Fetal Mediastinal Fibrosarcoma. Report of Two Cases.

Introduction: One-third of fetal soft tissue tumors are malignant and include congenital fibrosarcoma (CF). We report two fetal CFs arising in the posterior mediastinum. Case Presentation: In case 1, the CF resulted in a mediastinal shift, extensive infiltration of the tumor around adjacent structures, pulmonary hypoplasia, pleural effusion, and rapid growth. The pregnancy was terminated. Case 2 had multiple intrathoracic masses, thoracic hypoplasia, pleural effusion, and fetal death. Both were diagnosed as fibrosarcoma at fetopsy. Discussion: Although congenital CF tends to be locally aggressive with a low metastatic rate, it tends to grow rapidly and the tumor location can affect fetal survival. In Case 1, the tumor demonstrated locally aggressive behavior whereas multiple distant metastases such as lung, liver, adrenals, and left eye were detected in Case 2. The tumor was directly responsible for intrauterine fetal demise in the second case.

Primary Paraspinal and Spinal Epidural Non-Hodgkin Lymphoma in Childhood.

Primary paraspinal/spinal epidural lymphoma (PPSEL) is rare in childhood. Here, we retrospectively evaluated patients with PPSEL treated in our department. We also reviewed the cases reported in the literature. Fifteen of 1354 non-Hodgkin lymphoma cases diagnosed over a 38-year period were PPSEPL. There were 11 male individuals and 4 female individuals with a median age of 13 years. Most common symptoms were pain and limb weakness. Physical examination revealed spinal cord compression in 80% of patients. The most common tumor location was the lumbar region. Histopathologic subtypes were lymphoblastic lymphoma in 6 and Burkitt lymphom in 5 patients. Subtotal or near-total excision of the tumor with laminectomy was performed in 6 patients. Thirteen and 9 patients received chemotherapy and radiotherapy, respectively. Neurologic recovery was observed in 70% of patients. Seven patients were alive without disease at a median of 88 months. Overall and event-free survival rates were 61.7% and 50.1%, respectively. We reviewed clinical features, treatment, and outcome of 69 PPSEL cases reported in the literature. Neurologic recovery and long-term survival was achieved in 66.7% of them. Heterogeneity in diagnostic methods and treatment have made it difficult to establish the prognostic indicators for neurologic outcome and survival. Multicenter prospective studies with more cases are necessary to determine the prognostic factors.

Inflammatory milieu of muscle biopsies in juvenile dermatomyositis.

Juvenile dermatomyositis (JDM) is an inflammatory myopathy which causes severe morbidity and high mortality if untreated. In this study, we aimed to define the T-helper cell profile in the muscle biopsies of JDM patients. Muscle biopsies of twenty-six patients (50% female) were included in the study. Immunohistochemical expression of CD3, CD20, CD138, CD68, IL-17, Foxp3, IFN-É£, IFN-alpha and IL-4 was studied and muscle biopsies were scored using the JDM muscle biopsy scoring tool. Inflammatory cells were in small clusters in perimysium and perivascular area or scattered throughout the endomysium in most biopsies; however in 2 biopsies, lymphoid follicle-like big clusters were observed, and in one, there was a very dense and diffuse inflammatory infiltration nearly destroying all the muscle architecture. Seventy-three per cent of the biopsies had T cells, 88% had B cells, 57% had plasma cells, and all had macrophages. As for T-helper cell subtypes, 80% of the biopsies were Th1 positive, 92% Th17 positive and 30% Treg positive. No IL-4 positive inflammatory cell was detected, and only 2 biopsies showed IFN-alpha positivity. The mean JDM biopsy score was 17.6, meaning moderate to severe muscular involvement. Visual analogue score of the pathologist was strongly correlated with histopathological features. B cells, macrophages, plasma cells and T cells constitute the inflammatory milieu of the JDM muscle biopsies. As for T cells, JDM is a disease mainly related with Th1 and Th17 T-helper cell subtypes and to some extend Treg. Th2 cells are not involved in the pathogenesis.

Clinical and histopathological features of immunoglobulin G4-associated autoimmune hepatitis in children.

