Developmental Outcomes of Aicardi Goutières Syndrome.

Aicardi Goutières syndrome is a monogenic interferonopathy caused by abnormalities in the intracellular nucleic acid sensing machinery (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, or IFIH1). Most individuals affected by Aicardi Goutières syndrome exhibit some degree of neurologic impairment, from spastic paraparesis with relatively preserved cognition to tetraparesis and severe intellectual disability. Because of this heterogeneity, it is important to fully characterize the developmental trajectory in Aicardi Goutières syndrome. To characterize the clinical presentation in Aicardi Goutières syndrome, early features were collected from an international cohort of children (n = 100) with genetically confirmed Aicardi Goutières syndrome. There was a heterogeneous age of onset, with overlapping clusters of presenting symptoms: altered mental status, systemic inflammatory symptoms, and acute neurologic disability. Next, we created genotype-specific developmental milestone acquisition curves. Individuals with microcephaly or TREX1-related Aicardi Goutières syndrome secondary were the most severely affected and less likely to reach milestones, including head control, sitting, and nonspecific mama/dada. Individuals affected by SAMHD1, IFIH1, and ADAR attained the most advanced milestones, with 44% achieving verbal communication and 31% independently ambulating. Retrospective function scales (Gross Motor Function Classification System, Manual Ability Classification System, and Communication Function Classification System) demonstrated that two-thirds of the Aicardi Goutières syndrome population are severely affected. Our results suggest multifactorial influences on developmental trajectory, including a strong contribution from genotype. Further studies are needed to identify the additional factors that influence overall outcomes to better counsel families and to design clinical trials with appropriate clinical endpoints.

Continuous Intragastric Dextrose: A Therapeutic Option for Refractory Hypoglycemia in Congenital Hyperinsulinism.

Feeding problems are frequent in infants with congenital hyperinsulinism (HI) and may be exacerbated by continuous enteral nutrition (EN) used to maintain euglycemia. Our center's HI team uses dextrose solution given continuously via gastric tube (intrasgastric dextrose, IGD) for infants not fully responsive to conventional medical therapy or pancreatectomy. Here, we describe our practice as well as growth, feeding, and adverse events in infants with HI exposed to IGD. METHODS: This was a retrospective cohort of infants with HI treated with IGD from 2009-2017. Primary outcomes were weight-for-length and body mass index Z-scores (WFL-Z and BMI-Z) in the year following IGD initiation. Secondary outcomes included EN use and adverse events. We used multivariable regression to assess covariates of interest. RESULTS: We studied 32 subjects (13 female) with a median age at IGD initiation of 73 days (range 17-367); median follow-up was 11.2 months (range 5.0-14.2). WFL-Z did not change significantly over time (p > 0.05). EN use decreased significantly over time, i.e., at 0 months: 72% (95% CI 53-85) vs. at 12 months 39% (95% CI 22-59). No potential adverse events led to discontinuation of IGD. CONCLUSIONS: Over a median follow-up of nearly 1 year, IGD was well-tolerated, with no change in WFL-Z or BMI-Z from baseline.

Natural History of Fetal Lower Urinary Tract Obstruction with Normal Amniotic Fluid Volume at Initial Diagnosis.

