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Autosomal dominant polycystic kidney disease (ADPKD) is typically a late-onset disease caused by mutations in PKD1 or PKD2, but about 2% of patients with ADPKD show an early and severe phenotype that can be clinically indistinguishable from autosomal recessive polycystic kidney disease (ARPKD). The high recurrence risk in pedigrees with early and severe PKD strongly suggests a common familial modifying background, but the mechanisms underlying the extensive phenotypic variability observed among affected family members remain unknown. Here, we describe severely affected patients with PKD who carry, in addition to their expected familial germ-line defect, additional mutations in PKD genes, including HNF-1␤, which likely aggravate the phenotype. Our findings are consistent with a common pathogenesis and dosage theory for PKD and may propose a general concept for the modification of disease expression in other so-called monogenic disorders.

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Bonn, Germany) performed 19 fetal endoscopic procedures. Three procedures resulted in fetal death, three procedures were interrupted by iatrogenic hemorrhages and 13 procedures were successful. We matched each successfully treated fSBA infant with another nSBA infant of the same age and level of lesion, resulting in 13 matched pairs (mean age 14mo; SD 16mo; f ⁄ m=1.6; female-16, male-10). Matched fSBA and nSBA pairs were compared in terms of segmental neurological function and leg muscle ultrasound density (MUD). We also determined intraindividual difference in MUD (dMUD) between myotomes caudal and cranial to the myelomeningocele (reflecting neuromuscular damage by the myelomeningocele) and compared dMUD between fSBA and nSBA infants. Finally, we correlated dMUD with segmental neurological function. RESULTSWe found that, on average, the fSBA group were born at a lower gestational age than the nSBA group (median 32wks [range 25-34wks] vs 39wks [34-41wks]; p=0.001) and experienced more complications (chorioamnionitis, premature rupture of the amniotic membranes, oligohydramnios, and infant respiratory distress syndrome necessitating intermittent positive-pressure ventilation). Neurological function was better preserved after fSBA than after nSBA (median motor and sensory gain of two segments; better preserved knee-jerk [p=0.006] and anal [p=0.032] reflexes). The dMUD was smaller in fSBA than in nSBA infants (mean difference 24, 95% confidence interval [CI] 15-33; p<0.05), which was associated with better preserved segmental muscle function.INTERPRETATION Fetal endoscopic surgery is associated with spinal segmental neuroprotection, but it results in more complications. Before considering clinical implementation of fetal endoscopic myelomeningocele closure as standard care, the frequency of complications should be appropriately reduced and results assessed in larger groups over a longer period of time.

SummaryBackground Characterized native and recombinant Hevea brasiliensis (rHev b) natural rubber latex (NRL) allergens are available to assess patient allergen sensitization profiles.Objective Quantification of individual IgE responses to the spectrum of documented NRL allergens and evaluation of cross-reactive carbohydrate determinants (CCDs) for more definitive diagnosis. Methods Sera of 104 healthcare workers (HCW; 51 German, 21 Portuguese, 32 American), 31 spina bifida patients (SB; 11 German, 20 Portuguese) and 10 Portuguese with multiple surgeries (MS) were analysed for allergen-specific IgE antibody (sIgE) to NRL, single Hev b allergens and CCDs with ImmunoCAP TM technology. Results In all patient groups rHev b 5-sIgE concentrations were the most pronounced. Hev b 2, 5, 6.01 and 13 were identified as the major allergens in HCW and combined with Hev b 1 and Hev b 3 in SB. In MS Hev b 1 displayed an intermediate relevance. Different sIgE antibody levels to native Hevea brasiliensis (nHev b) 2 and rHev b 6.01 allowed discrimination of SB with clinical relevant latex allergy vs. those with latex sensitization. Sensitization profiles of German, Portuguese and American patients were equivalent. rHev b 5, 6.01 and nHev b 13 combined detected 100% of the latex-allergic HCW and 80.1% of the SB. Only 8.3% of the sera showed sIgE response to CCDs. Conclusions Hev b 1, 2, 5, 6.01 and 13 were identified as the major Hev b allergens and they should be present in standardized latex extracts and in vitro allergosorbents. CCDs are only of minor relevance in patients with clinical relevant latex allergy. Component-resolved diagnostic analyses for latex allergy set the stage for an allergen-directed immunotherapy strategy.

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Type 1 allergy against natural rubber latex is an increasing problem in health care workers and children with spina bi®da or urogenital malformations. The aim of our study was to evaluate the prevalence of latex IgE antibodies and cross-reacting fruit antibodies in patients with spina bi®da compared with atopic and non-atopic controls. Risk factors for sensitization should be determined. Sera of 148 patients with spina bi®da and 98 controls (44 with atopy) were screened for IgE antibodies against latex, banana and kiwi by¯uorescence enzyme immunoassay (CAP system). Atopies, allergic symptoms after latex contacts and the number of operations were compiled by a questionnaire. Patients with spina bi®da developed latex IgE antibodies (!0.7 kU/l) more frequently (40.5%) than atopic children (11.4%) or healthy controls (1.9%). All 18 symptomatic patients belonged to the spina bi®da group and had high values of latex antibodies. The risk for developing latex antibodies increases with the number of operations. There was no dierence in the history of atopic diseases and in a screening test of IgE antibodies against inhalative allergens between latex sensitized and not sensitized children with spina bi®da. Antibodies against banana were more frequent in the latex sensitized children with spina bi®da. (18.3% vs 3.4%, P = 0.002). Conclusion The high prevalence of latex antibodies in children with spina bi®da justi®es a primary prophylaxis by avoiding latex contacts, especially during anaesthesia and surgery, a correlation between the number of operations and the development of latex antibodies exists.