Periventricular nodular heterotopia in patients with a prenatal diagnosis of myelomeningocele/myeloschisis: associations with seizures and neurodevelopmental outcomes during early childhood.

PURPOSE: Historically, the presence of gray matter heterotopia was a concern for adverse postnatal neurocognitive status in patients undergoing fetal closure of open spinal dysraphism. The purpose of this study was to evaluate neurodevelopmental outcomes and the onset of seizures during early childhood in patients with a prenatal diagnosis of myelomeningocele/myeloschisis (MMC) and periventricular nodular heterotopia (PVNH). METHODS: All patients evaluated at the Center for Fetal Diagnosis and Treatment with a diagnosis of MMC between June 2016 to March 2023 were identified. PVNH was determined from prenatal and/or postnatal MRI. The Bayley Scales of Infant and Toddler Development (edition III or IV) were used for neurodevelopmental assessments. Patients were screened for seizures/epilepsy. RESULTS: Of 497 patients evaluated with a prenatal diagnosis of MMC, 99 were found to have PVNH on prenatal MRI, of which 35 had confirmed PVNH on postnatal imaging. From the 497 patients, 398 initially did not exhibit heterotopia on prenatal MRI, but 47 of these then had confirmed postnatal PVNH. The presence of PVNH was not a significant risk factor for postnatal seizures in early childhood. The average neurodevelopmental scores were not significantly different among heterotopia groups for cognitive, language, and motor domains. CONCLUSION: The presence of PVNH in patients with a prenatal diagnosis of MMC does not indicate an increased risk for neurodevelopmental delay at 1 year of age. We did not demonstrate an association with seizures/epilepsy. These findings can aid clinicians in prenatal consultation regarding fetal repair of open spinal dysraphism. Long-term follow-up is required to discern the true association between PVNH seen on prenatal imaging and postnatal seizures/epilepsy and neurodevelopmental outcomes.

The Delivery Room Resuscitation of Infants with Congenital Diaphragmatic Hernia Treated with Fetoscopic Endoluminal Tracheal Occlusion: Beyond the Balloon.

INTRODUCTION: Randomized controlled trials found that fetoscopic endoluminal tracheal occlusion (FETO) resulted in increased fetal lung volume and improved survival for infants with isolated, severe left-sided congenital diaphragmatic hernia (CDH). The delivery room resuscitation of these infants is particularly unique, and the specific delivery room events are largely unknown. The objective of this study was to compare the delivery room resuscitation of infants treated with FETO to standard of care (SOC) and describe lessons learned. METHODS: Retrospective single-center cohort study of infants treated with FETO compared to infants who met FETO criteria during the same period but who received SOC. RESULTS: FETO infants were more likely to be born prematurely with 8/12 infants born <35 weeks gestational age compared to 3/35 SOC infants. There were 5 infants who required emergent balloon removal (2 ex utero intrapartum treatment and 3 tracheoscopic removal on placental bypass with delayed cord clamping) and 7 with prenatal balloon removal. Surfactant was administered in 6/12 FETO (50%) infants compared to 2/35 (6%) in the SOC group. Extracorporeal membrane oxygenation use was lower at 25% and survival was higher at 92% compared to 60% and 71% in the SOC infants, respectively. CONCLUSION: The delivery room resuscitation of infants treated with FETO requires thoughtful preparation with an experienced multidisciplinary team. Given increased survival, FETO should be offered to infants with severe isolated left-sided CDH, but only in high-volume centers with the experience and capability of removing the balloon, emergently if needed. The neonatal clinical team must be skilled in managing the unique postnatal physiology inherent to FETO where effective interdisciplinary teamwork is essential. Empiric and immediate surfactant administration should be considered in all FETO infants to lavage thick airway secretions, particularly those delivered <48 h after balloon removal.

Immediate postdelivery airway management of neonates with prenatally diagnosed micrognathia: A retrospective observational study.

INTRODUCTION: Micrognathic neonates are at risk for upper airway obstruction, and many require intubation in the delivery room. Ex-utero intrapartum treatment is one technique for managing airway obstruction but poses substantial maternal risks. Procedure requiring a second team in the operating room is an alternative approach to secure the obstructed airway while minimizing maternal risk. The aim of this study was to describe the patient characteristics, airway management, and outcomes for micrognathic neonates and their mothers undergoing a procedure requiring a second team in the operating room at a single quaternary care children's hospital. METHODS: This was a retrospective descriptive study. Subjects had prenatally diagnosed micrognathia and underwent procedure requiring a second team in the operating room between 2009 and 2021. Collected data included infant characteristics, delivery room airway management, critical events, and medications. Follow-up data included genetic testing and subsequent procedures within 90 days. Maternal data included type of anesthetic, blood loss, and incidence of transfusion. RESULTS: Fourteen deliveries were performed via procedure requiring a second team in the operating room during the study period. 85.7% were male, and 50% had a genetic syndrome. Spontaneous respiratory efforts were observed in 93%. Twelve patients (85.7%) required an endotracheal tube or tracheostomy. Management approaches varied. Medications were primarily a combination of atropine, ketamine, and dexmedetomidine. Oxygen desaturation was common, and three patients experienced bradycardia. There were no periprocedural deaths. Follow-up at 90 days revealed that 78% of patients underwent at least one additional procedure, and one patient died due to an unrelated cause. All mothers underwent cesarean deliveries under neuraxial anesthesia. Median blood loss was 700 mL [IQR 700 mL, 800 mL]. Only one mother required a blood transfusion for pre-procedural placental abruption. DISCUSSION: Procedure requiring a second team in the operating room is a safe and effective approach to manage airway obstruction in micrognathic neonates while minimizing maternal morbidity. CONCLUSIONS: Though shown to be safe and effective, more data are needed to support the use of procedure requiring a second team in the operating room as an alternative to ex-utero intrapartum treatment for micrognathia outside of highly specialized maternal-fetal centers.

