%), and one soiling (14.3%). Genetic analysis identified three patients with heterozygous deletions, three with codon mutations, and three with frameshift mutations. Conclusions: MWS associated with Hirschsprung disease has a high rate of immediate surgical complications but some patients may achieve bowel function comparable with non-syndromic HD patients. A multidisciplinary follow-up is required for these patients. Level of evidence: Retrospective observational single cohort study, Level 3. [ABSTRACT FROM AUTHOR]

Introduction: Familial Mediterranean fever is the most frequent monogenic auto-inflammatory disorder that mostly affects Mediterranean population. Although this auto-inflammatory disease has historically been described as a recessive genetic disorder with homozygous or compound heterozygous mutations in the MEFV gene, an increasing number of cases are described with the detection of new single MEFV gene heterozygous mutations with modern molecular techniques.Case Description: We report the cases of Caucasian French descent father and daughter who exhibited joint and abdominal inflammatory attacks resembling Familial Mediterranean Fever. Genetic studies revealed in both a heterozygous mutation p.T577N in exon 8 of MEFV gene, and in which colchicine was effective for preventing the attacks.Conclusion: Single heterozygous mutation of MEFV can be responsible for typical Familial Mediterranean Fever clinical pattern and, what is more, in non-Mediterranean ethnic background patients. [ABSTRACT FROM AUTHOR]

We aimed to explore triggering receptor expressed on myeloid cells-1 (TREM-1) activation in familial Mediterranean fever (FMF), the most frequent monogenic auto-inflammatory disease, through the measurement of its serum soluble form, named sTREM-1. Blood samples from patients with FMF according to Livneh criteria followed in the French FMF national center and carrying two pathogenic MEFV mutations were collected. Serum level of sTREM-1 was assessed using ELISA. Demographic data, presence of FMF attack, association with histologically proven AA amyloidosis, and blood levels of C-reactive protein (CRP), serum amyloid A (SAA) protein, and creatinine were collected. TREM-1 was available in 56 patients (33.9% male, mean age 43 yr); AA amyloidosis was associated in six patients (19.6% in FMF). Mean sTREM-1 level did not differ significantly between patients having an attack or not and there was also no significant correlation between the level of sTREM-1 and CRP and SAA protein. However, the mean rate of sTREM-1 was significantly higher among FMF patients with AA amyloidosis versus without, though the concomitant SAA protein level was normal. Serum level of sTREM-1 was higher in patients with amyloidosis even though the concomitant SAA protein level was normal. sTREM-1 plasma levels could be an accurate tool to specifically identify FMF patients with amyloidosis. [ABSTRACT FROM AUTHOR]

Two distinct syndromes arise from pathogenic variants in the X-linked gene BCOR (BCL-6 corepressor): oculofaciocardiodental (OFCD) syndrome, which affects females, and a severe microphthalmia ('Lenz'-type) syndrome affecting males. OFCD is an X-linked dominant syndrome caused by a variety of BCOR null mutations. As it manifests only in females, it is presumed to be lethal in males. The severe male X-linked recessive microphthalmia syndrome ('Lenz') usually includes developmental delay in addition to the eye findings and is caused by hypomorphic BCOR variants, mainly by a specific missense variant c.254C > T, p.(Pro85Leu). Here, we detail 16 new cases (11 females with 4 additional, genetically confirmed, affected female relatives; 5 male cases each with unaffected carrier mothers). We describe new variants and broaden the phenotypic description for OFCD to include neuropathy, muscle hypotonia, pituitary underdevelopment, brain atrophy, lipoma and the first description of childhood lymphoma in an OFCD case. Our male X-linked recessive cases show significant new phenotypes: developmental delay (without eye anomalies) in two affected half-brothers with a novel BCOR variant, and one male with high myopia, megalophthalmos, posterior embryotoxon, developmental delay, and heart and bony anomalies with a previously undescribed BCOR splice site variant. Our female OFCD cases and their affected female relatives showed variable features, but consistently had early onset cataracts. We show that a mosaic carrier mother manifested early cataract and dental anomalies. All female carriers of the male X-linked recessive cases for whom genetic confirmation was available showed skewed X-inactivation and were unaffected. In view of the extended phenotype, we suggest a new term of X-linked BCOR-related syndrome. [ABSTRACT FROM AUTHOR]

