Hee Yeon Cho

Hydrothorax in a patient with Denys-Drash syndrome associated with a diaphragmatic defect

The Wilms tumor suppressor gene, WT1, plays an important role in the development of the urogenital system and the gonads, and clinical syndromes associated with WT1 mutations, such as WAGR syndrome, Denys-Drash syndrome and Frasier syndrome, typically manifest as renal and genitourinary abnormalities. WT1 may also play an important role in the development of the diaphragm, and recently several papers have reported an association between WT1 mutations and diaphragmatic hernias. In addition, WT1 mutations were also detected in some patients with Meacham syndrome, a rare malformation syndrome comprising congenital diaphragmatic hernia, double vagina, sex reversal, and cardiac malformations. Here, we report a case of an infant with typical clinical features of Deny-Drash syndrome and a heterozygous missense mutation, Arg366His, in the WT1 gene, in whom a diaphragm defect was detected after starting peritoneal dialysis. Diaphragmatic defects are rare but may be considered as clinical manifestations of WT1 mutation syndromes. In addition, we suggest that WT1 abnormalities should be suspected in patients with chronic renal failure who develop hydrothorax after peritoneal dialysis, especially in those with genitourinary abnormalities.

Quality of life in children with end-stage renal disease based on a PedsQL ESRD module.

BackgroundHealth-related quality of life (HRQOL) is an essential subject for children with end-stage renal disease (ESRD) and their families.MethodsWe performed a cross-sectional investigation of HRQOL in children undergoing renal replacement therapies, such as dialysis and renal transplantation, using the 34-item Pediatric Quality of Life Inventory 3.0 End-Stage Renal Disease (PedsQL 3.0 ESRD) module. We assessed 92 ESRD patients aged 2–18 from four Korean university hospitals.ResultsThe male:female ratio was 44:48, and the most common cause of ESRD was chronic glomerulonephritis. Fifty-five children were treated by dialysis, and 37 received renal transplantation. Transplant patients had better HRQOL than dialysis patients in two domains in parent proxy reports: “About my kidney disease” and “Worry.” In child self-reports, transplant patients had better HRQOL than dialysis patients in one domain: Treatment problems. However, there were no significant differences in total QOL scores between peritoneal dialysis (PD) and transplant patients in child self-reports. In addition, there were differences in the ESRD module scores between child self- and parent proxy reports. Children usually reported better QOL than their parents. Child self-reports showed significantly higher QOL scores than parent proxy reports in the domains of General fatigue, Family & peer interaction, and Worry. Children on PD self-reported a significantly higher QOL than children on hemodialysis (HD).ConclusionsThe PedsQL 3.0 ESRD module may be useful as an ESRD-specific instrument to evaluate HRQOL in children; however, a larger, longitudinal prospective study is warranted.

Polymorphisms of the MDR1 and MIF genes in children with nephrotic syndrome

Oral steroid treatment is the first line of therapy for childhood nephrotic syndrome (NS). Nonetheless, some patients are resistant to this treatment. Many efforts have been made to explain the differences in the response to steroid treatment in patients with NS based on the genetic background. We have investigated single nucleotide polymorphisms of the MDR1 [C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642)] and MIF (G-173C, rs755622) genes in 170 children with NS. Of these children, 69 (40.6%) were initial steroid non-responders, and 23 (13.5% of total) developed chronic kidney disease. Renal biopsy findings, which were available for 101 patients, showed that 35 patients had minimal change lesion and 66 had focal segmental glomerulosclerosis. The frequencies of the MDR1 1236 CC (18.8 vs 7.2%) or TC (53.5 vs 43.5%) genotype and C allele (45.5 vs 29.0%) were significantly higher in the initial steroid responders than in the non-responders. Analysis of MDR1 three-marker haplotypes revealed that the frequency of the TGC haplotype was significantly lower in the initial steroid responders than in the non-responders (15.8 vs 29.0%). There was no association between the MIF G-173C polymorphism and clinical parameters, renal histological findings, and steroid responsiveness. These data suggest that the initial steroid response in children with NS may be influenced by genetic variations in the MDR1 gene.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis associated with CLDN16 mutations

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), an autosomal recessive renal tubular disorder, is characterized by the impaired tubular reabsorption of magnesium and calcium in the thick ascending limb of the loop of Henle and an eventual progression to end-stage renal disease. Recent studies have reported that this disease is caused by mutations in the CLDN16 gene, which encodes the tight junction protein, paracellin-1. Paracellin-1 belongs to the claudin family and regulates the paracellular transport of magnesium and calcium. Here, we report on two Korean siblings with typical clinical features of FHHNC in association with compound heterozygous mutations, G233C and 800delG, in CLDN16. Their parents were asymptomatic heterozygous carriers of the single mutations. This is the first report of FHHNC in Korea, and the mutations reported are novel.

