Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility.

Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function.

Genetic Enteropathies Linked to Epithelial Structural Abnormalities and Enteroendocrine Deficiency: A Systematic Review.

OBJECTIVES: Congenital diarrhea and enteropathies linked to epithelial structural abnormalities constitute 3 different rare diseases: the tufting enteropathies (TE; EPCAM and SPINT2 mutations), microvillous inclusion disease (MVID; MYO5B and STX3 mutations), and tricho-hepato-enteric syndrome (THE; TTC37 and SKIV2L mutations). Moreover, enteroendocrine deficiencies (ED; PCSK1 and NEUROG3 mutations) share common clinical characteristics with TE, THE, and MVID in that the treatment requires, in most cases, long-term parenteral nutrition. Although numerous cases have been reported in the literature, aggregated data on morbidity and mortality are missing owing to the rarity of the diseases. METHODS: We performed a systematic review of all published cases and retrieved 86 articles describing 323 patients (164 boys and 135 girls). RESULTS: The mortality rate was 20.28%, with a median age at death of 13.5 months (range 0-228 months); the mortality risk was 30.8/1000 person-year; in half of the cases, death was caused by infections. Parenteral nutrition was required in 95.4% of patients and weaning off from parenteral nutrition was achieved in 29.35% at a median age of 23 months (range 3.3-276 months). The patients with ED linked to PCSK1 were nearly all weaned at a median age of 14 months, but most of the patients became overweight. MVID patients with MYO5B mutations were most often born preterm. ED linked to NEUROG3 mutation and THE patients usually presented with intrauterine growth retardation. CONCLUSIONS: This review presents data from 323 patients with congenital diarrhea linked to EPCAM TE, SPINT2 TE, TTC37 THE, SKIV2L THE, MYO5B MVID, STX3 MVID, NEUROG3 ED, and PCSK1 ED mutations.

Genetic contribution of ABCC2 to Dubin-Johnson syndrome and inherited cholestatic disorders.

BACKGROUND AND AIMS: The ABCC2 gene is implicated in Dubin-Johnson syndrome (DJS), a rare autosomal recessive liver disorder. The primary aim of this study was to determine the diagnostic value of ABCC2 genetic testing in the largest cohort of DJS reported to date. The high number of patients with cholestatic manifestations in this series prompted us to evaluate the genetic contribution of rare, potentially pathogenic ABCC2 variants to other inherited cholestatic disorders. METHODS: The cohort study included 32 patients with clinical DJS diagnosis, and 372 patients referred for the following disorders: low phospholipid-associated cholelithiasis (LPAC) syndrome, intrahepatic cholestasis of pregnancy (ICP) and benign recurrent intrahepatic cholestasis (BRIC). ABCC2 was screened by next-generation sequencing. RESULTS: Most patients with clinical DJS had positive genetic diagnosis (n = 30; 94%), with a great diversity of point mutations and copy number variations in ABCC2. Strikingly, eight (27%) of these patients showed transient cholestatic features at presentation: four neonatal cholestasis, two ICP, one contraceptive-induced cholestasis and one sporadic cholestasis. Conversely, the frequency of rare, heterozygous, potentially pathogenic ABCC2 variants in patients with LPAC, ICP or BRIC did not differ significantly from that of the general population. CONCLUSIONS: This large series reveals that DJS is a highly homogeneous Mendelian disorder involving a large spectrum of ABCC2 variants. Genetic testing is crucial to establish early DJS diagnosis in patients with atypical presentations, such as neonatal cholestasis. This study also provides no evidence for the contribution of rare, potentially pathogenic ABCC2 variants to other inherited cholestatic disorders.

Management of Biliary Atresia in France 1986 to 2015: Long-term Results.