Circulating serum amyloid A (SAA) is increased in various inflammatory conditions. The human SAA protein family comprises the acute phase SAA1/SAA2, known to activate a large set of innate and adaptive immune cells, and the constitutive SAA4. The liver synthesis of SAA1/SAA2 is well-established but there is still an open debate on extrahepatic SAA expression especially in macrophages. We aimed to investigate the ability of human primary monocytes and monocyte-derived macrophages to express SAA1, SAA2 and SAA4 at both the transcriptional and protein levels, as previous studies almost exclusively dealt with monocytic cell lines. Monocytes and derived macrophages from healthy donors were stimulated under various conditions. In parallel with SAA, pro-inflammatory IL1A, IL1B and IL6 cytokine expression was assessed. While LPS alone was non-effective, a combined LPS/dexamethasone treatment induced SAA1 and to a lesser extent SAA2 transcription in human monocytes and macrophages. In contrast, as expected, pro-inflammatory cytokine expression was strongly induced following stimulation with LPS, an effect which was dampened in the presence of dexamethasone. Furthermore, in monocytes polarized towards a pro-inflammatory M1 phenotype, SAA expression in response to LPS/dexamethasone was potentiated; a result mainly seen for SAA1. However, a major discrepancy was observed between SAA mRNA and intracellular protein levels under the experimental conditions used. Our results demonstrate that human monocytes and macrophages can express SAA genes, mainly SAA1 in response to an inflammatory environment. While SAA is considered as a member of a large cytokine network, its expression in the monocytes-macrophages in response to LPS-dexamethasone is strikingly different from that observed for classic pro-inflammatory cytokines. As monocytes-macrophages are major players in chronic inflammatory diseases, it may be hypothesized that SAA production from macrophages may contribute to the local inflammatory microenvironment, especially when macrophages are compactly organized in granulomas as in sarcoidosis. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 27-year-old woman affected by Pitt-Hopkins syndrome who developed a medulloblastoma and the patient was treated using a standard dose of craniospinal radiotherapy.

Inflammasomes are intracellular multiprotein signaling complexes, mainly present in myeloid cells. They commonly assemble around a cytoplasmic receptor of the nucleotide-binding leucine-rich repeat containing receptor (NLR) family, although other cytoplasmic receptors like pyrin have been shown to form inflammasomes. The nucleation of the multiprotein scaffolding platform occurs upon detection of a microbial, a danger or a homeostasis pattern by the receptor that will, most commonly, associate with the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) through homotypic domain interactions resulting in recruitment of procaspase-1. This will lead to the autoproteolytic activation of caspase-1, which regulates the secretion of proinflammatory IL1β and IL18 cytokines and pyroptosis, a caspase-1-mediated form of cell death. Pyroptosis occurs through cleavage of Gasdermin D, a membrane pore forming protein. Recently, non-canonical inflammasomes have been described, which directly sense intracellular pathogens through caspase-4 and -5 in humans, leading to pyroptosis. Inflammasomes are important in host defense; however, a deregulated activity is associated with a number of inflammatory, immune and metabolic disorders. Furthermore, mutations in inflammasome receptor coding genes are causal for an increasing number of rare autoinflammatory diseases. Biotherapies targeting the products of inflammasome activation as well as molecules that directly or indirectly inhibit inflammasome nucleation and activation are promising therapeutic areas. This review discusses recent advances in inflammasome biology, the molecular pathology of several inflammasomes, and current therapeutic approaches in autoinflammatory diseases and in selected common multifactorial inflammasome-mediated disorders. [ABSTRACT FROM AUTHOR]

These data prompted us to assess the contribution of I NLRP3 i and I UBA1 i somatic mutations, as well as of the main genes so far involved in SAID patients with cutaneous lesions in SchS pathophysiology. Absence of NLRP3 somatic mutations and VEXAS-related UBA1 mutations in a large cohort of patients with Schnitzler syndrome Schnitzler's syndrome (SchS) is an extremely rare systemic autoinflammatory disease (SAID) characterized by a late onset of urticarial rash, recurrent fever, bone pain, arthralgia, elevated acute-phase reactants, and a monoclonal gammopathy involving IgM chains (classical type) and rarely IgG (variant type). [Extracted from the article]