Novel Use of Dasiglucagon, a Soluble Glucagon Analog, for the Treatment of Hyperinsulinemic Hypoglycemia Secondary to Suspected Insulinoma: A Case Report.

INTRODUCTION: Hyperinsulinemic hypoglycemia is the most common cause of persistent hypoglycemia in children and adults. In adolescents and adults, hyperinsulinemic hypoglycemia is most frequently caused by an insulin-producing tumor. CASE PRESENTATION: A 17-year-old, previously healthy male presented with recurrent and severe episodes of hypoglycemia. Diagnostic evaluation was consistent with hyperinsulinemic hypoglycemia, and an insulinoma was suspected. Multiple imaging studies and surgical exploration failed to identify a lesion. Over the course of months, the patient was found to be refractory to conventional medical interventions. CONCLUSION: Upon approval from the US Food and Drug Administration and the Institutional Review Board, the patient was treated with dasiglucagon, a novel soluble glucagon analog, under a single-patient Investigational New Drug. The patient has tolerated the medication and has been able to achieve appropriate glycemic control.

The Impact of Comprehensive Fetal Care on Mortality of Children With Congenital Diaphragmatic Hernia when Delivery is Co-located in a Pediatric Hospital.

BACKGROUND: We evaluated the impact of delivery at a comprehensive fetal care center co-located in a pediatric hospital on extracorporeal membrane oxygenation (ECMO) exposure and survivorship of children with CDH. METHODS: This retrospective study includes maternal-fetal dyads with a prenatal diagnosis of isolated CDH who received any prenatal care at a single fetal center between February 2006 and March 2021. The principal variables included: (1) delivery setting (children born in the pediatric hospital ["inborn"] vs. children who were delivered elsewhere ["outborn"]), (2) exposure to ECMO (yes vs. no), and (3) survival-at-discharge from birth hospitalization (yes vs. no). Multivariable logistic regression was used to evaluate the association between delivery setting and ECMO cannulation, and whether delivery setting moderates the association between exposure to ECMO and survival-at-discharge. RESULTS: Among 418 maternal-fetal dyads, 77.0% of children were inborn and 32.0% of children were exposed to ECMO during their index hospitalization. Inborn children had more severe prenatal prognostic indicators but had a 57% lower odds of extracorporeal than outborn children. In multivariable logistic regression, delivery setting moderated the association between exposure to ECMO and survival-at-discharge. Although there was no statistically significant difference in mortality between inborn and outborn children who were not exposed to ECMO, inborn children exposed to ECMO had a 6.86 (1.98, 23.74) increased odds of death and outborn children exposed to ECMO had a 17.71 (4.69, 66.87) increased odds of death when both were compared to non-cannulated outborn children. CONCLUSIONS: Comprehensive fetal care with delivery co-located in a pediatric hospital was associated with decreased exposure to ECMO and a survivorship advantage among children with CDH who required extracorporeal support. LEVEL OF EVIDENCE: Level III.

Prevalence and patterns of executive function, adaptive function, and behavioral outcomes in preschool and school age children with congenital diaphragmatic hernia.

BACKGROUND: Executive function, adaptive function, and behavioral outcomes in congenital diaphragmatic hernia (CDH) survivors have not been well studied. AIM: To evaluate executive and neurobehavioral dysfunction in preschool and early school-aged children with CDH. STUDY DESIGN: Retrospective cohort study. SUBJECTS: All eligible CDH survivors ages 3 to 7 years enrolled in our follow-up program between February 2020 and February 2021. OUTCOME MEASURES: The Behavior Rating Inventory of Executive Function (BRIEF), the Adaptive Behavior Assessment System, 2nd Edition (ABAS-II), and the Child Behavior Checklist (CBCL) were used to assess functional and behavioral outcomes. Summary scores were compared to standard population norms. RESULTS: A total of 100 patients were enrolled during the study period. Of those, 73 parents completed at least one of the questionnaires, resulting in completion of the BRIEF, ABAS-II, and CBCL for 63, 68, and 63 patients, respectively. Preschool children had normal executive function (BRIEF-P) while global executive composite (P = 0.012) and the emotional regulation index (P = 0.010) for school age patients (BRIEF-2) were worse. CDH survivors had favorable adaptive functioning (ABAS-II). Mean CBCL scores for preschool attention problems (P = 0.018), school age attention problems (P = 0.001), and attention deficits hyperactivity problems (P = 0.027) were significantly worse. Prematurity, surrogate markers of disease severity, non-white race, and public insurance status were associated with worse neurobehavioral dysfunction in bivariable analysis. CONCLUSIONS: The majority of preschool and school age CDH survivors have age-appropriate executive, adaptive and behavioral functioning. CDH survivors, however, have lower executive function and attention scores compared with the general population.

