Transcutaneous Electrical Nerve Stimulation Increases Rectal Activity in Children.

OBJECTIVES: Neurostimulation is increasingly used in treating bladder and bowel dysfunction, but its effect on rectal motility is obscure. The aim of the study was to evaluate the acute effect of transcutaneous electrical nerve stimulation (TENS) on rectal motility in children with overactive bladder (OAB). METHODS: In this double-blind placebo-controlled study in 20 children with OAB (mean age 8.6 ±â€Š1.8 years; 7 girls), 48-hour urodynamic monitoring including rectal manometry was performed. After 24-hours of baseline investigation without stimulation the children were randomised to either active TENS (n = 10) or placebo (n = 10). Surface electrodes were placed over the sacral bone. The exterior of active and placebo stimulators was identical. Starting in the morning, the children received either continuous TENS stimulation or placebo until bedtime. Rectal contractions were defined as pressure runs exceeding 5 cm H2O and lasting ≥3 minutes. RESULTS: At baseline there was no significant difference in proportion of time with rectal contractions in the 2 groups (TENS group median 31% [range 12%-66%] vs placebo group median 31% [range 10%-66%]; P = 0.75); however, on the day of stimulation there was more time with rectal contractions in the group receiving TENS (median 51% [range 25%-78%]) compared with placebo (median 32% [range 4%-68%]; P = 0.02). Also, there was an increase in time with rectal contractions in the TENS group (P = 0.007) but not in the placebo group (P = 0.39). The night after the TENS was disabled, rectal activity in both groups returned to baseline level. CONCLUSIONS: TENS acutely increases time with rectal contractions in children undergoing urodynamic investigation. The effect disappears when the stimulator is turned off.

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

AIMS: To investigate the relevance of enuresis subtyping for selection of treatment modality and for long-term outcome in a large consecutive patient cohort. MATERIALS AND METHODS: We included all patients referred for urinary incontinence during a 5-year period but excluding recurrent urinary tract infections (UTI). Type and severity of incontinence, prior history, results of examinations performed, number of visits, and effect of all treatments provided, were included in a clinical database. RESULTS: Seven hundred twenty children aged 4-16 years (mean 8.5 ± 2.2 years, 239 girls) were included in the analysis (42% with monosymptomatic (MNE), 55% with non-MNE, and 3% with isolated daytime incontinence). Initial evaluation revealed only few underlying causes (one neurological and eight anatomical). Investigations showed significant differences between MNE and non-MNE patients as both maximal voided volume and nocturnal urine volume was lower in non-MNE patients (P < 0.001). Follow-up for average 1,587 days (3.4 years) was performed in 660 (92%) patients. A higher number of visits and a longer treatment period were needed for non-MNE patients (on average 4.7 ± 2.8 visits) than MNE patients (3.1 ± 1.6 visits, P < 0.001). The most common treatment regimen that resulted in dryness in both MNE (40%) and non-MNE (36%) was the alarm system. Interestingly, of the 539 patients who initially were referred due to desmopressin resistance 177 (33%) of these were dry on desmopressin monotherapy. CONCLUSIONS: The study indicated that MNE and non-MNE are two distinct disease entities with different optimal treatments and showed that the latter patients are more difficult and time-consuming to manage.

Rectal motility in pediatric constipation.

OBJECTIVES: Constipation is a common disorder in children, but little is known about its etiology. Rectal impedance planimetry determines segmental rectal cross-sectional area (CSA) and pressure, allowing detailed description of rectal motility. The aim of the present study was to compare rectal motility in healthy and constipated children. METHODS: We analyzed data from 10 children (1 girl) with constipation according to the Rome III criteria, mean age 8.8 years (standard deviation ±â€Š1.2), and 10 healthy children (5 girls), mean age 9.9 years (standard deviation ±â€Š1.5). CSA was determined at 3 levels (4, 5.5, and 7 cm from the anal verge). The resting rectal motility was recorded for 30 minutes followed by a distension protocol to assess compliance. Runs of phasic rectal contractions were defined as changes of >10% from baseline CSA and lasting at least 2 minutes. Rectal dimensions were expressed as mean CSA. RESULTS: A low-amplitude contraction pattern (3%-5% of baseline CSA) with a frequency of 6 to 8/minute was present in all of the children. There was significantly more time with phasic rectal contractions in constipated children (median 38%, range [0-100]) compared with healthy children (median 8.8%, range [0-57]) (P < 0.05). The rectal CSA was higher in constipated children (median 1802 mm [range 1106-2948]) compared with healthy children (1375 mm [range 437-1861]) (P < 0.05), but compliance did not differ (constipated: median 38 mm/H2O [range 12-86] vs healthy 33 mm/H2O [range 10-63]) (P = 30). CONCLUSIONS: In children with constipation, we found phasic rectal contractions for a significantly longer period compared with healthy children, and their rectum is larger than normal.

