Simpson-Golabi-Behmel syndrome type 1 with normal birth parameters.

A newborn baby born at 34 weeks and 5 days gestation was admitted for prematurity, dysmorphic features and congenital heart defects. Antenatal scan at 21 weeks showed a large-for-gestational-age foetus with a large abdominal circumference and liver, ventricular septal defect, right prominent renal pelvis and echogenic bowel. Antenatal genetic tests for overgrowth syndromes were negative. The mother had early onset pre-eclampsia. After birth, an overgrowth syndrome was still suspected despite the baby having normal birth parameters. Raw data of the trio whole exome sequencing from the amniocentesis sample were manually inspected. Hemizygous exon 7 deletion in the GPC3 gene was found, and a postnatal diagnosis of Simpson-Golabi-Behmel syndrome, a rare overgrowth syndrome, was made. This case report discusses the significance of antenatal findings, an atypical presentation of a rare syndrome and the obstacles of diagnostic genetic testing.

PATHFINDER-CHD: prospective registry on adults with congenital heart disease, abnormal ventricular function, and/or heart failure as a foundation for establishing rehabilitative, prehabilitative, preventive, and health-promoting measures: rationale, aims, design and methods.

BACKGROUND: Adults with congenital heart defects (ACHD) globally constitute a notably medically underserved patient population. Despite therapeutic advancements, these individuals often confront substantial physical and psychosocial residua or sequelae, requiring specialized, integrative cardiological care throughout their lifespan. Heart failure (HF) is a critical challenge in this population, markedly impacting morbidity and mortality. AIMS: The primary aim of this study is to establish a comprehensive, prospective registry to enhance understanding and management of HF in ACHD. Named PATHFINDER-CHD, this registry aims to establish foundational data for treatment strategies as well as the development of rehabilitative, prehabilitative, preventive, and health-promoting interventions, ultimately aiming to mitigate the elevated morbidity and mortality rates associated with congenital heart defects (CHD). METHODS: This multicenter survey will be conducted across various German university facilities with expertise in ACHD. Data collection will encompass real-world treatment scenarios and clinical trajectories in ACHD with manifest HF or at risk for its development, including those undergoing medical or interventional cardiac therapies, cardiac surgery, inclusive of pacemaker or ICD implantation, resynchronization therapy, assist devices, and those on solid organ transplantation. DESIGN: The study adopts an observational, exploratory design, prospectively gathering data from participating centers, with a focus on patient management and outcomes. The study is non-confirmatory, aiming to accumulate a broad spectrum of data to inform future hypotheses and studies. PROCESSES: Regular follow-ups will be conducted, systematically collecting data during routine clinical visits or hospital admissions, encompassing alterations in therapy or CHD-related complications, with visit schedules tailored to individual clinical needs. ASSESSMENTS: Baseline assessments and regular follow-ups will entail comprehensive assessments of medical history, ongoing treatments, and outcomes, with a focus on HF symptoms, cardiac function, and overall health status. DISCUSSION OF THE DESIGN: The design of the PATHFINDER-CHD Registry is tailored to capture a wide range of data, prioritizing real-world HF management in ACHD. Its prospective nature facilitates longitudinal data acquisition, pivotal for comprehending for disease progression and treatment impacts. CONCLUSION: The PATHFINDER-CHD Registry is poised to offer valuable insights into HF management in ACHD, bridging current knowledge gaps, enhancing patient care, and shaping future research endeavors in this domain.

Fetal Hemodynamics, Early Survival, and Neurodevelopment in Patients With Cyanotic Congenital Heart Disease.