Prenatally Diagnosed Large Lung Lesions: Timing of Resection and Perinatal Outcomes.

INTRODUCTION: Fetuses with large lung lesions including congenital cystic adenomatoid malformations (CCAMs) are at risk for cardiopulmonary compromise. Prenatal maternal betamethasone and cyst drainage for micro- and macrocystic lesions respectively have improved outcomes yet some lesions remain large and require resection before birth (open fetal surgery, OFS), at delivery via an Ex Utero Intrapartum Treatment (EXIT), or immediately post cesarean section (section-to-resection, STR). We sought to compare prenatal characteristics and outcomes in fetuses undergoing OFS, EXIT, or STR to inform decision-making and prenatal counseling. METHODS: A single institution retrospective review was conducted evaluating patients undergoing OFS, EXIT, or STR for prenatally diagnosed lung lesions from 2000 to 2021. Specimens were reviewed by an anatomic pathologist. Lesions were divided into "CCAMs" (the largest pathology group) and "all lung lesions" since pathologic diagnosis is not possible during prenatal evaluation when care decisions are made. Prenatal variables included initial, greatest, and final CCAM volume-ratio (CVR), betamethasone use/frequency, cyst drainage, and the presence of hydrops. Outcomes included survival, ECMO utilization, NICU length of stay (LOS), postnatal nitric oxide use, and ventilator days. RESULTS: Sixty-nine percent (59 of 85 patients) of lung lesions undergoing resection were CCAMs. Among patients with pathologic diagnosis of CCAM, the initial, largest, and final CVRs were greatest in OFS followed by EXIT and STR patients. Similarly, the incidence of hydrops was significantly greater and the rate of hydrops resolution was lower in the OFS group. Although the rate of cyst drainage did not differ between groups, maternal betamethasone use varied significantly (OFS 60.0%, EXIT 100.0%, STR 74.3%; p = 0.0378). Notably, all OFS took place prior to 2014. There was no difference in survival, ventilator days, nitric oxide, NICU LOS, or ECMO between groups. In multiple variable logistic modeling, determinants of survival to NICU discharge among patients undergoing resection with a pathologic diagnosis of CCAM included initial CVR <3.5 and need for <3 maternal betamethasone doses. CONCLUSION: For CCAMs that remain large despite maternal betamethasone or cyst drainage, surgical resection via OFS, EXIT, or STR are viable options with favorable and comparable survival between groups. In the modern era there has been a shift from OFS and EXIT procedures to STR for fetuses with persistently large lung lesions. This shift has been fueled by the increased use of maternal betamethasone and introduction of a Special Delivery Unit during the study period and the appreciation of similar fetal and neonatal outcomes for STR vs. EXIT and OFS with reduced maternal morbidity associated with a STR. Accordingly, efforts to optimize multidisciplinary perinatal care for fetuses with large lung lesions are important to inform patient selection criteria and promote STR as the preferred surgical approach in the modern era. LEVEL OF EVIDENCE: Level IV.

Thyroid Ultrasound Screening in Childhood Cancer Survivors following Radiotherapy.

INTRODUCTION: Childhood cancer survivors (CCS) are at risk for radiotherapy (RT) late effects, including second malignancies. Optimal screening for differentiated thyroid cancer (DTC) in CCS post-RT remains controversial. We assessed the outcome of thyroid ultrasound (US) surveillance in CCS exposed to RT. METHODS: 306 CCS were surveilled with thyroid US between 2002-2021. Surveillance was dependent on age at the time of primary diagnosis, interval from receipt of RT, and individual provider. Thyroid US, clinicopathologic features, and outcomes were described. Cutpoints of CCS RT age associated with varying risk of nodule presentation were explored. The selected cutpoints were used to define age categories, which were then used to compare thyroid nodule-related outcomes. Risk factors for thyroid nodule(s) were evaluated using multivariate logistic regression (odds ratio [OR] [95% confidence interval]). RESULTS: The most common CCS diagnoses were leukemia (32%), CNS tumor (26%), and neuroblastoma (18%). Patients received TBI (45%) and/or RT to craniospinal (44%), chest (11%), and neck regions (6%). About 49% (n = 150) of patients had thyroid nodule(s). Forty-four patients underwent surgery, and 28 had DTC: 19 with American Thyroid Association (ATA) low-risk classification, 2 with ATA intermediate-risk, and 7 with ATA high-risk disease. Age cutpoint analyses identified cutpoints 3 and 10; hence, ≤3, >3 to ≤10, and >10 years were used. Of the 9 patients with intermediate- or high-risk disease, 8 were ≤10 years and 1 was >10 years at the time of RT. Female sex (OR = 1.62 [1.13-2.12] p = 0.054) and greater interval between RT and first US (OR = 1.10 [1.04-1.16] p = 0.001) were independent risk factors for nodule presentation. CONCLUSIONS: Thyroid US surveillance may be beneficial for CCS exposed to RT at younger ages (≤10 years) for earlier detection of DTC, prior to developing advanced metastatic disease.

