Biallelic frameshift variants in PHLDB1 cause mild-type osteogenesis imperfecta with regressive spondylometaphyseal changes.

BACKGROUND: Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders characterised by susceptibility to fractures, primarily due to defects in type 1 collagen. The aim of this study is to present a novel OI phenotype and its causative candidate gene. METHODS: Whole-exome sequencing and clinical evaluation were performed in five patients from two unrelated families. PHLDB1 mRNA expression in blood and fibroblasts was investigated by real-time PCR, and western blot analysis was further performed on skin fibroblasts. RESULTS: The common findings among the five affected children were recurrent fractures and/or osteopaenia, platyspondyly, short and bowed long bones, and widened metaphyses. Metaphyseal and vertebral changes regressed after early childhood, and no fractures occurred under bisphosphonate treatment. We identified biallelic NM_001144758.3:c.2392dup and NM_001144758.3:c.2690_2693del pathogenic variants in PHLDB1 in the affected patients, respectively, in the families; parents were heterozygous for these variants. PHLDB1 encodes pleckstrin homology-like domain family B member-1 (PHLDB1) protein, which has a role in insulin-dependent Akt phosphorylation. Compared with controls, a decrease in the expression levels of PHLDB1 in the blood and skin fibroblast samples was detected. Western blot analysis of cultured fibroblasts further confirmed the loss of PHLDB1. CONCLUSION: Two biallelic frameshift variants in the candidate gene PHLDB1 were identified in independent families with a novel, mild-type, autosomal recessive OI. The demonstration of decreased PHLDB1 mRNA expression levels in blood and fibroblast samples supports the hypothesis that PHLDB1 pathogenic variants are causative for the observed phenotype.

Increased risk for kidney sequelae surrogates in survivors of Wilms tumor.

BACKGROUND: There is evidence of increased risk of hypertension, albuminuria, and development of chronic kidney disease (CKD) in long-term follow-up of survivors of Wilms tumor (WT). However, most studies were conducted in heterogeneous groups, including patients with solitary kidney. In addition, little is known about tubular dysfunction. This study aimed to investigate kidney sequelae, including CKD development, hypertension, and glomerular and tubular damage in WT survivors. METHODS: This cross-sectional, single-center study included 61 patients treated for WT. Surrogates for kidney sequelae were defined as presence of at least one of the following: decrease in GFR for CKD, hypertension detected by ambulatory blood pressure monitoring, albuminuria (albumin-to-creatinine ratio [ACR] > 30 mg/g), or increase in at least one tubular biomarker (beta-2-microglobulin, neutrophil gelatinase-associated lipocalin, kidney injury marker-1, and liver fatty acid-binding protein) in 24-h urine. RESULTS: Median age of patients was 11.7 years, with median follow-up of 8.8 years. Thirty-eight patients (62%) had at least one surrogate for kidney sequelae. Twenty-four patients (39%) had CKD, 14 patients (23%) had albuminuria, 12 patients (21%) had hypertension, and 11 patients (18%) had tubular damage. Urine ACR was significantly higher in patients with advanced tumor stage and patients with nephrotoxic therapy than their counterparts (p < 0.05), but neither eGFR nor tubular biomarkers showed any association with tumor- or treatment-related factors. CONCLUSIONS: A considerable number of patients with WT have kidney sequelae, especially early-stage CKD with a high prevalence. Albuminuria emerges as a marker associated with tumor stages and nephrotoxic treatment. A higher resolution version of the Graphical abstract is available as Supplementary information.

Endoscopic septum division of tubular esophageal duplication in two children and systematic review.

Tubular esophageal duplication is a rare congenital malformation The surgical treatment of this lesion can be challenging. We aimed to present our experience in two cases with tubular esophageal duplication. Both cases were endoscopically treated by a dual knife. The first patient underwent a single, while the second patient required three sessions of endoscopic septum division using an electrosurgical knife. Both showed satisfactory clinical, radiological and endoscopic response to treatment. Moreover, a systematic literature review has been performed. To identify all available studies, a detailed search on tubular esophageal duplication was performed according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. Tubular esophageal duplication was reported in 16 pediatric cases in 14 studies in the literature. Surgery was applied to 10 of these cases and endoscopic treatment was applied to two of them. In the follow-up, nine patients who underwent surgical treatment and two patients who underwent endoscopic treatment were uneventful. Tubular esophageal duplications can be successfully treated endoscopically. Endoscopic septum division is a minimally invasive procedure that allows full anatomical recovery and satisfactory therapeutic response.

