Phenotypic variation in a family with partial androgen insensitivity syndrome explained by differences in 5alpha dihydrotestosterone availability

Mutations in the androgen receptor (AR) gene result in a wide range of phenotypes of the androgen insensitivity syndrome (AIS). Inter- and intrafamilial differences in the phenotypic expression of identical AR mutations are known, suggesting modifying factors in establishing the phenotype. Two 46,XY siblings with partial AIS sharing the same AR gene mutation, R846H, but showing very different phenotypes are studied. Their parents are first cousins. One sibling with grade 5 AIS was raised as a girl; the other sibling with grade 3 AIS was raised as a boy. In both siblings serum levels of hormones were measured; a sex hormone-binding globulin (SHBG) suppression test was completed; and mutation analysis of the AR gene, Scatchard, and SDS-PAGE analysis of the AR protein was performed. Furthermore, 5alpha-reductase 2 expression and activity in genital skin fibroblasts were investigated, and the 5alpha-reductase 2 gene was sequenced. The decrease in SHBG serum levels in a SHBG suppression test did not suggest differences in androgen sensitivity as the cause of the phenotypic variation. Also, androgen binding characteristics of the AR, AR expression levels, and the phosphorylation pattern of the AR on hormone binding were identical in both siblings. However, 5alpha-reductase 2 activity was normal in genital skin fibroblasts from the phenotypic male patient but undetectable in genital skin fibroblasts from the phenotypic female patient. The lack of 5alpha-reductase 2 activity was due to absent or reduced expression of 5alpha-reductase 2 in genital skin fibroblasts from the phenotypic female patient. Exon and flanking intron sequences of the 5alpha-reductase 2 gene showed no mutations in either sibling. Additional intragenic polymorphic marker analysis gave no evidence for different inherited alleles for the 5alpha-reductase 2 gene in the two siblings. Therefore, the absent or reduced expression of 5alpha-reductase 2 is likely to be additional to the AIS. Distinct phenotypic variation in this family was caused by 5alpha-reductase 2 deficiency, additional to AIS. This 5alpha-reductase deficiency is due to absence of expression of the 5alpha-reductase iso-enzyme 2 as shown by molecular studies. The distinct phenotypic variation in AIS here is explained by differences in the availability of 5alpha-dihydrotestosterone during embryonic sex differentiation.     

Measurement of urinary flow rate using ultrasound in young boys and infants

PURPOSE: We present a technique for measuring urinary flow rates with ultrasound in male infants and children. MATERIALS AND METHODS: Urinary flow rate was measured simultaneously by an ultrasound probe placed around the base of the penis and by a funnel with a rotating disk at the bottom in 30 boys with a mean age of 6.7 years (range 4.5 to 10.5), and by ultrasound in 8 infants with a mean age of 10 months (range 1 to 28). Voided volume was measured with a graded cylinder or calculated from the weight change of diapers in infants. Ultrasound and rotating disk maximum flow rates were calculated. The ultrasound signal was calibrated by comparing the collected voided volume to the area under the curve for that void. The volume calculated from the rotating disk flow rate curve was also compared with the collected volume. RESULTS: Both methods yielded similar flow curves. However, ultrasound maximum flow rate significantly exceeded rotating disk maximum flow rate (13 +/- 6 ml. per second, range 5 to 22 versus 10 +/- 4 ml. per second, range 4 to 21, t test p <0.001). The underestimation of the flow rate by the rotating disk method may have been due to adherence of urine to the funnel wall. Rotating disk maximum flow rate was lower and voided volume was underestimated by up to 50% (average 15 +/- 2%) in 21 cases. Ultrasound maximum flow rate averaged 6 +/- 3 ml. per second (range 3 to 11.6 [oldest infant]) in the 8 infants. CONCLUSIONS: Urinary flow rates can be measured accurately using ultrasound in boys who produce small volumes and/or who are not toilet trained and also in infants. In future studies ultrasound will be applied to subsets of male infants with bladder dysfunction.     

Dependency of magnetocardiographically determined fetal cardiac time intervals on gestational age,gender and postnatal biometrics in healthy pregnancies

Background  

Magnetocardiography enables the precise determination of fetal cardiac time intervals (CTI) as early as the second trimester of pregnancy. It has been shown that fetal CTI change in course of gestation. The aim of this work was to investigate the dependency of fetal CTI on gestational age, gender and postnatal biometric data in a substantial sample of subjects during normal pregnancy.     