Phenotypic Characterization of Congenital Hyperinsulinism Due to Novel Activating Glucokinase Mutations.

The importance of glucokinase (GK) in the regulation of insulin secretion has been highlighted by the phenotypes of individuals with activating and inactivating mutations in the glucokinase gene (GCK). Here we report 10 individuals with congenital hyperinsulinism (HI) caused by eight unique activating mutations of GCK. Six are novel and located near previously identified activating mutations sites. The first recognized episode of hypoglycemia in these patients occurred between birth and 24 years, and the severity of the phenotype was also variable. Mutant enzymes were expressed and purified for enzyme kinetics in vitro. Mutant enzymes had low glucose half-saturation concentration values and an increased enzyme activity index compared with wild-type GK. We performed functional evaluation of islets from the pancreata of three children with GCK-HI who required pancreatectomy. Basal insulin secretion in perifused GCK-HI islets was normal, and the response to glyburide was preserved. However, the threshold for glucose-stimulated insulin secretion in perifused glucokinase hyperinsulinism (GCK-HI) islets was decreased, and glucagon secretion was greatly suppressed. Our evaluation of novel GCK disease-associated mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response. ARTICLE HIGHLIGHTS: Our evaluation of six novel and two previously published activating GCK mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response. These studies provide insights into the pathophysiology of GCK-hyperinsulinism and the dual role of glucokinase in ß-cells and α-cells to regulate glucose homeostasis.

Outcomes of ATA Low-Risk Pediatric Thyroid Cancer Patients Not Treated With Radioactive Iodine Therapy.

CONTEXT: The American Thyroid Association (ATA) Pediatric Guidelines recommend patients not receive radioactive iodine therapy (RAIT) for differentiated thyroid cancer (DTC) confined to the thyroid. Since publication, there is ongoing concern whether withholding RAIT will result in a lower rate of remission. OBJECTIVE: This study explores whether ATA low-risk patients treated with and without RAIT achieved similar remission rates. METHODS: Medical records of patients <19 years old diagnosed with DTC and treated with total thyroidectomy between 2010 and 2020 were reviewed. Multivariate logistic regression was performed to evaluate factors influencing RAIT administration and remission rate. RESULTS: Ninety-five patients with ATA low-risk DTC were analyzed: 53% (50/95) and 47% (45/95) were treated with and without RAIT, respectively. RAIT was used to treat 82% of patients before 2015 compared with 33% of patients after 2015 (P < .01). No significant difference in 1-year remission rate was found between patients treated with and without RAIT, 70% (35/50) vs 69% (31/45), respectively. With longer surveillance, remission rates increased to 82% and 76% for patients treated with and without RAIT, respectively. Median follow-up was 5.8 years (IQR 4.3-7.9, range 0.9-10.9) and 3.6 years (IQR 2.7-6.6; range 0.9-9.3) for both cohorts. No risk factors for persistent or indeterminate disease status were found, including RAIT administration, N1a disease, and surgery after 2015. CONCLUSION: Withholding RAIT for pediatric patients with ATA low-risk DTC avoids exposure to radiation and does not have a negative impact on remission rates. Dynamic risk stratification at 1-year after initial treatment is a suitable time point to assess the impact of withholding RAIT for these patients.

Extracorporeal Membrane Oxygenation for Neonates With Congenital Diaphragmatic Hernia: Prevalence of Seizures and Outcomes.

OBJECTIVES: We aimed to determine the prevalence of electrographic seizures and associated odds of adverse outcomes of electrographic seizures in neonates with congenital diaphragmatic hernia (CDH) receiving extracorporeal membrane oxygenation (ECMO). DESIGN: Retrospective, descriptive case series. SETTING: Neonatal ICU (NICU) in a quaternary care institution. PATIENTS: All neonates with CDH receiving ECMO undergoing continuous electroencephalographic monitoring (CEEG) and follow-up between January 2012 and December 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All eligible neonates with CDH receiving ECMO underwent CEEG (n = 75). Electrographic seizures occurred in 14 of 75 (19%): they were exclusively electrographic-only in nine of 14, both electrographic-only and electroclinical in three of 14, and electroclinical only in two of 14. Two neonates developed status epilepticus. We identified an association between presence of seizures, rather than not, and longer duration of initial session of CEEG monitoring (55.7 hr [48.2-87.3 hr] vs 48.0 hr [43.0-48.3 hr]; p = 0.001). We also found an association between presence of seizures, rather than not, and greater odds of use of a second CEEG monitoring (12/14 vs 21/61; odds ratio [OR], 11.43 [95% CI, 2.34-55.90; p = 0.0026). Most neonates with seizures (10/14), experienced their onset of seizures more than 96 hours after the start of ECMO. Overall, the presence of electrographic seizures, compared with not, was associated with lower odds of survival to NICU discharge (4/14 vs 49/61; OR 0.10 [95% CI 0.03 to 0.37], p = 0.0006). Also, the presence of seizures-rather than not-was associated with greater odds of a composite of death and all abnormal outcomes on follow-up (13/14 vs 26/61; OR, 17.5; 95% CI, 2.15-142.39; p = 0.0074). CONCLUSIONS: Nearly one in five neonates with CDH receiving ECMO developed seizures during the ECMO course. Seizures were predominantly electrographic-only and when present were associated with great odds of adverse outcomes. The current study provides evidence to support standardized CEEG in this population.

