Craniolacunia and the Development of the Fetal Calvaria: An Autopsy Series With Clinical and Histological Analysis.

BACKGROUND: Craniolacunia, also known as lückenschädel, is a congenital abnormality of the calvaria featuring well-circumscribed areas of marked thinning, interspersed with more-normal bone. It is most commonly associated with myelomeningocele and/or Chiari 2 malformation. METHODS: Records, photographs, and histologic sections were reviewed from 13 autopsy cases with craniolacunia. To investigate normal calvarial development, 23 parietal bone samples from fetuses/infants of 16-42 weeks gestation were examined. RESULTS: Parietal bone development had reproducible morphologic stages. Bone thickness increased with gestational age, while osteoblast numbers decreased. Craniolacunia was mainly seen in neonates. Five patients had Chiari 2 malformation, 1 had hydrocephalus, and 2 had other structural CNS abnormalities. One had trisomy 18. Four had no congenital abnormalities. Two sustained intrapartum skull fractures. Histologic sections were available in 5 cases. Lacunae in term infants had architecture similar to normal calvaria at 16-20 weeks. Adjacent bone had age appropriate architecture but increased osteoblast numbers. CONCLUSIONS: This is the largest autopsy series of craniolacunia and first systematic histologic analysis of craniolacunia and the developing fetal calvaria. Decreased cerebrospinal fluid pressure, due to myelomeningocele or other structural abnormality, may promote craniolacunia development. The risk of intrapartum fracture through lacunae emphasizes the continued clinical relevance of this diagnosis.

Current Utilization of Electron Microscopy in the Pediatric Pathology Setting: A Survey by the SPP Practice Committee.

BACKGROUND: Electron microscopy (EM), once an important component in diagnosing pediatric diseases, has experienced a decline in its use. To assess the impact of this, pediatric pathology practices were surveyed regarding EM services. METHODS: The Society of Pediatric Pathology Practice Committee surveyed 113 society members from 74 hospitals. Settings included 36 academic tertiary, 32 free-standing children's, and 6 community hospitals. RESULTS: Over 60% maintained in-house EM services and had more than 2 pathologists interpreting EM while reporting a shortage of EM technologists. Freestanding children's hospitals had the most specimens (100-200 per year) and more diverse specimen types. Hospitals with fewer than 50 yearly specimens often used reference laboratories. Seventeen had terminated all in-house EM services. Challenges included decreasing caseloads due to alternative diagnostic methods, high operating costs, and shortages of EM technologists and EM-proficient pathologists. Kidney, liver, cilia, heart, and muscle biopsies most often required EM. Lung/bronchoalveolar lavage, tumor, skin, gastrointestinal, nerve, platelet, and autopsy samples less commonly needed EM. CONCLUSIONS: The survey revealed challenges in maintaining EM services but demonstrated its sustained value in pediatric pathology. Pediatric pathologists may need to address the centralization of services and training to preserve EM diagnostic proficiency among pathologists who perform ultrastructural interpretations.

Neonatal Skin Structure: Pressure Injury Staging Challenges.

GENERAL PURPOSE: To review neonatal pressure injuries (PIs), including clinical features and challenges in evaluation and staging related to the unique anatomic features of preterm neonatal skin as well as the common sites and mechanisms of injury. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant will:1. Recognize the causes of PIs in preterm neonates.2. Choose the outcomes of PIs in preterm neonates.3. Distinguish the common characteristics of preterm neonates' skin.4. Summarize the challenges clinicians face when classifying the PIs of preterm neonates.

