Prevalence of liver complications in children receiving long-term parenteral nutrition.

BACKGROUND/OBJECTIVES: The hepatic prognosis of long-term home total parenteral nutrition (TPN)-dependent children is poorly documented. The objective was to study outcome data in home TPN-dependent children and to describe precisely their liver biopsies in the attempt to analyze risk factors for biochemical and histological hepatic abnormalities. SUBJECTS/METHODS: Medical records of 42 children receiving home TPN for more than 2 years between January 1998 and December 2007 in a single approved home total parenteral center were reviewed. Hepatic biochemical abnormalities were analyzed. Hepatic biopsies were classified by two independent pathologists. RESULTS: Duration of TPN was 7.9±0.8 years (mean±s.e.m.), with an average age at onset of 1.5±0.5 years. A total of 24 patients (57%) developed biochemical liver abnormalities in an average of 2.9±0.4 years after starting TPN. Risk factors for biochemical abnormalities were younger age at TPN commencement, longer duration of TPN, higher rate of catheter-related infections and higher volume and energy content of TPN. Liver biopsies were carried out in 43% of patients (mean age 3.2±0.9 years). Almost all patients had fibrosis (94%). Risk factors were dependent on each histological abnormality: fibrosis was significantly associated with a shorter length of bowel and a longer duration of TPN; cholestasis correlated with a lower percentage of total parenteral energy intake due to lipids; and steatosis had no risk factor identified. CONCLUSION: Our study reports a high rate of histological liver abnormalities and analyzes risk factors in children who underwent very long-term home TPN.

[Hypoplasia adrenal congenita of anencephalic type: two cases with pituitary abnormalities and review of literature]. / L'hypoplasie surrénale congénitale de type anencéphalique: deux cas avec anomalies hypophysaires, sans mutation de DAX-1 et SF-1 et revue de la littérature.

Hypoplasia adrenal congenita is an extremely uncommon disease of early onset. This condition can be lethal in the absence of treatment. Some forms are due to the congenital adrenal hypoplasia of anencephalic type whose origin is even unknown. Here, we present two cases of congenital adrenal hypoplasia of anencephalic type with pituitary abnormalities. The two male newborns died because adrenal insufficiency in the neonatal period. The adrenal glands were hypoplastic with a histological structure of anencephalic type Immunocytochemical study of the pituitary revealed an absence of the gonadotrophs. No mutation of DAX 1 and SF-1 was found.

[Aetiology and prognosis of prenatally diagnosed megacystis regarding gestational age at discovery. A six-year retrospective study]. / Étiologies et pronostic des mégavessies de diagnostic prénatal selon l'âge de découverte. Étude rétrospective sur six années.

OBJECTIVES: The purpose of this study is to describe the diagnosis, the care and the prognosis of the fetuses with an antenataly diagnosed megacystis. PATIENTS AND METHODS: Six year retrospective study about 46 cases of megacystis (26 diagnosed during 1st trimester; 14 during 2nd trimester; 9 during 3rd trimester) referred in the prenatal fetal medicine unit of the Femme-Mère-Enfant hospital in Lyon (France). RESULTS: The main aetiology is urethral occlusion, particularly for megacystis discovered during the 1st and the 2nd trimesters. Twenty-two terminations of pregnancy were performed (47.8%) and 6 pregnancies arrested spontaneously (13%). Eighteen children were born alive, but 2 died in neonatal period. Finally, 16 children survived (34.8%). Chromosomal abnormalities are frequent (22%). DISCUSSION AND CONCLUSION: Antenatal discovery of a megacystis is a complex situation, and often of poor fetal prognosis. It requires a multidisciplinary approach to allow the concerned couple to be determined on the best care of this pregnancy.

[Granulomatous pulmonary involvement preceding diagnosis of Crohn disease: a pediatric case report]. / Atteinte granulomateuse pulmonaire précédant le diagnostic de maladie de Crohn: à propos d'un cas pédiatrique.

Crohn disease (CD) is a chronic bowel disorder that may affect many other organs such as the eyes, hepatobiliary system, skin, and joints. Pulmonary involvement in association with CD is a classic but uncommon manifestation. It can be primitive with granulomas or secondary to treatments. We report on the case of a teenager in whom the onset of CD was dominated by respiratory symptoms. Because of this presentation, we also suspected opportunistic infections such as tuberculosis and other granulomatous pulmonary diseases such as sarcoidosis or hypersensitivity pneumonitis.

Campomelic dysplasia: echographic suspicion in the first trimester of pregnancy and final diagnosis of two cases.