Hydrocephalus and school-age neurodevelopmental outcomes in the management of myelomeningocele prenatal surgery trial: a secondary analysis.

OBJECTIVE: The purpose of this secondary analysis was to assess the role of hydrocephalus on neurodevelopmental outcomes in a cohort of school-age children enrolled in the Management of Myelomeningocele Study (MOMS) clinical trial. METHODS: The sample analyzed in this report consisted of 150 of 183 children aged 5-10 years (mean ± SD 7 years 8 months ± 1.2) who were randomly assigned between 20 and 26 weeks of gestational age to undergo either prenatal or postnatal surgery and were enrolled in the school-age follow-up study of MOMS. These 150 children (76 prenatal and 74 postnatal) were placed into three groups: no hydrocephalus (n = 22), unshunted hydrocephalus (n = 31), and shunted hydrocephalus (n = 97). Comparisons were made on the basis of measures of adaptive behavior, intelligence, reading and math skills, verbal and nonverbal memory, fine motor dexterity, and sensorimotor skills. Parent ratings of executive functions, inattention, and hyperactivity-impulsivity were also compared. RESULTS: There were no statistically significant differences in neurodevelopmental outcomes between the groups with no hydrocephalus and unshunted hydrocephalus, or between the prenatal and postnatal groups with shunted hydrocephalus, so these groups were combined (no/unshunted vs shunted hydrocephalus). The no/unshunted group showed significantly better performance (p < 0.05) than the shunted group in terms of adaptive behavior, intelligence, verbal and nonverbal memory, reading skills (but not math), fine motor dexterity, sensorimotor skills (but not visual-motor integration), and inattention (but not hyperactivity-impulsivity or executive function ratings). An assessment of the prenatal surgery group showed that the combined no/unshunted group performed better than the shunted group in terms of adaptive behavior and verbal memory skills. Both the prenatal and postnatal surgery subgroups with unshunted hydrocephalus performed as well as the group with no hydrocephalus despite significantly enlarged ventricles. CONCLUSIONS: Although the primary assessment of school-age outcomes in the MOMS clinical trial did not show better adaptive behavior and cognitive skills in the prenatal group, hydrocephalus and shunting were associated with poorer neurodevelopmental outcomes (both prenatal and postnatal groups). Disease severity and dynamic changes in hydrocephalus status may be the primary factors in the need for shunting and a major determinant of adaptive behavior and cognitive outcomes after prenatal surgery.

Effects of 1.5-T versus 3-T magnetic resonance imaging in fetuses: is there a difference in postnatal neurodevelopmental outcome? Evaluation in a fetal population with left-sided congenital diaphragmatic hernia.

BACKGROUND: The utilization of 3-T magnetic field strength in obstetric imaging is increasingly common. It is important to ensure that magnetic resonance (MR) imaging with higher magnetic field strength is safe for the fetus. Comparison of neurodevelopmental outcome in neonates undergoing prenatal MR imaging with 1.5-T versus 3-T is of interest but has not yet been examined. OBJECTIVE: We hypothesized no clinically meaningful difference in neurodevelopmental outcome between fetuses undergoing 1.5-T versus 3-T fetal MR imaging. As imaging a normal fetus for research purposes is illegal in Pennsylvania, this study was conducted in a population of fetuses with left congenital diaphragmatic hernia (left-CDH). MATERIALS AND METHODS: A retrospective review of neurodevelopmental outcome of fetuses with left-CDH scanned at 1.5-T (n=75) versus 3-T (n=25) magnetic field strength between July of 2012 and December of 2019 was performed. Neurodevelopmental outcomes were assessed using the Bayley Scales of Infant Development, 3rd Edition (BSID-III). RESULTS: There were no statistical differences in median age of assessment (1.5-T: 18 [12, 25] versus 3-T: 21 [11, 26], P=0.79), in mean BSID-III cognitive (1.5-T: 91 ± 14 versus 3-T: 90 ± 16, P=0.82), language (1.5-T: 92 ± 20 versus 3-T: 91 ± 20, P=0.91), and motor composite (1.5-T: 89 ± 15 versus 3-T: 87 ± 18, P=0.59) scores, subscales scores (for all, P>0.50), or in risk of abnormal neuromuscular exam (P=0.29) between neonates with left-CDH undergoing a 1.5-T versus 3-T MR imaging during fetal life. Additionally, the distribution of patients with average, mildly delayed, and severely delayed BSID-III scores was similar between the two groups (for all, P>0.50). The overall distribution of the composite scores in this CDH population was similar to the general population independent of exposure to 1.5-T or 3-T fetal MR imaging. Two 3-T patients (8%) and five 1.5-T patients (7%) scored within the significant delayed range for all BSID-III domains. Subjects with lower observed-to-expected fetal lung volume (O/E FLV) and postnatal need for ECMO had lower cognitive, language, motor, and subscales scores (for all, P<0.03) regardless of being imaged at 1.5-T versus 3-T. CONCLUSION: This preliminary study suggests that, compared to 1.5-T MR imaging, fetal exposure to 3-T MR imaging does not increase the risk of neurodevelopmental impairment in fetuses with left-CDH. Additional MR imaging studies in larger CDH cohorts and other fetal populations are needed to replicate and extend the present findings.

