Search

Rubinstein–Taybi syndrome (RSTS) is a rare syndrome characterized by intellectual disability, distinctive facial features and distal limb abnormalities. RSTS is indicated by clinical features and confirmed via genetic testing. In this prenatal case series, we report four cases of RSTS with various sonographic features. Some features, such as corpus callosum dysgenesis, are nonspecific, but they may be the first sign apparent, as they appear early in pregnancy. Others, like beaked nose, shawl scrotum, premature coccygeal ossification, and overly mature scrotal sac with excessive rugae, are distinctive, but they may only be apparent in advanced gestation. [ABSTRACT FROM AUTHOR]

Genetic workup is becoming increasingly common in the clinical assessment of neurological disorders. We evaluated its yield among middle-aged and elderly neurological patients, in a real-world context. This retrospective study included 368 consecutive Israeli patients aged 50 years and older (202 [54.9%] males), who were referred to a single neurogenetics clinic between 2017 and mid-2023. All had neurological disorders, without a previous molecular diagnosis. Demographic, clinical and genetic data were collected from medical records. The mean age at first genetic counseling at the clinic was 62.3 ± 7.8 years (range 50-85 years), and the main indications for referral were neuromuscular, movement and cerebrovascular disorders, as well as cognitive impairment and dementia. Out of the 368 patients, 245 (66.6%) underwent genetic testing that included exome sequencing (ES), analysis of nucleotide repeat expansions, detection of specific mutations, targeted gene panel sequencing or chromosomal microarray analysis. Overall, 80 patients (21.7%) received a molecular diagnosis due to 36 conditions, accounting for 32.7% of the patients who performed genetic testing. The diagnostic rates were highest for neuromuscular (58/186 patients [31.2%] in this group, 39.2% of 148 tested individuals) and movement disorders (14/79 [17.7%] patients, 29.2% of 48 tested), but lower for other disorders. Testing of nucleotide repeat expansions and ES provided a diagnosis to 28/73 (38.4%) and 19/132 (14.4%) individuals, respectively. Based on our findings, genetic workup and testing are useful in the diagnostic process of neurological patients aged ≥50 years, in particular for those with neuromuscular and movement disorders., Competing Interests: Declaration of competing interest The authors have no financial interests that are directly or indirectly related to the work submitted for publication., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study was to compare cortisol concentrations, nutritional composition, and the antioxidant status of human milk of women living in Bydgoszcz (Poland), taking into account maternal factors (fertility, area of residence, economic activity, and breastfeeding period). Methods: The basic composition of human milk was evaluated using the MIRIS HMATM analyzer. The level of cortisol was determined by the enzyme-linked immunosorbent method. In order to determine the antioxidant activity, the DPPH radical method was used. Results: It was observed that the concentration of cortisol in human milk in the group of women living in the city center was higher compared to the milk of women living on the outskirts of the city. In the group of women breastfeeding from 3 to 5 weeks after childbirth, the concentration of cortisol in milk was higher compared to the group of women breastfeeding less than 12 months of age and compared to the group of women lactating over 12 months of age. The antioxidant status of human milk was highest in the group of professionally active women and in the group of breastfeeding women from 3 to 5 weeks after childbirth. The basic composition and the caloric value of human milk differed statistically significantly in the study groups. Conclusions: Based on this study, it can be concluded that the composition and antioxidant status of human milk depends on maternal factors (fertility, professional activity, area of residence, and breastfeeding period). Higher cortisol concentrations in breast milk are probably determined by the area of residence (city center and associated higher noise/sound and stress levels) and lactation period (hormonal imbalance, fatigue, and postpartum period). Milk from economically active women shows greater protection against reactive oxygen species compared to milk from inactive women, protecting against the occurrence of diseases of civilization. Milk from breastfeeding women over 12 months of age also shows protection against reactive oxygen species, despite the fact that the highest level of antioxidant status of human milk occurs in the initial period of lactation. [ABSTRACT FROM AUTHOR]

