Publications by authors named "Mikako Warren"

37 Publications

Primary Adrenal Malignant Rhabdoid Tumor in a 14-Year-Old Female: A Case Report and Literature Review.

Int J Surg Pathol 2021 Jun 9:10668969211024331. Epub 2021 Jun 9.

Children's Hospital Los Angeles, Los Angeles, CA, USA.

Malignant rhabdoid tumor (MRT) is a rare, SWItch/sucrose nonfermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 ()-deficient, aggressive tumor, occurring predominantly in children below 3 years of age. Primary adrenal MRT is extremely rare, with only 3 cases reported in the literature. A previously healthy 14-year-old female presented with left upper quadrant/epigastric abdominal pain. Imaging studies revealed an 8.0 × 8.0 × 6.5 cm, heterogeneous, partially enhancing mass along the superior margin of the left kidney encasing the adrenal gland. Surgical resection of the tumor revealed a hypercellular heterogeneous neoplasm arising from the adrenal gland. It was composed predominantly of primitive small round blue cells with focal true rosettes and areas of vague glandular epithelial differentiation and chondroid differentiation. Classic rhabdoid-type cytoplasmic inclusions were focally present. Mitoses, tumor necrosis, and hemorrhage were readily seen. Tumor cells showed complete loss of SMARCB1 (INI1) nuclear staining, demonstrated strong, and diffuse positivity for glypican 3, patchy positivity for CD99, cytokeratin, Sal-like protein 4, Lin-28 homolog A, epithelial membrane antigen, and S100. Molecular studies revealed biallelic frameshift mutations in the gene (c.673delG and c.683dupT) without pathogenic copy number aberrations. The histologic, immunohistochemical, and molecular findings support a diagnosis of MRT. The unusual age, location, and mutations of this case expand the clinicopathologic and molecular spectrum of MRT.
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http://dx.doi.org/10.1177/10668969211024331DOI Listing
June 2021

Mycophenolate Mofetil Hepatotoxicity Associated with Mitochondrial Abnormality in Liver Transplant Recipients and Mice.

J Pediatr Gastroenterol Nutr 2021 May 18. Epub 2021 May 18.

Pathology and Laboratory Medicine, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA Gastroenterology, Hepatology and Nutrition, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.

Objectives: Mycophenolate mofetil (MMF) is a widely used immunosuppressive agent. MMF hepatotoxicity has been reported in non-transplant and renal transplant patients with minimal histologic description. This is the first study describing detailed histology and ultrastructure of MMF hepatotoxicity.

Methods: Four liver-transplant recipients (Cases 1-4) were suspected to have MMF hepatotoxicity. Cases 1-3 (2 females and 1 male; 3-17 years) had multiple biopsies for liver function test (LFT) abnormalities. Case 4 (female; 14 years) had a surveillance biopsy. Electron-microscopic examination (EM) was requested on Cases 1-3 for unexplained, persistent LFT elevation and histologic abnormalities despite therapy and Case 4 for unexplained histologic abnormalities despite a stable clinical course. To confirm the pathologic changes in the human allografts, livers from MMF-treated and untreated mice were also reviewed.

Results: While the allograft biopsies showed nonspecific histologic changes, EM revealed unequivocal mitochondrial abnormalities similar to those seen in primary and secondary mitochondrial disorders. In Cases 1 and 2, LFTs improved after stopping and reducing MMF, respectively. In Case 3, pre- and post-MMF treatment biopsies were performed and only the post-MMF biopsy demonstrated mitochondrial abnormalities. Mitochondrial abnormality in Case 4 was subclinical. The mouse study confirmed that MMF caused various stress changes in the mitochondria; number of mitochondria/cell (mean ± SD; MMF-treated group: 8.25 ± 8.426; untreated group: 76.37 ± 18.66), number of lipid droplets/cell (MMF-treated: 0.9691 ± 1.150; untreated: 3.649 ± 4.143) and sizes of mitochondria (μm, MMF-treated: 0.8550 ± 0.3409; untreated: 0.9598 ± 0.5312) were significantly increased in hepatocytes in the MMF-treated mice compared with the untreated mice (p < 0.0001).

Conclusions: Although MMF is safe for the majority of patients, MMF can cause mitochondrial stress, which may trigger more severe mitochondrial abnormalities in a small subset. MMF hepatotoxicity should be considered for MMF-treated patients with unexplained, persistent LFT abnormalities and nonspecific histologic findings. EM should be requested for these cases.

An infographic is available for this article at:http://links.lww.com/MPG/C361.
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http://dx.doi.org/10.1097/MPG.0000000000003171DOI Listing
May 2021

Hepatic Ago2 Regulates PPARα for Oxidative Metabolism Linked to Glycemic Control in Obesity and Post Bariatric Surgery.

