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Insalaco A.,Bambino Gesu Childrens Hospital | Prencipe G.,Bambino Gesu Childrens Hospital | Buonuomo P.S.,Bambino Gesu Childrens Hospital | Ceccherini I.,UOC Medical Genetics | And 4 more authors.
Clinical and Experimental Rheumatology | Year: 2014

Background. Cryopyrin-associated periodic syndromes (CAPS) comprise a spectrum of distinct, rare, autosomal dominant autoinflammatory disorders of increasing severity caused by NLRP3 gene mutations Methods. We describe a 13-year-old female who presented, in the initial phase of the disease, recurrent episodes of high fever, pericarditis, arthralgia, arthritis of the knees, abdominal pain and marked increase in inflammatory markers. In the subsequent months she developed recurrent episodes of chest pain, skin rash and swelling of the subcutaneous tissue, without fever, and with spontaneous resolution. Results. Molecular analysis of the CIAS1 gene revealed the presence of the Q703K variant and also a c.1105C>A mutation in the heterozygous state, that predicts a L369M amino acid substitution. The latter variant has never been reported. The L369M mutation was predicted to significantly affect protein structure (scoring as "dangerous" and "deleterious") by the Variant Effect Predictor tool. Therapy with anakinra was started with rapid disappearance of clinical symptoms and normalisation of CRP levels in 24 hours Conclusion. The rapid response to IL-1 inhibition suggests that the disease of this patient is driven by IL-1 and supports the conclusion that this novel mutation is pathogenic and may be associated with a new CAPS phenotype. The role played by the concomitant presence of the mutation Q703K remains to be clarified. © Clinical and Experimental Rheumatology 2014.

Pini Prato A.,Istituto Giannina Gaslini | Rossi V.,Istituto Giannina Gaslini | Rossi V.,University of Genoa | Mosconi M.,Istituto Giannina Gaslini | And 18 more authors.
Orphanet Journal of Rare Diseases | Year: 2013

Background: Associated anomalies have been reported in around 20% of Hirschsprung patients but many Authors suggested a measure of underestimation. We therefore implemented a prospective observational study on 106 consecutive HSCR patients aimed at defining the percentage of associated anomalies and implementing a personalized and up-to-date diagnostic algorithm. Methods. After Institutional Ethical Committee approval, 106 consecutive Hirschsprung patients admitted to our Institution between January 2010 and December 2012 were included. All families were asked to sign a specific Informed Consent form and in case of acceptance each patient underwent an advanced diagnostic algorithm, including renal ultrasound scan (US), cardiologic assessment with cardiac US, cerebral US, audiometry, ENT and ophthalmologic assessments plus further specialist evaluations based on specific clinical features. Results: Male to female ratio of our series of patients was 3,4:1. Aganglionosis was confined to the rectosigmoid colon (classic forms) in 74,5% of cases. We detected 112 associated anomalies in 61 (57,5%) patients. The percentage did not significantly differ according to gender or length of aganglionosis. Overall, 43,4% of patients complained ophthalmologic issues (mostly refraction anomalies), 9,4% visual impairment, 20,7% congenital anomalies of the kidney and urinary tract, 4,7% congenital heart disease, 4,7% hearing impairment or deafness, 2,3% central nervous system anomalies, 8,5% chromosomal abnormalities or syndromes and 12,3% other associated anomalies. Conclusions: Our study confirmed the underestimation of certain associated anomalies in Hirschsprung patients, such as hearing impairment and congenital anomalies of the kidney and urinary tract. Subsequently, based on our results we strongly suggest performing renal US and audiometry in all patients. Conversely, ophthalmologic assessment and cerebral and heart US can be performed according to guidelines applied to the general population or in case of patients with suspected clinical features or chromosomal abnormalities. This updated diagnostic algorithm aims at improving overall outcome thanks to better prognostic expectations, prevention strategies and early rehabilitation modalities. The investigation of genetic background of patients with associated anomalies might be the next step to explore this intriguing multifactorial congenital disease. © 2013 Pini Prato et al.; licensee BioMed Central Ltd.

Rusmini M.,UOC Medical Genetics | Federici S.,Laboratory Immunology Rheumatic Diseases | Caroli F.,UOC Medical Genetics | Grossi A.,UOC Medical Genetics | And 15 more authors.
Annals of the Rheumatic Diseases | Year: 2015

Objectives Systemic auto-inflammatory disorders (SAIDs) are a heterogeneous group of monogenic diseases sharing a primary dysfunction of the innate immune system. More than 50% of patients with SAID does not show any mutation at gene(s) tested because of lack of precise clinical classification criteria and/or incomplete gene screening. To improve the molecular diagnosis and genotype interpretation of SAIDs, we undertook the development of a next-generation sequencing (NGS)-based protocol designed to simultaneous screening of 10 genes. Methods Fifty patients with SAID, already genotyped for the respective causative gene(s), were massively sequenced for the coding portions of MEFV, MVK, TNFRSF1A, NLRP3, NLRP12, NOD2, PSTPIP1, IL1RN, LPIN2 and PSMB8. Three different bioinformatic pipelines (Ion Reporter, CLC Bio Genomics Workbench, GATK-based in-house workflow) were compared. Results Once resulting variants were compared with the expected mutation list, no workflow turned out to be able to detect all the 79 variants known in the 50 DNAs. Additional variants were also detected, validated by Sanger sequencing and compared to assess true and false positive detection rates of the three workflows. Finally, the overall clinical picture of 34 patients was re-evaluated in the light of the new mutations found. Conclusions The present gene panel has resulted suitable for molecular diagnosis of SAIDs. Moreover, genotype-phenotype correlation has confirmed that the interpretation of NGS data in patients with an undefined inflammatory phenotype is remarkably difficult, thus supporting the need of evidence-based and validated clinical criteria to be used concurrently with the genetic analysis for the final diagnosis and classification of patients with SAIDs. © 2015 BMJ Publishing Group Ltd & European League Against Rheumatism. All rights reserved.

Tassano E.,Laboratorio Of Citogentica | Gimelli S.,University of Geneva | Divizia M.T.,UOC Medical Genetics | Lerone M.,UOC Medical Genetics | And 4 more authors.
Molecular Cytogenetics | Year: 2015

Background: Thrombocytopenia-absent radius syndrome (TAR; MIM 274000) is a rare autosomal recessive disorder combining specific skeletal abnormalities with a reduced platelet count. TAR syndrome has been associated with the compound inheritance of an interstitial microdeletion in 1q21.1 and a low frequency noncoding RBM8A SNP. Results: Here, we report on a patient with scapulo-humeral hypoplasia, bilateral radio-ulnar agenesis with intact thumbs, bilateral proximal positioning of the first metacarpal, bilateral fifth finger clinodactyly, bilateral radial deviation of the hands, and thrombocytopenia. Molecular studies showed compound heterozygosity for the 1q21.1 microdeletion and the RBM8A rs139428292 variant in hemizygous state, inherited from the father and the mother, respectively. A second aborted fetus presented TAR features and 1q21.1 microdeletion. Discussion: The complex inheritance pattern resulted in reduced expression of Y14, the protein encoded by RBM8A, and a component of the core exon-junction complex (EJC) in platelets. Further studies are needed to explain how Y14 insufficiency and subsequent defects of the EJC could cause the skeletal, haematological and additional features of TAR syndrome. In this study, we discuss other factors that could influence the overall phenotype of patients affected by TAR syndrome. Conclusion: In this study, we discuss other factors that could influence the overall phenotype of patients affected by TAR syndrome. © 2015 Tassano et al.

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