[Treatment of chronic constipation in children]. / Behandling af kronisk obstipation hos børn--en gennemgang af et Cochranereview.

Chronic functional constipation is a common disorder in childhood. The treatment most often consists of the modalities education, disimpaction and maintenance. In a recent Cochrane review of maintenance treatment polyethylene glycol (PEG) seems to be superior to placebo and to other laxatives including lactulose. This conclusion is in line with practice at most paediatric departments in Denmark. Still, larger randomized controlled studies with the curing of constipation as the primary end point are needed.

Constipation in children with neurofibromatosis type 1.

BACKGROUND AND OBJECTIVES: Neurofibromatosis type 1 (NF1) is a hereditary, heterogenic, and multiorganic disease. The NF1 phenotype shows great variability in expressivity and often includes symptoms from the central and peripheral nervous systems. Bowel symptoms have been reported, but gastrointestinal function in NF1 remains to be described in detail. In this first systematic study of bowel function in children with NF1, we aimed to investigate symptoms of constipation and test the hypotheses that children with NF1 have abnormally large rectum and prolonged colonic transit time (CTT). METHODS: A total of 20 children with NF1 (age 8.2 ± 2.4 years) were evaluated with medical history; clinical examination; digital rectal examination; bowel and dietary diaries; Rome III criteria; measurement of rectal diameter by transabdominal ultrasound; and radiographic estimation of CTT. The control group for assessment of rectal diameter comprised 23 healthy children (mean age 9.1 ± 2.7 years). RESULTS: A total of 6 children with NF1 (30%) were constipated according to Rome III criteria. Average rectal diameter was significantly larger than for healthy children (32.9 ± 7.2 mm vs 21.4 ± 5.9 mm, P < 0.0001). Median CTT in NF1 children was 53 hours (range 26-101). Compared with existing normative data, CTT was prolonged (>84 hours) in 3 (19%). CONCLUSIONS: Symptoms of constipation were surprisingly common in children with NF1. Correspondingly, rectal diameters were abnormally large and a higher proportion than expected had prolonged CTT. The underlying pathophysiology remains obscure, but we hypothesise that abnormalities of the enteric nervous system or disturbed cellular growth could be present.

24-hour rectal manometry for overactive bladder.

PURPOSE: We describe prolonged rectal manometry used to characterize rectal motor activity patterns and possible rectum-bladder interaction during defecation and micturition in children with nonneuropathic overactive bladder. MATERIALS AND METHODS: We evaluated 10 children with a mean +/- SD age of 9.7 +/- 1.3 years with overactive bladder who underwent urodynamics and 24-hour rectal manometric recording. All records were analyzed visually. Rectal contractions were defined as pressure runs exceeding 5 cm H(2)O and lasting longer than 5 seconds. RESULTS: Three rectal motility patterns were noted in all children, including 1) slow tonic pressure waves with a frequency of 3 to 12 per hour, b) rectal motor complexes with a frequency of 3 to 10 per minute and c) single contractions 10 to 30 seconds in duration. The median nocturnal duration of rectal motor complexes was longer than that during the day (16.3 minutes, range 10.8 to 18.8 vs 11.0, range 8.9 to 12.6, p <0.05). As a percent of time, median total contraction time was greater at night than during the day (51.9%, range 42.6% to 56.9% vs 30.6%, range 19.4% to 49.3%, p <0.05). Characteristic rectal activity was seen during defecation and voiding but no bladder-rectum interaction was detected. CONCLUSIONS: We identified 3 rectal motility patterns in all children with overactive bladder. Like the upper gastrointestinal tract, the rectum shows some periodic motor activity, which is more frequent at night. No association was observed between bladder and rectal activity during micturition and defecation.

