Band 35, Heft 10

Objectives We present the results of our experience in the diagnosis and follow up of the positive cases for propionic, methylmalonic acidemias and cobalamin deficiencies (PA/MMA/MMAHC) since the Expanded Newborn Screening was implemented in Madrid Region. Methods Dried blood samples were collected 48 h after birth. Amino acids and acylcarnitines were quantitated by MS/MS. Newborns with alterations were referred to the clinical centers for follow-up. Biochemical and molecular genetic studies for confirmation of a disease were performed. Results In the period 2011–2020, 588,793 children were screened, being 953 of them were referred to clinical units for abnormal result (192 for elevated C3 levels). Among them, 88 were false positive cases, 85 maternal vitamin B12 deficiencies and 19 were confirmed to suffer an IEM (8 PA, 4 MMA, 7 MMAHC). Ten out 19 cases displayed symptoms before the NBS results (6 PA, 1 MMA, 3 MMAHC). C3, C16:1OH+C17 levels and C3/C2 and C3/Met ratios were higher in newborns with PA/MMA/MMAHC. Cases diagnosed with B12 deficiency had mean B12 levels of 187.6 ± 76.9 pg/mL and their mothers 213.7 ± 95.0; 5% of the mothers were vegetarian or had poor eating while 15% were diagnosed of pernicious anemia. Newborns and their mothers received treatment with B12 with different posology, normalizing their levels and the secondary alterations disappeared. Conclusions Elevated C3 are a frequent cause for abnormal result in newborn screening with a high rate of false positive cases. Presymptomatic diagnosis of most of PA and some MMA/MMAHC is difficult. Vitamin B12 deficiency secondary to maternal deprivation is frequent with an heterogenous clinical and biochemical spectrum.

Objectives We describe growth patterns and predicted adult height (PAH) in pubertal boys treated with letrozole and evaluate the potential predictors of growth responses. Methods We performed a retrospective analysis of data from 2002 to 2020. All subjects were treated for ≥6 months and had at least 3 height measurements to calculate the growth velocity (GV) before and during treatment. We evaluated growth measurements, bone age, and biochemical parameters before, during and after treatment. Results A total of 59 subjects aged 12.7 (± 1.7) years old were included. At treatment initiation, bone age was 13.1 (± 1.5) years and predicted adult height (PAH) was 163.8 (± 9.9) cm compared to mid-parental height of 172.4 (± 5.8) cm. Growth velocity decreased during letrozole therapy and rebounded after completion. Sub-analysis of 26 subjects with bone age data available at baseline and at least 1 year later showed a trend to modest increase in PAH. In boys simultaneously receiving growth hormone (rhGH), the change in PAH was significantly more (3.2 cm, p<0.05) compared to those treated with letrozole alone. Conclusions We show that letrozole appropriately slows down skeletal maturation and GV responses are variable. Possible negative predictors include lower baseline GV and advanced bone age. A small positive trend in PAH with letrozole therapy is augmented by simultaneous use of rhGH. Future randomized controlled trials are needed to better understand which group of patients will benefit from treatment.

Objectives Maturity-onset diabetes of the young (MODY), an autosomal dominant disease, is frequently misdiagnosed as type 1 or 2 diabetes. Molecular diagnosis is essential to distinguish them. This study was done to investigate the prevalence of MODY subtypes and patients’ clinical characteristics. Methods A total of 43 out of 230 individuals with diabetes were selected based on the age of diagnosis >6 months, family history of diabetes, absence of marked obesity, and measurable C-peptide. Next-generation and direct SANGER sequencing was performed to screen MODY-related mutations. The variants were interpreted using the Genome Aggregation Database (genomAD), Clinical Variation (ClinVar), and pathogenicity prediction tools. Results There were 23 males (53.5%), and the mean age at diabetes diagnosis was 6.7 ± 3.6 years. Sixteen heterozygote single nucleotide variations (SNVs) from 14 patients (14/230, 6%) were detected, frequently GCK (37.5%) and BLK (18.7%). Two novel variants were identified in HNF4A and ABCC8. Half of the detected variants were categorized as likely pathogenic. Most prediction tools predicted Ser28Cys in HNF4A as benign and Tyr123Phe in ABCC8 as a pathogenic SNV. Six cases (42.8%) with positive MODY SNVs had islet autoantibodies. At diagnosis, age, HbA 1c , and C-peptide level were similar between SNV-positive and negative patients. Conclusions This is the first study investigating 14 variants of MODY in Iran. The results recommend genetic screening for MODY in individuals with unusual type 1 or 2 diabetes even without family history. Treatment modifies depending on the type of patients’ MODY and is associated with the quality of life.