Idiopathic membranous nephropathy in children

Idiopathic membranous nephropathy (MN) is a rare cause of asymptomatic proteinuria (AP) or nephrotic syndrome (NS) in childhood. To improve our understanding of its clinical course, we retrospectively reviewed 19 cases of idiopathic MN seen in our hospital over a period of 28.5 years, i.e., from January 1977 to July 2005. Eight patients (39%) had AP and 11 (61%) presented with NS. All eight AP patients achieved remission, regardless of treatment modality. Oral corticosteroid was given to all 11 NS patients, but only three of them responded to corticosteroid. Of the eight steroid non-responders, three achieved remissions with the addition of cyclosporine, and the five who were not administered additional immunosuppressive drugs had persistent NS. At the latest evaluation, all six NS patients that achieved remission remained free of proteinuria and had a normal renal function. Moreover, two of the 5 steroid non-responders showed persistent nephrotic-range proteinuria but a stable renal function. The remaining three steroid non-responders progressed into chronic renal insufficiency, and this progression was preceded by renal vein thrombosis (RVT) in two of the three patients. Presentation with NS (P=0.045) and the development of RVT (P=0.010) were identified as poor prognostic factors.

Genetic basis of Bartter syndrome in Korea

BACKGROUND Bartter syndrome (BS) is clinically classified into antenatal or neonatal BS (aBS) and classic BS (cBS) as well as five subtypes based on the underlying mutant gene; SLC12A1 (BS I), KCNJ1 (BS II), CLCNKB (BS III), BSND (BS IV) and CASR (BS V). METHODS Clinico-genetic features of a nationwide cohort of 26 Korean children with BS were investigated. RESULTS The clinical diagnosis was aBS in 8 (30.8%), cBS in 15 (57.7%) and mixed Bartter-Gitelman phenotype in 3 cases (11.5%). Five of eight patients with aBS and all 18 patients with either cBS or mixed Bartter-Gitelman phenotype had CLCNKB mutations. Among the 23 patients (46 alleles) with CLCNKB mutations, p.W610X and large deletions were detected in 25 (54.3%) and 10 (21.7%) alleles, respectively. There was no genotype-phenotype correlation in patients with CLCNKB mutations. CONCLUSIONS Twenty-three (88.5%) of the 26 BS patients involved in this study had CLCNKB mutations. The p.W610X mutation and large deletion were two common types of mutations in CLCNKB. The clinical manifestations of BS III were heterogeneous without a genotype-phenotype correlation, typically manifesting cBS phenotype but also aBS or mixed Bartter-Gitelman phenotypes. The molecular diagnostic steps for patients with BS in our population should be designed taking these peculiar genotype distributions into consideration, and a new more clinically relevant classification including BS and Gitelman syndrome is required.

Two novel mutations in the aquaporin 2 gene in a girl with congenital nephrogenic diabetes insipidus.

Congenital nephrogenic diabetes insipidus (CNDI) is a rare inherited disorder characterized by insensitivity of the kidney to the antidiuretic effect of vasopressin. There are three inheritance patterns of CNDI: the X-linked recessive form associated with vasopressin V2 receptor gene mutations, and the autosomal recessive and dominant forms associated with aquaporin-2 gene (AQP2) mutations. The evaluation for polyuria and polydipsia in a one-month-old Korean girl revealed no response to vasopressin and confirmed the diagnosis of CNDI. Because the child was female without family history of CNDI, her disease was thought to be an autosomal recessive form. We analyzed the AQP2 gene and detected a compound heterozygous missense point mutation: 70Ala (GCC) to Asp (GAC) in exon 1 inherited from her father and 187Arg (CGC) to His (CAC) in exon 3 inherited from her mother. The first mutation is located within the first NPA motif of the AQP2 molecule and the second one right after the second NPA motif. This is the first report to characterize AQP2 mutations in Korean patients with autosomal recessive CNDI, and expands the spectrum of AQP2 mutations by reporting two novel mutation, 70Ala (GCC) to Asp (GAC) and 187Arg (CGC) to His (CAC).