To review neonatal pressure injuries (PIs), including clinical features and challenges in evaluation and staging related to the unique anatomic features of preterm neonatal skin, as well as the common sites and mechanisms of injury. A review of the literature and discussion of clinical experiences at a large children's hospital. Specific topics include the nature and mechanism of PIs, histomorphometric features of skin development in preterm neonates and how these features inform bedside evaluation of PI, and experience-based observations of challenges in evaluating PIs in this vulnerable population. Pressure injury staging in preterm neonates presents unique challenges: (1) The National Pressure Injury Advisory Panel PI staging model is based on visual identification of depth of injury, but because of the immaturity of the preterm neonate, skin lacks many of the visual cues present in adult PIs. Specific qualitative and quantitative differences in skin development impact the macroscopic appearance of skin at different gestational ages. (2) The most common cause of PIs in this population is related to noninvasive respiratory devices, but these injuries may be extremely small and difficult to evaluate visually. The National Pressure Injury Advisory Panel staging system can be difficult to implement accurately in the neonatal population. Further study is warranted to determine whether an alternative staging system may provide more accurate and actionable information for this population.

Preterm Infant Skin Structure Is Qualitatively and Quantitatively Different From That of Term Newborns.

BACKGROUND: The immature skin of preterm infants is uniquely vulnerable to pressure and chemical injury. We sought to qualitatively and quantitatively describe the histopathologic patterns of skin development in preterm infants. METHODS: Autopsy skin samples were examined for 48 liveborn preterm infants born at 18+ to 36 weeks, and control groups of term neonates and older infants/children. Quantitative variables included thickness of the stratum corneum, epidermis, and dermis. Qualitative features included stratum corneum, rete ridges, and hair follicles. RESULTS: Patterns of maturation were reproducible. Compact keratin appeared beginning at 21-22 weeks. Basketweave keratin appeared first around hair follicles, and then became more generalized from ∼28 weeks corrected gestational age (CGA) onward. Rete ridges began to appear at ∼30 weeks. Epidemal and dermal thickness increased with age. Infants who survived ≤7 days had thicker dermis than those who survived longer, even adjusted for CGA. CONCLUSIONS: Skin development in preterm infants has reproducible milestones. Significant structural changes occurring around 28-30 weeks may improve barrier function, with implications for use of topical compounds such as chlorhexidine. The findings also highlight challenges in evaluating pressure injuries in preterm infants, and postnatal changes in skin parameters.

Ceftriaxone-induced drug reaction mimicking acute splenic sequestration crisis in a child with hemoglobin SC disease.

BACKGROUND: Acute splenic sequestration crisis is a complication of sickle cell disease (SCD) occurring when intrasplenic red blood cell (RBC) sickling prevents blood from leaving the spleen, causing acute splenic enlargement. Although typically seen in young children, it has been reported in older children with hemoglobin (Hb)SC disease, eventually resulting in functional asplenia. Ceftriaxone is a frequently used antibiotic of choice for children with SCD, because of its efficacy against invasive pneumococcal disease. CASE REPORT: We report a case of a 9-year-old female with HbSC disease, who had a fatal reaction after receiving a dose of ceftriaxone in the outpatient clinic for fever. Her Hb level decreased abruptly from 9.3 to 2.3 mg/dL. RBC clumps with no visible hemolysis were observed in the postreaction sample. Autopsy examination revealed marked splenomegaly with acute congestion and sickled cells in the spleen and liver. Serologic testing revealed a positive direct antiglobulin test with polyspecific antibody, anti-C3, and anti-C3d, but negative with anti-immunoglobulin G. Ceftriaxone-dependent RBC antibodies were detected in her serum and RBC eluate when tested in the presence of the drug. CONCLUSION: We report a new presentation of ceftriaxone-induced drug reaction in a patient with SCD mimicking an acute splenic sequestration crisis. Review of the literature for cases of ceftriaxone-induced drug reactions in pediatric patients revealed nine previously reported cases of ceftriaxone-induced immune hemolytic anemia in children with SCD since 1995, but none with an initial presentation suggestive of acute splenic sequestration crisis.

Minimally Invasive Adenocarcinoma of the Lung as Second Malignant Neoplasm Following Pediatric Rhabdomyosarcoma.

