Bloom syndrome, caused by biallelic mutations in BLM, is characterized by prenatal-onset growth deficiency, short stature, an erythematous photosensitive malar rash, and increased cancer predisposition. Diagnostically, a hallmark feature is the presence of increased sister chromatid exchanges (SCEs) on cytogenetic testing. Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly. TOP3A encodes topoisomerase III alpha (TopIIIα), which binds to BLM as part of the BTRR complex, and promotes dissolution of double Holliday junctions arising during homologous recombination. We also identify a homozygous truncating variant in RMI1, which encodes another component of the BTRR complex, in two individuals with microcephalic dwarfism. The TOP3A mutations substantially reduce cellular levels of TopIIIα, and consequently subjects' cells demonstrate elevated rates of SCE. Unresolved DNA recombination and/or replication intermediates persist into mitosis, leading to chromosome segregation defects and genome instability that most likely explain the growth restriction seen in these subjects and in Bloom syndrome. Clinical features of mitochondrial dysfunction are evident in several individuals with biallelic TOP3A mutations, consistent with the recently reported additional function of TopIIIα in mitochondrial DNA decatenation. In summary, our findings establish TOP3A mutations as an additional cause of prenatal-onset short stature with increased cytogenetic SCEs and implicate the decatenation activity of the BTRR complex in their pathogenesis.

The GATA family zinc finger transcription factors GATA4 and GATA6 are known to play important roles in the development of the pancreas. In mice, both Gata4 and Gata6 are required for pancreatic development. In humans, GATA6 haploinsufficiency can cause pancreatic agenesis and heart defects. Congenital heart defects also are common in patients with GATA4 mutations and deletions, but the role of GATA4 in the developing human pancreas is unproven. We report five patients with deletions (n = 4) or mutations of the GATA4 gene who have diabetes and a variable exocrine phenotype. In four cases, diabetes presented in the neonatal period (age at diagnosis 1-7 days). A de novo GATA4 missense mutation (p.N273K) was identified in a patient with complete absence of the pancreas confirmed at postmortem. This mutation affects a highly conserved residue located in the second zinc finger domain of the GATA4 protein. In vitro studies showed reduced DNA binding and transactivational activity of the mutant protein.We show that GATA4 mutations/deletions are a cause of neonatal or childhood-onset diabetes with or without exocrine insufficiency. These results confirm a role for GATA4 in normal development of the human pancreas.

Highlights A methodology for obtaining EHR-derived datasets for COVID-19 research is proposed. It allowed effective reuse of EHRs in a tertiary Hospital during COVID-19 pandemic. ISARIC-WHO COVID-19 CRF was obtained for 4,489 patients with high coverage. Detailed Clinical Models provides the flexibility needed to expand the concept model. ISO 13606, SNOMED CT and LOINC standards were used for modeling and standardization.

Primary immune regulatory disorders (PIRD) are associated with autoimmunity, autoinflammation and/or dysregulation of lymphocyte homeostasis. Autoimmune lymphoproliferative syndrome (ALPS) is a PIRD due to an apoptotic defect in Fas-FasL pathway and characterized by benign and chronic lymphoproliferation, autoimmunity and increased risk of lymphoma. Clinical manifestations and typical laboratory biomarkers of ALPS have also been found in patients with a gene defect out of the Fas-FasL pathway (ALPS-like disorders). Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), we identified more than 600 patients suffering from 24 distinct genetic defects described in the literature with an autoimmune lymphoproliferative phenotype (ALPS-like syndromes) corresponding to phenocopies of primary immunodeficiency (PID) (NRAS, KRAS), susceptibility to EBV (MAGT1, PRKCD, XIAP, SH2D1A, RASGRP1, TNFRSF9), antibody deficiency (PIK3CD gain of function (GOF), PIK3R1 loss of function (LOF), CARD11 GOF), regulatory T-cells defects (CTLA4, LRBA, STAT3 GOF, IL2RA, IL2RB, DEF6), combined immunodeficiencies (ITK, STK4), defects in intrinsic and innate immunity and predisposition to infection (STAT1 GOF, IL12RB1) and autoimmunity/autoinflammation (ADA2, TNFAIP3,TPP2, TET2). CTLA4 and LRBA patients correspond around to 50% of total ALPS-like cases. However, only 100% of CTLA4, PRKCD, TET2 and NRAS/KRAS reported patients had an ALPS-like presentation, while the autoimmunity and lymphoproliferation combination resulted rare in other genetic defects. Recurrent infections, skin lesions, enteropathy and malignancy are the most common clinical manifestations. Some approaches available for the immunological study and identification of ALPS-like patients through flow cytometry and ALPS biomarkers are provided in this work. Protein expression assays for NKG2D, XIAP, SAP, CTLA4 and LRBA deficiencies and functional studies of AKT, STAT1 and STAT3 phosphorylation, are showed as useful tests. Patients suspected to suffer from one of these disorders require rapid and correct diagnosis allowing initiation of tailored specific therapeutic strategies and monitoring thereby improving the prognosis and their quality of life.

