Malformations Of Internal Organs Research Articles

Challenging problems of congenital cytomegalovirus infection therapy: case study

Cytomegalovirus infection is the most common congenital infection, causing development disorders of the fetus’ nervous system. The article describes two clinical cases of congenital cytomegalovirus infection, which highlight the crucial importance of an early administration of direct antiviral drugs (ganciclovir, valgancyclovir) for the generalized manifest forms of infection. The first clinical case study (a girl, most likely infected at the beginning of the second trimester of pregnancy) deals with the development of the classic triad of severe congenital CMV infection (small weight for gestational age, direct hyperbilirubinemia and petechial rash). Given that the intrauterine developmental anomalies specific for CMV were detected in the fetus on the 32nd week of pregnancy during her mother’s comprehensive test examination, the treatment of the infant girl with ganciclovir could have started immediately after her birth. The second clinical case study describes a congenital generalized cytomegalovirus infection in a child with malformations of internal organs and the central nervous system. The described two clinical cases of congenital cytomegalovirus infection highlight the crucial importance of ganciclovir and point to the fact that the isolated use of hyperimmune immunoglobulin does not stop the progression of the disease. The chance of a favorable outcome of the disease is much higher if the clinical diagnosis is established as early as possible after the birth of the child and etiotropic therapy is fully administered.

Clinical characteristics and offspring developmental malformation of 126 patients with septate uterus.

Clinical characteristics and offspring developmental malformation of 126 patients with septate uterus.

Biallelic variants in CENPF causing a phenotype distinct from Strømme syndrome.

abstractBiallelic loss‐of‐function (LoF) variants in CENPF gene are responsible for Strømme syndrome, a condition presenting with intestinal atresia, anterior ocular chamber anomalies, and microcephaly. Through an international collaboration, four individuals (three males and one female) carrying CENPF biallelic variants, including two missense variants in homozygous state and four LoF variants, were identified by exome sequencing. All individuals had variable degree of developmental delay/intellectual disability and microcephaly (ranging from −2.9 SDS to −5.6 SDS) and a recognizable pattern of dysmorphic facial features including inverted‐V shaped interrupted eyebrows, epicanthal fold, depressed nasal bridge, and pointed chin. Although one of the cases had duodenal atresia, all four individuals did not have the combination of internal organ malformations of Strømme syndrome (intestinal atresia and anterior eye segment abnormalities). Immunofluorescence analysis on skin fibroblasts on one of the four cases with the antibody for ARL13B that decorates primary cilia revealed shorter primary cilia that are consistent with a ciliary defect. This case‐series of individuals with biallelic CENPF variants suggests the spectrum of clinical manifestations of the disorder that may be related to CENPF variants is broad and can include phenotypes lacking the cardinal features of Strømme syndrome.

Аналіз факторів ризику при різних видах анестезіологічного супроводу новонароджених і немовлят із хірургічною патологією

High-quality anesthetic support during surgical correction of congenital malformations of internal organs and the postoperative period in newborns and infants is complicated by concomitant diseases, significantly affects the processes of metabolism, gas exchange, homeostasis, cerebral, peripheral hemodynamics, etc. before, during and after the surgical intervention. Purpose — to identify the leading risk factors associated with death in various types of anesthetic support for newborns and infants during surgical correction of congenital malformations. Materials and methods. The retrospective study included newborns with congenital malformations of the surgical profile, as well as infants who received and continued stepwise surgical treatment for congenital malformations, depending on the chosen combined anesthetic accompaniment (inhalation + regional anesthesia and inhalation + intravenous anesthesia). The study was carried out in the following stages: 1) to conduct surgical treatment and anesthetic support, 2) introduction of the child into anesthesia, 3) the traumatic stage of the operation, 4) within 1 hour after the operation, 5) 24 hours after the operation. Risk factors were determined by simple logistic regression with the calculation of the odds ratio, 95% confidence interval (95% CI). Results. Among the functional indicators of the vital functions of the body of children with congenital disorders before, during, immediately and 24 hours after surgery against the background of combined anesthesia, with a simple logistic regression analysis, the chance of a fatal case increases with deviations from the norm of peripheral saturation — at all stages of surgical support (7.8–15.0 times); cerebral oxygenation of the child — at the moments of induction into anesthesia and in the postoperative period (10.8 at the stage 2, 72.0 times at the stage 4); increased diastolic blood pressure at the stage of induction of the child into anesthesia (1.6 times). Conclusions. To prevent the chances of death under various types of anesthesia for children with congenital malformations during surgical treatment, it is advisable to more closely monitor blood pressure, cerebral, peripheral oximetry and promptly correct the impaired condition of the child. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of these Institutes. The informed consent of the patient was obtained for conducting the studies. No conflict of interest was declared by the authors. Key words: newborns, infants, congenital malformations, anesthesia, risk factors.

