Abnormal differentiation of the renal stem/progenitor pool into kidney tissue can lead to renal hypodysplasia (RHD), but the underlying causes of RHD are not well understood. In this multicenter study, we identified 20 Israeli pedigrees with isolated familial, nonsyndromic RHD and screened for mutations in candidate genes involved in kidney development, including PAX2, HNF1B, EYA1, SIX1, SIX2, SALL1, GDNF, WNT4, and WT1. In addition to previously reported RHD-causing genes, we found that two affected brothers were heterozygous for a missense variant in the WNT4 gene. Functional analysis of this variant revealed both antagonistic and agonistic canonical WNT stimuli, dependent on cell type. In HEK293 cells, WNT4 inhibited WNT3A induced canonical activation, and the WNT4 variant significantly enhanced this inhibition of the canonical WNT pathway. In contrast, in primary cultures of human fetal kidney cells, which maintain WNT activation and more closely represent WNT signaling in renal progenitors during nephrogenesis, this mutation caused significant loss of function, resulting in diminished canonical WNT/b-catenin signaling. In conclusion, heterozygous WNT4 variants are likely to play a causative role in renal hypodysplasia.

Despite significant technical improvements, hemodialysis in infants with end-stage renal disease (ESRD) is still associated with significant morbidity and mortality. The files of patients weighing less than 15 kg with ESRD who were treated with hemodialysis at our institute between 1995 and 2005 were reviewed for background and treatment characteristics, morbidity and outcome. The study group included 11 patients aged 7-75 months (mean 34.2 months) weighing 7.2-14.9 kg (mean 10.9 kg). Mean duration of dialysis was 11.3 months. Vascular access posed the major problem. Ten patients were dialyzed through a central venous cuffed catheter and one through an arteriovenous fistula. An average of three different vascular accesses was required per patient (range 1-9). Mechanical difficulties were the most common cause of central-line removal (56.5%), followed by infections (15.6%). Major complications causing significant morbidity were intradialytic hemodynamic instability, hyperkalemia, coagulation within the dialysis set, anemia, hypertension, inadequate fluid removal, and recurrent hospitalizations. Analysis of outcome revealed that eight patients underwent successful transplantation, one returned for hemodialysis after 4.5 years due to graft failure, and two died. Hemodialysis is a suitable option for low-weight pediatric patients with ESRD awaiting transplantation when performed in highly qualified centers.

Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive disorder caused by loss-of-function mutations in SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1), with clinical features of growth retardation, spondylo-epiphyseal dysplasia, nephrotic syndrome, and immunodeficiency. We report a patient with SIOD and SMARCAL1 splice mutation (IVS4-2 AϾG) in a nonconsanguineous Ashkenazi family, who came to our attention at 1 mo of age due to renal malformation and only later developed signs compatible with Schimke. Interestingly, residual SMARCAL1 mRNA levels in the patient's peripheral blood were lower compared with those observed in both asymptomatic brothers' carrying the same bi-allelic mutation, whereas the latter had levels similar to those found in heterozygous carriers (parents and sister). Examination of the carrier frequency of the splice mutation in the Ashkenazi population demonstrated 1 carrier in 760 DNA samples. In situ localization of SMARCAL1 in human kidneys as well as analysis of its temporal expression during murine nephrogenesis and in the metanephric organ culture suggested a role in the early renal progenitor population and after renal maturation. Thus, disease severity within the same family might be modified by the splicing machinery. The renal expression pattern of SMARCAL1 explains a broader spectrum of renal disease in SIOD than previously described. (Pediatr Res 63: 398-403, 2008) S chimke immuno-osseous dysplasia (SIOD) is characterized by autosomal recessive inheritance, spondyloepiphyseal dysplasia causing growth retardation, defective cellular immunity, progressive nephropathy leading to renal failure, hyperpigmented macules, and dysmorphic facial features (1-4). Half of SIOD patients also have hypothyroidism, half episodic cerebral ischemia, and a tenth bone marrow failure.SIOD is caused by mutations in SWI/SNF2 related, matrix associated, actin dependent regulator of chromatin, subfamily a-like 1(SMARCAL1) (5). SNF2 related proteins participate in the DNA nucleosome restructuring which commonly occurs during gene regulation and DNA replication, recombination, methylation, and repair (6,7).Recent analysis of detailed autopsies to correlate clinical and pathologic findings in SIOD identified T cell deficiency in peripheral lymphoid organs, defective chondrogenesis, focal segmental glomerulosclerosis (FSGS), cerebral ischemic lesions, and premature atherosclerosis (8).Herein, we report on a male patient, 6 y old, who came to our attention after birth due to renal malformation and later on developed growth retardation, bone dysplasia, and steroidresistant nephrotic syndrome and was shown to harbor a bi-allelic SMARCAL1 splice mutation. Investigation of his nonconsanguineous Ashkenazi family lead us to discover phenotypic diversity and variable expressivity of SMARCAL1 in the family along with low carrier frequency of the splice mutation in the Ashkenazi population. In addition, in situ localization of SMARCAL1 in the...

Renovascular hypertension in children is usually asymptomatic and diagnosed incidentally. Behavioral changes have not yet been well recognized as a part of the clinical spectrum of renovascular disease in children. We surveyed all children diagnosed with renovascular hypertension in our institute over a 15-year period. Eleven children were identified, of whom five (45%) had abnormal behavior, which had preceded the diagnosis of hypertension by 3-12 months. The symptoms included restlessness, sleep disturbances, temper tantrums, hyperactivity, aggressive behavior and attention deficit. In three children all behavioral symptoms disappeared following blood pressure normalization, and, in the other two a significant improvement was noted. It was concluded that behavioral symptoms may be a common and early manifestation of renovascular hypertension. Awareness of this association may bring about earlier diagnosis of the disease and prevent end-organ damage as well as unnecessary investigations for behavioral abnormalities.