Dental Anomalies in Ciliopathies: Lessons from Patients with BBS2, BBS7, and EVC2 Mutations

Objective: To investigate dental anomalies and the molecular etiology of a patient with Ellis–van Creveld syndrome and two patients with Bardet–Biedl syndrome, two examples of ciliopathies. Patients and Methods: Clinical examination, radiographic evaluation, whole exome sequencing, and Sanger direct sequencing were performed. Results: Patient 1 had Ellis–van Creveld syndrome with delayed dental development or tooth agenesis, and multiple frenula, the feature found only in patients with mutations in ciliary genes. A novel homozygous mutation in EVC2 (c.703G>C; p.Ala235Pro) was identified. Patient 2 had Bardet–Biedl syndrome with a homozygous frameshift mutation (c.389_390delAC; p.Asn130ThrfsTer4) in BBS7. Patient 3 had Bardet–Biedl syndrome and carried a heterozygous mutation (c.389_390delAC; p.Asn130ThrfsTer4) in BBS7 and a homozygous mutation in BBS2 (c.209G>A; p.Ser70Asn). Her clinical findings included global developmental delay, disproportionate short stature, myopia, retinitis pigmentosa, obesity, pyometra with vaginal atresia, bilateral hydronephrosis with ureteropelvic junction obstruction, bilateral genu valgus, post-axial polydactyly feet, and small and thin fingernails and toenails, tooth agenesis, microdontia, taurodontism, and impaired dentin formation. Conclusions: EVC2, BBS2, and BBS7 mutations found in our patients were implicated in malformation syndromes with dental anomalies including tooth agenesis, microdontia, taurodontism, and impaired dentin formation

Predictive factors of extubation failure in pediatric cardiac intensive care unit: A single-center retrospective study from Thailand

Introduction/objectiveExtubation failure increases morbidity and mortality in pediatric cardiac patients, a unique population including those with congenital heart disease or acquired heart disease. This study aimed to evaluate the predictive factors of extubation failure in pediatric cardiac patients and to determine the association between extubation failure and clinical outcomes.MethodsWe conducted a retrospective study in the pediatric cardiac intensive care unit (PCICU) of the Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand, from July 2016 to June 2021. Extubation failure was defined as the re-insertion of the endotracheal tube within 48 hours after extubation. Multivariable log-binomial regression with generalized estimating equations (GEE) was performed to explore the predictive factors associated with extubation failure.ResultsWe collected 318 extubation events from 246 patients. Of these, 35 (11%) events were extubation failures. In physiologic cyanosis, the extubation failure group had significantly higher SpO2 than the extubation success group (P < 0.001). The predictive factors associated with extubation failure included a history of pneumonia before extubation (RR 3.09, 95% CI 1.54–6.23, P = 0.002), stridor after extubation (RR 2.57, 95% CI 1.44–4.56, P = 0.001), history of re-intubation (RR 2.24, 95% CI 1.21–4.12, P = 0.009), and palliative surgery (RR 1.87, 95% CI 1.02–3.43, P = 0.043).ConclusionExtubation failure was identified in 11% of extubation attempts in pediatric cardiac patients. The extubation failure was associated with a longer duration of PCICU stay but not with mortality. Patients with a history of pneumonia before extubation, history of re-intubation, post-operative palliative surgery, and post-extubation stridor should receive careful consideration before extubation and close monitoring afterward. Additionally, patients with physiologic cyanosis may require balanced circulation via regulated SpO2

Cardiac dysfunctions in children with drug-resistant epilepsy

ObjectiveThere were reports of cardiac dysfunction that led to sudden unexpected death in epilepsy (SUDEP) in patients with epilepsy. Early detection of cardiac dysfunction can lead to early management to prevent sudden cardiac death in these patients. The objective of our study is to assess cardiac functions in children with drug-resistant epilepsy (DRE) compared with the normal population by using a standard echocardiogram (SE), tissue Doppler imaging (TDI) and myocardial strain evaluations (MSE).MethodTwenty-seven children who have been diagnosed with DRE based on the International League against Epilepsy (ILAE) were included in the study, along with 27 children whose ages match those of the normal control group.ResultsSeventeen children, median age 12 years old, were using more than four anti-seizure medications. Structural brain lesions were the most common cause of epilepsy, 55.6% (15). Generalized tonic–clonic seizures were the most common seizure type, 55.6% (15). Children with DRE had a lower early mitral valve E wave inflow velocity compared with the control group (p < 0.05). They also had lowered early diastolic velocities (e′) and myocardial performance index (MPI) when compared with the control group (p < 0.05). There was a statistically significant difference in left ventricular myocardial strain in children with DRE, with an average of −21.1 (IQR −23.5 and −19.4) and control, −25.5 (IQR −27.3 and −24.2).SignificanceChildren with DRE have an impairment of left ventricular diastolic function and myocardial strain, which could indicate decreased myocardial deformation and contraction compared with controls. These cardiological assessments can be used to evaluate children with DRE for early diagnosis and management of their cardiac dysfunction

Biventricular repair in children with atrioventricular septal defects and a small right ventricle: Anatomic and surgical considerations