Monochorionic diamniotic twin with a Down syndrome in one of the fetuses

A clinical observation of monochorionic diamniotic twins with discordance of cytogenetic and clinical manifestations of Down syndrome is presented. Pregnancy was complicated by feto-fetal transfusion syndrome at 17 weeks of gestation. An ultrasound scan revealed a ventriculomegaly in a donor. Laser coagulation of anastomoses was performed. Karyotype 46, XY was established in the recipient amniocytes. The pregnancy ended in childbirth at 33 weeks with newborn boys weighing 1789 and 2080g. One of the newborns (donor) had phenotypic signs of Down syndrome. When karyotyping peripheral blood lymphocytes of a child with clinical manifestations of Down syndrome, karyotype mos 47,XY,+21[12]/46,XY [88] was established, and a child with a normal phenotype was mos 47,XY,+21[14]/46,XY [86]. No malformations of internal organs were found. When analyzing the buccal epithelium by the FISH method, it was found that in all the analyzed interphase nuclei obtained from a child without clinical manifestations (recipient fetus), trisomy 21 was not detected. In 78% of the interphase nuclei of cells of a child with Down syndrome (fetus-donor), trisomy 21 was established. Thus, the presence of a clone of cells with trisomy 21 in the recipient is associated with twin chimerism.

When the disease goes beyond the skin, changes in the skin can be a sign of systemic disease

Infantile hemangioma may be accompanied by malformations of internal organs and blood vessels. In 1996 PHACE syndrome was defined as a disease which is characterized by the association of segmental infantile hemangioma with localization in the head/neck region and the presence of malformations in the posterior cranial fossa, abnormalities of arterial blood vessels including coarctation of the aorta, heart defects, as well as malformations of the eyes and central nervous system. This article presents a clinical case of a child who was diagnosed this syndrome at the age of 1.5 months based on the presence of segmental hemangioma, as well as large and small criteria specific for this disease. In addition to the main symptoms, the child had an accompanying pathology: Wolff–Parkinson–White syndrome. Therapy with non-selective b-blockers and polychemotherapy allowed stopping already developed and prevent possible complications associated with this syndrome. Parents gave their consent to use information about the child, including fotos, in the article.

Review of Pharmacological Strategies with Repurposed Drugs for Hereditary Hemorrhagic Telangiectasia Related Bleeding.

The diagnosis of hereditary hemorrhagic telangiectasia (HHT) is based on the Curaçao criteria: epistaxis, telangiectases, arteriovenous malformations in internal organs, and family history. Genetically speaking, more than 90% of HHT patients show mutations in ENG or ACVRL1/ALK1 genes, both belonging to the TGF-β/BMP9 signaling pathway. Despite clear knowledge of the symptoms and genes of the disease, we still lack a definite cure for HHT, having just palliative measures and pharmacological trials. Among the former, two strategies are: intervention at “ground zero” to minimize by iron and blood transfusions in order to counteract anemia. Among the later, along the last 15 years, three different strategies have been tested: (1) To favor coagulation with antifibrinolytic agents (tranexamic acid); (2) to increase transcription of ENG and ALK1 with specific estrogen-receptor modulators (bazedoxifene or raloxifene), antioxidants (N-acetylcysteine, resveratrol), or immunosuppressants (tacrolimus); and (3) to impair the abnormal angiogenic process with antibodies (bevacizumab) or blocking drugs like etamsylate, and propranolol. This manuscript reviews the main strategies and sums up the clinical trials developed with drugs alleviating HHT.

