John K. Petty

Novel FOXF1 Mutations in Sporadic and Familial Cases of Alveolar Capillary Dysplasia with Misaligned Pulmonary Veins Imply a Role for its DNA Binding Domain

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA‐binding domain, indicating its plausible role in FOXF1 function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis.

Familial small cell carcinoma of the ovary.

Ovarian tumors have a low incidence in childhood, accounting for 1% of malignancies within the ages of 0–17 years. Small cell carcinoma of the ovary is a rare histology and historically has a poor prognosis. We report a case of an 11‐year‐old female diagnosed with small cell carcinoma of the ovary and hypercalcemia (SCCOHT). There was a strong family history of the disease, a reduction in the age of onset in the proband, and the absence of BRCA mutations. This case suggests the phenomenon of genetic anticipation in an ovarian cancer. Pediatr Blood Cancer 2009; 53:1334–1336.

Experimental testicular tissue banking to generate spermatogenesis in the future: A multidisciplinary team approach.

Spermatogonial stem cell (SSC) loss due to cancer treatment, developmental disorder or genetic abnormality may cause permanent infertility. Cryopreservation of ejaculated sperm is an effective method of fertility preservation in adult males at risk of infertility. However this is not an option in pre-pubertal boys because spermatogenesis has not yet started, and it is difficult in adolescents who are not sexually mature. Therefore testicular tissue cryopreservation to preserve SSCs for future generation of spermatogenesis, either in vivo or in vitro, could be an option for these groups of patients. Although SSC transplantation has been successful in several species including non-human primates, it is still experimental in humans. There are several remaining concerns which need to be addressed before initiating trials of human SSC autotransplantation. Establishment of a testicular tissue banking system is a fundamental step towards using SSC technology as a fertility preservation method. It is important to understand the consultation, harvesting the testicular tissue, histological evaluation, cryopreservation, and long term storage aspects. We describe here a multidisciplinary approach to establish testicular tissue banking for males at risk of infertility.

Recommendations for venous thromboembolism prophylaxis in pediatric trauma patients: A national, multidisciplinary consensus study.

T incidence of venous thromboembolism (VTE) has been increasing in children, although the incidence remains lower than the incidence in adults. The incidence of VTE is higher in injured children than it is in the general population of uninjured hospitalized children, ranging from 0.02% to 0.33%. Increasing scrutiny is given to hospital-acquired VTE, as quality initiatives to prevent VTE, such as Children’s Hospitals Solutions for Patient Safety, gain national priority. Children with hospital-acquired VTE have increased length of stay and excess costs of

EUS and EUS-Guided Interventions Alter Clinical Management in Children With Digestive Diseases.

27,000. Several risk factors have been associated with VTE in injured children, including older age, injury severity, obesity, central venous catheter (CVC) use, mechanical ventilation, inotrope use, blood transfusion, pelvic or lower extremity fracture, spinal cord injury, and intensive care unit stay. However, it is not clear in any individual pediatric patient when the benefit of pharmacologic prophylaxis to reduce the risk of VTE outweighs the risk, particularly the risk of bleeding. The efficacy of anticoagulation to prevent VTE is unknown in this population. In addition, there are no pediatric studies on the effectiveness of mechanical prophylaxis to prevent VTE. In contrast, VTE prophylaxis with lowmolecular-weight heparin (LMWH) is routinely recommended for injured adults. Despite the paucity of evidence, medical providers from different specialties are routinely called upon to make management decisions regarding the use of VTE prophylaxis in injured children. We proposed to survey experts in the field of pediatric trauma and thrombosis to develop consensus regarding the prevention of VTE in pediatric trauma patients.

Prophylaxis against venous thromboembolism in pediatric trauma: A practice management guideline from the Eastern Association for the Surgery of Trauma and the Pediatric Trauma Society.

Objectives: Endoscopic ultrasound (EUS) ± fine needle aspiration (FNA) is a useful tool to evaluate gastrointestinal tract disorders in adults because of its established feasibility and safety. Its role in children has not been well established and continues to evolve. Our objective was to evaluate the utility and impact on clinical management of EUS and EUS-guided interventions in the pediatric population at our institution. Methods: Retrospective, single-center study including 43 patients undergoing EUS and EUS-FNA between August 2005 and January 2012. Results: Fifty-one EUS procedures were performed in 43 patients, 30 girls, median age 14.5 (range 4–18). The most common indications were suspected biliary obstruction in 11 of 51 (22%), pancreatic cysts in 10 of 51 (20%), acute or recurrent pancreatitis in 9 of 51 (18%), and abdominal pain in 8 of 51 (16%). The most common findings of EUS included normal 11 of 51 (22%), pancreas cyst 6 of 51 (12%), pancreatic pseudocyst 5 of 51 (10%), biliary system sludge or stones 9 of 51 (18%), and acute and chronic pancreatitis 5 of 51 (10%). EUS-FNA was performed in 13 cases: 7 solid masses or nodes, 4 pancreatic pseudocyst, 1 pancreatic cyst, and 1 celiac plexus block. FNA cyst drainage was successful in resolving all 4 pancreatic pseudocysts. EUS prompted a surgical procedure in 13 cases (25%), ERCP in 5 cases (10%), and repeat EUS in 5 cases (10%). EUS led to a new diagnosis in 34 of 43 (79%) patients and prompted further intervention in 24 of 51 (47%) procedures. Conclusions: In this large cohort study, we found that EUS and EUS-guided interventions assist in diagnosing and altering clinical management in pediatric patients and should be considered in cases with vexing pancreaticobiliary disorders.