Transient minimal hydronephrosis on contralateral kidney in infants with unilateral hydronephrosis: Is it an early sign of worsening of the affected kidney?

Background/aim: The criteria for surgical management of ureteropelvic junction obstruction are not well-defined, and there is a risk for loss of renal function before the operation. In this context, certain changes in contralateral kidney had been investigated in order to increase the sensitivity of diagnosis. In this study, we aimed to investigate whether contralateral transient minimal hydronephrosis (CTMH) can be considered as an "early alarm" sign for worsening of the affected kidney in infants with hydronephrosis. Materials and methods: A total of 182 infants (92 surgically treated and 90 conservatively followed-up) with unilateral hydronephrosis were retrospectively analyzed. Ultrasonography and renal scan findings were evaluated. Correlation between the appearance of CTMH, contralateral compensatory hypertrophy (CCH) on ultrasonography, and prognosis of the affected kidney were evaluated. Results: Among the surgically treated patients, 18 (19.6%) patients developed CTMH on average 7 months (0­13 months) before surgery. Among these 18 patients with CTMH, 12 patients (66.6%) had loss of renal function preoperatively, while this ratio was 29.7% on their counterparts (p = 0049). CCH was observed in 31 (33.7%) individuals in surgically treated patient group including all 18 patients with CTMH, while none of the conservatively followed-up patients developed CCH and/or CTMH. In the multiple logistic regression analysis, among the variables investigated, CTMH was found as an independent predictor of the deterioration in the affected kidney and of the poor prognosis (p = 0.011 and p = 0.0004, respectively). Conclusion: In our study, among the variables investigated, CTMH was found as an independent predictor of the deterioration in the affected kidney and poor prognosis in infants followed-up with isolated unilateral hydronephrosis. Additionally, CTMH can be considered as an "early alarm" sign for worsening of the affected kidney and the need for surgical intervention.

A homozygous HOXA11 variation as a potential novel cause of autosomal recessive congenital anomalies of the kidney and urinary tract.

Congenital anomalies of the kidney and urinary tract (CAKUT) is the leading cause of end-stage kidney disease in children. Until now, more than 50 monogenic causes for CAKUT have been described, all of which only explain 10% to 20% of all patients with CAKUT, suggesting the presence of additional genes that cause CAKUT when mutated. Herein, we report two siblings of a consanguineous family with CAKUT, both of which rapidly progressed to chronic kidney disease in early childhood. Whole-exome sequencing followed by homozygosity mapping identified a homozygous variation in HOXA11. We therefore showed for the first time an association between a homozygous HOXA11 variation with CAKUT in humans, expanding the genetic spectrum of the disease.

Comparison of the efficacy of physical examination and radiological imaging in detecting sacroiliitis in patients with juvenile spondyloarthropathies.

OBJECTIVES: To determine and compare the effectiveness of history, physical examination, conventional radiography and magnetic resonance imaging (MRI) in the detection of sacroiliitis in juvenile spondyloarthropathies. METHODS: One hundred and one patients with JSpA, 33 patients with other diseases and 24 children without rheumatologic complaints were included in the study. Subjects were evaluated using physical examination, laboratory findings, pelvic radiography and MRI. Abdominal or pelvic MRIs of 24 control patients who were obtained in the last 6 months were reevaluated and multivariate logistic regression analyses were used to calculate probability ratios of variables. RESULTS: In our study, the rate of active sacroiliitis was 52.4% and in most of them, erosive and sclerotic changes indicating destruction of the sacroiliac joints were recorded. The presence of sacroiliitis on direct x-ray, high JSPADAI score, and hip involvement on MRI were independent risk factors with high predictive potential for active sacroiliitis. Inflammatory lumbar pain, sacroiliac tenderness, modified Schober's limitation, acute phase elevation, HLA-B27 positivity and presence of uveitis failed to predict sacroiliitis. The best specificity was 100% with a high BASFI score (>5), then 94% with a high JSPADAI score (>4). None of the patients in the control group showed active sacroiliitis. CONCLUSIONS: All patients with possible JSpA should undergo sacroiliac MRI whether HLA-B27 positive or not. In this way, early diagnosis and treatment of axial joint involvement could be possible and it prevents unnecessary examination and loss of time.

