A Novel Mutation in Insulin-Like Growth Factor 1 Receptor (c.641-2A>G) Is Associated with Impaired Growth, Hypoglycemia, and Modified Immune Phenotypes.

INTRODUCTION: Insulin-like growth factor 1 receptor (IGF1R) mutations lead to systemic disturbances in growth and glucose homeostasis due to widespread IGF1R expression throughout the body. IGF1R is expressed by innate and adaptive immune cells, facilitating their development and exerting immunomodulatory roles in the periphery. CASE PRESENTATION: We report on a family presenting with a novel heterozygous IGF1R mutation with characterization of the mutation, IGF1R expression, and immune phenotyping. Twin probands presented clinically with short stature and hypoglycemia. Variable phenotypic expression was seen in 2 other family members carrying the IGF1R mutation. The probands were treated with exogenous growth hormone therapy and dietary cornstarch, improving linear growth and reducing hypoglycemic events. IGF1R c.641-2A>G caused abnormal mRNA splicing and premature protein termination. Flow cytometric immunophenotyping demonstrated lower IGF1R on peripheral blood mononuclear cells from IGF1R c.641-2A>G subjects. This alteration was associated with reduced levels of T-helper 17 cells and a higher percentage of T-helper 1 cells compared to controls, suggesting decreased IGF1R expression may affect CD4+ Th-cell lineage commitment. DISCUSSION: Collectively, these data suggest a novel loss-of-function mutation (c.641-2A>G) leads to aberrant mRNA splicing and IGF1R expression resulting in hypoglycemia, growth restriction, and altered immune phenotypes.

Myasthaenia gravis in pregnancy, delivery and newborn.

INTRODUCTION: Myasthaenia gravis (MG) is the most common disease of the neuromuscular junction; clinical presentation of the disease includes a variety of symptoms, the most frequent beign the only ocular muscles involvement, to the generalized myasthenic crisis with diaphragmatic impairment and respiratory insufficiency. It is most common in women between 20 ad 40 years. EVIDENCE ACQUISITION: We performed a comprehensive search of relevant studies from January1990 to Dicember 2019 to ensure all possible studies were captured. A systematic search of Pubmed databases was conducted. EVIDENCE SYNTHESIS: Pregnancy has an unpredictable and variable effect on the clinical course of MG; however, a stable disease before is likely not to relapse during pregnancy. exacerbations can still occur more often during the first trimester and the post partum period. The transplacental passage of antibodies results in a neonatal transient disease, whereas the major concern is related to foetal malformations such as fetal arthrogryposis and polyhydramnios. The overall neonatal outcome described in literature is variable, perinatal mortality in women with MG is generally the same as non affected patients, although in one study the risk of premature rupture of the membranes was higher. Treatment of MG in pregnangncy includes pyridostigmine and corticosteroids, although the latter have been associated with higher risk of cleft palate, premature rupture of the membranes and preterm delivery. These drugs appear also to be safe in breastfeeding. In MG patients spontaneous vaginal delivery should be encouraged, for surgery could cause acute worsening of myasthenic symptoms; also an accurate anesthesiological evaluation must be performed prior to both general and local anesthesia due to increased risk of complications. CONCLUSIONS: Most of the myasthenic women could have uneventful pregnancy with good obstetrical outcomes, both for mother and neonate. However, a careful planning of pregnancy and multidisciplinary team approach, composed by neurologists, obstetricians, neonatologists and anesthesiologists, is required to manage these pregnancies.

Zika virus infection of Hofbauer cells.

Recent studies have linked antenatal infection with Zika virus (ZIKV) with major adverse fetal and neonatal outcomes, including microcephaly. There is a growing consensus for the existence of a congenital Zika syndrome (CZS). Previous studies have indicated that non-placental macrophages play a key role in the replication of dengue virus (DENV), a closely related flavivirus. As the placenta provides the conduit for vertical transmission of certain viruses, and placental Hofbauer cells (HBCs) are fetal-placental macrophages located adjacent to fetal capillaries, it is not surprising that several recent studies have examined infection of HBCs by ZIKV. In this review, we describe congenital abnormalities associated with ZIKV infection, the role of HBCs in the placental response to infection, and evidence for the susceptibility of HBCs to ZIKV infection. We conclude that HBCs may contribute to the spread of ZIKV in placenta and promote vertical transmission of ZIKV, ultimately compromising fetal and neonatal development and function. Current evidence strongly suggests that further studies are warranted to dissect the specific molecular mechanism through which ZIKV infects HBCs and its potential impact on the development of CZS.

