Defective Lipid Droplet-Lysosome Interaction Causes Fatty Liver Disease as Evidenced by Human Mutations in TMEM199 and CCDC115.

BACKGROUND & AIMS: Recently, novel inborn errors of metabolism were identified because of mutations in V-ATPase assembly factors TMEM199 and CCDC115. Patients are characterized by generalized protein glycosylation defects, hypercholesterolemia, and fatty liver disease. Here, we set out to characterize the lipid and fatty liver phenotype in human plasma, cell models, and a mouse model. METHODS AND RESULTS: Patients with TMEM199 and CCDC115 mutations displayed hyperlipidemia, characterized by increased levels of lipoproteins in the very low density lipoprotein range. HepG2 hepatoma cells, in which the expression of TMEM199 and CCDC115 was silenced, and induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells from patients with TMEM199 mutations showed markedly increased secretion of apolipoprotein B (apoB) compared with controls. A mouse model for TMEM199 deficiency with a CRISPR/Cas9-mediated knock-in of the human A7E mutation had marked hepatic steatosis on chow diet. Plasma N-glycans were hypogalactosylated, consistent with the patient phenotype, but no clear plasma lipid abnormalities were observed in the mouse model. In the siTMEM199 and siCCDC115 HepG2 hepatocyte models, increased numbers and size of lipid droplets were observed, including abnormally large lipid droplets, which colocalized with lysosomes. Excessive de novo lipogenesis, failing oxidative capacity, and elevated lipid uptake were not observed. Further investigation of lysosomal function revealed impaired acidification combined with impaired autophagic capacity. CONCLUSIONS: Our data suggest that the hypercholesterolemia in TMEM199 and CCDC115 deficiency is due to increased secretion of apoB-containing particles. This may in turn be secondary to the hepatic steatosis observed in these patients as well as in the mouse model. Mechanistically, we observed impaired lysosomal function characterized by reduced acidification, autophagy, and increased lysosomal lipid accumulation. These findings could explain the hepatic steatosis seen in patients and highlight the importance of lipophagy in fatty liver disease. Because this pathway remains understudied and its regulation is largely untargeted, further exploration of this pathway may offer novel strategies for therapeutic interventions to reduce lipotoxicity in fatty liver disease.

Imaging findings of perforative appendicitis: a pictorial review.

Appendicitis is common in children. Early diagnosis depends on recognition of characteristic signs and symptoms: right lower quadrant or periumbilical pain, localized tenderness, fever, and leukocytosis. Because these classic features may be difficult to elicit or masked by other complaints, the incidence of perforative appendicitis in children is high. This paper reviews the imaging sequelae with emphasis on CT and sonography findings. Areas of focus include abdominopelvic abscess, peritonitis, pyelephlebitis, pyelethrombosis, and hepatic abscess. Secondary involvement of the urinary and gastrointestinal tracts is also discussed.

A structured interview for medical school admission, Phase 1: initial procedures and results.

PURPOSE: Despite their widespread use, medical school admission interviews often are unstructured and lack reliability. This report describes the development of a structured admission interview designed to eliminate bias and provide valid information for selecting medical students, with preliminary information about the interview's reliability and validity. METHOD: After screening applications, 490 applicants to a public medical school residency program were interviewed by two faculty members using a structured interview format. Interview scores were compiled and correlated with undergraduate grade-point averages (GPAs); Medical College Admission Test (MCAT) scores; Iowa Evaluation Form (IEF) scores, an in-house evaluation of applicants' noncognitive abilities; and eventual admissions status. RESULTS: Interrater agreement was good; the percentages of rater pairs whose scores differed by one point or less ranged from 87% to 98%. Scores on the structured interview revealed low to moderate correlations with other admission criteria: 10 (p < 0.05) for cumulative GPA, 0.18 (p < 0.01) for MCAT Biological Science, 0.08 (p > 0.05) MCAT Physical Science, and 0.10 (p < 0.05) MCAT Verbal Reasoning. None of the correlations between the overall interview scores and the IEF scores reached statistical significance (p = 0.05). Higher overall scores on the structured interview did predict a greater likelihood of being accepted into the medical school and the interview score accounted for 20% of the incremental variance in admission status beyond GPA, MCAT, and IEF scores. CONCLUSIONS: The moderate-to-low correlations with other admission criteria suggest that the interview provided information about candidate credentials not obtained from other sources and accounted for a substantial proportion of the variance in admission status. This finding supports the considerable time and resources required to develop a structured interview for medical student admissions. Final judgment on the validity and utility of this interview should be made after follow-up performance data have been obtained and analyzed.

Genitourinary complications of Crohn's disease in pediatric patients.

OBJECTIVE: The purpose of this study was to determine the incidence and types of genitourinary complications in pediatric patients with Crohn's disease. CONCLUSION: Genitourinary complications of Crohn's disease in children are not rare and may be the initial presentation of the condition.