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.

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.

Long-term tolerability of tolterodine extended release in children 5-11 years of age: results from a 12-month, open-label study.

OBJECTIVE: To evaluate the long-term tolerability of tolterodine extended release (ER) in children (aged 5-11 yr) with urgency urinary incontinence (UUI). METHODS: This was a multicenter, open-label extension of a 12-wk, double-blind, placebo-controlled study of tolterodine ER. Patients had UUI suggestive of detrusor overactivity (>/=1 diurnal incontinence episode per 24h for >/=5 of 7 d) and >/=6 voids per 24h at baseline and had completed the 12-wk double-blind study. Patients received tolterodine ER (2mg once daily) for 12 mo. The primary end points were the incidence and severity of adverse events (AEs) and the incidence and reasons for withdrawals. Visits were scheduled at 3, 6, 9, and 12 mo, and investigators were instructed to report all AEs. At 6 and 12 mo, vital signs were recorded and a physical examination was performed. RESULTS: A total of 318 patients were enrolled (double-blind tolterodine ER, n=221; placebo, n=97). The majority of patients were white (90%), mean+/-SD age was 7.6+/-1.5 yr, and 54% were boys. Forty-nine percent of patients reported >/=1 AE during the study, similar to that observed in the preceding 12-wk study (42%). The most frequent AEs were urinary tract infection (7%), nasopharyngitis (5%), headache (5%), and abdominal pain (4%); 111 (35%) patients withdrew. The most common reasons for withdrawal were lack of efficacy (12%), symptom improvement (8%), and withdrawn consent (6%). Ten patients (3%) withdrew because of AEs. CONCLUSION: Long-term treatment with tolterodine ER was well tolerated in children with UUI.

Plasma amino acids in Greenlanders and Danes: influence of seasons, residence, ethnicity, and diet.

Basal metabolic rate is elevated among circumpolar populations. It has been our hypotheses that this is reflected in the levels of plasma amino acids, that amino acid concentration in plasma differs between Greenlanders and Danes, and that this difference is related to residence, ethnicity, diet, and season. The purpose of the study was to measure plasma amino acids in Greenlanders and Danes and to analyze the influence of residence, ethnicity, diet, and season. Amino acids in plasma were measured in four groups of healthy subjects both during summer and winter: Group 1, Danes living in Denmark consuming European food; Group 2, Greenlanders living in Denmark consuming European food; Group 3, Greenlanders living in Greenland consuming European food; and Group 4, Greenlanders living in Greenland consuming mainly traditional Greenlandic food. Amino acids were determined by pre-column derivatization with o-phthaldialdehyde and reverse-phase high-performance liquid chromatography with gradient elution and fluorescence detection. Most plasma amino acids were lower during summer than winter in Greenlanders living in Greenland. Comparison of the four groups showed that residence in Greenland was the most important influencing factor for the concentration of plasma amino acids, whereas ethnicity and diet had only a very modest or no effect. These findings could not be attributed to changes in thyroid function. However, the level of physical activity was significantly higher in Groups 3 and 4 than in Groups 1 and 2. Because exercise reduces the amino acid pool in plasma, it is possibly that the higher physical activity among Greenlanders living in Greenland explains the reduction in plasma amino acids during summer. It is concluded that plasma amino acids were lower during summer than winter in Greenlanders living in Greenland compared with Greenlanders in Denmark and Danes. This difference might be due to the higher level of physical activity among Greenlanders in Greenland during the summer period.