OBJECTIVES: This study analyses the prognosis of biliary atresia (BA) in France since 1986, when both Kasai operation (KOp) and liver transplantation (LT) became widely available. METHODS: The charts of all patients diagnosed with BA born between 1986 and 2015 and living in France were reviewed. RESULTS: A total of 1428 patients were included; 1340 (94%) underwent KOp. Total clearance of jaundice (total bilirubin ≤20 µmol/L) was documented in 516 patients (39%). Age at KOp (median 59 days, range 6-199) was stable over time. Survival with native liver after KOp was 41%, 35%, 26%, and 22% at 5, 10, 20, and 30 years, stable in the 4 cohorts. 25-year survival with native liver was 38%, 27%, 22%, and 19% in patients operated in the first, second, third month of life or later, respectively (P = 0.0001). Center caseloads had a significant impact on results in the 1986 to 1996 cohort only. 16%, 7%, 7%, and 8% of patients died without LT in the 4 cohorts (P = 0.0001). A total of 753 patients (55%) underwent LT. Patient survival after LT was 79% at 28 years. Five-year patient survival after LT was 76%, 91%, 88%, and 92% in cohorts 1 to 4, respectively (P < 0.0001). Actual BA patient survival (from diagnosis) was 81%. Five-year BA patient survival was 72%, 88%, 87%, and 87% in cohorts 1986 to 1996, 1997 to 2002, 2003 to 2009, and 2010 to 2015, respectively (P < 0.0001). CONCLUSIONS: In France, 87% of patients with BA survive nowadays and 22% reach the age of 30 years without transplantation. Improvement of BA prognosis is mainly due to reduced mortality before LT and better outcomes after LT.

SKIV2L mutations cause syndromic diarrhea, or trichohepatoenteric syndrome.

Syndromic diarrhea (or trichohepatoenteric syndrome) is a rare congenital bowel disorder characterized by intractable diarrhea and woolly hair, and it has recently been associated with mutations in TTC37. Although databases report TTC37 as being the human ortholog of Ski3p, one of the yeast Ski-complex cofactors, this lead was not investigated in initial studies. The Ski complex is a multiprotein complex required for exosome-mediated RNA surveillance, including the regulation of normal mRNA and the decay of nonfunctional mRNA. Considering the fact that TTC37 is homologous to Ski3p, we explored a gene encoding another Ski-complex cofactor, SKIV2L, in six individuals presenting with typical syndromic diarrhea without variation in TTC37. We identified mutations in all six individuals. Our results show that mutations in genes encoding cofactors of the human Ski complex cause syndromic diarrhea, establishing a link between defects of the human exosome complex and a Mendelian disease.

A prospective pilot study: can the biliary tree be visualized in children younger than 3 months on Magnetic Resonance Cholangiopancreatography?

BACKGROUND: Magnetic resonance cholangiopancreatography (MRCP) could aid in the diagnosis of biliary atresia, a hepatic pathology with thin, irregular or interrupted biliary ducts. There is little published evidence of MRCP appearances in normal neonates and young infants. OBJECTIVE: To assess the use of MR cholangiopancreatography in visualizing the biliary tree in neonates and infants younger than 3 months with no hepatobiliary disorder, and to assess this visibility in relationship to the child's age, weight, and sedation and fasting states. MATERIALS AND METHODS: Between December 2008 and October 2010 our department performed MRI of the brain, orbits and face on 16 full-term neonates and infants. Each child was younger than 3 months (90 days) and without any hepatobiliary disorders. The children were scanned with a respiratory-gated 0.54 × 0.51 × 0.4-mm(3) 3-D MRCP sequence. We used a reading grid to assess subjectively the visibility of the extrahepatic bile ducts along with extrahepatic bile duct confluence. The visibility of the extrahepatic bile duct confluence was assessed against age, weight, and sedation and fasting states. RESULTS: The extrahepatic bile duct confluence was seen in 10 children out of 16 (62.5%). In the neonate sub-group (corrected age younger than 30 days), the MRCP was technically workable and the extrahepatic bile duct confluence was seen in four cases out of eight (50%). This visualization was up to 75% in the subgroup older than 30 days. However, statistically there was no significant difference in visibility of the extrahepatic bile duct confluence in relationship to age, weight or MRCP performance conditions (feeding, fasting or sedation). CONCLUSION: The complete normal biliary system (extrahepatic bile duct confluence included) is not consistently visualized in infants younger than 3 months old on non-enhanced MRCP. Thus the use of MRCP to exclude a diagnosis of biliary atresia is compromised at optimal time of surgery.