Primary pulmonary tumors are extremely rare in the pediatric population; however, sporadic cases of invasive pulmonary adenocarcinoma as a second malignant neoplasm (SMN) have been described in survivors of pediatric cancers. Pediatric patients with rhabdomyosarcoma (RMS) have a particularly increased risk of developing a SMN when compared to the general population, though pulmonary adenocarcinoma has not been previously described in a RMS patient. A 12-year-old female previously treated for stage IV pelvic RMS was found to have a left pulmonary nodule on surveillance computed tomography. The nodule was detected 4.25 years after the completion of treatment, which included resection, chemotherapy, and radiation to the abdomen and pelvis. Wedge resection of the pulmonary lesion was performed with negative margins. Histopathological examination revealed minimally invasive adenocarcinoma. Pulmonary adenocarcinoma may rarely present as a SMN in pediatric cancer survivors. The pathogenesis of this association is not yet entirely clear, but may include chemotherapy-induced mutagenesis and/or genetic predisposition. As pulmonary adenocarcinoma may present as a lung lesion radiographically indistinguishable from metastatic RMS, it should be considered in the differential diagnosis of any pediatric RMS survivor presenting with a new pulmonary nodule, especially in cases with late recurrence.

Sustained remission of severe Multicentric Castleman disease following multiagent chemotherapy and tocilizumab maintenance.

Castleman disease is a rare lymphoproliferative disorder, which presents in a unicentric or multicentric fashion. Multicentric Castleman disease (MCD) is associated with significant systemic symptoms, in part related to the underlying role of interleukin-6 in disease pathogenesis. Treatment for MCD has not been well established and prognosis has historically been poor. We present a case of severe MCD in a pediatric patient who has shown sustained remission following multi-agent chemotherapy and targeted maintenance therapy with the interleukin-6 receptor inhibitor, tocilizumab. This represents the first case report of sustained remission of MCD in a pediatric patient following discontinuation of tocilizumab therapy.

Familial LCAT deficiency in a child with nephrotic syndrome.

BACKGROUND: Lecitin cholesterol acyltransferase (LCAT) deficiency comprises a group of rare disorders related to HDL metabolism. These disorders are characterized by ophthalmologic, hematologic, and renal findings. Case diagnosis/treatment: A 15-year-old female who presented with nephrotic syndrome and hypertension was diagnosed with LCAT deficiency by renal biopsy and LCAT enzyme activity. Her edema and hypertension improved with diuretic and antihypertensive therapies. Continued care of her LCAT deficiency is ongoing. CONCLUSION: Although rare, LCAT deficiency should be in the differential diagnosis of nephrotic syndrome in the setting of abnormally low HDL cholesterol levels.

Perigestational dietary folic acid deficiency protects against medulloblastoma formation in a mouse model of nevoid basal cell carcinoma syndrome.

Hereditary nevoid basal cell carcinoma syndrome (NBCCS) is caused by PTCH1 gene mutations that result in diverse neoplasms including medulloblastoma (MB). Epidemiological studies report reduced pediatric brain tumor risks associated with maternal intake of prenatal vitamins containing folic acid (FA) and FA supplements specifically. We hypothesized that low maternal FA intake during the perigestational period would increase MB incidence in a transgenic NBCCS mouse model, which carries an autosomal dominant mutation in the Ptch1 gene. Female wild-type C57BL/6 mice (n = 126) were randomized to 1 of 3 diets with differing FA amounts: 0.3 mg/kg (low), 2.0 mg/kg (control), and 8.0 mg/kg (high) 1 mo prior to mating with Ptch1 (+/-) C57BL/6 males. Females were maintained on the diet until pup weaning; the pups were then aged for tumor development. Compared to the control group, offspring MB incidence was significantly lower in the low FA group (Hazard Ratio = 0.47; 95% confidence interval 0.27-0.80) at 1 yr. No significant difference in incidence was observed between the control and high FA groups. Low maternal perigestational FA levels may decrease MB incidence in mice genetically predisposed to tumor development. Our results could have implications for prenatal FA intake recommendations in the presence of cancer syndromes.

Unusual presentations of BK virus infections in pediatric renal transplant recipients.

