Sophie Heissat

French Retrospective Multicentric Study of Neonatal Hemochromatosis: Importance of Autopsy and Autoimmune Maternal Manifestations

Neonatal hemochromatosis is a rare disease that causes fetal loss and neonatal death in the 1st weeks of life and is one of the most common causes of liver failure in the neonate. The diagnosis is mostly made retrospectively, based on histopathologic features of severe liver fibrosis associated with hepatic and extrahepatic siderosis. Several etiologies may underlie this phenotype, including a recently hypothesized gestational alloimmune disease. Fifty-one cases of liver failure with intrahepatic siderosis in fetuses and neonates were analyzed retrospectively. Maternal and infant data were collected from hospitalization and autopsy reports. All available slides were reviewed independently by 3 pathologists. Immunologic studies were performed on maternal sera collected immediately after delivery. The diagnosis of neonatal haemochromatosis was retained in 33 cases, including 1 case with Down syndrome and 1 case with myofibromas. Liver siderosis was inversely proportional to fibrosis progression. In fetuses, iron storage was more frequent in the thyroid than in the pancreas. Perls staining in labial salivary glands was positive in 1 of 5 cases. Abnormal low signal intensity by magnetic resonance imaging was detected in the pancreas in 2 of 7 cases. Renal tubular dysgenesis was observed in 7 of 23 autopsy cases. Chronic villitis was seen in 7 of 15 placentas. Half of the mothers presented with an autoimmune background and/or autoantibodies in their sera. Our work highlights the importance of autopsy in cases of neonatal hemochromatosis and marshals additional data in support of the hypothesis that neonatal hemochromatosis could reflect maternal immune system dysregulation.

Mosaic 18q21.2 deletions including the TCF4 gene: a clinical report.

Pitt–Hopkins syndrome (PTHS) is characterized by distinctive facial dysmorphism, profound intellectual disability, and the possible occurrence of epilepsy and breathing anomalies. It is caused by haploinsufficiency of the TCF4 gene. No significant difference in clinical severity has been reported to date between PTHS patients carrying 18q21 deletions including the TCF4 gene, and those harboring TCF4 point mutations, suggesting a lack of genotype/phenotype correlation. Moreover, the size of 18q21 deletions including the TCF4 gene does not appear to have a significant effect on the phenotypic severity, suggesting that TCF4 haploinsufficiency is the most important prognostic factor in 18q deletions. We describe two unrelated patients presenting with clinical features reminiscent of PTHS and carrying mosaic interstitial 18q21 deletions characterized by array comparative genomic hybridization. One of the patients presented the lowest level of mosaic 18q21 deletion reported to date (5–10%). Our report and a review of the literature show that the mosaic status does not appear to have a significant effect on the clinical severity of 18q21 deletions, which are associated with a poor neurological outcome, whereas a mosaic TCF4 point mutation can result in a significantly milder phenotype. Malformations of internal organs are currently considered to be rare in PTHS. The patients described here had visceral anomalies, suggesting that a full morphological assessment, including heart and abdominal ultrasound scans, should be performed systematically in PTHS patients.

Relative exchangeable copper: a valuable tool for the diagnosis of Wilson disease

Measuring of the relative exchangeable copper seems to be a promising tool for the diagnosis of Wilson disease. The aim of our study is to determine the performance of REC for the diagnosis of Wilson disease in a population of patients with chronic liver diseases.

Successful endoscopic closure of a refractory button-battery tracheoesophageal fistula in a 3-year child using endoscopic submucosal dissection of the surrounding mucosa

