Isabella Giovannoni

Two novel mutations in African and Asian children with progressive familial intrahepatic cholestasis type 3.

BACKGROUND Defects in ABCB4 have been found to cause progressive familial intrahepatic cholestasis type 3. Liver histology is important, but not specific, for diagnosis. Genotyping is conclusive. AIM To determine the pathogenetic role of two novel ABCB4 mutations in two unrelated children from North Africa and South Asia. METHODS In both children liver histology showed extensive ductular reaction with portal and periportal fibrosis. Immunohistochemical analysis displayed absence of MDR3 protein expression at the canalicular pole. Genotype analysis was performed. RESULTS Genotyping revealed two novel mutations in ABCB4: the c.1783 C>T (p.R595X) mutation in exon 15 was detected in compound heterozygosity with the c.937_992 in/del in exon 9 in one case, whereas the homozygous p.R595X mutation was recognized in the second child. CONCLUSIONS Two novel loss-of-function mutations have been identified. Progressive familial intrahepatic cholestasis type 3 has a worldwide distribution and genetic analyses are conclusive for correct diagnosis.

Hepatic fibrinogen storage disease due to the fibrinogen γ375 Arg → Trp mutation "fibrinogen Aguadilla" is present in Arabs.

The mutation γ375Arg → Trp (fibrinogen Aguadilla) is one of four mutations (Brescia, Aguadilla, Angers, and AI duPont) capable of causing hepatic storage of fibrinogen. It has been observed in four children from the Caribbean, Europe, and Japan, suffering from cryptogenic liver disease. We report the first case of hepatic fibrinogen storage disease in Arabs due to a mutation in the fibrinogen γ-chain gene in a 3-year-old Syrian girl presenting with elevated liver enzymes. The finding of an impressive accumulation of fibrinogen in liver cells raised the suspicion of endoplasmic reticulum storage disease. Sequencing of the fibrinogen genes revealed a γ375Arg → Trp mutation (fibrinogen Aguadilla) in the child and in her father. In conclusion, when confronted with chronic hepatitis of unknown origin, one should check the plasma fibrinogen level and look carefully for the presence of hepatocellular intracytoplasmic globular inclusions to exclude hepatic fibrinogen storage disease.

Alpha‐1‐antitrypsin deficiency: from genoma to liver disease. PiZ mouse as model for the development of liver pathology in human

Homozygous individuals with alpha‐1‐antitrypsin deficiency (AATD) type PiZ have an increased risk of chronic liver disease and hepatocellular carcinoma (HCC). It is noteworthy that HCCs are composed by hepatocytes without accumulation of AAT, but the reason for this remains unclear. The aim of this study was to determine liver pathology in PiZ mice, focusing the attention on the distribution of AAT globules in normal liver, regenerative foci and neoplastic nodules.

Glycogenotic hepatocellular carcinoma with glycogen‐ground‐glass hepatocytes: histological, histochemical and microbiochemical characterization of the novel variant

incidence [47 of 2606 (1.8%)] in our study might be underestimated because (i) selective sampling was used for histological assessment in a subset of RP cases and (ii) the presence of PP ⁄ PSV LNs may not always have been described in the pathology reports. We also found a low rate [six of 2606 (0.2%)] of positive PP ⁄ PSV LNs. Consistent with our results, most of the isolated PP ⁄ PSV LNs in the above three studies were located around the posterior base of the prostate or lower SVs. Indeed, an immunohistochemical study in wholemount cystoprostatectomy specimens showed a significantly higher density of lymphatics in the area around the ejaculatory ducts, suggesting the importance of the mid-base region as a route of metastatic spread of PC to the LNs. In addition to two positive PP LNs at the posterior base, we identified two at the left posterior ⁄ posterolateral apex, where dominant tumour nodules in the prostate were located. Finley et al. showed that 30 [14.7%; 4 (2.0%) with metastasis] of 204 RPs had one or more LNs in the anterior prostatic fat pad that might correspond to anteriorly located PP LNs found in other studies. However, none of the studies have found PP LNs laterally. In the first report assessing PP ⁄ PSV LNs with patients’ follow-up, three of three cases with isolated PP ⁄ PSV LN metastasis and one of two cases with both PP ⁄ PSV and pelvic LN metastases developed recurrences between 3 and 7 months after RP. Based on these findings, it has been suggested that PC with isolated positive PP ⁄ PSV LNs should be considered pN1 disease. Conversely, in our cohort only one of six men with PP ⁄ PSV LN metastasis showed disease progression after RP. In summary, PC metastasis limited to the PP ⁄ PSV LNs can occur. Further studies including larger patient cohorts with longer follow-up are necessary to validate the conflicting findings regarding the prognostic significance of PP ⁄ PSV LN metastasis. Additionally, the difficulty of grossly identifying the PP ⁄ PSV LNs, even in the presence of metastasis (as small as 0.01 cm in a metastatic focus detected by cytokeratin immunostaining), suggests the importance of thorough histological examination of RP specimens.

Paternal isodisomy of chromosome 2 in a child with bile salt export pump deficiency.

