(1) Background: Sudden Infant Death Syndrome (SIDS) represents unexplained and sudden deaths during the sleep of infants under one year of age, despite thorough investigation. Screening for prolonged QTc or Long QT Syndrome (LQTS) should be conducted on all newborns to reduce the incidence of SIDS. Neonatal electrocardiogram (ECG) could identify congenital heart defects (CHD) early, especially those not detected at birth. Infants with prolonged QT intervals typically undergo genetic analysis for Long QT Syndrome; (2) Methods: The study involved infants aged 20-40 days, born clinically healthy, with initial ECG screening. Infants with prenatal diagnoses or signs/symptoms of CHD identified immediately after birth, as well as those who underwent ECG or echocardiogram for other clinical or historical indications, were excluded from the study. The data were analyzed using SPSS version 22.0; (3) Results: Of the 42,200 infants involved, 2,245 were enrolled, with 39.9% being males. Subsequently, 164 children (37.8% males) with prolonged QT intervals underwent further diagnostic investigations. Genetic mutations were identified in 11 out of 18 tested children. The most common mutations were LQT1 (54.5%), LQT2 (36.4%), and LQT3 (1 patient). Medications used included propranolol (39.8%), nadolol (22.2%), inderal (11.1%), metoprolol (11.1%), and no treatment (16.7%). The most common abnormalities were focal right bundle branch block (54.5%), left axis deviation (9.2%), and nonspecific ventricular repolarization abnormalities (7.1%). Multiple anomalies were found in 0.47% of children with focal right bundle branch block. Structural abnormalities were associated with specific features in 267 patients (11.9%), primarily isolated patent foramen ovale (PFO) at 61.4%; (4) Conclusions: The screening has proven effective in early diagnosing Long QT Syndrome and other cardiac rhythm anomalies, with additional benefits in detecting mutations and/or QTc prolongations in family members. Identifying other ECG abnormalities and congenital heart malformations further enhances the benefits of the screening.

Glycosylation, the most significant modification of proteins, plays an essential role in cellular processes. Congenital disorders of glycosylation (CDG) are multisystemic diseases resulting from mutations affecting glycosylation steps. Diagnosis of CDG relies on biochemical assays, such as isoelectric focusing. Despite its significance, CDG cases remain unreported in Cuba due to the lack of implemented diagnostic methods. This study aimed to evaluate transferrin glycoforms for diagnosing congenital N-glycosylation defects. We conducted a cross-sectional descriptive study using serum samples from 17 patients stored at the National Center for Medical Genetics of Cuba for suspected CDG. Results revealed abnormal glycosylation patterns in 7 patients, suggesting congenital N-glycosylation defects. We conclude that the implementation of transferrin glycoform analysis could pioneer a preliminary diagnosis of CDG in Cuba.

Neurofibromatosis type1 (NF1) is an autosomal dominant disorder caused by mutations in the NF1gene. Although congenital pseudarthrosis of the tibia (CPT) has frequently been associated with NF1, the underlying molecular mechanism of CPT in these NF1 patients is yet ill-understood. The aim of the present study was to detect NF1 mutations from genomic DNA and to harbor variants associated with CPT in NF1 patients. Whole-exome sequencing was first carried out with samples from two patients with CPT in one NF1 family, and a novel mutation c.2324A>G (p.E775G) in NF1 gene was identified. Additionally, a missense variant c.455C>T (p.P152L) in BCOR gene completely co-segregated with the CPT phenotype within this family. Subsequently, NF1 and NF2 genes in four other unrelated patients with both NF1 and CPT were screened using targeted sequencing. Four mutations in NF1 gene, including two known mutations (c.2288T>C/p.L763P, c.574 C>T/p.R192*) and two novel mutations (c.768delT/p.F256Lfs*25, c.2229_2230delTG/ p.V744Qfs*23) were detected. Further study confirmed that CPT was present in NF1 families, and NF1 mutations were closely associated with these complex phenotypes. Moreover, the data from the current study indicated that male gender might be a susceptibility factor for CPT in NF1. Therefore, we speculated that BCOR variants might be related to CPT phenotype among male NF1 patients.

Cytomegalovirus (CMV) is the leading infectious cause of brain defects and neurological dysfunctions, including sensorineural hearing loss (SNHL). A targeted screening in neonates failing the hearing screen is currently recommended in Italy according to national guidelines. However, SNHL may not be present at birth; also, congenital CMV (cCMV) may manifest with subtle signs other than SNHL. Therefore, inclusion of additional criteria for cCMV screening appears clinically valuable. Starting January 2021, we have implemented an expanded targeted cCMV screening at our center, with testing in case of maternal CMV infection during pregnancy, inadequate antenatal care, maternal HIV infection or immunosuppression, birthweight and/or head circumference.

Background: Nearly half of congenital heart defects (CHDs) related mortality occur during infancy although advancement in treatments have increased the survival rates. This study comprehensively examines overall and surgical mortality of CHD infants with the highest mortality in an effort to improve our understanding of CHD epidemiology. Methods: Participants were drawn from a dataset of 1,964,691 infants born between 2014 and 2018 in Korea. Target patients defined as those with crucial CHDs including classical critical CHDs and diverse categorical defects but excluding simple shunt defects. Overall mortality (procedural and natural mortality) and procedural mortality (interventional and surgical mortality) for infants were analyzed. Results: Performance rate of multiple procedures in infants with crucial CHDs was 16%. Overall and surgical mortalities of crucial CHDs were 8% and 7%. Mortalities of palliative procedures were relatively high. Procedural mortalities for infants were significantly decreased in tetralogy of Fallot (TOF), atrioventricular septal defects, and total anomalous pulmonary venous return (TAPVR) compared with overall mortalities for infants. Surgical mortalities for infants involving TOF and TAPVR were significantly lower, but those for infants involving hypoplastic left heart syndrome (HLHS) was higher than the those for all ages. Conclusions: Palliative procedural technique in infants must be improved to obtain better outcome particularly in palliative surgery of HLHS. The infantile procedural outcomes for TOF and TAPVR are excellent and important to overcome disastrous circumstances during infancy. This comprehensive study of overall and procedural mortalities of CHDs may lay a cornerstone for CHD epidemiology in Korean infants.

Background: clubfoot is a common congenital deformity. The Ponseti technique, involving early corrective manipulations followed by the application of long leg casts and Achilles tenotomy, is widely accepted as the preferred treatment. Rapid healing of the tendon after surgery has been documented, but the aspect regarding tendon structure and properties is not known. Three cases of Achilles tendon rupture in adolescent previously treated for clubfoot have been described in the literature. Since rupture is a rare event in this age group a possible correlation with previous surgery has been hypothesized. The primary aim of the study was to compare the ultrasound findings of the Achilles tendon, in patients treated for clubfoot, between patients treated with casting alone and the ones who underwent surgery (percutaneous tenotomy or Z-plasty lengthening). Methods: 22 asymptomatic patients, (34 feet) median age 12 years, previously treated for clubfoot, were recruited for this study; the patients underwent an Achilles tendon ultrasound examination during a follow-up outpatient visit. Results: a greater thickness and structural alterations with presence of hypoechoic areas of the operated tendons compared to those treated with plaster alone were observed (p value: 0.0498 and

Candida spp. is rarely found in the etiology of neonatal early-onset sepsis (EOS). However, candidemia is associated with increased mortality and morbidity, as in late-onset sepsis. Congenital candidiasis may present as mucocutaneous infection or, more rarely, as a systemic infection in term and preterm infants. Material and methods: Case reports of two cases of congenital systemic candidiasis (CSC) produced by Candida albicans and a review of the data in the literature. Results: Both neonates were male, born vaginally, with risk factors for congenital candidiasis. One of the infants was born at term and presented with an almost generalized maculopapular rash at birth; C. albicans grew in the blood culture sampled at 36 hours; parenteral fluconazole was started immediately, and no complications were noted. The other infant was born preterm, at 28 weeks of gestation, and presented signs of respiratory distress on the 4th day of life after initial successful treatment of the respiratory distress syndrome with surfactant and non-invasive respiratory support. C. albicans was present in the neonatal blood and gastric aspirate cultures, and in the maternal vaginal cultures (all sampled at birth); parenteral fluconazole therapy was administered for 30 days as investigations revealed both liver and renal involvement and the infant development bronchopulmonary dysplasia. Conclusion: As data in the literature suggests, despite occurring at any gestational age, CSC may present various clinical pictures, the rash may mimic many other neonatal conditions, and the systemic dissemination cannot be distinguished from bacterial EOS. Careful anamnesis and a high index of suspicion are important for the prompt recognition and treatment of CSC, optimizing the short- and long-term outcomes.

Zika virus (ZIKV) impacts the developing brain. Here a technique was applied to define, in 3D, developmental changes in the brain of ZIKV-infected mice. Postnatal day 1 mice were uninfected or ZIKV-infected, then analysed by iodine staining and micro-CT scanning (diffusible iodine contrast enhanced micro-CT; diceCT) at 3-, 6- and 10-days post infection (dpi). Multiple brain regions were visualised using diceCT; olfactory bulb, cerebrum, hippocampus, midbrain, interbrain, and cerebellum, along with the lens and retina of the eye. Brain regions were computationally segmented and quantitated, with increased brain volumes with developmental time in uninfected mice. Conversely, in ZIKV-infected mice, no quantitative differences were seen at 3 or 6 dpi, when there are no clinical signs, but qualitatively, diverse visual defects were identified at 6-10 dpi. By 10 dpi, ZIKV-infected mice had significantly lower body weight and reduced volume of brain regions compared to 10 dpi-uninfected or 6dpi ZIKV-infected mice. Nissl and immunofluorescent Iba1 staining on post-diceCT tissue were successful, but RNA extraction was not. Thus, diceCT shows utility for detecting both 3D qualitative and quantitative changes in the developing brain of ZIKV-infected mice, with the benefit, post-diceCT, of retaining the ability to apply traditional histology and immunofluorescent analysis to tissue.

The article presents the case of a 27-year-old female patient with idiopathic congenital complete heart block who was referred by her primary care physician for cardiological evaluation. The conduction disturbance was recognized at the age of 6 years and was asymptomatic. The disqualification from pacemaker implantation included detailed history of a patient’s symptoms, echocardiographic assessment of the heart, exercise testing and ECG Holter monitoring. The aid of salbutamol administered orally was also useful.

Abstract: Congenital cytomegalovirus (cCMV) infection poses significant risks to fetal development, particularly affecting the nervous system. This study reports a fetal autopsy case, examining cCMV infection and focusing on CMV DNA measurements in various fetal organs before formalin fixation, a novel approach for comprehensive CMV DNA evaluations in fetal organs affected by cCMV. A 20-week-old male fetus was diagnosed with cCMV following the detection of CMV DNA in ascites obtained via abdominocentesis in utero. After termination of pregnancy, multiple organs of the fetus, including the cerebrum, thyroid gland, heart, lungs, liver, spleen, kidneys, and adrenal glands, were extracted and examined for CMV DNA loads using real-time polymerase chain reaction. Histopathological examination involved hematoxylin-eosin and CMV-specific immunostaining. A correlation was found between CMV DNA loads and pathology, with higher CMV-infected cell numbers observed in organs positively identified with both staining methods, exhibiting CMV DNA levels of ≥1.0 × 104 copies/mL, compared to those detected solely by CMV-specific immunostaining, where CMV DNA levels ranged from 1.0 x 103 to 1.0 x 104 copies/mL. These results highlight a quantifiable relationship between organ infection extent and CMV DNA concentration, providing insights into cCMV pathogenesis and potentially informing future diagnostic and therapeutic strategies for cCMV infection.

Congenital heart disease (CHD) is the most commonly detected congenital anomaly and affects up to 1 % of all live-born neonates. Current guidelines support the use of Chromosomal Microarray Analysis (CMA) and Next Generation Sequencing (NGS) as diagnostic approaches to identify genetic causes. The aim of our study was to evaluate the diagnostic yield of CMA and NGS in a cohort of neonates with both isolated and syndromic CHD. The present study included 188 infants under 28 days of age with abnormal echocardiography findings hospitalized at the Department of Neonatology, UMC Ljubljana, between January 2014 and December 2023. Phenotypic data were obtained for each infant by retrospective medical chart review. We established the genetic diagnosis of 22 distinct syndromes in 17% of neonates. The most common genetic diagnoses were 22q11.2 microdeletion (22.7%) and CHARGE syndromes (22.7%), Noonan syndrome (9.1%), and Williams syndrome (9.1%). In addition, we detected variants of uncertain significance in 4.8% of neonates. Timely genetic diagnosis is important for the detection of syndrome-related comorbidities, prognosis, reproductive genetic risks and, when appropriate, genetic testing of other family members.

Blindness or visual impairment following congenital heart repair is a rare complication. It can be transient or permanent depending in underlying etiology and damage to optic pathway. We report first case of transient blindness following congenital heart repair due to unilateral subdural hematoma in occipital region.

Deep hypothermic circulatory arrest (DHCA) is safe, but subtle neurodevelopmental deficits may persist far beyond the perioperative period. We investigated the relationship between DHCA duration and neurodevelopmental outcomes in young children undergoing cardiac surgery with DHCA. Children aged < 42 months, including neonates who underwent cardiac surgery using DHCA without regional perfusion techniques, were included as the DHCA group. Children in the same age range undergoing cardiac surgery without DHCA were included as the control group. All patients underwent neurodevelopmental assessment using the Bayley Scales of Infant and Toddler Development (BSTID) by a trained pediatrician. Seventeen of 25 DHCA and six of 10 control patients completed the BSTID assessment. The groups showed no preoperative, operative, or postoperative significant differences. In adjusted multivariable analysis, prematurity and age at assessment were significant changing predictors of each of the BSTID components (p < 0.001), other than the gross motor component, where only age at assessment was a significant adjusting predictor. Longer DHCA was associated with lower fine and gross motor BSTID components; however, the association was not statistically significant (p = 0.06). Use of DHCA without regional perfusion techniques may be associated with less optimal neurodevelopmental outcomes if DHCA has a long duration.