Tethered cord release in patients after open fetal myelomeningocele closure: intraoperative neuromonitoring data and patient outcomes.

PURPOSE: The purpose of the study was to better understand the clinical course and impact of tethered cord release surgery on patients who have previously undergone open spinal dysraphism closure in utero. METHODS: This is a single-center retrospective observational study on patients undergoing tethered cord release after having previously had open fetal myelomeningocele (MMC) closure. All patients underwent tethered cord release surgery with a single neurosurgeon. A detailed analysis of the patients' preoperative presentation, intraoperative neuromonitoring (IONM) data, and postoperative course was performed. RESULTS: From 2009 to 2021, 51 patients who had previously undergone fetal MMC closure had tethered cord release surgery performed. On both preoperative and postoperative manual motor testing, patients were found to have on average 2 levels better than would be expected from the determined anatomic level from fetal imaging. The electrophysiologic functional level was found on average to be 2.5 levels better than the anatomical fetal level. Postoperative motor levels when tested on average at 4 months were largely unchanged when compared to preoperative levels. Unlike the motor signals, 46 (90%) of patients had unreliable or undetectable lower extremity somatosensory evoked potentials (SSEPs) prior to the tethered cord release. CONCLUSION: Tethered cord surgery can be safely performed in patients after open fetal MMC closure without clinical decline in manual motor testing. Patients often have functional nerve roots below the anatomic level. Sensory function appears to be more severely affected in patients leading to a consistent motor-sensory imbalance.

Impact of Definitive Surgery for Graves' Disease on Adolescent Disease-Specific Quality of Life and Psychosocial Functioning.

Introduction: Pediatric Graves' disease (GD) is associated with hyperthyroid symptoms that impact psychosocial and physical functioning. Total thyroidectomy (TT) is a definitive treatment option that replaces antithyroid medication. While studies have examined health-related quality of life (QOL) in adults, there are no data describing impacts of TT in pediatrics. In this prospective longitudinal study, we explored the impact of TT on disease-specific QOL and satisfaction with TT and scar appearance in adolescent patients with GD undergoing TT. Methods: Patients 12-19 years old pursuing TT for GD and their parents were recruited to complete surveys before and at least 6 months after TT. Surveys assessed motivations for pursuing TT, QOL, perceived stigmatization, self-esteem, scar appearance, and surgery satisfaction. Paired scores were compared using Wilcoxon signed-rank tests, and subscore associations were assessed using Spearman association tests. Results: Thirty-seven patient-parent dyads completed baseline surveys, including 20 patient-parent dyads completing pre- and post-TT surveys. At baseline, patients reported physical and cognitive symptomology, including tiredness, anxiety, and emotional susceptibility through ThyPRO. Psychosocial functioning at school was low through PedsQL. Disease-specific QOL significantly improved after TT, with notable improvements associated with resolution of goiter (median change = -26.14, p = 0.003), hyperthyroid symptoms (median change = -43.75, p = 0.002), tiredness (median change = -26.79, p = 0.017), cognitive impairment (median change = -14.58, p = 0.035), anxiety (median change = -33.33, p = 0.010), and emotional susceptibility (median change = -28.99, p = 0.035). Physical (median change = 18.75, p = 0.005) and school-related functioning (median change = 30.00, p = 0.002) also significantly improved post-TT. Reported GD-associated eye symptomology (thyroid eye disease) was the second lowest scoring ThyPRO subscore at baseline and improved after surgery (median change = 14.06, p = 0.03). Families reported median recovery by two months, high satisfaction with the outcomes of TT, and minimal concerns over scar appearance. No permanent surgical complications (i.e., recurrent laryngeal nerve damage or hypoparathyroidism) were sustained. Conclusions: In the setting of a high-volume surgeon with low complication rates, TT for GD in pediatric populations may have substantial beneficial effects on disease-specific QOL and psychosocial functioning, with minimal adverse complaints about scar appearance.

Clinicopathologic Characteristics of Pediatric Follicular Variant of Papillary Thyroid Carcinoma Subtypes: A Retrospective Cohort Study.