Quality of life of chronically ill children and adolescents: a cross-sectional study.

OBJECTIVE: The aim of this study was to describe the quality of life (QoL) of children with a chronic illness treated in a tertiary multidisciplinary pediatric department in comparison with the general population. STUDY DESIGN: A cross-sectional study was conducted in the tertiary multidisciplinary (nephrology, hepatogastroenterology, endocrinology, diabetology, transplantation) pediatric department of Timone Hospital in Marseille, France. Patients 8-17 years of age with a chronic disease were included during regular follow-up appointments. Medical and sociodemographic variables were obtained from medical records. Self-reported QoL was assessed using the VSPA (Vécu et Santé Perçu de l'Adolescent) questionnaire and parent-reported QoL was assessed using the VSPA questionnaire for parents. RESULTS: A total of 244 patients were included. Overall QoL did not differ significantly from that of the general population. Adolescent patients' self-reported QoL scores were lower than those of the general population in the domains of physical health and leisure, and parents reported QoL scores for adolescent patients lower than those of the general population for self-esteem and physical health. Adolescents' self-reported QoL scores were higher than in the general population for relationships with parents, healthcare professionals, and teachers as well as for school achievement. Parents also reported higher QoL scores in these areas for their children. CONCLUSION: Children and adolescents with a variety of chronic diseases had similar overall QoL scores to the general population but with different QoL profiles; their scores in some domains were higher than those of the general population.

Improving outcomes of biliary atresia: French national series 1986-2009.

BACKGROUND & AIMS: This study analyses the prognosis of biliary atresia (BA) in France since liver transplantation (LT) became widely available. METHODS: The charts of all BA patients living in France and born between 1986 and 2009 were reviewed. Patients were divided into 3 cohorts according to their years of birth: 1986-1996, 1997-2002, and 2003-2009. RESULTS: 1107 BA children were identified, 990 born in metropolitan France (incidence 1/18,400 live births). Kasai operation was performed in 1044 (94%), leading to complete clearance of jaundice (total serum bilirubin ≤ 20 µmol/L) in 38% of patients. Survival with native liver (SNL) after Kasai operation was 40%, 36%, and 30% at 5, 10, and 20 years, stable in the 3 cohorts. Median age at Kasai operation was 59 days, unchanged over time. Twenty-year SNL was 39%, 32%, 28%, and 19% after Kasai operation performed in the first, second, third months of life or thereafter (p=0.0002). 588 children underwent 692 LTs. Mortality without transplantation decreased over time: 16%, 7%, and 4% in the 3 cohorts (p<0.0001). Survival after transplantation was 83%, 82%, and 77% at 5, 10, and 20 years in the whole series. Five-year post-transplant survival was 75%, 90%, and 89% in the 3 cohorts (p<0.0001). In the whole series, overall BA patient survival was 81%, 80%, and 77% at 5, 10, and 20 years. Five-year BA patient overall survival increased over time: 72%, 88%, and 89% in the 3 cohorts (p<0.0001). CONCLUSIONS: BA patients currently have an 89% live expectancy, and a 30% chance to reach adulthood without transplantation. Early Kasai operation, without age threshold, reduces the need for liver transplantation until adulthood.

Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis.