Background The incidence of congenital cholesteatoma (CC) has rarely been discussed, particularly from the demographic viewpoint. Therefore, we conducted an epidemiological study of CC using local medical characteristics. Materials and methods The participants were 100 patients (101 ears) who underwent initial surgical treatment at university hospitals in two rural prefectures between 2006 and 2022. Sixty-eight percent of the patients were males and 32% were females, with a median age of 5 years. We reviewed the medical records for the date of birth, date of surgery, stage of disease, and first symptom of the disease. Result The total incidence of CC was calculated to be 26.44 per 100,000 births and tended to increase. No significant difference was found between the incidences in the two prefectures. The number of surgeries performed was higher in the second half of the study period. No difference in the stage of progress was observed based on age. Conclusion The incidence of CC was estimated to be 26.44 per 100,000 new-born births. The number of patients with CC has tended to increase; however, this can be attributed to an increase in the detection rate rather than the incidence.

Children and adolescents (C&A) with congenital heart defects (CHD) have decreased functional capacity and executive functioning (EF) due to brain abnormalities and decreased oxygen saturation. Exercise may improve EF via increased cognitive demands and cerebral blood supply. The purpose of this review was to identify current evidence describing the impact of physical activity (PA) interventions on EF in C&A with CHD. The following databases were searched from 2014-present: MEDLINE, EMBASE, CINAHL, Scopus, CENTRAL, and PsycInfo. Article inclusion criteria consisted of participants from birth to 18 years with CHD, interventions related to PA, and EF as an outcome. Articles were excluded if: adults were included, translation to English was impossible, and full access was unavailable. As a result of the review, 431 studies were screened. Three articles underwent full analyzation and only one met all criteria and this study found that with exercise there were significant improvements on self-reported cognitive functioning and parent-reported social functioning. Despite theoretical benefits, only one published study has investigated the role that PA interventions have on EF in C&A with CHD. Further investigation of the effect PA interventions have on EF in C&A with CHD is needed.

Background: Facial features are the first basic spring of medical knowledge in children and adults with congenital malformation. Children born with multiple contractures almost always receive the misdiagnosis of arthrogryposis multiplex. Larsen syndrome can easily be diagnosed at birth via the proper interpretations of its characteristic facial features and multiple dislocations. Instant diagnosis can facilitate the orthopaedic strategy for early treatment and follow-ups. Material and Methods: Six children (four boys and two girls, age range from a few months to 7 year-old) have been referred to our departments for diagnosis and treatment. All children received their first misdiagnosis by the paediatricians as having arthrogryposis multiplex congenita. The clinical phenotype was our first decisive tool for diagnosis. All children exhibited the classical phenotype of Larsen syndrome, dish-like facies associated with multiple joint dislocations. Radiological phenotypic characteristics confirmed our clinical diagnosis. three children out of six showed unpleasant cervical spine deformities. The first child of a-2- year old became tetraplegic after minor trauma. One child presented with rigid cervical kyphosis. The third child wasa product of first related marriage and was born congenital tetraplegia. genotype has been carried out for confirmation. Results: Three children underwent open reduction for congenital hip and knee dislocations. one child underwent spinal fusion CO-C7 because of tetraplegia. 3D reformatted and reconstruction CT scan of the craniocervical junction in two children showed unusual male segmentations along C2-3 causing effectively the development of rigid cervical kyphosis and one child with congenital tetraplegia showed serious malsegmentation of C1/C2 associated with hypoplasia of the anterior and the posterior rings of the atlas. These findings in the last two children made any surgical intervention quite sophisticated. Four of these children were compatible with the autosomal dominant type of Larsen syndrome and manifested heterozygous mutation in FLNB mapped 3p14.3, encoding and actin-binding protein, filamin B. One child showed no mutations in the FLNB, though his clinical and radiological phenotype and his family history of first related marriage were totally compatible within the diagnosis of autosomal recessive type of Larsen syndrome. Conclusion: The orthopaedic strategy in patients with Larsen syndrome can not be achieved unless a precise diagnosis is has to be established as early as possible. Arthrogryposis multiplex congenita has been the first false diagnosis which was the reason for improper management.The most diagnostic confusion /error occurs to the paediatricians is the multiple contractures which are akin to arthrogryposis multiplex congenita. In practice, arthrogryposis multiplex congenita is a symptom complex rather than a precise diagnostic entity. The second diagnostic misconception is the generalized ligamentous hyperlaxity which can mimic hypotonia. Hypotonia in a newborn can be falsely categorized within the floppy infant syndrome. We used 3D reformatted CT scan to further understand the craniocervical junction pathology in three children with cervical spine kyphosis. Strikingly, mal segmentation and defective ossifications of the atlanto-axial spine segments in a child with Larsen syndrome and congenital tetraplegia.

The inclusion of various chemical substances in personal care products (PCPs) and cosmetic formulations can be associated with disruption and damage to the nervous system. Microplastics, benzophenones, parabens, phthalates and metals are among the most common chemical substances found in cosmetics that have been shown to induce neurotoxic mechanisms. Although cosmetic neurotoxin exposure is believed to be minimal, different exposure scenarios of cosmetics suggest that these neurotoxins remain a threat. Special attention should be paid to early exposure in the first gestation weeks, when critical processes, like the migration and proliferation of the neural crest derived cells start to form the ENS. Importantly, cosmetic’s neurotoxins can cross the placenta barrier and so affect the future embryo, but are also secreted in the breast milk, so that babies remain exposed for longer periods, even after birth. In this review we explore how neurotoxins contained in cosmetic and PCPs may have a role in the pathogenesis of various neurodevelopment disorders and neurodegenerative diseases, and therefore also in congenital enteric aganglionosis as well as in postnatal motility disorders. Understanding the mechanisms of these chemicals used in cosmetic formulations and their role in neurotoxicity is crucial to determining the safety of use for cosmetic products during pregnancy.

Pulmonary artery stenosis represents a group of disorders involving main, branch or peripheral pulmonary arteries resulting either in pain, dyspnea, hemoptysis or even no symptoms. Early diagnosis and timely intervention are crucial for reducing mortality, while timely diagnosis is challenging due to the nonspecific symptoms. Computed tomography pulmonary angiography (CTPA) is useful in the diagnosis because it can provide more details about the abnormal changes in the lumen, vessel wall and adjacent mediastinal structures. Congenital and acquired pulmonary artery anomalies have some characteristics on CTPA, which can be useful for differential diagnosis. Awareness of these conditions and is important for the radiologists. This pictorial review provides an overview of CTPA imaging features of pulmonary artery stenosis.

Introduction: Antenatal diagnosis of cardiac abnormalities and counselling parents about postnatal care requires a multidisciplinary team which includes a paediatric cardiologist a neonatologist and a fetal medicine physician. Some of this expertise is not available in all centres with fetal medicine expertise, however with modern technology, this could be provided remotely. Our objective was to assess the feasibility and outcomes of a pre-natal multidisciplinary tele-echocardiography diagnostic and counselling services Materials and Methods: Two centres based in separate countries provided a joint diagnostic and counselling service over a period of 14 months. The primary centre undertook the fetal echocardiography with a Voluson E10 machine and images transmitted live using Zoom OPS system with video-consultation and counselling. The fetal echo was performed using the ISUOG Guidelines check list. Results: There was an initial feasibility period of 2 months during which 10 women whose fetuses had normal hearts were scanned to test the workability of the system. Over a period of 12 months, 513 high risk fetuses were then scanned and out of these 27 had congenital malformations. The most common were hypoplastic left heart syndrome (HHLS) and atrio-ventricular septal defect. Tele-echocardiography and counselling was successful in all the cases. Satisfaction with the service was 3.8/4 with the main limitation being the need for further referral to a tertiary centre for delivery. Conclusion: Tele-echocardiography is reliable and when combined with live counselling and support from a paediatric cardiologist, is an option acceptable to patients. The greatest benefit was from being counselled by a team of experts at a single consultation rather than having to travel to another centre for consultation. With rapidly evolving technology, making video transmission easier and less expensive, we feel that consideration should be given not only to the development of tele-echocardiography but extended to other aspects of fetal medicine.

In mice, mutations or targeted disruptions of the core circadian gene Bmal1 have been implicated in early onset of ocular pathologies, including premature/congenital cataract development. The aim of the present study was to analyze probands of consanguineous Pakistani cataract families to identify the novel pathogenic variants in the BMAL1 gene. We have studied 21 congenital cataract families. Ophthalmic examination was performed for the probands and available family members. Genomic DNA was isolated from peripheral blood. PCR and Sanger sequencing was performed for the entire coding region of the BMAL1 gene. Targeted Sanger sequencing of BMAL1 revealed a heterozygous variant c.41A>T; p.(Asp14Val) in one proband, but it did not co-segregate with the disease phenotype in the family. In addition, a nonsynonymous variant (rs2290037) was identified in five probands. Our study is the first one to analyze the role of BMAL1 gene mutations in humans for their association with congenital cataract. Although we were unable to find the variants associated with congenital cataract families from Pakistan, more studies from other populations will be informative to further prove the role of BMAL1 with the disease.

Atlas Posterior Arch Deficiency (APAD) is a rare anatomical variation of the atlas vertebra that can be detected using cone-beam computed tomography (CBCT). This study aims to evaluate the prevalence, classification, and clinical implications of APAD in an Italian cohort.

Background: The key objective of this research was to identify the dominant parameters and determine the patient status of pediatric patients with congenital heart disease in the ICU. The data we collected from the Congenital Heart Disease (CHD) Surgery Unit (ICU) in the National Heart Foundation Hospital and Research Institute, Dhaka, Bangladesh. Data from 300 ICU patients was collected and analyzed. We choose patients who are less than 12 years old at the time of ICU admission and whose ICU stay is longer than 24 hours. (2) Methods: According to the doctor’s advice, the dependent and independent variables are selected. The relationship between these parameters in the ICU was selected by linear modeling, which is associated with mortality risk. These parameters are used in the linear regression model and the ARIMA model for prediction. The prediction model is used for pediatric congenital heart disease patients in the ICU. (3) Results: The relation between CVP and BP (95% CI=0.2113,0.353 r=0.2841249), PEEP, and FiO2 (95% CI=0.6992,0.770 r=0.7367744) is statistically significant (p value<0.001). pH and PO2 were statistically significant, but there were correlations (95% CI=0.161,0.308 r=0.2362575). The statistically significant (p < 0.001) parameters were selected for prediction. In this study, BP, FiO2, and PO2 parameters were used in the linear regression model and the ARIMA model for prediction. We predict the next-hour patient’s status. The ARIMA model was found to have less error than the linear regression model. (4) Conclusions: This study helps identify the important parameters that are measured in the ICU to monitor patient status and predict the future value of those parameters, with the ultimate goal of providing physicians with an early signal of future patient conditions.

(1) Background: Cardiorespiratory fitness (CRF) is a prognostic factor regarding long time morbidity and mortality. To assess CRF the well-known gold standard is cardiopulmonary exercise testing (CPET), which is a time consuming and expensive test. Therefore, alternative methods for routine evaluation of CRF are needed for the general population as well as for specific patient groups such as children and young adults with congenital heart disease. The Stair Climbing Test (SCT) is a simple and resource saving test reported in the current literature. This test is used in various settings to assess different health associated risk factors including cardiorespiratory fitness, muscular resilience, therapy effectiveness or pre- and postoperative morbidity and mortality.

Background: Congenital Pulmonary Malformations (CPMs) are rare benign lesions potentially causing infective complications and/or malignant transformation requiring surgery even when asymptomatic. CPMs are infrequent in adult but potentially detected at any age. There is not a consensus indicating the correct extent of resection in both adults and paediatrics. This retrospective multicentric study aims to identify the appropriate surgical resection to prevent the recurrence of related respiratory symptoms. Methods: Between 2010 and 2020, a total of 96 patients (adult and pediatric) underwent surgery for CPMs in 4 centers. A 2:1 propensity score matching (considering sex and lesion side) was performed, identifying 2 groups: 50 patients underwent lobectomy (group A) and 25 sub-lobar resections (group B). Clinical and histopathological characteristics, early and late complications and symptom’s recurrence were retrospectively analyzed and compared between the two groups by univariate and multivariate analyses. Results: Patients who underwent lobectomy had a statistically significant lower rate of recurrence (4% vs 24% of group B, p = 0.014) and a lower rate of intraoperative complications (p = 0.014). Logistic regression identified sub-lobar resection (p=0.040), intra- and post-operative complications (p=0.105 and 0.022) and associated developed neoplasm (p=0.062) as possible risk factors for symptoms recurrence after surgery. Conclusions: Pulmonary lobectomy seems to be the most effective surgical treatment for CPMs, guaranteeing stable remission of symptoms and a lower rate of intra- and postoperative complications. To our knowledge this is one of the largest studies comparing lobectomy and sub-lobar resections in patients affected by CPMs, considering the low incidence worldwide.

We investigated the radioclinical outcomes of naviculectomy and limited/tailored soft-tissue releases in a short series of ambulatory children with complex/intractable congenital vertical talus subsets namely neglected, multiple operated and recurrent patients. We postulated that this technique will yield satisfactory radioclinical outcomes and minimal complications because it avoids extensive surgical release/trauma that is otherwise classically recommended for complex congenital vertical talus (CVT). The cohort consisted of five -four boys, one girl- complex CVT children with neglected, multiple operated and/or recurrent subsets. Patients were included if manipulative casting techniques were deemed unlikely to produce a plantigrade foot. Patients underwent naviculectomy with variable on-demand limited soft tissue releases. Two patients had bilateral affection and two had a non-idiopathic aetiology. The mean age was 5.2 years (4 to 6.25) and mean follow-up was 2.3 years (1 to 3). We reported satisfactory outcomes as per foot posture, function, overall parent satisfaction including pain and radiography per lateral views of talar-axis-first metatarsal base angle on the short/intermediate term. Whereas manipulative casting is unlikely to yield lasting outcomes in ambulatory children with complex subsets of CVT, extensive surgical soft-tissue releases have unfavourable long-term complications. As a substitute, naviculectomy as a form of resection arthroplasty created a practical and affordable third way between manipulative casting with minimally invasive surgery and the extensive surgical soft tissue releases on the short/intermediate term.