Sinusoidal Obstruction Syndrome During Chemotherapy of Pediatric Cancers and its Successful Management With Defibrotide.

Sinusoidal obstruction syndrome (SOS) is a life-threatening complication generally occurring after hematopoietic stem cell transplantation. SOS after standard dose chemotherapy in malignancies is rare. Between the year 1995 and 2016, 414 patients were diagnosed with acute lymphoblastic leukemia and 113 patients were diagnosed with Wilms tumor in our institution. Among these patients, 4 patients with acute lymphoblastic leukemia (0.96%) and 2 patients with Wilms tumor (1.7%) developed SOS during treatment. SOS behaves like a local disseminated intravascular coagulation. Defibrotide has proved to be effective in SOS. In this article, we report our experience with defibrotide in SOS.

Primary pericardial synovial sarcoma in an adolescent patient: magnetic resonance and diffusion-weighted imaging features.

Primary synovial sarcomas of the pericardium are extremely rare tumors, especially in pediatric population. As far as we know, only few cases have been reported in the literature. This uncommon location for synovial sarcomas could lead to misdiagnosis. Radiologists and clinicians should be aware of the imaging findings and differential diagnosis of pericardial synovial sarcoma. Herein we presented a 15-year-old boy who had primary pericardial synovial sarcoma with imaging features.

Children With Type 1 Spinal Muscular Atrophy Are at Increased Risk for Nephrolithiasis.

BACKGROUND: Nephrolithiasis is not a well-documented condition in children with spinal muscular atrophy (SMA). It is possible that this condition was underestimated before the era of nusinersen because of a much shorter life expectancy. We present our observational data on nephrolithiasis and its possible risk factors in children with type 1 SMA. METHODS: We retrospectively reviewed the charts of 20 children with genetically confirmed type 1 SMA. Thirteen patients (aged 9 to 55 months) who underwent urinary tract ultrasonography were included in the study. Medical records were retrospectively reviewed for demographic and clinical characteristics, ultrasound results, and metabolic abnormalities. RESULTS: Seven children (54%) had nephrolithiasis; 5 had multiple stones and two had a single stone. Two patients had microlithiasis (<3 mm), three had a stone in the size of 3 to 5 mm, and one had a stone in the size of more than 8 mm. Two patients with nephrolithiasis had urinary tract abnormalities. Patients with nephrolithiasis were more likely to have a history of urinary tract infections (UTIs) (P = 0.048) and higher urine specific gravity (P = 0.014) than patients without nephrolithiasis. Five of seven children with nephrolithiasis had a urine metabolic evaluation; all had hypercalciuria, three had hyperuricosuria, but none had hyperoxaluria, hypocitraturia, or hypomagnesemia. CONCLUSION: Children with SMA type 1 are at an increased risk for nephrolithiasis. Hypercalciuria and high urine specific gravity appear to be the most common risk factors for the occurrence of nephrolithiasis. In addition, UTI is more common in patients with type 1 SMA with nephrolithiasis.

Magnetic resonance imaging based kidney volume assessment for risk stratification in pediatric autosomal dominant polycystic kidney disease.