Mortality risk in pediatric motor vehicle crash occupants: accounting for developmental stage and challenging Abbreviated Injury Scale metrics

BACKGROUND Despite the increasing incidence of venous thromboembolism (VTE) in hospitalized children, the risks and benefits of VTE prophylaxis, particularly for those hospitalized after trauma, are unclear. The Pediatric Trauma Society and the Eastern Association for the Surgery of Trauma convened a writing group to develop a practice management guideline on VTE prophylaxis for this cohort of children using the Grading of Recommendations Assessment, Development, and Evaluation framework. METHODS A systematic review of MEDLINE using PubMed from January 1946 to July 2015 was performed. The search retrieved English-language articles on VTE prophylaxis in children 0 to 21 years old with trauma. Topics of investigation included pharmacologic and mechanical VTE prophylaxis, active radiologic surveillance for VTE, and risk factors for VTE. RESULTS Forty-eight articles were identified and 14 were included in the development of the guideline. The quality of evidence was low to very low because of the observational study design and risks of bias. CONCLUSIONS In children hospitalized after trauma who are at low risk of bleeding, we conditionally recommend pharmacologic prophylaxis be considered for children older than 15 years old and in younger postpubertal children with Injury Severity Score (ISS) greater than 25. For prepubertal children, even with ISS greater than 25, we conditionally recommend against routine pharmacologic prophylaxis. Second, in children hospitalized after trauma, we conditionally recommend mechanical prophylaxis be considered for children older than 15 years and in younger postpubertal children with ISS greater than 25 versus no prophylaxis or in addition to pharmacologic prophylaxis. Lastly, in children hospitalized after trauma, we conditionally recommend against active surveillance for VTE with ultrasound compared with routine daily physical examination alone for earlier detection of VTE. The limited pediatric data and paucity of high-quality evidence preclude providing more definitive recommendations and highlight the need for clinical trials of prophylaxis. LEVEL OF EVIDENCE Systematic review/meta-analysis, level III.

Injury patterns associated with hypotension in pediatric trauma patients: A National Trauma Database review

Objective: Survival risk ratios (SRRs) and their probabilistic counterpart, mortality risk ratios (MRRs), have been shown to be at odds with Abbreviated Injury Scale (AIS) severity scores for particular injuries in adults. SRRs have been validated for pediatrics but have not been studied within the context of pediatric age stratifications. We hypothesized that children with similar motor vehicle crash (MVC) injuries may have different mortality risks (MR) based upon developmental stage and that these MRs may not correlate with AIS severity. Methods: The NASS-CDS 2000–2011 was used to define the top 95% most common AIS 2+ injuries among MVC occupants in 4 age groups: 0–4, 5–9, 10–14, and 15–18 years. Next, the National Trauma Databank 2002–2011 was used to calculate the MR (proportion of those dying with an injury to those sustaining the injury) and the co-injury-adjusted MR (MRMAIS) for each injury within 6 age groups: 0–4, 5–9, 10–14, 15–18, 0–18, and 19+ years. MR differences were evaluated between age groups aggregately, between age groups based upon anatomic injury patterns and between age groups on an individual injury level using nonparametric Wilcoxon tests and chi-square or Fishers exact tests as appropriate. Correlation between AIS and MR within each age group was also evaluated. Results: MR and MRMAIS distributions of the most common AIS 2+ injuries were right skewed. Aggregate MR of these most common injuries varied between the age groups, with 5- to 9-year-old and 10- to 14-year-old children having the lowest MRs and 0- to 4-year-old and 15- to 18-year-old children and adults having the highest MRs (all P <.05). Head and thoracic injuries imparted the greatest mortality risk in all age groups with median MRMAIS ranging from 0 to 6% and 0 to 4.5%, respectively. Injuries to particular body regions also varied with respect to MR based upon age. For example, thoracic injuries in adults had significantly higher MRMAIS than such injuries among 5- to 9-year-olds and 10- to 14-year-olds (P =.04; P <.01). Furthermore, though AIS was positively correlated with MR within each age group, less correlation was seen for children than for adults. Large MR variations were seen within each AIS grade, with some lower AIS severity injuries demonstrating greater MRs than higher AIS severity injuries. As an example, MRMAIS in 0- to 18-year-olds was 0.4% for an AIS 3 radius fracture versus 1.4% for an AIS 2 vault fracture. Conclusions: Trauma severity metrics are important for outcome prediction models and can be used in pediatric triage algorithms and other injury research. Trauma severity may vary for similar injuries based upon developmental stage, and this difference should be reflected in severity metrics. The MR-based data-driven determination of injury severity in pediatric occupants of different age cohorts provides a supplement or an alternative to AIS severity classification for pediatric occupants in MVCs.

