Recombinant growth hormone therapy in children with Turner Syndrome in Korea: a phase III Randomized Trial.

BACKGROUND: Short stature is the most consistent characteristic feature of Turner syndrome (TS). To improve final heights of children with TS effectively, it is important to provide them with early and appropriate treatment using growth hormone (GH). The objective of this study was to assess the efficacy and safety of a new recombinant human GH, Growtropin®-II (DA-3002, Dong-A ST Co., Ltd) versus a comparator (Genotropin®, Pfizer Inc.) for Korean children with TS. METHODS: This open-label, active-controlled, parallel-group, randomized controlled phase III trial was conducted at 11 hospitals in Korea. Eligible patients (n = 58) were randomized to two groups: 1) DA-3002 group (administrated with DA-3002 at 0.14 IU [0.0450-0.050 mg] /kg/day); and 2) comparator group (administrated with the comparator at 0.14 IU [0.0450-0.050 mg] /kg/day). RESULTS: The change from baseline in annualized height velocity (HV) after a 52-week treatment period was 4.15 ± 0.30 cm/year in the DA-3002 group and 4.34 ± 0.29 cm/year in the comparator group. The lower bound of 95% two-sided confidence interval for group difference in the change of annualized HV (- 1.02) satisfied the non-inferiority margin (- 1.5). The change in height standard deviation score (HtSDS) at 52-week was 0.70 ± 0.23 for the DA-3002 group and 0.66 ± 0.39 for the comparator group, showing no significant (p = 0.685) difference between the two groups. The change of skeletal maturity defined as change in bone age/change in chronological age between the two groups was not significantly different (1.25 ± 0.58 for the DA-3002 group and 1.47 ± 0.45 for the comparator group, p = 0.134). Changes from baseline in serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) after 52 weeks of treatment did not differ significantly between the two groups (p = 0.565 and p = 0.388, respectively) either. The occurrence of adverse events was not statistically different between groups. CONCLUSIONS: This study demonstrates that the efficacy and safety of GH treatment with DA-3002 in children with TS are comparable with those of the comparator. It is expected to analysis the long-term effect of DA-3002 on the increase of final adult height in children with TS and possible late-onset complications in the future. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov. ClinicalTrials.gov identifier: NCT01813630 (19/03/2013).

Neutrophil-to-lymphocyte ratio to predict gastrointestinal bleeding in Henoch: Schönlein purpura.

BACKGROUND: Henoch-Schönlein purpura (HSP) is a common form of vasculitis in children. It typically involves small vessels of the skin, the gastrointestinal (GI) tract, joints, and kidneys. GI involvement is the most severe short-term complication and GI bleeding is a major complication of HSP, but there is no established predictive marker of GI bleeding. Blood neutrophil-to-lymphocyte ratio (NLR) has been proposed as a potentially useful marker of clinical outcome in diseases with an inflammatory component. The aim of this study was to clarify the association of NLR with HSP and investigate the usefulness of NLR as a marker to predict GI bleeding in children with HSP. METHODS: All patients with newly diagnosed HSP were reviewed retrospectively. White blood cell count, hemoglobin, platelet counts, mean platelet volume, neutrophil and lymphocyte count were evaluated. NLR and platelet-to-lymphocyte ratio (PLR) were calculated using complete blood count data. RESULTS: This study involved 141 HSP patients. GI involvement was found in 65 patients (46.1%), and, of these, 15 (10.6%) had GI bleeding. At the time of diagnosis, NLR was significantly higher (P = 0.001) and PLR significantly lower (P = 0.032) in patients with GI bleeding than in those without GI bleeding. On logistic regression analysis, NLR was the only independent predictor of GI bleeding (P = 0.004). The optimal cut-off of NLR for predicting GI bleeding was 2.86 (sensitivity, 73%; specificity, 68%). CONCLUSIONS: NLR, a simple and easily obtainable parameter, is a potential predictive marker of GI bleeding in children with HSP.

Clinical utility of spot urine protein-to-creatinine ratio modified by estimated daily creatinine excretion in children.