Congenital thrombotic thrombocytopenic purpura associated with unilateral moyamoya disease

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy disorder associated with congenital or acquired deficiency of the von Willebrand factor-cleaving protease, ADAMTS13. The central nervous system and kidneys are the two major organs of involvement in TTP. Moyamoya (puff of smoke) disease is a cerebral arteriopathy of unknown etiology characterized by narrowing or occlusion of the distal internal carotid or proximal anterior or middle cerebral arteries, which causes the formation of multiple tiny collateral networks. We report here a case of an 11-year-old boy with unilateral moyamoya disease and congenital TTP. The patient had a history of severe neonatal jaundice and thereafter recurrent episodes of hemolytic anemia associated with renal dysfunction and cerebral infarction. The plasma ADAMTS13 activity of the patient <3% of normal, and ADAMTS13 gene analysis revealed an abnormal splicing mutation (c.330+1 G > A) in one allele and a novel missense mutation (p.Ile1217Thr) in the other. This is the first case of a genetically confirmed congenital TTP associated with unilateral moyamoya disease. Although the causal relationship between the two diseases has not been established, TTP may be included as one of the causes of moyamoya syndrome.

Molecular genetic study of congenital nephrogenic diabetes insipidus and rescue of mutant vasopressin V2 receptor by chemical chaperones

Aim:  X‐linked nephrogenic diabetes insipidus is a rare disease caused by mutations in the arginine vasopressin V2 receptor (AVPR2) gene, which encodes vasopressin V2 receptor (V2R). More than a half of reported mutations in AVPR2 are missense mutations, and a large number of missense mutant receptors fail to fold properly and therefore are not routed to the cell surface.

PREVALENCE OF 25(OH) VITAMIN D INSUFFICIENCY AND DEFICIENCY IN PEDIATRIC PATIENTS ON CHRONIC DIALYSIS

♦ Background: 25(OH) Vitamin D [25(OH)D] is the major circulating form of vitamin D and the parameter used to reflect vitamin D status. Patients with chronic kidney disease (CKD) are likely to have low levels of 25(OH)D, and recent observations have linked suboptimal vitamin D status with adverse cardiovascular outcomes, inflammation, insulin resistance, and the rate of progression of renal insufficiency. Little is known about the magnitude of vitamin D deficiency in pediatric patients with stage 5 CKD on chronic dialysis. ♦ Objectives: The aim of the present cross-sectional study was to assess the prevalence of abnormal vitamin D status in children on chronic dialysis. ♦ Methods: Serum 25(OH)D, 1,25(OH)2 vitamin D [1,25(OH)2D], calcium, phosphorus, and parathyroid hormone (PTH) were evaluated in 59 pediatric patients on chronic dialysis. Weekly renal Kt/V and creatinine clearance (CCr) were evaluated as parameters reflecting residual renal function. In these patients, serum 25(OH)D concentrations less than 10 ng/mL were considered deficiency and concentrations of 10 - 30 ng/mL were considered insufficiency. ♦ Results: Of the 59 pediatric patients (mean age: 14.4 ± 5.1 years), 51 (86.4%) were on peritoneal dialysis (PD), and 8 (13.6%) were on hemodialysis. Vitamin D deficiency was found in 32.2% of the patients (n = 19), and vitamin D insufficiency, in 50.8% (n = 30). Patients with serum 25(OH)D concentrations less than 30 ng/mL were older than those with normal 25(OH)D concentrations (15.4 ± 4.5 years vs 9.2 ± 5.1 years, p = 0.000). Patients with 25(OH) D concentrations less than 30 ng/mL had higher PTH levels than did those with normal 25(OH)D concentrations (349.5 ± 318.3 pg/mL vs 142.5 ± 116.9 pg/mL, p = 0.001). In the univariate analysis, there was no correlation between serum 25(OH)D and serum 1,25(OH)2D (r = 0.242, p = 0.064), calcium (r = 0.108, p = 0.415), phosphorus (r = -0.050, p = 0.706), or body mass index (r = -0.046, p = 0.729). In PD patients, serum 25(OH)D was positively correlated with weekly renal Kt/V (r = 0.385, p = 0.005) and CCr (r = 0.443, p = 0.001). In addition, serum 25(OH)D and serum albumin were positively correlated (r = 0.297, p = 0.035) in the PD patients. ♦ Conclusions: The present study found a high prevalence of 25(OH)D deficiency and insufficiency in children on chronic dialysis. Serum 25(OH)D was associated with residual renal function in children on PD. Further studies to evaluate the consequences of vitamin D deficiency and the impact of therapeutic interventions are needed in pediatric CKD patients.