Management of congenital quantitative fibrinogen disorders: a Delphi consensus.

INTRODUCTION: No evidence-based guidelines for the management of patients suffering from afibrinogenaemia and hypofibrinogenaemia are available. AIM AND METHOD: The aim of this study was to harmonize patient's care among invited haemophilia experts from Belgium, France and Switzerland. A Delphi-like methodology was used to reach a consensus on: prophylaxis, bleeding, surgery, pregnancy and thrombosis management. RESULTS: The main final statements are as follows: (i) a secondary fibrinogen prophylaxis should be started after a first life-threatening bleeding in patients with afibrinogenaemia; (ii) during prophylaxis the target trough fibrinogen level should be 0.5 g L-1 ; (iii) if an adaptation of dosage is required, the frequency of infusions rather than the fibrinogen amount should be modified; (iv) afibrinogenaemic patients undergoing a surgery at high bleeding risk should receive fibrinogen concentrates regardless of the personal or family history of bleeding; (v) moderate hypofibrinogenaemic patients (i.e. ≥0.5 g L-1 ) without previous bleeding (despite haemostatic challenges) undergoing a surgery at low bleeding risk may not receive fibrinogen concentrates as prophylaxis; (vi) monitoring the trough fibrinogen levels should be performed at least once a month throughout the pregnancy and a foetal growth and placenta development close monitoring by ultrasound is recommended; (vii) fibrinogen replacement should be started concomitantly to the introduction of anticoagulation in afibrinogenaemic patients suffering from a venous thromboembolic event; and (viii) low-molecular-weight heparin is the anticoagulant of choice in case of venous thromboembolism. CONCLUSION: The results of this initiative should help clinicians in the difficult management of patients with congenital fibrinogen disorders.

Congenital defects in V(D)J recombination.

INTRODUCTION OR BACKGROUND: The V(D)J recombination is a DNA rearrangement process that generates the diversity of T and B lymphocyte immune repertoire. It proceeds through the generation of a DNA double-strand break (DNA-DSB) by the Rag1/2 lymphoid-specific factors, which is repaired by the non-homologous end joining (NHEJ) DNA repair pathway. V(D)J recombination also constitutes a checkpoint in the lymphoid development. SOURCES OF DATA: V(D)J recombination defect results in severe combined immune deficiency (SCID) with a lack of T and B lymphocytes. AREAS OF AGREEMENT: The V(D)J recombination represents one of the few programmed molecular events leading to DNA-DSBs that strictly relies on NHEJ. Two NHEJ factors, Artemis and XLF/Cernunnos, were identified through the molecular studies of SCID patients. Mutations in PRKDC and DNA Ligase IV genes also result in SCID. GROWING POINTS: Studies in mice have demonstrated that XLF/Cernunnos is dispensable for V(D)J recombination in lymphoid cells but not for the repair of genotoxic-induced DNA-DSBs, which raises the question of the implication of Rag1/2 factors in the DNA repair phase of V(D)J recombination. AREAS TIMELY FOR DEVELOPING RESEARCH: New factors of NHEJ, such as PAXX, are being identified. Patients with NHEJ deficiency (XRCC4) without immune deficiency were recently reported. We, therefore, may not have yet the complete picture of DNA-DSB repair in the context of V(D)J recombination.

Diagnosis of Schmallenberg virus infection in malformed lambs and calves and first indications for virus clearance in the fetus.

