Transient liver injury and severe neonatal cholestasis in infant with glucose-6-phosphate dehydrogenase deficiency due to a new mutation.

We report the case of a neonate with a new, previously undescribed, glucose-6-phosphate dehydrogenase (G6PD) gene mutation, which was revealed by severe cholestasis, hyperbilirubinemia, and transient liver dysfunction. The severity of the clinical phenotype with ongoing chronic hemolytic anemia suggests that this mutation belongs to class 1 G6PD deficiency. The hemizygous mutation «c.675G>c; p.Trp225Cys¼ was detected by genomic sequencing. Since severe G6PD deficiency can be revealed by cholestasis, it is important to check G6PD enzyme activity when faced with a case of liver dysfunction in the neonatal period.

Clinical Heterogeneity of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome: A French Multicenter Retrospective Study.

OBJECTIVE: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune disease caused by mutations in the forkhead box protein 3 gene (FOXP3), which encodes a key regulator of immune tolerance. The aim of this study was to describe the clinical heterogeneity of the disease in a national French cohort. METHODS: Multicenter retrospective study of patients diagnosed with IPEX syndrome caused by mutations in FOXP3. RESULTS: Thirty children from 26 families were included. Age at disease onset (median [first to third quartile]) was 1.5 mo [0-84] and at death 3.5 years [0-10.5] (n = 15) indicating a high heterogeneity. Initial presentation was diarrhoea (68%), type 1 diabetes (T1D; 25%), skin lesions (7%) and nephropathy (3%). During the course of the disease the following main symptoms were observed: diarrhoea (100%), skin lesions (85%), T1DM (50%), severe food allergies (39%), haematological disorders (28%), nephropathies (25%), hepatitis (14%) as well as the presence of a variety of autoantibodies. Immunosuppressive mono- or combination therapy led to improvement in eight children. Three boys displayed a stable disease course without any immunosuppressive medication. Overall 10-year survival rate was 43% (42% in transplanted patients and 52% in patients on immunosuppressive therapy). Five out of 22 identified FOXP3 mutations have not been described yet: c.-23 + 1G > A, c.-23 + 5G > A, c.264delC, c.1015C > T and c.1091A > G. The first two produced atypical, attenuated phenotypes. Missense and frameshift mutations affecting the forkhead domain were associated with poor survival (Gehan-Wilcoxon p = 0.002). CONCLUSION: The broad phenotypic heterogeneity of IPEX raises questions about modifying factors and justifies early FOXP3 sequencing in suspected cases.

Fetal phenotypes in otopalatodigital spectrum disorders.

Otopalatodigital spectrum disorders (OPDSD) include OPD syndromes types 1 and type 2 (OPD1, OPD2), Melnick-Needles syndrome (MNS), and frontometaphyseal dysplasia (FMD). These conditions are clinically characterized by variable skeletal dysplasia associated in males, with extra-skeletal features including brain malformations, cleft palate, cardiac anomalies, omphalocele and obstructive uropathy. Mutations in the FLNA gene have been reported in most FMD and OPD2 cases and in all instances of typical OPD1 and MNS. Here, we report a series of 10 fetuses and a neonatally deceased newborn displaying a multiple congenital anomalies syndrome suggestive of OPDSD and in whom we performed FLNA analysis. We found a global mutation rate of 44%. This series allows expanding the clinical and FLNA mutational spectrum in OPDSD. However, we emphasize difficulties to correctly discriminate OPDSD based on clinical criteria in fetuses due to the major overlap between these conditions. Molecular analyses may help pathologists to refine clinical diagnosis according to the type and the location of FLNA mutations. Discriminating the type of OPDSD is of importance in order to improve the genetic counseling to provide to families.

[Macrophage activation syndrome and autoimmunity due to visceral leishmaniasis]. / Syndrome d'activation macrophagique et auto-immunité cortico-sensible révélateurs d'une leishmaniose viscérale.

Hemophagocytic syndromes are a heterogeneous group of diseases characterized by an excessive immune response, mediated by activated cytotoxic T cells and macrophages. Among hemophagocytic syndromes, genetic and secondary forms can be distinguished. We report on the case of a male newborn who presented with macrophage activation syndrome associated with lymphoproliferation with favorable outcome under prednisone and cyclosporin. Hemopathy, infection, or genetic lymphohistiocytosis were initially ruled out. Severe autoimmunity was suspected because of positive antinuclear antibodies and Farr test associated with anemia and a positive Coombs test as well as cytolytic hepatitis with anti-liver, kidney microsome (LKM) antibodies. Treatment was therefore intensified by adding mycophenolate mofetil. This led to an unexpected deterioration of general health and lab exam results with recurrence of fever and inflammation. The initial investigations were revisited and completed by a liver biopsy, which revealed the presence of numerous leishmania parasites at the amastigote stage, enabling the diagnosis of visceral leishmaniasis. The patient's condition dramatically improved under liposomal amphotericin B treatment. Our observation shows that visceral leishmaniasis can present as lupus-like syndrome with lymphoproliferation. Moreover, the lack of leishmania on marrow aspiration cannot rule out the diagnosis of visceral leishmaniasis. Detection of leishmania by serological or molecular tests is mandatory in case of hepatosplenomegaly with hemophagocytic syndrome together with autoantibodies, in order to avoid useless and life-threatening exposure to immunosuppressive treatments.

