Christian Wilhelm

Alu-Alu recombination underlies the vast majority of large VHL germline deletions: Molecular characterization and genotype-phenotype correlations in VHL patients.

Von Hippel‐Lindau disease (VHL) is an autosomal dominant cancer syndrome. Affected individuals are predisposed to multiple tumors, primarily of the central nervous system (CNS), eyes, adrenals, and kidneys. The VHL tumor suppressor gene on chromosome 3p26–25 is partially or completely deleted in 20 to 30% of families with VHL. We identified deletions ranging from 0.5 kb to 250 kb affecting part of or the entire VHL and flanking genes in 54 families. In 33 of the index patients, the breakpoints were precisely characterized by DNA sequencing. Of the 66 breakpoints, 90% were located in Alu elements, revealing Alu‐mediated recombination as the major mechanism for large germline deletions of the VHL gene, which lies in a region of high Alu density. Interestingly, an AluYa5 element in VHL intron 2, the evolutionarily youngest Alu element and the only such element in the entire region, was found to be the most recombinogenic, involved in 7 out of the 33 deletions. In comparison to VHL patients in general, the 54 index cases and their affected relatives showed a higher occurrence of renal cell carcinomas (RCC) and of CNS hemangioblastomas. We not only noted the association of RCC with retention of the HSPC300 gene, but also observed a significant correlation between retention of HSPC300 and the development of retinal angiomas (AR). This study reveals that germline VHL deletions provide a particularly rich source for the study of Alu‐mediated unequal crossover events, and provides evidence for a protective role of the loss of the actin‐regulator gene HSPC300 for the development of both RCC and AR. Hum Mutat 30, 1–11, 2009.

Molecular analysis of the CHD7 gene in CHARGE syndrome: identification of 22 novel mutations and evidence for a low contribution of large CHD7 deletions

Purpose: Autosomal dominant CHARGE syndrome (OMIM no. 214800) is characterized by choanal atresia or cleft lip or palate, ocular colobomas, cardiovascular malformations, retardation of growth, ear anomalies, and deafness, and is caused by mutations in the CHD7 gene. Here, we describe the outcome of a molecular genetic analysis in 18 Finnish and 56 German patients referred for molecular confirmation of the clinical diagnosis of suspected CHARGE syndrome.Methods: Quantitative real-time polymerase chain reaction or multiplex ligation-dependent probe amplification assays did not reveal deletions in mutation negative cases, suggesting that larger CHD7 deletions are not a major cause of CHARGE syndrome.Results: In this group of 74 patients, we found mutations in 30 cases. 22 mutations were novel, including 11 frameshift, 5 nonsense, 3 splice-site, and 3 missense mutations. One de novo frameshift mutation was found in the last exon and is expected to result in a minimally shortened CHD7 polypeptide. Because the mutation is associated with a typical CHARGE syndrome phenotype, it may indicate the presence of an as yet unknown functional domain in the very carboxyterminal end of CHD7.Conclusions: Our mutation detection rate of 40.5% is reflective of screening an unselected sample population referred for CHD7 testing based on suspected clinical diagnosis of CHARGE syndrome and not for having met strict clinical criteria for this disorder.

Pathophysiology of Polyhydramnios in Twin Transfusion Syndrome

In 3 cases of severe twin transfusion syndrome we demonstrate that the concentration of atrial natriuretic factor (ANF) in the cord blood of recipient twins is significantly elevated compared to that of donor twins. The discrepancy between recipient and donor concentration correlates with the volume of transfusion. The following pathophysiological mechanism for explaining polyhydramnios in recipient twins is proposed: chronic overload in recipient twins causes enhanced release of ANF from the fetal heart. Consequently, increased fetal urine production leads to polyhydramnios, which is additionally enhanced by inhibition of ADH release.

Arterial rupture in classic Ehlers-Danlos syndrome with COL5A1 mutation.

The vascular type of Ehlers–Danlos syndrome (EDS IV) is associated with a high risk of life‐threatening medical complications, including ruptures of large arteries, the intestine, and the uterus during pregnancy. An arterial rupture occurring in an individual with EDS is regarded as almost diagnostic of EDS IV, which is caused by heterozygous mutations in COL3A1. Here however, we report on a man with skin lesions typical of EDS, easy bruising and recurrent inguinal hernias who had a spontaneous rupture of the left common iliac artery at the age of 42 years but in whom we detected no COL3A1 mutation. As he clinically fulfilled the diagnostic criteria for classic EDS (EDS I), we sequenced the major EDS I gene COL5A1 and identified a heterozygous de novo nonsense mutation, c.3184C>T (p.R1062X). As, to the best of our knowledge, this is the first report of a patient with COL5A1 mutation‐positive classic EDS and rupture of a large artery, we suggest that arterial rupture might be a rare complication of classic EDS. This finding has potential implications for genetic counseling and molecular genetic testing in Ehlers–Danlos syndrome.

Therapeutic strategies in cervical pregnancy

Cervical pregnancy is a rare condition associated with a high maternal morbidity rate. Standard recommendations for the management of this ectopic pregnancy are not available. This paper presents a case report and reviews the respective literature. In many cases hysterectomy was the ultimate solution. In order to avoid hysterectomy chemotherapy using methotrexate has been suggested. Local injections of prostaglandins or vasopressin have also been proposed. Based on data collected from the literature and our own experience it is concluded that the management of cervical pregnancy requires individualized therapeutic strategies to minimize the rate of hysterectomies.

Therapierefraktäre Emesis unter Cisplatin

Emesis unter Cisplatin (DPP)-haltiger Chemotherapie ist ein noch ungelostes Problem und fuhrt in bis zu 10% der Falle zum Abbruch einer potentiell kurativen Therapie. Wir untersuchten die antiemetisch

Transvaginal sonography of myometrial invasion depth in endometrial cancer

The myometrial invasion depth of endometrial cancer is an important prognostic factor. The preoperative assessment is decisive for the appropriate surgical treatment. In 96 patients with endometrial cancer, the myometrial invasion depth (greater than 50% or less than 50%) was measured preoperatively using transvaginal sonography (TVS). The sonographic results were compared to the histopathological findings. A sensitivity of 93% was obtained for invasion depths greater than 50%. The predictive value of an invasion depth less than 50% was 93% as well. In 16% of the cases the invasion depth was overestimated while, in only 3% it was underestimated. The diagnostic accuracy was 81%. Forty-five patients were examined preceding a diagnostic dilatation and curettage and fifty-one were examined following a diagnostic dilatation and curettage. The diagnostic accuracy in both groups was equivalent. Using transvaginal sonography, the spread of cancer to the cervix was observed in five of the seven cases in which it was postoperatively confirmed. TVS is a valuable, non-invasive diagnostic method for patients with endometrial cancer. When the TVS data are combined with results from other preoperative tests, the prognostic information obtained provides a useful basis in choosing the appropriate therapy.