Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation.

Defects in the human Ca(2+)-sensing receptor gene have recently been shown to cause familial hypocalciuric hypercalcaemia and neonatal severe hyperparathyroidism. We now demonstrate that a missense mutation (Glu128Ala) in this gene causes familial hypocalcaemia in affected members of one family. Xenopus oocytes expressing the mutant receptor exhibit a larger increase in inositol 1,4,5-triphosphate in response to Ca2+ than oocytes expressing the wild-type receptor. We conclude that this extracellular domain mutation increases the receptor's activity at low Ca2+ concentrations, causing hypocalcaemia in patients heterozygous for such a mutation.

Molecular analysis of cystinosis: probable Irish origin of the most common French Canadian mutation.

Infantile nephropathic cystinosis, an autosomal recessive disease characterized by a lysosomal accumulation of cystine, presents as failure to thrive, rickets and proximal renal tubular acidosis. The cystinosis gene, CTNS, which maps to chromosome 17p13, encodes a predicted 55 kDa protein with characteristics of a lysosomal membrane protein. We have conducted extensive linkage analysis in a French Canadian cystinosis cohort identifying a founding haplotype present in approximately half (21/40) of the chromosomes studied. Subsequent mutational analysis, in addition to identifying two novel mutations, has unexpectedly revealed a mutation which has been previously found in Irish (but not French) cystinotic families on these 21 French Canadian chromosomes. Haplotype analysis of two Irish families with this mutation supports the hypothesis that Celtic chromosomes represent an extensive portion of cystinosis chromosomes in French Canada. Our analysis underlines the genetic heterogeneity of the French Canadian population, reflecting a frequently unrecognized contribution from non-Gallic sources including the Irish.

Renal vein entrapment syndrome: frequency and diagnosis. A lesson in conservatism.

Two boys investigated for gross hematuria and left loin pain were found on ultrasound (US) to have left renal vein (LRV) entrapment associated with isomorphic urinary red blood cells, but normal renal venograms. Over the next 18 months ten children with gross hematuria were investigated and two more boys were discovered with the LRV entrapment syndrome, i.e., isomorphic red cells and a diagnostic US. Venography has a low yield in detecting renal venous compression, and since urinary red cell morphology may localize the origin of renal bleeding, we strongly recommend simple procedures, i.e., phase microscopy and renal US to evaluate all cases of hematuria before employing invasive or radiation dependent investigations. Since there is a range of LRV compression and associated dilatation in asymptomatic patients, strict criteria must be applied to diagnose renal vein entrapment.

A case of accidental inorganic mercury poisoning.

Mercuric chloride was accidentally ingested by a nineteen-month old boy. He exhibited severe symptoms of inorganic mercury poisoning including acute renal failure. The blood mercury level at the time of admission to hospital was 1920 ng/mL. Following emergency hemodialysis, BAL (2, 3-dimercaptopropanol) therapy and penicillamine treatment, blood levels fell to 500 ng Hg/mL and urine production restarted six days after exposure. Urine mercury reached a high of 2349 ng/mL but rapidly decreased to less than 100 ng/mL within eight days after resumption of voiding. The patient was discharged from hospital a month after admission and follow-up examinations have indicated no permanent renal damage. Blood, hair, and urine samples collected 19 months after the exposure showed normal mercury levels (blood, 6 ng Hg/mL; urine, 7 ng Hg/mL; and hair 500-900 ng Hg/g).

Idiopathic unilateral gross hematuria in the pediatric patient.

Microscopic hematuria is not an uncommon finding in the pediatric population. Since gross hematuria elicits parental and physician concern, its presence may result in extensive investigation. Unilateral hematuria is an unusual feature of gross hematuria, particularly in the pediatric patient. Although a number of structural and pathologic entities have been described to account for the laterality, in the majority of instances no overt underlying process has been uncovered. Unilateral hematuria appears to be benign, idiopathic, and has a prognosis no different than other idiopathic hematurias in the pediatric age group.