OBJECTIVE: Campomelic dysplasia (CD) is a rare skeletal dysplasia characterized by marked femoral and tibial angulations, hypoplasic scapulae, normal upper limbs and sex reversal in 3/4 of 46,XY fetuses. Most cases are lethal in the neonatal period. Heterozygous mutations in the SOX9 gene are responsible for CD. The diagnosis is not usually made until the mid-second trimester or later. METHODS: We describe 2 cases of CD suspected by ultrasonography in the first trimester. RESULTS: The 2 cases presented with hygroma colli along with anomalies in the lower but not the upper limbs. Terminations of pregnancy were obtained at 14+3 and 20+6 gestational weeks. Fetopathological examinations confirmed sonographic findings. CONCLUSION: When first trimester hygroma colli is accompanied by specific findings of the lower limbs, the diagnosis of CD can be investigated through SOX9 mutation analysis.

[Malignancy risk and Wiedemann-Beckwith syndrome: what follow-up to provide?]. / Risque tumoral et syndrome de Wiedemann-Beckwith: quelle surveillance proposer?

Wiedemann-Beckwith syndrome (WBS) is a syndrome of excessive growing with a high predisposition to developing embryologic tumours within the first years of life. This risk is evaluated between 7.5 and 10%; it varies with the mechanisms of mutations involved. These take place in two distinct domains of 11p15, which are under parental printing. Emerging techniques of cytogenetic and molecular biology now have shown correlations between genotypes and phenotypes, and can identify the 30% of WBS who are especially at risk of developing tumours. A specific follow-up, integrating the specificity of developing tumours of each 11p15 mutations involved, is now proposed to patients with WBS.

[Locally recurrent prostatic adenocarcinoma after exclusive radiotherapy: results of high intensity focused ultrasound]. / Adénocarcinome prostatique en récidive locale après radiothérapie exclusive: résultats du traitement par ultrasons focalisés.

OBJECTIVES: To determine the efficacy and adverse effects of high intensity focused ultrasound (HIFU) for the treatment of local recurrence of prostate cancer after exclusive external beam radiotherapy. MATERIAL AND METHODS: Seventy-two patients with histologically and biologically documented local recurrence after radiotherapy were treated by HIFU. The mean age was 68.27+/-5.93 years, and mean PSA was 6.64+/-7.26ng/ml. Thirty patients were treated according to standard parameters and 42 according to specific parameters. ASTRO 2005 criteria, specific for salvage therapy (Phoenix consensus), were used to define recurrence. Progression-free survival was calculated by the Kaplan-Meier method. RESULTS: Mean follow-up was 39+/-28 months. The negative biopsy rate was 80% and the median nadir PSA was 0.10ng/ml. Specific survival was 94% at three years and 90% at five years, and progression-free survival was 50% at three years and 44% at five years. The urinary incontinence rate was 44% (grade 1 : 12%, grade 2/3 : 32%) and the urethral stricture or bladder neck stenosis rate was 30%. The use of specific parameters reduced the incidence of severe incontinence (19% versus 50, P=0.005) and stenosis (24% versus 40). CONCLUSIONS: Treatment with HIFU achieved a five-year progression-free survival of 44%, but patients must be clearly informed about the high rate of adverse effects.

Development of the human fetal insular cortex: study of the gyration from 13 to 28 gestational weeks.

To describe the morphological stages of insular sulci and gyri development we carried out a macroscopical study on 21 human fetal brains, showing no anomalies, from 13 to 28 gestational weeks (GWs). Particular focus was given to morphological appearance during the development of insular and periinsular structures, especially the gyration and sulcation of the insula, central cerebral region and opercula, as well as the vascularization of these regions. The periinsular sulci and the central (insular and cerebral) sulci were the first macroscopical structures identified on the lateral surface of the human fetal cerebral hemisphere with earlier development on the right hemisphere. Here we describe five stages of insular gyral and sulcal development closely related to gestational age: stage 1: appearance of the first sulcus at 13-17 GWs, stage 2: development of the periinsular sulci at 18-19 GWs, stage 3: central sulci and opercularization of the insula at 20-22 GWs, stage 4: covering of the posterior insula at 24-26 GWs, stage 5: closure of the sylvian fissure at 27-28 GWs. We provide evidence that cortical maturation (sulcation and gyration) and vascularization of the lateral surface of the brain starts with the insular region, suggesting that this region is a central area of cortical development.

Decreased expression of Intestinal I- and L-FABP levels in rare human genetic lipid malabsorption syndromes.

