A homozygous mutation in KCTD7 links neuronal ceroid lipofuscinosis to the ubiquitin-proteasome system.

Neuronal ceroid lipofuscinosis (NCL) is a genetically heterogeneous group of lysosomal diseases that collectively compose the most common Mendelian form of childhood-onset neurodegeneration. It is estimated that ∼8% of individuals diagnosed with NCL by conservative clinical and histopathologic criteria have been ruled out for mutations in the nine known NCL-associated genes, suggesting that additional genes remain unidentified. To further understand the genetic underpinnings of the NCLs, we performed whole-exome sequencing on DNA samples from a Mexican family affected by a molecularly undefined form of NCL characterized by infantile-onset progressive myoclonic epilepsy (PME), vision loss, cognitive and motor regression, premature death, and prominent NCL-type storage material. Using a recessive model to filter the identified variants, we found a single homozygous variant, c.550C>T in KCTD7, that causes a p.Arg184Cys missense change in potassium channel tetramerization domain-containing protein 7 (KCTD7) in the affected individuals. The mutation was predicted to be deleterious and was absent in over 6,000 controls. The identified variant altered the localization pattern of KCTD7 and abrogated interaction with cullin-3, a ubiquitin-ligase component and known KCTD7 interactor. Intriguingly, murine cerebellar cells derived from a juvenile NCL model (CLN3) showed enrichment of endogenous KCTD7. Whereas KCTD7 mutations have previously been linked to PME without lysosomal storage, this study clearly demonstrates that KCTD7 mutations also cause a rare, infantile-onset NCL subtype designated as CLN14.

The persistent thrombus: complications, diagnosis, and novel treatment intervention.

OBJECTIVE: To review the findings and discuss the implications of the topic of pharmacomechanical thrombolysis in pediatric patients with persistent thrombus. DESIGN: A pediatric case presentation with a brief literature review on treatment of venous thrombosis and pharmacomechanical thrombolysis. INTERVENTIONS: None. MAIN RESULTS: Thrombotic events refractory to standard medical and surgical care remain a life-threatening clinical challenge in the pediatric population. Research on persistent deep venous thrombosis and treatment modalities is limited. We present a pediatric patient with a history of malignant osteosarcoma who was diagnosed with deep venous thrombosis. Despite appropriate anticoagulation therapy, the thrombus remained persistent. Pharmacomechanical thrombolysis was utilized and proved to be an effective method in providing diagnosis and treatment. CONCLUSION: Pharmacomechanical thrombolysis is a valuable and effective method in providing diagnosis and treatment of persistent thrombus.

Sustentaculoma: report of a case of a distinctive neoplasm of the adrenal medulla.

A case of a morphologically distinctive tumor of the adrenal medulla occurring in a 54-year-old woman is described. On microscopic examination, the tumor was well circumscribed and characterized by the presence of ill-defined, irregular nests of spindle cells with oval to elongated nuclei, tiny nucleoli, and abundant eosinophilic cytoplasm. The tumor was associated with a moderate infiltrate of lymphocytes and plasma cells with occasional lymphoid follicles. Necrosis, marked cellular atypia, and mitoses were absent. Immunohistochemical studies demonstrated the tumor cells to be strongly reactive for vimentin, S-100 protein, and CD56, and nonreactive for glial fibrillary acidic protein, chromogranin, synaptophysin, melanoma-associated antigens, and dendritic cell markers. Ultrastructural examination showed elongated cells with interdigitating cytoplasmic processes devoid of a basal lamina. No secretory granules were noted. The morphology, immunophenotype, and ultrastructure of this unique neoplasm suggest derivation from sustentacular cells of the adrenal medulla. We propose the designation "sustentaculoma" for this hitherto undescribed neoplasm of the adrenal gland.

Congenital or late-onset myopathy in patients with the T14709C mtDNA mutation.

Three patients with different clinical phenotypes harbored the same point mutation at nucleotide 14709 (T14709C) in the tRNAGlu gene of mitochondrial DNA (mtDNA). The first patient was a 21-month-old child with severe congenital myopathy, respiratory distress and mild mental retardation. Muscle biopsy showed about 12% cytochrome c oxidase (COX)-negative ragged-red fibers (RRFs), and markedly decreased activities of mitochondrial respiratory chain complexes I, III and IV. The other two patients were 51- and 55-year-old siblings with slowly progressive myopathy and diabetes mellitus. Muscle biopsy showed focal COX-negative RRFs and decreased activities of complexes I, III and IV. In all three patients, the T14709C mutation was abundant in muscle but present at lower levels in accessible tissues. Previously described patients with the same mutation also showed congenital or late-onset myopathy. Diabetes is frequently associated with both phenotypes and is a clinical clue to the molecular diagnosis.