Background and Purpose: Autosomal dominant Hyper IgE syndrome (AD-HIES) is a rare and complex primary immunodeficiency that affects multiple systems. Mutations in signal transducer and activator of transcription 3 (STAT3) gene cause AD-HIES. These mutations have a dominant-negative effect and the presence of such mutations is associated with a clinical phenotype. We aim to describe genetic and clinical characteristics of patients with AD-HIES in our clinic and to highlight the variability of clinical patterns in the same family., Methods: We describe six patients, four individuals of the same family and two unrelated patients. All patients were given a clinical score based on disease phenotype according to the National Institute of Health (NIH) score. Mutation analysis of STAT3 was done by PCR amplification of all coding exons followed by bidirectional sequencing using the BigDye kit v1.1 and an ABI3700 genetic analyzer (Applied Biosystems)., Results: All six patients had DNA binding region point mutations: a proband and his three children with p.Phe384Leu mutation, a patient with p.Arg382Trp substitution and a patient with p.Arg382Gln mutation. All of these mutations were previously reported. Patients differed in infectious, immunologic and somatic features. We observed an extreme variability in disease phenotype within the reported family with one genetically affected patient displaying an 'unaffected' phenotype., Conclusions: Although the genetic cause of AD-HIES is known, more studies are required to better understand the possible additional factors that may affect disease expressivity within families and the clinical diversity of the disease.

Objective: To increase the production of human milk, mothers must have an adequate, balanced, and healthy diet. This study investigated the effect of maternal food consumption on the macronutrient composition of breast milk. Methods: This cross-sectional descriptive study included 46 mothers. Food consumption and breast milk content of mothers were analysed on postnatal days 1, 5, and 15. Macro and micronutrient values consumed by the mothers were evaluated using the BeBis programme. Breast milk was analysed with Miris HMATM device. Results: In repeated measurements until mature milk was secreted (days 1st, 5th and 15th), the amount of carbohydrates and fat in breast milk gradually increased, whereas the amount of protein decreased. A significant negative correlation was observed between the amount of carbohydrates and energy consumed by mothers on the 5th day and the amount of breast milk proteins. There was a significant positive correlation between the amount of carbohydrates in the mothers' food consumption on the 15th day and the amount of carbohydrates in their breast milk. Conclusions: The effect of nutrient consumption of the mothers in the study group in the last 24 h on the macronutrient levels of breast milk was evaluated. It was observed that maternal food consumption affected the macronutrient composition of breast milk during the three follow-ups. In repeated measurements, the nutrients consumed by the mothers affected the breast milk (transitional milk, and mature milk) content. [ABSTRACT FROM AUTHOR]

The hyper-immunoglobulin E syndrome (HIES) is a primary immunodeficiency disease originally described as Job syndrome. The fundamental causative variant of the HIES is an autosomal dominant mutation in the signal transducer and activator of transcription 3 (STAT3) gene. It is characterized by recurrent staphylococcal cold skin abscess, sinopulmonary infection, eczema, head and face anomalies, frequent bone fractures, eosinophilia and extremely high serum IgE levels (IgE ≥ 2000 IU/mL). However, multiple other genetic defects are also known as HIES-like disorders. Apart from infectious manifestations, STAT3, DOCK8 and TYK2 gene mutations are associated with various malignancies. The most common malignancies reported in these patients are lymphomas, including Hodgkin's and non-Hodgkin's lymphomas (NHL) of B and T cells. This systematic review aimed to investigate the prevalence of malignancies in HIES and the factors associated with malignancy in these patients. In this survey, all articles published until April 1st, 2023, in Scopus, PubMed and Web of Science databases based on three groups of keywords related to HIES syndrome and malignancy were reviewed by three different researchers. Finally, 26 articles were evaluated from which 24 papers were meta-analyzed. In the current study, the demographic information of 1133 patients with HIES, which was mentioned in 24 articles enrolled in the project, was collected, and the information related to patients who had malignancy was analyzed and meta-analyzed. A total of 96 patients out of 1133 studied patients had at least one type of malignancy, the overall prevalence of malignancies reported in the articles was 6.5% (95% confidence interval 4.1–9%), and the total prevalence of malignancy in patients with NHL type and patients with squamous cell carcinoma (SCC) was 2.9% (95% confidence interval 1.7–4.4%) and 2.2% (95% confidence interval 0.3–4.1%), respectively. The results of this study indicated that in 6.5% of cases, HIES was complicated with malignancy, and considering the higher rate of these malignancies in women as well as in DOCK8 mutation sufferers, it is necessary for physicians to be aware of this association and includes malignancy screening in follow-up and periodic examinations of these patients. Indeed, more studies in this field will help to clarify the precise figures and predisposing factors of the relationship between HIES and malignancy. [ABSTRACT FROM AUTHOR]