Inflammasomes are multiprotein complexes nucleating around an NLR (Nucleotide-binding domain and Leucine-rich Repeat containing protein), which regulate the secretion of the pro-inflammatory interleukin (IL)-1β and IL-18 cytokines. Monocytes and macrophages, the main cells expressing the inflammasome genes, adapt to their surrounding microenvironment by a phenotypic polarization towards a pro-inflammatory M1 phenotype that promotes inflammation or an anti-inflammatory M2 phenotype important for resolution of inflammation. Despite the importance of inflammasomes in health and disease, little is known about inflammasome gene expression in relevant human cells and the impact of monocyte and macrophage polarization in inflammasome gene expression. We examined the expression of several members of the NLR, caspase and cytokine family, and we studied the activation of the well-described NLRP3 inflammasome in an experimental model of polarized human primary monocytes and monocyte-derived macrophages (M1/M2 phenotypes) before and after activation with LPS, a well-characterized microbial pattern used in inflammasome activation studies. Our results show that the differentiation of monocytes to macrophages alters NLR expression. Polarization using IFN-γ (M1 phenotype), induces among the NLRs studied, only the expression of NOD2. One of the key results of our study is that the induction of NLRP3 expression by LPS is inhibited in the presence of IL-4+IL-13 (M2 phenotype) at both mRNA and protein level in monocytes and macrophages. Unlike caspase-3, the expression of inflammasome-related CASP1 (encodes caspase-1) and CASP4 (encodes caspase-4) is up-regulated in M1 but not in M2 cells. Interestingly, the presence of LPS marginally influenced IL18 mRNA expression and secretion, unlike its impact on IL1B. Our data provide the basis for a better understanding of the role of different inflammasomes within a given environment (M1 and M2) in human cells and their impact in the pathophysiology of several important inflammatory disorders. [ABSTRACT FROM AUTHOR]

Early Infantile Epileptic Encephalopathy (EIEE) presents shortly after birth with frequent, severe seizures, a burst-suppression EEG pattern, and progressive disturbance of cerebral function. We present a case of EIEE associated with a de novo missense variant in ZEB2 . Heterozygous truncating mutations or deletions in ZEB2 are known to cause Mowat-Wilson syndrome (MWS), which is characterized by seizures with onset in the second year of life, distinctive dysmorphic facial features and malformations that were absent in this patient. This unique case expands the range of phenotypes associated with variants in ZEB2 and indicates that this gene should be included in the molecular investigation of EIEE cases. [ABSTRACT FROM AUTHOR]

Intellectual disability (ID) is a clinical sign reflecting diverse neurodevelopmental disorders that are genetically and phenotypically heterogeneous. Just recently, partial or complete deletion of methyl-CpG-binding domain 5 (MBD5) gene has been implicated as causative in the phenotype associated with 2q23.1 microdeletion syndrome. In the course of systematic whole-genome screening of individuals with unexplained ID by array-based comparative genomic hybridization, we identified de novo intragenic deletions of MBD5 in three patients leading, as previously documented, to haploinsufficiency of MBD5. In addition, we described a patient with an unreported de novo MBD5 intragenic duplication. Reverse transcriptase-PCR and sequencing analyses showed the presence of numerous aberrant transcripts leading to premature termination codon. To further elucidate the involvement of MBD5 in ID, we sequenced ten coding, five non-coding exons and an evolutionary conserved region in intron 2, in a selected cohort of 78 subjects with a phenotype reminiscent of 2q23.1 microdeletion syndrome. Besides variants most often inherited from an healthy parent, we identified for the first time a de novo nonsense mutation associated with a much more damaging phenotype. Taken together, these results extend the mutation spectrum in MBD5 gene and contribute to refine the associated phenotype of neurodevelopmental disorder. [ABSTRACT FROM AUTHOR]

Abstract: Background: The identification by CFTR mRNA studies of a new deep-intronic splicing mutation, c.870-1113_1110delGAAT, in one patient of our series with mild CF symptoms and in three CF patients of an Italian study, led us to evaluate the mutation frequency and phenotype/genotype correlations. Methods: 266 patients with CF and related disorders and having at least one undetected mutation, were tested at the gDNA level in three French reference laboratories. Results: In total, the mutation was found in 13 unrelated patients (5% of those already carrying a mutation) plus 4 siblings, including one homozygote and 12 heterozygotes having a severe CF mutation. The sweat test was positive in 10/14 documented cases, the diagnosis was delayed after 20years in 9/15 and pancreatic insufficiency was present in 5/16. Conclusion: c.870-1113_1110delGAAT should be considered as CF-causing with phenotype variability and overall delayed diagnosis. Its frequency highlights the potential of mRNA studies. [Copyright &y& Elsevier]

