Familial Cholestatic Syndromes

The term ‘familial’ is an unfortunate one. Although the definition includes ‘hereditary’, the inference is that it will usually have occurred in other family members. For many of the conditions described in this article this is often not the case, and for this reason, ‘familial’ conditions may be overlooked when reaching a diagnosis. Cholestasis is defined differently by clinicians, pathologists and biochemists. In addition, what is meant by cholestatic liver disease very often varies for paediatricians and adult hepatologists. However, the pathogenic mechanisms are increasingly similar. Biliary atresia, which is the most frequent cholestatic liver disease presenting to paediatricians, is strikingly different from most diseases as there appears to be no ‘late-onset’ equivalent and it is almost never familial. Several international collaborations have now been established in the hope of overcoming these hurdles (http://www.barcnetwork.org/, http://www.orpha. net/nestasso/EFBAR/, http://www.biliary-atresia.com/index_ frameset_ebar.html). On a day-to-day basis, paediatric hepatologists are faced with a group of infants with jaundice in whom the cause is not readily apparent. In many ways, this Richard Thompson Institute of Liver Studies King’s College Hospital Denmark Hill, London SE5 9RS (UK) E-Mail [email protected] © 2008 Nestec Ltd., Vevey/S. Karger AG, Basel 0517–8606/08/0663–0121$24.50/0 Accessible online at: www.karger.com/ane Thompson Ann Nestlé [Engl] 2008;66:121–126 122 Alagille Syndrome Alagille syndrome has always been a clinical diagnosis. In most cases, genetics would not be needed to diagnose an individual patient. Mutations were first identified in JAGGED1, which encodes a ligand in the Notch signalling pathway [5, 6] . Subsequently, in other patients, mutations have been identified in the gene encoding one of the Notch receptors, NOTCH2 [7] . All in all, mutations have only been found on a single allele of the gene in question. One presumes that a loss of both alleles would be lethal, and certainly the mouse data would support this [8] . It is now clear that a genetic diagnosis can be arrived at in the vast majority of such individuals [9] . In many ways, this has only complicated things, particularly, as all published data concerning the frequency of different features and, more importantly, outcome data relate to patients diagnosed clinically. Although most patients have an identifiable genetic ‘cause’, it has long been known that family members can have similar, though milder, features. It is now clear that these relatives often share the same genetic abnormality. By no stretch of imagination could these individuals be said to have Alagille syndrome. This problem is all the greater when realising that in the general population, we have no idea of the frequency of mutations in the genes involved. Therefore, the diagnosis should probably remain a clinical one, until the true penetrance of mutations is established and the mechanisms that determine the phenotype are understood. Arthrogryposis, Renal Dysfunction and Cholestasis