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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]

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]

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]

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]

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]

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]

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]

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]