What is the number of lymph nodes required for an "adequate" pelvic lymphadenectomy?

PURPOSE OF INVESTIGATION: To establish a definition of an adequate number of lymph nodes identified at a pelvic lymphadenectomy through statistical methods. METHODS: We conducted a retrospective study in cervical and endometrial carcinoma patients who underwent radical or staging surgery. The Student's t-test, Pearson's correlation, analysis of variance, and linear regression analysis were used. RESULTS: Five hundred and ninety four-sided pelvic lymphadenectomies were analyzed. The mean (range) number of pelvic lymph nodes identifed was 11.3 (0-42). The 1st, 5th and 10th percentiles were three, five, and six lymph nodes respectively. The number of lymph nodes was higher in the laparoscopic approach compared to laparotomy (11.9 vs 10.6, p < 0.01). CONCLUSIONS: The number of lymph nodes identified at a pelvic lymphadencetomy vary with type of surgery. We propose that using the 1st, 5th or 10th percentile is reasonable for the definition of an adequate number of lymph nodes to be identified at a pelvic lymphadenectomy.     

Expression and prognostic relevance of vascular endothelial growth factor (VEGF) and its receptor (FLT-1) in nephroblastoma

AIMS: To investigate the prognostic relevance of vascular endothelial growth factor (VEGF) and its receptor Flt-1 in nephroblastoma and whether tumour microvessel density (MVD) immunoreactivity, determined by the CD31 antigen, is related to the expression of VEGF and Flt-1. METHODS: The expression of VEGF and Flt-1 and MVD were investigated by means of immunohistochemical analysis in 62 Wilms's tumours. Patients were treated preoperatively with chemotherapy and had a mean follow up of 5.7 years. RESULTS: In general, VEGF and Flt-1 were expressed in normal kidney parenchyma and to a variable extent in the three main components of Wilms's tumour, namely: the blastemal, epithelial, and stromal cells. In tumour tissue, 52% and 47% of blastemal cells were positive for VEGF and Flt-1, respectively. A non-significant correlation was found between the expression of VEGF and Flt-1 in blastemal and epithelial cells and the clinicopathological stage. MVD was significantly higher in VEGF and Flt-1 positive tumours than in VEGF and Flt-1 negative tumours. Univariate analysis showed that the expression of VEGF and Flt-1 in blastemal cells was indicative of clinical progression and tumour specific survival. In addition, MVD expression was indicative of clinical progression. Epithelial staining was of no prognostic value. In a multivariate analysis, VEGF protein expression by blastemal cells was an independent prognostic marker for clinical progression. CONCLUSIONS: These results indicate that VEGF and Flt-1 protein expression are closely related to MVD and seem to be an important predictor for poor prognosis in treated patients with Wilms's tumour. Therefore, the expression of these molecules in primary Wilms's tumour may be useful in identifying those patients at high risk of tumour recurrence and in guiding antiangiogenic treatment.     

Gender identity disorders as a symptom of psychosis, schizophrenia in particular

In the Netherlands it has recently become possible for transsexual patients to receive hormonal treatment from the onset of puberty. Until the age of 16, pubertal development can be prevented with luteinizing hormone-releasing hormone (LHRH) agonists. From 16 years of age onwards, gender adjustment can be initiated by administration of hormones of the opposite sex. Surgical treatment can be offered once the patient reaches 18 years of age. Although such treatment will only be initiated with reticence and after a long phase of intense diagnostic screening, the question arises whether a clear differentiation can be made between pure gender identity disorders and secondary transsexual feelings that are part of an ongoing psychopathological development, such as schizophrenia. The potential diagnostic confusion is illustrated by a case history of a male schizophrenic patient. This patient had been treated hormonally for transsexualism for years before acute psychotic decompensation occurred. Neuroleptic treatment of the psychosis rapidly reduced the psychotic symptoms. In retrospect, the patient regards his transsexual period as a 'mistake'. Delusions about one's physical appearance and the urge to drastically change the way one looks appear to be relatively common in patients suffering from schizophrenia.