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Importance: Polymicrogyria is the most commonly diagnosed cortical malformation and is associated with neurodevelopmental sequelae including epilepsy, motor abnormalities, and cognitive deficits. Polymicrogyria frequently co-occurs with other brain malformations or as part of syndromic diseases. Past studies of polymicrogyria have defined heterogeneous genetic and nongenetic causes but have explained only a small fraction of cases., Objective: To survey germline genetic causes of polymicrogyria in a large cohort and to consider novel polymicrogyria gene associations., Design, Setting, and Participants: This genetic association study analyzed panel sequencing and exome sequencing of accrued DNA samples from a retrospective cohort of families with members with polymicrogyria. Samples were accrued over more than 20 years (1994 to 2020), and sequencing occurred in 2 stages: panel sequencing (June 2015 to January 2016) and whole-exome sequencing (September 2019 to March 2020). Individuals seen at multiple clinical sites for neurological complaints found to have polymicrogyria on neuroimaging, then referred to the research team by evaluating clinicians, were included in the study. Targeted next-generation sequencing and/or exome sequencing were performed on probands (and available parents and siblings) from 284 families with individuals who had isolated polymicrogyria or polymicrogyria as part of a clinical syndrome and no genetic diagnosis at time of referral from clinic, with sequencing from 275 families passing quality control., Main Outcomes and Measures: The number of families in whom genetic sequencing yielded a molecular diagnosis that explained the polymicrogyria in the family. Secondarily, the relative frequency of different genetic causes of polymicrogyria and whether specific genetic causes were associated with co-occurring head size changes were also analyzed., Results: In 32.7% (90 of 275) of polymicrogyria-affected families, genetic variants were identified that provided satisfactory molecular explanations. Known genes most frequently implicated by polymicrogyria-associated variants in this cohort were PIK3R2, TUBB2B, COL4A1, and SCN3A. Six candidate novel polymicrogyria genes were identified or confirmed: de novo missense variants in PANX1, QRICH1, and SCN2A and compound heterozygous variants in TMEM161B, KIF26A, and MAN2C1, each with consistent genotype-phenotype relationships in multiple families., Conclusions and Relevance: This study's findings reveal a higher than previously recognized rate of identifiable genetic causes, specifically of channelopathies, in individuals with polymicrogyria and support the utility of exome sequencing for families affected with polymicrogyria.

The combination of poor growth and parathyroid and mineral disorders complicates the diagnosis of renal bone disease in children with chronic renal insufficiency (CRI), and the role of dual X-ray absorptiometry (DXA) is unclear. We aimed to examine the role of DXA in assessing variation in size-adjusted bone mineral content (BMC) in children with CRI and compare it with a cohort with hypoparathyroidism (HPT) and pseudo-hypoparathyroidism (PHPIa). In 29 patients with CRI (21 male) with a median age of 11 years (10th, 90th centiles 4.4, 14.6) and 10 patients with HPT and PHPIa (three male), with a median age of 13.7 years (7, 16) lumbar spine (LS) and total body (TB) BMC were measured by DXA. Age-, gender- and height-matched data allowed calculation of percentage predicted bone area for age and gender (pBAr) and percentage predicted BMC for bone area and height. In the CRI group, the median glomerular filtration rate (GFR) was 27.4 ml/min per 1.73 m2 (7.1, 69.5), and the median duration of illness was 9.3 years (2.1, 12.1). Median height standard deviation score (Ht SDS) was -1.6 (-3.0, 0.3), and, as expected, median LS and TB pBAr were low at 82% (68, 974) and 76% (63, 92), respectively. LS and TB predicted BMC (pBMC) SDS (corrected for bone size) were generally high, with a median value of 0.4 (-0.9, 1.4) and 0.4 (-0.1,0.9), respectively. Analysis of the prepubertal subset of children (n=15) showed that median percentage predicted LS BMC for height was 104% (80, 116), whereas the median TB BMC for height was 96% (74, 108). Median Ht SDS of the HPT and PHPIa cohort was -0.3 (-2.9, 0.3) and median LS and TB pBAr were 90% (66, 100) and 91% (76, 98), respectively. Median LS and TB pBMC SDS were 0.6 (-0.4, 1.8) and 0.7 (0.3, 1.1), respectively. Median percentage predicted LS and TB BMC for height were 102% (82, 114) and 102% (92, 122). There was no relationship between pBMC SDS and duration of illness, GFR, vitamin D dose, serum intact parathyroid hormone (PTH), serum calcium/phosphate product or serum total alkaline phosphatase (ALP) in the CRI or the HPT cohort. However, one of the highest pBMC SDSs was recorded in a child with PHPIa before she started on any treatment. In children with CRI, BMC, when adjusted for co-existing growth retardation, is similar to that observed in children with hypoparathyroidism. The correct reading of BMC needs a correction for bone size.

