Charlotte Siggaard

Transabdominal Ultrasound of Rectum as a Diagnostic Tool in Childhood Constipation

PURPOSE We tested whether transverse rectal diameter measured by ultrasound could identify rectal impaction, investigated whether transverse diameter is enlarged in constipated children compared to healthy children and evaluated transverse diameter during treatment of constipation. MATERIALS AND METHODS A total of 51 children 4 to 12 years old were included in the study. Of the children 27 (mean age 7.0 +/- 1.8 years) had been diagnosed with chronic constipation by Rome III criteria and 24 (9.1 +/- 2.7 years) were healthy controls. All patients underwent a thorough medical history and physical examination, including digital rectal examination and measurement of rectal diameter by transabdominal ultrasound. Constipated children underwent repeat investigations after 4 weeks of laxative treatment. RESULTS Average rectal diameter of children with negative digital rectal examination was 21 +/- 4.2 mm (mean +/- SD), leading to the approximation that a value greater than 29.4 mm (mean +/- 2 SD) indicates rectal impaction. All children with rectal impaction identified by digital examination had a rectal diameter larger than 29.4 mm. Moreover, constipated children had a significantly larger rectal diameter (42.1 +/- 15.4 mm) than healthy children (21.4 +/- 6.0 mm, p <0.001). After 4 weeks of laxative treatment constipated children had a significant reduction in rectal diameter (mean 26.9 +/- 5.6 mm, p <0.001). CONCLUSIONS Transverse rectal diameter seems to be a valuable tool to identify rectal impaction and may replace digital rectal examination. Constipated children have a significantly larger rectal diameter compared to healthy children, and when constipation is treated the diameter is reduced significantly.

INTRA-INDIVIDUAL VARIABILITY IN NIGHTTIME URINE PRODUCTION AND FUNCTIONAL BLADDER CAPACITY ESTIMATED BY HOME RECORDINGS IN PATIENTS WITH NOCTURNAL ENURESIS

PURPOSE We evaluated the intra-individual variability and reproducibility of nighttime urine production on wet nights and functional bladder capacity estimated by long-term home recordings of monosymptomatic nocturnal enuresis. In particular, the intention was to evaluate the validity of 1 versus 2 weeks of recording when estimating urine volume on wet nights and 1 versus 2 weekends of recording when estimating functional bladder capacity. MATERIALS AND METHODS We analyzed 120, 2-week home recordings of nighttime urine volume from patients with monosymptomatic nocturnal enuresis 6 to 16 years old (mean age 9.1) with at least 3 wet nights per week. Most patients were nonresponders or partial responders to desmopressin. Nighttime urine volume was estimated by weighing diapers before and after sleep, and measuring morning urine volume. Of the home recordings 62 included frequency volume charts for 2 weekends, which were evaluated for functional bladder capacity defined as the largest voided volume observed. RESULTS No significant overall week-to-week differences were observed in average urine volume on wet nights and functional bladder capacity. There was a large intra-individual variability in all measured variables, which was most pronounced for functional bladder capacity and least pronounced for urine volume on wet nights. With regard to repeatability, the limits of agreement of urine volume on wet nights were -32% and 36% (95% confidence interval) as opposed to -54% and 48% for functional bladder capacity. CONCLUSIONS In this study intra-individual week-to-week estimates of average urine volume on wet nights demonstrated acceptable variability and repeatability in contrast to functional bladder capacity. A reliable estimate of urine volume on wet nights could be obtained by 7 nights of home recording, whereas 4 days of daytime recording were necessary when estimating functional bladder capacity. Similar studies of patients who respond to desmopressin are needed.

International Children's Continence Society's recommendations for therapeutic intervention in congenital neuropathic bladder and bowel dysfunction in children.

We present a consensus view of members of the International Childrens Continence Society on the therapeutic intervention in congenital neuropatic bladder and bowel dysfunction in children.

The circadian defect in plasma vasopressin and urine output is related to desmopressin response and enuresis status in children with nocturnal enuresis.

PURPOSE We correlated the circadian rhythm of plasma arginine vasopressin and urine output profile to desmopressin response, presence or absence of an enuretic episode, and age and gender in children with nocturnal enuresis. MATERIALS AND METHODS We studied 125 children 6 to 17 years old (mean age 10.4 +/- 3 years) with monosymptomatic nocturnal enuresis. Circadian inpatient studies were performed with standardized fluid intake, 7 blood sampling times and 6 urine collection periods. Subsequently, nocturnal urine volume was measured at home by diaper weighing for 4 weeks in 78 patients (2 weeks without treatment followed by 2 weeks of dose titration from 20 to 40 mug desmopressin at bedtime). RESULTS The circadian studies showed that all groups of patients had an attenuated arginine vasopressin rhythm, females generally had lower circadian plasma arginine vasopressin levels than males, desmopressin responders with enuresis during the study night had the largest nocturnal urine excretion rate and most pronounced arginine vasopressin deficiency, and nocturnal urine output was significantly greater during nights with enuresis than nights without. Part of this polyuria was caused by increased sodium excretion. The home recordings confirmed higher nocturnal urine volume on enuresis nights. CONCLUSIONS In addition to providing further pathophysiological support for the role of a nocturnal arginine vasopressin deficiency behind nocturnal polyuria in a subset of patients with enuresis, the results emphasize the clinical value of estimating nocturnal urine production on wet nights before selecting a therapeutic modality.