We investigated, for the first time, the expression of I- and L-FABP in two very rare hereditary lipid malabsorption syndromes as compared with normal subjects. Abetalipoproteinemia (ABL) and Anderson's disease (AD) are characterized by an inability to export alimentary lipids as chylomicrons that result in fat loading of enterocytes. Duodeno-jejunal biopsies were obtained from 14 fasted normal subjects, and from four patients with ABL and from six with AD. Intestinal FABP expression was investigated by immuno-histochemistry, western blot, ELISA and Northern blot analysis. In contrast to normal subjects, the cellular immunostaining for both FABPs was clearly decreased in patients, as the enterocytes became fat-laden. In patients with ABL, the intestinal contents of I- (60.7 +/- 13.38 ng/mg protein) and L-FABP (750.3 +/- 121.3 ng/mg protein) are significantly reduced (50 and 35%, P < 0.05, respectively) as compared to normal subjects (I-135.3 +/- 11.1 ng, L-1211 +/- 110 ng/mg protein). In AD, the patients also exhibited decreased expression (50%, P < 0.05; I-59 +/- 11.88 ng, L-618.2 +/- 104.6 ng/mg protein). Decreased FABP expression was not associated with decreased mRNA levels. The results suggest that enterocytes might regulate intracellular FABP content in response to intracellular fatty acids, which we speculate may act as lipid sensors to prevent their intracellular transport.

[Renal tubular dysgenesis and mutation in the renin gene]. / Dysgénésie tubulaire proximale et mutation du gène de la rénine.

Renal tubular dysgenesis is a severe and rare disorder of the renal development characterized by fetal anuria, oligohydramnios and early death from pulmonary hypoplasia and refractory arterial hypotension. We report on a female patient who presented with anuria in the neonatal period, requiring peritoneal dialysis until 5 months of age with unexpected diuresis recovery at 2 months of age. Clinical, histological and pathophysiological issues are discussed for this disease related to a mutation in the renin gene.

Overexpression of the antiapoptotic gene Bfl-1 in B cells from patients with familial systemic lupus erythematosus.

Genetic determinants taking part in the development of systemic lupus erythematosus (SLE) are complex and not fully characterized. Dysregulated expression of genes involved in the control of apoptosis has been previously suggested. We report here a consanguineous family with SLE manifestations in three siblings associated in one of them with severe lymphoproliferative features. Laboratory studies showed no defect in CD95-mediated cell death. Screening expression of Bcl-2 family genes that regulate mitochondrial apoptosis pathway showed an overexpression of the antiapoptotic Bfl-1 gene. Real time RT-PCR analysis indicated that overexpression of Bfl-1 was restricted to B-cells, with normal expression in T-cells. Those results suggest that overexpression of Bfl-1 could result in impaired B-lymphocyte homeostasis and inappropriate immune response leading to autoimmune manifestations.

hSNF5/INI1-deficient tumours and rhabdoid tumours are convergent but not fully overlapping entities.

Rhabdoid tumours (RTs) are rare but highly aggressive tumours of childhood. Their rarity and their miscellaneous locations make the diagnosis particularly challenging for pathologists. Central nervous system and peripheral RTs have been associated with biallelic inactivation of the hSNF5/INI1/SMARCB1 (hSNF5/INI1) tumour suppressor gene. Immunohistochemistry (IHC) with a monoclonal anti-hSNF5/INI1 antibody has recently been proposed as an efficient diagnostic tool for RTs. We have conducted a retrospective study of 55 tumours referred to our institution with a suspicion of RT. This analysis included pathological review, IHC with anti-hSNF5/INI1 antibody, and molecular investigation using quantitative DNA fluorescent analysis and sequencing of the nine exons of hSNF5/INI1. The molecular lesion could be detected in 37 of the 39 cases exhibiting negative staining for hSNF5/INI1. In the two discrepant cases, the lack of detection of genetic abnormality was probably owing to the presence of a high number of non-tumour cells in the samples. This indicates that hSNF5/INI1 IHC is very sensitive and highly specific for the detection of hSNF5/INI1 loss-of-function. Among the 38 cases with typical RT histological features, six failed to exhibit hSNF5/INI1 mutation and stained positive for hSNF5/INI1. This strongly supports the evidence of a second genetic locus, distinct from hSNF5/INI1, associated with RT. Conversely, seven tumours with histological features poorly compatible with RT stained negative for hSNF5/INI1; they nevertheless exhibited an age of onset and a clinical behaviour similar to RT. This suggests that hSNF5/INI1 inactivation is not strictly limited to typical RT but characterizes a wider family of hSNF5/INI1-deficient tumours. Consequently, we believe that anti-hSNF5/INI1 IHC should be performed widely, even when the pathological characteristics are not typical. The molecular investigation should be performed in infants when a rhabdoid predisposition syndrome is suspected.