BACKGROUND: The spot urine protein-to-creatinine ratio (UPCR) is widely used to predict 24-h urine protein (24-h UP) excretion. In patients with low daily urine creatinine excretion (UCr), however, the UPCR may overestimate 24-h UP. The aim of this study was to predict 24-h UP using UPCR adjusted by estimated 24-h UCr in children. METHODS: This study included 442 children whose 24-h UP and spot UPCR were measured concomitantly. Estimated 24-h UCr was calculated using three previously existing equations. We estimated the 24-h UP excretion from UPCR by multiplying the estimated UCr. The results were compared with the measured 24-h UP. RESULTS: There was a strong correlation between UPCR and 24-h UP (r = 0.801, P < 0.001), and the correlation improved after multiplying the UPCR by the measured UCr (r = 0.847, P < 0.001). Using the estimated UCr rather than the measured UCr, there was high accuracy and strong correlation between the estimated UPCR weighted by the Cockcroft-Gault equation and 24-h UP. Improvement was also observed in the subgroup (proteinuria vs. non-proteinuria) analysis, particularly in the proteinuria group. CONCLUSIONS: The spot UPCR multiplied by the estimated UCr improved the accuracy of prediction of the 24-h UP in children.

A Pediatric Case of Severe Fever with Thrombocytopenia Syndrome in Korea.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease and elderly people living in rural areas have the greatest risk of infection. We report the first pediatric case of SFTS in Korea and the clinical characteristics and disease progression in children. A 10-year-old child from Chonnam province visited the hospital with myalgia and a history of fever over the previous 8 days. Her father noticed a tick on her head and removed it before fever developed. Because the symptoms continued, her father consulted the community health center and SFTS virus was detected both from the tick (Haemaphysalis longicornis) and the patient's blood. On hospitalization, fever and severe myalgia were improved and no gastrointestinal and hemorrhagic symptoms were observed. The patient was successfully treated with a combination of steroids, IVIG, and ribavirin. In this report, a pediatric case of SFTS presents a mild clinical course but close attention must be paid to the screening of children with mild symptoms consisting of SFTS.

Congenital Syphilis Presenting with Only Nephrotic Syndrome: Reemergence of a Forgotten Disease.

Syphilis infection has re-emerged after years of declining incidence. The prevalence of congenital syphilis (CS) has increased in Korea and other countries during the last few decades. Untreated infants develop symptoms such as rhinorrhea, anemia, jaundice, cutaneous lesions, hepatosplenomegaly, and pseudoparalysis within weeks or months. Significant renal disease is uncommon in CS, and clinical renal involvement varies from mild transient proteinuria to frank nephrosis. We report a 2-month-old infant with CS who presented with only nephrotic syndrome (NS). The previously healthy infant presented with NS and showed no other syphilitic manifestations. Remission of the NS was achieved with adequate penicillin treatment. No recurrence of proteinuria was observed during the 1 year of follow-up. Although rare, this long forgotten disease continues to affect pregnant women, resulting in prenatal or postnatal mortality. We still consider the possibility of syphilitic nephropathy and therefore serologic testing for congenital NS.

Comparison between transient and permanent congenital hypothyroidism on a thyroid function test after re-evaluation.

PURPOSE: Congenital hypothyroidism (CH) is diagnosed with neonatal screening and is treated early in the neonatal period. Among these patients, transient CH (TCH) is included and requires re-evaluation. The purpose of this study was to find the best way to discontinue levothyroxine and to find trends in thyroid function tests (TFTs) after re-evaluation. METHODS: We retrospectively reviewed 388 patients diagnosed with CH. They were classified as permanent CH (PCH) and TCH. The total number of the PCH and TCH groups was 83 (51 boys and 32 girls). We compared clinical parameters to predict TCH and to identify the trends of TFT. RESULTS: The first thyroid-stimulating hormone (TSH) value after discontinuation and the average TSH value for 1, 2, and 3 years were all significantly higher in the PCH group (P<0.01). The first fT4 value after discontinuation and the average fT4 value for 1, 2, and 3 years were all significantly higher in the TCH group (P<0.01). The optimal cutoff value on the receiver operating characteristic curve for PCH prediction with an average of 3 years of TSH was greater than 9.05 µIU/mL, which was predicted with a sensitivity of 100% and a specificity of 100%. CONCLUSION: When the TSH value ranges from 10 µIU/mL to 20 µIU/mL, clinicians can discontinue levothyroxine if the next result is around 10 µIU/mL or shows a decreasing trend.