Background & Aims: PEDFIC 2, an ongoing, open-label, 72-week study, evaluates odevixibat, an ileal bile acid transporter inhibitor, in patients with progressive familial intrahepatic cholestasis. Methods: PEDFIC 2 enrolled and dosed 69 patients across two cohorts; all received odevixibat 120 µg/kg per day. Cohort 1 comprised children from PEDFIC 1, and cohort 2 comprised new patients (any age). We report data through 15 July 2020, with Week 24 of PEDFIC 2 the main time point analysed. This represents up to 48 weeks of cumulative exposure for patients treated with odevixibat from the 24-week PEDFIC 1 study (cohort 1A) and up to 24 weeks of treatment for those who initiated odevixibat in PEDFIC 2 (patients who received placebo in PEDFIC 1 [cohort 1B] or cohort 2 patients). Primary endpoints for this prespecified interim analysis were change from baseline to Weeks 22-24 in serum bile acids (sBAs) and proportion of positive pruritus assessments (≥1-point drop from PEDFIC 2 baseline in pruritus on a 0-4 scale or score ≤1) over the 24-week period. Safety monitoring included evaluating treatment-emergent adverse events (TEAEs). Results: In cohort 1A, mean change from PEDFIC 1 baseline to Weeks 22-24 of PEDFIC 2 in sBAs was -201 µmol/L (p <0.0001). For cohort 1B and cohort 2, mean changes from odevixibat initiation to weeks 22-24 in sBAs were -144 and -104 µmol/L, respectively. The proportion of positive pruritus assessments in the first 24-week period of PEDFIC 2 was 33%, 56%, and 62% in cohorts 1A, 1B, and 2, respectively. Most TEAEs were mild or moderate. No drug-related serious TEAEs occurred. Conclusions: Odevixibat in patients with progressive familial intrahepatic cholestasis was generally well tolerated and associated with sustained reductions in sBAs and pruritus. Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT03659916). Impact and Implications: Disrupted bile flow is a hallmark feature of patients with progressive familial intrahepatic cholestasis and can result in build-up of bile constituents in the liver with spill over into the bloodstream; other effects that patients can experience include extremely itchy skin, and because not enough bile reaches the gut, patients can have problems digesting food, which may lead to poor growth. Odevixibat is an orally administered medication that shunts bile acids away from the liver. The current study, called PEDFIC 2, suggested that odevixibat can improve the problematic signs and symptoms of progressive familial intrahepatic cholestasis and was generally safe for patients.

Partial splenectomy in children undergoing liver transplantation or venous shunt for severe hypersplenism: A case control comparative study.

BACKGROUND AND AIM: Hypersplenism is a consequence of portal hypertension and splenomegaly secondary to cirrhosis or portal cavernoma in children. In order to avoid persistent hypersplenism and splenomegaly after liver transplantation (LT) or venous shunt (VS), partial splenectomy (PS) may represent a relevant therapeutic option. The aim of this retrospective study was to evaluate the results of PS performed in children presenting hypersplenism. METHODS: The following end-points were evaluated: (1) reversion of hypersplenism and its durability over time, (2) postoperative outcome, (3) courses of spleen size and volume and (4) comparison to a control group in which PS was not performed. RESULTS: Between 1996 and 2020, 16 children underwent PS associated with LT (8 cases) for cirrhosis or VS (8 cases) for portal cavernoma. From Day 0 to 1 month, mean platelet and white blood cell counts (WBC) dramatically improved from 48 ±â€¯19 at day 0 to 176 ±â€¯70 × 109/L (P < 0.0001) and from 2469 ±â€¯853 to 7198 ±â€¯3982/L (P = 0.001) respectively. PS allowed significant reduction of splenic length and volume from 176 ±â€¯33 to 112 ±â€¯24 cm (P < 0.0001) and from 1228 ±â€¯464 to 450 ±â€¯297 cm3 (P = 0.0003) respectively. After a mean follow-up of 92.6 ±â€¯84.7 months (range: 4.1-210.7), 14 patients are alive with normal platelet and WBC counts and persistent spleen size reduction. Compared to control group, PS was associated with a significant platelet count rise from baseline to one year. CONCLUSIONS: PS appears to be effective for treatment of hypersplenism and splenomegaly in combination with LT or VS without compromising outcome.