Since mid-December 2011, samples from malformed lambs and calves are sent to CODA-CERVA in Belgium for diagnosis of Schmallenberg virus (SBV), a novel Orthobunyavirus that was first detected by researchers of the Friedrich-Loeffler-Institut (FLI, Germany) in German cattle in autumn 2011 and was later shown to be involved in congenital malformations in lambs, goat kids and calves. Surprisingly, by making use of real time RT-PCR (rRT-PCR) assays developed by the FLI, presence of SBV RNA could only be confirmed in part of the SBV suspected newborns examined. To investigate possible causes for non-confirmation by rRT-PCR, a comparative analysis between different organs and tissues (cerebrum, cerebellum, brain stem, spinal cord, thymus, spleen, lymph nodes, meconium) originating from respectively 90 and 81 malformed lambs and calves was undertaken. Furthermore, thoracic fluids of respectively 55 malformed lambs and calves were examined by a virus neutralization test (VNT) to evaluate the presence of neutralizing anti-SBV antibodies in these animals. Our results show that among the different organs tested by rRT-PCR, brain stem material is the most appropriate tissue for SBV detection while it could also be detected in all other tissues but to a more variable degree. The VNT test showed that 95% of the malformed lambs were positive for anti-SBV neutralizing antibodies while this was only the case for 44% of malformed calves. These immunological data suggest that a humoral immune response could assist in the clearance of SBV from the fetus during gestation and that SBV specific antibody testing should be considered together with rRT-PCR analysis for confirmation of SBV infection.

Multiple sclerosis, immunomodulators, and pregnancy outcome: a prospective observational study.

BACKGROUND: There is still uncertainty about the management of pregnant women exposed to immunomodulatory therapy for treatment of multiple sclerosis (MS) in pregnancy. OBJECTIVE: To assess the safety of interferon (IFN)-beta1a, IFN-beta1b, and glatiramer acetate (GA) for treatment of MS during pregnancy. METHODS: A prospective observational cohort study was performed with patients enrolled through a drug risk assessment by the Teratology Information Service (TIS), Berlin, from 1996 to 2007. Pregnancy outcomes for four groups of women were compared: two exposed groups (IFN, n = 69; GA, n = 31), MS patients without exposure to IFN or GA (n = 64) and a healthy comparative group (n = 1556). RESULTS: Spontaneous abortion rates were in normal range for all groups except the small subgroup of IFN-beta1b exposed (n = 21), where 28% aborted spontaneously. There were two major birth defects in the GA group (club feet and atrioventricular canal) and none in the IFN cohort. Preterm delivery was not significantly different between exposed cohorts and healthy controls. The adjusted mean birth weight was in normal range in all groups (>3200 g), but newborns exposed to IFN had a significantly lower birth weight. CONCLUSION: Our findings suggest that neither GA nor IFN constitutes a major risk for prenatal developmental toxicity.

Genetic syndromic immunodeficiencies with antibody defects.

This article reviews the major syndromic immunodeficiencies with significant antibody defects, many of which may require intravenous immunogammaglobulin therapy. The authors define syndromic immunodeficiency as an illness associated with a characteristic group of phenotypic abnormalities or laboratory features that comprise a recognizable syndrome. Many are familial with a defined inheritance pattern. Immunodeficiency may not be a major part of the illness and may not be present in all patients; thus, these conditions differ from primary immunodeficiency syndromes, in which immune abnormalities are a consistent and prominent feature of their disease.

Congenital asplenia and group B streptococcus sepsis in the adult: case report and review of the literature.

Asplenia is associated with an increased incidence of fatal and life-threatening sepsis caused by encapsulated pathogens. Isolated congenital asplenia is a very rare condition, with only 33 cases reported in the literature. The authors report another case of this condition complicated by overwhelming Group B streptococcus sepsis secondary to paronychia that was managed successfully.

A review of non-cystic fibrosis pediatric bronchiectasis.

With the implementation of vaccination programs and the use of antibiotics, developed countries have seen a decline in infection-related pediatric bronchiectasis. However, significant morbidity from bronchiectasis is still seen and both infectious and noninfectious causes of bronchiectasis in the pediatric population remain. A review of the literature will be presented including causes of pediatric bronchiectasis, clinical symptoms and signs, laboratory evaluation and imaging, as well as treatment options. This review stresses the importance of early evaluation and treatment in children with recurrent cough, sinusitis, potential foreign-body aspiration, or gastroesophageal reflux to prevent the complications of ongoing respiratory disease and bronchiectasis.

Emerging infections and pregnancy: assessing the impact on the embryo or fetus.