Familial renal glucosuria: a clinicogenetic study of 23 additional cases.

BACKGROUND: Familial renal glucosuria (FRG) is an inherited renal tubular disorder characterized by persistent isolated glucosuria in the absence of hyperglycemia that is caused by mutations in the sodium-glucose cotransporter SGLT2 coding gene, SLC5A2. OBJECTIVE: We conducted molecular and phenotype analyses of a cohort of 23 unrelated Korean children with FRG. METHODS: Mutational analysis of the SLC5A2 gene was conducted in this multicenter study organized by the Korean Society of Pediatric Nephrology. RESULTS: A total of 21 different SLC5A2 mutations were detected, including 19 novel mutations. All patients had at least one mutated allele; ten patients had homozygous or compound heterozygous mutations and 13 patients had a single heterozygous mutation. Most mutations were private. Patients with two mutations were diagnosed earlier with larger amounts of urinary glucose excretion than patients with single mutations. Pedigree analysis data were consistent with the inheritance of a codominant trait with incomplete penetrance. CONCLUSIONS: These findings extend the allelic heterogeneity in FRG and confirm previous observations of inheritance and genotype­phenotype correlation in patients with this disease.

Classic and backdoor pathways of androgen biosynthesis in human sexual development.

Both genes and hormones regulate human sexual development. Although ovarian hormones are not essential for female external genitalia development, male sexual development requires the action of testicular testosterone and dihydrotestosterone (DHT). DHT is the most active endogenous androgen formed by the conversion of testosterone in genital skin. This synthesis route from cholesterol to DHT is called the conventional classic pathway. Recent investigations have reported an alternative ("backdoor") route for DHT formation that bypasses fetal testicular testosterone. This alternative route plays a crucial role in human hyperandrogenic disorders like congenital adrenal hyperplasia caused by P450c21 deficiency, polycystic ovary syndrome, and P450 oxidoreductase deficiency. In addition, mutations in AKR1C2 and AKR1C4, genes encoding 3α-reductases, have been implicated in disorders of sexual development, indicating that both the classic and backdoor routes are required for normal human male sexual development. More recently, androsterone was found to be the primary androgen of the human backdoor route. Androsterone and steroidal substrates specific to the backdoor route are predominantly found in the placenta, liver, and adrenal glands rather than in the testes. These findings are essential to understanding human sexual development.

Severe hypernatremia in soft drink ketoacidosis and hyperglycemic hyperosmolar state at the onset of type 2 diabetes mellitus: a case series of three adolescents.

Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are diabetic emergencies. Some patients with a hyperglycemic crisis can present with an overlap of DKA and HHS. The coexistence of DKA and HHS is associated with higher mortality than in isolated DKA and HHS. In addition, electrolyte derangements caused by global electrolyte imbalance are associated with potentially life-threatening complications. Here, we describe three cases of mixed DKA and HHS with severe hypernatremia at the onset of type 2 diabetes mellitus. All patients had extreme hyperglycemia and hyperosmolarity with acidosis at the onset of diabetes mellitus. They consumed 2 to 3 L/d of high-carbohydrate drinks prior to admission to relieve thirst. They showed severe hypernatremia with renal impairment. Two patients recovered completely without any complications, while one died. Severe hypernatremia with mixed DKA and HHS is rare. However, it may be associated with excess carbohydrate beverage consumption. Reduced physical activity during the COVID19 pandemic and unhealthy eating behaviors worsened the initial presentation of diabetes mellitus. We highlight the impact of lifestyle factors on mixed DKA and HHS.

Fulminant type 1 diabetes mellitus in Korean adolescents.