Introduction: Follicular patterned thyroid nodules with nuclear features of papillary thyroid carcinoma (PTC) encompass a range of diagnostic categories with varying risks of metastatic behavior. Subtypes include the invasive encapsulated follicular variant of PTC (Ienc-fvPTC) and infiltrative fvPTC (inf-fvPTC), with tumors lacking invasive features classified as noninvasive follicular thyroid neoplasms with papillary-like features (NIFTPs). This study aimed to report the clinical and histological features of pediatric cases meeting criteria for these histological subtypes, with specific focus on Ienc-fvPTC and inf-fvPTC. Methods: In this retrospective cohort study, pediatric patients with thyroid neoplasms showing follicular patterned growth and nuclear features of PTC noted on surgical pathology between January 2010 and January 2021 were retrospectively reviewed and classified according to the recent 2022 World Health Organization (WHO) criteria. Clinical and histopathologic parameters were described for NIFTP, Ienc-fvPTC, and inf-fvPTC subtypes, with specific comparison of Ienc-fvPTC and inf-fvPTC cases. Results: The case cohort included 42 pediatric patients, with 6 (14%), 25 (60%), and 11 (26%) patients meeting criteria for NIFTP, Ienc-fvPTC, and inf-fvPTC, respectively. All cases were rereviewed, and 5 patients originally diagnosed with Ienc-fvPTC before 2017 were reappraised as having NIFTPs. The NIFTP cases were encapsulated tumors without invasive features, lymph node or distant metastasis, or disease recurrence. Ienc-fvPTC tumors demonstrated clearly demarcated tumor capsules and capsular/vascular invasion, while inf-fvPTC tumors displayed infiltrative growth lacking a capsule. inf-fvPTC cases had increased prevalence of malignant preoperative cytology, lymph node metastasis, and distant metastasis (p < 0.01). These cases were treated with total thyroidectomy, lymph node dissection, and subsequent radioactive iodine therapy. Preliminary genetic findings suggest a predominance of fusions in inf-fvPTC cases versus point mutations in Ienc-fvPTC (p = 0.02). Conclusions: Pediatric NIFTP and fvPTC subtypes appear to demonstrate alignment between clinical and histological risk stratification, with indolent behavior in Ienc-fvPTC and invasive features in inf-fvPTC tumors.

Mosaic GLUD1 Mutations Associated with Hyperinsulinism Hyperammonemia Syndrome.

INTRODUCTION: The hyperinsulinemia-hyperammonemia syndrome (HIHA) is the second most common cause of congenital hyperinsulinism and is caused by activating heterozygous missense mutations in GLUD1. In the majority of HIHA cases, the GLUD1 mutation is found to be de novo. We have identified 3 patients in whom clinical evaluation was suggestive of HIHA but with negative mutation analysis in peripheral blood DNA for GLUD1 as well as other known HI genes. METHODS: We performed next-generation sequencing (NGS) on peripheral blood DNA from two children with clinical features of HIHA in order to look for mosaic mutations in GLUD1. Pancreas tissue was also available in one of these cases for NGS. In addition, NGS was performed on peripheral blood DNA from a woman with a history of HI in infancy whose child had HIHA due to a presumed de novo GLUD1 mutation. RESULTS: Mosaic GLUD1 mutations were identified in these 3 cases at percent mosaicism ranging from 2.7% to 10.4% in peripheral blood. In one case with pancreas tissue available, the mosaic GLUD1 mutation was present at 17.9% and 28.9% in different sections of the pancreas. Two unique GLUD1 mutations were identified in these cases, both of which have been previously reported (c.1493c>t/p.Ser445Leu and c.820c>t/p.Arg221Cys). CONCLUSION: The results suggest that low-level mosaic mutations in known HI genes may be the underlying molecular mechanism in some children with HI who have negative genetic testing in peripheral blood DNA.

Indeterminate Thyroid Fine-Needle Aspirations in Pediatrics: Exploring Clinicopathologic Features and Utility of Molecular Profiling.

INTRODUCTION: The diagnostic utility of molecular profiling for the evaluation of indeterminate pediatric thyroid nodules is unclear. We aimed to assess pediatric cases with indeterminate thyroid fine-needle aspiration (FNA) alongside clinicopathologic features and mutational analysis. METHODS: A retrospective review of 126 patients with indeterminate cytology who underwent FNA between January 2010 and December 2021 at the Children's Hospital of Philadelphia was performed. Indeterminate cases defined by The Bethesda System for Reporting Thyroid Cytopathology (AUS/FLUS or TBSRTC III; FN/SFN or TBSRTC IV; SM or TBSRTC V) were correlated to clinicopathologic and genetic characteristics. RESULTS: Of the 114 surgical cases, 48% were malignant, with the majority of malignant cases diagnosed as follicular variant of papillary thyroid carcinoma (28/55). Risk of malignancy increased with TBSRTC category: 23% for AUS/FLUS, 51% for FN/SFN, and 100% for SM nodules. There were significant differences in surgical approach (p < 0.01), performance of lymph node dissection (p < 0.01), histological diagnosis (p < 0.01), primary tumor focality/laterality (p = 0.04), and lymphatic invasion (p = 0.02) based on TBSRTC classification, with resultant differences in post-surgical risk stratification per American Thyroid Association (ATA) Pediatric Guidelines (p = 0.01). Approximately 89% (49/55) of cases were classified as ATA low risk, and 5 of 6 patients with ATA intermediate- or high-risk disease had SM cytology. Somatic molecular testing was performed in 40% (51/126) of tumors; 77% (27/35) of malignant cases and 38% (6/16) of benign cases harbored driver alteration(s). Of the driver-positive malignant cases, 52% (14/27) were associated with low risk (DICER1, PTEN, RAS, and TSHR mutations), 33% (9/27) were associated with high risk (BRAF mutations and ALK, NTRK, and RET fusions), and 15% (4/27) had unreported risk for invasive disease (APC, BLM, and PPM1D mutations and TG-FGFR1 fusion). Incidence of high-risk drivers increased with TBSRTC category. Approximately 23% (8/35) of patients harboring thyroid malignancy did not have an identifiable driver alteration. CONCLUSIONS: Molecular analysis is useful to discriminate benign and malignant thyroid nodules with indeterminate cytology. Patients with driver genetic alteration(s) and indeterminate cytology should consider surgical management secondary to the high incidence (82%; 27/33) of thyroid malignancy in these patients.