Six novel mutations in the arginine vasopressin gene in 15 kindreds with autosomal dominant familial neurohypophyseal diabetes insipidus give further insight into the pathogenesis.

Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is caused by postnatal arginine vasopressin (AVP) deficiency resulting from mutations in the AVP gene encoding the AVP pre-prohormone. To advance the understanding of adFNDI further, we have searched for mutations in the AVP gene in 15 unrelated kindreds in which diabetes insipidus appeared to be segregating. In nine kindreds, seven different previously described mutations were identified. In each of the other six kindreds, unique novel mutations were identified. Two of these (225A>G and 227G>A) change a nucleotide in the translation initiation codon of the signal peptide, whereas the other four (1797T>C, 1884G>A, 1907T>G, and 2112C>G) predict amino-acid substitutions in the neurophysin II moiety of the AVP prohormone, namely V67A (NP36), G96D (NP65), C104G (NP73), and C116W (NP85). Among these, the mutation predicting the V67A (NP36) substitution is remarkable. It affects a region of the neurophysin II not affected by any other mutations, produces only a minor change, and its inheritance suggests an incomplete penetrance. Our findings both confirm and further extend the mutation pattern that has emerged in adFNDI, suggesting that the mutations affect amino-acid residues known or reasonably presumed to be important for the proper folding and/or dimerization of the neurophysin II moiety of the AVP prohormone.

Impaired trafficking of mutated AVP prohormone in cells expressing rare disease genes causing autosomal dominant familial neurohypophyseal diabetes insipidus

objective and study design  Two different mutations in the arginine vasopressin (AVP) gene associated with autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) predict Y21H (AVP2) and V67A (NP36) amino acid substitutions of the AVP prohormone. They are unique in that they change, respectively, the AVP moiety and a region of the neurophysin II domain not so far affected by any mutations. To test whether they affect the cellular handling of the AVP prohormone in a similar manner to previously investigated mutations, they were examined by heterologous expression in cell lines.

Age Related Nocturnal Urine Volume and Maximum Voided Volume in Healthy Children: Reappraisal of International Children's Continence Society Definitions

PURPOSE We determined normal, age related reference data regarding maximum voided volume and nocturnal urine production using the same methodology as in clinical practice. MATERIALS AND METHODS A total of 62 girls and 86 boys without enuresis (mean +/- SD age 9.64 +/- 2.63 years, range 3 to 15) completed 4 days (2 weekends) of frequency-volume charts and 14 days of home recording of nocturnal urine production. From these recordings maximum voided volume with and without first morning void was derived for each subject. Also, average nocturnal urine volume with and without nocturia was calculated. Percentiles were produced by dividing the population into 1-year age groups. RESULTS Based on 2,836 daytime voids and 1,977 overnight recordings, maximum voided volume and nocturnal urine volume showed a significant linear relationship with age but not with gender. Maximum voided volume with first morning void was significantly higher than without (403 +/- 137 ml vs 281 +/- 112 ml, p <0.0001) and the 50th percentile line of maximum voided volume with first morning void was 80 to 100 ml higher than Koffs formula (30 x [age + 1] ml). Conversely the 50th percentile of maximum voided volume without first morning void was almost identical to Koffs formula. Regarding nocturnal measurements, nocturia was noted on 128 nights (6.5%) and nocturnal urine volume on nights with nocturia was significantly higher than on nights without nocturia (365 +/- 160 ml vs 248 +/- 75 ml, respectively, p <0.0001). The 97.5th nocturnal urine volume percentile line of healthy children deviated markedly from the current International Childrens Continence Society definition of nocturnal polyuria, especially at low and high ages. CONCLUSIONS We demonstrate clearly that the universally used formula 30 x (age + 1) ml is indeed valid for a population of healthy Danish children but only if the first morning void is disregarded. Furthermore, we question the validity of the current International Childrens Continence Society formula for nocturnal polyuria (nocturnal urine volume greater than 130% of maximum voided volume for age), and instead we propose the formula, nocturnal urine volume greater than 20 x (age + 9) ml.

Expression of three different mutations in the arginine vasopressin gene suggests genotype–phenotype correlation in familial neurohypophyseal diabetes insipidus kindreds

Objective and study design  The autosomal dominant form of familial neurohypophyseal diabetes insipidus (adFNDI) is a rare disease characterized by a severe and progressive deficiency of AVP secondary to mutations in the gene encoding the AVP precursor. Whereas a number of studies have investigated the pathogenetic mechanisms behind the disease only few studies have included detailed clinical characterization of the affected patients, thereby making genotype–phenotype correlations difficult. The aims of the present study were to investigate the cellular effects of three different adFNDI mutations (A19T, L81P and C110X) by heterologous expression in a neurogenic cell line and to correlate these findings to the corresponding clinical phenotype as determined by extensive clinical tests.

Outcome of a standardized approach to childhood urinary symptoms-long-term follow-up of 720 patients.

To investigate the relevance of enuresis subtyping for selection of treatment modality and for long‐term outcome in a large consecutive patient cohort.

Outcome of a standardized approach to childhood urinary symptoms

To investigate the relevance of enuresis subtyping for selection of treatment modality and for long‐term outcome in a large consecutive patient cohort.