The role of pre-gravida preparation in the successful development of pregnancy

An integrated approach of pre-gravida training plays an important role in the preservation of the reproductive health of the nation. Due to the multi-stage organization, young families can go to outpatient clinics early, before the expected pregnancy, in order to undergo the necessary clinical and laboratory examinations, to rule out potential risk for miscarriage, to obtain the necessary recommendations for the use of vitamin and mineral complexes or the need to use progesteronecontaining medications, to acquire awareness of the management of pregnancy in the early stages. All those measures will signifi cantly reduce the percentage of births of children with congenital malformations of internal organs and organ systems. An integrated approach is not only the interaction of all parts of obstetric and gynecological care, but also cooperation with specialists of related disciplines.

Endoglin Protein Interactome Profiling Identifies TRIM21 and Galectin-3 as New Binding Partners.

Endoglin is a 180-kDa glycoprotein receptor primarily expressed by the vascular endothelium and involved in cardiovascular disease and cancer. Heterozygous mutations in the endoglin gene (ENG) cause hereditary hemorrhagic telangiectasia type 1, a vascular disease that presents with nasal and gastrointestinal bleeding, skin and mucosa telangiectases, and arteriovenous malformations in internal organs. A circulating form of endoglin (alias soluble endoglin, sEng), proteolytically released from the membrane-bound protein, has been observed in several inflammation-related pathological conditions and appears to contribute to endothelial dysfunction and cancer development through unknown mechanisms. Membrane-bound endoglin is an auxiliary component of the TGF-β receptor complex and the extracellular region of endoglin has been shown to interact with types I and II TGF-β receptors, as well as with BMP9 and BMP10 ligands, both members of the TGF-β family. To search for novel protein interactors, we screened a microarray containing over 9000 unique human proteins using recombinant sEng as bait. We find that sEng binds with high affinity, at least, to 22 new proteins. Among these, we validated the interaction of endoglin with galectin-3, a secreted member of the lectin family with capacity to bind membrane glycoproteins, and with tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin-protein ligase. Using human endothelial cells and Chinese hamster ovary cells, we showed that endoglin co-immunoprecipitates and co-localizes with galectin-3 or TRIM21. These results open new research avenues on endoglin function and regulation.

Characterization of a mutation in the zona pellucida module of Endoglin that causes Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is a vascular rare disease characterized by nose and gastrointestinal bleeding, skin and mucosa telangiectasias, and arteriovenous malformations in internal organs. HHT shows an autosomal dominant inheritance and a worldwide prevalence of approximately 1:5000 individuals. In >80% of patients, HHT is caused by mutations in either ENG (HHT1) or ACVRL1 (HHT2) genes, which code for the membrane proteins Endoglin and Activin A Receptor Type II-Like Kinase 1 (ALK1), respectively, both belonging to the TGF-β/BMP signaling pathway. In this work, we describe a novel mutation in exon 9 of ENG (c.1145 G > A) found in five affected members of a family, all of them with characteristic symptoms of HHT. This mutation involves Cys382 residue of the Endoglin protein (p.Cys382 > Tyr) in the zona pellucida (ZP) module of its extracellular region. This is a critical residue involved in a conserved intrachain disulphide bond and in the correct folding of the protein. In fact, transfection studies in human cells using Endoglin expression vectors demonstrated that the p.Cys382 > Tyr mutation results in a marked reduction in the levels of the Endoglin protein. These results demonstrate the pathogenic role for this variant in HHT1 and confirm the key function of Cys382 in Endoglin expression.