BACKGROUND AND AIM: We aimed to examine the frequency and the characteristics of immunoglobulin G4 (IgG4)-associated autoimmune hepatitis among pediatric patients with autoimmune hepatitis. METHODS: Immunostaining for IgG and IgG4 was performed in liver biopsies of 40 pediatric patients with autoimmune hepatitis. The patients with more than 10 IgG4-positive plasma cells/high-power field were defined as IgG4-associated autoimmune hepatitis. Clinic, laboratory, and histopathological results were compared between groups. RESULTS: Among the 40 pediatric patients, 34 patients were type 1 and 6 patients were type 2 autoimmune hepatitis. Six patients (15%), four of the type 1 and two of the type 2 autoimmune hepatitis patients, were diagnosed with IgG4-associated autoimmune hepatitis. Clinical, laboratory, and histopathological data were initially similar in both forms. There was a positive correlation between IgG4-positive plasma cell count and degree of portal (r: 0.406, P: 0.009) and lobular inflammation (r: 0.37, P: 0.019), grade of interface hepatitis (r: 0.33, P: 0.03), and fibrosis (r: 0.318, P: 0.046). Time required for normalization of liver transaminases and serum IgG level was significantly shorter in IgG4-associated autoimmune hepatitis (3.3 ± 0.5 vs 6.6 ± 3.5 for alanine aminotransferase, 3.7 ± 0.8 vs 6.7 ± 1.2 for aspartate aminotransferase, 4.3 ± 1.2 vs 7.1 ± 2.7 for gamma-glutamyl transpeptidase, and 7.2 ± 3.1 vs 12.8 ± 4.5 for IgG). CONCLUSIONS: Immunoglobulin G4-associated autoimmune hepatitis can be found in pediatric age group and also in type 2 autoimmune hepatitis patients. As steroid response may be better in IgG4-associated autoimmune hepatitis, biopsy specimens should be evaluated for this entity at diagnosis.

Primary Osteosarcoma of the Rib: A Case Report and Review of the Literature.

Osteosarcoma is the most common primary malignant tumor of the bone. The most common sites of osteosarcoma in children are the metaphysis of long bones, especially the distal femur, proximal tibia, and proximal humerus. It occurs very rarely in flat bones. Here we report a 14-year-old adolescent boy with primary osteosarcoma of the fifth rib and a review of literature.

Role of CXCR1 (CKR-1) in inflammation of experimental mesangioproliferative glomerulonephritis.

CXCR1 (CKR-1), a receptor of IL-8, is expressed in various cells including neutrophils and monocytes, both of which play a major role in proliferating glomerular diseases. We investigated time-dependent expression of CXCR1 and the effect of single-dose cyclosporine A (CsA) treatment on this expression in experimental mesangioproliferative glomerulonephritis induced by anti-thymocyte serum (ATS). Wistar rats were divided into three groups. Group 1 (control, n = 24) received non-immune serum. Group 2 (nephritis, n = 24) received ATS. Group 3 (nephritis + CsA, n = 24) received ATS and CsA concomitantly. Kidneys from six rats in each group were removed at sixth hour, 3 days, 5 days, and 7 days. ATS induced proteinuria compared to controls (p < 0.001) and CsA precluded the development of proteinuria. Glomerular inflammation and mesangial proliferation were significantly higher in ATS group than control and CsA-treated rats (p < 0.001). ATS injection caused marked interstitial inflammation that was precluded by CsA (p < 0.001). CXCR1 was not expressed in control kidneys. However, ATS induced expression of CXCR1 in both glomeruli and tubulointerstitium. CsA treatment precluded CXCR1 expression in both glomeruli and tubulointerstitium only in the first 6 h. CXCR1 may contribute to inflammation in experimental mesangioproliferative glomerulonephritis. CsA may be beneficial by inhibiting CXCR1 expression and corresponding inflammation.

Magnetic resonance elastography in evaluation of liver fibrosis in children with chronic liver disease.