Primary care pediatricians encounter a wide range of complex conditions in their daily clinical practice. It is not uncommon for their patients to get exposed to medical errors. Diagnostic errors, defined as missed, delayed, or wrong diagnosis, are of great importance as they may cause significant harm to the pediatric patient with severe disease. These errors often occur when the symptoms and signs of a disease are atypical or missing. Data on the most frequent misdiagnosed situations in pediatrics is scarce. One of these groups of conditions is that regarding cardiac diseases. The pediatric cardiology field has met rapid development over the past few decades. Primary care providers play a key role in diagnosis, management, and referral of children with heart disease, both congenital and acquired, because many common cardiac complaints are first addressed in the primary care setting. The scope of this review is to investigate the cardiac entities that are often missed by the general pediatricians. In particular, it aims to spot the most common of them, to describe their clinical presentation, their diagnostic options, red flags, and tips, and to provide the ways to avoid erroneous, delayed, or missed diagnosis.

This report elucidates the first surgical correction of an infundibular muscular ventricular septal defect (VSD) in a one-year-old Ragdoll cat via cardiac arrest using cardiopulmonary bypass, a method that is rarely used in feline cardiac surgery. VSDs can lead to congestive heart failure and pulmonary hypertension, particularly in patients with large shunts. This case involved a VSD that was atypically located and classified under the Soto classification instead of the standard Kirklin classification. Detailed echocardiography revealed that the defect required intervention owing to left heart and main pulmonary artery enlargement. Despite the VSD being located on the contralateral side, as anticipated in the preoperative examinations, the choice of median sternotomy allowed for successful closure of the defect. Conversely, the insertion of two cannulas into the ascending aorta resulted in damage to the adjacent thoracic duct, causing transient chylothorax, which resolved with conservative treatment. Cardiac arrest induced by a cardioplegic solution facilitated the surgical procedure, although it has led to anemia in cats. However, on postoperative day 490, the patient exhibited only minor residual shunting with normalized heart size, and remained healthy. This technique appears to be a viable treatment option for congenital heart disease in cats.

Background: Atrial fibrillation (AF) is increasingly recognized in pediatric patients, presenting unique challenges in management due to its association with various underlying heart conditions. This study aimed to evaluate the prevalence, management strategies, and outcomes of AF in this population. Methods: A retrospective analysis was conducted at a tertiary pediatric cardiology center, including patients aged ≤18 years diagnosed with AF between January 2015 and December 2023. The study focused on demographic details, clinical presentations, treatments, and outcomes. Descriptive statistics were employed to assess treatment efficacy, recurrence rates, and complications. Results: The study included 36 pediatric patients (median age: 15 years, IQR: 13-17; 58% male). Of these, 52.8% had acquired heart disease, 16.7% had congenital heart anomalies, and 16.7% presented with lone AF. The initial management strategies involved electrical cardioversion in 53.3% of patients and pharmacological conversion with amiodarone in 46.7%. Rhythm control therapy was administered to over 80% of the cohort, and 63.9% were placed on oral anticoagulation, predominantly for rheumatic and congenital heart diseases. The overall success rate of rhythm control was 96.2%, with an AF recurrence rate of 3.8%. Ischemic stroke was the most common complication, occurring in three patients, all with underlying rheumatic heart disease. Conclusion: AF in pediatric patients is predominantly associated with rheumatic and congenital heart diseases, though a significant proportion of patients present with lone AF. Despite effective rhythm control in most cases, neurological complications, particularly ischemic strokes in patients with underlying heart disease, remain a critical concern. These findings underscore the need for more comprehensive studies to better understand the etiology, risk factors, and optimal management strategies for pediatric AF.

Lower cutoff levels in screening programs have led to an increase in the proportion of detected cases with transient hypothyroidism, leading to increase of the overall incidence of primary congenital hypothyroidism (CH) in several countries. We have performed retrospective evaluation on the data from 251,008 (96.72%) neonates screened for thyroid-stimulating hormone (TSH) level in dried blood spot specimens taken 48 hours after birth, between 2002 and 2015, using DELFIA method. A TSH value of 15 mIU/L was used as the cutoff point until 2010 and 10 mIU/L thereafter. Primary CH was detected in 127 newborns (1/1976) of which 81.1% had permanent and 18.9% had transient CH. The incidence of primary CH was increased from 1/2489 until to 2010 to 1/1585 thereafter (p=0.131). However, the incidence of permanent CH was slightly increased (p=0.922), while the transient CH incidence had 8-fold increasing after lowering the TSH cutoff level (p<0.001). In cases with permanent CH, we observed lower frequency for thyroid dysgenesis (82.7 vs. 66.7%) and higher frequency for normal in-situ thyroid gland (17.3 vs. 33.3%), for the period with reduced TSH cutoff value. Our findings support the impact of lower TSH cutoff on the increasing incidence of congenital hypothyroidism.

Congenital diseases of the large intestine have scarcely been reported and mostly include fistula, atresia, or colonic duplication. Cases of partial colonic agenesis have rarely been described. The purpose of this study was to report a cohort of dogs and cats diagnosed with partial colonic agenesis. The colon was measured during colonoscopy or contrast-radiography and compared to the average length described in the literature. Six dogs and 17 cats were retrospectively included. Depending on the case, partial colonic agenesis could represent an incidental finding or the likeliest cause of clinical signs. Diarrhea was reported in most cases, and no specific clinical or biological abnormality was observed. Median age of presentation was variable and long asymptomatic periods were common. Abdominal ultrasound was useful and identified a short colon in 14/17 cats but only in one dog. Endoscopy was useful to confirm the diagnosis and to identify associated lesions and complications. Among others, colonic stenosis was reported in 8/9 cases that had lifelong clinical signs and the shortest colon length. This anatomical abnormality could promote chronic inflammation that might generate fibrosis and ultimately stenosis.

Background/Objectives: Congenital Radioulnar Synostosis (CRS) is a rare elbow joint disorder resulting from abnormal fusion of the radius and ulna during fetal development. Methods: Although predominantly sporadic, familial cases exist with autosomal dominant inheritance. Diagnosis relies on clinical evaluation and radiological findings, showcasing synostosis. Surgical decisions hinge on factors like age and symptom severity. Results: Multiple surgical treatments have been described but derotation osteotomy offers predictable results. Challenges include potential complications and cultural considerations influencing final forearm positioning. Conclusions: A nuanced approach is crucial for optimal management, highlighting the need for ongoing research to refine diagnostic and therapeutic strategies for improved outcomes in CRS patients.

Permanent neonatal diabetes may occur either in isolation or associated with multi-organ syndromes. It is caused by mutations in the genes responsible for pancreatic β cell mass or function. We report new cases of consanguineous parents from Saudi Arabia with a homozygous deletion of exons 1and 2, and exon 5-9 of the GLIS3 gene, who presented with permanent neonatal diabetes associated with intrauterine growth retardation, severe congenital hypothyroidism without other manifestation in the liver, renal or eyes in the 1^st one and cystic renal changes in the 2^nd patient. Mutations in the GLI-similar 3 (GLIS3) gene encoding the transcription factor GLIS3 are a rare cause of neonatal diabetes and congenital hypothyroidism with only 15 reported patients worldwide to date.

Congenital syphilis still represents a worldwide public health problem. If left untreated, can lead to fetal demise and high neonatal morbidity and mortality. Unfortunately, in the last decade there has been a resurgence of cases in the US. This review discusses the ongoing problem of this preventable congenital infection, vertical transmission and clinical manifestations while providing a guidance for the evaluation and management of infants born to mothers with reactive serologic tests for syphilis

This study aimed to evaluate the role of chest radiographs and electrocardiograms in predicting the hemodynamics of congenital heart disease (CHD). This retrospective study included 50 patients with a diagnosis of CHD who had undergone any form of cardiac intervention, either surgical or nonsurgical between September 2019 and September 2020. Chest radiographs and electrocardiograms were evaluated and compared with the diagnostic gold standard echocardiography. Chest radiographs had the highest sensitivity, specificity, and accuracy, with all being 100%, in detecting situs and cardiac position. There was a very good agreement between chest radiographs and echocardiography in the detection of both situs and cardiac position (κ = 1.00, p &lt; 0.001), while moderate agreement was observed for the detection of cardiomegaly, position of aortic knuckle, main pulmonary artery dilation, and right pulmonary artery dilation. Electrocardiograms had a high sensitivity (100.00%), but modest specificity and accuracy for the detection of left ventricle pressure overload. For the detection of left atrial enlargement and left ventricle volume overload, electrocardiograms had high specificity (94.12% and 94.29%, respectively) but low sensitivity and modest accuracy. There was a moderate agreement between electrocardiograms and echocardiography in the detection of right ventricle pressure overload (κ = 0.43, p = 0.002) and left ventricle volume overload (κ = 0.46, p &lt; 0.001). The study findings indicate that chest radiographs and electrocardiograms alone are not adequate for the assessment of hemodynamics of CHD and reinstates the recommendation that in addition to routine chest radiographs and electrocardiograms, echocardiography should be performed.

Purpose: To investigate the molecular basis of congenital glaucoma in a family with GAPO (growth retardation, alopecia, pseudoanodontia, and progressive optic atrophy) syndrome. Methods: We report ocular features of 3 girls with GAPO syndrome born of consanguineous marriage in a multi- generation consanguineous family. The proband (4year old girl) and her younger sibling (1 year old girl) were operated for bilateral congenital glaucoma in both eyes. The elder sibling (10year old female) had features of GAPO syndrome but did not manifest features of glaucoma. Results: A genetic evaluation using whole exome sequencing revealed a homozygous ANTXR1 mutation in all 3 affected siblings with GAPO. No other mutations were detected in the genes associated with glaucoma. A rare missense mutation in TGFBI gene was shared in the two siblings with congenital glaucoma and GAPO syndrome.Conclusions: Mutations in TGFBI gene could have a role in the pathogenesis of congenital glaucoma.

A higher incidence of primary congenital hypothyroidism (CH) has been related to in-creased sensitivity in neonatal screening tests. The benefit of treatment in mild cases remains a topic of debate. We evaluated the cost-benefit of reducing the blood-spot TSH cut-off (b-TSH) from 10 (Group 2) to 6 mIU/L (Group 1) in a public neonatal screening program. During the study period, 40% of 123 newborns with CH (n= 162,730; incidence = 1:1,323) had b-TSH between 6 and 10 mIU/L. Group 1 patients had fewer clinical symptoms (p=0.02), lower serum TSH (p

Congenital malformations are functional and structural alterations in embryonic or foetal development resulting from a variety of factors including maternal health status. This study aimed to investigate the association between maternal birth weight (MBW) and the prevalence of congenital malformations in the offspring using data from a nationwide birth cohort study in Japan including 103,060 pregnancies. A binary logistic regression model with adjustment for various covariates revealed that MBW of &lt;2,500 g (low MBW) was associated with increased risk of congenital heart disease (adjusted odds ratio: 1.388, [95% confidence interval: 1.075–1.792]), angioma (1.491 [1.079–2.059]), and inguinal hernia (1.746, [1.189–2.565]), while MBW of ≥4,000 g (high MBW) with congenital anomalies of the urinary tract (2.194, [1.261–3.819]), and arrhythmia (1.775, [1.157–2.725]), compared with those with MBW of 3,000-3,499 g. Low MBW was associated with cleft lip and/or palate (1.473, [1.052–2.064]), congenital heart disease (1.615, [1.119–2.332]), genital organs(1.648, [1.130–2.405]), hypospadias (1.804, [1.130–2.881]), and inguinal hernia (1.484, [1.189–1.851]) in male infants and CAKUT (1.619, [1.154–2.273]) in female infants, whereas high MBW was associated with congenital heart disease(1.745, [1.058–2.877]) and CAKUT (2.470, [1.350–4.517]) in male infants. The present study is the first to demonstrate a link between MBW and congenital malformations in Japanese children. While these results must be interpreted with caution, MBW should be considered a major predictor of congenital malformation risk.

Chikungunya virus (CHIKV) is an alphavirus that causes febrile illness punctuated by severe polyarthralgia. After the emergence of CHIKV in the Western Hemisphere, multiple reports of congenital infections were published that documented neurological complications, cardiac defects, respiratory distress, and miscarriage. The Western Hemisphere is endemic to several alphaviruses and whether antigenic cross-reactivity can impact the course of infection has not been explored. Recent advances in biomedical engineering have produced cell co-culture models that replicate the cellular interface at the maternal fetal axis. We employed a trans-well assay to determine if cross-reactive antibodies affected the movement and replication of CHIKV across placental cells and into an embryoid body. The data show that antibodies to Venezuelan equine encephalitis virus (VEEV) significantly reduced CHIKV viral load in embryoid bodies. The data highlight that viral pathogenesis can be cell-specific and that exploiting antigenic cross-reactivity could be an avenue for reducing the impact of congenital CHIKV infections.

Rhombencephalosynapsis (RES) is a rare, congenital developmental disorder of the central nervous system. Even after many years of its identification, the etiology and pathogenesis of RES remain unclear. It occurs in combination with many syndromes and thus has overlapping symptoms. The clinical presentation of this disorder varies depending on the severity of the maldevelopment of vermis. Here, we present a case of a 60-year-old Indian female diagnosed with Rhombencephalosynapsis. Clinical and MRI characteristics of RES along with treatment options have been discussed.