Nationwide Study of Turner Syndrome in Ukrainian Children: Prevalence, Genetic Variants and Phenotypic Features

Objective: We aimed to investigate the prevalence of Turner syndrome (TS) in the Ukrainian population, the frequency of karyotype variants, the age of children at diagnosis, the degree of short stature and phenotypic features in TS girls.Methods: A retrospective analysis was made in 538 TS girls aged 0.11-18.2 years within the time period of 2005-2015 with detailed examination of 150 patients.Results: The prevalence of TS in Ukraine is 77.5 in 100.000 live female births. The average age at diagnosis is 9.33±4.93 years. The relative proportions of karyotypic abnormalities found were: 45,X (59.3%); mosaicism 45,X/46,XX (22.9%); and structural abnormalities in chromosome X (17.8%). The most frequently encountered findings were growth delay (98.8%), shortening of the 4th and 5th metacarpal bones (74.6%), abnormal nails (73.3%), broad chest (60.7%), short neck (58.6%), hypertelorism of nipples (51.4%), malformations of the cardiovascular (19.6%) and urinary systems (13.8%) and pathology related to vision (20.1%) and hearing (22.0%).Conclusion: In the Ukrainian population, the highest proportion of patients with TS had a karyotype 45,X. TS was accompanied by a lower frequency of malformations of internal organs compared to other countries.

ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder

ACTB encodes β-actin, an abundant cytoskeletal housekeeping protein. In humans, postulated gain-of-function missense mutations cause Baraitser-Winter syndrome (BRWS), characterized by intellectual disability, cortical malformations, coloboma, sensorineural deafness, and typical facial features. To date, the consequences of loss-of-function ACTB mutations have not been proven conclusively. We describe heterozygous ACTB deletions and nonsense and frameshift mutations in 33 individuals with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations (including those of the heart and the renal tract), growth retardation, and a recognizable facial gestalt (interrupted wavy eyebrows, dense eyelashes, wide nose, wide mouth, and a prominent chin) that is distinct from characteristics of individuals with BRWS. Strikingly, this spectrum overlaps with that of several chromatin-remodeling developmental disorders. In wild-type mouse embryos, β-actin expression was prominent in the kidney, heart, and brain. ACTB mRNA expression levels in lymphoblastic lines and fibroblasts derived from affected individuals were decreased in comparison to those in control cells. Fibroblasts derived from an affected individual and ACTB siRNA knockdown in wild-type fibroblasts showed altered cell shape and migration, consistent with known roles of cytoplasmic β-actin. We also demonstrate that ACTB haploinsufficiency leads to reduced cell proliferation, altered expression of cell-cycle genes, and decreased amounts of nuclear, but not cytoplasmic, β-actin. In conclusion, we show that heterozygous loss-of-function ACTB mutations cause a distinct pleiotropic malformation syndrome with intellectual disability. Our biological studies suggest that a critically reduced amount of this protein alters cell shape, migration, proliferation, and gene expression to the detriment of brain, heart, and kidney development.

Diagnostic value of neuroimaging techniques in newborn infants with malformations of internal organs

Aim of the study to determine the frequency and nature of brain lesions by the neuroimaging techniques (MRI and NSG) determining Objective: to establish the frequency and nature of brain lesions that cause CNS functional and irreversible disorders in newborn infants with malformations of internal organs in the perioperative period, by applying neuroimaging techniques. Materials and methods. 243 case histories of neonatal patients with congenital malformations of internal organs were analyzed. Their gestational age was 32 to 41 weeks (37.9±1.4 weeks). All the patients underwent neurosonography three times (within the first 24 hours after birth or in the preoperative period, in the postoperative period, and 1 week after surgery); their neurological status was evaluated. Neurological changes and structural disorders, as evidenced by neurosonography, served as an indication for brain magnetic resonance imaging (MRI) in 15 (6.2%) neonates. Results . In the perioperative period, more than 40% of children (n=102) had neurological changes as both temporary and organic hypoxic-ischemic encephalopathy, as confirmed by neuroimaging techniques. In 53 (52%) cases, pathological changes revealed by neurosonography and brain MRI were seen as an extension of the outer and inner cerebrospinal fluid spaces (n=36), cerebral cysts of various locations (n=1), intrathecal (n=3) and intraventricular (n=42) hemorrhages, and acute cerebrovascular accident (n=1). Conclusion. Newborn infants with congenital abnormalities of internal organs need a comprehensive examination aimed to timely identify risk factors for perinatal organic and transient lesions of the nervous system at the stages of the perioperative period.