BACKGROUND: Magnetic resonance elastography (MRE) has been used to stage liver fibrosis in adults. We aimed to assess the agreement between the Ishak scoring system and magnetic resonance elastography-measured liver stiffness (MRE-LS) in children. This study included all the children who underwent abdominal MRE and liver biopsies between February 2018 and January 2021. The correlation between MRE-LS and Ishak fibrosis stage, MRE parameters, and clinical and biochemical markers affecting this relationship was investigated. RESULTS: A total of 52 patients (31 male; a median age of 11.8 years) were included in the study. The MRE-LS values were significantly different between Ishak fibrosis stages (p = 0.036). With a cut-off value of 2.97 kilopascals, MRE-LS had sensitivity, specificity, PPV, NPV and accuracy values of 90.9%, 82.9%, 58.8%, 97.1%, and 84.6%, respectively, for differentiating mild/moderate fibrosis (F0, 1, 2, 3) from severe fibrosis (F ≥ 4). Although MRE-LS was moderately correlated with Ishak fibrosis score and histological activity index and weakly correlated with aspartate aminotransferase, hepatic steatosis, and R2*, only Ishak fibrosis score was a significant predictor of MRE-LS. MRE-measured spleen stiffness was weakly correlated with the Ishak fibrosis score. CONCLUSIONS: MRE has high sensitivity and specificity for evaluating liver fibrosis in children. MRE may be used to evaluate liver fibrosis in pediatric patients.

Al-Gazali Skeletal Dysplasia Constitutes the Lethal End of ADAMTSL2-Related Disorders.

Lethal short-limb skeletal dysplasia Al-Gazali type (OMIM %601356), also called dysplastic cortical hyperostosis, Al-Gazali type, is an ultra-rare disorder previously reported in only three unrelated individuals. The genetic etiology for Al-Gazali skeletal dysplasia has up until now been unknown. Through international collaborative efforts involving seven clinical centers worldwide, a cohort of nine patients with clinical and radiographic features consistent with short-limb skeletal dysplasia Al-Gazali type was collected. The affected individuals presented with moderate intrauterine growth restriction, relative macrocephaly, hypertrichosis, large anterior fontanelle, short neck, short and stiff limbs with small hands and feet, severe brachydactyly, and generalized bone sclerosis with mild platyspondyly. Biallelic disease-causing variants in ADAMTSL2 were detected using massively parallel sequencing (MPS) and Sanger sequencing techniques. Six individuals were compound heterozygous and one individual was homozygous for pathogenic variants in ADAMTSL2. In one of the families, pathogenic variants were detected in parental samples only. Overall, this study sheds light on the genetic cause of Al-Gazali skeletal dysplasia and identifies it as a semi-lethal part of the spectrum of ADAMTSL2-related disorders. Furthermore, we highlight the importance of meticulous analysis of the pseudogene region of ADAMTSL2 where disease-causing variants might be located. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Mediastinal germ cell tumors in childhood.

BACKGROUND: Mediastinal germ cell tumors (GCTs) are rare and usually located in anterior mediastinum. We aimed to review clinical and pathological characteristics of these tumors. PROCEDURE: Between 1973 and 2011, 24 children with mediastinal GCTs were diagnosed. Hospital files were reviewed for presenting complaints, clinical, radiological and other laboratory data, surgical practices, treatments, and outcomes. RESULTS: Median age was 4.5 years (0.2-16) (male/female: 10/14). Most common initial complaints were dyspnea, cough, anorexia/fatigue, fever, and chest pain. Primary tumors were located in anterior mediastinum (n = 22), posterior mediastinum (n = 1), and sternum (n = 1). Thirteen of 24 cases had mature teratomas (54.2%); four (16.7%) endodermal sinus tumor (EST); four (16.7%) immature teratomas; and one (4.2%) each of embryonal carcinoma, teratocarcinoma, and malignant teratoma. Mature teratomas underwent only surgical resection and were under follow-up without disease. Four cases with ESTs received chemotherapy and radiotherapy (n = 3), three underwent surgical resections: three died, one was followed for 284 months in remission. All but one immature teratomas were treated with surgery and all were under follow-up without disease. Two patients with embryonal carcinoma and malignant teratoma didn't undergo surgery; both received chemotherapy and radiotherapy but died with disease. The patient with teratocarcinoma was treated with surgery and chemotherapy but died with disease. CONCLUSIONS: No adjuvant therapy is needed for mature teratomas. Immature teratomas must be under close follow-up for recurrences. Prognosis for mediastinal malignant GCTs was poor. These cases need intensive chemotherapies and effective local control measures as surgery -/+ radiotherapy to ensure long-term survival.