Some preterm and sick neonates have altered biochemical profiles and follow-up newborn screening (NBS) collections are recommended. The Victorian NBS program historically recommended recollections for babies with birth weight &lt;1500g (managed by the maternity service provider) and 3 weeks post-transfusion (managed by the laboratory). We aimed to determine adherence to current guidelines and review the guidelines to improve NBS performance. To do this we audited data from 348,584 babies between January 2018 and June 2022. Babies with a recorded birth weight of &lt;1500g were filtered for inclusion. For the overall review and visualization of the protocol, we sourced information from the literature, our professional society and tertiary hospital services. A total of 2647 babies had a birth weight recorded between 200 and 1499g. Of these 2036 (77%) had a second sample collected, indicating that &gt;1 in 5 babies were not receiving a follow-up collection. Our timing of recollections for transfused babies, requiring a 3-week follow-up collection, was longer than in other Australasian jurisdictions. A new combined “sick-prem-protocol” was launched to support recollections and after a one-year review achieve 95% compliance. We recommend NBS laboratories audit preterm and sick neonate recollections to ensure appropriate follow-up. This should be supported with a visual process map to aid education and compliance.

Congenital heart disease (CHD) is a prevalent congenital disorder diagnosed with high frequency, affecting approximately 0.8% to 1.2% of all live births. Research has demonstrated that the use of pulse oximetry and clinical examination as a screening tool for CHD diagnosis has proven extremely valuable. We conducted a retrospective longitudinal study over a 3-year period that involved screening 1188 newborns admitted to the NICU during the first 72 hours of life within this timeframe. 201 newborns were diagnosed with CHD. Almost all (n=198) had a positive screening test during the 72-hour period, while 3 had a negative screening test, but were later diagnosed using echocardiography. The prevalence rate was 16.67%. A confusion matrix was constructed with 198 true positives (TP), 3 false negatives (FN), no false positives (FP), and 987 true negatives (TN). The sensitivity of the screening test was 98.51%, while the specificity 100%, with no false positives. In our study, a total of 9 deaths occurred. Using the Kaplan-Meier method, the survival probability appeared to be slightly above 0.9 (95.5%), indicating that almost all patients survived past 72 hours after being diagnosed with CHD. Pulse oximetry is an effective, low cost and easy-to-use method and a useful tool to assess and lead to the diagnosis of CHD.

High-flow oscillatory ventilation (HFOV) is a common rescue treatment in infants and children with respiratory failure. This type of ventilation is an effective technique in numerous diseases that affect a child in the postnatal period, such as ARDS, meconium aspiration syndrome (MIS), postnatal pulmonary bleeding and idiopathic pulmonary hypertension (IPH). Although this ventilation technique is commonly recognized as a valuable therapeutic option in the general pediatric population, this is not the same for children with congenital cardiovascular diseases. The key mechanism of oscillatory ventilation is continuous positive pressure administered within the airways via a small tidal volume at high frequency. Tidal volumes are between 1 and 3 ml/kg delivered at 5 – 15 Hz equivalent to 300 – 900 breaths per minute. Few older studies conducted on humans and animals highlight that HFOV may be dangerous for congenital heart patients. According to these evidences, hemodynamic parameters such as blood pressure, wedge pressure, central venous pressure, heart rate and inotrope level can be dangerously changed for patients with congenital heart disease, therefore oscillatory ventilation should be avoided. Numerous retrospective studies have pointed out how oscillatory ventilation constitutes a valid therapeutic option in children with congenital heart disease. Recently, new evidences have highlighted how hemodynamic parameters are modified in a non-significant way by this type of ventilation, remaining beneficial as in the normal pediatric population. This narrative review aims to describe the mechanisms of oscillatory ventilation and collect all the available evidences to support its use in pediatric patients with congenital heart problems.

Context: Mutations in Cytochrome P450 oxidoreductase (POR) cause a form of congenital adrenal hyperplasia (CAH). We are reporting a novel R550W mutation in POR identified in a 46, XX patient with signs of aromatase deficiency. Objective: Analysis of aromatase deficiency from R550W mutation in POR. Design, Setting, and Patient: Both the child and the mother had signs of virilization. Ultrasound revealed the presence of uterus and ovaries. No defects in CYP19A1 were found, but further analysis with a targeted Disorders of Sexual Development NGS panel (DSDSeq.V1, 111 genes) on a NextSeq (Illumina) platform in Madrid and Barcelona, Spain, revealed compound heterozygous mutations c.73_74delCT/p.L25FfsTer93 and c.1648C>T/p.R550W in POR. WT and R550W POR were produced as recombinant proteins and tested with multiple cytochrome P450 enzymes at University Children’s Hospital, Bern, Switzerland. Main Outcome Measure and Results: R550W POR showed 41% of the WT activity in cytochrome c and 7.7% activity for reduction of MTT. Assays of CYP19A1 showed a severe loss of activity and CYP17A1, as well as CYP21A2 activities, were also lost by more than 95%. Loss of CYP2C9, CYP2C19, and CYP3A4 activities was observed for the R550W-POR. Predicted adverse effect on aromatase activity as well as a reduction in binding of NADPH was confirmed. Conclusions: Pathological effects due to POR R550W were identified, expanding the knowledge of molecular pathways associated with aromatase deficiency. Screening of the POR gene may provide a diagnosis in CAH without defects in genes for steroid metabolizing enzymes.

AIM: The study aims to identify if mutations in the SLC4A11 gene are present in Filipino families affected with Congenital Hereditary Endothelial Dystrophy (CHED). METHODS: This is a family cohort study that investigated the genetic profile of a selected family in Northern Luzon, Philippines, whose members were diagnosed with Congenital Hereditary Endothelial Dystrophy (CHED). A patient who was diagnosed with CHED prior to this study, served as the proband for this family. A detailed family history and a complete ophthalmologic examination were done to each of the family members. A total of six affected members and three unaffected members were included in this study. DNA was isolated from peripheral blood samples of family members, and polymerase chain reaction (PCR) was used to amplify the gene’s entire coding region, (19 exons and 2 putative promoter regions), and finally, the amplified regions were analyzed using DNA sequencing. RESULTS: Consanguinity was not present in the family. Corneal haze was reported to be present since birth or shortly thereafter in all affected patients. Slit-lamp examination showed edematous corneas. Molecular studies of the SLC4A11 gene revealed four novel homozygous point mutations variably present in six affected members as well as three unaffected members. One unaffected family member (I-1) had a novel sense mutation absent in other family members. All affected siblings showed little phenotypic variability. CONCLUSION: This is the first report that gives us a genetic profile of a Northern Luzon family with members affected by CHED. This study supports earlier findings that the mutations in the SLC4A11 gene are not consistently the same among different ethnic groups worldwide, probably due to the disease’s genetic heterogeneity. Our study documented five novel mutations adding to the growing list of mutations probably responsible for acquiring the CHED phenotype. It is possible that there are more novel mutations waiting to be discovered in this hereditary disease. Screening for these specific mutations in other families may prove useful for genetic counseling, prenatal diagnosis and the future development of gene therapy.

Influenza virus can cause several complications during pregnancy. Therefore, we aimed to inves-tigate the effects of influenza on the development of congenital abnormalities (CAs) by analyzing the database of the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCS-CA). In our multicenter, case-control, population-based study, we processed clinician-reported outcomes and diagnoses collected in the HCCSCA. The case group included newborns with dif-ferent non-chromosomal birth defects, while controls were newborns without CAs. Maternal in-fluenza, as a risk factor for CAs, was analyzed by using a logistic regression model and odds ra-tios with 95% confidence intervals (CIs). Our results showed that maternal influenza in the first trimester was associated with increased odds of developing non-chromosomal CAs (OR: 1.41, CI: 1.28–1.55). There were increased odds of neural tube defects (OR: 2.22, CI: 1.78–2.76), orofacial clefts (OR: 2.28, CI: 1.87–2.78) and congenital heart defects (OR: 1.28, CI: 1.10–1.49) after influenza infection. In all cases, we found a protective effect of folic acid supplementation in the first tri-mester. The odds of non-chromosomal birth defects are higher after maternal influenza in the first -trimester. Folic acid or pregnancy vitamin supplementation and antipyretic therapy may reduce the effect of maternal influenza during the first trimester.

Congenital muscular dystrophy with laminin α2 chain-deficiency (LAMA2-CMD) is a severe neuromuscular disorder without a cure. Using transcriptome and proteome profiling as well as functional assays, we previously demonstrated significant metabolic impairment in skeletal muscle from LAMA2-CMD patients and mouse models. Reactive oxygen species (ROS) increase when oxygen homeostasis is not maintained and here, we investigate whether oxidative stress indeed is involved in the pathogenesis of LAMA2-CMD. We also analyse the effects of two antioxidant molecules, N-acetyl-L-cysteine (NAC) and vitamin E, on disease progression in the dy2J/dy2J mouse model of LAMA2-CMD. We demonstrate increased ROS levels in LAMA2-CMD mouse and patient skeletal muscle. Furthermore, NAC treatment (150 mg/kg IP for 6 days/week during 3 weeks) led to muscle force loss prevention, reduced central nucleation and decreased the occurrence of apoptosis, inflammation, fibrosis and oxidative stress in LAMA2-CMD muscle. In addition, vitamin E (40 mg/kg oral gavage for 6 days/week during 2 weeks) improved morphological features and reduced inflammation and ROS levels in dy2J/dy2J skeletal muscle. We suggest that NAC and to some extent vitamin E might be potential future supportive treatments for LAMA2-CMD as they improve numerous pathological hallmarks of LAMA2-CMD.

Introduction: Congenital heart defects (CHD) are the most frequent group of major congenital anomalies, accounting for almost 1% of all births. They comprise a very heterogeneous group of birth defects in terms of their severity, clinical management, epidemiology and embryologic origins. Taking this heterogeneity into account is an important imperative to provide reliable prognostic information to patients and their caregivers, as well as to compare results between centers or to assess alternative diagnostic and treatment strategies. The Anatomic and Clinical Classification of CHD (ACC-CHD) aims to facilitate both the CHD coding process and data analysis in clinical and epidemiological studies. Objectives: 1) To describe the long-term childhood survival of newborns with CHD and 2) To develop and validate predictive models of infant mortality based on the ACC-CHD. Materials and Methods: This study is based on data from a population-based, prospective cohort study: Epidemiological Study of Children with Congenital Heart Defects (EPICARD). The final study population comprised 1881 newborns with CHD after excluding cases that were associated with chromosomal and other anomalies. Statistical analysis included non-parametric survival analysis and flexible parametric survival models. The predictive performance of models was assessed by Harrell’s C index and the Royston-Sauerbrei R2 with internal validation by bootstrap. Results: The overall 8-year survival rate for newborns with isolated CHD was 0.96 [0.93- 0.95]. There was a substantial difference between the survival rate of the categories of ACC-CHD. The highest and lowest 8-year survival rates were 0.995 [0.989-0.997] and 0.34 [0.21-0.50] for “interatrial communication abnormalities and ventricular septal defects” and "functionally univentricular heart", respectively. Model discrimination as measured by Harrell’s C was 87% and 89% for the model with ACC-CHD alone and the full model, which included other known predictors of infant mortality, respectively. The predictive performance as measured by R2 was 45% and 50%, for the ACC-CHD alone and the full model. These measures were essentially the same after internal validation by bootstrap. Conclusion: The ACC-CHD classification provided the basis of a highly discriminant survival model with good predictive ability for the 8-year survival of newborns with CHD. Prediction of individual outcomes remains an important clinical and statistical challenge.

Background: Opinions on the impact of cancer on patients with haemophilia literature are contradicting. There is a lack of data on the clinical presentation and management of cancer in patients with haemophilia (PWH). Methods: Papers were found following a comprehensive search in PubMed, Google Scholar, and Scopus using the terms “cancer” and “haemophilia” without time limits and using the English language as a filter. The references of all retrieved original articles and reviews were assessed for additional relevant articles. Results: Overall, 116 papers were collected. Managing cancer in patients with congenital bleeding disorders, such as haemophilia A and B, requires careful evaluation of bleeding risk and the effect of antitumor treatments on blood coagulation. Generally, patients with haemophilia do not have an increased risk of developing cancer compared to the general population; increased risk is found in the presence of HIV or hepatitis infection. However, if a patient with haemophilia develops cancer, the treatment must be managed to minimise the risk of bleeding. Bleeding and thrombotic complications are important causes of morbidity and mortality in critically ill patients with cancer; replacement therapy with factor VIII or IX or others should be maintained during antitumor treatment. Conclusion: Overall, managing cancer in patients with haemophilia requires careful evaluation and individualised planning involving a multidisciplinary team of physicians experienced in haematology, oncology, and surgery.

Congenital cytomegalovirus (cCMV) infection resulting from non-primary maternal infection or reactivation during pregnancy can cause serious fetal-neonatal sequelae. We describe a male newborn born at term, with signs of perinatal asphyxia, and intractable acute provoked seizures, in the context of severe cCMV infection. The newborn was delivered in a referral hospital by emergency caesarean section due to fetal distress. Due to signs of asphyxia at birth and clinical moderate encephalopathy (Sarnat 2), he was transferred to our center for therapeutic hypothermia. Continuous full video-electroencephalography monitoring showed no seizures during the first 72 hours, however, soon after rewarming, he presented refractory status epilepticus. Cranial ultrasonography revealed bilateral ventricular and intraparenchymal hemorrhage. Routine infectious screen-ing on urine, blood, cerebrospinal fluid, and nasopharyngeal secretions revealed positive CMV DNA Polymer-ase Chain Reaction (PCR) on all samples. The CMV DNA performed on the bloodspot (Guthrie) card taken at birth yielded a positive result, confirming the intrauterine transmission and congenital origin of the infection. Maternal non-primary CMV infection in pregnancy is transmitted to the fetus in 0.5-2% of cases. When transmitted, it may cause serious fetal abnormalities, complications in the immediate neonatal period, and se-vere sequelae later in childhood. During pregnancy, it is useful to monitor maternal serology for CMV, even in previously immunized mothers, to identify signs of new infection or viral reactivation and implement measures to prevent neonatal sequelae. The possible advantages of standardized CMV screening of all newborns are a pertinent discussion point, as this may enable us to identify affected neonates timeously and prevent long term disabilities.

