Background and aims: GATA2 deficiency is a rare disorder encompassing a broadly variable and continuously evolving phenotype. First described in 2011, up to 500 patients have been reported. Here, we describe 31 Italian patients (26 families) aiming to describe novel symptoms and investigating genotype-phenotype associations. Methods: All the Italian Association of Pediatric Hematology and Oncology (AIEOP) centers were contacted. Patients with pathogenic, likely pathogenic, or variants of unknown significance (VUS) in the GATA2 gene were enrolled in this study. Results: Patients' median age at onset of symptoms was 12.5 years. Infections (39%), hematological malignancies (23%) and undefined cytopenia (16%) were frequently reported at the onset. Their prevalence increased during the follow-up and further clinical manifestations, i.e hepatosplenomegaly, haemorrhagic diathesis, thrombosis, bone marrow failure (BMF), lymphedema, pulmonary alveolar proteinosis and sensorineural deafness, occurred. Clinical penetrance was highly variable, with severely affected pediatric patients coexisting with asymptomatic adults in the same pedigree. Once established the diagnosis, congenital deafness became part of the clinical picture of GATA2 deficiency in two individuals. The majority of patients (55%) underwent hematopoietic stem cell transplantation, performed in case of myeloid neoplasia (13/17) and BMF (3/17), but also in one patient with immunodeficiency. The event free survival and overall survival were 23% and 90% at the age of 20 and 16% and 78% at the age of 40, respectively. The majority of GATA2 variants were located at zinc-finger 2 (ZF2) domain of the GATA2 protein. Null (52%) and missense (42%) mutations were the most frequent variants. Intronic variants were found in 6% of the cohort. Four missense mutations out of the 7 cases of lymphedema were described. Family screening was essential to identify asymptomatic patients (6%). Conclusions: Our study highlights new (pilonidal cyst/sacrococcygeal fistula, cholangiocarcinoma and gastric adenocarcinoma) phenotypes and shows that lymphedema may be associated with missense mutations in patients with GATA2 deficiency. Keywords: GATA2 deficiency, Inborn errors of immunity, Cytopenia, Sensorineural deafness, Lymphedema
Chromosome 22q11.2 deletion is the most common chromosomal alteration associated with DiGeorge syndrome (DGS), even though this is not the only underlying cause of DGS. In rare patients, mutations in a single gene, TBX1 , have been described resulting in a DGS phenotype. Recently, it has been reported that at least part of the TBX1 mutant phenotype is due to excessive bone morphogenetic proteins (BMP) signaling. Evidence suggests that miRNA may modulate the expression of critical T‐box transcriptional regulators during midface development and Bmp‐signaling. We report on a 7‐year‐old Caucasian male born to a mother affected with gestational diabetes (GDM) who had a 371Kb‐interstitial deletion of 3p12.3 identified by array CGH, involving the ZNF717 , MIR1243 , and 4273 genes. The child presented with a DiGeorge anomaly (DGA) associated with unilateral renal agenesis and language delay. The immunological evaluation revealed a severe reduction and impairment of T lymphocytes. FISH analysis and TBX1 sequencing were negative. Among the miRNA‐4273 predicted target genes, we found BMP3 , which is involved in several steps of embryogenesis including kidney and lung organogenesis and in insulin gene expression. Since, DGA is not commonly found in newborns of diabetic mothers, we hypothesize that the pathogenesis of DGA associated with GDM is multifactorial, involving both genetic and/or epigenetic cofactors.
Severe combined immunodeficiencies (SCIDs) are a group of inborn errors of the immune system, usually associated with severe or life-threatening infections. Due to the variability of clinical phenotypes, the diagnostic complexity and the heterogeneity of the genetic basis, they are often difficult to recognize, leading to a significant diagnostic delay (DD). Aim of this study is to define presenting signs and natural history of SCID in a large cohort of patients, prior to hematopoietic stem cell or gene therapies. To this purpose, we conducted a 30-year retro-prospective multicenter study within the Italian Primary Immunodeficiency Network. 111 patients, diagnosed as typical or atypical SCID according to the European Society for Immune Deficiencies criteria, were included. Patients were subsequently classified based on the genetic alteration, pathogenic mechanism and immunological classification. A positive relationship between the age at onset and the DD was found. SCID patients with later onset were identified only in the last decade of observation. Syndromic SCIDs represented 28% of the cohort. Eight percent of the subjects were diagnosed in Intensive Care Units. Fifty-three percent had an atypical phenotype and most of them exhibited a discordant genotype-immunophenotype. Pre-treatment mortality was higher in atypical and syndromic patients. Our study broadens the knowledge of clinical and laboratory manifestations and genotype/phenotype correlation in patients with SCID and may facilitate the diagnosis of both typical and atypical forms of the disease in countries where newborn screening programs have not yet been implemented.
Abstract Purpose Inborn errors of immunity (IEI) represent a heterogeneous group of rare genetically determined diseases. In some cases, patients present with complex or atypical phenotypes, not fulfilling the accepted diagnostic criteria for IEI and, thus, at high risk of misdiagnosis or diagnostic delay. This study aimed to validate a platform that, through the opinion of immunologist experts, improves the diagnostic process and the level of care of patients with atypical/complex IEI. Methods Here, we describe the functioning of the IEI-Virtual Consultation System (VCS), an innovative platform created by the Italian Immunodeficiency Network (IPINet). Results In the validation phase, from January 2020 to June 2021, 68 cases were entered on the IEI-VCS platform. A final diagnosis was achieved in 35/68 cases (51%, 95% CI 38.7 to 64.2). In 22 out of 35 solved cases, the diagnosis was confirmed by genetic analysis. In 3/35 cases, a diagnosis of secondary immunodeficiency was made. In the remaining 10 cases, an unequivocal clinical and immunological diagnosis was obtained, even though not substantiated by genetic analysis. Conclusion From our preliminary study, the VCS represents an innovative and useful system to improve the diagnostic process of patients with complex unsolved IEI disorders, with benefits both in terms of reduction of time of diagnosis and access to the required therapies. These results may help the functioning of other international platforms for the management of complex cases.
Abstract Background/Objectives Ataxia telangiectasia (A‐T) is a multiorgan disorder with increased vulnerability to cancer. Despite this increased cancer risk, there are no widely accepted guidelines for cancer surveillance in people affected by A‐T. We aimed to understand the current international practice regarding cancer surveillance in A‐T and agreed‐upon approaches to develop cancer surveillance in A‐T. Design/Methods We used a consensus development method, the e‐Delphi technique, comprising three rounds. Round 1 consisted of a Delphi questionnaire and a survey that collected the details of respondents' professional background, experience, and current practice of cancer surveillance in A‐T. Rounds 2 and 3 were designed based on previous rounds and modified according to the comments made by the panellists. The pre‐specified consensus threshold was ≥75% agreement. Results Thirty‐five expert panellists from 13 countries completed the study. The survey indicated that the current practice of cancer surveillance varies widely between experts and centres'. Consensus was reached that evidence‐based guidelines are needed for cancer surveillance in people with A‐T, with separate recommendations for adults and children. Statements relating to the tests that should be included, the age for starting and stopping cancer surveillance and the optimal surveillance interval were also agreed upon, although in some areas, the consensus was that further research is needed. Conclusion The international expert consensus statement confirms the need for evidence‐based cancer surveillance guidelines in A‐T, highlights key features that the guidelines should include, and identifies areas of uncertainty in the expert community. This elucidates current knowledge gaps and will inform the design of future clinical trials.