Henoch-Schönlein syndrome and IgA nephropathy: a case report suggesting a common pathogenesis.

An 8-year-old Caucasian male presented with two episodes of gross hematuria but was otherwise asymptomatic. Serum IgA levels were markedly elevated and a renal biopsy showed mesangial proliferative glomerulonephritis with immunofluorescent and electron microscopy findings consistent with IgA nephropathy (IgAN). Two years later he developed abdominal pain, rectal bleeding, gross hematuria and a classic purpuric rash of Henoch-Schönlein syndrome (HSS). Serum IgA levels continued to be elevated and 3 years later in follow-up he is clinically well. These observations support the concept that HSS and IgAN are variants of the same process. The reverse situation has been reported in a 15-year-old female who developed HSS at 4 years of age and IgAN at age 15 years.

Autosomal dominant hypoparathyroidism: a proband with concurrent nephrogenic diabetes insipidus.

In this paper we report an extended family with well documented autosomal dominant hypoparathyroidism which was ascertained through a proband with coincident nephrogenic diabetes insipidus. Clinical findings were limited to a slight decrease in overall stature and to clinical signs of hypocalcaemia. Intelligence was normal and two patients were asymptomatic. Published reports have established that autosomal dominant, autosomal recessive, and sex linked recessive familial isolated hypoparathyroidism exist. However, in almost half the reported families an X linked dominant aetiology cannot be excluded and, at present, clinical criteria provide only minimal aid in distinguishing between the different genetic types. There remains a need for detailed documentation of further families were the pattern of inheritance is clear.

Epidemiology of hemolytic-uremic syndrome in Canadian children from 1986 to 1988. The Canadian Pediatric Kidney Disease Reference Centre.

OBJECTIVE: To define the epidemiologic features of childhood hemolytic-uremic syndrome (HUS) on a national level in Canada, to determine the proportion of patients in whom Escherichia coli O157:H7 was isolated from stools, and to examine risk factors for more severe HUS. DESIGN: From January 1986 to December 1988, patients with HUS were reported prospectively to the Canadian Pediatric Kidney Disease Reference Centre, a national registry for pediatric renal disorders, or were identified retrospectively through a medical records search at participating institutions. SETTING: All children's hospitals in Canada and the children's wards of general hospitals in Canadian cities with populations greater than 350,000. PATIENTS: Two hundred twenty-six children, including 126 girls. MEASUREMENTS AND MAIN RESULTS: The average annual incidence of HUS in children younger than 15 years was 1.44 per 100,000; the peak age-specific incidence was 3.11 per 100,000 younger than 5 years. The incidence of HUS varied by region; the risk of HUS in Alberta was 2.9 times that in Ontario (p less than 0.0001). Of the 169 patients whose stools were screened, E. coli O157:H7 was isolated in 87 (51%). Risk factors for prolonged dialysis or death included young age, seizures, elevated white blood cell count at admission to hospital, and shorter, more severe prodromal illness. The rate of dialysis was higher in female patients (55% vs 39%; p = 0.02). CONCLUSIONS: HUS is relatively common in Canadian children younger than 5 years, and is strongly associated with E. coli O157:H7 infection. Reasons for the striking regional variation in the incidence of HUS and for the increased rate of dialysis in female patients are unexplained and deserve further investigation.

Efficacy of chlorhexidine cleansing in reducing contamination of bagged urine specimens.