Right atrial isomerism (RAI) is a complex entity whose treatment and outcome are heterogeneous. The aim of this study was to analyze the results obtained after cardiac surgery in patients with RAI. A retrospective study was conducted; it included patients diagnosed with RAI who underwent cardiac surgery; their follow-up was from January 1, 2010 to March 31, 2020. Demographic characteristics and perioperative conditions were described. Thirty-eight patients with RAI were included, the median age was 4 years (IQR 2-9.2), and 57.9% were men. The main diagnoses were atrioventricular canal (63.2%) and pulmonary stenosis (55.3%). The most common surgical procedures were modified Blalock‐Taussig shunt (65.8%) and total cavopulmonary connection with an extracardiac conduit fenestrated without cardiopulmonary bypass (15.9%). The use of inhaled nitric oxide was a marker of postoperative mortality in critically ill patients (OR: 10.33; 95% CI: 1.04 - 102.08; p = 0.02). The overall survival was 86.8%, with a better outcome in those who did not require reintubation (Log Rank, p < 0.01). The survival of RAI was similar to other centers of reference. Individuals with RAI should be evaluated rigorously to determine an adequate repair strategy, considering high morbidity and mortality.

The iodine intake in a pregnant woman has been closely correlated with development of transient congenital hypothyroidism which leads to decline in neurocognitive abilities of the child later in life as the effects are very subtle at birth. Both low and excess ingestion of iodine has been found to contribute to this cause, although iodine deficiency is more commonly observed in women of underdeveloped nations. It poses risks not only to the foetus but also to the mother leading to obstetric complications such as still birth and spontaneous abortions. It can be prevented using WHO recommended daily iodine supplementation in deficient regions or decreasing the excess load in groups exposed to high iodine. Programmes designed to screen the new-born at birth can also help in improving the quality of life of the child. The deficient iodine condition is managed by administration of levothyroxine in dosage range of 10-15 mcg/kg/day. Generally, the prognosis of infants starting treatment early in life have a better neurocognitive outcome as compared to the treated infants late age at a later age. Avoidance of agents causing iodine exposure has resulted in decrease in the abnormal thyroid function levels.

Background: Systemic-to pulmonary collaterals (SPC) are common in congenital heart disease (CHD). Particularly in single ventricle anatomy and Fontan circulation, SPC can both complicate the postoperative course and lead to clinical deterioration in the long term. Treatment of SPC is controversial. The aim of our study was (1) to analyze retrospectively patients who underwent SPC embolization using Concerto™ Helix nylon-fibred microcoils (CHM) and (2) to describe the interventional technique. Methods: In this a single-center retrospective observational cohort study, we analyzed clinical and imaging data of all patients who underwent transcatheter embolization of SPC using CHM from January 2016 to December 2023. Results: In 38 consecutive patients (65.8 % male, median age 41 months, range 2 – 490), a total number of 141 CHM had been implanted into 64 SPC in 49 procedures. The majority were arterial SPC (n = 59/64) originating from the thoracic aorta or its branches; 5/64 were veno-venous SPC. Primary closure succeeded in all procedures. The CHM diameters ranged from 3 to 8 mm, with 5 mm being the most commonly used diameter. The mean coil / SPC ratio was 2.6 (range 1.3 – 5.3). CHM implantation was performed via 4 French sheaths. Both detachment and stable positioning was simple and safe. Neither non-target embolization nor coil migration occurred. One complication occurred with a minor vascular injury without clinical relevance. Conclusion: CHM are easy to use and appropriate for SPC embolization in all age groups, including infants, with a low complication rate. The coils are particularly suitable for closure of collaterals with small diameter or tortuous course.

Rubella infection is typically mild or asymptomatic except when infection occurs during pregnancy. Infection in early pregnancy can cause miscarriage, stillbirth, or congenital rubella syndrome. Only individuals that are still susceptible to rubella infection during child-bearing age are vulnerable to this burden. Rubella containing vaccine (RCV) is safe and effective, providing life-long immunity. However, average age-at-infection increases with increasing vaccination coverage, which could potentially lead to increased disease burden as well, if the absolute risk of infection during child-bearing age increases. Dynamics of rubella transmission were explored using EMOD, a software tool for building stochastic, agent-based infection models. Simulations of pre-vaccine, endemic transmission of rubella virus introduced RCV at varying levels of coverage to determine the expected future trajectories of disease burden. Introducing RCV reduces both rubella virus transmission and disease burden for a period of around 15 years. Increased disease burden is only possible more than a decade post-introduction, and only for contexts with low current burden and high transmission intensity. Low or declining rubella virus transmission intensity is concurrently associated with both greater disease burden and greater vaccine effectiveness. The risk of increasing burden through vaccination only exists for locations with persistently high infectivity, high connectivity, and high fertility. A trade-off between the risk of a small, future burden increase and a large, immediate burden decrease strongly favors RCV introduction.

Bicuspid Aortic valve Stenosis (BCAS) with an incidence of 3% of the world's population constitutes the most frequent Congenital Heart Disease whereas all other subtypes collectively constitute 1% of all life births. Most and the extreme severity spectrum of valvular Aortic Stenosis (VAS) in adulthood are cases of congenital bicuspid aortic valve. It seems that the congenital occurrence of the bicuspid aortic valve is a major prerequisite of the pathological calcifications and fibrosis seen in adults. Those progressive changes can't be explained by sole hemodynamic destructive forces but other factors inherent to the bicuspid valve tissue are also contributing. Therapeutic options of (VAS) are relatively stagnant and have been limited to invasive and surgical options. Prudent observation of the risk factors of some CHDs including BCAS was the epigenetic effect of planetary electromagnetic field on the delicate process of endothelial mesenchymal transformation (EndoMT). The incidence of BCAS is progressively increasing as we depart north from the equator to the north pole. A deeper understanding of the cellular and molecular mechanisms underlying EndoMT in congenital as well as acquired heart diseases is expected to open a new era in reversing heart disease in the human species. The potential to manipulate EndoMT and its signaling pathways or to reverse it with external electromagnetic power is an exciting therapeutic option for a wide array of congenital and acquired heart diseases including bicuspid aortic stenosis (BCAS) in the human species.

21-hydroxylase deficiency (21OHD), the most common form of congenital adrenal hyperplasia (CAH), is associated with pathogenic variants in CYP21A2 gene. The clinical form of the disease ranges from classic or severe to non-classic (NC) or mild late onset. The CYP21A2 gene is located on the long arm of chromosome 6, within the RCCX region, one of the most complex loci in the human genome. The 3’untranslated sequence of CYP21A2 exon 10 overlap the last exon of TNXB gene (these genes lie on the opposite strands of DNA and have the opposite transcriptional direction) that encodes an extracellular matrix glycoprotein tenascin-X (TNX). A recombination event between TNXB and its pseudogene TNXA causes a 30-kb deletion producing a chimeric TNXA/TNXB gene (CAH-X chimera) where both CYP21A2 and TNXB genes are impaired. This genetic condition characterizes a subset of patients with 21OHD who display the hypermobility phenotype of Ehlers Danlos Syndrome (hEDS) (CAH-X Syndrome). The aim of this study was to assess the prevalence of CAH-X syndrome in an Italian cohort of patients with 21OHD. At this purpose, 196 probands were recruited. Multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing were used to identify the CAH-X genotype. Twenty-one individuals showed the heterozygous continuous deletion involving the CYP21A2 and part of the TNXB gene. EDS-related clinical manifestations were identified in most patients carrying the CAH-X chimera. A CAH-X prevalence of 10.7% was estimated in our population.

Diagnosing congenital heart disease (CHD) remains challenging because of its complex morphology. Representing the intricate structures of CHD on conventional two-dimensional flat screens is difficult owing to wide variations in the pathologies. Technological advancements, such as three-dimensional printed heart models (3DPHM) and virtual reality (VR), could potentially address the limitations of viewing complex structures using conventional methods. This study aimed to investigate the usefulness and clinical value of four visualization modalities across three different cases of CHD, including ventricular septal defect, double outlet right ventricle, and tetralogy of fallot. Seventeen cardiac specialists were invited to participate in this study, which was aimed at assessing the usefulness and clinical value of four visualization modalities, namely, DICOM images, 3DPHM, VR, and 3D PDF. Of these modalities, 76.4% of the specialists ranked VR as the best for understanding the spatial associations among cardiac structures and for presurgical planning. Meanwhile, 94.1% ranked 3DPHM as the best modality for communicating with patients and their families. Of the various visualization modalities, VR was the best tool for assessing anatomical locations and vessels, comprehending the spatial relationships among cardiac structures, and for presurgical planning. The 3DPHM models were the best tool for medical education as well as communication. In summary, both 3DPHM and VR have their own advantages and outperform the other two modalities, i.e., DICOM images and 3D PDF, in terms of visualizing and managing CHD.

CYP1B1 loss-of-function (LoF) is the main known genetic alteration present in recessive primary congenital glaucoma (PCG), an infrequent disease characterized by delayed embryonic development of the ocular iridocorneal angle and caused by poorly understood molecular mechanisms. To model CYP1B1 LoF underlying PCG, we developed a cyp1b1 knockout (KO) zebrafish line using CRISPR/Cas9 genome editing. This line carries the c.535_667del frameshift mutation that results in a 72% mRNA reduction with residual mRNA predicted to produce an inactive truncated protein (p.(His179Glyfs*6)). Craniofacial defects and jaw maldevelopment were observed in 23% of somatic mosaic F0 crispant larvae (144 hpf). These early phenotypes were not detected in KO F3 larvae (144 hpf) but 27% of adult fishes (4 months) showed uni or bilateral craniofacial alterations, indicating the existence of incomplete penetrance and variable expressivity. These phenotypes increased to 86% in the adult offspring of inbred progenitors with craniofacial defects. No glaucoma-related phenotypes were observed in the cyp1b1 mutants. Transcriptomic analyses of the offspring (7dpf) of KO cyp1b1 progenitors with adult-onset craniofacial defects revealed that differentially expressed genes were functionally enriched in groups related with extracellular matrix and cell adhesion, cell growth and proliferation, lipid metabolism (retinoids, steroids, and fatty acids, and oxidation-reduction processes which included several cytochrome P450 genes) and inflammation. In summary, this study shows the complexity of phenotypes and molecular pathways associated with cyp1b1 LoF, with species-dependency, and provides evidence for dysregulation of extracellular matrix gene expression as one of the mechanisms underlaying pathogenicity associated with cyp1b1 disruption.

Standardized protocols were specifically designed and developed for clinical information collection and obtaining trio genomic information from infants affected with congenital anomalies (CA) and their parents, as well as securing human biological resources. Two large areas of these protocols include clinical and genomic information collection on CA which were difficult to diagnose using pre-existing screening methods. The following are three essential items for the clinical information collection protocol: establishment of a consent system for collecting and utilizing research resources, establishment of criteria for target patient selection, and collection of clinical and epidemiological information. A total of 138 cases consisting of 45 families of infants with CA and their parent trios have provided human-derived resources and genomic information. Whole genome sequencing data have been generated for all participants, and standardized protocols for resource collection and manufacturing have been developed. Phenotype information according to the Human Phenotype Ontology term and major test findings were recorded. It is important to keep updating and recording clinical symptoms and genetic diagnosis that are newly added or changed over time. The unique significance of this study is to develop a protocol that enables long-term tracking by adding growth and development tests that reflect important characteristics of newborns. By using these clinical and genetic information collection protocols for CA, it will be possible to establish an essential platform for early genetic diagnosis and diagnostic research, and further present new genetic diagnostic guidelines in the near future.

Breakthroughs in surgical and medical techniques have significantly improved outcomes for children with congenital heart disease (CHD), but research continues to address the ongoing challenge of organ dysfunction after surgery. Our study explored circular RNAs (circRNAs) within plasma-derived extracellular vesicles (EVs) in children undergoing CHD surgery. Post-surgery EV circRNAs showed dramatic expression changes between organ dysfunction (OD) and control groups. Tissue injury-related pathways were consistent across pre- and post-surgery in OD. The top two significant predicted tissue sources of these circRNAs originated from the respiratory system, aligning with the major organ dysfunction type (respiratory failure). Five of these circRNAs, namely circ-CELSR1, circ-PLXNA1, circ-OBSL1, circ-DAB2IP, circ-KANK1, significantly correlated between PELOD (Pediatric Logistic Organ Dysfunction), supporting the potential of circRNAs as prognostic markers. These findings pave the way for EV circRNAs as promising tools for managing post-surgical organ dysfunction and potentially guiding therapeutic strategies in children with CHD.

Syndactyly is the most common congenital malformation of the hand, leading to the fusion of the digits, frequently affecting the ring and middle fingers. The incidence is one out of 2500 children, predominantly occurring in boys and Caucasians. Clinically, the malformation may present as soft tissue or bony fusion, resulting in the union of the fingers characterised as complete or incomplete. This fusion may involve the phalanges but may also extend to the carpal/tarsal bones, even to the metacarpal’s or metatarsal’s level, rarely to the distal end of the forearm and lower leg. Mostly isolated but may occur together with other disorders or malformations such as synostosis, acro-syndactyly, cleft hand, clinodactyly, or polydactyly. Syndromic syndactyly can be observed in cases of Apert Syndrome, Poland’s Syndrome, Pfeiffer Syndrome and many others. A girl born in June of 2019 was diagnosed with congenital malformation of the right hand at birth —affecting the right middle, ring and little fingers, respectively. After X-ray imaging, the fusion of the third and fourth proximal phalanges to a common metacarpal was identified, forming a unique diagnosis of clino-syndactyly with metacarpal aplasia. Surgical intervention was advocated for, including a wedge osteotomy to correct the synchondrosis at the phalangeal base and a dorsal flap to close the interdigital space created during the correction of the III and IV. fingers. A trapezoid flap for the release of the syndactyly of the IV and V. fingers was applied. The paper aims to present the surgical correction and its results regarding an atypical case of syndactyly with clinodactyly and metacarpal aplasia.