Endocrinology 2021 Apr;162(4)

Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Argonaute 2 (Ago2) is the main component of the RNA-induced silencing complex. We recently showed that liver-specific Ago2-deficiency in mice (L-Ago2 knockout [KO] mice) enhances mitochondrial oxidation and alleviates obesity-associated pathophysiology. However, the precise mechanisms behind the role of hepatic Ago2 in regulating the mitochondrial oxidation associated with glucose metabolism are still unclear. Here, we show that hepatic Ago2 regulates the function of peroxisome proliferator-activated receptor α (PPARα) for oxidative metabolism. In both genetically and diet-induced severe obese conditions, L-Ago2 KO mice developed obesity and hepatic steatosis but exhibited improved glucose metabolism accompanied by lowered expression levels of pathologic microRNAs (miRNAs), including miR-802, miR-103/107, and miR-152, and enhanced expression of PPARα and its target genes regulating oxidative metabolism in the liver. We then investigated the role of hepatic Ago2 in the outcomes of vertical sleeve gastrectomy (VSG) in which PPARα plays a crucial role in a drastic transcription reprogram associated with improved glycemia post VSG. Whereas VSG reduced body weight and improved fatty liver in wild-type mice, these effects were not observed in hepatic Ago2-deficient mice. Conversely, glucose metabolism was improved in a hepatic Ago2-dependent manner post VSG. Treating Ago2-deficient primary hepatocytes with WY-14643, a PPARα agonist, showed that Ago2-deficiency enhances sensitivity to WY-14643 and increases expression of PPARα target genes and mitochondrial oxidation. Our findings suggest that hepatic Ago2 function is intrinsically associated with PPARα that links Ago2-mediated RNA silencing with mitochondrial functions for oxidation and obesity-associated pathophysiology.
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http://dx.doi.org/10.1210/endocr/bqab007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875175PMC
April 2021

Microvillus inclusion disease with novel MYO5B pathogenic variants.

Histopathology 2021 Jul 14;79(1):119-121. Epub 2021 Apr 14.

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

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http://dx.doi.org/10.1111/his.14348DOI Listing
July 2021

PD-L1 expression in angiomatoid fibrous histiocytoma.

Sci Rep 2021 Jan 26;11(1):2183. Epub 2021 Jan 26.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, MS 43, 4650 Sunset Boulevard, Los Angeles, CA, 90027, USA.

Angiomatoid fibrous histiocytoma (AFH) is a rare tumor of intermediate malignancy. Treatment options for unresectable and/or metastatic tumors are very limited. Immunotherapy with PD-1/PD-L1 inhibitors may be worth exploring. The aim of this study was to evaluate the expression of PD-L1 in AFHs. PD-L1 expression was assessed on 36 AFHs from 36 pediatric patients by immunohistochemical staining of PD-L1 (clone 22C3). Positivity was defined as membranous expression in ≥ 1% of either tumor or immune cells. The correlations between PD-L1 expression and clinicopathologic features were assessed. Two patients had lymph node metastasis. All patients underwent surgical resection; three of them also had systemic chemotherapy. Three patients had recurrence after initial resection; all patients were alive with a median follow-up of 2.5 years. Overall, twenty-two (61%) tumors were positively stained for PD-L1 and positivity was seen on both tumor and immune cells in eighteen of the 22 tumors. A positive correlation was found between tumor cell PD-L1 expression and CD8+ T-cell infiltration. There were no statistically significant differences between the status of PD-L1 expression and the clinicopathological features assessed. PD-L1 expression was identified in 61% of AFHs with a predominantly adaptive pattern. Our findings provide a rationale for future studies evaluating the potential of checkpoint immunotherapy for patients with unresectable and/or metastatic tumor.
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http://dx.doi.org/10.1038/s41598-021-81746-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838166PMC
January 2021

Congenital Myenteric Hypoganglionosis.

Am J Surg Pathol 2021 Aug;45(8):1047-1060

Departments of Pathology and Pediatrics, Loma Linda University and Children's Hospital, Loma Linda, CA.

Congenital myenteric hypoganglionosis is a rare developmental disorder characterized clinically by severe and persistent neonatal intestinal pseudoobstruction. The diagnosis is established by the prevalence of small myenteric ganglia composed of closely spaced ganglion cells with sparse surrounding neuropil. In practice, the diagnosis entails familiarity with the normal appearance of myenteric ganglia in young infants and the ability to confidently recognize significant deviations in ganglion size and morphology. We review clinical, histologic, and immunohistochemical findings from 12 patients with congenital myenteric hypoganglionosis in comparison with similar data from age-matched controls and clearly delineate the diagnostic features of the condition. Practical guidelines are provided to assist surgical pathologists, who are likely to encounter this condition only infrequently. The diagnosis typically requires full-thickness intestinal biopsy as the abnormality is confined to the myenteric plexus in many patients. Immunohistochemistry for Hu C/D may be used to confirm hypoganglionosis. Reduced staining for calretinin and NeuN implicates a selective deficiency of intrinsic primary afferent neurons in this disease.
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http://dx.doi.org/10.1097/PAS.0000000000001670DOI Listing
August 2021

Bronchiectasis and Bronchiolectasis With Severe Herniating Pattern Associated With Gain-of-Function Mutation: Detailed Clinicopathological Findings.

Pediatr Dev Pathol 2021 Mar-Apr;24(2):131-136. Epub 2021 Jan 13.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California.

gain-of-function (GOF) mutations are associated with a rare autosomal dominant immunodeficiency disorder with main clinical manifestations including chronic mucocutaneous candidiasis (CMC) and bronchiectasis. In addition, these patients show higher incidences of cerebral and extracerebral aneurysm, malignancies and various autoimmune conditions compared to the general population. Although previous publications have reported clinical findings in patients with GOF mutation, they did not include histopathologic features. Herein, we describe the first case with detailed histologic findings in the lung of a 5-year-old patient with a GOF mutation, who presented with CMC and bronchiectasis. The biopsy showed severe bronchiolectasis with extensive airway dilatation and occasional disruptions. Peribronchiolar inflammation was not always present and evident mainly in areas of airway disruption; inflammation may have not been a main driver of the airway damage in this case. The airway dilatation often showed an interesting herniating pattern, possibly implying a connective tissue etiology. This case also demonstrates the diagnostic utility of whole exome sequencing as GOF mutations are not detected by routine workup. The definitive diagnosis will lead to more specific treatments and increased surveillance for serious conditions, such as cerebral aneurysms and malignancies.
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http://dx.doi.org/10.1177/1093526620985950DOI Listing
January 2021

Successful Induction Treatment With Rituximab of Isolated Pauci-Immune Pulmonary Capillaritis Presenting as Diffuse Alveolar Hemorrhage in a Pediatric Patient.

