Schimke immuno-osseous dysplasia (SIOD, MIM 242900) is an autosomal-recessive pleiotropic disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency. Using genome-wide linkage mapping and a positional candidate approach, we determined that mutations in SMARCAL1 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), are responsible for SIOD. Through analysis of data from persons with SIOD in 26 unrelated families, we observed that affected individuals from 13 of 23 families with severe disease had two alleles with nonsense, frameshift or splicing mutations, whereas affected individuals from 3 of 3 families with milder disease had a missense mutation on each allele. These observations indicate that some missense mutations allow retention of partial SMARCAL1 function and thus cause milder disease.

Schimke immuno-osseous dysplasia is a multi-system autosomal recessive disorder with variable expression that affects the skeletal, renal, immune, vascular, and haematopoietic systems. Medical therapy is limited especially for more severely affected individuals.

Background: Congenital nephrotic syndrome (CNS) is defined as nephrotic syndrome that manifests within the first 3 months of life. Mutations in the NPHS1 gene encoding nephrin, are a major cause for CNS. Currently, more than 173 different mutations of NPHS1 have been published as causing CNS, affecting most exons. Methods: We performed mutation analysis of NPHS1 in a worldwide cohort of 20 families (23 children) with CNS. All 29 exons of the NPHS1 gene were examined using direct sequencing. New mutations were confirmed by demonstrating their absence in 96 healthy control individuals. Results: We detected disease-causing mutations in 9 of 20 families (45%). Seven of the families showed a homozygous mutation, while two were compound heterozygous. In another 2 families, single heterozygous NPHS1 mutations were detected. Out of 10 different mutations discovered, 3 were novel, consisting of 1 splice site mutation and 2 missense mutations. Conclusion: Our data demonstrate that the spectrum of NPHS1 mutations is still expanding, involving new exons, in patients from a diverse ethnic background.

Sequelae of Escherichia coli O157:H7-associated hemolytic uremic syndrome (HUS) 2-3 years following an outbreak in Washington State have been prospectively studied to identify predictors of adverse sequelae. Logistic regression analysis was used to examine associations between findings in the acute course and long-term renal and gastrointestinal outcomes. Twenty-one percent of patients had gastrointestinal sequelae, which included cholelithiasis resulting in cholecystectomy (3/29), persistent pancreatitis (2/29), late colon stricture (1/29), and/or glucose intolerance (1/29). Logistic regression analysis found long-term gastrointestinal sequelae were higher in patients who, during HUS, had hypertension [odds ratio (OR) = 21.2, 95% confidence interval (CI) = 1.9-164.4, P = 0.01] or gastrointestinal complications (OR = 21.2, 95% CI = 1.9-164.4, P = 0.01). Renal sequelae were seen in 35% of patients. One patient (4%) had persistent hypertension and 9 (31%) had minor urinary findings (hematuria or proteinuria). Thrombocytopenia lasting longer than 10 days during the acute illness was associated with a risk for subsequent renal sequelae (OR = 15.0, 95% CI = 1.98-1,703.0, P = 0.009). We conclude a high incidence of gastrointestinal sequelae, especially cholelithiasis presenting long after the acute illness, may be seen with HUS. The short follow-up period may underestimate the extent and severity of eventual renal sequelae.