Viruses are the most common congenital infections and an important cause of fetal malformations, morbidity, and mortality. The effects of these infections, which are transmitted in-utero (transplacentally), during childbirth or in the puerperium depend on the timing of the infections. These vary from miscarriages (usually with infections in very early pregnancy), congenital malformations (where the infections occur during organogenesis) and morbidity (with infections occurring late in pregnancy, during childbirth or after delivery). The most common of these viruses are cytomegalovirus, hepatitis, parvovirus B-19, rubella, varicella and zika. There are currently very few efficacious antiviral agents licensed for use in pregnancy and therefore for most of these infections, prevention by means of immunisation (where there is a vaccine), administration of immunoglobulins to those exposed to the virus to offer passive immunity or appropriate measures to avoid being infected would be options to minimise the infections and their consequences. In this review, we discuss the current understanding of some of the congenital infections and their consequences on both the mother and fetus and their management focusing mainly on prevention.

Background: Lower limb length discrepancy (LLD) in children and adolescents, often due to congenital or acquired conditions, is treated to achieve limb equality and alignment, optimizing function and minimizing cosmetic concerns for an active adulthood. This study evaluated the Health-Related Quality of Life (HRQoL) and physical functioning of adults who underwent unilateral limb lengthening with circular external fixators (EFs) in childhood. Methods: Fifty patients treated at a median age of 14.9 years completed the Short Form 36 (SF-36) and Stanmore Limb Reconstruction Score (SLRS) questionnaires in adulthood, with a median follow-up of 8.9 years. Results: Among the 50 patients, 38 underwent a single limb lengthening (21 tibia, 12 femur, 5 both), while 12 required multiple cycles. The median residual LLD was 0.4 cm, with 12 patients (24%) having over 2 cm. Complications occurred in 67% of procedures, mainly due to prolonged healing. Physical and mental health scores were significantly lower than normative data. The mean Physical Component Summary was 52.2 ± 7.2 (p = 0.20). The mean Mental Component Summary was 43.9 ± 8.6 (p = 0.001), notably lower in congenital LLD cases. Many SLRS items (Pain, Social, Physical Function, Work, and Emotions) strongly correlated with SF-36 items. Conclusions: The study highlights the challenges in treating LLD, emphasizing the significant mental health impact, especially in congenital cases, and the necessity for comprehensive long-term care strategies. These findings suggest that future therapeutic strategies should focus on both physical and psychological outcomes to improve overall recovery in LLD treatment.

Primary congenital glaucoma (PCG) is a heterogeneous, inherited, and severe optical neuropathy caused by apoptotic degeneration of the retinal ganglion cell layer. Whole-exome sequencing analysis of one PCG family identified two affected siblings who carried a low-frequency homozygous nonsense GUCA1C variant (c.52G>T/p.Glu18Ter/rs143174402). This gene encodes GCAP3, a member of the guanylate cyclase activating protein family, involved in phototransduction and with a potential role in intraocular pressure regulation. Segregation analysis supported the notion that the variant was coinherited with the disease in an autosomal recessive fashion. GCAP3 was detected immunohistochemically in the adult human ocular ciliary epithelium and retina. To evaluate the ocular effect of GUCA1C loss-of-function, a guca1c knockout zebrafish line was generated by CRISPR/Cas9 genome editing. Immunohistochemistry demonstrated the presence of GCAP3 in the non-pigmented ciliary epithelium and retina of adult wild-type fishes. Knockout animals presented up-regulation of the glial fibrillary acidic protein in Müller cells and evidence of retinal ganglion cell apoptosis, indicating the existence of gliosis and glaucoma-like retinal damage. In summary, our data provide evidence for the role of GUCA1C as a candidate gene in PCG and offer new insights into the function of this gene in the ocular anterior segment and the retina.

Deficiency of Cytochrome P450 Steroid 21-hydroxylase (CYP21A2) represents 90% of cases in congenital adrenal hyperplasia (CAH), an autosomal recessive disease caused by defects in cortisol biosynthesis. Computational prediction along with functional studies are often the only way to classify variants to understand the links to disease-causing effects. Here we investigated the pathogenicity of uncharacterized variants in the CYP21A2 gene reported in the Brazilian and Portuguese populations. Physicochemical alterations, residue conservation, and effect on protein structure were accessed by computational analysis. The enzymatic performance was obtained by functional assay with the wild-type and mutant CYP21A2 proteins expressed in HEK293 cells. Computational analysis showed that p.W202R, p.E352V, and p.R484L have severely impaired the protein structure, while p.P35L, p.L199P, and p.P433L have moderate effects. The p.W202R, p.E352V, p.P433L, and p.R484L variants showed residual 21OH activity consistent with the simple virilizing phenotype. The p.P35L and p.L199P variants showed partial 21OH efficiency associated with the non-classical phenotype. Additionally, p.W202R, p.E352V and p.R484L also modified the protein expression level. We have determined how the selected CYP21A2 gene mutations affect the 21OH activity through structural and activity alteration contributing to the future diagnosis and management of 21OH deficiency.

Zika virus (ZIKV) is a flavivirus that originated in Africa but emerged in Latin America in 2015. In this region, other flaviviruses such as Dengue (DENV), West Nile, and Yellow Fever Virus (YFV) also circulate, allowing for possible antigenic cross-reactivity to impact viral infections and immune responses. Studies have found antibody mediated enhancement between DENV and ZIKV, but the impact of YFV antibodies on ZIKV infection has not been fully explored. ZIKV infections cause congenital syndromes, such as microcephaly, necessitating further research into ZIKV vertical transmission through the placental barrier. Recent advancements in biomedical engineering have generated co-culture methods that allow for in vitro recapitulation of the maternal: fetal interface. This study utilized a transwell assay, which is a co-culture model utilizing human placental syncytiotrophoblasts, fetal umbilical cells, and a differentiating embryoid body to replicate the maternal: fetal axis. To determine if cross reactive YFV vaccine antibodies impact the pathogenesis of ZIKV across the maternal fetal axis, maternal syncytiotrophoblasts were inoculated with ZIKV or ZIKV incubated with YFV vaccine anti-sera, and viral load was measured 72 hours post inoculation. The data show that the impact of YFV on ZIKV replication is cell line dependent. In differentiating embryoids, the presence of YFV antibodies enhanced ZIKV infection. Since viral pathogenesis, and the impact of antigenic cross-reactive antibodies, is cell line specific at the maternal-fetal axis, this suggests there may be discreet mechanisms that impact congenital ZIKV infections.

Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is an exceedingly rare genetic disorder characterized by the inability to perceive pain, inability to sweat, and various neurological and orthopedic complications. This is a case report of a 3-year-old female patient diagnosed with CIPA syndrome who presented repeatedly to Children’s Clinical University Hospital (CCUH) in Riga, Latvia with severe orthopedic manifestations. The patient had repeated fractures, several surgeries, and extensive spread of the disease throughout the left leg, which caused significant functional impairment and decreased quality of life. Despite aggressive orthopedic interventions including surgical interventions and physical therapy, the patient's condition remained challenging to manage due to the inherent limitations posed by the insensitivity to pain. The council of doctors discussed the patient's condition and changes, deciding that reconstructive surgery is not feasible, and amputation is recommended. Through this case report, we aim to highlight the unique orthopedic challenges encountered in the management of CIPA patients, emphasizing the importance of a multidisciplinary approach involving orthopedic surgeons, pediatricians, geneticists, and physiotherapists. Additionally, we discuss the need for further research to elucidate optimal management strategies and improve outcomes in this rare and complex patient population.

The purpose of this qualitative study was to describe parent perceptions of the home exercise pro-gram (HEP) for their infant with congenital muscular torticollis (CMT), and how these perceptions evolved over a physical therapy (PT) plan of care. Twelve participants were recruited from a pediatric PT clinic, and nine completed interviews at three time points. Qualitative description and an iterative approach for thematic analysis of 27 interviews yielded three themes that corresponded to the research questions. The participants’ responses were categorized into three main themes: 1) parents’ perceptions of three key exercises within the HEP; 2) internal and external sources of stress; and 3) sources of empowerment and disempowerment. Regarding the HEP, parents articulated common sentiments for three frequently prescribed exercises for the management of CMT: 1) Tummy time was the fast favorite, 2) ipsilateral cervical rotation was perceived as stressful, and 3) contralateral cervical lateral flexion felt uncomfortable. Additionally, participants disclosed internal and external sources of stress (guilt, uncertainty, and the demands of returning to work) and sources of disempowerment (inconsistent messaging from providers, feeling overwhelmed) and empowerment (being able to see the bigger picture and clear communication and education about the diagnosis) with respect to managing their infant’s CMT. These themes provide insight into the evolution of parent perceptions over a PT plan of care for CMT. Participants’ insights suggest a need for consistent messaging regarding the diagnosis and evidence-based management of CMT, addressing parent stress, and modifying how exercises are taught. This study contributes updated research on parents’ experience with physical therapy and the HEP for their infant’s CMT.

The cytosolic PNGase (peptide:N-glycanase; Png1 in yeast; NGLY1/Ngly1 in human/mice), also known as peptide-N4-(N-acetyl-beta-glucosaminyl)-asparagine ami-dase, is a well-conserved deglycosylation enzyme (EC 3.5.1.52) which catalyzes the non-lysosomal hydrolysis of an N(4)-(acetyl-β-D-glucosaminyl) asparagine residue into N-acetyl-β-D-glucosaminylamine and a peptide containing an aspartate residue. This enzyme (NGLY1) plays essential roles in clearance of misfolded or unassembled gly-coproteins through a process named ER-associated degradation (ERAD). Accumulating evidence also points out that NGLY1 deficiency can cause an autosomal recessive hu-man genetic disorder associated with abnormal development and congenital disorder of deglycosylation. In addition, the loss of NGLY1 can affect multiple cellular pathways, including but not limited to NFE2L1 pathway, Creb1/Atf1-AQP pathway, BMP path-way, AMPK pathway, and SLC12A2 ion transporter, which might be the underlying reasons for a constellation of clinical phenotypes of NGLY1 deficiency. The current comprehensive review indeed uncovers the detailed NGLY1’s structure and its im-portant roles for participation in ERAD, involvement in CDDG and potential treatment for NGLY1 deficiency.

Advancements in genomics, bioinformatics and genome editing have uncovered new dimensions in gene regulation. Post-transcriptional modifications by the alternative splicing of mRNA transcripts are critical regulatory mechanisms of mammalian gene expression. In the heart, there is an expanding interest in elucidating the role of alternative splicing in transcriptome regulation. Substantial efforts have been directed towards investigating this process in heart development and failure. However, few studies have shed light on alternative splicing products and their dysregulation in congenital heart defects (CHDs). While elegant reports have shown the crucial roles of RNA binding proteins (RBPs) in orchestrating splicing transitions during heart development and failure, the impact of RBPs dysregulation or genetic variation on CHDs has not been fully addressed. Herein, we review the current understanding of alternative splicing and RBPs’ roles in heart development and CHDs and discuss the impacts of perinatal splicing transition and its dysregulation in CHDs. We further summarize discoveries made of causal splicing variants in key transcription factors that have been implicated in CHDs. Improved understanding of the roles of alternative splicing in heart development and CHDs may potentially inform novel preventive and therapeutic advancements for newborn infants with CHDs.

Background: This study presents the experience gained in the Newborn Intensive Care Unit (NICU) at “M. S. Curie” Emergency Clinical Hospital for Children in Bucharest after performing a series of bedside surgery interventions on newborns with congenital diaphragmatic hernia (CDH). We evaluate the advantages, complications, immediate and long-term outcome as well as the morbidity. Methods: We conducted a retrospective analysis of the data for all patients operated on-site be-tween 2011 and 2020, in terms of pre- and post-operative stability, procedures performed, com-plications and outcomes. Results: Our study is based on data from ten cases of newborns, term or small for gestation age with birthweights ranging from 2300 to 3300 grams, operated, on average, on the fifth day of life. The main reasons for operating on-site were the hemodynamical instability and the need to ad-minister inhaled Nitic Oxide (iNO) and HFOV ventilation. There were no unforeseen events dur-ing surgery, no immediate postoperative complications and no surgery related mortality. One noticed drawback was the unfamiliarity of the surgery team with the new operating environment. Conclusions: Our experience indicates that bedside surgery improves the likelihood of survival for critically ill neonates suffering from CDH. No immediate complications could be associated with this practice. Keywords: congenital diaphragmatic hernia, severe pulmonary hypertension, bedside surgery, NICU infrastructure

Background: We aimed to investigate the effectiveness of postnatal ultrasonography in determining congenital anomalies of the kidney and urinary tract in term infants with or without a history of congenital anomalies of the kidney and urinary tract in the prenatal period. Methods: In this retrospective cohort study, the records of term infants aged between six weeks and three months undergoing urinary system ultrasonography during routine child care were examined. Results: Congenital anomalies of the kidney and urinary tract was determined in 121 (4.62%) of the 2620 cases included in the study. The most common anomaly was hydronephrosis (in 69.4% of the congenital anomalies of the kidney and urinary tract cases and 3.21% of all cases). Thirty-two of the 84 (38.1%) hydronephrosis cases detected by postnatal ultrasonography, three of the nine (33.3%) renal agenesis cases, four of the seven (57.1%) horseshoe kidneys cases, one of the four (25%) multicystic dysplastic kidney cases and two of the two (100%) duplex system cases could not be detected by prenatal ultrasonography. On the other hand, hydronephrosis was not detected at postnatal ultrasonography in 29 (1.1%) cases which detected mild or moderate hydronephrosis by prenatal ultrasonography scanning. Conclusions: In our study, it was observed that approximately one-third of the cases of hydronephrosis, unilateral renal agenesis, duplex system, horseshoe kidney, and ectopic kidney could not be detected at prenatal ultrasonography screening. We therefore believe that, in addition to prenatal ultrasonography screening, postnatal ultrasonography screening of all children for urinary tract anomalies would be beneficial.