Targeted-Capture Next-Generation Sequencing in Diagnosis Approach of Pediatric Cholestasis.

BACKGROUND: Cholestasis is a frequent and severe condition during childhood. Genetic cholestatic diseases represent up to 25% of pediatric cholestasis. Molecular analysis by targeted-capture next generation sequencing (NGS) has recently emerged as an efficient diagnostic tool. The objective of this study is to evaluate the use of NGS in children with cholestasis. METHODS: Children presenting cholestasis were included between 2015 and 2020. Molecular sequencing was performed by targeted capture of a panel of 34 genes involved in cholestasis and jaundice. Patients were classified into three categories: certain diagnosis; suggested diagnosis (when genotype was consistent with phenotype for conditions without any available OMIM or ORPHANET-number); uncertain diagnosis (when clinical and para-clinical findings were not consistent enough with molecular findings). RESULTS: A certain diagnosis was established in 169 patients among the 602 included (28.1%). Molecular studies led to a suggested diagnosis in 40 patients (6.6%) and to an uncertain diagnosis in 21 patients (3.5%). In 372 children (61.7%), no molecular defect was identified. CONCLUSIONS: NGS is a useful diagnostic tool in pediatric cholestasis, providing a certain diagnosis in 28.1% of the patients included in this study. In the remaining patients, especially those with variants of uncertain significance, the imputability of the variants requires further investigations.

Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of inherited paediatric liver diseases resulting from mutations in genes that impact bile secretion. We aimed to evaluate the effects of odevixibat, an ileal bile acid transporter inhibitor, versus placebo in children with PFIC. METHODS: Patients eligible for this 24-week, randomised, double-blind, completed, phase 3 study were paediatric outpatients diagnosed with PFIC1 or PFIC2 who had pruritus and elevated serum bile acids at screening. Patients were randomly assigned (1:1:1) using an interactive web-based system to once a day oral placebo, odevixibat 40 µg/kg, or odevixibat 120 µg/kg. Randomisation was done in a block size of six and stratified by PFIC type and patient age; patients, clinicians, and study staff were blinded to treatment allocation. Patients were enrolled at one of 33 global sites. Two primary endpoints were evaluated: proportion of positive pruritus assessments (PPAs; ie, scratching score of ≤1 or ≥1-point decrease as assessed by caregivers using the Albireo observer-reported outcome [ObsRO] PRUCISION instrument) over 24 weeks, and proportion of patients with serum bile acid response (ie, serum bile acids reduced by ≥70% from baseline or concentrations of ≤70 µmol/L) at week 24. Efficacy and safety were analysed in randomly allocated patients who received one or more doses of study drug. This study is registered with ClinicalTrials.gov, NCT03566238. FINDINGS: Between June 21, 2018, and Feb 10, 2020, 62 patients (median age 3·2 [range 0·5-15·9] years) were randomly allocated to placebo (n=20), odevixibat 40 µg/kg per day (n=23), or odevixibat 120 µg/kg per day (n=19). Model-adjusted (least squares) mean proportion of PPAs was significantly higher with odevixibat versus placebo (55% [SE 8] in the combined odevixibat group [58% in the 40 µg/kg per day group and 52% in the 120 µg/kg per day group] vs 30% [SE 9] in the placebo group; model-adjusted mean difference 25·0% [95% CI 8·5-41·5]; p=0·0038). The percentage of patients with serum bile acid response was also significantly higher with odevixibat versus placebo (14 [33%] of 42 patients in the combined odevixibat group [10 in the 40 µg/kg per day group and four in the 120 µg/kg per day group] vs none of 20 in the placebo group; adjusting for stratification factor [PFIC type], the proportion difference was 30·7% [95% CI 12·6-48·8; p=0·0030]). The most common treatment-emergent adverse events (TEAEs) were diarrhoea or frequent bowel movements (13 [31%] of 42 for odevixibat vs two [10%] of 20 for placebo) and fever (12 [29%] of 42 vs five [25%] of 20); serious TEAEs occurred in three (7%) of 42 odevixibat-treated patients and in five (25%) of 20 placebo-treated patients. INTERPRETATION: In children with PFIC, odevixibat effectively reduced pruritus and serum bile acids versus placebo and was generally well tolerated. Odevixibat, administered as once a day oral capsules, is a non-surgical, pharmacological option to interrupt the enterohepatic circulation in patients with PFIC. FUNDING: Albireo Pharma.

