Congenital hyperinsulinism (HI) is an inappropriate insulin secretion by the pancreatic β-cells secondary to various genetic disorders. The incidence is estimated at 1/50, 000 live births, but it may be as high as 1/2, 500 in countries with substantial consanguinity. Recurrent episodes of hyperinsulinemic hypoglycemia may expose to high risk of brain damage. Hypoglycemias are diagnosed because of seizures, a faint, or any other neurological symptom, in the neonatal period or later, usually within the first two years of life. After the neonatal period, the patient can present the typical clinical features of a hypoglycemia: pallor, sweat and tachycardia. HI is a heterogeneous disorder with two main clinically indistinguishable histopathological lesions: diffuse and focal. Atypical lesions are under characterization. Recessive ABCC8 mutations (encoding SUR1, subunit of a potassium channel) and, more rarely, recessive KCNJ11 (encoding Kir6.2, subunit of the same potassium channel) mutations, are responsible for most severe diazoxide-unresponsive HI. Focal HI, also diazoxide-unresponsive, is due to the combination of a paternally-inherited ABCC8 or KCNJ11 mutation and a paternal isodisomy of the 11p15 region, which is specific to the islets cells within the focal lesion. Genetics and 18F-fluoro-L-DOPA positron emission tomography (PET) help to diagnose diffuse or focal forms of HI. Hypoglycemias must be rapidly and intensively treated to prevent severe and irreversible brain damage. This includes a glucose load and/or a glucagon injection, at the time of hypoglycemia, to correct it. Then a treatment to prevent the recurrence of hypoglycemia must be set, which may include frequent and glucose-enriched feeding, diazoxide and octreotide. When medical and dietary therapies are ineffective, or when a focal HI is suspected, surgical treatment is required. Focal HI may be definitively cured when the partial pancreatectomy removes the whole lesion. By contrast, the long-term outcome of diffuse HI after subtotal pancreatectomy is characterized by a high risk of diabetes, but the time of its onset is hardly predictable.
Sporadic persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or nesidioblastosis is a heterogeneous disorder characterized by profound hypoglycemia due to inappropriate hypersecretion of insulin. An important diagnostic goal is to distinguish patients with a focal hyperplasia of islet cells of the pancreas (FoPHHI) from those with a diffuse abnormality of islets (DiPHHI) because management strategies differ significantly. 16 infants with sporadic PHHI resistant to diazoxide and who underwent pancreatectomy were investigated. Selective pancreatic venous sampling coupled with peroperative surgical examination and analysis of extemporaneous frozen sections allowed us to identify 10 cases with FoPHHI and 6 cases with DiPHHI. We show here that in cases of FoPHHI, but not those of
A distinctive subset of renal carcinomas is associated with Xp11.2 translocations and resulting TFE3 gene fusions (PRCC-TFE3, PSF-TFE3, NONO-TFE3, ASPL-TFE3), encoding related aberrant transcription factors. We report the cloning of a novel clathrin heavy-chain gene (CLTC)-TFE3 gene fusion resulting from a t(X;17)(p11.2;q23) in a renal carcinoma arising in a 14-year-old boy. The fusion transcript joined the 5 0 exons of CLTC on chromosome band 17q23 to the 3 0 exons of TFE3. CLTC encodes a major subunit of clathrin, a multimeric protein on cytoplasmic organelles, and is a known recurrent fusion partner of the ALK tyrosine kinase gene in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumors. The predicted CLTC-TFE3 product retains the nuclear localization and DNA-binding domains of TFE3, but lacks the multimerization domain of CLTC. The present renal tumor demonstrated morphologic and immunohistochemical features of both PRCC-TFE3 and ASPL-TFE3 carcinomas, including strong nuclear immunoreactivity for the TFE3 C-terminal and only minimal expression of epithelial proteins. However, unlike most renal carcinomas, it also focally expressed melanocytic proteins. The present report highlights the promiscuity of certain genes involved in chromosomal translocations. Further analysis of the shared features of CLTC and other TFE3 fusion partners may shed light on the essential biology of TFE3 fusion proteins.
Intra-operative examination of small pancreatic specimens taken from the different parts of the gland allows one to determine the type of lesion (focal or diffuse) in neonatal onset hyperinsulinaemic hypoglycaemia, and to decide on the most appropriate surgical treatment.