Objectives: To assess stature and skeletal disproportion in children with chronic renal disease., Methods: Cross-sectional study of height (HT), sitting height (SH), subischial leg length (SILL), sitting height/height ratio (SH:HT) and disproportion score (SH SDS minus SILL SDS) in 56 children (M:35) with median age 11.4 years (range 4.5,18.7) with chronic renal disease., Results: There were 19 children with chronic renal insufficiency, 6 receiving peritoneal dialysis and 31 after renal transplant. The median HTSDS for the whole group was -1.21 (-2.8, 0.35). The median SH:HT ratio in non-transplanted children and renal transplant were 0.51 (0.49, 0.53) and 0.50 (0.48, 0.53), respectively (p = 0.02). The median disproportion score of the whole group was -3.2 (-4.8, -1.8). There was a significant correlation between disproportion score and SH:HT (r = 0.5, p = 0.005). SH:HT ratio was negatively related to duration of illness (r = 0.4, p = 0.005)., Conclusion: Children with chronic renal disease have significant body disproportion and this may be due to a disproportionately greater effect of disease and treatment on spinal growth., (Copyright 2003 S. Karger AG, Basel)

Background: Stereologic methods have emerged as the technique of choice in assessing glomerular basement membrane (GBM) thickness, following conceptual modeling comparing the stereologic technique of harmonic mean of the orthogonal intercept estimation (Th) with the model based method of arithmetic mean estimation (ATH), with no direct comparison undertaken. We undertook to establish the gold standard for GBM estimation and use this technique to establish a range for GBM thickness in children., Methods: Intra-observer and inter-glomerular variation was estimated in 34 cases with (presumed) normal GBM thickness, using Th, ATH and a rapid direct measurement technique, with intra-observer variation measured in 35 cases with GBM attenuation. A total of 34,011 measurements were undertaken to establish a range for Th in children on 212 biopsies from 199 patients (127 male) demonstrating minimal change nephropathy (N = 153), focal segmental glomerulosclerosis (24), no abnormality (24), and acute tubular necrosis (8), which were used as surrogates for normals., Results: Th demonstrated less variation than ATH in both the normal and attenuated groups. GBM thickness increased throughout childhood, from 194 +/- 6.5 nm (mean +/- SE) at one year to 297 +/- 6.0 nm at 11 years, with a reduced rate of increase after age 11 years., Conclusion: Stereologic methods are superior to model based techniques in estimating GBM thickness and should be regarded as the technique of choice in this area. GBM thickness was observed to increase during childhood with no gender effect demonstrable as a main effect or interaction.

We describe the case of a paediatric kidney transplant patient who developed cyclosporin neurotoxicity on day 7 post-transplant. Consequently, her cyclosporin was stopped and she was commenced on rapamycin. Over the next 3 weeks her creatinine remained elevated and she had several episodes of biopsy proven rejection, despite increasing the initial dose of rapamycin by tenfold. Her whole blood rapamycin levels also remained well below the target range of 10-20 ng/ml. On day 38 post-transplant, the decision was made to add tacrolimus to her immunosuppression. At the same time, phenytoin, which had been commenced during her episode of cyclosporin neurotoxicity, was withdrawn. After this point her rapamycin blood levels rapidly increased to within the therapeutic range and she improved clinically. We propose that phenytoin, as a p450 cytochrome enzyme inducer, increased the metabolism of rapamycin in this patient and hence decreased the initial therapeutic effectiveness of this drug.