Most serious button-battery ingestions are not witnessed and they can cause life threatening complications. We present here the case of a 3-year-old girl who swallowed a button battery in January 2016 with a delayed diagnosis being made after 10 days. A 5-mm tracheoesophageal fistula was endoscopically diagnosed (▶Fig. 1). The first attempts at closure involved the deployment of two successive esophageal covered stents between January and May (▶Fig. 2). The fistula decreased in size but persisted, so we then attempted controlled wound healing with a nasogastric tube, but the fistula still remained. Next, we tried a side fistula abrasion with argon plasma coagulation. Unfortunately, these techniques did not allow full recovery, even though the fistula reduced notably. After 1 year, we tried endoscopic submucosal dissection (ESD) of the mucosa surrounding the fistula, resecting a 1-cm mucosal patch centered on the fistula. After injecting the submucosa and making the mucosal incision, we used a DualKnife (Olympus) to dissect the fibrotic area. After the dissection, the fistula was closed with three clips anchored into the submucosa of the resected area (▶Fig. 3; ▶Video1). We arranged a radiologic check with contrast, which Video 1 Views of the fistula and previous attempts to close it. The endoscopic submucosal dissection procedure is performed to resect the surrounding mucosa, which is subsequently clipped to close the fistula. ▶ Fig. 1 Appearance of the tracheoesophageal fistula in a 3-year-old girl after ingestion of a button battery.

Relevance of C5b9 immunostaining in the diagnosis of neonatal hemochromatosis

Background:Neonatal hemochromatosis caused by a gestational alloimmune mechanism or gestational alloimmune liver disease (GALD) is a rare perinatal disorder characterized by intra- and extrahepatic iron overload. It is believed to result from complement-mediated liver injury, in which the classical complement pathway is activated by maternal antibody/fetal antigen complexes, leading to hepatocyte lysis by the membrane attack complex C5b9. According to some authors, C5b9 expression in more than 75% of liver parenchyma is specific for GALD.Methods:We conducted a retrospective multicentric immunohistochemical study with anti-C5b9 in GALD cases (n = 25) and non-GALD cases with iron overload (n = 36) and without iron overload (n = 18).Results:C5b9 was expressed in 100% of GALD cases but involved more than 75% of the liver parenchyma in only 26% of the cases. C5b9 was detected in 26.75% of the non-GALD cases with more than 75% of positive parenchyma in maternal erythrocytic alloimmunization, herpes and enterovirus hepatitis, bile acid synthetic defect, DGUOK mutation, Gaucher disease, cystic fibrosis, and giant-cell hepatitis with autoimmune hemolytic anemia.Conclusion:Diagnosis and therapeutic management of GALD cannot only be based on C5b9 expression in liver samples as it is not specific of this disease.

Evaluation of the accuracy of exchangeable copper and relative exchangeable copper (REC) in a mouse model of Wilson’s disease

Wilsons disease (WD) is caused by mutations in the ATP7B gene responsible for a toxic copper overload mainly in the liver and the central nervous system. Phenotypic heterogeneity may challenge the diagnostic confirmation. Exchangeable copper (CuEXC) has recently been proposed as a new marker of WD, and its ratio to the total serum copper (Cus), Relative Exchangeable Copper (REC = CuEXC/Cus), as a diagnostic marker. This study aimed to investigate whether this could be confirmed in Atp7b-/- mice, an engineered WD animal model. Atp7b-/- (n = 137) and wild type (WT; n = 101) mice were investigated under the same conditions at 6-8, 20, 39, or 50 weeks of age. Twenty-four Atp7b-/- mice received D-penicillamine treatment from 39 to 50 weeks of age. Serum and liver [histology and intrahepatic copper (IHCu)] data were evaluated. In the WT group, all serum and liver data were normal. Atp7b-/- livers developed a chronic injury from isolated moderate inflammation (6-8 weeks: 16/33 = 48%) to inflammatory fibrosis with cirrhosis (50 weeks: 25/25 = 100% and 16/25 = 64% respectively). Cus and CuEXC increased until week 39, whereas IHCu and REC were stable with increasing age and much higher than in WT mice (mean ± SD: 669 ± 269 vs. 13 ± 3 μg/g dry liver and 39 ± 12 vs. 11 ± 3%, respectively). A threshold value of 20% for REC provided a diagnostic sensitivity and specificity of 100%, regardless of sex, age, or the use of D-penicillamine. Eleven weeks of 100 mg/kg D-penicillamine reduced liver fibrosis (p = 0.001), IHCu (p = 0.026) and CuEXC (p = 0.175). In conclusion, this study confirms REC as a WD diagnostic marker in a mouse model of chronic liver disease caused by copper overload. Further studies are needed to assess the usefulness of CuEXC to monitor the evolution of WD, particularly during treatment.