BACKGROUND: Fetuses with cyanotic congenital heart disease (CHD) exhibit profound fetal circulatory disturbances that may affect early outcomes. OBJECTIVES: This study sought to investigate the relationship between fetal hemodynamics and early survival and neurodevelopmental (ND) outcomes in patients with cyanotic CHD. METHODS: In this longitudinal observational study, fetuses with cyanotic CHD underwent late gestational fetal cardiovascular magnetic resonance (CMR) to measure vessel blood flow and oxygen content. Superior vena cava (SVC) flow was used as a proxy for cerebral blood flow. Primary outcomes were 18-month mortality and Bayley Scales of Infant Development-III assessment. RESULTS: A total of 144 fetuses with cyanotic CHD were assessed. By 18 months, 18 patients (12.5%) died. Early mortality was associated with reduced combined ventricular output (P = 0.01), descending aortic flow (P = 0.04), and umbilical vein flow (P = 0.03). Of the surviving patients, 71 had ND outcomes assessed. Cerebral oxygen delivery was the fetal hemodynamic variable most strongly associated with cognitive, language, and motor outcomes (P < 0.05). Fetal SVC flow was also associated with cognitive, language, and motor outcomes (P < 0.01), and it remained an independent predictor of cognitive (P = 0.002) and language (P = 0.04) outcomes after adjusting for diagnosis. Diminished SVC flow also performed better than other fetal CMR and echocardiographic predictors of cognitive ND delay (receiver-operating characteristic curve area: 0.85; SE 0.05). CONCLUSIONS: Among fetuses with cyanotic CHD, diminished fetal combined ventricular output is associated with mortality, whereas cerebral blood flow and oxygen delivery are associated with early cognitive, language, and motor development at 18 months of age. These results support the inclusion of fetal CMR to help identify patients at risk of adverse ND outcomes.

Epidemiology and Definition of Heart Failure in Adult Congenital Heart Disease.

Adults with congenital heart disease (ACHD) are facing lifelong complications, notably heart failure (HF). This review focuses on classifications, incidence, prevalence, and mortality of HF related to ACHD. Diagnosing HF in ACHD is intricate due to anatomic variations, necessitating comprehensive clinical evaluations. Hospitalizations and resource consumption for ACHD HF have significantly risen compared with non-ACHD HF patients. With more than 30% prevalence in complex cases, HF has become the leading cause of death in ACHD. These alarming trends underscore the insufficient understanding of ACHD-related HF manifestations and management challenges within the context of aging, complexity, and comorbidity.

Special Considerations for Mechanical Circulatory Support or Device Therapy in Adult Congenital Heart Disease Heart Failure.

Heart failure has become the leading cause of mortality in adult congenital heart disease (ACHD) patients after the fifth decade of life. There is scanty evidence supporting the use of guideline-directed medical therapy in ACHD, especially in systemic right ventricle or single ventricle physiology. In complex patients, diagnosing heart failure and timely referral for advanced therapies are challenging. Mechanical circulatory support has been significantly developed over the past decade and has recently emerged as a feasible therapeutic option for these patients. This review summarizes current evidence of mechanical circulatory support in this population, its potential uses, and challenges.

Pulse oximetry test for screening congenital heart diseases: a systematic review.

OBJECTIVE: To determine the accuracy of the Pulse Oximetry Test (POT) in screening for Congenital Heart Diseases (CHD) in newborns in the first 48 hours of life. METHOD: Systematic review of diagnostic test accuracy with meta-analysis. The selection of studies was carried out in June 2021. Studies were selected with newborns, in a hospital or home environment, without a previous diagnosis of CHD, regardless of gestational age at birth, who underwent POT within the first 48 hours after birth. Registration on the PROSPERO platform - CRD42021256286. RESULTS: Twenty-nine studies were included, totaling a population of 388,491 newborns. POT demonstrated sensitivity of 47% (95% CI: 43% to 50%) and specificity of 98% (95% CI: 98% to 98%). Subgroup analyses were carried out according to the different testing period, inclusion of retests in protocols and population of premature newborns. CONCLUSION: POT is a test with moderate sensitivity and high specificity. It is more effective when carried out within 24h - 48h of birth; in protocols that present retests, within two hours after the first measurement. It does not show satisfactory effectiveness for premature newborns.

Time to childbirth and assisted reproductive treatment in women with congenital heart disease.