To determine the effectiveness of precleansing with chlorhexidine gluconate-cetrimide in reducing the contamination rate of bagged urine specimens, 62 infants admitted to a children's hospital were randomly assigned to either receive (32 infants) or not receive (30) cleansing before bag application. Perimeatal swabs were taken before bag application and, in the treated group, after cleansing. Of the specimens from the treated group 69% were found to be contaminated, compared with 73% of those from the no-cleansing group. Chlorhexidine was ineffective in eliminating the perimeatal flora in 75% of the infants. The same organisms were present on the perimeatal swab and in the urine specimen in 95% of the infants in the treated group and 96% of those in the no-cleansing group. To estimate the contamination rate of urine specimens routinely cultured in the laboratory, 200 consecutive specimens (142 midstream and 58 bagged) were cultured. The contamination rate of the midstream urine specimens was 15%, compared with 66% for the bagged specimens. The cost of laboratory processing of contaminated bagged urine specimens at the hospital in 1983 may have been as high as $13 365. Chlorhexidine cleansing does not appear to be cost-effective. Further randomized controlled studies are needed to evaluate the effectiveness of other cleansing agents in reducing the contamination rate of bagged urine specimens.

Role of respiratory viruses in exacerbations of primary nephrotic syndrome.

To determine whether respiratory virus infections (URI) are associated with exacerbation of nephrotic syndrome (NS) in childhood, a prospective two-winter study of 32 children with NS was done. We obtained pre- and post-season viral serologic studies, biweekly nose and throat viral cultures, daily urinalysis, biweekly telephone follow-up for URI and renal complaints, and clinical assessments as indicated. When a URI occurred, viral cultures were done weekly if the child was at home and twice weekly if hospitalized. Sixty-one URIs occurred; the agent was identified in 33 (51.6%) (respiratory syncytial virus 14, influenza virus five, parainfluenza virus five, varicella zoster virus four, adenovirus three, Mycoplasma pneumoniae one, and Chlamydia trachomatis one). Forty-one exacerbations occurred, 71% with URI; 29% had no URI during the preceding 10 days (P less than 0.01). Total relapse occurred in 29 of 41 exacerbations, 69% with URI and 31% without URI (P less than 0.01). Patients with unstable NS had more exacerbations than those with stable NS (15 of 19 (79%) vs four of 13 (31%), P less than 0.001) and more URI (2.32 vs 1.46 per child, P less than 0.05). Exacerbations in patients with minimal change, mesangioproliferative, and focal glomerulosclerosis occurred in 40%, 60%, and 64%, respectively. We conclude that exacerbations and relapses of childhood NS are temporally related to URI. Inasmuch as multiple viral agents were associated with exacerbations, nonspecific host response to infection, not viral antigen or antibody response, may be the link to NS.

A prospective study of exposure to verotoxin-producing Escherichia coli among Canadian children with haemolytic uraemic syndrome. The CPKDRC co-investigators.

Haemolytic uraemic syndrome (HUS) is a leading cause of acute renal failure in childhood. Although infection with Escherichia coli O 157. H7 has been associated with HUS in North America and Europe, only a limited number of studies have examined the role of other verotoxin-producing E. coli (VTEC) serotypes in this condition. To address this issue, we conducted a comprehensive, prospective microbiological study of patients treated for HUS at eight Canadian hospitals in the summer of 1990. Of the 34 consecutive patients with HUS enrolled over 4 months, E. coli O 157. H7 was isolated from the stools of 26, and other E. coli serotypes were isolated from four patients. In four subjects no pathogenic E. coli serotypes were identified on stool culture. Using oligonucleotide probes specific for VT-1 and VT-2, verotoxin genes were detected in the stool isolates of all patients with E. coli O 157. H7, and from two with other E. coli serotypes. Two other patients had at least a fourfold rise in anti-verotoxin antibodies. Strong evidence of exposure to a verotoxin was present in 30/34 (88%). Patients with E. coli O 157. H7 infection were more likely to develop an antibody response to VT-2 than to VT-1 (22/22 vs 12/22; P = 0.002). These results further strengthen the association of HUS with verotoxin-producing E. coli in North America, and confirm that E. coli serotypes other than O 157.H7 are isolated in a small proportion of summertime HUS episodes.

