Julian Midgley

Clinical genetics and the Hutterite population: a review of Mendelian disorders.

The Hutterian Bretheren is an isolated population living on the North American prairies, the current community exceeding 40,000 in number. Their unique genetic history has contributed to a founder effect, which is reflected in the Mendelian disorders present in this population today. Genetic studies in the Hutterite population have led to the identification of a number of genes over the last several years and highlights the power of this population for gene identification. However, for the more than 30 autosomal recessive conditions currently recognized in this population, the gene or Hutterite specific mutation remains to be identified for over half and novel autosomal recessive syndromes continue to be recognized. This review summarizes what is currently understood about the molecular etiology of the Mendelian disorders and highlights the cardinal features of those disorders that are unique to or over‐represented in this population.

Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1. Furthermore, expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1&Dgr; yeast strains, whereas expression of disease-associated variants did not. Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist. In Drosophila, Sply mutants, which lack SGPL1, displayed a phenotype reminiscent of nephrotic syndrome in nephrocytes. WT Sply, but not the disease-associated variants, rescued this phenotype. Together, these results indicate that SGPL1 mutations cause a syndromic form of SRNS.

Invasive Streptococcus pneumoniae Infection Causing Hemolytic Uremic Syndrome in Children: Two Recent Cases

INTRODUCTION Streptococcus pneumoniae is an uncommon cause of hemolytic uremic syndrome (HUS) with a unique pathophysiology that differs from Shiga toxin-related HUS. METHODS Case descriptions for each patient are provided. Each strain of S pneumoniae was subjected to a pulsed-field gel electrophoresis (PFGE) analysis, Shiga toxin assay and polymerase chain reaction to detect Shiga toxin genes. A review of the current literature was conducted. CASE PRESENTATIONS Two patients with S pneumoniae-related HUS that presented to the Alberta Childrens Hospital, Calgary, Alberta, within four weeks of each other in 2001 are described. Both presented with pneumonia and empyema with associated HUS. Both patients required dialysis, one patient for 10 days and the other for 18 days. Neither patient demonstrated evidence of Shiga toxin-related disease. S pneumoniae isolated from blood or pleural fluid was penicillin susceptible. One isolate was serotype 3 and the other was serotype 14. The two strains had different PFGE patterns. Both patients recovered well with no persistent renal dysfunction. CONCLUSIONS S pneumoniaecontinues to be an uncommon but important cause of HUS. Most cases can be confirmed or at least considered probable without performing a renal biopsy.

Acute Renal Replacement Therapy in Children with Diarrhea-Associated Hemolytic Uremic Syndrome: A Single Center 16 Years of Experience

Acute kidney injury (AKI) is becoming more prevalent among hospitalized children, its etiologies are shifting, and new treatment modalities are evolving; however, diarrhea-associated hemolytic uremic syndrome (D+HUS) remains the most common primary disease causing AKI in young children. Little has been published about acute renal replacement therapy (ARRT) and its challenges in this population. We describe our single centers experience managing 134 pediatric patients with D+HUS out of whom 58 (43%) required ARRT over the past 16 years. In our cohort, all but one patient were started on peritoneal dialysis (PD). Most patients, 47 (81%), received acute PD on a pediatric inpatient ward. The most common recorded complications in our cohort were peritoneal fluid leaks 13 (22%), peritonitis 11 (20%), and catheter malfunction 5 (9%). Nine patients (16%) needed surgical revision of their PD catheters. There were no bleeding events related to PD despite a mean platelets count of 40.9 (±23.5) × 103/mm3 and rare use of platelets infusions. Despite its methodological limitations, this paper adds to the limited body of evidence supporting the use of acute PD as the primary ARRT modality in children with D+HUS.

Hypertension and obstructive sleep apnea in Caucasian children

AIM To evaluate the prevalence of hypertension and/or left ventricular hypertrophy (LVH) in children with a diagnosis of obstructive sleep apnea (OSA). METHODS A cross-sectional case series of consecutive, otherwise healthy children aged > 4 years, with polysomnography-proven OSA [apnea hypopnea index (AHI) > 1.5/h] is described. Echocardiography was performed on all subjects and left ventricular mass was calculated. Study subjects underwent additional investigation with 24-h ambulatory blood pressure (BP) monitoring. RESULTS Thirty children (21 males) were studied. Mean age was 8.9 years. Mean body mass index was 19.87 kg/cm(2). Mean AHI was 14.3/h. 10/30 (33%) of the study population met criteria for pre-hypertension (n = 3) or masked hypertension (n = 7) based on standard ambulatory monitoring criteria. All 10 children had systolic hypertension throughout the night with 5 of these also having elevated daytime systolic readings. There was a relationship between AHI and BP showing an increase of 1.162 percentile units in mean diastolic night BP (age, gender and height specific) per unit increase in AHI (P = 0.018). There were no subjects with LVH and/or right ventricular hypertrophy. CONCLUSION In our population of otherwise healthy Caucasian children, there was a high prevalence of hypertension that would not have been identified using standard office/clinic protocols.