[Histological and molecular study of fetal human adrenal cortex (12-36 wk)]. / Etude histologique et moléculaire de la corticosurrénale foetale humaine (12e-36e SD). La corticosurrénale foetale humaine (12e-36e SD).

Histological and functional characteristics of the fetal human adrenals was studied in 119 normal fetuses aged 12 to 36 weeks development (WD). Immunocytochemical detection of steroidogenesis enzyme (3beta-HSD and P450 c21) and evaluation of cell proliferation using two nuclear markers (Ki-67 and PCNA) were performed in 70 of them. The human fetal adrenal cortex is composed of two morphologically distinct zones: the definitive peripheral zone and the fetal inner zone. From the 12th WD, we observed expression of an adherence protein (NCAM) and two steroidogenesis enzymes (3beta-HSD and P450 c21) in the definitive zone cells, attesting to the capacity of these cells to synthesize mineralocorticoids and/or cortisol. In the fetal zone, only P450 c21 immunoreactivity was detected. From the 14th WD, a transitional zone between the definitive zone and the fetal zone was identified by immunocytochemistry, with expression of 3b-HSD from the 21st WD. Only cells of the definitive zone proliferated from the 12th to 25th WD. The indexes of proliferation of PCNA and Ki-67, 40% and 25% respectively, decreased gradually and were lower than 1% at the 25th WD.

Fetal type IV glycogen storage disease: clinical, enzymatic, and genetic data of a pure muscular form with variable and early antenatal manifestations in the same family.

We report on a family of three consecutive fetuses affected by type IV glycogen storage disease (GSD IV). In all cases, cervical cystic hygroma was observed on the 12-week-ultrasound examination. During the second trimester, fetal hydrops developed in the first pregnancy whereas fetal akinesia appeared in the second pregnancy. The diagnosis was suggested by microscopic examination of fetal tissues showing characteristic inclusions exclusively in striated fibers, then confirmed by enzymatic studies on frozen muscle. Antenatal diagnosis was performed on the third and fourth pregnancies: cervical cystic hygroma and low glycogen branching enzyme (GBE) activity on chorionic villi sample (CVS) were detected in the third pregnancy whereas ultrasound findings were normal and GBE activity within normal range on CVS in the fourth pregnancy. Molecular analysis showed that the mother was heterozygous for a c.1471G > C mutation in exon 12, leading to the replacement of an alanine by a tyrosine at codon 491 (p.A491T); the father was heterozygous for a c.895G > T mutation in exon 7, leading to the creation of a stop codon at position 299 (p.G299X). GSD IV has to be considered in a context of cervical cystic hygroma with normal karyotype, particularly when second trimester hydrops or akinesia develop. Enzymatic analysis of GBE must be performed on CVS or amniotic cells to confirm the diagnosis. Characteristic intracellular inclusions are specific to the disease and should be recognized, even in macerated tissues after fetal death. Genetic analysis of the GBE gene may help to shed some light on the puzzling diversity of GSD IV phenotypes.

[Conjunctival tumors in children. A histopathologic study of 42 cases]. / Tumeurs de la conjonctive bulbaire de l'enfant. Résultats de l'examen histologique de 42 lésions opérées.

PURPOSE: The aim of this study was to describe the clinicopathological characteristics of 42 conjunctival tumors surgically removed in children. PATIENTS AND METHODS: Records of all conjunctival tumors surgically removed in children during the 11-year period 1990-2001 were collected from the records of the Department of Ophthalmology, Edouard Herriot Hospital, Lyon. In all cases, the tumor was resected with no additional treatment. Sections of all cases were reviewed by the same pathologist. RESULTS: A total of 42 cases (40 patients) were included in the study. The mean age of the subjects at the time of surgical excision was 10 years, with a range of 1-17 years; 45% were male. The most frequent indication for tumor removal was suspected growth. The clinical diagnosis was accurate in 91% of cases. The tumor was localized at the limbus in 57% of cases. Most tumors were pigmented nevi, accounting for 83% of the lesions. The histopathological diagnoses in decreasing order of frequency were: nevi (35), angioma (2), dermolipoma (2), dermoid (1), papilloma (1), and squamous cell carcinoma (1). In one case, the histological study revealed squamous cell carcinoma in a child suffering from xeroderma pigmentosum. CONCLUSIONS: This retrospective study suggests that malignancy of pigmented conjunctival lesions is extremely rare in children. Although squamous cell carcinoma is rare in children, surgical excision and histological study are necessary when a conjunctival lesion is associated with xeroderma pigmentosum or immunodeficiency.