Introduction: In the pediatric context, most children with autosomal dominant polycystic kidney disease (ADPKD) maintain a normal glomerular filtration rate (GFR) despite underlying structural kidney damage, highlighting the critical need for early intervention and predictive markers. Due to the inverse relationship between kidney volume and kidney function, risk assessments have been presented on the basis of kidney volume. The aim of this study was to use magnetic resonance imaging (MRI)-based kidney volume assessment for risk stratification in pediatric ADPKD and to investigate clinical and genetic differences among risk groups. Methods: This multicenter, cross-sectional, and case-control study included 75 genetically confirmed pediatric ADPKD patients (5-18 years) and 27 controls. Kidney function was assessed by eGFR calculated from serum creatinine and cystatin C using the CKiD-U25 equation. Blood pressure was assessed by both office and 24-hour ambulatory measurements. Kidney volume was calculated from MRI using the stereological method. Total kidney volume was adjusted for the height (htTKV). Patients were stratified from A to E classes according to the Leuven Imaging Classification (LIC) using MRI-derived htTKV. Results: Median (Q1-Q3) age of the patients was 6.0 (2.0-10.0) years, 56% were male. There were no differences in sex, age, height-SDS, or GFR between the patient and control groups. Of the patients, 89% had PKD1 and 11% had PKD2 mutations. Non-missense mutations were 73% in PKD1 and 75% in PKD2. Twenty patients (27%) had hypertension based on ABPM. Median htTKV of the patients was significantly higher than controls (141 vs. 117 ml/m, p = 0.0003). LIC stratification revealed Classes A (38.7%), B (28%), C (24%), and D + E (9.3%). All children in class D + E and 94% in class C had PKD1 variants. Class D + E patients had significantly higher blood pressure values and hypertension compared to other classes (p > 0.05 for all). Discussion: This study distinguishes itself by using MRI-based measurements of kidney volume to stratify pediatric ADPKD patients into specific risk groups. It is important to note that PKD1 mutation and elevated blood pressure were higher in the high-risk groups stratified by age and kidney volume. Our results need to be confirmed in further studies.

Phenotypic and Molecular Spectrum of a Turkish Cohort with Hereditary Multiple Osteochondromas.

OBJECTIVE: Hereditary multiple osteochondromas is an autosomal dominant disorder caused by heterozygous pathogenic variants in EXT1 or EXT2. We aimed to evaluate the clinical and molecular findings of a Turkish cohort with hereditary multiple osteochondroma. MATERIALS AND METHODS: Thirty-two patients aged 1.3-49.6 years from 22 families were enrolled. Genetic analyses were made by EXT1 and/or EXT2 sequencing and chromosomal microarray analyses. RESULTS: We found 17 intragenic pathogenic variants in EXT1 (13/17) and EXT2 (4/17), 12 of which are novel. Four probands had EXT1 deletions, including 2 patients with partial EXT1 microdeletions involving exons 2-11 and 5-11, and 2 patients with whole-gene deletions. In 21 variants, the frequency of truncating and missense variants was 76.1% and 23.8%, respectively. Two families had no detectable variants in EXT1 and EXT2. All patients had multiple osteochondromas at the long bones, mainly at the tibia, forearm, femur, and humerus. Bowing deformity of the forearms (9/32) and the lower extremities (2/32), and scoliosis (6/32) were observed. The clinical severity was not different between patients with EXT1 or EXT2 variants. One patient with an EXT2 variant and another with an EXT1 microdeletion had the most severe phenotype with class III disease. Four patients with no EXT1 or EXT2 variants had milder phenotypes. Intrafamilial variability in disease severity was not observed. CONCLUSION: We report a hereditary multiple osteochondroma cohort with clinical and molecular data including 12 novel intragenic variants in EXT1 or EXT2, and 4 microdeletions involving EXT1. Taken together, our data expand the existing knowledge of the phenotype-genotype spectrum in hereditary multiple osteochondroma.

Comparison of color doppler US and CT portography in evaluating portal hypertension in children.

OBJECTIVES: To compare grayscale and color Doppler ultrasound (CDUS) findings to that of multidetector computed tomography (MDCT) portography in the evaluation of portal hypertension in children. METHODS: Thirty children (mean age, 11.4 years) with definitive clinical and laboratory diagnoses of portal hypertension were included in the study. Liver parenchymal changes, portal vein thrombosis, cavernous transformation, splenomegaly, recanalization of the paraumbilical vein, ascites collateral vessels, and hemodynamic parameters were evaluated prospectively. RESULTS: Liver parenchymal heterogeneity (n = 21) was detected more often by CDUS than MDCT (P = 0.002). CDUS and MDCT established similar results for increased right/left lobe ratio, lobulation of the liver contour, ascites, and splenomegaly. Portal vein thrombosis, cavernous transformation, and recanalization of the paraumbilical vein were comparable between CDUS and MDCT (κ = 1, P < 0.01). Collaterals were detected more by MDCT portography than by CDUS. Esophageal collaterals and azygous vein dilatation were seen only by MDCT portography (P < 0.01, P = 0.024; respectively). CONCLUSIONS: CDUS was superior to MDCT in identifying parenchymal changes and hemodynamic parameters. MDCT was superior in detecting abnormal collateral circulation. The combination of these two modalities provides more comprehensive information than either alone in the diagnosis and follow-up of portal hypertension.