Pulmonary function is compromised in children with mediastinal lymphoma.

PURPOSE: Lymphomas account for nearly 20% of the malignancies in childhood and the majority of patients with Hodgkin's Disease (HD) and non-Hodgkin's lymphoma (NHL) have radiological evidence of mediastinal involvement at presentation. Children with mediastinal tumors are at risk for the development of lethal airway obstruction during general anesthesia. This study quantitates the degree of the airway obstruction and the functional significance of tracheal compression in a cohort of 51 children with HD and NHL. RESULTS: Thirty patients with HD (mean age, 14.6 years) and 21 with NHL (mean age, 9.2 years) were included in this study. Twenty-five children (49%) had respiratory symptoms at the time of presentation. Respiratory complaints were much more common in children with NHL (76%) when compared with those with HD (30%). Pulmonary function was also significantly worse in the NHL patients who had a mean upright forced vital capacity (FVC) of 66 +/- 21%. The comparable value for the children with HD was 85 +/- 15% (P = .031). Patients with respiratory symptoms at presentation had both obstructive and restrictive deficits of pulmonary function. Their mean upright forced expiratory volume in 1 second (FEV1) was 69 +/- 22% and the FVC was 69 +/- 18%. Children with large mediastinal masses also had significantly decreased pulmonary function compared with those with small tumors. The upright FEV1 for these two groups was 72 +/- 18% versus 98 +/- 15% (P = .016). Their FVC values were 68 +/- 20% and 91 +/- 17%, respectively (P = .049). Mean tracheal compression was measured at 44% in the children with large tumors versus 27% for those with small lesions (P = .048). CONCLUSION: Children with mediastinal lymphomas have both obstructive and restrictive deficits on pulmonary function testing. Pulmonary function is significantly decreased in patients with NHL, children who present with respiratory symptoms, and those with very large mediastinal masses (mediastinal mass ratio > 45%). The extent of tracheal compression correlates with the size of the mediastinal mass.

Standard method of diagnosis versus use of a computer database in the evaluation of skeletal dysplasias.

OBJECTIVE: The objective of this study was to compare reference textbooks and the computer database, OSSUM, for accuracy and ease of use in the diagnosis of skeletal dysplasias. Materials and methods. Twenty cases of clinically and and radiologically established skeletal dysplasias were evaluated as unknowns by four pediatric radiologists. Readers 1 and 2 evaluated group A (10 cases) using reference texts and group B (10 cases) using OSSUM. Readers 3 and 4 evaluated group B using reference texts. The radiologists independently listed their roentgenographic findings, the top three diagnoses, confidence level, difficulty level, and time spent on each case. RESULTS: The correct diagnosis was made in 68% of both the reference text cases and the OSSUM cases. Difficulty level was significantly higher (3.5 vs 2.9, P = 0.0013) and confidence significantly lower (3.3 vs. 2.3, P = 0.0001) when using OSSUM. Average time spent on cases was 25 min with references and 30 min with OSSUM (P > 0.05). However, there was a decrease in both the time (38 min vs 23 min, P = 0.05) and the difficulty (3.9 vs 3.1, P = 0.001) between the first five and the last five cases. The composite of four readers correctly identified 90% of the skeletal dysplasias when the results of both methods were combined. CONCLUSIONS: In the ability to reach a correct diagnosis, no difference was detected between the OSSUM and reference texts methods. The increased time necessary, greater difficulty and decreased confidence levels with OSSUM are expected to improve with increasing program familiarity. Use of both textbooks and the database was complementary.

Pediatric great vessel anomalies: initial clinical experience with spiral CT angiography.

PURPOSE: To evaluate the use of spiral computed tomographic (CT) angiography for the diagnosis of pediatric great vessel anomalies. MATERIALS AND METHODS: Techniques used in adult CT angiography were modified to allow imaging of 15 children aged 1 month to 12 years. Two-dimensional axial images and three-dimensional shaded surface display images of the airway and great vessels were generated from volumetric CT data and evaluated prospectively. Findings were correlated with results obtained at surgery (five patients), autopsy (one patient), bronchoscopy (one patient), or other imaging studies (eight patients). RESULTS: In 14 patients, CT angiography accurately demonstrated vessel anomalies, including double or right aortic arch (seven cases), aberrant subclavian artery (six cases), innominate artery compression syndrome (one case), unilateral pulmonary artery agenesis (one case), and pulmonary artery enlargement (three cases). One patient had normal vasculature. CONCLUSION: CT angiography is feasible in children and can be used to delineate abnormal great vessel anatomy.

Imaging manifestations of cat-scratch disease.