BKV has emerged as a significant pathogen in the field of transplantation, predominantly causing BKV nephropathy in renal transplant recipients and hemorrhagic cystitis in HSCT recipients. However, case reports describe more diverse complications, and we too present three unusual cases of BKV infections in pediatric renal transplant recipients. First, we describe a case of biopsy-proven renal damage secondary to BKV prior to the onset of viremia, demonstrating that BKV nephropathy can occur without preceding viremia. We also present two renal transplant recipients with persistent BK viruria, one with BKV-associated hemorrhagic cystitis and the other with microscopic hematuria. Therefore, we conclude that BKV manifestations may be more diverse than previously thought and suggest clinical utility in urine BKV qPCR testing in specific transplant recipients.

Successful management of factor IX inhibitor-associated nephrotic syndrome in a hemophilia B patient.

BACKGROUND: Nephrotic syndrome (NS) is a recognized complication of immune tolerance induction (ITI) therapy, a treatment strategy used to treat inhibitors in patients with hemophilia B receiving factor IX concentrate. CASE DIAGNOSIS/TREATMENT: We present a 4-year-old boy with hemophilia B and an inhibitor who underwent ITI, and developed NS 19 months into this therapy. A percutaneous renal biopsy was safely performed with factor IX (FIX) concentrate administration both preceding and following the procedure. The patient's inhibitor level had increased to 1.4-1.6 Bethesda Units just prior to the onset of proteinuria. Histology confirmed segmental membranous nephropathy (MGN). The patient was continued on FIX concentrate as ITI and also received 4 weekly doses of rituximab and ongoing immunosuppression with mycophenolate mofetil. This resulted in the complete resolution of his inhibitor and his NS. He continues with a modified ITI regimen and remains inhibitor-free without proteinuria >12 months post-biopsy. CONCLUSIONS: Hemophilia B patients undergoing ITI should be regularly screened for NS. At first detection of proteinuria, with proper precautions, a percutaneous kidney biopsy can be performed safely in patients with low levels of inhibitor. Our patient had segmental MGN with complete remission of NS.

Pediatric Low-Grade Spindle Cell Neoplasm With A Novel AK5::ALK Fusion: A Case Report.

OBJECTIVES: Spindle cell neoplasms (SCN) share a single commonality of spindle-shaped cells on histopathology but are diverse in etiology. Expanding our collective knowledge of these neoplasms could further research in targeted therapies. We present a case of pediatric cutaneous SCN with a novel etiology, and the methods used to identify its origination. CASE PRESENTATION AND RESULTS: A 1.5-year-old child presented with a 7-month history of a rapidly enlarging, erythematous, non-painful scalp mass without ulceration or bleeding. The child underwent ultrasound and magnetic resonance imaging, revealing a 2.9 × 3 × 2 cm vascular mass without intracranial connections. The mass was successfully resected at surgery. Subsequent histopathologic and genetic testing indicated a SCN harboring a previously undescribed gene rearrangement between adenylate kinase 5 (AK5) and anaplastic lymphoma kinase (ALK). The patient received close clinical follow-up and at 6 months post-surgery had no recurrent disease. CONCLUSIONS: ALK rearrangements are common amongst many tumor types, but to our knowledge, AK5::ALK rearrangement has never been reported in SCN. Considering the rapid development of targeted clinical therapies, including those targeting ALK activity, this finding could be significant in the treatment of future patients with similar clinicopathologic and genetic presentation.

Single cell spatial transcriptomic profiling of childhood-onset lupus nephritis reveals complex interactions between kidney stroma and infiltrating immune cells.

Children with systemic lupus erythematosus (SLE) are at increased risk of developing kidney disease, termed childhood-onset lupus nephritis (cLN). Single cell transcriptomics of dissociated kidney tissue has advanced our understanding of LN pathogenesis, but loss of spatial resolution prevents interrogation of in situ cellular interactions. Using a technical advance in spatial transcriptomics, we generated a spatially resolved, single cell resolution atlas of kidney tissue (>400,000 cells) from eight cLN patients and two controls. Annotated cells were assigned to 35 reference cell types, including major kidney subsets and infiltrating immune cells. Analysis of spatial distribution demonstrated that individual immune lineages localize to specific regions in cLN kidneys, including myeloid cells trafficking to inflamed glomeruli and B cells clustering within tubulointerstitial immune hotspots. Notably, gene expression varied as a function of tissue location, demonstrating how incorporation of spatial data can provide new insights into the immunopathogenesis of SLE. Alterations in immune phenotypes were accompanied by parallel changes in gene expression by resident kidney stromal cells. However, there was little correlation between histologic scoring of cLN disease activity and glomerular cell transcriptional signatures at the level of individual glomeruli. Finally, we identified modules of spatially-correlated gene expression with predicted roles in induction of inflammation and the development of tubulointerstitial fibrosis. In summary, single cell spatial transcriptomics allows unprecedented insights into the molecular heterogeneity of cLN, paving the way towards more targeted and personalized treatment approaches.