Focusing on Asthma and Chronic Obstructive Pulmonary Disease with COVID-19.

INTRODUCTION: We aimed to evaluate clinical and laboratory findings of hospitalized asthma and chronic obstructive pulmonary disease (COPD) patients with COVID-19 and demonstrate that they have different symptoms and/or laboratory results and outcomes than COVID-19 patients with comorbidity (CoV-com) and without comorbidity (CoV-alone). METHODOLOGY: The data of the demographic, clinical, laboratory findings of hospitalized CoV-alone, asthma, COPD patients with COVID-19 (CoV-asthma, CoV-COPD, respectively), and CoV-com were analyzed. RESULTS: Out of 1082 patients hospitalized for COVID-19, 585 (54.1%) had CoV-alone, 40 (3.7%) had CoV-asthma, 46 (4.3%) had CoV-COPD and 411 (38%) had CoV-com. Cough, shortness of breath, fever and weakness were the most common four symptoms seen in all COVID-19 patients. Shortness of breath, myalgia, headache symptoms were more common in CoV-asthma than the other groups (p < 0.001, p < 0.01, p < 0.05 respectively). Sputum was more common in CoV-COPD than other groups (p < 0.01). COPD group most frequently had increased values, different from the other groups with CRP>5ng/mL in 91.3%, D-dimer > 0.05mg/dL in 89.1%, troponin > 0.014micg/L in %63.9, INR>1.15 in 52.2%, CK-MB>25U/L in 48.5%, PT>14s in 40.9% of patients (p < 0.05, p < 0.001, p < 0.001, p < 0.001, p < 0.05, p < 0.001, respectively). NT-ProBNP was found to have the highest AUC value and the best differentiating parameter for CoV-asthma from CoV-alone. Typical CT findings were present in 44.4% of CoV-alone, 57.5% of CoV-asthma, 28.3% of CoV-COPD and 38.9% of CoV-com groups. CoV-COPD and CoV-com patients died more frequently than other groups (17.8%, 18.5%). CONCLUSIONS: CoV-asthma and CoV-COPD patients might have different symptoms and laboratory parameters than other COVID-19 patients which can guide the physicians.

Treatment of pediatric Burkitt lymphoma in Turkey.

This study aimed to assess the demographic data and treatment results of children who were diagnosed with Burkitt lymphoma and treated according to the Berlin-Frankfurt-Münster-95 (BFM) protocol in a single institution. A total of 48 patients (37 boys, 77%) with a median age of 8 years (range 2 to 16 years) at diagnosis, were evaluated. Primary tumor sites were abdomen (70.8%), head and neck (22.9%), peripheral lymph node (2%), bone (2%), and testis (2%). The 5-year overall survival (OS) and event-free survival (EFS) were 78.1±4% and 76.6±6%, respectively. In univariate analysis, hemoglobin level less than 10 g/dL, cerebrospinal fluid (CSF) positivity and dialysis requirement at diagnosis were found to be important reverse predictor factors for EFS (P; 0.001, 0.001, 0.004, respectively). In multivariate analysis, hemoglobin level less than 10 g/dL and dialysis at diagnosis were found to be important reverse predictor factors for EFS (P; 0.0001). The EFS of our patients was lower than the values achieved with BFM-95 protocol in other centers. This study provides evidence that low hemoglobin level, CSF positivity and dialysis at diagnosis were important predictor factors for EFS in children with Burkitt lymphoma.

Abdominal manifestations of polyarteritis nodosa demonstrated with CT.

We report a rare case of polyarteritis nodosa (PAN) presenting in childhood. The child had multiple visceral aneurysms and later developed ascending colitis and jejunitis. The diagnosis was established with multidetector CT and CT angiography.