Diarrhoea in close contacts as a risk factor for childhood haemolytic uraemic syndrome. The CPKDRC co-investigators.

To determine whether the risk factors for childhood haemolytic uraemic syndrome (HUS) are similar to risk factors previously reported for Escherichia coli O 157. H7 gastroenteritis, we conducted a case-control study at eight paediatric hospitals in the summer of 1990. Thirty-four consecutive children with HUS were prospectively enrolled; all had diarrhoea and 88% had laboratory evidence of exposure to verotoxin-producing E. coli (VTEC). The 102 controls were otherwise healthy children with minor acute injuries. Parents of all subjects responded to a questionnaire about each child's exposure to various foods, methods of food preparation, sources of water, travel, and individuals with diarrhoea. Children with HUS were significantly more likely than controls to have had close contact with an individual with diarrhoea in the 2 weeks before the onset of illness (74 v. 29%, P < 0.00001; odds ratio 7.0, 95% CI 2.7-18.5). The onset of diarrhoea in the contacts occurred a median of 6 days (range, 1- > 14 days) before the onset of diarrhoea in the HUS patients. Exposure to undercooked ground meat was not significantly more common in the patients with HUS (15 v. 8%; P = 0.05). These data provide evidence consistent with person-to-person transmission of VTEC in a substantial proportion of episodes of childhood HUS.

Sequelae of haemolytic uraemic syndrome.

Twenty two patients with previous episodes of haemolytic uraemic syndrome (HUS) were investigated for evidence of deficits in cognitive, behavioural, and academic function. Patients were pair matched with 22 controls for age (+/- 1 year), gender, and socioeconomic status. HUS patients had numerically lower cognitive and achievement scores and higher behavioural problem ratings than their controls on every measure. None of the group differences was significant at the 0.01 level. Significance values between 0.10 and 0.01 were obtained for the Wechsler full scale and verbal intelligence quotient scores and for several of the achievement measures and behaviour ratings. These results were conservatively interpreted as trends and are considered to provide preliminary indications of a post-HUS deficit in behaviour, verbal intelligence, and the verbally based skills of reading comprehension and vocabulary. The findings provide interim guidelines for follow up care but require confirmation and elaboration in a larger study.

Risk of hemolytic uremic syndrome after sporadic Escherichia coli O157:H7 infection: results of a Canadian collaborative study. Investigators of the Canadian Pediatric Kidney Disease Research Center.

OBJECTIVES: The objectives of this study were to better estimate the age-specific risks of hemolytic uremic syndrome (HUS) and hemolytic anemia after Escherichia coli O157:H7 infection among a representative cohort of both referred and nonreferred children with documented illness from the province of Alberta and to compare this with the rates in children evaluated at referral centers in the rest of Canada. STUDY DESIGN: Children with HUS or E. coli O157:H7 gastroenteritis were eligible if they were < 15 years of age. Hemoglobin, blood smear, urinalysis, and serum creatinine were obtained 8 to 10 days after the onset of diarrhea to ascertain for hemolysis, anemia, thrombocytopenia, and renal injury. Subjects were monitored for 1 month. RESULTS: From June 1991 to March 1994, HUS was diagnosed in 205 children. Of these 77% had evidence of E. coli O157:H7 infection. A further 582 children had E. coli O157:H7 gastroenteritis, of whom 18 had hemolytic anemia. The risk of HUS after E. coli O157:H7 infection in Alberta was 8.1% (95% confidence interval, 5.3 to 11.6) compared with 31.4% in referral centers in the rest of Canada. In Alberta the highest age-specific risk of HUS/hemolytic anemia was 12.9% in those < 5 years of age. CONCLUSIONS: These data will help guide clinical care and provide a basis for estimating the sample sizes required in future treatment trials for the secondary prevention of HUS.

Neuropsychological sequelae of haemolytic uraemic syndrome. Investigators of the HUS Cognitive Study.