We describe a child with progressive familial intrahepatic cholestasis (PFIC) of type 2 inherited as uniparental isodisomy of chromosome 2. Bile salt export pump (BSEP) deficiency is a severe, genetically determined subtype PFIC caused by mutations in ABCB11, the gene encoding a bile salt transporter protein. Clinical and pathological diagnosis in PFIC2 is corroborated by an ample array of ABCB11 mutations, inherited in an autosomal recessive fashion. We report clinical, pathological, and molecular studies in a child with PFIC2. A 5.5‐year‐old boy harbored a described pathogenic mutation (p.R832C) in ABCB11. The mutation was found to be homozygous in the patient and heterozygous in DNA from paternal, but not maternal blood. Having ruled out maternal gene deletion and somatic mosaicism, we showed that the child had inherited an isodisomic paternal chromosome 2, including the 2q31.1 region where ABCB11 is located. The present report is the first description of uniparental isodisomy in a hepatic heritable disorder. Recognizing isodisomic transmission may have a significant impact on genetic counseling helping to define the risk of recurrence in subsequent pregnancies.

The Impact of Specific Viruses on Clinical Outcome in Children Presenting with Acute Heart Failure

The presence and type of viral genomes have been suggested as the main etiology for inflammatory dilated cardiomyopathy. Information on the clinical implication of this finding in a large population of children is lacking. We evaluated the prevalence, type, and clinical impact of specific viral genomes in endomyocardial biopsies (EMB) collected between 2001 and 2013 among 63 children admitted to our hospital for acute heart failure (median age 2.8 years). Viral genome was searched by polymerase chain reaction (PCR). Patients underwent a complete two-dimensional echocardiographic examination at hospital admission and at discharge and were followed-up for 10 years. Twenty-seven adverse events (7 deaths and 20 cardiac transplantations) occurred during the follow-up. Viral genome was amplified in 19/63 biopsies (35%); PVB19 was the most commonly isolated virus. Presence of specific viral genome was associated with a significant recovery in ejection fraction, compared to patients without viral evidence (p < 0.05). In Cox-regression analysis, higher survival rate was related to virus-positive biopsies (p < 0.05). When comparing long-term prognosis among different viral groups, a trend towards better prognosis was observed in the presence of isolated Parvovirus B19 (PVB19) (p = 0.07). In our series, presence of a virus-positive EMB (mainly PVB19) was associated with improvement over time in cardiac function and better long-term prognosis.

Genetics and Molecular Modeling of New Mutations of Familial Intrahepatic Cholestasis in a Single Italian Center

Familial intrahepatic cholestases (FICs) are a heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. Three distinct forms are described: FIC1 and FIC2, associated with low/normal GGT level in serum, which are caused by impaired bile salt secretion due to defects in ATP8B1 encoding the FIC1 protein and defects in ABCB11 encoding bile salt export pump protein, respectively; FIC3, linked to high GGT level, involves impaired biliary phospholipid secretion due to defects in ABCB4, encoding multidrug resistance 3 protein. Different mutations in these genes may cause either a progressive familial intrahepatic cholestasis (PFIC) or a benign recurrent intrahepatic cholestasis (BRIC). For the purposes of the present study we genotyped 27 children with intrahepatic cholestasis, diagnosed on either a clinical or histological basis. Two BRIC, 23 PFIC and 2 BRIC/PFIC were identified. Thirty-four different mutations were found of which 11 were novel. One was a 2Mb deletion (5’UTR- exon 18) in ATP8B1. In another case microsatellite analysis of chromosome 2, including ABCB11, showed uniparental disomy. Two cases were compound heterozygous for BRIC/PFIC2 mutations. Our results highlight the importance of the pathogenic role of novel mutations in the three genes and unusual modes of their transmission.

Naevoid Basal Cell Carcinoma Syndrome in a 22-month-old Child Presenting with Multiple Basal Cell Carcinomas and a Fetal Rhabdomyoma

© 2015 The Authors. doi: 10.2340/00015555-1892 Journal Compilation

Fibrinogen storage disease and cirrhosis associated with hypobetalipoproteinemia owing to fibrinogen Aguadilla in a Turkish child

Fibrinogen gene mutations can rarely result in hepatic fibrinogen storage disease (HFSD). Herein, we report on the first Turkish family carrying the mutation p.Arg375Trp (fibrinogen Aguadilla) in the γ‐chain of the fibrinogen (FGG) gene.

Bile salt export pump deficiency: A de novo mutation in a child compound heterozygous for ABCB11. Laboratory investigation to study pathogenic role and transmission of two novel ABCB11 mutations.

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal disorders. PFIC type 2 is due to mutation in ABCB11, the gene encoding the bile salt export pump (BSEP) protein. The aim of the study was to describe a child with a de novo mutation in a compound heterozygous for ABCB11 gene. We report a 1.7‐year‐old girl who presented with pruritus, jaundice and liver dysfunction of PFIC type 2. Immunohistochemistry and molecular analysis are described. Liver biopsy showed micronodular cirrhosis and immunohistochemical staining for BSEP, the protein encoded by ABCB11, displayed a patchy and faint reactivity. Molecular analysis revealed two novel mutations of ABCB11. We give details that one mutation is transmitted by the mother while the second one appears a de novo mutation as mutations or a potential mosaicism were ruled out in the natural father. We further speculate that the ABCB11 mutations do not prevent BSEP glycoprotein to be expressed at the canalicular pole of hepatocytes, but interfere with its ability to export bile salts. As in most instances, mutational analysis is performed following the histochemical demonstration of an undetectable BSEP on liver biopsy specimen. This case stresses that clinical PFIC with an attenuated rather than absent BSEP immunostaining can still be due to ABCB11 mutations presumably encoding a functionally deficient protein.