Cytochrome P450 oxidoreductase (POR) is the redox partner of steroid and drug-metabolizing cytochromes P450 located in the endoplasmic reticulum. Mutations in POR cause a broad range of metabolic disorders. The POR variant rs17853284 (P228L) identified by genome sequencing has been linked to lower testosterone levels and reduced P450 activities. We expressed POR wild type and the P228L variant in bacteria, purified the proteins, and performed protein stability and catalytic functional studies. Variant P228L affected the stability of the protein as evidenced by lower unfolding temperatures and higher sensitivity to urea denaturation. A significant reduction of small molecule metabolism was observed with POR P228L while activities of CYP3A4 were reduced by 25%, and activities of CYP3A5, and CYP2C9 were reduced by more than 40% compared to WT POR. The 17,20 lyase activity of CYP17A1 responsible for production of main androgen precursor dehydroepiandrosterone, was reduced to 27% of WT in presence of P228L variant of POR. Based on in silico and in vitro studies we predict that the change of proline to leucine may change the rigidity of the protein, causing conformational changes in POR, leading to altered electron transfer to redox partners. A single amino acid change can affect protein stability and cause a severe reduction in POR activity. Molecular characterization of individual POR mutations is crucial for a better understanding of the impact on different redox partners of POR.

Prenatal diagnosis of clubfoot traditionally relied on two-dimensional ultrasonography. To enhance diagnosis and predict postnatal outcomes, we examined the parameters that differentiate pathological clubfoot using three-dimensional ultrasonography. In our retrospective study, we examined the findings of prenatal ultrasound and the postnatal outcomes of pregnancies with suspected congenital clubfoot between 2018 and 2021. Based on the three-dimensional perspective, we measured the angles of varus, equinus, calcaneopedal block and forefoot adduction and compared the sonographic variables between the postnatal treated and non-treated groups. We evaluated 31 pregnancies (47 feet) with suspected clubfoot using three-dimensional ultrasonography. After delivery, a total of 37 feet (78.7%) underwent treatment involving serial casting only or additional Achilles tenotomy. The treated group showed significantly greater hindfoot varus deviation (60.5° vs. 46.6°, p=0.026) and calcaneopedal block deviation (65.6° vs. 26.6°, p &lt;0.05) compared to the non-treated group. The calcaneopedal block had an area under the curve of 0.98 with a diagnostic threshold of 46.2 degrees (sensitivity of 97%, specificity of 90%, positive predictive value of 97%, and negative predictive value of 90%). During prenatal evaluation of clubfoot using three-dimensional ultrasonography, the calcaneopedal block deviation has the potential to predict postnatal treatment.

The implications of the adult congenital heart disease anatomic and physiological classification (AP-ACHD) for risk assessment have not been adequately studied. A retrospective cohort study was conducted using data from an ongoing national, multicentre registry of patients with ACHD and atrial arrhythmias (AA) receiving apixaban (PROTECT-AR study, NCT03854149). At enrollment, patients were stratified according to Anatomic class (AnatC, range I to III) and physiological stage (PhyS, range B to D). Follow-up was conducted between May 2019 and September 2021. The primary outcome was a composite of death from any cause, any major thromboembolic event, major or clinically relevant non-major bleeding, or hospitalization. Cox proportional-hazards regression modeling was used to evaluate the risks for the outcome among AP-ACHD classes. Over a median 20-month follow-up period, 47 of 157 (29.9%) ACHD patients with AA experienced the composite outcome. Adjusted hazard ratios (aHR) with 95% confidence intervals [CI] for the outcome in PhyS C and PhyS D were 1.84 (95% CI 0.73 to 4.61) and 7.88 (95% CI 1.54 to 40.41) respectively, as compared with PhyS B. The corresponding aHRs in AnatC II and AnatC III were 1.10 (95% CI 0.39 to 3.06) and 0.99 (95% CI 0.24 to 4.10) respectively, as compared with AnatC I. In conclusion, the PhyS component of the AP-ACHD classification was an independent predictor of net adverse clinical events among ACHD patients with AA receiving apixaban.

Brachycephalic dogs are not only affected by brachycephalic obstructive airway syndrome (BOAS), but also comprise up to 30% of canine patients seen by veterinary dermatologists, with English Bulldogs and Pugs particularly overrepresented. Some skin diseases are associated with the abnormal anatomic conformation of brachycephalic dogs, while for others there is a underlying genetic basis or a general predisposition. Anatomic alterations associated with brachycephaly, leading to fold formation of the skin and stenosis of the ear canal, together with primary immunodeficiencies described in some breeds, favor the development of pyoderma, Malassezia dermatitis and otitis externa/media. Frequently neglected but often lifelong dermatological problems of brachycephalic dogs are an important consideration when discussing genetic and medical conditions affecting the welfare of those dogs. Here we review the current state of knowledge concerning dermatological problems of brachycephalic dogs, and combine it with clinical experience in the management of these challenging disorders.

Congenital heart disease (CHD) is among the 4 more common causes of infant mortality in Latin America. Pulse oximetry screening (POS) is useful for early diagnosis and improved outcomes of critical CHD. We describe POS implementation efforts in Latin American countries guided and/or coordinated by the Ibero American Society of Neonatology (SIBEN) as well as the unique challenges that are faced for universal implementation. SIBEN collaborates to improve neonatal quality of care and outcomes. A few years ago, a Clinical Consensus on POS was finalized. Since then, we participated in 12 Latin American countries to educate neonatal nurses and neonatologists on POS and to help with its implementation. The findings reveal that despite wide disparities in care that exist between and within countries, and the difficulties and challenges for implementing POS, significant progress was made. We conclude that universal POS is not easy to implement in Latin America but, when executed, not only it has been of significant value for babies with CHD but also for many with other hypoxemic conditions. The successful and universal implementation of POS in the future is essential to reduce the mortality associated with CHD and other hypoxemic conditions and will ultimately lead to the survival of many more Latin American babies. POS saves newborns’ lives in Latin America.

We identified a novel heterozygous hypofibrinogenemia, γY278H (Hiroshima). To demonstrate the cause of reduced plasma fibrinogen levels (functional level: 1.12 g/L and antigenic level: 1.16 g/L), we established γY278H fibrinogen-producing Chinese hamster ovary (CHO) cells. An enzyme-linked immunosorbent assay demonstrated that synthesis of γY278H fibrinogen inside CHO cells and secretion into the culture media were not reduced. Then, we established an additional five variant fibrinogen-producing CHO cell lines (γL276P, γT277P, γT277R, γA279D, and γY280C) and performed further investigations. We have already established 33 γ-module variant fibrinogen-producing CHO cell lines including 6 cell lines in this study, but only the γY278H and γT277R cell lines showed disagreement, namely recombinant fibrinogen production was not reduced but the patients’ plasma fibrinogen level was reduced. Finally, we performed fibrinogen degradation assays and demonstrated that the γY278H and γT277R fibrinogens were easily cleaved by plasmin whereas their polymerization in the presence of Ca2+ and “D:D” interaction was normal. In conclusion, our investigation suggested that patient γY278H showed hypofibrinogenemia because γY278H fibrinogen is secreted normally from the patient’s hepatocytes but had accelerated degradation by plasmin in the circulation.

BACKGROUNDː The so-called Low Cardiac Output Syndrome (LCOS) is one of the most common complications in pediatric patients with congenital heart disease undergoing corrective surgery. LCOS requires high concentrations of inotropes to support cardiac contractility and improve cardiac output, allowing for a better systemic perfusion. To date, serum lactate concentrations and central venous oxygen saturation (ScVO2) are the most commonly used perfusion markers, but they are not completely reliable to identify a state of global tissue hypoxia. The study aims to evaluate whether the venoarterial carbon dioxide difference/arterial-venous oxygen difference ratio [P(v-a)CO2/C(a-v)O2] can be a good index to predict the development of LCOS in the aforemen-tioned patients, so as to treat it promptly. METHODSː This study followed a population of 98 children undergoing corrective cardiac surgery from June 2018 to October 2020 at the Department of Cardiac Surgery of University Hospital Inte-grated Trust and their subsequent admission at the Postoperative Cardiothoracic Surgery Intensive Care Unit. During the study, central arterial and venous blood gas analysis were carried out before and after cardiopulmonary bypass (CPB) (pre-CPB and post-CPB), at admission to intensive care unit, before and after extubation and at any time of instability or modification of the patient’s clinical and therapeutic conditions. RESULTSː The data analysis shows that 46.9% of the children developed a LCOS (in line with the current literature) but that there is no statistically significant association between the P(v-a)CO2/C(a-v)O2 ratio and LCOS onset. Despite the limits of statistical significance, however, a 31% increase in the ratio emerged from the pre-CPB phase to the post-CPB phase when LCOS is present. CONCLUSIONSː This study confirms a statistically significant association between the most used markers in adult patients (serum lactate concentration, ScVO2 and oxygen extraction ratio-ERO2) measured in the pre-CPB phase and the incidence of LCOS onset, especially in patients with he-modynamic instability before surgery.

Introduction The Pericapsular Nerve Group (PENG) block is a novel technique that allows for analgesia of the anterior hip capsule via the articular branches of the accessory obturator nerve and femoral nerve, which have a significant role in the innervation of the hip capsule. PENG blockade is effective in both adult and pediatric patients. However, there are no studies in the available literature on patients under five years of age. Herein, we describe our experience with two pediatric patients with hip dysplasia. Purpose This study aimed to evaluate the analgesic effect of the pericapsular nerves group (PENG) in small children undergoing hip surgery. Patients and methods This study included two patients, aged 2 and 4 years old, who qualified for hip surgery. General or spinal anesthesia with the addition of a PENG block was performed. During the procedure, the basic hemodynamic parameters were monitored. After the surgery, the patients received 15mg/kg-1 iv paracetamol every 6 hours to prevent rebound pain. The pain was assessed using the FALCC score. The 15mg/kg-1 metamizole was administered if the FLACC score was 3. In the FLACC score 4, the application of 0,2mg/kg-1 Nalpain was ordered. Results The patient's hemodynamic parameters were stable and within normal range. FLACC scores from all patients ranged from 0 and 3 in the first 24 h period. One patient required metamizole 12 hours after surgery. No evidence of block complications was observed. Conclusions This case series showed that PENG block provided adequate postoperative analgesia and assured opioid-free pain management. However, we are convinced that future randomized, controlled trials are needed in this field.

The 22q11.2 deletion syndrome is a multisystemic disorder characterized by a marked variability of phenotypic features making the diagnosis challenging for clinicians. The wide spectrum of clinical manifestations includes congenital heart defects, most frequently conotruncal cardiac anomalies, thymic hypoplasia and predominating cellular immune deficiency, laryngeal developmental defects, midline anomalies with cleft palate and velar insufficiency, structural airway defects, facial dysmorphism, parathyroid and thyroid gland hormonal dysfunctions, speech delay, developmental delay, neurocognitive and psychiatric disorders. Significant progress has been made in understanding the complex molecular genetic etiology of the 22q11.2 deletion syndrome underpinning the heterogeneity of clinical manifestations. The deletion is caused by chromosomal rearrangements in meiosis and is mediated by non-allelic homologous recombination events between low copy repeats or segmental duplications in the 22q11.2 region. A range of genetic modifiers, environmental factors as well as the impact of hemizygosity on the remaining allele contribute to the intricate genotype-phenotype relationships. This comprehensive review has been aimed at highlighting the molecular genetic background of 22q11.2 deletion syndrome in correlation with a clinical multidisciplinary approach.

Turner syndrome (TS) is a chromosomal disorder that is caused by a missing or structurally ab-normal second sex chromosome. Subjects with TS are at an increased risk of developing intrauterine growth retardation, low birth weight, short stature, congenital heart diseases, infertility, obesity, dyslipidemia, hypertension, insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular diseases (stroke and myocardial infarction). The underlying pathogenetic mechanism of TS is unknown. The assumption that X chromosome-linked gene haploinsufficiency is associated with the TS phenotype is questioned since such genes have not been identified. Thus, other pathogenic mechanisms have been suggested to explain this phenotype. Morphogenesis encompasses a series of events that includes cell division, the production of migratory precursors and their progeny, differentiation, programmed cell death, and integration into organs and systems. The precise control of the growth and differentiation of cells is essential for normal development. The cell cycle frequency and the number of proliferating cells are essential in cell growth. 45,X cells have a failure to proliferate at a normal rate, leading to a decreased cell number in a given tissue during organogenesis. A convergence of data indicates an association between a prolonged cell cycle and the phenotypical features in Turner syndrome. This review aims to examine old and new findings concerning the relationship between a prolonged cell cycle and TS phenotype. These studies reveal a diversity of phenotypic features in TS that could be explained by reduced cell proliferation. The implications of this hypothesis for our understanding of the TS phenotype and its pathogenesis are discussed. It is not surprising that 45,X monosomy leads to cellular growth pathway dysregulation with profound deleterious effects on both embryonic and later stages of development. The prolonged cell cycle could represent the beginning of the pathogenesis of TS, leading to a series of phenotypic consequences in embryonic/fetal, neonatal, pediatric, adolescence, and adulthood life.

Zika virus (ZIKV) is a flavivirus that originated in Africa but emerged in Latin America in 2015. In this region, other flaviviruses such as Dengue (DENV), West Nile, and Yellow Fever Virus (YFV) also circulate, allowing for possible antigenic cross-reactivity to impact viral infections and immune responses. Studies have found antibody mediated enhancement between DENV and ZIKV, but the impact of YFV antibodies on ZIKV infection has not been fully explored. ZIKV infections cause congenital syndromes, such as microcephaly, necessitating further research into ZIKV vertical transmission through the placental barrier. Recent advancements in biomedical engineering have generated co-culture methods that allow for in vitro recapitulation of the maternal: fetal interface. This study utilized a transwell assay, which is a co-culture model utilizing human placental syncytiotrophoblasts, fetal umbilical cells, and a differentiating embryoid body to replicate the maternal: fetal axis. To determine if cross reactive YFV vaccine antibodies impact the pathogenesis of ZIKV across the maternal fetal axis, maternal syncytiotrophoblasts were inoculated with ZIKV or ZIKV incubated with YFV vaccine anti-sera, and viral load was measured 72 hours post inoculation. Here we report that BeWo and HUVEC cells are permissive to ZIKV and that the impact of YFV post-vaccination antibodies on ZIKV replication is cell line dependent. Embryoid bodies are also permissive to ZIKV and the presence of YFV antibodies collected 1 to 6 months post vaccination enhances ZIKV infection. Our data show that each of the cell lines and EBs have a unique response to ZIKV complexed with post-vaccination serum suggesting there may be cell-specific mechanisms that impact congenital ZIKV infections. Since ZIKV infections can cause severe congenital syndromes, it is crucial to understand any potential enhancement or protection offered from cross-reactive, post-vaccination antibodies.