The teratogenicity of several infections when acquired during pregnancy is well documented. However, for emerging infections (defined as those for which the incidence has risen in the past two decades or threatens to rise in the near future), the prenatal effects are often unknown, raising concern among women and their health care providers. Investigation of these effects is essential to ensure that pregnant women are appropriately assessed, advised, and treated, but such investigation is often challenging. The impact of emerging infections on the embryo or fetus is difficult to predict and varies depending on the agent and gestational timing of infection. Some women might be asymptomatic or have only mild or nonspecific symptoms, and thus, not be identified as infected, even when the embryo or fetus is severely affected. In addition, diagnosing congenital infection is often complicated. This article will discuss challenges to studying the teratogenicity of emerging infections, advantages, and disadvantages of different study designs, and examples of previous studies of the effects of emerging infections on the embryo or fetus.

Reduced birth defects caused by maternal immune stimulation in diabetic ICR mice: lack of correlation with placental gene expression.

Diabetes mellitus alters placental structure and function, events that may be related to embryopathy. Three different methods of maternal immune stimulation that modulate placental function and that result in approximately equal reduction of diabetic embryopathy were studied: footpad injection with complete Freund's adjuvant, intraperitoneal injection with granulocyte-macrophage colony stimulating factor (GM-CSF), or intraperitoneal injection with interferon-gamma (IFN-gamma). A gene microarray was then used to examine expression of 151 placental genes. We hypothesized that maternal immune stimulation may overcome an embryopathy-inducing effect of diabetes on placenta, that might be detected by a shared profile of placental gene expression changes induced by the different immune stimulation procedures. However, the immune stimulation that caused the greatest reduction in birth defect incidence, IFN-gamma, did not change the placental gene expression profile as compared to control or diabetes. Complete Freund's adjuvant and GM-CSF significantly changed placental gene expression relative to control or diabetes, but differentially affected such genes. No common pattern of improved cytokine, cell-cycle, apoptotic, transcription factor, or other gene expression was identified, that might explain the ability of this procedure to reduce birth defects. These data suggest that maternal immune stimulation reduces birth defects in diabetic mice by a mechanism independent of placenta.

Diabetes teratogenicity is accompanied by alterations in macrophages and T cell subpopulations in the uterus and lymphoid organs.

Insulin-dependent diabetes mellitus is a well-known teratogen, which might cause growth retardation, malformations and fetal death. We have previously shown, that potentiation of the maternal immune system (immunopotentiation) might protect the embryo from diabetes teratogenicity. Therefore, in the present study we further inquired whether diabetes teratogenicity might be associated with alterations in the level of immune effector cells in systemic and local lymphoid organs as well as in the uterus throughout pregnancy and whether the protection exerted by maternal immunopotentiation might be realized through its effect on those cells. Streptozotocin-induced diabetes in ICR mice was found to reduce pregnancy rate and fetal weight while increasing the resorption rate and the percentage of litters with malformed fetuses. These teratogenic effects were accompanied by a decreased percentage of cells expressing Mac-1, Thy-1.2, CD4 or CD8 in the spleen and inguinal as well as paraaortic lymph nodes, except for Mac-1 expression by splenocytes, which increased significantly in the beginning of pregnancy and decreased later. A different pattern was observed in the uterus, when the percentage of cells expressing these markers tended to increase in the beginning of pregnancy and decrease later. Intrauterine immunopotentiation with rat splenocytes was found to improve the reproductive performance of diabetic animals. This protective effect was accompanied by a general normalization of the level of the various cell surface markers, when in most cases their expression returned to that found in nonimmunopotentiated mice. Our results suggest that the protection exerted by maternal immunopotentiation on the embryo against diabetes teratogenicity might be mediated via its effect on the level of immune effector cells localized to uterus and lymphoid organs, which was found to be altered in diabetic mice.

Immunostimulation by complete Freund's adjuvant, granulocyte macrophage colony-stimulating factor, or interferon-gamma reduces severity of diabetic embryopathy in ICR mice.