Fulminant type 1 diabetes has recently been identified as a new subtype of idiopathic diabetes that is mostly found in Japanese adults. The aim of this study was to investigate the frequency as well as the clinical and laboratory characteristics of fulminant type 1 diabetes among Korean children with childhood-onset type 1 diabetes. One-hundred and fifty patients that had been newly diagnosed with type 1 diabetes over the past 10 years were included. These patients came from three hospitals. Out of the 150 patients, two female patients fulfilled the criteria for fulminant type 1 diabetes. They were negative for islet autoantibodies. The patients with fulminant type 1 diabetes had an older age of onset and a lower HbA1c than the patients with autoimmune or idiopathic type 1 diabetes. In addition, the patients with fulminant type 1 diabetes had increased serum aspartate aminotransferase, alanine aminotransferase and amylase levels, and decreased fasting serum C-peptide levels. The frequency of fulminant type 1 diabetes was 1.33% among all patients newly diagnosed with type 1 diabetes under the age of 16. Although this type of diabetes is more commonly an adult-onset disease, it is possible that fulminant type 1 diabetes has not yet been fully recognized in children and adolescence, and may be more common than initially thought.

Efficacy and adverse events related to the initial dose of methimazole in children and adolescents with Graves' disease.

PURPOSE: The first-line antithyroid drug for children and adolescents with Graves' disease (GD) is methimazole (MMI). This study evaluated the relationship between the initial MMI dose and the clinical course of GD after treatment. METHODS: We studied the efficacy of the initial MMI dose and the relationship between the initial MMI dose and adverse events (AEs). We retrospectively enrolled 22 males and 77 females and divided those subjects into 3 groups according to the initial dose of MMI: <0.4 mg/kg/day (group A; n=32); 0.4-0.7 mg/kg/day (group B; n=39); and >0.7 mg/kg/day (group C; n=28). RESULTS: The mean time to the normalization of free thyroxine (fT4) levels upon initial treatment was 5.64, 8.61, and 7.98 weeks in groups A, B, and C, respectively (P=0.116). The incidence of liver dysfunction, neutropenia, and skin rash was 12.5%, 20.5%, and 42.9% in groups A, B, and C, respectively (P=0.018). Neutropenia, as a severe AE, was absent in group A, but its prevalence was 7.7% in group B and 21.4% in group C (P=0.015). When comparing only groups B and C, the incidences of liver dysfunction and neutropenia were higher in group C (P=0.04 and P=0.021, respectively). CONCLUSION: The mean time to the normalization of fT4 levels did not differ among the 3 groups, but the incidence of AEs was higher in the groups that received high MMI doses. High doses of MMI (>0.7 mg/kg/day) should be reconsidered as an initial treatment for children and adolescents with GD.

Risk factors for renal involvement in Henoch-Schönlein purpura.

OBJECTIVE: Henoch-Schönlein purpura is a systemic vasculitis that mainly occurs in children. Renal impairment is a major complication of Henoch-Schönlein purpura, but there is no established predictive marker for renal involvement. Thus, in this study, we investigated the risk factors for renal involvement in children with Henoch-Schönlein purpura. METHOD: The medical records of children newly diagnosed as having Henoch-Schönlein purpura between 2005 and 2020 were reviewed retrospectively. Selected laboratory data were recorded before treatment initiation. The date and the age at diagnosis; sex; and the presence of arthralgia, gastrointestinal and renal involvement were obtained retrospectively. RESULTS: This study included a total of 186 patients with Henoch-Schönlein purpura. Among them, 36.0% had renal involvement; 28.4% had only microscopic hematuria, 53.7% had non-nephrotic range proteinuria, and 17.9% had nephrotic-range proteinuria during follow-up. The mean age was higher (p = 0.016) and female sex was predominant (p = 0.001) in patients with renal involvement than in those without renal involvement. Blood neutrophil/lymphocyte ratio (p = 0.002) and platelet/lymphocyte ratio (p = 0.002) were significantly higher than that of the patients without renal involvement. No statistically significant differences were observed in the hemoglobin concentration, platelet count, presence of arthralgia, and gastrointestinal involvement between patients with and without renal involvement. Logistic regression analysis revealed female sex (odd ratio = 3.213) and neutrophil/lymphocyte ratio (odd ratio = 1.329) as risk factors for renal involvement. CONCLUSIONS: Female sex and high neutrophil/lymphocyte ratio were risk factors for renal involvement in Henoch-Schönlein purpura.