A synthetic methodology to afford unusual glycoconjugate building blocks useful for the solid-phase synthesis of C-linked antifreeze glycoprotein (AFGP) analogues is described. Such compounds are urgently required in order to elucidate the molecular mechanism by which AFGPs function. All reactions are general in nature and accommodate structural variation in the carbohydrate moiety, polypeptide backbone, and amino acid side chain.

Two neonates were found on US to have branching linear calcification in the renal parenchyma, right sided in one and bilateral in the other. CT confirmed the presence of branching calcification in the kidneys and demonstrated calcified thrombus in the inferior vena cava in both babies. Antenatal detection of adrenal haemorrhage in one baby and presence of calcification at the age of 3 days in the other indicate that thrombosis probably occurred before birth. The kidneys remained normal in size, and uptake of 99mTc-labelled dimercaptosuccinic acid (99mTc-DMSA) was normal on follow-up examination. The presence of branching calcification and normal renal size probably indicates good prognosis for renal function in neonates in whom renal venous thrombosis is found and may indicate prenatal thrombosis.

Background: Paediatric nephrology is a small subspecialty whose patients are widely scattered geographically within Scotland making provision of uniform and optimal care difficult., Aim: We set out to determine what services are provided throughout Scotland as well as seeking paediatricians' views on improving services for children and adolescents with renal disease., Method: All 12 paediatric units in Scotland were visited and a senior consultant within each unit undertook to complete a questionnaire on behalf of his or her unit., Results: Questionnaires were returned by 11/12 centres (92%). The scope of renal services offered varied widely. Most (10/11) favoured a 'shared care' approach using the comprehensive paediatric nephrology service in Glasgow as a focal point. Outreach services and a telephone advisory service were suggested by 7/10 and 6/10 units respectively. The development of a Scottish paediatric nephrology group was supported by 10/11 centres returning the questionnaire., Conclusion: There is both a need and an interest in developing a national strategy for paediatric nephrology in Scotland.

Neutrophil-mediated tissue damage has been implicated in the pathogenesis of diarrhoea-associated haemolytic uraemic syndrome (D+ HUS). This study evaluates priming and activation of the neutrophil oxidative burst in D+ HUS using chemiluminescent techniques. Peripheral blood neutrophils from 11 children with acute D+ HUS were examined. No difference was found in the oxidative burst of neutrophils from patients and controls. Serum elastase levels were measured in 8 patients and found to be significantly elevated. Although elastase results suggest neutrophil activation, chemiluminescence studies do not confirm this in the peripheral blood neutrophil. This does not support a significant role for circulating agents in priming and activating the peripheral blood neutrophil.

Objective: To assess the value of an ultrasound examination in children with a proven urinary tract infection., Patients and Methods: The results of renal ultrasound and 99mTc-dimercapto-succinic acid (DMSA) studies were compared in 112 children with a first documented symptomatic Escherichia coli urinary tract infection., Results: Ultrasound was particularly effective in detecting the presence of obstruction, renal swelling and parenchymal change consistent with acute pyelonephritis. However, ultrasound failed to detect half of the kidneys with photon deficient areas on 99mTc DMSA scan and was unreliable in detecting the presence of scarring., Conclusion: An ultrasound examination alone should not be relied on in the child with an acute urinary tract infection.

Seventy-nine children with the Haemolytic Uraemic Syndrome were referred to our unit between 1972 and 1988. The typical summer peak incidence was seen. A diarrhoeal prodrome occurred in 71 (90%). Fifty-nine (75%) required dialysis and 74 (94%) blood transfusion. Extra-renal disease was documented: neurological 32 (40%); abdominal 11 (14%); diabetes mellitus one case. Fifty-one (61%) had acute hypertension. The acute mortality rate was 9%. Children with neurological features had greater biochemical disturbances and longer duration of dialysis. Fifty-nine children were followed for a mean 47.4 months. Forty-four (75%) are healthy. Nine (15%) have renal impairment, two have proteinuria, one hypertension and one has a residual hemiparesis. There were two late deaths. Presence of acute neurological features increased risk of early death or survival with sequelae. Prolonged dialysis was significantly associated with poorer outcome. However, there were no reliable early indicators of poor prognosis.