ObjectiveWe sought to characterize morphology and to evaluate a strategy of using biventricular repair in patients with a small right ventricle and an unbalanced atrioventricular septal defect.MethodsThirty-eight children with a small right ventricle and an atrioventricular septal defect underwent operative therapy. Thirty-two had biventricular repair, and 6 had single-ventricle palliation. A small right ventricle was defined on the basis of echocardiographic measurements expressed as the atrioventricular valve index (ie, right atrioventricular valve/left atrioventricular valve area) and as the ratio of right ventricular to left ventricular length. Validation of measurements in patients with a small right ventricle and an atrioventricular septal defect was achieved by comparison with balanced case-matched control subjects with atrioventricular septal defects.ResultsChildren with a small right ventricle and an atrioventricular septal defect had a lower atrioventricular valve index (mean, 0.41 ± 0.1 vs 0.52 ± 0.1 [control], P < .0001) and lower right ventricular/left ventricular length ratio (0.78 ± 0.1 vs 0.99 ± 0.17 [control], P < .0001). Children with a small right ventricle undergoing single-ventricle palliation had the smallest right ventricular dimensions. There were 4 operative deaths. Three patients with a small right ventricle and an atrioventricular septal defect who underwent biventricular repair and had an atrioventricular valve index of less than 0.50 required early reoperation for right ventricular inadequacy. A restrictive atrial fenestration was created in 11 infants. Survival at 10 years was 87% for patients undergoing biventricular repair versus 100% for control subjects (P = .042).ConclusionsExtending the use of biventricular repair in properly selected patients with a small right ventricle and an atrioventricular septal defect is feasible. An atrial fenestration improves the physiologic tolerance to repair in selected patients. The use of biventricular repair in children with atrioventricular valve indexes of less than 0.50 requires caution

Prenatal Sonographic Features of CHARGE Syndrome

CHARGE syndrome is a rare autosomal dominant disorder, associated with coloboma (C), heart defects (H), choanal atresia (A), retardation of growth and/or central nervous system (R), genitourinary anomalies (G) and ear abnormalities (E). Prenatal diagnosis of the syndrome is very rare but may be suspected when a combination of such abnormalities is identified. We describe a prenatally suspected case of CHARGE syndrome due to unique findings of cardiac defects (DORV) in combination with minor clues, including a structurally malformed ear with persistent non-response to an acoustic stimulation (which has never been prenatally described elsewhere), renal malrotation and growth restriction. Postnatal diagnosis was made based on confirmation of the prenatal findings and additional specific findings of bilateral coloboma, choanal atresia and ear canal stenosis. Finally, molecular genetic testing by whole exome sequencing of the neonate and her parents revealed a novel de novo heterozygous frameshift c.3506_3509dup variant in the CHD7 gene, confirming the clinical diagnosis of CHARGE syndrome. In conclusion, we describe unique prenatal features of CHARGE syndrome. Educationally, this is one of the rare examples of CHARGE syndrome, comprising all of the six specific anomalies as originally described; it is also supported by the identification of a specific genetic mutation. The identified genetic variant has never been previously reported, thereby expanding the mutational spectrum of CHD7. Finally, this case can inspire prenatal sonographers to increase awareness of subtle or minor abnormalities as genetic sonomarkers

Prenatal Sonographic Features of CHARGE Syndrome

CHARGE syndrome is a rare autosomal dominant disorder, associated with coloboma (C), heart defects (H), choanal atresia (A), retardation of growth and/or central nervous system (R), genitourinary anomalies (G) and ear abnormalities (E). Prenatal diagnosis of the syndrome is very rare but may be suspected when a combination of such abnormalities is identified. We describe a prenatally suspected case of CHARGE syndrome due to unique findings of cardiac defects (DORV) in combination with minor clues, including a structurally malformed ear with persistent non-response to an acoustic stimulation (which has never been prenatally described elsewhere), renal malrotation and growth restriction. Postnatal diagnosis was made based on confirmation of the prenatal findings and additional specific findings of bilateral coloboma, choanal atresia and ear canal stenosis. Finally, molecular genetic testing by whole exome sequencing of the neonate and her parents revealed a novel de novo heterozygous frameshift c.3506_3509dup variant in the CHD7 gene, confirming the clinical diagnosis of CHARGE syndrome. In conclusion, we describe unique prenatal features of CHARGE syndrome. Educationally, this is one of the rare examples of CHARGE syndrome, comprising all of the six specific anomalies as originally described; it is also supported by the identification of a specific genetic mutation. The identified genetic variant has never been previously reported, thereby expanding the mutational spectrum of CHD7. Finally, this case can inspire prenatal sonographers to increase awareness of subtle or minor abnormalities as genetic sonomarkers