Areal and Volumetric Bone Mineral Density Changes After Renal Transplantation in Children: A Longitudinal Study

INTRODUCTION The effect of renal transplantation on areal bone mineral density (aBMD) in children has previously been studied. However, most previous reports did not include estimation of volumetric bone mineral density (vBMD) or analyze longitudinal data in these patients. In addition, updated reference standards for aBMD in children have recently been made available. METHODS This retrospective study describes the longitudinal effect of renal transplantation on aBMD and vBMD in a cohort of 40 pediatric kidney transplant recipients. Lumbar spine aBMD measurements were obtained using dual-energy X-ray absorptiometry prior to transplant and yearly thereafter. vBMD values and z-scores were estimated as described in the most recently published references. RESULTS A significant decrease in average aBMD and vBMD z-scores was observed within 1 year posttransplant, which did not recover during follow-up. The negative effect of transplantation on vBMD was blunted and vBMD z-scores were higher compared to aBMD. Linear mixed-effects model analysis demonstrated that lumbar spine aBMD and vBMD z-scores were inversely related to yearly prednisone dose (g/m2) but this effect was diminished as glomerular filtration rate was increased. CONCLUSIONS Bone mineral density was negatively affected by renal transplantation in this cohort of pediatric patients. Estimation of vBMD appears to be appropriate for interpretation of the BMD changes occurring after renal transplant in children. The inverse relation between BMD z-scores and yearly prednisone dose suggests that ongoing posttransplant corticosteroid therapy may be responsible for the negative effect of transplantation on bone mineral density in this cohort.

Discordance between skin biopsy and kidney biopsy in an X-linked carrier of Alport syndrome.

Alport syndrome (AS) is the most common form of hereditary nephritis. Females with X-linked AS are heterozygous carriers of the disease mutation. Carrier status in females without a family history has traditionally been diagnosed by kidney biopsy; more recently skin biopsy has been utilized. We report on a 14-year-old girl with long-standing hematuria and intermittent proteinuria who underwent kidney and skin biopsy to establish a definitive diagnosis. Electron microscopy showed extensive thinning of glomerular basement membrane (GBM), with no evidence of lamination. Immunofluorescence staining showed continuous GBM staining for the α3(IV) and α5(IV) collagen chains, whereas the epidermal basement membrane showed discontinuous α5(IV) collagen staining consistent with an X-linked carrier of AS. Few reports have shown discordance between kidney and skin biopsy findings as seen in this case, presumably due to X chromosome lyonization. We therefore suggest that simultaneous kidney and skin biopsies may be more accurate in the assessment of potential female carriers of AS than either kidney biopsy or skin biopsy alone.

Glomerular Filtration Rate Trends During Follow-up in Children With Steroid-Sensitive Nephrotic Syndrome

Background: Overall prognosis of children with steroid-sensitive nephrotic syndrome (SSNS) is regarded as generally favorable. However, only a few recent studies have evaluated changes in kidney function and blood pressure over time in children with SSNS. Objectives: We describe clinical features of SSNS patients and characterize changes in calculated estimated glomerular filtration rate (eGFR) and use of antihypertensive medications during follow-up. Design: This is a retrospective cohort study. Setting: This study was conducted in a Canadian pediatric nephrology center. Patients: This study included patients aged 1 to 18 years with SSNS. Measurements: eGFR was calculated from recorded serum creatinine and height measurements using the modified Schwartz equation. Methods: eGFR was calculated at yearly intervals, and the trend of eGFR was assessed using linear mixed effects model. Patients were also evaluated for use of antihypertensive medications during follow-up. Results: Seventy-eight patients—median age, 3.2 years (interquartile range [IQR], 2.65) and median follow-up of 4.37 (IQR, 5.6)—were evaluated. Sixty-three (80.8%) had at least 1 relapse. Twenty-two (28.2%) and 20 (25.6%) were steroid dependent and frequently relapsing, respectively. Forty-three patients (55.1%) received at least 1 steroid-sparing agent, and of these, 18 (41.8%) received a calcineurin inhibitor. One patient had eGFR ≤90 mL/min/1.73 m2 during observation. eGFR remained unchanged over the follow-up period in this cohort of patients. Four patients (5.1%) were on antihypertensive medications at the end of follow-up. Limitations: Patients who had frequent relapses had more measurements available for serum creatinine and height, creating a sampling bias. The number of eGFR measurements was overall small, making it difficult to ascertain eGFR trend. Conclusion: eGFR remained unchanged over time in this cohort, and a small proportion of patients required antihypertensive therapy at the end of follow-up. Our study highlights the needs for carefully constructed long-term observational studies of children with nephrotic syndrome.

Effective use of rituximab in combination with low dose cyclophosphamide in childhood onset systemic lupus erythematosus (SLE) with relapsing class IV nephritis

All patients received pulse therapy with: IV cyclophosphamide 0.5 g/m2 with IV methylprednisolone (IVMP) 250 mg on days 1 and 23; IV rituximab 375 mg/m2 on days 2, 9, 16 and 23. Results All 3 patients had a dramatic improvement in urine protein-creatinine ratios, and normalization of blood pressure. Despite low-dose daily corticosteroids, all patients had an increase in generalized SLE activity by 4 weeks following rituximab therapy, which responded to re-introduction of MMF. No side effects apart from expected decrease in B-cell counts were noted.