Objective To study the potential for prenatal magnetic resonance imaging to predict pulmonary hypoplasia in congenital diaphragmatic hernia.Design Prospective observational study.Setting Tertiary care centre. Participants Thirteen cases of congenital diaphragmatic hernia (11 left, 2 right) without associated anomalies and 74 controls.Methods Measurements by magnetic resonance imaging of fetal lung volume were achieved. In the control fetuses, a regression analysis was performed to associate fetal lung volume with gestational age. This yielded a formula allowing calculation of the expected fetal lung volume as a function of gestational age. In the cases with congenital diaphragmatic hernia, the observed/expected fetal lung volume ratio was compared with perinatal outcome.Main outcome measures Neonatal mortality and pulmonary hypoplasia, which was de®ned as lung/body weight ratios less than 0.012. ResultsThe expected fetal lung volume was derived from the following formula: Fetal lung volume (mL) exp (1.24722 1 0.08939 £ gestational age in weeks). The observed/expected fetal lung volume ratio was signi®cantly lower in congenital diaphragmatic hernia (median: 0.31, range: 0.06±0.63), than in controls (median: 0.99, range: 0.42±1.94). This ratio was signi®cantly less in the infants with congenital diaphragmatic hernia who died (median: 0.26, range: 0.06±0.63) compared with those who survived (median: 0.46, range: 0.35±0.56). The observed: expected fetal lung volume ratio was signi®cantly correlated with the post mortem lung: body weight ratio. Conclusion In isolated congenital diaphragmatic hernia, fetal lung volume measurement by magnetic resonance imaging is a potential predictor of pulmonary hypoplasia and postnatal outcome. Further studies are required to establish the clinical value of magnetic resonance imaging for the prenatal assessment of fetal lungs.
Objective To study the potential for prenatal magnetic resonance imaging to predict pulmonary hypoplasia in congenital diaphragmatic hernia.Design Prospective observational study.Setting Tertiary care centre. Participants Thirteen cases of congenital diaphragmatic hernia (11 left, 2 right) without associated anomalies and 74 controls.Methods Measurements by magnetic resonance imaging of fetal lung volume were achieved. In the control fetuses, a regression analysis was performed to associate fetal lung volume with gestational age. This yielded a formula allowing calculation of the expected fetal lung volume as a function of gestational age. In the cases with congenital diaphragmatic hernia, the observed/expected fetal lung volume ratio was compared with perinatal outcome.Main outcome measures Neonatal mortality and pulmonary hypoplasia, which was de®ned as lung/body weight ratios less than 0.012. ResultsThe expected fetal lung volume was derived from the following formula: Fetal lung volume (mL) exp (1.24722 1 0.08939 £ gestational age in weeks). The observed/expected fetal lung volume ratio was signi®cantly lower in congenital diaphragmatic hernia (median: 0.31, range: 0.06±0.63), than in controls (median: 0.99, range: 0.42±1.94). This ratio was signi®cantly less in the infants with congenital diaphragmatic hernia who died (median: 0.26, range: 0.06±0.63) compared with those who survived (median: 0.46, range: 0.35±0.56). The observed: expected fetal lung volume ratio was signi®cantly correlated with the post mortem lung: body weight ratio. Conclusion In isolated congenital diaphragmatic hernia, fetal lung volume measurement by magnetic resonance imaging is a potential predictor of pulmonary hypoplasia and postnatal outcome. Further studies are required to establish the clinical value of magnetic resonance imaging for the prenatal assessment of fetal lungs.
Scedosporium apiospermum is an opportunistic fungus in humans. The incidence of S. apiospermum infection in patients with acquired neutropenia (e.g., patients receiving chemotherapy and bone marrow transplant recipients) is steadily increasing. S. apiospermum has poor in vitro susceptibility to "conventional" antifungal agents, rendering the management of infections complex. Patients with chronic granulomatous disease (CGD) are highly susceptible to fungal infections, which are mostly due to Aspergillus species. We describe two children with CGD and invasive pulmonary infection due to S. apiospermum. Both patients were treated with antifungal therapy including azole derivatives (itraconazole or voriconazole) and surgical resection of infected tissues. These cases highlight that scedosporium infection can closely mimic aspergillus infection and should be considered in any case in which there is a failure to respond to appropriate "conventional" antifungal therapy. We also suggest that the emergence of this pathogen may have been favored by long-term use of amphotericin B in both patients.
We report three cases of systemic lupus erythematosus (SLE) associated with necrotizing histiocytic lymphadenitis (Kikuchi's disease) and immunologically proven human parvovirus B19 infection. Simultaneous occurrence of SLE and Kikuchi's disease was a characteristic of the three cases. Kikuchi's disease is an uncommon disease that usually affects young women and is characterized by painless unilateral cervical lymph-node enlargement. T-cell regions of affected lymph nodes are exclusively involved with patchy paracortical necrosis surrounded by a polymorphous cell population of histiocytes and macrophages. However, lymphadenopathy in patients with SLE may be histologically indistinguishable from Kikuchi's necrotizing lymphadenitis. The cause of Kikuchi's disease remains uncertain, although infectious agents have been proposed. A positive IgM-specific anti-human parvovirus B19 antibody test in our three cases suggests that B19 can induce a necrotizing histiocytic lymphadenitis and possibly a clinical SLE flare. High-dose (1 mg/kg/day) and medium-dose (0.5 mg/kg/day) oral prednisone was an effective treatment for constitutional and visceral symptoms of Kikuchi's and SLE diseases.
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