Objectives Primary congenital hypothyroidism (CH) is a preventable cause of mental retardation. Iatrogenic hyperthyroidism has occasionally been reported using the recommended LT4 dosage. Currently, information regarding iatrogenic hyperthyroidism and predictive factors for permanent hypothyroidism (P-CH) among Thai patients is lacking. The aim of this study is to determine the prevalence and factors for predicting iatrogenic hyperthyroidism at one month after LT4 initiation and for predicting P-CH in primary CH infants. Methods This retrospective cohort study involved 87 infants with primary CH. Patients were classified by thyroid status at one month after LT4 initiation. At 3 years, patients were reevaluated after LT4 cessation and assigned as P-CH or transient CH (T-CH). Differences between groups were analyzed. Results One month after LT4 initiation, 35.6% of patients were classified as having iatrogenic hyperthyroidism. An initial LT4 dose of 10.2 μg/kg/day (sensitivity 64.5%, specificity 71.4%) was a suitable cutoff value for predicting iatrogenic hyperthyroidism, wherein 55.6 and 21.6% of patients were treated with initial doses of ≥10.2 and <10.2 μg/kg/day, respectively (p=0.004). Initial LT4 dose was the only predictive factor for thyroid status after initial treatment. At reevaluation, 47.4% of patients were diagnosed with P-CH. LT4 dosage at 3 years of age was significantly higher in patients with P-CH (3.3 vs. 2.85 μg/kg/day, p=0.02) and the only relevant factor for predicting P-CH. Conclusions Iatrogenic hyperthyroidism is common among infants with primary CH when treated with the recommended LT4 dosage. LT4 dose was the only factor for predicting iatrogenic hyperthyroidism after LT4 initiation and the diagnosis of P-CH.

Objectives Cerebral edema (CE) remains one of the most feared complications of diabetic ketoacidosis (DKA) with severe morbidity and mortality. The use of computerized tomography (CT) scan in the setting of suspected cerebral edema in DKA has been minimally studied. The objective of our study was to evaluate the utility of CT scans in children with suspected cerebral edema, and secondarily to analyze the various patient characteristics of those with and without cerebral edema. Methods We performed a retrospective chart review of all the children with DKA secondary to T1DM admitted to our tertiary PICU in order to obtain demographic data, laboratory results, and their treatment course. Differences between the groups of suspected CE and no suspected CE were compared using linear and logistic regression for continuous and binary variables respectively. Results We identified 251 patients with DKA, 12 of which had suspected CE; 67% (8/12) of those patients received head CT and 87.5% (7/8) of them were read as normal. On the other hand, 33% (4/12) did not receive CT scan of head, and yet three of the four patients were treated for CE. Conclusions In our cohort of patients, CT results did not influence CE treatment or lack thereof; most patients with suspected CE were treated with or without head CT findings of CE, indicating that imaging has very little utility in our cohort of patients. In some cases, the use of head CT delayed the onset of treatment for CE.

Objectives Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive disorder of the fatty acid oxidative metabolism. This study aimed to investigate the epidemiological characteristics, the spectrum of variation, clinical phenotype, and prognosis of MCADD in Chinese newborns. Methods We retrospectively analysed newborn screening (NBS) data in the Zibo area from January 2016 to March 2022 and summarized 42 cases recently reported in Chinese neonates. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and next-generation sequencing (NGS) were used to detect the concentrations of carnitine in the blood spots and for diagnosis. Results A total of 183,082 newborns were detected, and six patients were diagnosed with MCADD (1/3,0514). The primary octanoylcarnitine (C8) and the octanoylcarnitine/decanoylcarnitine ratio (C8/C10) were elevated in all patients. Gene analysis revealed four known and four novel variants of the ACADM gene. Five patients were asymptomatic and developed normally under dietary guidance. One child died of vaccination-induced MCADD, presenting with hypoglycemia and elevated acylcarnitines. Conclusions The incidence of MCADD in Chinese newborns varies geographically from 1/222,903 to 1/30,514, and the most common pathogenic variant is c.449_452 del CTGA (p. T150Rfs∗4) in ACADM gene with a frequency of 27.7%. HPLC-MS/MS and genetic analysis are beneficial for early prevention and good prognosis of MCADD.