OBJECTIVE: To investigate the time to first childbirth and to compare the prevalence of assisted reproductive treatment (ART) in women with congenital heart disease (CHD) compared with women without CHD. METHODS: All women in the national register for CHD who had a registered first childbirth in the Swedish Pregnancy Register between 2014 and 2019 were identified. These individuals (cases) were matched by birth year and municipality to women without CHD (controls) in a 1:5 ratio. The time from the 18th birthday to the first childbirth and the prevalence of ART was compared between cases and controls. RESULTS: 830 first childbirths in cases were identified and compared with 4137 controls. Cases were slightly older at the time for first childbirth (28.9 vs 28.5 years, p=0.04) and ART was more common (6.1% vs 4.0%, p<0.01) compared with controls. There were no differences in ART when stratifying for the complexity of CHD. For all women, higher age was associated with ART treatment (OR 1.24, 95% CI 1.20 to 1.28). CONCLUSIONS: Women with and without CHD who gave birth to a first child did so at similar ages. ART was more common in women with CHD, but disease severity did not influence the need for ART. Age was an important risk factor for ART also in women with CHD and should be considered in consultations with these patients.

Nucleated Red Blood Cell Counts Differentiate Cardiac from Respiratory Causes of Cyanosis at Birth.

Tissue hypoxia increases erythropoietin production and release of immature erythrocytes that can be measured using nucleated red blood cell counts (nRBC). We hypothesized that hypoxia due to congenital heart disease (CHD) is chronic and is better tolerated than hypoxia due to respiratory disease (RD), which is an acute stress in newborns leading to higher nRBC. This study assesses the utility of nRBC as a marker to differentiate hypoxia due to CHD vs RD in term neonates. This was a single-center, retrospective study of term neonates with cyanosis from 2015 to 2022. Neonates < 37 weeks of gestation, with hypoxic-ischemic encephalopathy, and those with other causes of cyanosis were excluded. The patients were divided into 2 groups: cyanotic CHD and cyanotic RD. Clinical and laboratory data done within 12 h and 24-36 h after birth were collected. Data are represented as median and Interquartile range. Of 189 patients with cyanosis, 80 had CHD and 109 had RD. The absolute nRBC count at ≤ 12 h of age was lower in the CHD (360 cells/mm3) compared to RD group (2340 cells/mm3) despite the CHD group having significantly lower baseline saturations. A value of 1070 cells/mm3 was highly sensitive and specific for differentiating CHD from RD. The positive predictive value for this cut-off value of 1070 cells/mm3 was 0.94 and the negative predictive value was 0.89. The absolute nRBC is a simple screening test and is available worldwide. A nRBC < 1070 cells/mm3 in cyanotic newborns should hasten the search for CHD etiology with the possible need for prostaglandin therapy.

Whole-exome sequencing of pathogenic genes in a family with congenital heart disease: A case report.

RATIONALE: Congenital heart disease (CHD) is the most common birth defect and an important cause of noninfectious deaths in infants and children. It has high prevalence globally, placing an enormous burden on society and families. Studies of individuals with hereditary or sporadic CHD have provided strong evidence for its genetic basis. The aim of this study was to identify causative gene variants in a Chinese family with congenital heart disease. PATIENT CONCERNS AND DIAGNOSES: Three generations of a CHD family were recruited. Proband III.9 was diagnosed with congenital heart disease at age 11 months, and the echocardiogram showed arterial ductus arteriosus, with a left-to-right shunt at the level of the arteries. Precedent III.10 was a twin of Proband III.9 who was diagnosed with congenital heart disease at age 11 months, in whom the echocardiogram revealed an arterial ductus arteriosus, an unenclosed patent ductus arteriosus, and a left to right shunt at the level of the arteries (second figure). III.8 was diagnosed with congenital heart disease at age 15, but echocardiography in this study showed no abnormalities. No cardiac abnormalities were detected in any of his parents, grandparents, or maternal grandparents. We performed whole-exome sequencing on CHD sufferers and their unexpressing family members to investigate the genetic causes of CHD in this family line. Exome sequencing identified 4 mutation sites in this family line. The variant c.3245A>G (p.His1082Arg) of the AMER1 gene was consistent with concomitant X-chromosome recessive inheritance, the variant c.238G>C (p.Val80Leu) of the KCNE1 gene was consistent with autosomal accessory inheritance, and the other 2 variants did not conform to the law of the mode of inheritance of the disease. OUTCOMES: The first identified variant, c.3245A>G (p.His1082Arg) of the AMER1 gene, with X-chromosome recessive inheritance, and the variant c.238G>C (p.Val80Leu) of the KCNE1 gene, which has been reported as autosomal dominant, may be the causative agent of CHD in this family line. These findings broaden the genetic scope of congenital heart disease and could help in the development of targeted drugs for the treatment of congenital heart disease.

