A hemophagocytic lymphohistiocytosis case with newly defined UNC13D (C.175G>C; p.Ala59Pro) mutation and a rare complication

Hemophagocytic lymphohistiocytosis (HLH) represents a severe hyperinflammatory condition with cardinal symptoms of prolonged fever, cytopenias, hepatosplenomegaly, and hemophagocytosis by activated, morphologically benign macrophages with impaired function of natural killer cells and cytotoxic T lymphocytes. A 2-month-old girl, who was admitted with fever, was diagnosed with HLH and her genetic examination revealed a newly defined mutation in the UNC13D (c.175G>C; p.Ala59Pro) gene. She was treated with dexamethasone, etoposide, and intrathecal methotrexate. During the second week of treatment, after three doses of etoposide, it was noticed that there was a necrotic plaque lesion on the soft palate. Pathologic examination of debrided material in PAS and Grocott staining revealed lots of septated hyphae, which was consistent with aspergillosis infection. Etoposide was stopped and amphotericin B treatment was given for six weeks. HLH 2004 protocol was completed to eight weeks with cyclosporine A orally. There was no patient with invasive aspergillosis infection as severe as causing palate and nasal septum perforation during HLH therapy. In immuncompromised patients, fungal infections may cause nasal septum perforation and treatment could be achieved by antifungal therapy and debridement of necrotic tissue. © 2015 Turkish Society of Hematology. All rights reserved

Adult-Onset Ataxia with Neuropathy and White Matter Abnormalities Due to a Novel SAMD9L Variant

Variants in tumor suppressor genes and in genes encoding DNA repairing proteins are associated with syndromes conferring neurologic features and increased risk for malignancy. The best example for these conditions is ataxia-telangiectasia (AT). A more rare and recent disease is an ataxia-pancytopenia syndrome (ATXPC) associated with heterozygous gain-of-function variants in the tumor suppressor gene SAMD9L (MIM 159550). Here, we describe a patient with a complex cerebellar syndrome associated with a novel SAMD9L pathogenic variant.publishedVersio

Fatal Central Nervous System Lymphocytic Vasculitis after Treatment for Burkitt Lymphoma in a Patient with a SH2D1A Mutation

Very rarely, patients with X-linked lymphoproliferative syndrome type 1 present central nervous system vasculitis. We report a patient carrying a SH2D1A mutation that, after treatment for lymphoma developed fatal central nervous system vasculitis. He lacked signs of ongoing Epstein-Barr virus infection. We propose that impaired T cell homeostasis caused by SAP deficiency facilitates aberrant CD8 T cell activation against vascular antigens promoting clinical manifestations.info:eu-repo/semantics/publishedVersio

Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort

Background: Pathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and genotype-phenotype associations could help diagnostics and potentially lead to personalized care. Therefore, we assessed the PHTS genotype and phenotype spectrum in a large cohort study. Methods: Information was collected of 510 index patients with pathogenic or likely pathogenic (LP/P) PTEN variants (n = 467) or variants of uncertain significance. Genotype-phenotype associations were assessed using logistic regression analyses adjusted for sex and age.Results: At time of genetic testing, the majority of children (n = 229) had macrocephaly (81%) or developmental delay (DD, 61%), and about half of the adults (n = 238) had cancer (51%), macrocephaly (61%), or cutaneous pathology (49%). Across PTEN, 268 LP/P variants were identified, with exon 5 as hotspot. Missense variants (n = 161) were mainly located in the phosphatase domain (PD, 90%) and truncating variants (n = 306) across all domains. A trend towards 2 times more often truncating variants was observed in adults (OR = 2.3, 95%CI = 1.5-3.4) and patients with cutaneous pathology (OR = 1.6, 95%CI = 1.1-2.5) or benign thyroid pathology (OR = 2.0, 95%CI = 1.1-3.5), with trends up to 2-4 times more variants in PD. Whereas patients with DD (OR = 0.5, 95%CI = 0.3-0.9) or macrocephaly (OR = 0.6, 95%CI = 0.4-0.9) had about 2 times less often truncating variants compared to missense variants. In DD patients these missense variants were often located in domain C2.Conclusion: The PHTS phenotypic diversity may partly be explained by the PTEN variant coding effect and the combination of coding effect and domain. PHTS patients with early-onset disease often had missense variants, and those with later-onset disease often truncating variants

Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort

Funding Information: This work (L.A.J.H. and J.R.V.) was financially supported by the PTEN Research Foundation . E.R.W. and D.G.E. are supported by the NIHR Manchester Biomedical Research Centre (Grant Reference Number 1215–200074 ). E.T. is supported by Region Stockholm (Grant ID, 2020-500306 DS ). L.R. is supported by the Estonian Research Council (Grant ID PRG471 ). Funding Information: This research is supported (not financially) by the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS)—Project ID No 739547. ERN GENTURIS is partly co-funded by the European Union within the framework of the Third Health Programme “ERN-2016—Framework Partnership Agreement 2017–2021”. Publisher Copyright: © 2022 The AuthorsBackground: Pathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and genotype-phenotype associations could help diagnostics and potentially lead to personalized care. Therefore, we assessed the PHTS genotype and phenotype spectrum in a large cohort study. Methods: Information was collected of 510 index patients with pathogenic or likely pathogenic (LP/P) PTEN variants (n = 467) or variants of uncertain significance. Genotype-phenotype associations were assessed using logistic regression analyses adjusted for sex and age. Results: At time of genetic testing, the majority of children (n = 229) had macrocephaly (81%) or developmental delay (DD, 61%), and about half of the adults (n = 238) had cancer (51%), macrocephaly (61%), or cutaneous pathology (49%). Across PTEN, 268 LP/P variants were identified, with exon 5 as hotspot. Missense variants (n = 161) were mainly located in the phosphatase domain (PD, 90%) and truncating variants (n = 306) across all domains. A trend towards 2 times more often truncating variants was observed in adults (OR = 2.3, 95%CI = 1.5–3.4) and patients with cutaneous pathology (OR = 1.6, 95%CI = 1.1–2.5) or benign thyroid pathology (OR = 2.0, 95%CI = 1.1–3.5), with trends up to 2–4 times more variants in PD. Whereas patients with DD (OR = 0.5, 95%CI = 0.3–0.9) or macrocephaly (OR = 0.6, 95%CI = 0.4–0.9) had about 2 times less often truncating variants compared to missense variants. In DD patients these missense variants were often located in domain C2. Conclusion: The PHTS phenotypic diversity may partly be explained by the PTEN variant coding effect and the combination of coding effect and domain. PHTS patients with early-onset disease often had missense variants, and those with later-onset disease often truncating variants.publishersversionPeer reviewe

Studies of genetic mosaicism in rare diseases

Mosaicism in human genetics refers to an individual harboring two or more genetic compositions, all derived from the same fertilized egg. Common signs of genetic mosaicism are asymmetric growth, skin aberrations or vascular malformations. Each clinical picture is in itself rare, but together mosaic disorders form a growing group of identifiable characteristic abnormalities. Interestingly, several pharmacological treatment possibilities for these conditions have evolved in the last couple of years. In study I, we found mosaic hotspot PIK3CA variants in two patients with ectopic muscles and muscular overgrowth, by performing whole genome sequencing and digital PCR. This adds information about timing of PIK3CA mutagenesis during embryogenesis in correlation to phenotype and confirms the diagnostic entity PIK3CA-related muscular overgrowth with ectopic muscles. In study II, we describe a genetic mechanism in DICER1-related overgrowth. We show that a constitutional DICER1 variant encoding the RNase IIIa domain causes a severe subtype of DICER1 syndrome with intellectual disability, macrocephaly, extensive bilateral lung cysts, early onset of Wilms tumor, and well-differentiated fetal lung adenocarcinoma. This phenotype is similar to, but distinct from, the phenotype reported in two patients with GLOW syndrome caused by mosaic hotspot variants encoding the RNase IIIb domain. In study III, we add knowledge of genotype-phenotype correlations in male focal dermal hypoplasia patients by describing a previously unknown disease-causing variant in a male patient, and by highlighting that focal dermal hypoplasia can be suspected in patients with characteristic limb malformations, such as ectrodactyly, or ocular manifestations, even in the absence of typical skin findings. In study IV, we used droplet digital PCR to analyze blood- and sperm-derived DNA from 87 parents to children with intellectual disability syndromes caused by de novo variants. We found germline mosaicism in two fathers and showed that analysis of blood alone may underestimate germline mosaicism. Taken together, these studies have improved our understanding of methodological approaches in mosaicism diagnostics. In addition, these studies contribute to our understanding of the phenotypic and/or genetic spectrum of PIK3CA-related overgrowth, DICER1-related overgrowth, focal dermal hypoplasia and germline mosaicism in rare diseases