Congenital Pouch Colon (CPC) is a rare anorectal anomaly common to North Western India specifically Rajasthan. Despite efforts to understand the clinical genetic makeup of CPC, no attempt on identifying non-coding RNAs was done. We have earlier reported CPC's rare variants from whole exome sequencing across 18 affected samples in a total of 64 subjects. A Smith-Waterman algorithm was used to infer a couple of lncRNAs from WES samples of CPC with predictions from the Noncode database. Further screening and quantification using PCR, we ascertained interactions using Micro Scale Thermophoresis (MST). We report the role of lnc-EPB41-1-1 shown to be promiscuously interacting with KIF13A substantiating their role in regulation.

Cost-effective and functionalized scaffolds are in high demand for stem-cell-based regenerative medicine to treat refractory bone defects in craniofacial abnormalities and injuries. One potential strategy is to utilize pharmacological and cost-effective plant polyphenols and biocompatible proteins, such as gelatin. Nevertheless, the use of chemically modified proteins with plant polyphenols in this strategy has not been standardized. Here, we demonstrated that gelatin chemically modified with epigallocatechin gallate (EGCG), the major catechin isolated from green tea, can be a useful material for dedifferentiated fat cells and adipose-derived stem cells and can induce bone regeneration in a rat congenial cleft-jaw model in vivo. Vacuum-heated gelatin sponge modified with EGCG (vhEGCG-GS) induced superior osteogenesis from these two cell types compared with vacuum-heated gelatin sponge (vhGS). The EGCG-modification converted the water wettability of vhGS to a hydrophilic property (contact angle: 110° to 3.8°) and the zeta potential to a negative surface charge; the modification enhanced the cell adhesion property and promoted calcium phosphate precipitation. These results suggest that the EGCG-modification with chemical synthesis can be a useful platform to modify the physicochemical property of gelatin. This alteration is likely to provide a preferable microenvironment for multipotent progenitor cells, inducing superior bone formation in vivo.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) affecting 1 in 5,000 newborns. We constructed the interactome of 74 HLHS-associated genes identified from a large-scale mouse mutagenesis screen, augmenting it with 408 novel protein-protein interactions (PPIs) using our High-precision Protein-Protein Interaction Prediction (HiPPIP) model. The interactome is available on a webserver with advanced search capabilities (http://severus.dbmi.pitt.edu/wiki-HLHS). 364 genes including 73 novel interactors were differentially regulated in tissues/iPSC-derived cardiomyocytes of HLHS patients. Novel PPIs facilitated the identification of TOR signaling and endoplasmic reticulum stress modules. 60.5% of the interactome consisted of housekeeping genes that may harbor large-effect mutations and drive HLHS etiology but show limited transmission. Network proximity of diabetes, Alzheimer’s disease, and liver carcinoma-associated genes to HLHS genes suggested a mechanistic basis for their comorbidity with HLHS. Interactome genes showed tissue-specificity for sites of extracardiac anomalies (placenta, liver and brain). The HLHS interactome shared significant overlaps with the interactomes of ciliopathy and microcephaly-associated genes, with the shared genes respectively enriched for genes involved in intellectual disability and/or developmental delay, and neuronal death pathways. This supported the increased burden of ciliopathy variants and prevalence of neurological abnormalities observed among HLHS patients with developmental delay and microcephaly respectively.

A patient in her early 20s presented with constant and progressive lower abdominal and back pain, mainly on the right side of the abdomen, purulent vaginal discharge and pyrexia. Radio-logical assessment revealed a possible tuboovarian abscess and incidental diagnosis of ipsilateral renal agenesis. The patient was treated for pelvic inflammatory disease (PID), however after antibiotic administration and since the symptoms were not resolving, an abdominal MRI was requested which revealed a uterus didelphys with two cervices, an obstructed haemivagina and evidence of haematocolpos. The diagnosis of OHVIRA syndrome was confirmed and the patient underwent an excision of the vaginal septum, drainage of the haematopyocolpos and laparoscopic drainage of the tuboovarian abscess. She achieved a good recovery.

Congenital Disorders of Glycosylation (CDG) are a heterogenous group of primarily autosomal recessive mendelian diseases caused by disruptions in the synthesis of lipid linked oligosaccha-rides and their transfer to proteins. CDGs affect multiple organ systems and vary in presentation, even within families. Here we describe a chemically induced mouse mutant, tvrm76, with early onset photoreceptor degeneration. The recessive mutation was mapped to Chromosome 9 and as-sociated with a missense mutation in the Dpagt1 gene encoding UDP-N-acetyl-D-glucosamine:dolichyl-phosphate N-acetyl-D-glucosaminephosphotransferase (EC 2.7.8.15). The mutation is predicted to cause a substitution of aspartic acid with glycine at residue 166 of DPAGT1. Increased expression of Ddit3, and elevated levels of HSPA5 (BiP) sug-gest the presence of early-onset endoplasmic reticulum (ER) stress. These changes were associated with induction of photoreceptor apoptosis in tvrm76 retinas. Mutations in human DPAGT1 cause Myasthenic Syndrome 13 and severe forms of Congenital Disorder of Glycosylation Type Ij. In contrast, Dpagt1tvrm76 homozygous mice present with congenital photoreceptor degeneration without overt muscle or muscular junction involvement. Our results suggest the possibility of DPAGT1 mutations in human patients that present primarily with retinitis pigmentosa with little or no muscle disease. Variants in DPAGT1 should be considered when evaluating cases of non-syndromic retinal degeneration.

Mutations in KRT1 (keratin 1) or KRT10 (keratin 10) underlie a spectrum of diseases known as keratinopathic ichthyoses. Epidermolytic ichthyosis (EI) is caused by heterozygous missense mutations in the genes KRT1 or KRT10, mutations in the gene KRT2 (keratin 2) lead to superficial epidermolytic ichthyosis, and congenital reticular ichthyosiform erythroderma is caused by frameshift mutations in the genes KRT10 or KRT1, which lead to the phenomenon of revertant mosaicism. Epidermolytic ichthyosis is also present in a mosaic pattern known as epidermolytic (acantholytic) nevus, isolated or diffuse. In the latter case, gonadic involvement is possible, leading to a rare pedigree in which a parent with diffuse epidermolytic nevus (linear EI) gives birth to a child affected by EI. We present here an update on the phenotypic presentations of keratinopathic ichthyoses and their molecular mechanisms.

Objective: In this pilot study, we described the gross motor development of infants aged 4 to 24 months with congenital heart disease (CHD) and assessed through a systematic develop­mental screening programme, with individualised motor interventions. Methods: Thirty infants who had cardiac repair underwent gross motor evaluations using the AIMS at 4 months, and the Bayley-III at 12 and 24 months. Results: Based on AIMS, 80% of 4-month-old infants had a delay in gross motor development and required physical therapy. Gross motor abilities significantly improved by 24 months. Infants who benefited from regular physiotherapy tended to show better improvement in motor scores. Conclusion: Our study highlights the importance of early motor screening in infants with CHD and suggests a potential benefit of early physical therapy in those at-risk. Further research is needed to assess the effectiveness of systematic developmental screening and individualized inter­vention programmes at identifying at risk patients, and their impact on developmental outcomes.

Congenital breast asymmetry represents a particular challenge to the classical techniques of plastic surgery due to a young group of patients. This study compares traditional breast augmentation using silicone implants to the more innovative lipograft technique regarding long-term results. To achieve this, we not only captured subjective parameters like satisfaction with outcome and symmetry, but also objective parameters such as breast volume and anthropometric measurements. Objective examination was performed manually and by using the Vectra® H2 photogrammetry scanning system. Patients who underwent implant augmentation and lipograft both showed no significant differences in patient´s satisfaction with surgical outcome (p = 0.55) and symmetry (p = 0.69). Furthermore, a breast symmetry of 93 % in both groups was reported. Likewise, no statistically significant volume difference between left and right breast was observed in both groups (p<0.41). However, on average, lipograft patients needed 1.3 procedures more until the desired result was achieved. In contrast, patients treated with implant-based breast augmentation usually need several implant changes during their life. In conclusion, both methods should be considered for patients with congenital breast asymmetry.

Background: developmental dysplasia of the hip (DDH) is a condition characterized by abnormal hip development in infancy. Early diagnosis allows for effective treatment, while late presentation often necessitates complex surgical interventions. Current recommendations advise screening between the 6th and 8th week postnatal using ultrasound, typically employing the Graf method. However, there's no universal consensus on whether ultrasound screening significantly increases treatment compared to clinical examination-guided ultrasound. This study aims to explore the feasibility of prenatal ultrasound for early identification of DDH risk. Methods: This prospective observational study involved 100 pregnant women undergoing fetal hip ultrasound during the second and third trimesters. Using the modified Graf method, alpha and beta angles were calculated on the fetus. Postnatally, alpha and beta angles were compared with prenatal values. Results: Prenatal ultrasound at 24th week showed inconclusive results because of the difficulty in identification of Graf landmarks, while ultrasound at 34th week has proved to be a reliable and safe method for quantitative determination of alpha and beta angles. Significant correlations were found between prenatal and postnatal alpha and beta angles. Moreover, significant differences in prenatal alpha and beta values were observed in patients developing mature/immature hips postnatally. Conclusions: Prenatal diagnostics show promise for predicting infant hip development. Further research is warranted to validate correlation strength and clinical applicability.

Mexico shows a high birth prevalence of congenital hypothyroidism (CH) due to thyroid dysgenesis (TD). PAX8 defects underlie only 1% of these cases and NKX2-1 does not seem to be involved. Here, we analyzed other TD-related genes in 128 non-related Mexican patients (females 77.3%; 6 months to 16.6 years) with non-syndromic CH-TD diagnosis established by clinical evaluation, thyroid hormone serum profiling, and scintigraphy (74%) or ultrasonography (26%). We performed Sanger sequencing of FOXE1, NKX2-5, and TSHR and evaluated copy number variations (CNVs) in TSHR, FOXE1, PAX8, and NKX2-1 by multiplex ligation-dependent probe amplification. Odds ratios for TD risk were explored for FOXE1 polyalanine stretches [polyAla-rs71369530] in cases and controls (N=116). Five rare missense changes cataloged as benign (NKX2-5:p.(Ala119Ser)-rs137852684), of unknown significance (FOXE1:p.(Ala335Gly)-rs543372757; TSHR:p.(Asp118Asn)-rs1414102266), and likely pathogenic (FOXE1:p.(Gly124Arg)-rs774035532; TSHR:p.(Trp422Arg)-rs746029360) accounted for 1.5% (N=2/128) of clinically relevant genotypes (supported in part by protein modeling) in CH-TD. No CNVs were identified, nor did polyAla &gt;14 alanines in FOXE1 significantly protect against TD. The present and previously published data collectively show that small clinically relevant germline variants in PAX8, FOXE1, and TSHR are found in only a very small proportion (2.5%) of isolated CH-TD Mexican patients.

We present here a case of complex uterine anomaly – Obstructed HemiVagina with Ipsilateral Renal Agenesis (OHVIRA), also known as Herlyn-Werner-Wunderlich syndrome in a 13-year-old girl with the history of recurrent urinary tract infections (rUTI). In emergency room, trans-abdominal sonography revealed ovarian cyst and renal agenesis, without any suspicion of vaginal obstruction. This led to delay in the diagnosis of this uncommon anomaly. Finally, MRI findings confirmed the presence of OHVIRA syndrome. As the congenital anomalies of kidney and urinary tract (CAKUT) are in almost one third of cases associated with genital malformations, urologist should carefully search for patients with rUTI. The patient underwent simultaneous laparoscopy and vaginoscopy, what was in our opinion the most appropriate therapeutic decision. In this article we are also going to discuss the role of laparoscopy in the management of OHVIRA syndrome as well as other surgical techniques described in the literature.

New insights into the causes and mechanisms of congenital heart disease (CHD) have been gained through the use of next-generation sequencing. Examination of the whole exome sequence detects detrimental gene variations modifying single or contiguous nucleotides, that are characterised as pathogenicity based on statistical assessments of families. and correlates with congenital heart disease, elevated expression during heart development, and reduction of harmful protein-coding mutations in the general population. Patients with CHD and extracardiac abnormalities enriched for gene classes meeting these criteria. CHDs and extracardiac defects, supporting a common set of pathways in the organogenesis of CHDs. Single-cell transcriptomics data reveal the expression of genes associated with CHD in specific cell lineages, and emerging evidence suggests that genetic variants disrupt multicellular genes essential for cardiogenesis. Metrics and units are being tracked in whole genome sequence studies.

INPP5K (Inositol Polyphosphate 5-Phosphatase K, or SKIP (for Skeletal muscle and Kidney enriched Inositol Phosphatase) is a member of the phosphoinositide 5-phosphatases family. Its protein structure is comprised of a N-terminal catalytic domain which hydrolyses both PtdIns(4,5)P2 and PtdIns(3,4,5)P3, followed by a SKICH domain at the C-terminus which is responsible for protein-protein interactions and subcellular localization of INPP5K. Strikingly, INPP5K is mostly concentrated in the endoplasmic reticulum, although it is also detected at the plasma membrane, in the cytosol and the nucleus. Recently, mutations in INPP5K have been detected in patients with a rare form of autosomal recessive congenital muscular dystrophy with cataract, short stature and intellectual disability. INPP5K functions extend from control of insulin signaling, endoplasmic reticulum stress response and structural integrity, myoblast differentiation, cytoskeleton organization, cell adhesion and migration, renal osmoregulation, to cancer. The goal of this review is thus to summarize and comment recent and less recent data in the literature on INPP5K, in particular on the structure, expression, intracellular localization, interactions and functions of this specific member of the 5-phosphatases family.