The prognostic factors in children undergoing pulmonary metastatectomy.

A retrospective analysis was performed to determine the prognostic factors affecting survival in children who underwent pulmonary metastatectomy. Seventeen patients who underwent pulmonary metastatectomy between 2000-2006 were evaluated retrospectively by means of age, sex, primary diagnosis, time of metastasis appearance, number of nodules found on imaging examinations, type of management, surgical data, and outcome. Video-assisted thoracoscopic surgery (VATS) was used in 11 patients, and all patients underwent thoracotomy consequently. The nodule was composed of tumor cells in 13 (76%) patients and had positive surgical margins in 5 (38%). The time of metastasis appearance, number of metastases and completeness of the nodule excision did not affect survival (p=0.31, p=0.87 and p=0.56, respectively). Nodule size >1 cm was associated with dismal survival (p=0.008). Time elapsed until the diagnosis of pulmonary metastasis, number of metastases and the completeness of metastatectomy do not have an impact on survival. The only significant prognostic factor is the size of the largest metastatic nodule. The presence of a metastatic nodule >1 cm is associated with a worse outcome in pediatric patients. VATS is an adjunct method to thoracotomy in the surgical management of pulmonary metastasis in children.

Glomerulonephritis with crescents in childhood; etiologies and significance of M2 macrophages.

BACKGROUND: Crescentic glomerulonephritis (CGN) is a rapidly progressive and rare cause of glomerulonephritis in childhood. The aim of this study is to evaluate demographic data of children with crescentic glomerulonephritis, to classify the etiologies and to investigate the correlation between the severity of kidney disease and the expression of CD163+ macrophages. METHODS: Between the years 2000 and 2016 in a single center, patients under 18 years of age with kidney biopsies containing crescents were included in the study. A total of 88 children were enrolled. The expression of CD163 in kidney tissues was detected by immunohistochemistry in 61 patients. Clinical features and outcome were collected from their medical records. RESULTS: The most common etiology was Henoch-Schönlein purpura (HSP) nephritis/Immunglobulin A vasculitis (26.1%), followed by lupus nephritis (22.7%) and idiopathic crescentic glomerulonephritis (18.2%). CD163 positive cell counts in patients with GFR levels less and more than 60 ml/min/1.73 m2 at their last visit were 7.6±6.6 cells vs. 2.0±3.0 cells (p=0.057) per one glomerulus and 52.2±18.2 cells/hpf vs. 33.3±10.0 cells/hpf (p < 0.05) in tubulointerstitium, respectively. Tubulointerstitital CD163+ cells were also found to be higher in patients with end stage kidney disease than complete and partial responders (68 cells/hpf vs 39 cells/hpf, p < 0.05). CONCLUSIONS: CD163 positive cell counts, particularly in tubulointerstitial areas, have been associated with poor prognosis of CGN.

A novel mutation in the DGUOK gene in a Turkish newborn with mitochondrial depletion syndrome.

Deoxyguanosine kinase (DGUOK) catalyzes the first step of the mitochondrial deoxypurine salvage pathway, the phosphorylation of purine deoxyribonucleosides. Mutations in the DGUOK gene have been linked to inherited mitochondrial (mt)DNA depletion syndromes, neonatal liver failure, nystagmus, and hypotonia. We now report a novel homozygous c.34C > T (p.Arg12X) mutation found in an affected newborn of asymptomatic consanguineous parents. Respiratory distress started in the first hours after birth. The patient died at the age of 42 days due to liver failure. This genotype, which is to be expected for a homozygous stop codon mutation in exon 1, is associated with a severe clinical presentation.

Distinctive Features of Hepatic Steatosis in Children: Is It Primary or Secondary to Inborn Errors of Metabolism?