Epstein-Barr virus-associated smooth muscle tumors in a composite tissue allograft and a pediatric liver transplant recipient.

Epstein-Barr virus (EBV) is known to establish latent infections in B-lymphocytes that can cause lymphoproliferative disorders particularly in immunocompromised patients. More recently, the development of rare EBV-associated smooth muscle tumors has been reported in transplant recipients. We herein describe 2 new cases of EBV-associated post-transplant smooth muscle tumors (EBV-PTSMT), including the first in a facial composite tissue graft recipient. Among the striking features shared by these 2 patients were their young ages, the fact that they were naïve for EBV before the transplantation, that they developed a post-transplant lymphoproliferative disorder before the diagnosis of EBV-PTSMT, and that they responded favorably to reduction of immunosuppression. Radiological and histologic features of EBV-PTSMT are shown. Finally, pathophysiology and therapeutic management of EBV-PTSMT are discussed based on a comprehensive review of the literature.

[New insights into perinatal hemochromatosis]. / Nouveaux concepts dans l'hémochromatose périnatale.

Perinatal hemochromatosis (PH) includes neonatal acute liver failure (ALF) with cirrhosis and extrahepatic iron overload sparing the reticuloendothelial system. This is the main cause of neonatal ALF. Prognosis is very poor, usually with neonatal death or neonatal orthotopic liver transplantation occurring in more than 70%. The recurrence rate is more than 90%. Diagnosis is hard to make and is proved after exclusion of other neonatal ALF causes. A recent physiopathological hypothesis proposed HP as a maternofetal alloimmune disease against the fetal liver. A maternal antibody may activate the terminal complement cascade, responsible for the membrane attack complex directed against fetal hepatocytes. Maternal prenatal treatment after a pregnancy complicated by PH modifies the course and the prognosis of this disease. In France, approval of prenatal IVIG treatment is required after analysis of clinical and pathological data by a national multidisciplinary committee.

[Post-diarrheal haemolytic uremic syndrome: when shall we consider it? Which follow-up?]. / Syndrome hémolytique et urémique post-diarrhéique : Quand y penser ? Quel suivi ?

Haemolytic uremic syndrome (HUS) is characterized by thrombotic microangiopathy with acute renal failure, haemolytic anaemia with schizocytes and thrombocytopenia. Typical forms (D(+) HUS) are caused by gastrointestinal infection with Escherichia coli species producing verotoxines (or Shiga toxins, STEC). It is estimated that 5-8 % of infected individuals will develop HUS following STEC infection. E. coli O157:H7 is the most commonly involved serotype and can lead to D(+) HUS in 15 % of young infected children. Vehicles of STEC transmission are contaminated food (ground beef, unpasteurised dairy products, unwashed and uncooked fruit and vegetables), person-to-person transmission and contact with farm animals with STEC. After an average incubation period of 3 to 8 days, patients develop painful bloody diarrhoea followed by systemic toxinemia. This may lead to thrombotic microangiopathy with endothelial damage and activation of local thrombosis. Since 1996, the Institut de Veille Sanitaire (InVS) centralises all notified French cases of D(+) HUS in children less than 15 years of age and investigates cases regrouped by time and place for the presence of STEC risk factors. The average annual incidence ranges between 0.6 and one for 100 000 children younger than 15 years and with a peak at 1 year of age. Fifty-one percent of HUS occur between June and September. Patients with a suspicion of STEC infection or bloody diarrhoea should not receive antibiotics, antimotility agents, narcotics and non-steroidal anti-inflammatory drugs. Maintenance optimal hydration provides nephroprotection. The management of HUS remains supportive. Dialysis was required for 46 % of HUS cases in 2009. For similar indication, peritoneal dialysis has to be a first choice treatment. Neurological injury is the most frequent non-renal complication and the first cause of death. Early initiation of plasmapheresis might improve the prognosis. Overall mortality rate ranges between 1 and 5 %. One third of patients suffer from long-term renal morbidity such as proteinuria, arterial hypertension and decrease of glomerular filtration rate. The longer the duration of anuria, the greater the risk of sequellae. Any patient with a history of HUS needs a long-term renal follow-up.

[Child pleuropulmonary blastoma]. / Pleuropneumoblastome de l'enfant.