Social Determinants of Health Including Child Opportunity Index Leading to Gaps in Care for Patients With Significant Congenital Heart Disease.

BACKGROUND: Gaps in care (GIC) are common for patients with congenital heart disease (CHD) and can lead to worsening clinical status, unplanned hospitalization, and mortality. Understanding of how social determinants of health (SDOH) contribute to GIC in CHD is incomplete. We hypothesize that SDOH, including Child Opportunity Index (COI), are associated with GIC in patients with significant CHD. METHODS AND RESULTS: A total of 8554 patients followed at a regional specialty pediatric hospital with moderate to severe CHD seen in cardiology clinic between January 2013 and December 2015 were retrospectively reviewed. SDOH factors including race, ethnicity, language, and COI calculated based on home address and zip code were analyzed. GIC of >3.25 years were identified in 32% (2709) of patients. GIC were associated with ages 14 to 29 years (P<0.001), Black race or Hispanic ethnicity (P<0.001), living ≥150 miles from the hospital (P=0.017), public health insurance (P<0.001), a maternal education level of high school or less (P<0.001), and a low COI (P<0.001). Multivariable analysis showed that GIC were associated with age ≥14 years, Black race or Hispanic ethnicity, documenting <3 caregivers as contacts, mother's education level being high school or less, a very low/low COI, and insurance status (C statistic 0.66). CONCLUSIONS: One-third of patients followed in a regional referral center with significant CHD experienced a substantial GIC (>3.25 years). Several SDOH, including a low COI, were associated with GIC. Hospitals should adopt formal GIC improvement programs focusing on SDOH to improve continuity of care and ultimately overall outcomes for patients with CHD.

TBX5 variants and cardiac phenotype: A systematic review of the literature and a novel variant.

T-Box Transcription Factor 5 (TBX5) variants are associated with Holt-Oram syndrome. Holt-Oram syndrome display phenotypic variability, regarding upper limb defects, congenital heart defects, and arrhythmias. To investigate the genotype-phenotype relationship between TBX5 variants and cardiac disease, we performed a systematic review of the literature. Through the systematic review we identified 108 variants in TBX5 associated with a cardiac phenotype in 277 patients. Arrhythmias were more frequent in patients with a missense variant (48% vs 30%, p = 0.009) and upper limb abnormalities were more frequent in patients with protein-truncating variants (85% vs 64%, p = 0.0008). We found clustering of missense variants in the T-box domain. Furthermore, we present a family with atrial septal defects. By whole exome sequencing, we identified a novel missense variant p.Phe232Leu in TBX5. The cardiac phenotype included atrial septal defect, arrhythmias, heart failure, and dilated cardiomyopathy. Clinical examination revealed subtle upper limb abnormalities. Thus, the family corresponds to the diagnostic criteria of Holt-Oram syndrome. We provide an overview of cardiac phenotypes associated with TBX5 variants and show an increased risk of arrhythmias associated to missense variants compared to protein-truncating variants. We report a novel missense variant in TBX5 in a family with an atypical Holt-Oram syndrome phenotype.

Congenital heart disease detection by pediatric electrocardiogram based deep learning integrated with human concepts.