BACKGROUND: Increased risk of fetal malformation is a complication occurring in pregnant women with type 1 diabetes. Local (uterine) immune stimulation has been shown to reduce diabetes-induced teratogenesis in mice. Limited information is available regarding the ability of diverse methods of maternal immune stimulation to cause this effect or regarding timing requirements of the immune stimulation. METHODS: Diabetes was induced in pregnant ICR mice by streptozocin (STZ) injection. Three different techniques of maternal immune stimulation, complete Freund's adjuvant (CFA), granulocyte-macrophage colony-stimulating factor (GM-CSF), or interferon-gamma (IFN-gamma), were then used to stimulate the immune system of the mice. RESULTS: Approximately 50% of fetuses from hyperglycemic (>26 mM/liter blood glucose) dams were malformed, with neural tube defects predominating. Maternal immune stimulation during the time of normoglycemia, i.e., prior to the onset of hyperglycemia, was necessary to reduce teratogenic effects associated with hyperglycemia for each of the immune stimulants. The immune-stimulated diabetic mice then produced significantly lower and approximately equal numbers of malformed fetuses: CFA 20.9%, GM-CSF 23.3%, and IFN-gamma 13.9%. CONCLUSIONS: These results suggest that mechanistically diverse forms of nonspecific immune activation result in protection against diabetes-related teratogenesis, but only if given prior to onset of hyperglycemia.

Reduced birth defects caused by maternal immune stimulation may involve increased expression of growth promoting genes and cytokine GM-CSF in the spleen of diabetic ICR mice.

Maternal immune stimulation in mice decreases fetal abnormalities caused by diverse etiologies. Growth factors produced by activated immune cells were proposed to be key mediators that may exert their effects on placenta or embryo. Diabetes disrupts the secretion of cytokines, which may associate with diabetic embryopathy. Three different methods of maternal immune stimulation that result in approximately equal reduction of diabetic embryopathy were used in the present studies: footpad injection with complete Freund's adjuvant (CFA), intraperitoneal (i.p.) injection with granulocyte-macrophage colony-stimulating factor (GM-CSF), or i.p. injection with interferon-gamma (IFN-gamma). A gene microarray was then used to examine expression of a selected gene panel in splenic leukocytes. We hypothesized that maternal immune stimulation may act by overcoming altered gene expression patterns of immune cells in the diabetic mice, which partially mitigates the teratogenic effect of diabetes. It further seemed likely that a shared profile of splenic gene expression changes induced by the different immune stimulation procedures may be identified and related to reduced teratogenesis. The three procedures produced a common altered gene expression profile. Significantly affected genes included apoptotic and anti-apoptotic genes, and genes controlling cellular proliferation, and likely reflect a state of immune activation. The GM-CSF gene was up-regulated by all three immune stimulation procedures. The protein product of this gene regulates placental development, and was recently associated with reduced cleft palate in immune-stimulated pregnant mice after exposure to urethane. These data suggest that further studies of GM-CSF as mediator of reduced birth defects in teratogen-challenged, immune-stimulated mice are warranted.

Regression of congenital fibrosarcoma to hemangiomatous remnant with histological and genetic findings.

We report a rare case of congenital fibrosarcoma (CFS) showing regression during the course of disease, in which the histological and genetic alterations were investigated. This CFS, located on the patient's right hand, was a hemangiopericytomatous hypervascular tumor showing frequent mitosis and necrosis. Small lymphocytes, predominantly cytotoxic T cells and natural killer cells, infiltrated the tumor. At the age of 3 months, the patient received a partial resection of the tumor. At the age of 1 year, the hemangiopericytomatous tumor with a dilated vascular lumen remained, although most of the tumor cells exhibited focal necrosis with calcification and no mitotic activity. Lymphocytes increased in number and intermingled with the tumor cells. At the age of 4 years, vascular tissue consisting of inner endothelial cells and surrounding pericytomatous actin-positive cells remained at the previous tumor locus. With reverse transcription-polymerase chain reaction analysis, ETV6-NTRK3 fusion transcripts were detected in tumor samples at 3 months and at 1 year, but not from those at 4 years of age. These genetic and histological changes suggest that the CFS either completely disappeared by apoptosis or showed mature transformation to hemangiomatous tissue with aging.