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. RESULTS: The clinical studies showed a later age of onset in the family carrying the A19T mutation (3.4 years, range 2-9 years) compared with families with the L81P and C110X mutations [0.75 year, range 0.5-1 year and 1.0 year (n = 1), respectively]. No other differences could be demonstrated in the clinical phenotype between families. Expression studies showed that each of the three mutant genes caused significant reduction of the amount of immunoreactive AVP in the cell culture medium and severe impairment of the intracellular trafficking and processing of the AVP prohormone, supporting the disease causing nature of all three mutations. However, the A19T mutation was associated with some capacity for processing and trafficking consistent with the clinical observations. Immunoflourescence studies provided evidence of reticular accumulation of protein within the ER in the A19T and C110X mutants but a unique accumulation of much larger aggregates in the L81P, which were localized both within and immediately outside the ER. CONCLUSION: The study suggests a genotype-phenotype correlation with regard to age of onset of diabetes insipidus symptoms and provides support by expression studies.

Relationship between mercury in blood and 24-h ambulatory blood pressure in Greenlanders and Danes.

BACKGROUND: Intake of mercury with food items from sea mammals and fish has been suggested to be involved in cardiovascular disease, but the relationship between mercury in blood and 24-h ambulatory blood pressure (BP) has never been studied. METHODS: We measured mercury in blood and 24-h BP in four groups of healthy subjects: group 1, Danes living in Denmark consuming European food; group 2, Greenlanders living in Denmark consuming European food; group 3, Greenlanders living in Greenland consuming European food; and group 4, Greenlanders living in Greenland consuming mainly traditional Greenlandic food. RESULTS: Mercury in blood was highest in Greenlanders and increased when they lived in Greenland and consumed traditional Greenlandic food (group 1: 2.2 microg/L (median), group 2: 4.8 microg/L, group 3: 10.8 microg/L, and group 4: 24.9 microg/L). The 24-h BP was the same in all three groups of Greenlanders. However, 24-h diastolic BP was lower among Greenlanders than Danes (71 v 76 mm Hg, P < .000) and 24-h pulse pressure was higher (54 v 50 mm Hg, P < .000). Mercury in blood was significantly and positively correlated to pulse pressure (rho = 0.272, P < .01). CONCLUSIONS: Pulse pressure was higher and diastolic BP was lower in Greenlanders than Danes. Pulse pressure increased with higher mercury content in the blood. Although genetic factors must be responsible to some extent for the difference in pulse pressure between Greenlanders and Danes, the present results seem to support the hypothesis that mercury intake from maritime food is involved in cardiovascular disease.

Differential cellular handling of defective arginine vasopressin (AVP) prohormones in cells expressing mutations of the AVP gene associated with autosomal dominant and recessive familial neurohypophyseal diabetes insipidus.

An unusual mutation in the arginine vasopressin (AVP) gene, predicting a P26L amino acid substitution of the AVP prohormone, is associated with autosomal recessive familial neurohypophyseal diabetes insipidus (FNDI). To investigate whether the cellular handling of the P26L prohormone differed from that of the Y21H prohormone associated with autosomal dominant inheritance of FNDI, the mutations were examined by heterologous expression in cell lines. Immunoprecipitation demonstrated retarded processing and secretion of the Y21H prohormone, whereas the secretion of the P26L prohormone seemed to be unaffected. Confocal laser scanning microscopy showed accumulation of the Y21H prohormone in the endoplasmic reticulum, whereas the P26L prohormone and/or processed products were localized in secretory granules in the cellular processes. RIA analysis showed reduced amounts of immunoreactive Y21H-AVP and P26L-AVP in the cell culture medium. Thus, the recessive mutation does not seem to affect the intracellular trafficking but rather the final processing of the prohormone. Our results provide an important negative control in support of the hypothesis that autosomal dominant inheritance of FNDI is caused by mutations in the AVP gene that alter amino acid residues important for folding and/or dimerization of the neurophysin II moiety of the AVP prohormone and subsequent transport from the endoplasmic reticulum.

