Reinhold Cremer

Mutations in Multiple PKD Genes May Explain Early and Severe Polycystic Kidney Disease

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-1β, 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.

Diagnostic approach to the hyper-IgE syndromes: Immunologic and clinical key findings to differentiate hyper-IgE syndromes from atopic dermatitis

BACKGROUND Hyper-IgE syndromes (HIES) are primary immunodeficiency disorders characterized by Staphylococcus aureus abscesses, recurrent pneumonia, increased serum IgE levels, and eczema. The association of heterozygous signal transducer and activator of transcription 3 (STAT3) mutations with autosomal dominant (AD)-HIES allows the differentiation of AD-HIES from disorders associated with eczema and increased serum IgE levels, such as other primary immunodeficiencies and atopic dermatitis. OBJECTIVE To facilitate early diagnosis of AD-HIES to initiate appropriate therapy. METHODS The clinical phenotype (suggested by a National Institutes of Health [NIH] score of >or=40 points), STAT3 genotype, and T(H)17 cell counts were compared in a cohort of 78 patients suspected of having HIES. RESULTS Heterozygous STAT3 missense mutations and in-frame deletions were identified in 48 patients, all but 2 with an NIH score >or=40 points. Patients with STAT3 mutations with HIES showed significantly lower T(H)17 cell counts compared with patients with wild-type STAT3 and control subjects. Only 1 patient with wild-type STAT3 had both an NIH score >or=40 points and abnormal T(H)17 cell counts (<or=0.2% of CD4(+) cells), with this exception being identified with a homozygous dedicator of cytogenesis 8 protein (DOCK8) mutation. Pathologic shedding of primary teeth was present in 3 patients with wild-type STAT3 and 33 patients with STAT3 mutations. Internal abscesses and severe infections were exclusively seen in patients with STAT3 mutations, who also had increased pneumatocele formation and skeletal or connective tissue manifestations compared with patients with wild-type STAT3. CONCLUSION We expanded the number of STAT3 mutations and validated that the NIH score sensitively identifies patients with HIES. Based on our patient cohort, we propose key findings that, when combined with T(H)17 cell numbers, predict patients with AD-HIES with STAT3 mutations, supporting early diagnosis of AD-HIES.

On the allergenicity of Hev b 1 among health care workers and patients with spina bifida allergic to natural rubber latex

BACKGROUND Recent studies have caused much controversy about the prevalence of IgE antibodies to Hev b 1 among health care workers (HCWs) and patients with spina bifida (SB) who are allergic to latex. This investigation was carried out to verify the results reported. METHOD Serum samples from 140 patients with SB as well as from 105 HCWs allergic to latex were tested by enzyme allergosorbest test (EAST) and EAST-inhibition assay to evaluate the rate and degree of sensitization to highly purified Hev b 1. RESULTS Eighty-one percent of patients with SB who were allergic to latex had IgE antibodies against Hev b 1. The prevalence of anti-Hev b 1 antibodies among HCWs allergic to latex was 52.3%. In 15 of 33 serum samples from patients with SB that were randomly tested, the IgE binding to commercial latex allergens could be completely inhibited by Hev b 1; in only six cases was the maximum inhibition of IgE binding to latex by Hev b 1 less than 50%. Testing two monoclonal anti-Hev b 1 antibodies with extracts of five brands of latex gloves revealed a predominant presence of Hev b 1 protein as a monomer or its aggregates. Molecular analysis of human leukocyte antigen-D region genes DRB and DQB1 suggested no statistically significant correlation between the human leukocyte antigen alleles tested and IgE responsiveness to Hev b 1. CONCLUSIONS Our results indicate that Hev b 1 not only makes significant contributions to the IgE binding to latex, but it is also the unique sensitizer in about 45% of patients with SB who are allergic to latex.

Quantitative analysis of immunoglobulin E reactivity profiles in patients allergic or sensitized to natural rubber latex (Hevea brasiliensis)

Background Characterized native and recombinant Hevea brasiliensis (rHev b) natural rubber latex (NRL) allergens are available to assess patient allergen sensitization profiles.

Does fetal endoscopic closure of the myelomeningocele prevent loss of neurologic function in spina bifida aperta

Background Spina bifida aperta (SBA) is associated with shuntdependent hydrocephalus and with meningomyelocele (MMC). Fetal endoscopic closure of the MMC may reduce shunt-dependency, but the benefit upon motor function in individual patients is still unclear. An increase in differentiated muscle ultrasound density (dMUD) provides an objective parameter for the extent of muscle damage caudal to the MMC. In this perspective, we aimed to compare dMUD and neurological function between SBA children treated by fetal endoscopic closure (fSBA) and by neonatal closure (nSBA) of the MMC.

Latex allergy in spina bifida patients – prevention by primary prophylaxis

Background The effect of latex prophylaxis has not been investigated in spina bifida children, a high‐risk group for latex allergy. As repeated operations have been identified as a major cause of latex sensitization, we wanted to find out whether primary latex prophylaxis during surgery could prevent latex allergy in children with spina bifida.

Fetal endoscopic myelomeningocele closure preserves segmental neurological function

Aim  Our aim was to compare the effect of prenatal endoscopic with postnatal myelomeningocele closure (fetally operated spina bifida aperta [fSBA]) versus neonatally operated spina bifida aperta [nSBA]) on segmental neurological leg condition.

PCR-based cloning, isolation, and IgE-binding properties of recombinant latex profilin (rHev b 8).

Background: Profilin (Hev b 8) in natural rubber latex (NRL) has been assumed to be an important allergen. Since latex profilin has a molecular mass similar to two other latex allergens (Hev b 1 and Hev b 6.03) in the 14‐kDa range, it is difficult to obtain sufficient amounts of purified native profilin for investigations and diagnostics. The present study aimed to produce recombinant latex profilin (rHev b 8) and study its IgE‐binding reactivity.

Effects of latex avoidance on latex sensitization, atopy and allergic diseases in patients with spina bifida

To cite this article: Blumchen K, Bayer P, Buck D, Michael T, Cremer R, Fricke C, Henne T, Peters H, Hofmann U, Keil T, Schlaud M, Wahn U, Niggemann B. Effects of latex avoidance on latex sensitization, atopy and allergic diseases in patients with spina bifida. Allergy 2010; 65: 1585–1593.

Longitudinal study on latex sensitization in children with spina bifida

The course of latex sensitization is rarely documented, and only a few reports about the influence of prophylaxis in the occupational environment have been published concerning health care workers. Therefore we did a follow‐up study in the high risk group of patients with spina bifida and evaluated the efficacy of latex prophylaxis. For this purpose we measured IgE antibodies (FEIA) against latex and inhalative allergens in the sera of 67 patients with spina bifida and reevaluated them 0.6 to 4.1 years later, having instructed the patients about prophylactic measures and established a latex‐free environment for surgery of all spina bifida patients in our hospital. 37% of the patients did not develop latex antibodies during the follow‐up period, 27% showed decreasing levels of antibodies (12% to non‐detectable levels), 19% had an increase in latex sensitization (6% newly sensitized), and 9% showed no change in levels of latex antibodies. From our data it may be concluded that surgery without strict latex prophylaxis is the main cause of new sensitization and worsening of preexisting latex antibody levels. Mild sensitization can be reduced by prophylactic measurements to non‐detectable antibody levels. With consistent prophylaxis, even symptomatic patients can be operated without risk of allergic complications or increasing antibodies.