Brachydactyly type E is characterized by variable shortening of the metacarpals and/or metatarsals [Temtamy and Aglan, 2008;Mundlos, 2009]. PTHLH is one of the genes associated with this type of brachydactyly, and since its involvement in this trait was discovered [Klopocki et al., 2010;Maass et al., 2010], nine intragenic point mutations [Klopocki et al., 2010;Wang et al., 2015;Jamsheer et al., 2016;Thomas-Teinturier et al., 2016] have been described as causative of BDE with short stature, PTHLH type (OMIM#613382). Most of the reported patients have had short stature or stature within the lower range of normality and some of them present normal stature at diagnosis [Klopocki et al., 2010;Jamsheer et al., 2016;Thomas-Teinturier et al., 2016], though final height is usually below the target height [Thomas-Teinturier et al., 2016].There are no data in the bibliography about the recurrence of these nine mutations in other non-related families, and hence, it is difficult to make genotype-phenotype correlations. Given this state-of-affairs, we considered it important to report our patient with BDE, who harbors the p.R56 Ã mutation first described recently [Jamsheer et al., 2016].The patient was Caucasian girl who was referred to the endocrinologist at 9 years and 10 months old for pubarche and apocrine sweat from 7 years of age. She was born at 39 weeks of gestation, with low weight for gestational age (weight 1950 g, À3.32 SD; length 47 cm, À1.47 SD). After the neonatal period, she had been a healthy girl with a normal growth rate. Her parents were healthy and non-consanguineous. The mother's height was 169 cm and the age of her menarche was 13 years old. The father was 172 cm tall, and hence, the girl's target height was 164 cm. Parents did not present brachydactyly.At the time of the first visit, she had a normal height (137.9 cm, 0 SD) with mild overweight (weight 44.3 kg, 1.2 SD; body mass index 23.3 kg/m 2 , 1.7 SD). The physical examination revealed a P2 B1 Tanner stage, round face, long philtrum, short neck, descended and widely separated nipples, and small hands and feet, with shortening of all the metacarpals and the distal phalanges of the first and third fingers (Fig. 1A) and shortening of third, fourth, and fifth metatarsals (Fig. 1B). A hand roentgenogram showed premature fusion of the epiphyses in the shortened bones and cone-shaped epiphyses (Fig. 1A) with a bone age of approximately 12 years when she was 9 years and 8 months old (Fig. 1C). Blood tests and an abdominal ultrasound examination were performed, results ruling out congenital adrenal hyperplasia and adrenal tumors.At the age of 10 years and 8 months, she had a bone age of 13.5 years (Fig. 1C), and her growth rate did not show a clear pubertal growth spurt. She had the menarche when she was 11 years old. In the most recent visit, when she was 12 years old, she was 148.7 cm tall (À0.4 SD) and her growth rate in the previous year had been 4.2 cm/year; this suggests an early completion of growth resulting in short stature for her target height, ...