With the clinical implementation of genomic microarrays, the detection of cryptic unbalanced rearrangements in patients with syndromic developmental delay has improved considerably. Here we report the molecular karyotyping and phenotypic description of six new unrelated patients with partially overlapping microdeletions at 10p12.31p11.21 ranging from 1.0 to 10.6 Mb. The smallest region of overlap is 306 kb, which includes WAC gene, known to be associated with microtubule function and to have a role in cell division. Another patient has previously been described with a 10 Mb deletion, partially overlapping with our six patients. All seven patients have developmental delay and a majority of the patients have abnormal behaviour and dysmorphic features, including bulbous nasal tip, deep set eyes, synophrys/thick eyebrows and full cheeks, whereas other features varied. All patients also displayed various visual impairments and six out of seven patients had cardiac malformations. Taken together with the previously reported patient, our study suggests that the detected deletions may represent a new contiguous gene syndrome caused by dosage-sensitive genes that predispose to developmental delay. [ABSTRACT FROM AUTHOR]

Fetal bowel anomalies may reveal cystic fibrosis (CF) and the search for CF transmembrane conductance regulator ( CFTR) gene mutations is part of the diagnostic investigations in such pregnancies, according to European recommendations. We report on our 18-year experience to document comprehensive CFTR genotypes and correlations with ultrasound patterns in a series of 694 cases of fetal bowel anomalies. CFTR gene analysis was performed in a multistep process, including search for frequent mutations in the parents and subsequent in-depth search for rare mutations, depending on the context. Ultrasound patterns were correlated with the genotypes. Cases were distinguished according to whether they had been referred directly to our laboratory or after an initial testing in another laboratory. A total of 30 CF fetuses and 8 cases compatible with CFTR-related disorders were identified. CFTR rearrangements were found in 5/30 CF fetuses. 21.2% of fetuses carrying a frequent mutation had a second rare mutation, indicative of CF. The frequency of CF among fetuses with no frequent mutation was 0.43%. Correlation with ultrasound patterns revealed a significant frequency of multiple bowel anomalies in CF fetuses. The results emphasize the need to search for rearrangements in the diagnosis strategy of fetal bowel anomalies. The diagnostic value of ultrasound patterns combining hyperechogenic bowel, loop dilatation and/or non-visualized gallbladder reveals a need to revise current strategies and to offer extensive CFTR gene testing when the triad is diagnosed, even when no frequent mutation is found in the first-step analysis. [ABSTRACT FROM AUTHOR]

Waardenburg syndrome (WS) is an auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair and skin. Depending on additional symptoms, WS is classified into four subtypes, WS1-WS4. Absence of additional features characterizes WS2. The association of facial dysmorphic features defines WS1 and WS3, whereas the association with Hirschsprung disease (aganglionic megacolon) characterizes WS4, also called "Waardenburg-Hirschsprung disease." Mutations within the genes MITF and SNAI2 have been identified in WS2, whereas mutations of EDN3, EDNRB, and SOX10 have been observed in patients with WS4. However, not all cases are explained at the molecular level, which raises the possibility that other genes are involved or that some mutations within the known genes are not detected by commonly used genotyping methods. We used a combination of semiquantitative fluorescent multiplex polymerase chain reaction and fluorescent in situ hybridization to search for SOX10 heterozygous deletions. We describe the first characterization of SOX10 deletions in patients presenting with WS4. We also found SOX10 deletions in WS2 cases, making SOX10 a new gene of WS2. Interestingly, neurological phenotypes reminiscent of that observed in WS4 (PCWH syndrome [peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS, and Hirschsprung disease]) were observed in some WS2-affected patients with SOX10 deletions. This study further characterizes the molecular complexity and the close relationship that links the different subtypes of WS. [ABSTRACT FROM AUTHOR]

Overgrowth is rarely associated with chromosomal imbalances. Here we report on four children from two unrelated families presenting with overgrowth and a terminal duplication of the long arm of chromosome 15 diagnosed using cytogenetic and FISH studies. In both cases, chromosome analysis of the parents showed a balanced translocation involving 15q26.1-qter. Molecular and cytogenetic studies showed three copies of the insulin-like growth factor 1 receptor (IGF1 R) gene. This finding suggests that overgrowth observed in our patients might be causally related to a dosage effect of the IGF1R gene, in contrast to severe growth retardation observed in patients with terminal deletion of 15q. The present observation emphasises the importance of chromosome analysis in patients with overgrowth and mental retardation. Moreover, it further delineates a specific phenotype related to trisomy 15q26.1-qter with macrosomia at birth, overgrowth, macrocephaly and mild developmental delay being the major clinical features. [ABSTRACT FROM AUTHOR]