Chest 2020 11;158(5):e225-e227

Department of Pediatric Pulmonology and Sleep Medicine, Children's Hospital Los Angeles, University of Southern California School of Medicine, Los Angeles, CA.

Diffuse alveolar hemorrhage often presents as dyspnea, cough, or hemoptysis, and it is mediated by both immune and nonimmune processes. Isolated pauci-immune capillaritis (IPPC) is a rare diagnosis in which capillaritis, small-vessel vasculitis of the lung, is found on biopsy in the absence of an underlying systemic disorder. Traditionally, IPPC has been treated similarly to anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis with cyclophosphamide and glucocorticoids. However, few cases describing management options are available in the literature, especially among pediatric patients. Our report of successful induction of remission in an adolescent girl suggests that the combination of IV rituximab and pulse methylprednisolone may be a viable option for disease control in pediatric patients with IPPC.
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http://dx.doi.org/10.1016/j.chest.2020.06.022DOI Listing
November 2020

Clinicopathologic Characteristics of Late Acute Antibody-Mediated Rejection in Pediatric Liver Transplantation.

Transplantation 2020 Oct 7. Epub 2020 Oct 7.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA.

Background: An early and accurate diagnosis of liver antibody-mediated rejection (AMR) followed by timely intervention is important for clinical management but remains challenging. The aim of this study was to assess the clinicopathologic characteristics and outcomes of late acute AMR in pediatric liver transplantation recipients.

Methods: We performed a retrospective review of 739 ABO-identical/compatible allograft liver biopsies from 199 pediatric transplantation recipients.

Results: Based on Banff 2016 AMR criteria, 3 recipients fulfilled the criteria for definite for late acute AMR, 2 met the criteria for suspicious for AMR, and 2 were indeterminate for AMR. We further assessed the clinicopathologic characteristics of these 7 patients. All 7 patients had at least 1 biopsy with a histopathologic pattern compatible with acute AMR. Additionally, we observed accompanied moderately to markedly dilated portal/central veins and endothelialitis disproportionate to the degree of bile duct injury in all 7 patients; periportal/perivenular hepatocyte necrosis was seen in 6/7 patients; and arteritis was seen in 3/7 patients. In each case, microvascular C4d deposition was present in at least 1 biopsy. Posttransplant donor specific anti-HLA antibodies were detected in 5 patients. Two of 7 patients were retransplanted, and 2 died after developing refractory AMR. The remaining 5 patients were alive with stable graft function at a median follow-up of 4.1 years.

Conclusions: Our data suggest that acute AMR in pediatric liver grafts is rare, can develop late, and may be associated with graft loss or patient death. The recurrent histopathologic findings of moderately to markedly dilated portal/central veins and endothelialitis disproportionate to the degree of bile duct injury are features that appear unique to pediatric acute AMR of liver grafts.
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http://dx.doi.org/10.1097/TP.0000000000003469DOI Listing
October 2020

Persistent Toe-Walking in a Developmentally Normal 7-year-old Girl.

Pediatr Rev 2020 Oct;41(Suppl 1):S3-S5

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California.

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http://dx.doi.org/10.1542/pir.2017-0031DOI Listing
October 2020

Phox2b Immunohistochemical Staining in Detecting Enteric Neural Crest Cells in Hirschsprung Disease.

Pediatr Dev Pathol 2021 Jan-Feb;24(1):19-26. Epub 2020 Sep 25.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California.

Background: It can be challenging to recognize undifferentiated/immature ganglion cells, especially single forms. Ganglion cells and glia are derived from enteric neural crest cells (ENCCs), a group of autonomic nervous system (ANS)-lineage neural crest progenitors that regulates. Phox2b is an excellent marker for neoplastic and non-neoplastic ANS cells (eg, peripheral neuroblastic tumors [pNTs]). We hypothesized that Phox2b immunohistochemical staining (IHC) would also be useful for detecting ENCCs.

Methods: Hematoxylin and eosin, calretinin IHC, and Phox2b IHC were reviewed on 21 pull-through specimens and on a cohort of 12 rectal biopsies.

Results: Phox2b IHC demonstrated nuclear positivity in all of the ganglion cells across the different phases of differentiation without background staining. The Phox2b result correlated with the morphological findings, calretinin IHC results, and diagnoses based on the routine diagnostic method. The intensity was uniformly strong in the undifferentiated/immature forms and became variable in the mature forms; this pattern was similar to that seen in pNTs.

Conclusion: Phox2b IHC was highly sensitive and specific for detecting ganglion cells. It worked especially well for immature ganglion cells, seen in premature neonates, and scattered single forms in transition zones. In basic research settings, Phox2b can be a useful marker for early differentiation of ENCCs.
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http://dx.doi.org/10.1177/1093526620953372DOI Listing
September 2020

Noncongenital Pediatric Mature Teratoma of the Mandible.

JAMA Otolaryngol Head Neck Surg 2020 11;146(11):1085-1086

Children's Hospital of Los Angeles, Division of Plastic and Maxillofacial Surgery, Los Angeles, California.