[Elevated level of CA 125 antigen in women in reproductive age without neoplastic diseases in pelvis minor]. / Podwyzszony poziom antygenu CA 125 w chorobach nienowotworowych miednicy mniejszej u kobiet w wieku rozrodczym.

Behaviour of CA 125 antigen in women in reproductive age without neoplastic diseases in pelvis minor was presented. The study material was divided into 4 groups: 29 women with endometriosis, 16 women with inflammation of pelvis minor, 7 women with cirrhosis, developmental malformation of reproductive organs and pregnancy, 8 women of middle gynaecological age 6.75 had endometriosis. It has been revealed that the inflammatory state of the uterine adnexa and the appendix as well as cirrhosis, developmental malformation of reproductive organs may evolve with elevated level of CA 125 marker. It has also been shown that endometriosis in pelvis minor may be expressed by a raised level of CA 125 marker.

[Immunology of reproduction]. / Immunologiia reproduktsii.

The paper presents the results of studies of the role of immune factors in the pathogenesis of infertility, impaired gestation, and perinatal abnormalities, which have been performed at the Research Center of Obstetrics, Gynecology, and Perinatology, Russian Academy of Medical Sciences, in the past decade. It gives an evaluation of the contribution of antispermatic antibodies to infertility of unclear genesis, the systemic and local factors of immunity in females with endometriosis, the immune and interferon status in those with sexually transmitted infections, the role of immune factors and intrauterine infection in gestational abnormalities, the involvement of autoimmune mechanisms in reproductive disturbance. The trends of further studies are outlined.

Maternal immunopotentiation affects the teratogenic response to hyperthermia.

Immune responses occurring between the embryo and mother have been shown to influence the embryo's tolerance to teratogens, including chemical teratogens and diabetes-induced teratogenic insult. In this study, we tried to evaluate whether maternal immunostimulation alters the embryo's response to heat shock, one of few teratogens which directly affect the embryo. In order to induce structural anomalies, both intact ICR female mice and mice which had been immunostimulated with xenogeneic rat splenocytes before mating, were exposed to two consecutive exposures to heat (43.6 +/- 0.2 degrees C) for 10 min on day 9 of pregnancy. The number of malformed fetuses, resorptions, and fetal weight were assessed on day 19 of pregnancy. Heat shock-induced apoptosis, and the level of heat shock protein (HSP) 60 expression, were examined in embryonic cells at different time points within 24 h after heating. All these indices differed dramatically in immunized and non-immunized heat shocked females. Heat shocked non-immunized females demonstrated an increased level of resorptions (approximately, 21% versus 8.6% in controls) and the proportion of fetuses with such anomalies as encephalocele and open eyes reached 28% and 21%, respectively. Maternal immunostimulation was associated with a significant decrease in the proportion of fetuses with encephalocele (12.8%), open eyes (8.9%), and resorptions (8%). The maximum level of heat shock-induced apoptosis in cell populations from the embryos of non-immunized females, was approximately, 30% versus 7% in cells of embryos of immunized mice. Heat shock was also followed by a significant increase in HSP60 expression, but only in the cells of embryos of non-immunized females. Together, these findings suggest that the tolerance of mouse embryos to a heat shock-induced teratogenic insult may, to some extent, depend on the character of the maternal immune responses.

[Rubella in Russia: the detection of congenital rubella and the vaccination strategy and procedures]. / Krasnukha v Rossii: vyiavlenie vrozhdennoi krasnukhi, strategiia i taktika vaktsinatsii.

The work on the evaluation of the role of rubella infection in the development of congenital malformations in newborn infants, as well as the immunogenic activity and tolerability of live attenuated vaccine Rudivax (Pasteur Mérieux Connaught) was carried out in the process of selective immunization in the Perm region. The study made it possible to find out 15% of malformations in the structure of the congenital pathology of newborn infants, which appeared due to the infection of the fetus with rubella virus and were manifested by multiple development defects, congenital C.N.S. defects and valvular defects. The results of using vaccine Rudivax in the epidemiological trial demonstrated that the vaccine had high immunological activity and was well tolerated. The absence of postvaccinal complications after the injection of the live vaccine and the absence of the extinction of immunity in the presence antibodies were indicative of the possibility vaccination without preliminary serological examination.