Evaluation of developmental metrics for utilization in a pediatric advanced automatic crash notification algorithm

BACKGROUND Hypotension after trauma is most commonly assumed to be hemorrhagic, or hypovolemic, in origin. However, hypotension may occur in pediatric patients with isolated head injury, challenging accepted tenets of trauma care. We sought to quantify the contribution of head injury to the development of hypotension after pediatric trauma. METHODS This is a retrospective cohort analysis using the National Trauma Data Bank registry 2009. Children aged 0 to 15 years were classified by injury pattern sustained during trauma using discharge diagnosis International Classification of Diseases, Ninth Revision, codes into isolated head, hemorrhagic, spinal cord, or other injury type. The primary outcome was hypotension for age at arrival to the emergency department. Risk of hypotension was estimated and compared by injury pattern using absolute and relative risks (RRs) stratified by age group (0–4 years, 5–11 years, 12–15 years). RESULTS Rates of hypotension ranged from 1.8% to 2.3% by age, with the highest incidence in the 12- to 15-year group. The RR of hypotension from isolated head injury (RR, 2.5; 95% confidence interval, 2.0–3.2 vs. other) was not significantly different from the RR for hemorrhagic injury (RR, 2.7; 95% confidence interval, 2.1–3.5 vs. other) in the 0- to 4-year-old group. For the older age groups, the RR of hypotension from isolated head injury was significantly lower than from hemorrhagic injury. CONCLUSION Hypotension occurs after isolated head injury in children, and the risk of hypotension is as great as hemorrhagic injuries in children aged 0 to 4 years. This finding should now lead us to confirm whether a cause-effect relationship exists and, if so, isolate the responsible mechanism. In turn, this could reveal an opportunity to tailor treatments to address the underlying mechanism for hypotension in these children. LEVEL OF EVIDENCE Prognostic and epidemiologic study, level III.

Letter to the Editor: “Post-traumatic liver and splenic pseudoaneurysms in children: Diagnosis, management, and follow-up screening using contrast enhanced ultrasound (CEUS)” by Durkin et al J Pediatr Surg 51 (2016) 289-292

ABSTRACT Objective: Appropriate treatment at designated trauma centers (TCs) improves outcomes among injured children after motor vehicle crashes (MVCs). Advanced Automatic Crash Notification (AACN) has shown promise in improving triage to appropriate TCs. Pediatric-specific AACN algorithms have not yet been created. To create such an algorithm, it will be necessary to include some metric of development (age, height, or weight) as a covariate in the injury risk algorithm. This study sought to determine which marker of development should serve as a covariate in such an algorithm and to quantify injury risk at different levels of this metric. Methods: A retrospective review of occupants age < 19 years within the MVC data set NASS-CDS 2000–2011 was performed. R2 values of logistic regression models using age, height, or weight to predict 18 key injury types were compared to determine which metric should be used as a covariate in a pediatric AACN algorithm. Clinical judgment, literature review, and chi-square analysis were used to create groupings of the chosen metric that would discriminate injury patterns. Adjusted odds of particular injury types at the different levels of this metric were calculated from logistic regression while controlling for gender, vehicle velocity change (delta V), belted status (optimal, suboptimal, or unrestrained), and crash mode (rollover, rear, frontal, near-side, or far-side). Results: NASS-CDS analysis produced 11,541 occupants age < 19 years with nonmissing data. Age, height, and weight were correlated with one another and with injury patterns. Age demonstrated the best predictive power in injury patterns and was categorized into bins of 0–4 years, 5–9 years, 10–14 years, and 15–18 years. Age was a significant predictor of all 18 injury types evaluated even when controlling for all other confounders and when controlling for age- and gender-specific body mass index (BMI) classifications. Adjusted odds of key injury types with respect to these age categorizations revealed that younger children were at increased odds of sustaining Abbreviated Injury Scale (AIS) 2+ and 3+ head injuries and AIS 3+ spinal injuries, whereas older children were at increased odds of sustaining thoracic fractures, AIS 3+ abdominal injuries, and AIS 2+ upper and lower extremity injuries. Conclusions: The injury patterns observed across developmental metrics in this study mirror those previously described among children with blunt trauma. This study identifies age as the metric best suited for use in a pediatric AACN algorithm and utilizes 12 years of data to provide quantifiable risks of particular injuries at different levels of this metric. This risk quantification will have important predictive purposes in a pediatric-specific AACN algorithm.