All reported mutations in the choroideremia (CHM) gene result in the truncation or complete absence of Rab escort protein 1 (REP1). Molecular analysis was carried out on 57 families diagnosed with CHM. Confirmation of the clinical diagnosis is important as end-stage CHM may be clinically similar to the end stages of other retinal degenerative diseases such as RP. The primary means of confirming the diagnosis of CHM is to sequence all 15 exons. An alternative method involves detection of the REP1 protein, as described in MacDonald et al. [1998]. A monoclonal antibody to REP1 does not detect truncated REP1 by immunoblot analysis, presumably due to instability and subsequent degradation of the truncated protein. This analysis provides relatively fast confirmation of the diagnosis, however, protein samples are not always available and are susceptible to degradation, affecting the accurate interpretation of results. CHM gene mutations were found in 54 of 57 families studied. The majority of mutations (>42%) were transitions and transversions. Complete deletions of the CHM gene and deletion/insertion mutations each accounted for almost 4% of the total, while over 9% had large intragenic and other partial deletions. Almost 28% of the mutations were deletions of fewer than 5 base pairs (bp) and almost 13% were splice site mutations. Despite the fact that mutations are found throughout the gene with no common mutation for the disorder, identical mutations have been characterized in unrelated individuals. The majority of these mutations are C to T transitions, changing an arginine residue (CGA) to a stop codon (TGA). Four of the five CGA codons in the CHM gene are sites of recurring mutations.

BackgroundFine needle aspiration biopsy (FNAB) is an accurate test commonly used to determine whether thyroid nodules are malignant in adults. However, less is known about its diagnostic accuracy for this purpose in children, where conduct of FNAB is less frequent, more technically challenging, and pre-test probabilities of malignancy are often higher. The purpose of this systematic review is to evaluate the diagnostic accuracy of FNAB for the detection of malignancy in pediatric thyroid nodules.MethodsWe will search electronic bibliographic databases (MEDLINE, EMBASE, the Cochrane Library, and Evidence-Based Medicine) from their date of inception, reference lists of included articles, proceedings from relevant conferences, and the table of contents of the Journal of Pediatric Surgery (January 2007–present). Two reviewers will independently screen titles and abstracts and identify diagnostic accuracy studies involving FNAB of the thyroid in children. We will include studies comparing FNAB to a reference standard of surgical histopathology or clinical follow-up for detection of malignancy in pediatric thyroid nodules. Two investigators will independently extract data and assess risk of bias using the Quality of Diagnostic Accuracy Studies-II tool. Pooled estimates of sensitivity, specificity, and positive and negative likelihood ratios will be calculated using bivariate random-effects and hierarchical summary receiver operating characteristic models. In the presence of between-study heterogeneity, we will conduct stratified meta-analyses and meta-regression to determine whether diagnostic accuracy estimates vary by country of origin, use of ultrasound guidance during FNAB, qualifications of the individuals performing/interpreting FNAB, adherence to the Bethesda criteria for cytology classification, length of clinical follow-up, timing of data collection, patient selection methods, and presence of verification bias.DiscussionThis meta-analysis will determine the diagnostic accuracy of FNAB for detection of malignancy in pediatric thyroid nodules and explore whether heterogeneity observed across studies may be explained by variations in patient population, FNAB technique or interpretation, and/or study-level risks of bias. This will be the first study to determine the accuracy of Bethesda cytological classification levels of FNAB (benign, atypical, follicular, suspicious, malignant). We expect that our results will help in guiding clinical decision-making in children with thyroid nodules.Systematic review registrationPROSPERO No. CRD42014007140

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