Duplicación parcial 4q en un neonato originado por reordenamiento der (20), t(4;20) (q21;q13.1)mat

Reportamos el caso de un neonato con malformaciones congénitas múltiples por complemento cromosómico desbalanceado 46,XY,der(20),t(4;20)(q21;q13.1)mat originado por una translocación recíproca aparentemente balanceada entre los cromosomas 4 y 20 de la madre con un cariotipo 46, XX t(4;20) (q21;q13.1) de novo. El cariotipo del probando mostró una duplicación del segmento distal del brazo largo del cromosoma 4 (Trisomía parcial 4q). El fenotipo fue alterado, presentando diversas malformaciones congénitas craneofaciales y de órganos internos, condiciones adversas que condujeron a su precoz fallecimiento. Este caso de Duplicación 4q o Trisomía parcial 4q es el primero que se detecta en nuestra institución, se realizó un estudio cromosómico familiar para investigar el compromiso hereditario y detectar posibles portadores, también fueron determinados sus riesgos para brindar así una adecuada consejería genética.

A rare cause of recurrent iron deficiency anemia: Osler Weber Rendu Syndrome

Osler-Weber-Rendu Syndrome (hereditary hemorrhagic telengiectasis) is a hereditary disease with autosomal dominant inheritance characterized by muco-cutaneous telengiectasis, arterio-venous malformations in internal organs. The disease is manifested by telengiectasis in oral mucosa, ear, nasal mucosa, fingertips and finger-beds and recurrent hemorrhage. Epistaxis is among the typical findings of the disease. Coexistence with arterio-venous malformations is common. It may lead to gastrointestinal hemorrhage and neurologic problems due to mucosal telengiectasis. Herein, we presented a case who had recurrent iron deficiency anemia and diagnosed with Osler-Weber-Rendu Syndrome as the result of radiologic and endoscopic examinations performed due to the presence of oral telengiectasis.

ZEB2, a new candidate gene for asplenia

Primary asplenia is a rare condition with poorly known etiology. Mowat-Wilson syndrome (MWS) is characterized by typical facial dysmorphisms, intellectual disability, microcephaly, epilepsy and the possible presence of internal organ malformations. It is caused by heterozygous mutations or deletions in the ZEB2 gene. Nearly 180 patients have been reported to date, but only one with asplenia. We report here spleen hypo/aplasia in 4 out of 6 MWS patients, with severe infectious complications for 3 of them. Our report shows that spleen hypo/aplasia is part of the MWS phenotype and makes ZEB2 a possible candidate gene for primary asplenia.

Two cases of hepatic adenomas in patients with wolf‐hirschhorn syndrome: A new rare complication?

Wolf-Hirschhorn syndrome (WHS) is a rare microdeletion syndrome associated with a characteristic facial appearance, failure to thrive, psychomotor delays, and various major malformations of internal organs; many medical complications have been described (feeding difficulties, epilepsy, hearing problems). Benign or malignant oncologic problems are not a typical feature of the natural history of these patients. We report on two patients with WHS patients in whom hepatic adenoma (HA) were diagnosed during adolescence. The clinical evolution of liver involvement was different between the two. We discuss the possibility of considering HA as a rare medical problem in the follow-up of WHS patients. © 2013 Wiley Periodicals, Inc.