OBJECTIVE: The aim of this study was to define the natural history of lower urinary tract obstruction (LUTO) with normal midgestational amniotic fluid volumes. MATERIALS AND METHODS: We performed a retrospective review of 32 consecutive patients with LUTO with normal midgestational amniotic fluid volume followed at 11 North American Fetal Therapy Network (NAFTNet) centers from August 2007 to May 2012. Normal amniotic fluid volume was defined as an amniotic fluid index (AFI) of ≥9 cm. RESULTS: The mean gestational age (GA) and AFI at enrollment were 23.1 ± 2.1 weeks and 15.8 ± 3.9 cm, respectively. The mean GA at delivery was 37.3 ± 2.8 weeks. The mean creatinine level at discharge was 1.2 ± 0.8 mg/dL. Perinatal survival was 97%. Twenty-five patients returned for serial postnatal assessment. Renal replacement therapy (RRT) was required in 32%. Development of oligohydramnios and/or anhydramnios, development of cortical renal cysts, posterior urethral valves, prematurity, and prolonged neonatal intensive care unit stay were associated with need for RRT (p < 0.05) by univariate analysis. By multivariate analysis, preterm delivery remained predictive of need for RRT (p = 0.004). CONCLUSION: Prenatal diagnosis of LUTO with normal midgestational amniotic fluid volumes is associated with acceptable renal function in the majority of patients. Approximately one-third of these children require RRT. Surrogate markers of disease severity appear to be predictive of need for RRT.

Long-term neurofunctional outcome, executive functioning, and behavioral adaptive skills following fetal myelomeningocele surgery.

BACKGROUND: Myelomeningocele (MMC) represents the first nonlethal anomaly to be treated by prenatal intervention. Case series and a prospective, randomized study show that fetal surgery for MMC before 26 weeks' gestation may preserve neurological function. Long-term follow-up is a fundamental component to evaluate the overall efficacy of any new medical or surgical procedure. To further delineate the long-term impact of fMMC surgery, we continued to follow children treated in our institution before the Management of Myelomeningocele Study trial by the means of parental questionnaires to assess changes in functional, developmental, and cognitive status as these unique patients grow older. OBJECTIVE: The objective of the study was to evaluate the long-term neurological outcome, executive functioning (EF), and behavioral adaptive skills (BAS) following fetal myelomeningocele (fMMC) surgery. STUDY DESIGN: Prior to the Management of Myelomeningocele Study trial, 54 patients underwent fMMC surgery at our institution. Parents of 42 children (78%) participated in structured questionnaires focusing on neurofunctional outcome. EF and BAS were measured by the Behavior Rating Inventory of Executive Function (BRIEF) and the Adaptive Behavioral Assessment System II. The BRIEF is organized into 3 primary indices including the following: Global Executive Composite, Metacognition Index, and Behavioral Regulation Index. The Adaptive Behavioral Assessment System II results in a general adaptive composite score. Based on SD intervals, EF and BAS were categorized as being average, borderline, or impaired. RESULTS: At a median follow-up age of 10 years (range, 8-14 years), 33 (79%) are community ambulators, 3 (9%) are household ambulators, and 6 (14%) are wheelchair dependent. Preschool ambulation was predictive of long-term ambulation (P < .01), whereas the need for tethered cord surgery was associated with persistent deterioration of ambulatory status (P = .007). Normal bladder function was found in 26%. Although the majority scored within the average range for the Behavioral Regulation Index, Metacognition Index, and Global Executive Composite indices, significantly more children who had fMMC surgery had deficits in EF in all 3 BRIEF indices compared with the population norms. The general adaptive composite scores were also more likely to fall below average following fMMC surgery. Normal early neurodevelopmental outcomes were predictive of normal EF and BAS (P < .01). Need for shunting was associated with a significant impairment of BAS (P = .02). CONCLUSION: The present study suggests that fMMC surgery improves long-term functional outcome. The majority of fMMC children can successfully complete everyday tasks at home and at school. Abnormalities of BAS appear to be more common than impairments in EF and therefore offer an area for early screening and interventional therapy for these at-risk children. Non-shunted fMMC children with normal early neurodevelopmental outcome are less likely to experience problems with EF and BAS. fMMC surgery improves long-term ambulatory status. Symptomatic spinal cord tethering with or without intradural inclusion cyst is associated with functional loss. More than expected fMMC children are continent, but bowel and bladder control continue to be an ongoing challenge for the fMMC children.

Fetal myelomeningocele repair: the post-MOMS experience at the Children's Hospital of Philadelphia.