Pediatric renal solitary fibrous tumor: report of a rare case and review of the literature.

Solitary fibrous tumors (SFTs) are unusual spindle cell neoplasms initially described in the pleura but have since been discovered in many extrapleural locations. SFT of the kidney is extremely rare, the majority occurring in middle-aged adults. To date, only two pediatric cases of renal SFT have been reported. We report a case of large SFT in the kidney of a 3-year-old boy that was clinically and radiologically thought to be a nephroblastoma. This case is the first pediatric renal SFT to be reported with detailed histopathologic and cytogenetic analyses. SFT should be included in the differential diagnosis of pediatric renal tumors.

Thyroid-like follicular carcinoma of the kidney in a young patient with history of pediatric acute lymphoblastic leukemia.

Thyroid-like follicular carcinoma of the kidney (TLFCK) is a rare histological variant of renal cell carcinoma not currently included in the World Health Organization classification of renal tumors. Only 24 previous cases of TLFCK have been reported to date. We report a case of TLFCK in a 19-year-old woman with history of pediatric acute lymphoblastic leukemia. This patient is the youngest with TLFCK to be reported to date and the first with history of lymphoblastic leukemia. The development of TLFCK in a young patient with history of lymphoblastic leukemia is interesting and suggests that genes involved in leukemogenesis may also be important for TLFCK pathogenesis. Recognition of TLFCK is important to distinguish it from other conditions that show thyroid-like features, as a misdiagnosis can result in adverse patient care.

Further evidence of Fukutin mutations as a cause of childhood onset limb-girdle muscular dystrophy without mental retardation.

The dystroglycanopathies comprise a clinically and genetically heterogeneous group of muscular dystrophies characterized by deficient glycosylation of alpha-dystroglycan. Mutations in the fukutin (FKTN) gene have primarily been identified among patients with classic Fukuyama congenital muscular dystrophy (FCMD), a severe form of dystroglycanopathy characterized by CMD, cobblestone lissencephaly and ocular defects. We describe two brothers of Caucasian and Japanese ancestry with normal intelligence and limb-girdle muscular dystrophy (LGMD) due to compound heterozygous FKTN mutations. Muscle biopsy showed a dystrophy with selectively reduced alpha-dystroglycan glycoepitope immunostaining. Immunoblots revealed hypoglycosylation of alpha-dystroglycan and loss of laminin binding. FKTN gene sequencing identified two variants: c.340G>A and c.527T>C, predicting missense mutations p.A114T and p.F176S, respectively. Our results provide further evidence for ethnic and allelic heterogeneity and the presence of milder phenotypes in FKTN-dystroglycanopathy despite a substantial degree of alpha-dystroglycan hypoglycosylation in skeletal muscle.

Chloroquine-induced lipidosis mimicking Fabry disease.

Intracellular accumulation of phospholipids may be a consequence of inherited or acquired metabolic disorders. In Fabry disease, deficiency of alpha-galactosidase A results in storage of globotriasylceramide in numerous cells including endothelium, striated muscle (skeletal, cardiac), smooth muscle, and renal epithelium among others; the ultrastructural appearance of the inclusions is of whorled layers of alternating dense and pale material ('zebra bodies' or myeline figures). Chloroquine therapy may result in storage of biochemically and ultrastructurally similar inclusions in many of the same cells as Fabry disease and often results in similar clinical manifestations. We report a 56-year-old woman with rheumatoid arthritis treated with chloroquine, who developed muscle weakness and renal insufficiency; information regarding therapy was not emphasized at the time of renal biopsy, leading to initial erroneous interpretation of Fabry disease. Following muscle biopsy, genetic and enzyme evaluation, and additional studies on the kidney biopsy, a diagnosis of chloroquine toxicity was established. One year following cessation of chloroquine, renal and muscle dysfunction greatly improved. In chloroquine toxicity, inclusions in glomeruli are not only in visceral epithelial, endothelial and mesangial cells but are in infiltrating monocytes/macrophages, which are most commonly present in the mesangium. Curvilinear bodies, the ultrastructural features of chloroquine toxicity in striated muscle, are not present in renal cells. This report documents differences in appearance, cells affected and morphological differential diagnostic features to distinguish these two entities.