Mendelian tumour syndromes are caused by rare mutations, which usually lead to protein inactivation. Few studies have determined whether or not the same genes harbour other, more common variants, which might have a lower penetrance and/or cause mild disease, perhaps indistinguishable from sporadic disease and accounting for a considerable proportion of the unexplained inherited risk of tumours in the general population. Germline variants at the APC locus are excellent candidates for explaining why some individuals are predisposed to colorectal adenomas, but do not have the florid phenotype of familial adenomatous polyposis. We have screened 164 unrelated patients with 'multiple' (3-100) colorectal adenomas for germline variants throughout the APC gene, including promoter mutations. In addition to three Ashkenazi patients with I1307K, we found seven patients with the E1317Q variant. E1317Q is significantly associated with multiple colorectal adenomas (OR = 11. 17, 95% CI = 2.30-54.3, p < 0.001), accounting for approximately 4% of all patients with multiple colorectal adenomas. In addition, four patients with truncating APC variants in exon 9 or in the 3' part of the gene were identified. Germline APC variants account for approximately 10% of patients with multiple adenomas. Unidentified predisposition genes almost certainly exist. We argue that it is worthwhile to screen multiple adenoma patients for a restricted number of germline APC variants, namely the missense changes E1317Q and I1307K (if of Ashkenazi descent), and, if there is a family history of colorectal tumours, for truncating mutations 5' to exon 5, in exon 9 and 3' to codon 1580.

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Summary Several cohort studies have investigated the molecular basis of von Willebrand disease (VWD); however these have mostly focused on European and North American populations. This study aimed to investigate mutation spectrum in 26 index cases (IC) from Turkey diagnosed with all three VWD types, the majority (73%) with parents who were knowingly related. IC were screened for mutations using multiplex ligation-dependent probe amplification and analysis of all von Willebrand factor gene (VWF) exons and exon/intron boundaries. Selected missense mutations were expressed in vitro. Candidate VWF mutations were identified in 25 of 26 IC and included propeptide missense mutations in four IC (two resulting in type 1 and two in recessive 2A), all influencing VWF expression in vitro. Four missense mutations, a nonsense mutation and a small in-frame insertion resulting in type 2A were also identified. Of 15 type 3 VWD IC, 13 were homozygous and two compound heterozygous for 14 candidate mutations predicted to result in lack of expression and two propeptide missense changes. Identification of intronic breakpoints of an exon 17–18 deletion suggested that the mutation resulted from non-homologous end joining. This study provides further insight into the pathogenesis of VWD in a population with a high degree of consanguineous partnerships.

Zusammenfassung Die Hormonbestimmung aus dem Speichel bietet einige Vorteile gegen?ber der aus dem Blut: Im Speichel kann die Konzentration der freien, biologisch aktiven Hormone gemessen werden, im Blut sind die Steroidhormone zum Gro?teil inaktiv. Der Beitrag erl?utert am Beispiel der Steroidhormone was bei der Speicheldiagnostik zu beachten ist, um zu aussagef?higen Resultaten zu gelangen. F?r Cortisol, DHEA und Melatonin werden ausgehend von deren Bedeutung f?r den Organismus Hinweise zur Bestimmung gegeben sowie ein Ausblick auf therapeutische Optionen bei auff?lligen Hormonbefunden. Die Erl?uterung zweier Beispielbefunde zeigt das Vorgehen in der Praxis.

ZusammenfassungBei vielen chronischen Erkrankungen werden Veränderungen der Darmmikrobiota als ätiologischer Mit-Faktor diskutiert. Doch was haben beispielsweise rheumatoide Arthritis und Diabetes mit dem Darm zu tun? Nach derzeitiger Erkenntnislage scheinen Barrierestörungen (Leaky Gut) mit daraus resultierenden, latenten chronischen Entzündungen der Schlüssel zu sein. Entsprechend wichtig sind die frühzeitige Erkennung und Behandlung solcher vom Darm ausgehenden „silent“ oder „low-grade inflammations“.