Objectives The glucagon stimulation test (GST) is used for the simultaneous assessment of central adrenal insufficiency (CAI) and growth hormone deficiency. The new Roche cortisol II (C II) assay was recently introduced, confounding interpretation of the GST. The performance of the GST in diagnosing central adrenal insufficiency (CAI), utilising the C II assay, was therefore compared with that of the overnight metyrapone test (ONMTPT). Methods A diagnostic accuracy study was performed by retrospectively analysing folders and laboratory records of 25 children and adolescents investigated for hypopituitarism with the GST and the ONMTPT between September 2016 and December 2019. The peak serum cortisol (C) of the GST, the post-metyrapone serum 11-deoxycortisol and adrenocorticotropin levels of the ONMTPT were recorded. Diagnostic performance of the GST at a previously suggested cut-off of 374 nmol/L was evaluated. Results Seventeen boys and 8 girls, aged 1.7–16.3 years (median 7.3 years) were identified. The sensitivity of the post-GST C-level at 374 nmol/L was 0.40 (95% confidence interval [CI] 0.17–0.69), specificity 0.64 (95% CI 0.39–0.84), positive predictive value 0.44 (95% CI 0.19–0.73), negative predictive value 0.60 (95% CI 0.36–0.80), accuracy 0.54 (95% CI 0.35–0.72), positive likelihood ratio (+LR) 0.93 (95% CI 0.49–1.77) and negative LR 1.12 (95% CI 0.40–3.15). The area under the receiver of operating characteristics (ROC) curve was 0.379 (95% CI 0.142–0.615). Conclusions This study suggests that the GST at any C II cut-off cannot replace the ONMTPT as a diagnostic test for CAI in children. Findings should be confirmed in a larger study.

Objectives To explore the dose-response relationship between physical activity and the improvement of cardiometabolic risks in children with obesity, and provide a reference for the recommendation of physical activity for obese children. Methods A total of 96 children with obesity were recruited to participate in an exercise intervention program. An ActiGraph GT3X+ three-axis accelerometer was used to measure their physical activity. The dose groups (Q1∼Q4) were divided based on the quartiles of physical activity. The analysis of variance was used to compare the changes in body composition and cardiometabolic risk factors before and after the intervention. Results All intervention groups showed a significant reduction in weight, body mass index, body fat percent, fat mass, fat free mass, and skeletal muscle mass (p<0.01), and the change in the Q4 and Q3 groups was greater than in the Q2 and Q1 groups. Triglyceride, total cholesterol, low-density lipoprotein cholesterol, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were significantly reduced after intervention in all groups (p<0.01), and the change in SBP, and DBP in the Q4 group was higher than in the Q1 group (p<0.05). Conclusions Exercise interventions could effectively improve body composition and cardiometabolic risk factors. A higher exercise dose is associated with significant improvements in body composition, and cardiometabolic health.

Objectives This study aimed to determine the prevalence and predictors of euthyroid sick syndrome (ESS) in pediatric intensive care, and to establish a link between thyroid function tests and mortality. Methods Between January 2015 and March 2020, children admitted to our pediatric intensive care unit (PICU) and tested for free triiodothyronine (fT3), free thyroxine (fT4), and thyrotropin (TSH) levels were included. Patients with decreased fT3, with normal or decreased fT4, and normal or decreased TSH levels were assigned to the ESS group. The association between biochemical indicators and ESS, as well as the relationship between fT3 and mortality, were examined. Results A total of 141 (36%) of 386 children included to study were classified in the ESS group. The ESS group had a higher rate of 28-day mortality (12 [8.5%] vs. 9 [3.7%]). Blood urea nitrogen (BUN), albumin, platelet, lactate, and pediatric index of mortality 3 [PIM3 (%)] were significantly associated with ESS (odds ratios in order: 1.024, 0.422, 0.729, 1.208, 1.013). Multivariate regression analysis showed that BUN, albumin, platelet, and lactate were independently associated with ESS progression. The area under curve (AUC [95%CI]) for fT3 was 0.644 (0.555–0.789) to detect mortality. Children with a fT3 level lower than 2.31 pg/mL had significantly higher 28-day mortality (log rank test, p=0.001). Conclusions Our study identified BUN, albumin, lactate, and platelet count as independent risk factors for ESS progression in children. Furthermore, our findings indicated a correlation between fT3 and mortality, which makes fT3 an ideal candidate to be included in mortality indices.

Objectives Glycemic outcomes in children with type 1 diabetes (T1D) vary widely, despite uniform care. We hypothesized that glycemic outcomes in children with T1D are affected by the marital relationship satisfaction of the child’s parents. Methods We evaluated a prospective sample of 51 families with a child with newly diagnosed T1D, including 36 married parent families. We assessed indicators of marital relationship satisfaction and used multiple regression models to determine whether marital relationship satisfaction at diagnosis was associated with mean HbA 1c 18–24 months after diagnosis. Results Marital status and parental relationship satisfaction at the time of the child’s T1D diagnosis were associated with HbA 1c 18–24 months later. These differences persisted after adjusting for demographic factors associated with glycemia. Conclusions The quality of the primary diabetes caregiver’s relationship with a spouse predicts glycemic outcomes for children with T1D. Interventions to improve spousal relationships and caregiver support could improve glycemic control in children with T1D.