BACKGROUND: Severe haemolytic uraemic syndrome (HUS) in childhood can cause stroke, hemiplegia, cortical blindness, and psychomotor retardation. These outcomes are evident at the time of discharge immediately after the acute illness. Less is known about the neuropsychological outcomes of less severely affected children who recover from acute HUS. AIMS: This multicentre case control study investigated the hypothesis that children who survive an acute episode of HUS without recognizable neurological injuries have greater impairment of cognitive, academic, and behavioural functions than controls. DESIGN: Children with HUS were eligible if they had no evidence of severe neurological dysfunction when discharged from one of six Canadian hospitals. Controls had been admitted to hospital for a non-HUS illness and were matched by age, sex, first language, and socioeconomic status. All subjects underwent evaluation of behaviour, academic achievement, cognitive function, and verbal abilities using standardised tests administered by a psychometrist blinded to the case or control status. RESULTS: Ninety-one case control pairs were enrolled. No important differences between patients with HUS and paired controls were evident on tests of IQ, behaviour, verbal abilities, or academic achievement. There was no increased risk of attention deficit disorder among patients with HUS. There was no correlation between the severity of acute renal failure and neuropsychological measures, although scores on some verbal ability tests were lower in those with the highest serum creatinine concentrations during illness. CONCLUSIONS: Children discharged from hospital without apparent neurological injury after an episode of acute HUS do not have an increased risk of subclinical problems with learning, behaviour, or attention.

Evaluation of the HUD lead hazard control grant program: early overall findings.

This study evaluates the effectiveness of lead hazard control methods used in the Lead Hazard Control (LHC) grant program of U.S. Department of Housing and Urban Development. The LHC Program awards funds to local jurisdictions to address lead hazards in privately owned, low-income dwellings. Grantees in 14 cities, states, or counties collected environmental data in over 2600-treated dwellings making this the largest study of residential lead hazard control ever undertaken. Grantees employed a range of treatments, the most common being replacement of windows and repair of deteriorated lead-based paint. In this paper, dust lead loading levels and blood lead levels of children (6 months-6 years, if present) were observed at four periods of time (preintervention, immediate, and 6- and 12-months postintervention) in 1212 dwellings. Dust lead loading levels were also observed in a subset of these dwellings at 24- and 36-months postintervention. The geometric mean floor and window dust lead loadings declined at least 50 and 88% (P<0.0001), respectively, immediately postintervention. Three years later, floor dust lead loadings remained at or below the immediate postintervention levels. Window dust lead loadings had moderate increases, but remained substantially reduced from preintervention levels and below clearance standards. At 1 year after intervention, geometric mean age-adjusted blood lead levels had declined from 11.0 to 8.2 microg/dL, a 26% decline (P<0.0001). The LHC Program interventions produced blood lead declines similar to or greater than the percentage changes reported in earlier 1-year lead intervention studies.

Prevalence of hypertension in children with primary vesicoureteral reflux.

This study was undertaken to determine the prevalence of hypertension in children with primary, uncomplicated vesicoureteral reflux (VUR) and to evaluate the relationship between blood pressure (BP), grade and duration of reflux, and renal scarring. Subjects were identified retrospectively during a 17-year period; of 146 subjects who agreed to participate, 129 (88.4%) were female. Mean age at diagnosis was 5.0 years (range, 1 month to 16 years), and at follow-up was 14.4 years (range, 5 months to 21 years). Mean duration of follow-up was 9.6 years. Renal scarring was detected in 34.3% of patients by intravenous pyelogram, ultrasonography, or both. The BP at diagnosis was linearly related to the grade of reflux, but values were not higher than expected norms for age. At follow-up, mean systolic and diastolic BP were at the 41.6 percentile and the 18.7 percentile, respectively. No patient's BP was above the 55th percentile. After a mean follow-up period of 10 years, we conclude that primary, uncomplicated VUR, regardless of the number of documented urinary tract infections, duration and severity of reflux, modality of therapy, presence of renal scarring, and duration of follow-up, is not associated with the development of hypertension. Hypertension does not appear to be a complication of VUR and urinary tract infection unless there is preexisting dysplasia.