Investigating whether serum IGF-1 and IGFBP-3 levels reflect the height outcome in prepubertal children upon rhGH therapy: LG growth study database.

Serum insulin-like growth factor-1 (IGF-I) and IGF binding protein-3 (IGFBP-3) levels can be used to monitor the safety of recombinant human growth hormone (rhGH) therapy. In this study, we evaluated the changes in serum IGF-I and IGFBP-3 levels during rhGH therapy as a marker of height outcome in prepubertal children. Totally, 705 prepubertal children with short stature were enrolled from the LG Growth Study Database. Data for three groups of subjects were obtained as follows: Idiopathic GH deficiency (IGHD; n = 486); idiopathic short stature (n = 66); small for gestational age (n = 153). Serum IGF-I and IGFBP-3 levels at the baseline and after the 1st and 2nd year of rhGH therapy, as well as the Δheight standard deviation score (SDS), were obtained. Δheight SDS after the 1st and 2nd year of rhGH therapy had notably increased compared to that at the baseline for all three groups. IGF-I and IGFBP-3 levels in all three groups were significantly increased compared to those at the baseline (p <0.001). Δheight SDS was positively correlated with ΔIGF-1 SDS after the 1st year of therapy, ΔIGFBP-3 SDS after the 2nd year of therapy in the IGHD group, and ΔIGF-I SDS and ΔIGFBP-3 SDS after the 2nd year of therapy (p < 0.05), regardless of whether the height at the baseline was a covariate. The increase in IGF-I and IGFBP-3 levels during rhGH therapy was related to the growth response in children with IGHD. Therefore, it may be valuable to measure the change in serum IGF-I and IGFBP-3 levels, especially the latter, during rhGH treatment to predict the growth response upon long-term treatment.

Acute Kidney Injury in Pediatric Diabetic Ketoacidosis.

OBJECTIVE: To assess the incidence and clinical characteristics of acute kidney injury (AKI) and identify the associated risk factors for AKI in children with type 1 diabetes mellitus (T1DM) and diabetic ketoacidosis (DKA). METHODS: This was a retrospective study performed over 15 y in a single Korean center. Children aged ≤18-y-old with T1DM and DKA were enrolled and divided into 2 groups according to the presence of AKI. RESULTS: This study included 90 episodes of DKA in 58 children with T1DM. AKI occurred in a total of 70 hospitalizations (77.8%) of 44 children: 18 (20.0%) with stage 1 AKI, 39 (43.3%) with stage 2 AKI, and 13 (14.4%) with stage 3 AKI. The number of AKI decreased to 28 (47.4%) and 13 (28.3%) after 12 h and 24 h of admission, respectively. The white blood cell count (P = 0.001) and anion gap levels (P = 0.025) were significantly higher and serum bicarbonate level (P = 0.004) was lower in the AKI group. Logistic regression analysis revealed that a longer duration of TIDM and high anion gap were independent predictors of developing severe AKI in pediatric DKA with T1DM (odds ratio, 1.225, P = 0.013; odds ratio, 1.130, P = 0.038). CONCLUSIONS: AKI frequently occurred in TIDM children with DKA. Longer duration of TIDM and elevated anion gap are associated with occurrence of severe AKI.

Efficacy and safety of the recombinant human growth hormone in short children born small for gestational age: A randomized, multicentre, comparative phase III trial.