Novel mutations in TTC37 associated with tricho-hepato-enteric syndrome.

The Tricho-Hepato-Enteric (THE) syndrome is an autosomal recessive condition marked by early and intractable diarrhea, hair abnormalities, and immune defects. Mutations in TTC37, which encodes the putative protein Thespin, have recently been associated with THE syndrome. In this article, we extend the pattern of TTC37 mutations by the description of 11 novel mutations in 9 patients with a typical THE syndrome. The mutations were spread along the gene sequence, none of themrecurrent. Different types of mutation were observed: frameshift mutations, splice-site altering mutations, or missense mutations, most of them leading to the creation of a premature stop codon. Concurrently, we investigated the pattern of TTC37 expression in a panel of normal human tissues and showed that this gene is widely expressed, with high levels in vascular tissues, lymph node, pituitary, lung, and intestine. In contrast, TTC37 is not expressed in the liver, an organ that is not consistently affected in THE syndrome. Last, we suggested a model for the putative structure of the unknown Thespin protein.

Quality of life of transplanted children and their parents: a cross-sectional study.

BACKGROUND: Transplantation is a saving therapeutic that has heavy consequences. The quality of life (QoL) of transplanted children and their parents has been little studied and should help physicians better manage these patients. The objectives of the study were to assess: (1) the QoL of transplanted children and parents and compare it with that of children with other chronic conditions associated with long-term consequences, and (2) potential variables modulating the QoL. METHODS: This cross-sectional study was performed in a multidisciplinary paediatric unit (Timone Hospital, Marseille, France). Children were less than 18 years old; had a liver, kidney or heart transplant; and had a time since transplantation of 1-10 years. Socio-demographics and clinical data were recorded from medical forms. The QoL was assessed using the VSP-A (Vécu et Santé Perçue de l'Adolescent et de l'Enfant) and the WhoQoL self-reported questionnaires. RESULTS: Forty-five families were included (response rate: 76%). The transplanted organs were the liver for 20 children, the kidney for 15 children, and the heart for 10 children. The QoL of transplanted children reported by their parents was better than that of children with inborn errors of metabolism and similar to that of childhood leukaemia survivors. The QoL of parents of transplanted children was better than that of parents of children with inborn errors of metabolism and did not differ from French norms. The QoL did not differ according to the nature of the transplanted organ, sex or the main sociodemographic data. The main modulators decreasing QoL were residual treatment level, medications switch and the presence of another regular treatment. CONCLUSION: Transplanted children and their families reported a fairly preserved QoL compared to children with other chronic health conditions. Special attention should be given to QoL modulators related to therapeutic management (medication switches, regular treatments) that might be amenable to improve the QoL. Trial registration Ethics committee of Aix-Marseille University, France (reference number: 2014-08-04-03, 24/4/2015; https://www.univ-amu.fr/fr/public/comite-dethique ).

Chronic inflammatory diseases of the bowel: diagnosis and follow-up.