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http://dx.doi.org/10.1001/jamaoto.2020.2572DOI Listing
November 2020

Rebaudioside affords hepatoprotection ameliorating sugar sweetened beverage- induced nonalcoholic steatohepatitis.

Sci Rep 2020 04 21;10(1):6689. Epub 2020 Apr 21.

Gastroenterology, Hepatology and Nutrition, 90027, Los Angeles, CA, USA.

Sugar-sweetened beverage consumption is a known independent risk factor for nonalcoholic steatohepatitis (NASH). Non-caloric sweeteners (NCS) are food additives providing sweetness without calories and are considered safe and/or not metabolized by the liver. The potential role of newer NCS in the regulation of NASH, however, remain unknown. Our study aimed to determine the impact of newer NCS including Rebaudioside A and sucralose on NASH using high fat diet induced obesity mouse model by substituting fructose and sucrose with NCS in the drinking water. We characterized the phenotype of NCS- treated obesity and investigated the alterations of hepatic function and underlying mechanisms. We found that NCS have no impact on weight gain and energy balance in high fat diet induced obesity. However, in comparison to fructose and sucrose, Rebaudioside A significantly improved liver enzymes, hepatic steatosis and hepatic fibrosis. Additionally, Rebaudioside A improved endoplasmic reticulum (ER) stress related gene expressions, fasting glucose levels, insulin sensitivity and restored pancreatic islet cell mass, neuronal innervation and microbiome composition. We concluded that Rebaudioside A significantly ameliorated murine NASH, while the underlying mechanisms requires further investigation.
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http://dx.doi.org/10.1038/s41598-020-63688-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174355PMC
April 2020

Association of a de novo nonsense mutation of the TRIM8 gene with childhood-onset focal segmental glomerulosclerosis.

Pediatr Nephrol 2020 06 19;35(6):1129-1132. Epub 2020 Mar 19.

Genetics Division, LAC+USC Medical Center, Department of Pediatrics, Keck School of Medicine, University of Southern California, 1801 Marengo Street General Laboratory Building Rm1G24, Los Angeles, CA, 90033, USA.

Background: Focal segmental glomerulosclerosis (FSGS) is an etiologically heterogeneous disorder. Genetic FSGS may be either limited to the kidney or part of a genetic syndrome with other systemic involvement. At least 21 and 34 genes have been reported for renal-limited and syndromic FSGS, respectively. The TRIM8 gene encodes a tripartite motif protein, which is an E3 ubiquitin-protein ligase that promotes proteasomal degradation of the suppressor of cytokine signaling 1 (SOCS1) and participates in the activation of interferon-gamma signaling. The TRIM8 gene is expressed in various tissues including the kidney and the central nervous system (CNS). An association between a mutation in the TRIM8 gene and childhood-onset FSGS has not been well established.

Case-diagnosis: We describe an 8-year-old Hispanic male with infantile onset motor and developmental delay, seizures, and proteinuria secondary to FSGS. Next generation sequencing revealed a heterozygous de novo pathogenic variant in the TRIM8 gene (C1380T>A, p.Tyr460*). Immunohistochemical staining using anti-TRIM8 and anti-SOCS1 antibodies showed no significant TRIM8 expression and strong expression of SOCS1 in the renal biopsy tissue.

Treatment And Conclusions: De novo truncating mutations of TRIM8 have been previously reported in childhood-onset epileptic encephalopathy. A molecular analysis of TRIM8 should be considered in children with FSGS and clinical abnormalities of the central nervous system.
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http://dx.doi.org/10.1007/s00467-020-04525-3DOI Listing
June 2020

Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab.

Blood 2020 03;135(13):1049-1057

Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

Overactivated complement is a high-risk feature in hematopoietic stem cell transplant (HSCT) recipients with transplant-associated thrombotic microangiopathy (TA-TMA), and untreated patients have dismal outcomes. We present our experience with 64 pediatric HSCT recipients who had high-risk TA-TMA (hrTA-TMA) and multiorgan injury treated with the complement blocker eculizumab. We demonstrate significant improvement to 66% in 1-year post-HSCT survival in treated patients from our previously reported untreated cohort with same hrTA-TMA features that had 1-year post-HSCT survival of 16.7%. Responding patients benefited from a brief but intensive course of eculizumab using pharmacokinetic/pharmacodynamic-guided dosing, requiring a median of 11 doses of eculizumab (interquartile range [IQR] 7-20). Treatment was discontinued because TA-TMA resolved at a median of 66 days (IQR 41-110). Subjects with higher complement activation measured by elevated blood sC5b-9 at the start of treatment were less likely to respond (odds ratio, 0.15; P = .0014) and required more doses of eculizumab (r = 0.43; P = .0004). Patients with intestinal bleeding had the fastest eculizumab clearance, required the highest number of eculizumab doses (20 vs 9; P = .0015), and had lower 1-year survival (44% vs 78%; P = .01). Over 70% of survivors had proteinuria on long-term follow-up. The best glomerular filtration rate (GFR) recovery in survivors was a median 20% lower (IQR, 7.3%-40.3%) than their pre-HSCT GFR. In summary, complement blockade with eculizumab is an effective therapeutic strategy for hrTA-TMA, but some patients with severe disease lacked a complete response, prompting us to propose early intervention and search for additional targetable endothelial injury pathways.
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http://dx.doi.org/10.1182/blood.2019004218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099329PMC
March 2020

Use of electron microscopy when screening liver biopsies from neonates and infants: experience from a single tertiary children's hospital (1991-2017).

