Novel Variants and Phenotypes in NEUROG3-Associated Syndrome.

CONTEXT: Biallelic pathogenic variants in the NEUROG3 gene cause malabsorptive diarrhea, insulin-dependent diabetes mellitus (IDDM), and rarely hypogonadotropic hypogonadism. With only 17 reported cases, the clinical and mutational spectra of this disease are far from complete. OBJECTIVE: To identify the underlying genetic etiology in 3 unrelated Thai patients who presented with early-onset malabsorptive diarrhea, endocrine abnormalities, and renal defects and to determine the pathogenicity of the newly identified pathogenic variants using luciferase reporter assays and western blot. METHODS: Three unrelated patients with congenital diarrhea were recruited. Detailed clinical and endocrinological features were obtained. Exome sequencing was performed to identify mutations and in vitro functional experiments including luciferase reporter assay were studied to validate their pathogenicity. RESULTS: In addition to malabsorptive diarrhea due to enteric anendocrinosis, IDDM, short stature, and delayed puberty, our patients also exhibited pituitary gland hypoplasia with multiple pituitary hormone deficiencies (Patient 1, 2, 3) and proximal renal tubulopathy (Patient 2, 3) that have not previously reported. Exome sequencing revealed that Patient 1 was homozygous for c.371C > G (p.Thr124Arg) while the other 2 patients were homozygous for c.284G > C (p.Arg95Pro) in NEUROG3. Both variants have never been previously reported. Luciferase reporter assay demonstrated that these 2 variants impaired transcriptional activity of NEUROG3. CONCLUSIONS: This study reported pituitary gland hypoplasia with multiple pituitary hormone deficiencies and proximal renal tubulopathy and 2 newly identified NEUROG3 loss-of-function variants in the patients with NEUROG3-associated syndrome.

Comparison of Clinical Manifestations, Laboratory, Neuroimaging Findings, and Outcomes in Children With Posterior Reversible Encephalopathy Syndrome (PRES) in Children With and Without Renal Disease.

BACKGROUND: To demonstrate and compare the clinical manifestations, laboratory findings, and neuroimaging findings of posterior reversible encephalopathy syndrome (PRES) in children with and without underlying renal disease. METHODS: The study included 23 children with a diagnosis of PRES from January 2009 to March 2019. All data, including clinical manifestations, laboratory findings, underlying medical illness, and neuroimaging results, were obtained. RESULTS: Sixteen had underlying renal disease. The median age of PRES onset was 10.3 years in children with renal disease and 9.8 years in children without renal disease. Higher blood pressure at the baseline, on admission, and at the onset of PRES was found in the renal disease group more than in the nonrenal disease group (P < 0.05). Seizures were likely seen in the renal disease group compared with the nonrenal disease group (P = 0.03). Generalized tonic-clonic seizures were the most common seizure type in both groups. An initial CT scan revealed vasogenic edema in 75% of the renal group and 85.7% of the nonrenal group. During a long-term follow-up, all children recovered without significant neurological deficits or subsequent epilepsy. CONCLUSIONS: Hypertension and higher baseline blood pressure are more common in children with renal disease who develop PRES compared with nonrenal disease. Seizures are more common in the renal disease group. A computed tomographic (CT) scan can help with PRES diagnosis when magnetic resonance imaging is not available. All children with PRES recovered without significant neurological deficits or subsequent epilepsy.

Vitamin C deficiency and impact of vitamin C administration among pediatric patients with advanced chronic kidney disease.

BACKGROUND: Vitamin C deficiency is common in chronic kidney disease (CKD) due to losses through dialysis and dietary intake below requirement. We investigated prevalence of vitamin C deficiency and impact of vitamin C treatment in deficient/insufficient patients. METHODS: A prospective cohort study in patients aged 1-18 years with CKD stages 4 and 5D collected demographic data including underlying disease, treatment, and anthropometric assessment. Vitamin C intake was assessed using 24-h dietary recall. Hemoglobin, iron status, serum vitamin C, and serum oxalate were measured at baseline and after treatment. Vitamin C (250 mg/day) was given orally for 3 months to deficient/insufficient patients. RESULTS: Nineteen patients (mean age 12.00 ± 4.1 years) showed prevalence of 10.6% vitamin C insufficiency and 78.9% deficiency. There were no associations between vitamin C level and daily vitamin C intake (p = 0.64) or nutritional status (p = 0.87). Median serum vitamin C was 1.51 (0.30-1.90) mg/L. In 16 patients receiving treatment, median serum vitamin C increased from 1.30 (0.23-1.78) to 3.22 (1.77-5.96) mg/L (p = 0.008) without increasing serum oxalate (79.92 (56.6-106.84) vs. 80.47 (56.88-102.95) µmol/L, p = 0.82). However, 62.5% failed to achieve normal vitamin C levels. Ordinal regression analysis revealed patients with non-oligoanuric CKD were less likely to achieve normal vitamin C levels (ß = - 3.41, p = 0.03). CONCLUSION: We describe high prevalence of vitamin C insufficiency/deficiency among pediatric CKD patients. Vitamin C levels could not be solely predicted by nutritional status or daily intake. The treatment regimen raised serum vitamin C without increasing serum oxalate; however, it was largely insufficient to normalize levels, particularly in non-oligoanuric CKD. Graphical abstract .