Pre-implantation genetic testing for Marfan syndrome using mini-sequencing

Marfan syndrome (MFS1) is an autosomal dominant condition causing aortopathy including fatal aortic dissection. This study aimed to perform clinical PGT-M in a family with a history of MFS1 for two generations. A family with two members affected by MFS1 approached the hospital for PGT-M. The couple decided to join the project following extensive counselling and informed consent was obtained. The mutation contributory to MFS1 was identified using whole-exome sequencing (WES). A novel PGT-M protocol using multiplex fluorescent PCR and mini-sequencing was developed and tested. Ten blastocysts were subjected to PGT-M in two clinical PGT cycles. Mini-sequencing revealed four normal and six affected embryos. Microsatellite-based linkage analysis confirmed mutation analysis results in all samples. The embryos diagnosed as normal (non-MFS1) were chosen for transfer. A pregnancy was obtained in the third embryo transfer. Invasive prenatal diagnosis confirmed the normal genotype of the baby. This study demonstrated comprehensive management using the application of clinical-based diagnosis, WES for mutation identification within the MFS1 gene, mini-sequencing for embryo selection and microsatellite-based linkage analysis for backup of PGT-M results and contamination detection to assist couples in having a healthy child when there was a family history of Marfan syndrome.Impact Statement What is already known on this subject? Marfan syndrome (MFS1, OMIM#154700) is an autosomal dominant condition causing aortopathy including fatal aortic dissection. Pre-implantation genetic testing (PGT) is an alternative to traditional invasive prenatal diagnosis (PND) giving the couples the chance of starting pregnancy with the confidence that the baby will be unaffected. Most of the previous PGT reports employed microsatellite-based linkage analysis. A few PGT studies used sequencing, mini-sequencing and mutation analysis; however, the details of the techniques were not described. What do the results of this study add? Single-cell PCR protocol using multiplex fluorescent PCR and mini-sequencing was developed and validated. Two clinical PGTs cycles for Marfan syndrome were performed. A healthy baby was resulted. The details of multiplex fluorescent PCR and mini-sequencing protocols are described in this study so that the procedures can be reproduced. What are the implications of these findings for clinical practice and/or further research? Embryo selection can help the family suffering from Marfan syndrome for two generations to start a pregnancy with confidence that their child will be unaffected. This study also shows the use of a mini-sequencing protocol for PGT, which can be a universal protocol for other mutations by changing the PCR primers and mini-sequencing primers

Dental Anomalies in Ciliopathies: Lessons from Patients with <i>BBS2</i>, <i>BBS7,</i> and <i>EVC2</i> Mutations

Objective: To investigate dental anomalies and the molecular etiology of a patient with Ellis–van Creveld syndrome and two patients with Bardet–Biedl syndrome, two examples of ciliopathies. Patients and Methods: Clinical examination, radiographic evaluation, whole exome sequencing, and Sanger direct sequencing were performed. Results: Patient 1 had Ellis–van Creveld syndrome with delayed dental development or tooth agenesis, and multiple frenula, the feature found only in patients with mutations in ciliary genes. A novel homozygous mutation in EVC2 (c.703G>C; p.Ala235Pro) was identified. Patient 2 had Bardet–Biedl syndrome with a homozygous frameshift mutation (c.389_390delAC; p.Asn130ThrfsTer4) in BBS7. Patient 3 had Bardet–Biedl syndrome and carried a heterozygous mutation (c.389_390delAC; p.Asn130ThrfsTer4) in BBS7 and a homozygous mutation in BBS2 (c.209G>A; p.Ser70Asn). Her clinical findings included global developmental delay, disproportionate short stature, myopia, retinitis pigmentosa, obesity, pyometra with vaginal atresia, bilateral hydronephrosis with ureteropelvic junction obstruction, bilateral genu valgus, post-axial polydactyly feet, and small and thin fingernails and toenails, tooth agenesis, microdontia, taurodontism, and impaired dentin formation. Conclusions: EVC2, BBS2, and BBS7 mutations found in our patients were implicated in malformation syndromes with dental anomalies including tooth agenesis, microdontia, taurodontism, and impaired dentin formation

Table1_Predictive factors of extubation failure in pediatric cardiac intensive care unit: A single-center retrospective study from Thailand.docx

Introduction/objectiveExtubation failure increases morbidity and mortality in pediatric cardiac patients, a unique population including those with congenital heart disease or acquired heart disease. This study aimed to evaluate the predictive factors of extubation failure in pediatric cardiac patients and to determine the association between extubation failure and clinical outcomes.MethodsWe conducted a retrospective study in the pediatric cardiac intensive care unit (PCICU) of the Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand, from July 2016 to June 2021. Extubation failure was defined as the re-insertion of the endotracheal tube within 48 hours after extubation. Multivariable log-binomial regression with generalized estimating equations (GEE) was performed to explore the predictive factors associated with extubation failure.ResultsWe collected 318 extubation events from 246 patients. Of these, 35 (11%) events were extubation failures. In physiologic cyanosis, the extubation failure group had significantly higher SpO2 than the extubation success group (P ConclusionExtubation failure was identified in 11% of extubation attempts in pediatric cardiac patients. The extubation failure was associated with a longer duration of PCICU stay but not with mortality. Patients with a history of pneumonia before extubation, history of re-intubation, post-operative palliative surgery, and post-extubation stridor should receive careful consideration before extubation and close monitoring afterward. Additionally, patients with physiologic cyanosis may require balanced circulation via regulated SpO2.</p