PURPOSE: The incidence of hepatic steatosis among children has been increasing; however, data distinguishing simple steatosis from a more complex disorder are lacking. METHODS: This study identified the etiologies resulting in hepatic steatosis through a retrospective review of pediatric liver biopsies performed in the last 10 years. A total of 158 patients with hepatic steatosis proven by histopathological evaluation were enrolled in the study, and baseline demographic features, anthropometric measurements, physical examination findings, laboratory data, ultrasonographic findings, and liver histopathologies were noted. RESULTS: The two most common diagnoses were inborn errors of metabolism (IEM) (52.5%) and nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) (29.7%). The three most common diseases in the IEM group were glycogen storage disorders, Wilson's disease, and mitochondrial disease. The rates of consanguineous marriage (75.6%; odds ratio [OR], 26.040) and positive family history (26.5%; OR, 8.115) were significantly higher (p=0.002, p<0.001, respectively) in the IEM group than those in the NAFLD/NASH group. Younger age (p=0.001), normal anthropometric measurements (p=0.03), increased aspartate aminotransferase levels (p<0.001), triglyceride levels (p=0.001), and cholestatic biochemical parameters with disrupted liver function tests, as well as severe liver destruction of hepatic architecture, cholestasis, fibrosis, and nodule formation, were also common in the IEM group. CONCLUSION: Parents with consanguinity and positive family history, together with clinical and biochemical findings, may provide a high index of suspicion for IEM to distinguish primary steatosis from the consequence of a more complex disorder.

A rare type of renal cell carcinoma in a girl: hybrid renal cell carcinoma.

Hybrid renal cell carcinoma (HRCN) is a rare type of renal tumor with characteristic pathologic features, including oncocytic and chromophobe cellular content, and shows more favorable prognosis than renal cell carcinoma. The early-stage tumors show favorable outcome, and postoperative regular clinical and radiological follow-up is adequate in most cases. However, close follow-up is mandatory for tumors with histopathologically coexistence of squamous, papillary, and/or eosinophilic RCC component. This report describes a 12-year-old girl with a stage I HRCN who was closely followed after nephrectomy with no further treatment.

Merkel cell carcinoma in a child.

Merkel cell carcinoma, a rare tumor of the skin with aggressive behavior, is usually fatal when advanced disease is present. Merkel cell carcinoma occurs mostly in white race between 60 and 80 years of age, however, it can occur in any races and ages. It is extremely rare in children. We present here a Merkel cell carcinoma in a boy. Its features and treatment modalities were discussed in the literature light.

Determinants of Riboflavin Responsiveness in Multiple Acyl-CoA Dehydrogenase Deficiency.

BACKGROUND: Multiple acyl-CoA dehydrogenase (MADD) deficiency, which is a rare metabolic disorder involving electron transport flavoproteins, has a wide array of clinical phenotypes. In this article, we describe 25 patients with MADD deficiency and present the clinical and laboratory characteristics and diagnostic challenges associated with riboflavin-responsive MADD deficiency. METHODS: Hospital records of patients with biallelic mutations in ETFA, ETFB, or ETFDH genes diagnosed in a single center were analyzed retrospectively. Demographic, clinical, and laboratory characteristics of patients with riboflavin-responsive and riboflavin-unresponsive MADD deficiency were compared using Mann-Whitney U and Fisher's exact tests. RESULTS: Respiratory distress and depressed consciousness were significantly more common in patients with riboflavin-unresponsive MADD deficiency (P = 0.015 and P < 0.001), who presented at a younger age (P < 0.001). Patients with riboflavin-responsive MADD deficiency had favorable outcomes but also had life-threatening complications, longer diagnostic delay (median of two years versus 30 days; P < 0.001), and multiple differential diagnoses, resulting in unnecessary investigations and maltreatment. Biopsies showed lipid storage, and complete autopsy was performed in one newborn with riboflavin-unresponsive MADD deficiency, revealing multiple abnormalities. Metabolic profiles were not distinguishable between riboflavin-responsive and riboflavin-unresponsive MADD deficiency (P > 0.05). Four novel variants were detected in ETFDH, one of which (c.1790C>T) may confer riboflavin responsiveness. Siblings with the common myopathic ETFDH c.1130T>C mutation presented with a new phenotype dominated by chronic fatigue without apparent myopathy. CONCLUSIONS: Symptoms and outcomes significantly differed between riboflavin-responsive and unresponsive MADD deficiency, but metabolic profiles did not. Functional studies are needed to better characterize the novel ETFDH variants. As treatment is available for riboflavin-responsive MADD deficiency, physicians should maintain a high index of suspicion for MADD deficiency in all age groups.