Early detection is critical to achieving improved treatment outcomes for child patients with congenital heart diseases (CHDs). Therefore, developing effective CHD detection techniques using low-cost and non-invasive pediatric electrocardiogram are highly desirable. We propose a deep learning approach for CHD detection, CHDdECG, which automatically extracts features from pediatric electrocardiogram and wavelet transformation characteristics, and integrates them with key human-concept features. Developed on 65,869 cases, CHDdECG achieved ROC-AUC of 0.915 and specificity of 0.881 on a real-world test set covering 12,000 cases. Additionally, on two external test sets with 7137 and 8121 cases, the overall ROC-AUC were 0.917 and 0.907 while specificities were 0.937 and 0.907. Notably, CHDdECG surpassed cardiologists in CHD detection performance comparison, and feature importance scores suggested greater influence of automatically extracted electrocardiogram features on CHD detection compared with human-concept features, implying that CHDdECG may grasp some knowledge beyond human cognition. Our study directly impacts CHD detection with pediatric electrocardiogram and demonstrates the potential of pediatric electrocardiogram for broader benefits.

Critical congenital heart disease: contemporary prenatal screening performance and outcomes in a multi-centre perinatology service.

BACKGROUND: Prenatal detection of critical congenital heart disease (CCHD) optimises perinatal decision-making and neonatal outcomes. The objective of this study was to determine the prenatal screening performance, care pathways and perinatal outcomes for prenatally and postnatally diagnosed cases of CCHD over a four-year period. STUDY DESIGN: This retrospective cohort study in a tertiary centre and its two affiliated secondary sites examined all cases of CCHD, including cases of pregnancy termination and in-utero fetal death, neonatal death and liveborn babies that underwent cardiac catheterization or surgery in the first six weeks of life. Prenatal and postnatal data were ascertained from the first trimester assessment for all patients diagnosed prenatally. Cases requiring intervention that were first identified in the postnatal period were included to determine prenatal detection rates. Follow-up for all cases of CCHD continued to one year of age. RESULTS: In a consecutive cohort of 49,950 pregnancies in a 4-year period 01/2019 to 12/2022, a prenatal diagnosis of CCHD was made in 96 cases, yielding a prevalence of 1.9 per 1000 births. The prenatal detection for right duct-dependant heart pathology and congenital heart block was 100%, 85% for left duct-dependant pathology and 93% for transposition of the great arteries (TGA). In the prenatally diagnosed group, 37% of cases were complicated by extracardiac structural abnormalities, a genetic diagnosis or both. All cases of prenatal detection were identified in the context of routine anatomy screening rather than specialist Fetal Cardiac screening services. Almost half of all pregnancies complicated by CCHD did not undergo neonatal cardiac intervention, by virtue of parental choice determined either prenatally or after birth. An additional eight babies were diagnosed with CCHD in the neonatal period, such that the prenatal detection rate for CCHD was 92% (96/104, 95% CI = 84%-96%). Survival at 1-year for infants deemed suitable for CCHD surgery was 85%. CONCLUSION: In a large unselected population, optimal rates of prenatal detection of critical congenital heart disease can be achieved by a protocolised approach to mid-trimester fetal anatomy ultrasound, underpinned by a programme of sonographer education and training. The cardiac abnormalities most likely to evade prenatal detection are left-sided obstructive lesions.

Patients' prognosis with congenital heart disease followed by ten years: survival and associated factors.

OBJECTIVE: To evaluate the prognosis and influence of associated factors in patients with congenital heart disease admitted for the first time to the Intensive Care Unit of the Hospital da Criança Santo Antônio/Irmandade da Santa Casa de Misericórdia de Porto Alegre, especially those factors associated with death. METHODS: Patients were prospectively and consecutively allocated over a period of one year (August 2005 to July 2006). Now, 15 years after the initial selection, we collected data from these patients in the database of the Cytogenetics Laboratory of the Universidade Federal de Ciências da Saúde de Porto Alegre and in the medical records of the hospital. RESULTS: Of the 96 patients, 11 died and 85 were alive until 20 years old. Four patients died in the Intensive Care Unit. The survival probability up to 365 days of life was 95.8%. The survival assessment identified that the deaths occurred mainly before the patients completed one thousand days of life. We found that complex heart disease was independently associated with an odds ratio of 5.19 (95% confidence interval - CI:1.09-24.71; p=0.038) for death. CONCLUSIONS: Knowledge about the factors that interfere with the prognosis can be crucial in care practice planning, especially considering that congenital heart disease is an important cause of mortality in the first year of life.

Cutis verticis gyrata associated with congenital heart disease.