Sixteen children (11 male, 5 female) who developed renal venous thrombosis in the neonatal period or early infancy have been followed for periods varying from 29 months to 16 years (median 12 years) after initial diagnosis. Twelve patients presented with a hyperosmolar state, and in 4 the illness was preceded by severe birth asphyxia. The diagnosis was based on the findings of clinical and/or radiological renal enlargement (15 cases), haematuria (16 cases) and elevation in plasma urea (16 cases). Thrombocytopenia (13 cases), red cell fragmentation (13 cases) and oliguria (13 cases) were frequent associated findings. All 16 patients survived the acute illness, 1 patient died 3 years later from an unrelated event. On follow-up evaluation, 11 patients have normal renal function (glomerular filtration rate greater than 80 ml/min per 1.73 m2), 5 developed hypertension, 2 of whom responded to unilateral nephrectomy. Urinary concentrating capacity was subnormal (less than 800 mosmol/kg) in 7 of the 15 cases studied. Follow-up renal imaging studies were undertaken in 14 patients, and the imaging procedure was normal in only 2 of these. Of the remainder, 8 showed unilateral abnormality and 4 bilateral abnormality. Intellectual development was normal in 12 patients, mildly impaired in 1, and severely impaired in 3.

Six children with shunt nephritis are reported of whom two did not show complete recovery of renal function. Follow up and outcome in relation to the delay in diagnosis and renal biopsy appearances are discussed.

Renacidin is a urinary stone dissolving agent composed primarily of gluconic and citric acids and their magnesium salts, buffered to a pH of 4. We describe its use in a child with oxalosis, disabling renal colic and deteriorating renal function in whom its use was associated with hypermagnesemia and rapid progression of the renal failure. Possible mechanisms for the deterioration in renal function are discussed.

Between 1985 and 1987 102 children, age 0-14 years, presented with a first acute symptomatic E. coli urinary tract infection. Investigations included early 99mtechnetium dimercaptosuccinic acid (DMSA) scan (which was performed at a median of 27 days), ultrasonography, micturating cysto-urethrography and indirect voiding radionuclide cystography using 99mTc DTPA. Follow-up DMSA scan was carried out after 6 months. Twenty-one of 102 of initial DMSA studies showed diminished uptake of radionuclide and 12 showed cortical scarring. Twenty-nine patients had significant vesicoureteral reflux (VUR). The finding of diminished uptake on the initial scan was significantly associated with fever, systemic upset, length of symptoms and a peripheral blood leucocytosis, (p less than 0.05). In addition the finding was associated with fever and loin pain in the older child. Both diminished uptake and scarring were more common in refluxing kidney units. We propose that, in children with UTI, diminished uptake on early DMSA scan localises infection in the renal parenchyma.

Two premature infants who presented with neonatal ascites due to apparent spontaneous rupture of the bladder are described. In both children the site of bladder rupture was clearly shown, but neither at time of presentation nor at subsequent review at age 7 years and 7 months, respectively, was any other renal tract abnormality detected.

Between 1979 and 1985, six of 26 patients undergoing continuous ambulatory peritoneal dialysis developed fungal peritonitis. All had received antibacterial therapy with cefamandole and/or netilmicin prior to the diagnosis. The causal organisms were Candida albicans (three), Candida glabrata (one), Cryptococcus laurentii (one) and Saccharomyces cerevisiae (one). Treatment comprised catheter removal preceded by antifungal drugs (flucytosine and/or amphotericin B) in four patients and catheter removal alone in two. All patients were transferred to haemodialysis and five of the six developed extensive intra-abdominal adhesions. The most prudent management of fungal peritonitis in children would seem to be early cannula removal.

Two cases of cytomegalovirus associated renal allograft dysfunction were monitored by serial 99mTc DTPA imaging and cytomegalovirus specific fluorescent antibody tests. One case of primary cytomegalovirus disease associated with pneumonitis, hepatitis and pyrexia occurred 25 days after transplantation. The second case, due to cytomegalovirus reactivation/reinfection had fewer symptoms and occurred 78 days following transplantation. 99mTc DTPA perfusion index at the height of the cytomegalovirus associated illness remained unaltered in both cases, and did not suggest the presence of acute rejection. This non-reactive response was associated with a rapid return of graft function. The combined use of these rapid diagnostic tests during suspected rejection episodes may be useful in indicating cytomegalovirus associated allograft dysfunction and preventing the addition of further potentially harmful immunosuppressants.