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. RESULTS: Both mutations resulted in significantly reduced amounts of immunoreactive AVP in the cell culture medium as determined by radioimmunoassay analysis. Metabolic labelling combined with immunoprecipitation demonstrated that processing and secretion of the mutant prohormones was reduced but not prevented. Finally, confocal laser scanning microscopy showed that normal AVP prohormone and/or its processed products were localized in the tips of the cellular processes, whereas both mutant prohormones were accumulated in the endoplasmic reticulum (ER) and in the case of the V67A prohormone, also in perinuclear structures outside the ER. CONCLUSION: Both mutations result in reduced AVP prohormone processing and secretion probably due to retention in the ER. This supports, at least partly, the hypothesis that the mutations lead to the production of a mutant hormone precursor that fails to fold and/or dimerize properly and, as a consequence, is retained by the ER protein quality control machinery. Perinuclear accumulation of the V67A prohormone outside the ER indicates that additional mechanisms could be involved.

Autosomal dominant familial neurohypophyseal diabetes insipidus.

Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is a rare disorder caused by progressive postnatal arginine vasopressin (AVP) deficiency resulting from mutations in the AVP gene encoding the AVP pre-prohormone. It has been suggested that these mutations exert their effect on the cellular handling of the AVP prohormone by leading to the synthesis of mutant hormone precursor that fails to be processed and/or folded properly in the endoplasmic reticulum (ER). As a consequence, it is retained by the ER protein quality control machinery resulting in protein accumulation and initiation of cellular processes leading to degeneration of the AVP producing neuron. This review summarizes the current knowledge on adFNDI and discusses different hypotheses concerning its pathogenesis.

Ethnic, geographic and dietary influences upon vasoactive hormones and blood pressure among Greenland Inuit and Danes.

AIM: To study levels of vasoactive hormones and urinary excretion of sodium and potassium between groups of Greenland Inuit and Danes, and to analyse the relationship between these hormones and 24-h blood pressure, including nightly blood pressure dips and pulse pressure. METHODS: 145 Greenlandic participants were categorized in three groups according to degree of westernization, based on dietary habits and current place of residence; 41 Danes were included as controls. Twenty-four-hour blood pressure was measured. Venous plasma concentrations of vasoactive hormones were measured. Urine was collected for 24 hours for analysis of excretion of sodium and potassium. RESULTS: The Inuit population of Greenland had a lower diastolic blood pressure, a higher pulse pressure and lower nocturnal blood pressure dip than Danes had. Angiotensin II in plasma and urine excretion of potassium were higher among Greenlanders compared with Danes, irrespective of diet and place of residence. Aldosterone and urine excretion of sodium were significantly higher among participants in Denmark compared with participants in Greenland. Brain natriuretic peptide and atrial natriuretic peptide were independently and negatively associated with diastolic blood pressure, and vasopressin was positively associated with systolic blood pressure and pulse pressure. Ethnic differences in the effect of vasoactive hormones or urinary sodium and potassium excretion could not explain the difference in blood pressure. CONCLUSION: It is suggested that a high dietary intake of potassium and low sodium intake among Greenlanders may affect blood pressure. Further attention should be drawn to the occurrence of high pulse pressure and high activity in the renin-angiotensin system in Inuit populations.

Autosomal dominant neurohypophyseal diabetes insipidus due to substitution of histidine for tyrosine(2) in the vasopressin moiety of the hormone precursor.

The autosomal dominant form of familial neurohypophyseal diabetes insipidus (adFNDI) has been linked to 40 different mutations of the gene encoding the vasopressin-neurophysin II (AVP-NPII) precursor. All of these mutations have been located in either the signal peptide or neurophysin II moiety. We now report a three-generation Turkish kindred in which severe adFNDI cosegregates with a novel missense mutation in the part of the AVP-NPII gene encoding the AVP moiety. This mutation (T-->C at position 285 in the genomic sequence) was found in only one allele and predicts a substitution of histidine for tyrosine at position 2 in AVP. Like other adFNDI mutations, this substitution is expected to impair folding and processing of the precursor, in this case by interfering with normal binding of the AVP and NPII moieties. It is associated clinically with inability to concentrate urine during fluid deprivation, a greater than 80% deficiency of AVP secretion, and absence of the posterior pituitary bright spot on magnetic resonance imaging. These findings are consistent with the hypothesis that mutations in the AVP-NPII gene cause adFNDI by directing the production of a folding incompetent precursor that prevents the expression of the normal allele via a cytotoxic effect on the magnocellular neurons.