Cat-scratch disease affects an estimated 22,000 people in the United States each year, more than half of whom are children or adolescents [1]. It is caused by Bartonella henselae, a gram-negative bacillus usually introduced by the scratch of a cat [2]. In the past, diagnosis was made if three of the following four criteria were met: (1) history of cat exposure with inoculation, (2) positive skin test: (3) absent laboratory and histopathologic evidence of other diseases, and (4) biopsy findings of granulomatous inflammation [3]. Recent identification of the causative organism has led to new diagnostic tests, including serum assays for B. henselae antibodies [4]. Although response of the disease to antibiotics is poor, spontaneous recovery generally occurs within months to years [3].

Fibromatoses of childhood: the spectrum of radiographic findings.

Fibrous tumor of childhood include several disorders with variable biologic behavior. In the review by Coffin and Dehner [1] of 190 soft-tissue neoplasms in 183 children, 27% were fibroblastic or myofibroblastic in origin. Although nearly all fibrous lesions are benign, they may be locally aggressive. The purpose of this essay is to describe clinical characteristics and to illustrate radiologic features of commonly encountered fibrous lesions of childhood. Familiarity with the presentation and variable appearance may aid the radiologist in suggesting the diagnosis of fibromatosis.

Pediatric blunt abdominal trauma: periportal tracking at CT.

Periportal zones of decreased attenuation at computed tomography (CT) have been described in a variety of disorders. In the setting of blunt abdominal trauma, the zones have been attributed to dissection of blood along the portal tracts. Because of the observation of isolated periportal tracking (PPT) in children after blunt trauma, the authors retrospectively reviewed CT scans of the abdomen obtained in 114 children to determine the frequency of PPT, liver injury, and peritoneal fluid. PPT was present in 22% of patients (25 of 114); it was associated with liver injury in 10 and was the only liver abnormality in 15. Pathologic correlation was available in two patients: In one it revealed marked periportal lymphedema and in the other, PPT of blood. This study indicates that both hemorrhage and lymphatic edema may be represented as PPT in children after blunt abdominal injury.

The normal and abnormal scrotum in children: evaluation with color Doppler sonography.

The use of color Doppler sonography to evaluate the symptomatic testes in children with scrotal pain or swelling was prospectively studied with a fourth-generation color sonographic unit with a 7-MHz linear transducer. The 32 patients were 1 day to 18 years old (mean age, 8.6 years). Results were correlated with scintigraphic findings in 23 patients, with the final diagnosis established by surgery in 12 patients, and with clinical follow-up in all patients. Eight cases of testicular torsion, including two of acute torsion and six of late torsion, were correctly detected by color Doppler sonography and confirmed surgically. In the remaining patients, perfusion of the testis was correctly detected by color Doppler examination. The final diagnoses in these patients included torsion of the appendix testis (15 patients), epididymitis (five patients), epididymo-orchitis (one patient), yolk sac tumor of the testis (one patient), hydrocele (one patient), and local reaction to an insect bite (one patient). The ability to detect blood flow in the normal contralateral testis was also evaluated in 28 patients. Blood flow was demonstrated in normal testes larger than 1 cm3. Detection of flow in the very small normal prepubertal testis was often difficult, and no flow was identified in one testis. Flow was identified in central arteries in only six of 13 testes smaller than 1 cm3. We conclude that color Doppler sonography is helpful in the initial evaluation of pediatric testes, providing accurate evaluation of the involved hemi-scrotum in our patients and also providing the benefit of both structural and flow information. Until our sensitivity to low-velocity flow improves, we would not suggest the exclusive use of color Doppler sonography in the evaluation of testicular perfusion in the prepubertal patient. We advocate the addition of testicular scintigraphy to corroborate the presence of testicular perfusion when flow in intratesticular arteries cannot be established with certainty by color Doppler sonography.

Abdominal (liver, spleen) and bone manifestations of cat scratch disease.

Cat scratch disease is usually a self-limiting illness. Patients may develop systemic complications including hepatic granulomas, splenic abscesses, mesenteric adenitis, osteolytic lesions, as well as dermatologic and CNS complications. In this paper the literature is reviewed and two cases are discussed which present the imaging findings in patients with hepatic, splenic, mesenteric, and bony manifestations of cat scratch disease.

Melanotic neuroectodermal tumor of infancy. MR findings and a review of the literature.

Melanotic neuroectodermal tumor of infancy is an uncommon neoplasm occurring primarily in the child one year or less in age. Difficulty in deciding the cellular origin of this tumor has led to numerous names, including congenital melanocarcinoma, melanotic epithelial odontoma, melanotic ameloblastoma, and retinal anlage tumor, to list a few. Electron microscopy and histochemical studies, however, have now established the neural crest as the most likely origin. The most frequent site of occurrence is the maxilla followed by the skull, the brain and the mandible. The genital organs are the most frequent extracranial site. Within the skull, there is a predilection for the anterior fontanel. The following is a case report of a young child with melanotic neuroectodermal tumor of infancy arising at the anterior fontanel. Included is a discussion of magnetic resonance (MR) findings, which to our knowledge, have not been previously reported in this tumor.