Bilateral Wilms tumors: Treatment results from a single center.

Aydin B, Akyüz C, Yalçin B, Ekinci S, Oguz B, Akçören Z, Yildiz F, Varan A, Kurucu N, Büyükpamukçu M, Kutluk T. Bilateral Wilms tumors: Treatment results from a single center. Turk J Pediatr 2019; 61: 44-51. The management of bilateral Wilms tumor (BWT) is challenging, particularly due to its presentation at a younger age, rarity, and difficulty for treatment decisions and surgical evaluation comparing to unilateral WT. In this study, the outcome of BWT patients from a single center who were treated by the Turkish Pediatric Oncology Group (TPOG) Wilms Tumor Regimen were retrospectively reviewed. From 1990 to 2016, 30 patients with synchronous BWT were treated with a preoperative chemotherapy of vincristine and actinomycin-D (VA). Chemotherapy was continued until safe nephron sparing surgery (NSS) could be performed for as long as radiological tumor response continued; otherwise, the chemotherapy was intensified by adding doxorubicin (D) alternating with VA every 6 weeks. The median followup of patients was 59 months (4-297 months). The median duration of preoperative chemotherapy was 81 days and ranged between 14 days and 198 days. Preoperative chemotherapy was modified in seven patients (23%) to the VAD regimen. Twenty-two patients (73%) had a radical nephrectomy on the larger tumor and NSS on the contralateral kidney, and 6 patients (20%) had bilateral NSS. Postoperative tumor stages for stage I, II and III were 60%, 22% and 14%, respectively. The 5-year event free survival (EFS) rates were 100%, 90% and 51% for stages I, II and III (p=0.02), respectively. Unfavorable histology and nephrogenic rests were reported in 20% and 20% of patients, respectively. The 5-year overall survival (OS) and EFS rates were 50% and 25%, respectively, in patients with anaplasia, while the same rates were 96% and 96% in patients with favorable histology tumors (p=0.05 and p < 0.001). The 10-year EFS and OS rates for all patients were 82% and 86%, respectively. Our results are comparable with the literature. VA is effective as initial preoperative treatment of BWT and allows for safe resection.

Focal nodular hyperplasia of the liver and elevated alpha fetoprotein level in an infant with isolated hemihyperplasia.

A case of focal nodular hyperplasia of the liver in a 43-day-old baby girl with isolated hemihyperplasia and elevated serum alpha-fetoprotein is presented. The child referred to our hospital with bilateral renal masses detected by prenatal and postnatal ultrasonography. A mass lesion was detected in segment 6 of liver and was diagnosed as focal nodular hyperplasia. We present this case to emphasize the presence of focal nodular hyperplasia in a patient with isolated hemihypertrophy and elevated serum alpha-fetoprotein level.

An unusual association between familial mediterranean fever and IgM nephropathy.

OBJECTIVE: To report a case with the diagnosis of IgM nephropathy and familial Mediterranean fever (FMF). CLINICAL PRESENTATION AND INTERVENTION: A 9-year-old boy was admitted to our hospital with recurrent abdominal pain since the age of 4 years. Laboratory investigations revealed a sedimentation rate of 88 mm/h, C-reactive protein: 83.2 mg/l (0-10 mg/l), white blood cell count: 12,700/mm(3), fibrinogen: 622 mg/dl (200-400 mg/dl) and serum amyloid A: 186 mg/l (0-5.8 mg/l). Urinalysis revealed +2 proteinuria. A 24-hour urinary protein excretion was 12 mg/m(2)/h. M694V homozygous mutation was identified in exon 10. Percutaneous renal biopsy showed mesangial cell proliferation and increased mesangial matrix in the glomeruli, without amyloid accumulation. Immunofluorescence study showed IgM (+1) and C1q (+1) deposits. Treatment with 1 mg/day colchicine was started. Six weeks later, proteinuria had disappeared and the patient was asymptomatic. CONCLUSION: This case illustrates the unusual association of FMF with non-amyloid glomerulopathy. Glomerular diseases such as IgM nephropathy may be seen as a manifestation of FMF.