Variability of forebrain commissures in callosal agenesis: a prenatal magnetic resonance imaging study

Introduzione e Scopo dello Studio L’agenesia completa del corpo calloso (ACC) anche quando isolata può essere espressione di eterogeneità anatomica. Lo scopo dello studio è descrivere la variabilità delle altre strutture commissurali in un’ ampia corte di feti con apparente agenesia completa isolata del corpo calloso con risonanza magnetica (RMN) in epoca pretale Materiale e Metodi In tutti i feti con a ACC riferiti all’ analisi con RM dal 2004 al 2014 presso la Neuroradiologia Pediatrica dell’ Ospedale Buzzi di Milano è stata valutata, da parte di due neuroradiologi esperti con più di 10 anni di esperienza in questo campo, la presenza di altre strutture commissurali: la commissura anteriore (CA) e la commissura ippocampale (CI) Risultati Complessivamente sono stati reclutati 62 casi: 3/62 (4,8%) non presentavano nessuna struttura commissurale cerebrale; 23/62 (37,1%) presentavano solo la CA, 20/62 (32,3%) presentavano sia la CA che la CI in una forma vestigiale, mentre i rimanenti 16/62 casi evidenziavano la presenza di una commissura ibrida (CIB) risultanza della fusione della CI vestigiale con un corpo rudimentale e prematuro del corpo calloso. I reperti prenatali sono stati successivamente confermati dalle immagini ottenute con la RM post-natale quando disponibili. Conclusioni Nella maggioranza dei feti della nostra corte era stata documentata allo studio prenatale con RM la presenza almeno di una commissura (CA); in circa la metà di essi era stata identificata in concomitanza la presenza di una seconda commissura: CI in una forma vestigiale o la CIB composta dalla fusione di due commissure; la CI vestigiale e il prematuro corpo del corpo calloso. Ulteriori studi sono necessari al fine di verificare se tale variabilità commissurale nei feti affetti da ACC isolata possa associarsi a diverse caratteristiche genetiche e avere un impatto sull’ outcome neurologico a lungo termine di questi giovani pazienti.Background and Purpose Agenesis of corpus callosum (ACC), even when isolated, may be characterized by anatomical variability. The aim of this study was to describe the types of other forebrain commissures, in a large cohort of randomly enrolled fetuses with apparently isolated ACC at prenatal magnetic resonance (MR) imaging. Materials and Methods From 2004 to 2014 in all fetuses with apparently isolated ACC submitted to prenatal MR imaging, the presence of the anterior (AC) or a vestigial hippocampal commissure (HC) was assessed "in consensus" by two pediatric neuroradiologists. Results Overall 62 cases of ACC were retrieved from our database. In 3/62 fetuses (4,8%) no forebrain commissure was visible at prenatal MR imaging, 23/62 cases (37,1%) presented only the AC, 20/62 cases (32,3%) showed both the AC and a residual vestigial HC, whereas in the remaining 16/62 cases (25,8%) a hybrid structure (HS) merging a residual vestigial HC and a rudiment of CC body was detectable. Postnatal MR imaging, when available, confirmed prenatal forebrain commissure findings. Conclusions The vast majority of fetuses with apparently isolated ACC showed at least one forebrain commissure at prenatal MR imaging, and about half of cases also a second commissure: a vestigial HC or a hybrid made of HC and rudiment CC body. It remains to be assessed if such variability is the result of different genotype and if it may have any impact on the long term neurodevelopmental outcom

IL RIPOSIZIONAMENTO STRATEGICO E LA VALORIZZAZIONE DELLE POTENZIALITA' INESPRESSE: IL CASO "CANTINE COLOMBA BIANCA".

La tesi rappresenta un lavoro di analisi dello sviluppo strategico seguito da una cooperativa vinicola situata nella provincia con un elevata vocazione vinicola. Le condizioni di instabilità ed elevata competitività del settore hanno spinto le aziende a modificare le proprie strategie di crescita, raggiungendo un nuovo posizionamento competitivo. La prima parte è rappresentata da un approfondimento teorico sui concetti di analisi strategica, riposizionamento competitivo e analisi del settore. Successivamente viene illustrato il caso aziendale della cooperativa Colomba Bianca