The JAK/STAT signaling pathway plays a key role in cytokine signaling and is involved in development, immunity, and tumorigenesis for nearly any cell. At first glance, the JAK/STAT signaling pathway appears to be straightforward. However, on closer examination, the factors influencing the JAK/STAT signaling activity, such as cytokine diversity, receptor profile, overlapping JAK and STAT specificity among non-redundant functions of the JAK/STAT complexes, positive regulators (e.g., cooperating transcription factors), and negative regulators (e.g., SOCS, PIAS, PTP), demonstrate the complexity of the pathway's architecture, which can be quickly disturbed by mutations. The JAK/STAT signaling pathway has been, and still is, subject of basic research and offers an enormous potential for the development of new methods of personalized medicine and thus the translation of basic molecular research into clinical practice beyond the use of JAK inhibitors. Gain-of-function and loss-of-function mutations in the three immunologically particularly relevant signal transducers STAT1, STAT3, and STAT6 as well as JAK1 and JAK3 present themselves through individual phenotypic clinical pictures. The established, traditional paradigm of loss-of-function mutations leading to immunodeficiency and gain-of-function mutation leading to autoimmunity breaks down and a more differentiated picture of disease patterns evolve. This review is intended to provide an overview of these specific syndromes from a clinical perspective and to summarize current findings on pathomechanism, symptoms, immunological features, and therapeutic options of STAT1, STAT3, STAT6, JAK1, and JAK3 loss-of-function and gain-of-function diseases. [ABSTRACT FROM AUTHOR]

Inborn errors of immunity (IEI) include a variety of heterogeneous genetic disorders in which defects in the immune system lead to an increased susceptibility to infections and other complications. Accurate, prompt diagnosis of IEI is crucial for treatment plan and prognostication. In this study, clinical utility of clinical exome sequencing (CES) for diagnosis of IEI was evaluated. For 37 Korean patients with suspected symptoms, signs, or laboratory abnormalities associated with IEI, CES that covers 4,894 genes including genes related to IEI was performed. Their clinical diagnosis, clinical characteristics, family history of infection, and laboratory results, as well as detected variants, were reviewed. With CES, genetic diagnosis of IEI was made in 15 out of 37 patients (40.5%). Seventeen pathogenic variants were detected from IEI-related genes, BTK, UNC13D, STAT3, IL2RG, IL10RA, NRAS, SH2D1A, GATA2, TET2, PRF1, and UBA1, of which four variants were previously unreported. Among them, somatic causative variants were identified from GATA2, TET2, and UBA1. In addition, we identified two patients incidentally diagnosed IEI by CES, which was performed to diagnose other diseases of patients with unrecognized IEI. Taken together, these results demonstrate the utility of CES for the diagnosis of IEI, which contributes to accurate diagnosis and proper treatments. [ABSTRACT FROM AUTHOR]

Human milk oligosaccharides (HMOs) are multifunctional carbohydrates in breast milk, which are composed by a variety of structures. This study aimed to identified HMOs concentration profile, milk microbiota composition, and the associations with major maternal characteristics in Han Chinese mothers in the one-year lactation period. Seventeen healthy mothers aged from 28 to 36 years, who gave birth to healthy term infants, were recruited. Carbohydrates were detected using the MIRIS human milk analyzer (HMA), and twenty-three HMOs were quantified using ultra-performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-MS). Results showed that carbohydrates were relatively stable, while total HMO concentrations ranged from 1.74 to 9.72 g/L and decreased gradually over lactation in breast milk. Based on the structure, seven sialylated HMOs concentration showed the significant decline (p < 0.05) after three months in lactation. In addition, the relationships between maternal factors, containing the lactation period, genetic status, delivery mode, parity, and milk microbiota profile, and the HMO composition in healthy women, which still need further investigations, were observed. [ABSTRACT FROM AUTHOR]

Background: Tandem breastfeeding is defined as two or more offspring of different ages who are breastfed by their mother at the same time. Breastfeeding during pregnancy and tandem breastfeeding have not been widely investigated. Research Aim: To determine the influence of tandem breastfeeding on the macronutrient content of human milk. Methods: This longitudinal study used a prospective and a retrospective group. Human milk samples from tandem-breastfeeding participants (n = 18) were compared to samples from non-tandem-breastfeeding participants (n = 31). Samples were collected during the last month of pregnancy (pregnancy milk), 72 hr after birth (colostrum) and 14–60 days post-delivery (mature milk). Macronutrients were measured by mid-infrared spectroscopy. Results: Fat content in pregnancy milk was lower than in mature milk (p <.01). Protein content was higher in pregnancy milk than in colostrum and mature milk (p <.01 and p <.001, respectively). Inversely, carbohydrate content in pregnancy milk was lower than in colostrum and mature milk (p =.02 and p <.01, respectively). Fat and energy contents in pregnancy milk of tandem-breastfeeding participants were lower than in mature milk of non-tandem-breastfeeding participants (p <.001 and p <.01, respectively), and protein content was higher than in mature milk (p <.001). Carbohydrate content in colostrum and mature milk of tandem-breastfeeding participants was higher than that of non-tandem-breastfeeding participants (p <.001 for both). Conclusion: Human milk produced during pregnancy had different macronutrient content than human milk produced after delivery. Colostrum and mature milk of tandem-breastfeeding participants were similar to human milk produced by non-tandem-breastfeeding participants, with the exception of carbohydrate content. [ABSTRACT FROM AUTHOR]