Objectives Nephrocalcinosis is associated with conditions that cause hypercalcemia and the increased urinary excretion of calcium, phosphate, and/or oxalate. A monogenic etiology is found in almost 30% of childhood-onset nephrocalcinosis which is also a common manifestation of primary hyperparathyroidism. We discuss a child with nephrocalcinosis and features mimicking primary hyperparathyroidism. Case presentation A 7-year-old girl presented with nephrocalcinosis. Hypercalciuria, hyperphosphaturia, mild hypercalcemia, hypophosphatemia and elevated parathyroid hormone levels along with normal serum creatinine and absence of hypokalemic alkalosis suggested primary hyperparathyroidism. However, she was ultimately diagnosed with Bartter syndrome type 2 based on the presence of homozygous pathogenic variation in KCNJ1 gene. Conclusions This is the second reported case of late-onset Bartter syndrome type 2 without hypokalemic alkalosis. Patients with Bartter syndrome may present with high parathyroid hormone levels and hypercalcemia in addition to hypercalciuria. Thus, the present case suggests that the KCNJ1 gene should be included in genetic analysis even in older children with isolated nephrocalcinosis.

Objectives A recent large retrospective cohort study of cases of hyponatremia in Prader–Willi syndrome (PWS), conducted at nine reference centers, showed that severe hyponatremia was rare in PWS (0.5%); furthermore, all cases involved adults. Here, we describe three pediatric cases of severe hyponatremia in PWS, with neurological symptoms. Case presentation The cases involved two girls and one boy, and only one patient showed uniparental disomy. All patients had hyponatremia during infancy and presented with clinical symptoms, such as convulsions. All three patients improved with intravenous fluids and fluid restriction, with no sequelae. Conclusions We report three pediatric cases of symptomatic hyponatremia of unknown cause in PWS. In patients with PWS, especially those with neurological symptoms such as convulsions, it is necessary to take hyponatremia into consideration.

Objectives Congenital hypogonadotropic hypogonadism combined with anosmia or hyposmia is considered Kallmann syndrome (KS). It is often accompanied by bone defects. Case presentation Here, we report a girl and her mother with KS caused by a novel mutation in the fibroblast growth factor receptor 1 gene ( FGFR1 ). Interestingly, the daughter presented syndactyly and oligodactyly of the feet. Conclusions The presence of bone malformations in a KS patient should direct the geneticist towards a search for specific mutations in FGFR1 . Our finding contributes to enrich the spectrum of FGFR1 mutations in patients with KS.

Objectives Mini-puberty is the physiological and transient activation of the hypothalamic–pituitary–gonadal axis occurring during the first months after birth. In preterm infants, the hormonal surge is more pronounced and longer-lasting than in at-term-peers. To date, only few cases of vaginal bleeding in the setting of an exaggerated mini-puberty have been reported. Case presentation At the corrected age of 3 months, an ex-very-preterm girl presented with breast enlargement and recurrent vaginal bleeding. A remarkable increase in gonadotropins and estradiol levels was detected, while pelvic ultrasound highlighted a large right ovarian cyst. As brain and pituitary MRI showed negative findings, an exaggerated mini-puberty was suspected and no additional investigations were undertaken. The subsequent progressive regression of clinical, biochemical and sonographic findings confirmed the diagnosis. Conclusions Although exaggerated mini-puberty of infancy in ex-preterm girls is a rare event, it is important to raise knowledge of this para-physiological condition in order to avoid unnecessary investigations and treatment.

Objectives Diabetic ketoacidosis is a common emergency in type 1 diabetes mellitus patients. But rarely, they may present with alkalemia instead of acidosis. Diabetic ketoalkalosis which has been reported in adults can also be present in children with type 1 DM. The usual factors causing alkalemia were not found in our patients. This entity may manifest in both newly diagnosed and treated patients. Case presentation The first patient, an 8 year male presented with features of DKA, was diagnosed for the first time as type 1 DM, but was found to have alkalemia. The second patient, a 7 year female was a known case of Type 1 DM on insulin, who presented with dehydration and alkalemia. Both were treated with hydration and insulin and made complete recovery. Conclusions A normal or alkalotic pH does not essentially eliminate DKA and needs to be evaluated further to identify the underlying acid–base disturbance.