Urinary Ultrasound and Other Imaging for Ureteropelvic Junction Type Hydronephrosis (UPJHN).

Ultrasound is the main imaging study used to diagnose ureteropelvic junction (UPJ) obstruction. On ultrasound, abnormal dilatation of the pelvicalyceal system of varying degrees is seen, whereas the ureter is normal in caliber. A properly performed study provides essential information regarding laterality, renal size, thickness, and architecture of the renal cortex and degree of dilatation of the pelvicalyceal system. Doppler ultrasound may identify a crossing vessel, when present. This imaging method also has been used differentiating obstructive from non-obstructive hydronephrosis by renal arterial resistive index measurements. Abdominal radiographs may show soft tissue fullness, bulging of the flank, and displacement of bowel loops from the affected side. The voiding/micturating cystourethrogram helps exclude other causes of upper tract dilatation, including vesicoureteral reflux, urethral valves, and ureteroceles. Computerized Tomography angiography with multiplanar reformation and three-dimensional images may be used to depict suspected crossing vessels as a cause of UPJ obstruction in older children and adults. Magnetic Resonance Urography has progressed significantly in recent years due to the development of both hardware and software that are used to generate high-resolution images. This imaging technique currently allows for the detailed assessment of urinary tract anatomy, while also providing information regarding renal function, including differential renal function, and the presence or absence of obstructive uropathy.

A novel combined treatment for plasminogen deficiency with lung involvement.

Plasminogen deficiency is characterized by fibrin-rich pseudomembrane formation on all mucosal surfaces, particularly the conjunctiva. Respiratory system involvement is common; fibrin often obstructs the upper or lower respiratory tract, causing death. Although many treatments have been applied, no definitive treatment (especially of the respiratory involvement) yet exists. Although excision of tracheobronchial tree membranes affords temporary improvement, this should be performed only for patients in severe respiratory distress; the procedure triggers fibrin redeposition. Here, we share our experience with an 8-year-old plasminogen-deficient female with severe lung involvement; we successfully delivered local tissue plasminogen activator followed by nebulized fresh frozen plasma.

Bilateral Synchronous Testicular Germ Cell Tumors in Children: Case Report and Review of the Literature.

Bilateral testicular tumors are very rare in pediatric patients and only a few case reports have been reported. These patients have a high risk of sterility due to bilateral orchiectomy and subsequent gonadotoxic treatments. Therefore, if possible, testis-sparing surgery should be performed in patients with benign masses and testicular tissue preservation may be recommended in order to maintain fertility in later life. We present a 23 months old boy with synchronous bilateral testicular tumor managed with unilateral orchiectomy and testis-sparing surgery and testicular tissue cryopreservation performed to the controlateral side. We also review the literature on bilateral testis tumors in children.

Adrenal masses in children: Imaging, surgical treatment and outcome.

BACKGROUND/OBJECTIVE: This study aims to evaluate the current surgical approach to adrenal masses in the pediatric age group. METHODS: We retrospectively analyzed cases that underwent surgery for adrenal masses between 2007 and 2017. Patients were assessed regarding age, sex, primary diagnosis, image defined risk factors (IDRF), surgical treatment method, complications, duration of hospital stay, and follow-up. RESULTS: We examined 50 patients who underwent surgery for adrenal mass (mean age: 4.8 years; range: 5 days-14 years). For IDRF assessment, Ultrasonography was used in 42, Computed Tomography in 36, and Magnetic Resonance Imaging in 36 patients. Lesions were present on the right in 25, left in 21, and bilateral in 4 patients. Histopathological findings were neuroblastoma (n = 29), ganglioneuroma (n = 6), adrenal cortex tumor (n = 5), ganglioneuroblastoma (n = 4), pheochromocytoma (n = 3), cyst (n = 1), and adrenal hematoma (n = 2). Laparotomy was performed on 37 patients, and laparoscopy on 13 patients. None of the cases had any operative complications. CONCLUSION: The crucial factors determining the surgical approach to adrenal masses in pediatric cases are the histopathology of the mass, volume, and IDRF. Minimally invasive procedures could be reliably performed in appropriate cases.