Localized islet nuclear enlargement hyperinsulinism (LINE-HI) due to ABCC8 and GCK mosaic mutations.

Objective: Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in children. In addition to typical focal or diffuse HI, some cases with diazoxide-unresponsive congenital HI have atypical pancreatic histology termed Localized Islet Nuclear Enlargement (LINE) or mosaic HI, characterized by histologic features similar to diffuse HI, but confined to only a region of pancreas. Our objective was to characterize the phenotype and genotype of children with LINE-HI. Design: The phenotype and genotype features of 12 children with pancreatic histology consistent with LINE-HI were examined. Methods: We compiled clinical features of 12 children with LINE-HI and performed next-generation sequencing on specimens of pancreas from eight of these children to look for mosaic mutations in genes known to be associated with diazoxide-unresponsive HI (ABCC8, KCNJ11, and GCK). Results: Children with LINE-HI had lower birth weights and later ages of presentation compared to children with typical focal or diffuse HI. Partial pancreatectomy in LINE-HI cases resulted in euglycemia in 75% of cases; no cases have developed diabetes. Low-level mosaic mutations were identified in the pancreas of six cases with LINE-HI (three in ABCC8, three in GCK). Expression studies confirmed that all novel mutations were pathogenic. Conclusion: These results indicate that post-zygotic low-level mosaic mutations of known HI genes are responsible for some cases of LINE-HI that lack an identifiable germ-line mutation and that partial pancreatectomy may be curative for these cases.

Fetal thoracic teratomas: mediastinal or pericardial?

BACKGROUND: Mediastinal and pericardial teratomas have overlapping imaging features that may make accurate prenatal diagnosis challenging. OBJECTIVE: To identify prenatal imaging features that may aid in distinguishing between mediastinal and pericardial teratomas. MATERIALS AND METHODS: Prenatally diagnosed pericardial and mediastinal teratomas evaluated at our fetal center from 1995 to 2020 were included in this Institutional Review Board-approved study. Lesion volume was calculated using prospectively reported ultrasound (US) measurements and the formula of a prolate ellipsoid, which was then normalized to head circumference. Prenatal US and magnetic resonance imaging (MRI) studies were anonymized with two fetal imagers reviewing the US studies and two different fetal imagers reviewing the MRI studies. These experienced reviewers scored location of the mass in the craniocaudal axis and in the transverse axis. MRI reviewers also scored the presence of inferior cardiac compression by the lesion and whether there was identifiable thymic tissue. Reviewer disagreements were resolved by consensus review. RESULTS: Eleven pericardial teratomas and 10 mediastinal teratomas were identified. All cases underwent detailed fetal anatomic US and fetal echocardiogram and 10/11 (91%) pericardial teratomas and 8/10 (80%) mediastinal teratomas underwent fetal MRI. Median volume was higher for mediastinal teratomas compared to pericardial teratomas (42.5 mL [interquartile range (IQR) 15.9 - 67.2 mL] vs. 8.1 mL [IQR 7.7 - 27.7 mL], P=0.01) and median volume/head circumference was also statistically higher in mediastinal teratomas (1.33 [IQR 0.78 - 2.61] vs. 0.43 [IQR 0.38 - 1.10], P=0.01). Logistic regression analysis demonstrated a statistical difference between teratoma types with respect to location in the craniocaudal axis by both modalities with mediastinal teratomas more commonly located in the upper and upper-middle thorax compared to pericardial teratomas, which were more commonly found in the middle thorax (US, P=0.03; MRI, P=0.04). Logistic regression analysis also demonstrated a statistical difference between teratoma types with respect to position along the transverse axis by both modalities with mediastinal teratomas more commonly located midline or left paramedian and pericardial teratomas more often right paramedian in location (US, P<0.01; MRI, P=0.02). Inferior cardiac compression observed by MRI was associated more commonly with mediastinal teratomas compared to pericardial teratomas (87.5% [7/8] vs. 10% [1/10], P<0.01). Identifiable thymus by MRI was more commonly observed in cases of pericardial teratomas, however, this difference was not statistically significant (P=0.32). CONCLUSION: Mediastinal teratomas are associated with larger lesion size and inferior cardiac compression when compared to pericardial teratomas. These features combined with lesion location in the craniocaudal and transverse axes may allow for more accurate prenatal diagnosis and optimal perinatal and surgical management.