Pleuropulmonary blastoma is an extremely rare and aggressive thoracic tumour seen exclusively in children. The initial symptoms are respiratory and non specific and the chest X-ray done in that context reveals a thoracic mass. The chest CT scan then leads to the diagnosis of a cystic, mixt or solid mass. The diagnosis will be affirmed on anatomopathology of the tumour or biopsy. There are three different histological types: type I, cystic, type II, cystic and solid and type III, solid exclusively. Type I is less aggressive and its treatment is essentially surgical. Types II and III are highly aggressive and require surgery associated to polychemotherapy. In all cases, surgery is essential and should be the most complete possible. Extension and follow-up exams will include bone scan and brain imagery searching for metastasis as well as abdominal ultrasound searching associated renal lesions because 30% of pleuropulmonary blastoma are part of a familial predisposition syndrome.

[Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: a rare preneoplastic condition]. / L'hyperplasie neuroendocrine pulmonaire idiopathique: une lésion prénéoplasique méconnue.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is an uncommon preneoplastic condition, often associated with typical carcinoid tumours. The observations reported below concern two women, both suffering from chronic pulmonary symptoms. These patients underwent computed tomography that showed a solitary nodule in the first patient and multiple sub centimetre nodules in the second. In both cases histological studies of the pulmonary biopsies revealed: a proliferation of neuroendocrine cells dispersed in the bronchial and bronchiolar epithelium, more specifically superficial to the basement membrane; some tumourlets; a typical carcinoid tumour was also found in the first patient's biopsy. The choice of treatment remains difficult, mainly because the existing studies are restricted to small numbers of patients or isolated cases, a consequence of the low prevalence of this disease. Considering its slow evolution, management by long-term clinical, endoscopic and radiologic surveillance may be considered. If a carcinoid tumour is present or appears during the surveillance, the standard treatment is still surgical resection.

[Thymic carcinoid tumor revealed by a Cushing's syndrome: usefulness of positron emission tomography]. / Tumeur carcinoïde du thymus révélée par un syndrome de Cushing: intérêt de la tomographie par émission de positons.

Ectopic adrenocorticotropic (ACTH) syndrome is a rare condition, generally due to lung or carcinoid tumors. 18-fluorodeoxy-glucose positron emission tomography ((18)FDG-PET) can be useful where conventional localization techniques often fail. A 50-year-old man presented with sudden diffuse oedema, hypokaliemic alkalosis, Diabetes mellitus and high serum levels of ACTH and cortisol. Ectopic ACTH syndrome was confirmed leading to ketoconazole treatment. Chest-computed tomography only revealed an aspecific anterior mediastinal nodule that was hypermetabolic on the whole body-(18)FDG-PET. A thymic tumor was suspected and the patient had a thymectomy that revealed an atypical carcinoid tumor with pleural carcinosis. The postoperative course was favorable with clinical and biochemical remission of neoplastic Cushing's syndrome.

Tubulovillous adenoma of the vulva.

BACKGROUND: We report the second case of enteric-type villous adenoma of the vulva. The differential diagnosis, histogenesis, and pathogenesis are discussed. CASE: A 66-year-old woman had a tumor resected from the posterior aspect of the vulva. The tumor was characterized by its villous architecture, with columnar epithelium and goblet cells. This vulvar tubulovillous adenoma was identical to a tumor resected 6 months before from this patient's rectal wall. CONCLUSION: These two tumors behaved benignly, and the vulvar adenoma possibly originated with the müllerian vestige.

Endothelial cell marker expression in dysplastic lesions of the liver: an immunohistochemical study.

BACKGROUNDS/AIMS: Hepatocellular carcinoma usually contains continuous capillary vessels lacking the differentiation markers specific for normal sinusoidal endothelial cells. We therefore aimed to search for alterations in endothelial cell marker expression in precancerous liver lesions. METHODS: Expression of the endothelial cell markers CD31, CD34 and BNH9 was analyzed in 138 dysplastic lesions from 40 cirrhotic patients (20 with and 20 without hepatocellular carcinoma). RESULTS: No expression of the three endothelial cell markers was detected in cirrhotic nodules and in non dysplastic regenerative macronodules. The three markers were detected in 29.8% of dysplastic lesions and 47% of hepatocellular carcinomas. At least one marker was detected in 75% of dysplastic lesions and 100% of hepatocellular carcinomas. The three markers were more frequently expressed in areas of small cell than of large cell change (34 vs 10%). No correlation was found with the grade of dysplasia, the occurrence of arterialization and the association with hepatocellular carcinoma. CONCLUSIONS: Alterations in the hepatic microcirculation comparable to those observed in hepatocellular carcinoma are present in a significant proportion of dysplastic lesions of the liver and may be indirect markers of the process of liver carcinogenesis.