Thrombosis in Extracorporeal Membrane Oxygenation (ECMO) Circuits.

Thrombosis in extracorporeal membrane oxygenation (ECMO) circuits remains a frequent complication. We characterize the location, extent, structure, and clinical implications of thrombi in 53 ECMO circuits from 46 pediatric patients. The tubing, pump, and oxygenator were examined for visible thrombi. Representative samples of thrombi were collected for histologic, immunofluorescence, and immunohistochemical analysis. Thrombi were found in 81% of ECMO circuits. The most clinically significant were inflow oxygenator membrane surface thrombi (11% of circuits), arterial tubing thrombi (30%), and venous tubing (26%) or connector thrombi (26%). Oxygenator membrane surface thrombi resulted in rapidly increasing delta pressure across the oxygenator over 1-2 days, oxygenator failure, and circuit replacement. Oxygenator membrane surface thrombi were associated with intravascular venous thrombosis and bacterial infection before starting ECMO. Arterial cannula/tubing thrombi led in one case to aortic and mesenteric artery thrombosis followed by bowel infarction. In 11% of cases, venous tubing thrombi grew large enough to break off and embolize to the pump, resulting in increased hemolysis. Antifibrinolytic therapy during ECMO was associated with an increased risk of pump thromboembolism. Other less clinically significant thrombi included pump axle thrombi with thrombus fragments trapped in the oxygenator (45%), and deep oxygenator membrane thrombi (15%). Examination of ECMO circuits after removal is a useful quality improvement tool that can elucidate the cause of circuit problems, indicate patients at increased risk of thrombosis, and suggest areas for possible improvements.

Massive Post-traumatic Femoral Cyst Resulting in Pathologic Fracture in a Child: A Case Report.

CASE: A 10-year-old boy experienced a pathologic diaphyseal femur fracture through a large cyst encompassing 40% of femoral length. At age 5, he had had a traumatic ipsilateral diaphyseal femur fracture, treated with flexible nailing. Biopsy at age 10 revealed a simple bone cyst with components of aneurysmal bone cyst. Curettage, antegrade nailing, and allograft resulted in successful osseous healing. CONCLUSION: Post-traumatic cysts of long bones are rare and have not been reported to cause pathologic fracture in children. This case highlights that close scrutiny of follow-up radiographs of long bone fractures may identify clinically important post-traumatic cysts.

Clinical and Histopathologic Predictors of Disaccharidase Deficiency in Duodenal Biopsy Specimens.

OBJECTIVES: Disaccharidase (DS) activity in duodenal biopsy specimens is the gold standard for diagnosing DS deficiency. We investigated strategies to reduce the need for DS testing and whether clinical or histopathologic factors predict DS deficiency. METHODS: A retrospective chart review analyzed 1,678 DS results in children, biopsy indication(s), and duodenal histopathology. RESULTS: One or more DSs were abnormal in 42.8%. Sufficient lactase predicted sucrase, palatinase, and maltase sufficiency (negative predictive value 97.7%). Three patients had sucrase-isomaltase deficiency (0.2%). DS deficiency was more common in biopsy specimens for positive celiac serology (78.0%). Villous blunting, intraepithelial lymphocytosis, and active inflammation predicted DS deficiency; a combination of any two had an 81.4% positive predictive value. CONCLUSIONS: Utilization could be reduced by only testing cases with normal duodenal histopathology and ongoing clinical suspicion for DS deficiency after reviewing pathology. In cases with suspected celiac disease and/or mucosal injury, DS deficiency is common and likely secondary, limiting test utility.