OBJECTIVE: Growth hormone (GH) treatment is known to be effective in increasing stature in children with a short stature born small for gestational age (SGA). This multicentre, randomized, open-label, comparative, phase III study aimed to evaluate the efficacy and safety of Growtropin-II (recombinant human GH) and to demonstrate that the growth-promoting effect of Growtropin-II is not inferior to that of Genotropin in children with SGA (NCT ID: NCT02770157). METHODS: Seventy five children who met the inclusion criteria were randomized into 3 groups in a ratio of 2:2:1 (the study group [Growtropin-II, n = 30], control group [Genotropin, n = 30], and 26-week non-treatment group [n = 15]). The study and control groups received subcutaneous injections of Growtropin-II and Genotropin, respectively for 52 weeks, whereas the non-treatment group underwent a non-treatment observation period during weeks 0 to 26 and a dosing period during weeks 27 to 52 and additional dosing till week 78 only in re-consenting children. RESULTS: No significant differences in demographic and baseline characteristics between the groups were observed. The mean ± standard deviation change difference in annualized height velocity (aHV) (study group - control group) was 0.65 ±2.12 cm/year (95% confidence interval [CI], -0.53 to 1.83), whereas the lower limit for the 2-sided 95% CI was -0.53 cm/year. Regarding safety, treatment-emergent adverse events (TEAEs) occurred in 53.33% children in the study group and 43.33% children in the control group; the difference in the incidence of TEAEs between the 2 treatment groups was not statistically significant (P  = .4383). A total of 17 serious adverse events (SAEs) occurred in 13.33% children in the treatment groups, and no significant difference in incidence between groups (P  = .7065) was seen. Two cases of adverse drug reaction (ADR) occurred in 2 children (3.33%): 1 ADR (injection site swelling or pain) occurred in 1 child (3.33%) each in the study and control groups. CONCLUSIONS: This study demonstrates that the change in aHV from the baseline till 52 weeks with Growtropin-II treatment is non-inferior to that with Genotropin treatment in children with short stature born SGA. Growtropin-II is well-tolerated, and its safety profile is comparable with that of Genotropin over a 1-year course of treatment.

Familial glucocorticoid deficiency with a point mutation in the ACTH receptor: a case report.

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by severe glucocorticoid deficiency associated with failure of adrenal responsiveness to ACTH but no mineralocorticoid deficiency. We report a 2 month-old boy of nonconsanguineous parents, presented with hyperpigmentation. Physical examination showed diffuse dark skin of body including, oral mucosa, gum, hands, nails and scrotum. Laboratory evaluation revealed low serum cortisol (0.3 microg/dL), with very high plasma ACTH level (18,000 pg/mL), and serum cortisol level did not increase after ACTH stimulation test. Serum sodium, potassium, plasma renin activity, aldosterone and 17-hydroxyprogesterone were normal. Sequence analysis of the ACTH receptor (MC2R) gene showed a homozygous mutation of D103N. Diagnosis of FGD was made and treatment started with oral hydrocortisone.

Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc.

CONTEXT: Mitochondrial cytochrome P450scc converts cholesterol to pregnenolone in all steroidogenic tissues. Although progesterone production from the fetally-derived placenta is necessary to maintain pregnancy to term, four patients with mutations in the gene encoding P450scc (CYP11A1), have been described, one in a 46,XX female and three in underandrogenized 46,XY individuals, all with primary adrenal failure. OBJECTIVE: Our aim was to determine whether P450scc mutations might be found in other children and to explore genotype/phenotype correlations. METHODS AND PATIENTS: We performed mutational analysis of CYP11A1 in individuals with 46,XY disorders of sex development and primary adrenal failure, followed by functional studies of P450scc activity and of P450scc RNA splicing. RESULTS: Among nine 46,XY infants with adrenal failure and disordered sexual differentiation, two infants had compound heterozygous mutations in CYP11A1. One patient harbored the novel P450scc missense mutations L141W and V415E, which retained 38 and 0% activity, respectively. The other carried a CYP11A1 frameshift mutation c835delA (0% activity) and a splice site mutation [IVS3+(2-3)insT] that prevented correct splicing of P450scc mRNA. CONCLUSIONS: P450scc deficiency is a recently recognized disorder that may be more frequent than originally thought. The phenotypic spectrum ranges from severe loss-of-function mutations associated with prematurity, complete underandrogenization, and severe, early-onset adrenal failure, to partial deficiencies found in children born at term with clitoromegaly and later-onset adrenal failure. In contradistinction to congenital lipoid adrenal hyperplasia caused by steroidogenic acute regulatory protein mutations, adrenal hyperplasia has not been reported in any of the six patients with P450scc deficiency.