Cutis verticis gyrata (CVG) is a very rare benign disorder characterised by convoluted folds and deep furrows of the scalp that mimic cerebral sulci and gyri. Associations with other pathologies as neuropsychiatric and/or ophthalmologic disorders, secondary cases to inflammatory or neoplastic processes, as well as cases associated to genetic disorders as Turner's syndrome have been reported, but there is no literature describing an association with a congenital structural heart defect and no other underlying condition. We report a case of primary CVG in a 3-week-old female infant associated with an echocardiographic diagnosis of cor triatriatum. Other systemic examination findings and investigations were unremarkable, and the patient has normal neurodevelopment at 1 year old. Aside from the neuropsychiatric and ophthalmologic pathologies commonly associated with primary non-essential CVG, it should be noted that isolated congenital cardiac lesions are also possible, so as to increase our index of suspicion in patients with the disorder.

Investigation of infant deaths associated with critical congenital heart diseases; 2018-2021, Türkiye.

BACKGROUND: The aim of this study was to examine the characteristics of infant mortality associated with critical congenital heart disease (CCHD). METHODS: In a cross-sectional study, data for the study were obtained through Death Notification System, Birth Notification System and Turkish Statistical Institute birth statistics. RESULTS: Of all infant deaths, 9.8% (4083) were associated with CCHD, and the infant mortality rate specific to CCHD was 8.8 per 10,000 live births. CCHD-related infant deaths accounted for 8.0% of all neonatal deaths, while the CCHD specific neonatal death rate was 4.6 per 10,000 live births. Of the deaths 21.7% occurred in the early neonatal, 30.3% in the late neonatal and 48.0% in the post neonatal period. Group 1 diseases accounted for 59.1% (n = 2415) of CCHD related infant deaths, 40.5% (n = 1652) were in Group 2 and 0.4% (n = 16) were in the unspecified group. Hypoplastic left heart syndrome was the most common CCHD among infant deaths (n = 1012; 24.8%). The highest CCHD related mortality rate was found in infants with preterm birth and low birth-weight while multiparity, maternal age ≥ 35 years, twin/triplet pregnancy, male gender, maternal education in secondary school and below, and cesarean delivery were also associated with higher CCHD related infant mortality rate. There was at least one non-cardiac congenital anomaly/genetic disorder in 26.1% of all cases. CONCLUSION: CCHD holds a significant role in neonatal and infant mortality in Türkiye. To mitigate CCHD-related mortality rates, it is crucial to enhance prenatal diagnosis rates and promote widespread screening for neonatal CCHD.

The use of high-resolution SNP arrays to detect congenital cardiac defects.

OBJECTIVE: Copy number variations (CNVs) detected by high-resolution single nucleotide polymorphism microarrays (SNP arrays) have been associated with congenital heart defects (CHDs). The genetic mechanism underlying the development of CHDs remains unclear. METHODS: High-resolution SNP arrays were used to detect CNVs and traditional chromosomal analyses, respectively, were carried out on 60 and 249 fetuses from gestational 12-37 weeks old, having isolated or complex CHDs that were diagnosed using prenatal ultrasound. RESULTS: Twenty of the 60 fetuses (33.5%) had abnormalities, of which 23 CNVs (12 pathogenic, five probable pathogenic and six of undetermined significance) were detected by SNP arrays, and two distinct CNVs were present in three of these fetuses. In addition, in 39 patients with isolated congenital heart disease who had normal karyotypes, abnormal CNVs were present in 28.2% (11/39), and in patients with complex coronary artery disease, 19.0% (4/21) had abnormal karyotypes and 42.9% (9/21) had abnormal CNVs. In patients with complex coronary artery disease, 19.0% (4/21) had abnormal karyotypes and 42.9% (9/21) had abnormal CNVs. CONCLUSIONS: In conclusion, genome-wide high-resolution SNP array can improve the diagnostic rate and uncover additional pathogenic CNVs. The submicroscopic deletions and duplications of Online Mendelian Inheritance in Man (OMIM) genes found in this study have haploinsufficient (deletion) or triplosensitive (duplication) traits, which further clarify the etiology and inheritance of CHDs.