Ultrastruct Pathol 2020 Jan 3;44(1):32-41. Epub 2020 Jan 3.

Genetics Division, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

: Although the role of electron microscopy is diminishing in several areas of adult pathology, it remains an essential tool for the study of pediatric liver biopsies.: Clinical charts, histologic slides and EM materials of native liver biopsies from patients <1 year old (1991-2017) were reviewed.: 677 biopsies were performed on 353 males and 324 females. This study presents the concrete numbers for both the indications and the diseases, and describes the role of EM. EM was performed on 24.7% of liver biopsies and demonstrated key pathologic findings in 10 cases (6%), which led to the appropriate biochemical and/or genetic testing to confirm the diagnoses. The cases included five cases of glycogen storage disease with characteristic findings with cytoplasmic glycogen accumulation, two cases of mitochondrial disorder with pleomorphic mitochondria with crystalloid inclusions and one case each of Niemann-Pick Disease with abundant myelinosomes, Alpha-1 antitrypsin deficiency with deposits in the endoplasmic reticulum and infantile Refsum disease with trilamellar inclusions and lack of peroxisomes. In this study, we describe the detailed histologic and EM findings of each case .: EM played an important screening and diagnostic role in the challenging cases and was also used to rule out detectable pathologic conditions.
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http://dx.doi.org/10.1080/01913123.2019.1709934DOI Listing
January 2020

Severe Late-Onset Acute Cellular Rejection in a Pediatric Patient With Isolated Small Intestinal Transplant Rescued With Aggressive Immunosuppressive Approach: A Case Report.

Transplant Proc 2019 Nov;51(9):3181-3185

Gastroenterology, Hepatology and Nutrition, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California. Electronic address:

Small intestinal transplantation is performed for patients with intestinal failure who failed other surgical and medical treatment. It carries notable risks, including, but not limited to, acute and chronic cellular rejection and graft malfunction. Late severe acute intestinal allograft rejection is associated with increased risk of morbidity and mortality and, in the majority of cases, ends with total enterectomy. It usually results from subtherapeutic immunosuppression or nonadherence to medical treatment. We present the case of a 20-year-old patient who underwent isolated small bowel transplant for total intestinal Hirschsprung disease at age 7. Due to medication nonadherence, she developed severe late-onset acute cellular rejection manifested by high, bloody ostomy output and weight loss. Ileoscopy showed complete loss of normal intestinal anatomic landmarks and ulcerated mucosa. Graft biopsies showed ulceration and granulation tissue with severe architectural distortion consistent with severe intestinal graft rejection. She initially received intravenous corticosteroids and increased tacrolimus dose without significant improvement. Her immunosuppression was escalated to include infliximab and finally antithymocyte globulin. Graft enterectomy was considered repeatedly; however, clinical improvement was noted eventually with evidence of histologic improvement and salvage of the graft. The aggressive antirejection treatment was complicated by development of post-transplant lymphoproliferative disorder that resolved with reducing immunosuppression. Her graft function is currently maintained on tacrolimus, oral prednisone, and a periodic infliximab infusion. We conclude that a prompt and aggressive immunosuppressive approach significantly increases the chance of rescuing small bowel transplant rejection.
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http://dx.doi.org/10.1016/j.transproceed.2019.08.012DOI Listing
November 2019

Reduction of large soft-tissue Gaucheromas with substrate reduction therapy.

J Inherit Metab Dis 2020 03 28;43(2):375-376. Epub 2019 Nov 28.

Genetics Division, Department of Pediatrics, LAC+USC Medical Center, University of Southern California, Los Angeles, California.

Soft-tissue masses are rarely seen in Gaucher disease. We previously reported a case of a 30-year-old patient with Gaucher disease type 3, receiving β-glucocerebrosidase enzyme replacement therapy (ERT), who presented with slowly enlarging masses infiltrated with Gaucher cells along her back. Substrate reduction therapy introduced in addition to ERT, resulted in significant reduction of the large masses.
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http://dx.doi.org/10.1002/jimd.12188DOI Listing
March 2020

Expanding the spectrum of dicer1-associated sarcomas.

Mod Pathol 2020 01 19;33(1):164-174. Epub 2019 Sep 19.

Division of Hematology, Oncology and Blood and Marrow Transplantation, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

DICER1 syndrome is a hereditary cancer predisposition syndrome caused by deleterious germline DICER1 mutations. Characteristic "hotspot" somatic mutations of DICER1 have been identified in DICER1-associated tumors. With the exception of genitourinary embryonal rhabdomyosarcoma and anaplastic sarcoma of the kidney, sarcomas are rarely reported in DICER1 syndrome. Herein, we report the clinical, histopathologic, and molecular findings of a germline DICER1-associated ovarian sarcoma in a 5-year-old female, a somatic DICER1-associated metastatic peritoneal sarcoma in a 16-year-old female, and a somatic DICER1-associated primary intracranial sarcoma in a 4-year-old male. A comprehensive review of the literature, including 83 DICER1-associated sarcomas, illustrates an unequivocal histologic pattern mimicking pleuropulmonary blastoma, regardless of the site of origin. The features include undifferentiated small round blue cells, poorly differentiated spindle cells, and large bizarre pleomorphic cells (anaplasia), often with rhabdomyoblastic and/or chondroid differentiation, and rare bone/osteoid formation. This unique heterogeneous histologic pattern should raise suspicion for pathogenic DICER1 mutation(s) warranting a detailed review of the family history and DICER1 mutation analysis. In addition to expanding the phenotypic spectrum of DICER1-associated conditions, identification of pathogenic DICER1 variants facilitates optimized genetic counseling, caregiver education and judicious imaging-based surveillance.
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http://dx.doi.org/10.1038/s41379-019-0366-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528621PMC
January 2020

IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma.