Prevalence and associated factors of renal dysfunction and proteinuria in cyanotic congenital heart disease.

BACKGROUND: Cyanotic nephropathy (CN), seen in 30-50% of patients with congenital cyanotic heart disease (CCHD), affects both tubular and glomerular function, resulting in proteinuria and azotemia. Microalbuminuria is an early marker for glomerular damage and an independent predictor of progressive renal disease. METHODS: A cross-sectional study was conducted. A total of 116 patients aged 1 month to 15 years with CCHD at Chiang Mai University Hospital between 2015 and 2016 were assessed and 94 patients were enrolled. To determine the prevalence and associated factors of significant albuminuria in CCHD patients, baseline characteristics, oxygen saturation, surgery, hemoglobin (Hb), hematocrit (Hct), spot urine albumin, urine protein, and creatinine were obtained. Binary logistic-regression modeling was used to identify associated factors. RESULTS: Prevalence of CN in children with CCHD was 58.51% and 92.55% according to albuminuria and proteinuria staging respectively. Prevalence of significant proteinuria, significant albuminuria, and decreased GFR was 88.30%, 41.49% and 31.91% respectively. Participants with significant albuminuria had fewer previous surgeries (p = 0.05), a longer waiting time for surgery (p = 0.02), enalapril usage (p = 0.04), pulmonary hypertension (p = 0.03), higher Hct z-score (p = 0.03) and lower platelet count (p = 0.001) compared with those without significant albuminuria. Using multivariate logistic regression analysis, waiting duration for surgery (p = 0.04), Hct >40% (p = 0.02), and platelet count <290,000/mm3 (p = 0.04) were predictive of microalbuminuria. CONCLUSIONS: Cyanotic nephropathy can be detected in the first decade of life with the presentation of microalbuminuria. High Hct level and low platelet count were identified as a predictor of microalbuminuria, whereas early cardiac surgery decreased the risk of developing significant albuminuria.

Clinical Course, Outcomes and Complications of Thai Pediatric Pure Type versus Mixed Type Lupus Membranous Nephritis.

Background: Due to the relative infrequency of lupus membranous nephritis (LMN) compared to other types of lupus nephritis (LN) in pediatric patients, the current literature on pediatric LMN is limited. The knowledge regarding clinical manifestations, outcomes and infectious complications are mainly based on studies in the adult population. Similar to disease expression in SLE, the renal manifestations of LMN are affected by environmental factors and vary among racial and ethnic groups. Objective: To describing clinical features, common infectious complications, and outcomes of pediatric-onset LMN in Thailand and the correlation between pure and mixed types of LMN classified by renal pathology. Material and Method: This was a retrospective analysis of 40 patients with LMN as seen in the Pediatric Nephrology Clinic, Maharaj Nakorn Chiang Mai from January, 2003 to December, 2012. Patients were categorized into pure and mixed types of LMN the comparisons of the clinical course, results of treatment and infectious complications between the two types had been analyzed and recorded data for 2 years. Results: Kidney biopsy was performed. Of the 40 patients with LMN, 50% were diagnosed as mixed-type LMN. The clinical symptoms presented including rash, hypertension, edema, serositis and arthritis were found at 57.7%, 45%, 40%, 25% and 25% respectively. All of the patients were treated with an immunosuppressive drug such as: Cyclophosphamide, Azathioprine, Cyclosporine or Mycophenolate mofetil, together with systemic steroids. During the two years follow up, every patient had normal GFR. Twenty nine patients (72.5%) had renal remission in proteinuria with complete remission in 7 patients (17.5%) and partial remission in 22 patients (55%). An average time from the onset to remission was 12 months. GFR and proteinuria were not significant difference between the two groups after treatment. The infections found in patients who received cyclophosphamide include herpes infection, salmonellosis, lung abscess, nocardiosis, giardia intestinalis and cerebral cysticercosis. Furthermore, steroid side effect was avascular necrosis of the hip joint. Conclusion: The mixed-type LMN patients had a higher blood pressure, higher BUN and positive LE cell than those of the pure-type LMN patients. Hypertension at initial presentation can be a predictor of proliferative lesion in renal pathology. However, a proliferative lesion accompanied with LMN does not affect renal outcomes. With similar renal outcomes, the immunosuppressive with low adverse effects may be considered as a preferable treatment.