Forty-two children aged one to sixteen years with persistent and severe hypertension were investigated by renal vein renin measurements. There were no serious complications in the 49 procedures performed and technical failure occurred on three occasions. Arteriography was performed in 35. Asymmetrical renin release was found in 22 patients and of these 15 underwent surgery. This was successful in 12 patients (80%) who became normotensive. Ten had unilateral disease (100% cure rate) but only 2 (40%) with bilateral disease became normotensive. Renal vein renin studies combined with arteriography have a useful role in the investigation and management of childhood hypertension.

Between 1979 and 1985, 26 patients on continuous ambulatory peritoneal dialysis had 97 episodes of peritonitis. These occurred over a period of 336 patient months, giving an incidence of one episode every 3.5 patient months. The micro-organisms comprised Gram-positive and Gram-negative bacteria as well as fungi which accounted for six episodes. Gram-positive bacteria were isolated in 49 of the 97 episodes (50.5%) with Staphylococcus epidermidis predominating. The incidence of culture-negative peritonitis was high (27.8%). Because of failure to respond to treatment, or because of frequent recurrences, 42% patients were transferred to haemodialysis. The changing bacterial ecology has necessitated an alteration in choice of antibiotics. Cefamandole and/or gentamicin are no longer appropriate since 46% strains of S. epidermidis are now methicillin-resistant. Our 'best guess' choice for bacterial peritonitis would now start with netilmicin, vancomycin being added if indicated. For fungal peritonitis we would now start with a primary course of anti-fungal agents followed by early removal of the catheter if there is no response to treatment.

Plasma from 24 children with hemolytic uremic syndrome (HUS) (10 in acute, 14 in remission phase), 42 first degree relatives and 24 controls were studied for PGI2 supporting activity (PSA) from human umbilical arterial rings and the concentration of PGI2 metabolite (PGI2m). HUS patients in acute phase showed very low or absent level of plasma PSA, which remained depressed 3 months following presentation. Plasma from 2 out of 5 acute HUS patients showed inhibition against PGI2-like activity, and depressed preservation of PGI2 effect. The mean value of PGI2m in acute phase of HUS patients was elevated initially, but fell below control range by the day 14 and remained decreased at the end of 3rd month. Patients on long term remission showed a significantly lower concentration of plasma PGI2m. Eight of 14 HUS patients in remission and 18 of 42 family members had lower PSA levels than the controls. These studies confirmed a decreased PSA in HUS and suggest that persistently low PSA levels may reflect an inherited predisposition.

Over a six year period to 1985, 64 episodes of bacterial peritonitis in children on CAPD yielded 59 Gram-positive and 15 Gram-negative isolates. The former included 27 strains of Staphylococcus epidermidis (45.8%) and 24 Staph. aureus (40.7%). Staph. epidermidis is now the commonest cause of infection in these patients and like Staph. aureus is spread by leaks and disconnections. It is also more resistant to antibiotics than Staph. aureus and this causes problems in the choice of antibiotics with failure to control peritonitis and subsequent complications such as diminished efficacy of therapy, peritoneal adhesions, recourse to haemodialysis and superinfection with fungi. Both species showed 100% sensitivity to vancomycin, rifampicin and netilmicin. Other sensitivity figures for Staph. epidermidis were methicillin 52%, benzylpenicillin 15%, cefamandole 52%, cefotaxime 52%, amoxycillin-clavulanic acid 52%, gentamicin 63%, co-trimoxazole 48%, fusidic acid 59% and erythromycin 52%. Apart from benzylpenicillin (8%), Staph. aureus was much more sensitive, the figures being 96% for methicillin and 92-100% for the others. Our initial choice of 'best-guess' therapy early in the series was cefamandole with the addition of gentamicin or tobramycin for Gram-negatives. This is now inappropriate, based on relatively poor clinical results and increasing resistance to antibiotics, and we would now use vancomycin as first choice, with netilmicin added to cover Gram-negatives.

A technique has been developed for the ultrasonic investigation of renal disease in infants using a specially designed water-bath with a conventional ultrasonic scanner. This permits ultrasonic studies of the renal tract from the neonatal period onwards; the procedure does not distress the child and the water acts as an excellent coupling medium.