Nat Cell Biol 2019 08 1;21(8):1003-1014. Epub 2019 Aug 1.

Division of Human Biology, Solid Tumor and Translational Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.
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http://dx.doi.org/10.1038/s41556-019-0363-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686884PMC
August 2019

NTRK-rearranged mesenchymal tumour in a 3-year-old female: a diagnostic quandary.

Histopathology 2019 11 2;75(5):772-775. Epub 2019 Aug 2.

Division of Hematology, Oncology and Blood and Marrow Transplantation, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

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http://dx.doi.org/10.1111/his.13920DOI Listing
November 2019

Histologic and ultrastructural features in early and advanced phases of Zellweger spectrum disorder (infantile Refsum disease).

Ultrastruct Pathol 2018 May-Jun;42(3):220-227. Epub 2018 Feb 26.

c Genetics Division, Department of Pediatrics, Keck School of Medicine , University of Southern California , Los Angeles , California , USA.

Zellweger spectrum disorders (ZSD) are rare autosomal recessive inherited metabolic disorders and include severe (Zellweger syndrome) and milder phenotypes [neonatal adrenoleukodystrophy and infantile Refsum disease (IRD)]. ZSD are characterized by impaired peroxisomal functions and lack of peroxisomes detected by electron microscopy (EM). ZSD are caused by mutations in any of the 14 PEX genes. Patients with ZSD commonly demonstrate nonspecific hepatic symptoms within the first year, often without clinical suspicion of ZSD. Thus, recognition of pathologic findings in the liver is critical for the early diagnosis. We herein demonstrate the histologic and ultrastructural features in liver biopsies in the early and advanced phases from a 16-year-old male with IRD. The initial biopsy at 5 months of age showed a lack of peroxisomes by EM, and this finding played a critical role in the early diagnosis. In contrast, the second biopsy at 14 years of age, after long-term diet therapy, demonstrated significant disease progression with near-cirrhotic liver. In addition to lack of peroxisomes, EM revealed abundant trilamellar inclusions within large angulated lysosomes in many of the hepatocytes and Kupffer cells. Mitochondrial abnormalities were identified only in the second biopsy and were mainly identified in damaged cells; thus they were likely nonspecific secondary changes. This is the first report demonstrating histological and ultrastructural features of liver biopsies in the early and advanced phases from a child with ZSD. Trilamellar inclusions are considered to be an ultrastructural hallmark of ZSD, but they may not be apparent in the early phases.
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http://dx.doi.org/10.1080/01913123.2018.1440272DOI Listing
October 2018

Rare MYC-amplified Neuroblastoma With Large Cell Histology.

Pediatr Dev Pathol 2018 Sep-Oct;21(5):461-466. Epub 2018 Feb 9.

1 Department of Pathology & Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California.

Background Although MYCN (aka N-myc) amplification is reported in ∼20% of neuroblastomas, MYC (aka C-myc) amplification appears to be a rare event in this disease. As of today, only 2 MYC-amplified neuroblastomas have been briefly mentioned in the literature. Methods We studied here the clinicopathological features of 3 MYC-amplified neuroblastomas. Results All 3 patients (2 females and 1 male) had stage 4 disease. One female is currently alive and well 52 months after the diagnosis, while the other female and male patients died of disease 24 and 20 months after the diagnosis, respectively. Further analysis on 2 tumors revealed unfavorable histology with MYC protein overexpression but with neither MYCN amplification nor MYCN protein overexpression. Both of these tumors exhibited "large cell neuroblastoma" histology with enlarged, uniquely open nuclei and nucleolar hypertrophy, along with "aberrant" desmin expression. Conclusions MYC-amplified neuroblastomas are extremely rare and seem to present with distinct clinicopathological features.
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http://dx.doi.org/10.1177/1093526617749670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469889PMC
June 2019

Cytologic and Ultrastructural Findings of Bronchoalveolar Lavage in Patients With Chronic Granulomatous Disease.

Pediatr Dev Pathol 2018 Jul-Aug;21(4):347-354. Epub 2017 Oct 19.

1 Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California.

Background Chronic granulomatous disease (CGD) is a hereditary immunodeficiency caused by mutations in genes encoding nicotinamide adenine dinucleotide phosphate oxidase enzyme complex, which lead to the inability to kill intracellular pathogens. Patients with CGD are susceptible to recurrent bacterial and fungal infections in their early lives. Although the recent survival rate has been significantly improved, early diagnosis is critical to prevent multiple organ impairment. In 1950s, CGD was first described as a disease with recurrent infections and visceral infiltration of granulomas and pigmented histiocytes. Bronchoalveolar lavage (BAL) is commonly performed for patients with CGD; however, no study has described the cytologic features of alveolar macrophages. Methods Cytology of 20 BALs from 11 CGD patients was examined. The greatest diameters of randomly selected 100 alveolar macrophages in each BAL were measured using image analysis and compared with 20 disease control BALs from non-CGD patients. Macrophages from 2 groups were compared with repeated measures mixed-model analysis. Ultrastructural analysis was performed on a representative CGD BAL. Results BALs from CGD patients showed variable numbers of neutrophils and lipid-laden macrophages. Macrophages in CGD BALs were significantly larger than disease control BALs ( P < .0001) and showed "foamy" vacuolated cytoplasm. Ultrastructural analysis revealed the macrophages filled with enlarged lysosomes containing lipofuscin-like materials, which made their appearance "foamy." Conclusion In this study, we demonstrate novel BAL findings in CGD patients. The presence of enlarged "foamy" alveolar macrophages is not specific for CGD, but CGD should be considered as a differential diagnosis when foamy macrophages are present.
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http://dx.doi.org/10.1177/1093526617736188DOI Listing
May 2019

Utility of Phox2b immunohistochemical stain in neural crest tumours and non-neural crest tumours in paediatric patients.

