Risk factors for Dandy-Walker malformation: a population-based assessment.

Dandy-Walker malformation (DWM) is the most common congenital malformation of the cerebellum, but its causes are largely unknown. An increasing number of genes associated with congenital cerebellar malformations have been identified; however, few studies have examined the potential role of non-genetic, potentially modifiable risk factors. From the National Birth Defects Prevention Study, we examined maternal, paternal, and infant characteristics and maternal conditions and periconceptional exposures (from 1 month before to 3 months after conception) among infants with DWM (n = 160) and unaffected controls (n = 10,200), delivered between 1997 and 2009. Odds ratios, crude (cOR) and adjusted (aOR) were computed using logistic regression. Maternal factors associated with DWM included non-Hispanic black race/ethnicity (aOR = 2.0, 95%CI: 1.3-3.2). Among maternal conditions, a history of infertility increased the risk for DWM (all: aOR = 2.4, 95%CI: 1.3-4.6; multiple: aOR = 3.9, 95%CI: 1.7-8.9). The lack of association with many maternal exposures supports the hypothesis of a major contribution of genetic factors to the risk for DWM; however, the observed associations with maternal non-Hispanic black race/ethnicity and maternal history of infertility indicate that further research into factors underlying these characteristics may uncover potentially modifiable risk factors, acting alone or as a component of gene-environment interactions.

Assessment of congenital anomalies in infants born to pregnant women enrolled in clinical trials.

In 2011 and 2012, the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, held a series of meetings to provide guidance to investigators regarding study design of clinical trials of vaccines and antimicrobial medications that enroll pregnant women. Assessment of congenital anomalies among infants born to women enrolled in these trials was recognized as a challenging issue, and a workgroup with expertise in epidemiology, pediatrics, genetics, dysmorphology, clinical trials, and infectious diseases was formed to address this issue. The workgroup considered 3 approaches for congenital anomalies assessment that have been developed for use in other studies: (1) maternal report combined with medical records review, (2) standardized photographic assessment and physical examination by a health professional who has received specific training in congenital anomalies, and (3) standardized physical examination by a trained dysmorphologist (combined with maternal interview and medical records review). The strengths and limitations of these approaches were discussed with regard to their use in clinical trials. None of the approaches was deemed appropriate for use in all clinical trials. Instead, the workgroup acknowledged that decisions regarding the optimal method of assessment of congenital anomalies will likely vary depending on the clinical trial, its setting, and the agent under study; in some cases, a combination of approaches may be appropriate. The workgroup recognized the need for more research on approaches to the assessment of congenital anomalies to better guide investigators in optimal design of clinical trials that enroll pregnant women.

A diagnostic paradigm including cytomegalovirus testing for idiopathic pediatric sensorineural hearing loss.

OBJECTIVES/HYPOTHESIS: To determine the feasibility and cost effectiveness of incorporating cytomegalovirus (CMV) testing to determine the etiology of pediatric hearing loss. STUDY DESIGN: Retrospective study of children presenting with sensorineural hearing loss (SNHL) at one institution from 2008 to 2013. METHODS: Children aged 3 years or younger who presented to the senior author (A.P.) between May 2008 and September 2013 with confirmed SNHL were evaluated. These children underwent a sequential diagnostic paradigm that incorporated CMV testing if no obvious etiology could be determined from the history or physical examination. RESULTS: One hundred eleven children with SNHL were evaluated between 2008 and 2013. Eighty-three children underwent CMV testing, imaging, and a genetic evaluation. Those with confirmed or probable CMV-induced SNHL made up 30% of all children tested (n = 25), the largest group identified. CMV screening had the lowest cost compared to genetic testing or imaging for all types of hearing loss, except for those with auditory neuropathy spectrum disorder. CONCLUSION: We present the first sequential diagnostic paradigm utilizing CMV testing for children presenting with SNHL. The relatively high incidence of CMV-induced SNHL, the low cost for this assay, and the indirect benefits from early diagnosis support the role of early CMV testing for these patients. LEVEL OF EVIDENCE: 4.

A cost savings approach to SPRED1 mutational analysis in individuals at risk for neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a clinically diagnosed autosomal dominant disorder requiring routine clinical management, particularly during the pediatric years. An overlapping disorder, Legius syndrome, at times is clinically indistinguishable from NF1 and results in a small percentage of individuals being mischaracterized. Distinguishing these two entities is increasingly important for prognosis, reproductive planning, and clinical management. The goal of our study was to evaluate the cost impact of genetic testing for patients with solely pigmentary findings. The costs of genetic testing in patients aged 1.5-18 years were modeled using a simulated population, assuming the clinical management approach of a single NF1 clinic. Two genetic testing algorithms (SPRED1 testing alone, and NF1 mutation analysis with reflex to SPRED1) were compared against a baseline of no genetic testing. The cost for SPRED1 mutation analysis for each individual meeting NF1 diagnostic criteria without neoplastic or boney manifestation, when compared to the no-testing approach with routine follow-up mutations between the ages of 10 and 14 years, was minimal (range of $4-$16). Based on the clinical practice of one NF1 clinic, we found that the cost difference to perform SPRED1 mutation analysis on individuals who meet diagnostic criteria for NF1 without neoplastic or boney manifestation were minimal. Therefore it is important that "when to test decisions" remain a physician/patient discussion, as individual benefits may be greatest at a different age than when it is most cost efficient.

Perspectives on the care and management of infants with trisomy 18 and trisomy 13: striving for balance.

PURPOSE OF REVIEW: At the time of diagnosis of the trisomy 18 and trisomy 13, parents and care providers face difficult and challenging decisions regarding management. Because of the increased infant mortality and developmental outcome associated with both conditions, the conventional approach to management has been to withhold technological support. In recent years, an active dialogue on this topic has emerged. The purpose of this review is to summarize the literature on the outcome of infants with trisomy 18 and 13 and to discuss the key themes in this emerging dialogue. RECENT FINDINGS: In recent years, several important studies have appeared that have analyzed the issues relevant to this topic, including parental autonomy, best interest of the child standard, and quality of life. Some authorities state that in areas of ambiguity it is best to defer to parents' views, whereas others indicate concern that the best interest standard has given way to parental autonomy. Information on the actual experience of parents of children with trisomy 18 and 13 has been limited until recently. SUMMARY: The author recommends a balanced approach to counseling families of the newborn with trisomy 18 and 13 at the time of diagnosis. The counseling process should include presentation of accurate survival figures, avoidance of language that assumes outcome, communication of developmental outcome that does not presuppose perception of quality of life, and respect for the family's choice, whether it be comfort care or intervention.