Mosaic 18q21.2 deletions including the TCF4 gene: A clinical report

Pitt-Hopkins syndrome (PTHS) is characterized by distinctive facial dysmorphism, profound intellectual disability, and the possible occurrence of epilepsy and breathing anomalies. It is caused by haploinsufficiency of the TCF4 gene. No significant difference in clinical severity has been reported to date between PTHS patients carrying 18q21 deletions including the TCF4 gene, and those harboring TCF4 point mutations, suggesting a lack of genotype/phenotype correlation. Moreover, the size of 18q21 deletions including the TCF4 gene does not appear to have a significant effect on the phenotypic severity, suggesting that TCF4 haploinsufficiency is the most important prognostic factor in 18q deletions. We describe two unrelated patients presenting with clinical features reminiscent of PTHS and carrying mosaic interstitial 18q21 deletions characterized by array comparative genomic hybridization. One of the patients presented the lowest level of mosaic 18q21 deletion reported to date (5-10%). Our report and a review of the literature show that the mosaic status does not appear to have a significant effect on the clinical severity of 18q21 deletions, which are associated with a poor neurological outcome, whereas a mosaic TCF4 point mutation can result in a significantly milder phenotype. Malformations of internal organs are currently considered to be rare in PTHS. The patients described here had visceral anomalies, suggesting that a full morphological assessment, including heart and abdominal ultrasound scans, should be performed systematically in PTHS patients.

유전성출혈모세혈관확장증의 증례 및 문헌 고찰

유전성출혈모세혈관확장증은 피부 및 점막에 있는 말단 혈관이 비정상적으로 확장된 모세혈관 확장증과 내부 장기, 특히 폐, 뇌, 간 부위의 동정맥기형 발생을 특징으로 하는 상염색체 우성 유전질환이다. 이 질병을 가진 환자들은 종종 오랜 시간 동안 진단이 되지 않은 채로 지내다가 생명을 위협할 수 있는 심각한 출혈, 뇌졸중, 뇌농양과 같은 합병증이 발생하기도 한다. 따라서 이 질환의 조기 진단 및 적절한 선별검사가 매우 중요하다. 유전성출혈모세혈관확장증의 조기 진단을 통해 증상 없이 존재하다 합병증을 유발할 수 있는 폐, 간, 뇌 부위의 동정맥기형에 대한 선별 검사를 시행함으로써 이 질병에 이환된 환자와 가족에 대한 예방적 관리가 가능하다. 피부 및 점막에 발생하는 모세혈관확장증은 특징적인 소견을 보이며 치과의사에 의해 쉽게 발견되므로 치과의사는 유전성출혈모세혈관확장증에 대해 잘 알고 조기 진단에 기여할 필요가 있다. 최근 이 질환으로 진단된 증례가 있어 문헌 고찰과 함께 보고하고자 한다. Hereditary hemorrhagic telangiectasia is a rare autosomal dorminant disease that features abnormal and fragile vascular dilations of terminal vessels in skin and mucous membranes, as well as arteriovenous malformations of internal organs, particularly lungs, brain, and liver. Often patients have not been diagnosed with HHT for a long time, and undiagnosed HHT patients unnecessarily develop serious complications such as severe life-threatening hemorrhage, stroke or brain abscess. Therefore, early detection and appropriate screening is very important. Early detection of HHT allows the appropriate screening for the presence of silent disease such as AVMs in the lungs, liver, or brain, and preventive treatment in the patient and their affected family members. Dentists should be familiar with HHT because the telangiectases on skin and oral mucosa are often the most dramatic and most easily identified component of HHT. Recently, we experienced a case of HHT. We present the case with a review of the literature.

Mosaic Trisomy 9 Presenting with Congenital Heart Disease, Facial Dysmorphism and Pigmentary Skin Lesions: Intricate Issues of Genetic Counseling

Chromosomal mosaicism for full aneuploidy involving chromosome 9 is an uncommon chromosomal abnormality. Mosaic trisomy 9 clinical manifestations are highly variable and difficult to predict. The authors present a case of mosaic trisomy 9 with typical clinical manifestations(facial dysmorphism, various internal organ malformations and severe psychomotor retardation), pigmentary mosaic skin lesions along the lines of Blaschko and evidence of maternal uniparental disomy in skin.