BACKGROUND: Fetal myelomeningocele (fMMC) repair has become accepted as a standard of care option in selected circumstances. We reviewed our outcomes for fMMC repair from referral and evaluation through surgery, delivery and neonatal discharge. MATERIAL AND METHODS: All patients referred for potential fMMC repair were reviewed from January 1, 2011 through March 7, 2014. Maternal and neonatal data were collected on the 100 patients who underwent surgery. RESULTS: 29% of those evaluated met the criteria and underwent fMMC repair (100 cases). The average gestational age was 21.9 weeks at evaluation and 23.4 weeks at fMMC repair. Complications included membrane separation (22.9%), preterm premature rupture of membranes (32.3%) and preterm labor (37.5%). Average gestational age at delivery was 34.3 weeks and 54.2% delivered at ≥35 weeks. The perinatal loss rate was 6.1% (2 intrauterine fetal demises and 4 neonatal demises); 90.8% of women delivered at the Children's Hospital of Philadelphia and 3.4% received transfusions. With regard to the neonates, 2 received ventriculoperitoneal shunts prior to discharge; 71.1% of neonates had no evidence of hindbrain herniation on MRI. Of the 80 neonates evaluated, 55% were assigned a functional level of one or more better than the prenatal anatomic level. CONCLUSION: In an experienced program, maternal and neonatal outcomes for patients undergoing fMMC repair are comparable to results of the MOMS trial.

Maternal, fetal, and neonatal care in open fetal surgery for myelomeningocele.

Fetal myelomeningocele closure (fMMC) was demonstrated in a randomized, prospective clinical trial to improve outcomes for children diagnosed prenatally. Complex care of the maternal/fetal dyad undergoing fetal surgery requires a well-coordinated multidisciplinary team. Nurses in many roles are essential members of the team that cares for these women across the continuum. In this article we discuss the care of the woman, fetus, and family from initial contact through the discharge of the neonate.

Preschool neurobehavioral outcome following fetal myelomeningocele surgery.

OBJECTIVE: It was the aim of this study to assess the prevalence of preschool neurobehavioral problems in children following fetal myelomeningocele (fMMC) surgery. METHODS: Prior to the Management of Myelomeningocele Study, 30 fMMC patients underwent a standardized neurodevelopmental examination at 5 years of age. The prevalence of behavioral problems was assessed by the Child Behavior Check List (CBCL), which includes a total problem score and 2 broad-band indices (internalizing and externalizing problems). fMMC children were classified as having normal, at-risk or clinically significant scores based on calculated T scores. RESULTS: Twenty-two (73%) fMMC families completed the evaluation. Mean age at delivery following fMMC surgery was 35.5 ± 1.6 weeks. The prevalence of 'at-risk' or 'clinically significant' scores for internalizing, externalizing and total behavioral problems was similar to general population norms. No difference in overall internalizing (p = 0.19), externalizing (p = 0.54) and total behavioral (p = 0.18) scores was found between non-shunted and shunted fMMC children. However, shunted fMMC children were more likely to experience anxiety and depressive (p = 0.02), pervasive developmental (p = 0.03) and withdrawn (p = 0.06) behavior. Oppositional defiant, attention deficit and hyperactivity problems were not found. No correlation was found between overall neurodevelopmental outcome and abnormal CBCL scores. CONCLUSIONS: fMMC surgery and subsequent preterm delivery is not associated with increased behavioral problems, impaired social interactions and restricted behavior patterns. Shunted fMMC children were more likely to have scores in the 'at-risk' or 'clinically significant' range for multiple CBCL subindices. Early detection of behavioral problems following fMMC surgery provides an opportunity for targeted and timely intervention enabling affected fMMC children to be socially successful.

Fetal myelomeningocele surgery: preschool functional status using the Functional Independence Measure for children (WeeFIM).