A 2-year study of patient safety competency assessment in 29 clinical laboratories.

Competency assessment is critical for laboratory operations and is mandated by the Clinical Laboratory Improvement Amendments of 1988. However, no previous reports describe methods for assessing competency in patient safety. We developed and implemented a Web-based tool to assess performance of 875 laboratory staff from 29 laboratories in patient safety. Question categories included workplace culture, categorizing error, prioritization of patient safety interventions, strength of specific interventions, and general patient safety concepts. The mean score was 85.0%, with individual scores ranging from 56% to 100% and scores by category from 81.3% to 88.6%. Of the most difficult questions (<72% correct), 6 were about intervention strength, 3 about categorizing error, 1 about workplace culture, and 1 about prioritization of interventions. Of the 13 questions about intervention strength, 6 (46%) were in the lowest quartile, suggesting that this may be a difficult topic for laboratory technologists. Computer-based competency assessments help laboratories identify topics for continuing education in patient safety.

Necrotizing Enterocolitis in Two Siblings and an Unrelated Infant with Overlapping Chromosome 6q25 Deletions.

The pathogenesis of necrotizing enterocolitis (NEC) remains poorly understood but is thought to be multifactorial. There are no specific recurring chromosomal abnormalities previously associated with NEC. We report 3 cases of intestinal necrosis associated with large chromosome 6 deletions. The first patient was found to have a 7.9-Mb deletion of chromosome 6 encompassing over 40 genes, arr[GRCh37] 6q25.3q26(155699183_163554531)×1. The second patient had a 19.5-Mb deletion of chromosome 6 generated by an unbalanced translocation with chromosome 18, 46,XY,der(6)t (6;18)(q25.1;p11.23), arr[GRCh37] 6q25.1q27(151639526_ 171115067)×1, 18p11.32p11.23(131700_7694199)×3, which included the whole 7.9-Mb region deleted in the first patient. The third patient was the younger sibling of the second patient with an identical derivative chromosome 6. The shared abnormal chromosome 6 region includes multiple genes of interest, particularly EZR. Mouse models have demonstrated that Ezr is expressed in microvillar epithelium and helps regulate cell-cell adhesion in the gut. We hypothesize that deletion of this shared region of 6q leads to gastrointestinal vulnerability which may predispose patients to intestinal necrosis.

Pathologist Effort in the Performance of Fetal, Perinatal, and Pediatric Autopsies: A Survey of Practice.

CONTEXT: -Autopsy is an important tool for quality assurance and improving patient care. Fetal, perinatal, and pediatric autopsies have the additional benefit of identifying conditions that may have increased risk of recurrence. In contrast to adult autopsies, special collections and testing are frequently used. Pathologist effort in fetal, perinatal, and pediatric autopsy has not been well documented. OBJECTIVE: -To prospectively quantify pathologist time required to complete fetal, perinatal, and pediatric autopsies, and to gather information on special studies and whether or not a cause of death was identified. DESIGN: -The Society for Pediatric Pathology Practice Committee disseminated a survey to pathologists to complete for each autopsy performed. Surveys recorded age/gestation, time spent on chart review, prosection, and microscopy, special testing performed, time spent on a discussion or presentation of findings, and whether a cause of death was found. RESULTS: -We report results of 351 surveys. Pathologist effort in fetal cases was, on average, 5.9 hours; in perinatal cases, 9.8 hours; and in pediatric cases, 15.4 hours. Reflecting complexity, a total of 603 collections for ancillary studies were performed, most commonly karyotype, frozen tissue, and microbiology cultures. A cause of death was identified in 295 of 351 cases (84%). Most cases were presented at conferences. CONCLUSIONS: -Fetal, perinatal, and pediatric autopsies are time intensive and frequently complex. They have high clinical value, guiding risk assessment and reproductive decision-making by families. Understanding the time contribution by pathologists allows departments and hospitals to predict staffing.