Plasma Neutrophil Gelatinase-Associated Lipocalin as a Predictor of Renal Parenchymal Involvement in Infants With Febrile Urinary Tract Infection: A Preliminary Study.

BACKGROUND: Urinary tract infection (UTI) is the most common bacterial infection in infants. Renal parenchymal involvement is an important prognostic factor; however, early detection of parenchymal involvement in UTI may be difficult during infancy. This study aimed to assess whether a recently established biomarker of UTI, neutrophil gelatinase-associated lipocalin (NGAL), can serve as a useful marker for the detection of cortical defects (CD) and to determine the appropriate diagnostic cut-off value of NGAL in infants with febrile UTI. METHODS: Infants hospitalized for febrile UTI were divided into two groups according to the presence of cortical defects on dimercaptosuccinic acid (DMSA) scintigraphy. Among 64 enrolled infants, 43 (67%) had CD (UTI-CD) and 21 (33%) had no CD (UTI-ND). The white blood cell count, C-reactive protein, and plasma NGAL (pNGAL) levels were determined before antibiotic therapy and compared between the two groups. RESULTS: pNGAL level was significantly higher in the UTI-CD group than in the UTI-ND group (340 µg/L vs 214 µg/L, P=0.002). Multivariate analysis showed that pNGAL level was the only independent predictor of CD (odds ratio 2.759, P=0.039). In the ROC curve analysis, pNGAL showed the highest area under the curve (0.745; 95% confidence interval, 0.561-0.821; P=0.014). The appropriate cut-off value of pNGAL was 267 µg/L (sensitivity, 72.1%; specificity, 71.4%). CONCLUSIONS: pNGAL was found to be a useful marker for early prediction of renal parenchymal involvement in infants with febrile UTI.

Vitamin D 1alpha-hydroxylase gene mutations in patients with 1alpha-hydroxylase deficiency.

CONTEXT: Vitamin D 1alpha-hydroxylase deficiency, also known as vitamin D-dependent rickets type 1, is an autosomal recessive disorder characterized by the early onset of rickets with hypocalcemia and is caused by mutations of the 25-hydroxyvitamin D 1alpha-hydroxylase (1alpha-hydroxylase, CYP27B1) gene. The human gene encoding the 1alpha-hydroxylase is 5 kb in length, located on chromosome 12, and comprises nine exons and eight introns. We previously isolated the human 1alpha-hydroxylase cDNA and gene and identified 19 different mutations in 25 patients with 1alpha-hydroxylase deficiency. OBJECTIVES, PATIENTS, AND METHODS: We analyzed the 1alpha-hydroxylase gene of 10 patients, five from Korea, two from the United States, and one each from Argentina, Denmark, and Morocco, all from nonconsanguineous families. Each had clinical and radiographic features of rickets, hypocalcemia, and low serum concentrations of 1,25-dihydroxyvitamin D(3). RESULTS: Direct sequencing identified the responsible 1alpha-hydroxylase gene mutations in 19 of 20 alleles. Four novel and four known mutations were identified. The new mutations included a nonsense mutation in exon 6, substitution of adenine for guanine (2561G-->A) creating a stop signal at codon 328; deletion of adenine in exon 9 (3922delA) causing a frameshift; substitution of thymine for cytosine in exon 2 (1031C-->T) causing the amino acid change P112L; and a splice site mutation, substitution of adenine for guanine in the first nucleotide of intron 7 (IVS7+1 G-->A) causing a frameshift. CONCLUSIONS: Mutations in the 1alpha-hydroxylase gene previously were identified in 44 patients, to which we add 10 more. The studies show a strong correlation between 1alpha-hydroxylase mutations and the clinical findings of 1alpha-hydroxylase deficiency.