The hyper-IgE syndromes (HIES) are a heterogeneous group of inborn errors of immunity sharing manifestations including increased infection susceptibility, eczema, and raised serum IgE. Since the prototypical HIES description 55 years ago, areas of significant progress have included description of key disease-causing genes and differentiation into clinically distinct entities. The first two patients reported had what is now understood to be HIES from dominant-negative mutations in signal transduction and activator of transcription 3 (STAT3-HIES), conferring a broad immune defect across both innate and acquired arms, as well as defects in skeletal, connective tissue, and vascular function, causing a clinical phenotype including eczema, staphylococcal and fungal skin and pulmonary infection, scoliosis and minimal trauma fractures, and vascular tortuosity and aneurysm. Due to the constitutionally expressed nature of STAT3, initial reports at treatment with allogeneic stem cell transplantation were not positive and treatment has hinged on aggressive antimicrobial prophylaxis and treatment to prevent the development of end-organ disease such as pneumatocele. Research into the pathophysiology of STAT3-HIES has driven understanding of the interface of several signaling pathways, including the JAK-STAT pathways, interleukins 6 and 17, and the role of Th17 lymphocytes, and has been expanded by identification of phenocopies such as mutations in IL6ST and ZNF341. In this review we summarize the published literature on STAT3-HIES, present the diverse clinical manifestations of this syndrome with current management strategies, and update on the uncertain role of stem cell transplantation for this disease. We outline key unanswered questions for further study. [ABSTRACT FROM AUTHOR]

Copyright of Revista Brasileira de Crescimento e Desenvolvimento Humano is the property of Centro de Estudos de Crescimento e Desenvolvimento do Ser Humano and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The autosomal‐dominant hyper‐IgE syndrome (HIES), caused by mutations in STAT3, is a rare primary immunodeficiency that predisposes to mucocutaneous candidiasis and staphylococcal skin and lung infections. This infection phenotype is suggestive of defects in neutrophils, but data on neutrophil functions in HIES are inconsistent. This study was undertaken to functionally characterize neutrophils in STAT3‐deficient HIES patients and to analyze whether the patients' eosinophilia affects the neutrophil phenotype in S. aureus infection. Neutrophil functions and cell death kinetics were studied in eight STAT3‐deficient patients. Moreover, the response of STAT3‐deficient neutrophils to S. aureus and the impact of autologous eosinophils on pathogen‐induced cell death were analyzed. No specific aberrations in neutrophil functions were detected within this cohort. However, the half‐life of STAT3‐deficient neutrophils ex vivo was reduced, which was partially attributable to the presence of eosinophils. Increased S. aureus‐induced cell lysis, dependent on the staphylococcal virulence controlling accessory gene regulator (agr)‐locus, was observed in STAT3‐deficient neutrophils and upon addition of eosinophils. Accelerated neutrophil cell death kinetics may underlie the reported variability in neutrophil function testing in HIES. Increased S. aureus‐induced lysis of STAT3‐deficient neutrophils might affect pathogen control and contribute to tissue destruction during staphylococcal infections in HIES. In our study, STAT3‐deficient neutrophils from patients with autosomal‐dominant HIES showed accelerated cell death kinetics in the presence of eosinophilia in granulocyte preparations. STAT3 deficiency did not affect basic neutrophil function tests. Yet, increased S. aureus‐induced cell death was observed in STAT3 deficiency and upon addition of eosinophils to neutrophils. [ABSTRACT FROM AUTHOR]