Approximately one fourth of cases of inflammatory bowel disease (IBD) occur during childhood and children are more prone than their adult counterparts to have severe disease at presentation. To investigate these diseases MR imaging is no longer an emerging tool. Numerous reviews and articles have been published on this topic underlying the advances of imaging but also the complexity and the financial impact on management of such diseases. In children it seems reasonable to consider US as the first imaging examination to perform, especially when the diagnosis of IBD is unknown. However, we believe that recent and future technical progress, especially the ability of MR to display reproducible data, and the need for gold standard evaluation of new medical therapies will increase the role of MR enterography.

Child with liver transplant recovers from COVID-19 infection. A case report.

We present the case of a 55-month-old girl who recovered from coronavirus disease 2019 (COVID-19) infection 5 months after undergoing liver transplantation; she had a co-infection with Epstein-Barr virus (EBV). To the best of our knowledge, this is the first case report of a COVID-19 infection in a pediatric patient with liver transplantation. Additionally, this is also the first report of confirmed co-infection between COVID-19 and EBV. On the basis of this case, we suggest that liver transplantation is not associated with COVID-19 symptom severity and development. Moreover, COVID-19 and EBV co-infections do not seem to aggravate the clinical outcome.

Exclusion of EGFR, HRAS, DSP, JUP, CTNNB1, PLEC1, and EPPK1 as functional candidate genes in 7 families with syndromic diarrhoea.

Syndromic diarrhoea (SD) is a rare disease associating intractable diarrhoea and hair abnormalities. In an attempt to identify the gene causative for SD, we studied several functional candidate genes, based on their implication in overlapping phenotypes in mice (EGFR) or in humans (HRAS, JUP, DSP EPPK1, PLEC1, and CTNNB1) in 8 patients affected by SD. Except for EGFR and HRAS, all selected genes encode for cell adhesion proteins. Using direct sequencing or linkage analysis, we excluded all of the candidate genes as the disease-causing gene in our group of patients; however, the hypothesis of intercellular junctions defect in SD remains seductive.

Chronic hepatitis associated with antiribosomal-P autoantibodies in a 14-year-old girl.

We reported the first pediatric case of auto-immune hepatitis with positive anti-P antibodies. On the basis of our findings, adding auto anti-P screening in pediatric seronegative HAI may be recommended.

Somatic mutation, a cause of biliary atresia: A hypothesis.

Despite many years of research, the causes of biliary atresia still remain elusive. Infection, immune disorder, toxins or maternal microchimerism have been cited as potential triggers of biliary atresia. This is a rare disease with a stable incidence over the years although with sizeable ethnic variations. This stability suggests that environmental factors have in fact only a slight influence. During the search for etiologies, twin studies have often helped disentangle the genetic from the environmental. For this condition, twin studies have mainly demonstrated a lack of concordance between twins (either monozygotic or dizygotic), ruling out Mendelian, infectious or toxic causes. Indeed, for toxic or infectious embryopathy, the concordance for twins (especially monozygotic) is about 80%. Paradoxically, these data suggest that biliary atresia has neither a genetic nor an environmental cause. One way of severing the Gordian knot is to hypothesize a role for post zygotic somatic mutation, leading to genetic mosaicism (as a cause of biliary atresia). In recent years, post zygotic mutation has been identified as a cause of non-cancerous disease ranging from dysmorphic syndrome to specific organ abnormalities. A potential model for this condition could be post zygotic mutation or copy number variations in genes or regulatory regions, triggering the cascade of events leading to inflammatory and obliterative cholangiopathy. These events could be enhanced by genetic susceptibility explaining the ethnic variations. In these models, the rate of mosaicism in different parts of the liver could explain the success rate of the Kasai procedure. This hypothesis can be tested: as most children with biliary atresia are eligible for the Kasai procedure, genetic material from the liver and ductal plate can be collected easily. If the hypothesis is correct, whole genome sequencing or copy number variation studies at individual cell level should allow to identify the expected low level of genetic mosaicism. Thus, we hypothesize that postzygotic somatic mutation may play a part in the physiopathology of biliary atresia.