Sensitivities and specificities of premier E. coli O157 and premier EHEC enzyme immunoassays for diagnosis of infection with verotxin (Shiga-like toxin)-producing Escherichia coli. The SYNSORB Pk Study investigators.

This study describes the performance of two rapid enzyme immunoassays, Premier E. coli O157 and Premier EHEC (Meridian Diagnostics Inc., Cincinnati, Ohio) for the detection in stools of Escherichia coli O157 and verotoxins (Shiga-like toxins), respectively. Both tests were performed on stools from 876 children presenting to eight emergency departments with diarrhea. Standard culture, including E. coli O157:H7 isolation, was performed, and paired sera were taken for anti-O157-lipopolysaccharide antibody determination. Stools from patients enrolled in the study, and those yielding discordant results, were sent to a reference laboratory for repeat testing and further investigation, including cytotoxicity and non-O157 verotoxin-producing E. coli culture. Results were classified as field results (obtained in the eight site laboratories) and resolved results (obtained after repeat testing in the central laboratory). The "gold standard" for sensitivity of both tests and for specificity of Premier E. coli O157 was isolation of E. coli O157:H7 or a fourfold anti-O157 antibody rise. Specimens positive by the Premier EHEC test and negative for E. coli O157 culture were examined for non-O157 verotoxin-producing E. coli. The field sensitivity of Premier E. coli O157 was 86%, that of Premier EHEC was 89%, and the specificity of Premier E. coli O157 was 98%. Ten of 13 discordant Premier E. coli O157 results were reassigned as true results after repeat testing. Ten non-O157 verotoxin-producing E. coli isolates were recovered from Premier EHEC-positive, E. coli O157 culture-negative stools. Only one specimen gave an unequivocally false-positive Premier EHEC result. Both tests are highly sensitive and are specific if correctly performed. The Premier EHEC test will be particularly valuable as a practical routine test for the detection of non-O157 verotoxin-producing E. coli.

Epidemic Escherichia coli O157:H7 gastroenteritis and hemolytic-uremic syndrome in a Canadian inuit community: intestinal illness in family members as a risk factor.

OBJECTIVE: To evaluate risk factors for childhood hemolytic-uremic syndrome (HUS) and gastroenteritis during an epidemic of Escherichia coli O157:H7 infection. DESIGN: Case-control study. SETTING: Remote Inuit community of Arviat in northern Canada. PARTICIPANTS: Of the 565 Arviat residents less than 15 years of age, 19 had HUS and 65 more had E. coli O157:H7 gastroenteritis. The 19 children with HUS were compared with 19 age- and gender-matched children with uncomplicated E. coli O157:H7 gastroenteritis, and both HUS and gastroenteritis patients were compared with 19 healthy control subjects. INTERVENTIONS: Questionnaire administered face-to-face to parents of participants in the home. MAIN OUTCOME MEASURES: Rates of exposure to foods, travel, sources of water, and gastrointestinal illness in family members. RESULTS: Patients with HUS and those with uncomplicated E. coli O157:H7 gastroenteritis differed only on measures of clinical severity. In the 7 days before the onset of gastrointestinal symptoms, children with HUS and those with uncomplicated gastroenteritis were more likely to have been exposed to a family member with diarrhea than were the healthy control subjects (odds ratio = 9 for HUS vs healthy control subjects; 95% confidence interval 2 to 43; p < 0.01). Undercooked ground meat and foods traditionally consumed by the Inuit were not implicated as risk factors in E. coli O157:H7 infection. CONCLUSIONS: These findings emphasize the potential for extensive intrafamilial transmission of verotoxin-producing E. coli once infection is introduced into certain communities.