Objective: The influence of seasonal variation upon human milk macronutrient content has not been elucidated. This study aimed to compare the macronutrient content of HM produced by lactating mothers during the winter and the summer seasons., Study Design: Macronutrient content of colostrum milk samples collected from lactating mothers of healthy term infants between March 2012 and February 2016 was measured by mid-infrared spectroscopy and compared., Result: The carbohydrate content of the colostrum was significantly higher in the summer season than in the winter season (6.2 ± 1.3 vs. 5.5 ± 1.4, p-value < 0.001). Protein, fat, and energy contents were similar in summer and winter in both groups (protein 2.7 ± 2.1 vs. 2.6 ± 2.2 g/100 ml, fat 2.6 ± 1.9 vs. 2.35 ± 1.9 g/100 ml, and energy 62 ± 19.1 vs. 60.5 ± 21 kcal/100 ml, respectively)., Conclusion: The carbohydrate content in colostrum obtained from mothers of term infants was affected by seasonal variations., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: Autosomal dominant hyper-IgE syndrome (AD-HIES) is included among primary immunodeficiencies, and results from heterozygous mutations in the signal transduction and activator of transcription 3 ( STAT3) gene. AD-HIES leads to impaired Th17 cell differentiation and IL-17 production, and is associated with increased susceptibility to bacteria and fungi. It was reported that several patients with AD-HIES were treated with hematopoietic stem cell transplantation (HSCT). The efficacy of HSCT in treating AD-HIES is variable. This study aims to evaluate the long-term clinical and immunological efficacy of HSCT for AD-HIES. Methods: We have followed for more than 8 years two patients with AD-HIES who were treated with HSCT. Their ability of IL-17 production was evaluated by flow cytometry. Results: Both patients indicated the normal ability of IL-17 production and their serum IgE levels decreased after HSCT. On the other hand, they suffered from pulmonary complications of AD-HIES such as pneumatoceles and bronchiectasis even after HSCT; however, the frequency of infections was decreased. Conclusions: Although the dysfunction of STAT3 in non-hematological tissues such as the lungs could not be corrected by HSCT, AD-HIES patients with risk factors for pulmonary complications may benefit from immunological correction by HSCT before severe pulmonary complications occur. Future studies should investigate risk factors for pulmonary complications in AD-HIES patients. [ABSTRACT FROM AUTHOR]

Maternal obesity has been associated with changes in the macronutrient concentration of human milk (HM), which have the potential to promote weight gain and increase the long-term risk of obesity in the infant. This article aimed to provide a synthesis of studies evaluating the effects of maternal overweight and obesity on the concentrations of macronutrients in HM. EMBASE, MEDLINE/PubMed, Cochrane Library, Scopus, Web of Science, and ProQuest databases were searched for relevant articles. Two authors conducted screening, data extraction, and quality assessment independently. A total of 31 studies (5078 lactating women) were included in the qualitative synthesis and nine studies (872 lactating women) in the quantitative synthesis. Overall, maternal body mass index (BMI) and adiposity measurements were associated with higher HM fat and lactose concentrations at different stages of lactation, whereas protein concentration in HM did not appear to differ between overweight and/or obese and normal weight women. However, given the considerable variability in the results between studies and low quality of many of the included studies, further research is needed to establish the impact of maternal overweight and obesity on HM composition. This is particularly relevant considering potential implications of higher HM fat concentration on both growth and fat deposition during the first few months of infancy and long-term risk of obesity. [ABSTRACT FROM AUTHOR]

Human milk (HM) is the first dietary exposure in infancy and the best nutritional option for growth and healthy development of the newborn and infant. The concentrations of macronutrients, namely proteins, carbohydrates and lipids, change during lactation stages. HM has been studied extensively in the first 6 months of lactation, but there are limited data regarding milk composition beyond 1 or 2 years postpartum. The aim of our study was to describe longitudinal changes in HM macronutrient concentrations during the prolonged lactation of healthy mothers from the 1st to the 48th month. For the macronutrient content of milk of mothers breastfeeding for longer than 18 months, fat and protein increased and carbohydrates decreased significantly, compared with milk expressed by women breastfeeding up to 12 months. Moreover, the concentration of fat, protein and carbohydrates in HM over 2 years of lactation from the 24th to the 48th month remained at a stable level. However, analyzed macronutrients were positively (carbohydrate, r = 0.51) or negatively (fat, r = −0.36 and protein, r = −0.58) correlated with the amount of feeding. Our results create a greater potential for understanding the nutritional contribution of HM over 2 years of lactation and showed that the source of calories in breast milk for older children is mainly fat, while carbohydrates play a greater role in infant nutrition in the early stage. The observed changes of macronutrient concentrations from the 1st to the 48th month of lactation are probably related to the adaptation of milk composition to the increased energy demand of the intensively growing child. [ABSTRACT FROM AUTHOR]