Histopathology 2018 Mar 21;72(4):685-696. Epub 2017 Dec 21.

Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Aims: This study evaluated the utility of Phox2b in paediatric tumours. Previously, tyrosine hydroxylase (TH) was the most widely utilised sympathoadrenal marker specific for neural crest tumours with neuronal/neuroendocrine differentiation. However, its sensitivity is insufficient. Recently Phox2b has emerged as another specific marker for this entity.

Methods And Results: Phox2b immunohistochemistry (IHC) was performed on 159 paediatric tumours, including (group 1) 65 neural crest tumours with neuronal differentiation [peripheral neuroblastic tumours (pNT)]: 15 neuroblastoma undifferentiated (NB-UD), 10 NB poorly differentiated (NB-PD), 10 NB differentiating (NB-D), 10 ganglioneuroblastoma intermixed (GNBi), 10 GNB nodular (GNBn) and 10 ganglioneuroma (GN); (group 2) 23 neural crest tumours with neuroendocrine differentiation [pheochromocytoma/paraganglioma (PCC/PG)]; (group 3) 27 other neural crest tumours including one composite rhabdomyosarcoma/neuroblastoma; and (group 4) 44 non-neural crest tumours. TH IHC was performed on groups 1, 2 and 3. Phox2b was expressed diffusely in pNT (n = 65 of 65), strongly in NB-UD and NB-PD and with less intensity in NB-D, GNB and GN. Diffuse TH was seen in all NB-PD, NB-D, GNB and GN, but nine of 15 NB-UD and a nodule in GNBn did not express TH (n = 55 of 65). PCC/PG expressed diffuse Phox2b (n = 23 of 23) and diffuse TH, except for one tumour (n = 22 of 23). In composite rhabdomyosarcoma, TH was expressed only in neuroblastic cells and Phox2b was diffusely positive in neuroblastic cells and focally in rhabdomyosarcoma. All other tumours were negative for Phox2b (n = none of 44).

Conclusion: Phox2b was a specific and sensitive marker for pNT and PCC/PG, especially useful for identifying NB-UD often lacking TH. Our study also presented a composite rhabdomyosarcoma/neuroblastoma of neural crest origin.
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http://dx.doi.org/10.1111/his.13412DOI Listing
March 2018

A Complete Histologic Approach to Gastrointestinal Biopsy From Hematopoietic Stem Cell Transplant Patients With Evidence of Transplant-Associated Gastrointestinal Thrombotic Microangiopathy.

Arch Pathol Lab Med 2017 Nov 10;141(11):1558-1566. Epub 2017 Aug 10.

From the Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California (Dr Warren); and the Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (Drs Jodele, Dandoy, Myers, Wallace, Nelson, and El-Bietar).

Context: - Transplant-associated thrombotic microangiopathy is a serious complication of hematopoietic stem cell transplant that may progress to multi-organ dysfunction. Transplant-associated thrombotic microangiopathy may involve the intestinal vasculature (intestinal transplant-associated thrombotic microangiopathy [iTMA]), causing patients to experience debilitating symptoms of ischemic colitis, including disproportionately severe abdominal pain and gastrointestinal bleeding, requiring heavy narcotic use and frequent transfusion support. Pathophysiology remains poorly investigated but may include endothelial damage mediated by inflammatory markers and the complement system. Endoscopy of hematopoietic stem cell transplant patients often produces biopsy samples, in which mucosal lamina propria capillaries are sufficient for an evaluation of iTMA features.

Objective: - To provide a detailed review of histologic features of iTMA.

Data Sources: - We conducted a systematic review of studies assessing histologic features of iTMA. Studies were identified by PubMed search and included a cohort study performed by our group.

Conclusions: - The histologic hallmark of iTMA is endothelial cell injury that leads to hemorrhage and thrombosis of the capillaries. Histologic features include endothelial cell swelling, endothelial cell separation, perivascular mucosal hemorrhage, intraluminal schistocytes, intraluminal fibrin, intraluminal microthrombi, loss of glands, and total denudation of mucosa. Identification of features consistent with iTMA has immediate implications for clinical management that could potentially improve outcome and survival.
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http://dx.doi.org/10.5858/arpa.2016-0599-RADOI Listing
November 2017

Gene fusions PAFAH1B1-USP6 and RUNX2-USP6 in aneurysmal bone cysts identified by next generation sequencing.

Cancer Genet 2017 04 24;212-213:13-18. Epub 2017 Mar 24.

Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229.