OBJECTIVE: To study preschool functional status in children following fetal myelomeningocele (fMMC) surgery. MATERIAL AND METHODS: Prior to the NICHD-MOMS trial, 30 fMMC underwent standardized neurodevelopmental examination at 5 years of age. Functional status was determined with the Functional Independence Measure (WeeFIM), which assesses self-care, mobility, and cognitive independence. RESULTS: Evaluations were completed in 26 (87%). Mean cognitive (93.0 ± 21.9), self-care (66.5 ± 23.9), mobility (82.3 ± 19.5), and total (77.9 ± 20.3) functional quotient of fMMC children were significantly lower than age-matched population norms (P < 0.01). Complete caregiver independence was achieved by 22 (84%), 10 (38%), 16 (62%), and 15 (58%) fMMC children for cognition, self-care, mobility, and total functional outcome, respectively. Cognitive, mobility, and total independence were higher in non-shunted than shunted fMMC children (P = 0.02, P = 0.02, and P < 0.01, respectively) and in fMMC children with average neurodevelopmental scores (P < 0.001, P = 0.01, and P < 0.01, respectively). Self-care independence tended to be higher in the non-shunted group and in fMMC children with normal neurodevelopmental outcome (P = 0.07 and P = 0.09, respectively). CONCLUSION: The majority of fMMC children achieved cognitive and mobility independence, but continue to require significant assistance in self-care. Non-shunted and fMMC children with normal neurodevelopmental outcome were more likely to be independent in daily living activities. Better understanding of the extent of functional limitations following fMMC surgery will allow for more effective early interventions geared toward maximizing independence in everyday tasks in all environments.

Norrie disease gene sequence variants in an ethnically diverse population with retinopathy of prematurity.

PURPOSE: Retinopathy of prematurity (ROP) is a leading cause of visual loss in the pediatric population. Mutations in the Norrie disease gene (NDP) are associated with heritable retinal vascular disorders, and have been found in a small subset of patients with severe retinopathy of prematurity. Varying rates of progression to threshold disease in different races may have a genetic basis, as recent studies suggest that the incidence of NDP mutations may vary in different groups. African Americans, for example, are less likely to develop severe degrees of ROP. We screened a large cohort of ethnically diverse patients for mutations in the entire NDP. METHODS: A total of 143 subjects of different ethnic backgrounds were enrolled in the study. Fifty-four patients had severe ROP (Stage 3 or worse). Of these, 38 were threshold in at least one eye (with a mean gestational age of 26.1 weeks and mean birth weight of 788.4 g). There were 36 patients with mild or no ROP, 31 parents with no history of retinal disease or prematurity, and 22 wild type (normal) controls. There were 70 African American subjects, 55 Caucasians, and 18 of other races. Severe ROP was noted in 29 African American subjects, 17 Caucasians, and 8 of other races. Seven polymerase chain reaction primer pairs spanning the NDP were optimized for denaturing high performance liquid chromatography and direct sequencing. Three primer pairs covered the coding region, and the remaining four spanned the 3' and 5' untranslated regions (UTR). RESULTS: Six of 54 (11%) infants with severe ROP had polymorphisms in the NDP. Five of the infants were African American, and one was Caucasian. Two parents were heterozygous for the same polymorphism as their child. One parent-child pair had a single base pair (bp) insertion in the 3' UTR region. Another parent-child pair had two mutations: a 14 bp deletion in the 5' UTR region of exon 1 and a single nucleotide polymorphism in the 5' UTR region of exon 2. No coding region sequence changes were found. No polymorphisms were observed in infants with mild or no ROP, or in the wild type controls. CONCLUSIONS: Of the six sequence alterations found, five were novel nucleotide changes: One in the 5' UTR region of exon 2, and four in the 3' UTR region of exon 3. The extent of NDP polymorphisms in this large, racially diverse group of infants is moderate. NDP polymorphisms may play a role in the pathogenesis of ROP, but do not appear to be a major causative factor.