Aneurysmal bone cyst (ABC) is a locally aggressive, expansile, typically multilocular cystic bone tumor. ABC was previously thought to be a non-neoplastic lesion; however, it is now considered to be neoplasm that features recurrent chromosomal translocations resulting in gene fusions between ubiquitin specific peptidase 6 (USP6) and multiple partners, including COL1A1, CDH11, TRAP150, ZNF90 and OMD. Using next generation sequencing (NGS), we uncovered two fusion partners of USP6 in two ABCs: platelet activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1), which is known to contribute to tumorigenesis in lung cancer, and runt-related transcription factor 2 (RUNX2), which is known to regulate osteoblastic differentiation, osteosarcoma tumorigenesis and its metastasis. In our study, the PAFAH1B1-USP6 fusion consisted of the promoter of PAFAH1B1 fused to the 5'-untranslated region (5'-UTR) of USP6 and was discovered in a typical ABC. The RUNX2-USP6 fusion had the promoter and a short coding region of RUNX2 fused to the translation start codon of USP6 and was detected in an unusually aggressive ABC with an osteosarcoma-like soft tissue extension. Our findings not only expanded the repertoire of the partner genes of USP6 in ABC but also can serve as a reference for future studies to better understand the correlation between various gene fusions and the progression of ABC.
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http://dx.doi.org/10.1016/j.cancergen.2017.03.007DOI Listing
April 2017

Undifferentiated myxoid lipoblastoma with PLAG1-HAS2 fusion in an infant; morphologically mimicking primitive myxoid mesenchymal tumor of infancy (PMMTI)--diagnostic importance of cytogenetic and molecular testing and literature review.

Cancer Genet 2016 Jan-Feb;209(1-2):21-9. Epub 2015 Nov 18.

Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Electronic address:

Lipoblastoma is a benign myxoid neoplasm arising in young children that typically demonstrates adipose differentiation. It is often morphologically indistinguishable from primitive myxoid mesenchymal tumor of infancy (PMMTI), which is characterized by a well-circumscribed myxoid mass with a proliferation of primitive mesenchymal cells with mild cytologic atypia. PMMTI occurs in the first year of life and is known to have locally aggressive behavior. No specific genetic rearrangements have been reported to date. In contrast, the presence of PLAG1 (Pleomorphic Adenoma Gene 1) rearrangement is diagnostic for lipoblastoma. We hereby demonstrate the combined application of multiple approaches to tackle the diagnostic challenges of a rapidly growing neck tumor in a 3-month-old female. An incisional tumor biopsy had features of an undifferentiated, myxoid mesenchymal neoplasm mimicking PMMTI. However, tumor cells showed diffuse nuclear expression by immunohistochemical (IHC) stain. Conventional cytogenetic and fluorescence in situ hybridization (FISH) analyses as well as next generation sequencing (NGS) demonstrated evidence of PLAG1 rearrangement, confirming the diagnosis of lipoblastoma. This experience warrants that undifferentiated myxoid lipoblastoma can mimic PMMTI, and the combination of cytogenetic and molecular approaches is essential to distinguish these two myxoid neoplasms. Literature on lipoblastomas with relevant molecular and cytogenetic findings is summarized. Our case is the first lipoblastoma diagnosed with a PLAG1 fusion defined by NGS technology.
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http://dx.doi.org/10.1016/j.cancergen.2015.11.004DOI Listing
June 2016

Importance of Phox2B Immunohistochemical Stain for Detecting Metastatic Neuroblastoma Cells in Bone Marrow Specimens.

Pediatr Dev Pathol 2016 May-Jun;19(3):254-5. Epub 2015 Nov 24.

Department of Pathology & Laboratory Medicine Children's Hospital Los Angeles, Los Angeles, CA, USA.

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http://dx.doi.org/10.2350/15-11-1736-LET.1DOI Listing
August 2016

Calretinin-Immunoreactive Hypoinnervation in Down Syndrome (DS): Report of an Infant with Very Short-Segment Hirschsprung Disease and Comparison to Biopsy Findings in 20 Normal Infants and 11 Infants with DS and Chronic Constipation.

Pediatr Dev Pathol 2016 Mar-Apr;19(2):87-93. Epub 2015 Jul 31.

1 Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

In Down syndrome (DS) constipation is common, and the incidence of Hirschsprung disease (HD) is 1-2%. Rectal suction biopsies (RSBs) in DS may show discordant features; calretinin immunoreactivity (CRir) often helps resolve discrepancies. We report a case of unequivocal very short-segment HD (vsHD) in an infant with DS who had aganglionosis with abnormal acetylcholine esterase (AChE) activity in 3 RSBs. The CRir patterns were scanty positive rather than the expected absent CRir innervation in the lamina propria (LP). The resection specimen was grossly typical for short-segment HD, with a 5.5-cm, narrow but normally ganglionated segment proximal to the verified very short distal anganglionic zone. Unequivocal calretinin hypoinnervation was limited to the distal 2 cm, substantiating the warning of Kapur that small numbers of CRir nerves in the LP do not exclude a diagnosis of vsHD. We evaluated RSBs from 11 DS and 20 randomly selected normal infants <6 months of age with chronic constipation. The normal infants had abundant mucosal calretinin innervation and AChE histochemistry. We observed variable CRir hypoinnervation in RSBs in DS infants (including 6/7 with "normal" original diagnosis and 1/4 with HD). Our findings caution against overdependence on "normal" calretinin immunohistochemistry and suggest that AChE may be more reliable than CRir in the context of DS. An unknown number of patients with DS may have enteric nervous system disorders functionally similar to HD, which are possibly related to abnormal or imbalanced autonomic innervation, of which distal calretinin hypoinnervation is one manifestation, despite the presence of ganglia.
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http://dx.doi.org/10.2350/15-01-1602-OA.1DOI Listing
June 2016