Band 36, Heft 2

The past 50 years of research in pediatric bone and mineral metabolism have led to remarkable progress in the identification and characterization of disorders that affect the developing skeleton. Progress has been facilitated through advances in both technology and biology and this paper provides a brief description of some but not all of the key findings, including identification of the calcium sensing receptor and the polypeptides parathyroid hormone and parathyroid hormone-related protein as well as their shared receptor and signal generating pathways; the elucidation of vitamin D metabolism and actions; discovery of fibroblast growth factor 23 (FGF23), the sodium-phosphate co-transporters and the other components that regulate phosphate metabolism. Moreover, the past half-century of research has led to the delineation of the molecular bases for genetic forms of hypoparathyroidism, pseudohypoparathyroidism, and primary hyperparathyroidism as well as the determination of the genetic causes of osteogenesis imperfecta, osteopetrosis, hypophosphatasia, and other disorders of mineral/bone homeostasis. During the next decade we expect that many of these fundamental discoveries will lead to the development of innovative treatments that will improve the lives of children with these disorders.

Objectives FreeStyle Libre 1 (FGM) has been approved by the FDA for children older than 4 years. It enables noninvasive glucose monitoring without the need for finger pricking. Parents of very young children often use the device off-label. Thus, we aimed to evaluate the safety of and user experience with FreeStyle Libre ® 1 and determine its impact on sleep and glycemic control. Methods This was an ambi-directional cohort study. We recruited parents of very young children with type 1 diabetes mellitus (T1DM) who were less than 5 years old when they started using FGM at the King Saud University Diabetes Center. The parents filled out a survey evaluating their experience with the system. In addition, the glucose metrics of the children were also obtained from the Libre View system. Results We included 31 children with mean age of the children when they started using FGM was 3.88 ± 1.10 years (range, 1.46–5.4 years), and the mean sensor use was 2.3 ± 1.3 years. During the use of the device, the parents had increased sleep duration of 0.71 h (p-value=0.04), had earlier bedtime by 2.8 h (p-value=0.04), and were able to sleep in a separate room from their children. In addition, the time in range improved by 9.9%, the time above range decreased by 8.8%, and the HbA 1c level reduced by 1.56%. Conclusions The safety profile of FGM used for very young children with T1DM is the same for older children, which leads to improved metabolic control and sleep quality of both the parent and the child.

Objectives Extracellular vesicles (EVs) are small vesicles released by nearly all types of cells. They deliver different types of substances, including proteins and nucleic acids, to nearby or distant cells and play a role in the mediation of cell-to-cell communication. The aim of this study was to explore the association between EVs and insulin resistance in adolescents with obesity or type 2 diabetes mellitus (DM2). Methods The subjects were eight adolescents with DM2 (DM2 group; four males and four females; age: 18.1 ± 2.3 years), 18 adolescents with simple obesity (obesity group; 12 males and six females; age: 12.2 ± 3.4 years), and 20 controls (control group; 10 males and 10 females; age: 13.0 ± 1.4 years). As markers of EVs, serum CD9/CD63 and sonic hedgehog N-terminal (Shh-N) levels were measured using enzyme-linked immunosorbent assay. Results The CD9/CD63 level in the control group was similar to that in the DM2 group, whereas the obesity group had a significantly higher CD9/CD63 level. In the entire study group, correlations were observed between serum Shh-N level and Homeostasis Model Assessment of insulin resistance (HOMA-IR) score (r=0.371, p=0.0143), Homeostasis Model Assessment-β cell function score (r=0.382, p=0.0115), serum insulin level (r=0.350, p=0.0171), and serum adiponectin level (r=0.367, p=0.0122). Multiple regression analysis revealed that serum Shh-N level was the most significant risk factor for HOMA-IR score and serum insulin level. Conclusions Shh is correlated with insulin resistance via its association with adiponectin in adolescents.

Objectives Diabetic ketoacidosis (DKA) is a life-threatening acute metabolic decompensation condition due to insulin deficiency and elevation of pancreatic enzymes is common. The goal of this study was to determine the laboratory findings and biochemical characteristics associated with pancreatic enzyme elevation during DKA. Methods The files of patients hospitalized in the pediatric intensive care unit with the diagnosis of DKA between March 2020 and 2022 were reviewed retrospectively. Demographic data, length of stay at hospital, initial biochemistry, hemogram, blood gas values, amylase, and lipase in the first 24 h were noted. Those with elevated amylase and/or lipase values were grouped. Patients were grouped according to the severity of DKA. These groups were analyzed statistically. Results Amylase and/or lipase were found to be elevated in 21 (28%) of diagnosed with DKA. pH and HCO 3 were significantly lower, length of stay in the intensive care unit, and triglyceride levels were significantly higher in patients with high amylase and/or lipase when compared with the control group (p<0.05). Although lipase values have a negative correlation with blood gas parameters and a positive correlation with TG and cholesterol values, correlation degree was found to be weak (p<0.05). Lipase was significantly higher in the severe diabetic ketoacidosis group than the moderate group (p<0.001). Conclusions Elevations in amylase and lipase values can be encountered frequently in patients with DKA. Considering that the metabolic deterioration due to DKA may have an effect on this, we recommend that the patient should be followed closely and the enzyme level should be monitored intermittently.

Objectives Alexithymia and low health literacy are the barriers of self-management. This study aims to examine the relationship between alexithymia, health literacy and diet quality in obese adolescents, and their effects on anthropometric and biochemical markers. Methods The 20-item Toronto alexithymia scale (TAS-20) was used to determine the alexithymic traits of the adolescents, and “The Newest Vital Sign” (NVS) scales were used to determine their health literacy levels. Diet quality was evaluated with the Healthy Eating Index-2010 (HEI-2010). Results 39.7% of the obese adolescents were alexithymic, and 69.4% of alexithymics and 35.1% of non-alexithymics had metabolic syndrome. Alexithymic adolescents were lack of adequate health literacy. There were positive correlations between alexithymia scores and insulin, triglyceride, systolic and diastolic blood pressure levels, and all anthropometric values except height (p<0.05). There was a negative correlation between alexithymia scores and health literacy scores (p<0.05). There were negative correlations between health literacy and alexithymia scores, insulin, total cholesterol, triglyceride, ALT, systolic, diastolic blood pressure levels and all anthropometric values except height, and positive correlation was observed between health literacy scores and diet quality (p<0.05). Total HEI score was negatively correlated with waist circumference, neck circumference, body weight, BMI, triglyceride, AST, ALT, systolic and diastolic blood pressure, and positively correlated with health literacy and HDL levels (p<0.05). Conclusions As alexithymia severity increased in obese adolescents, the degree of obesity and the incidence of metabolic syndrome increased while the level of health literacy decreased. The increase in health literacy levels, on the other hand, decreased the level of alexithymia and increased the quality of the diet.

Objectives Premature atherosclerosis and ischemic heart disease represent a major cause of comorbidities among children with Turner syndrome. The identification of non-traditional risk aspects is crucial for the early identification and management of such comorbidities through establishing effective preventive measures. The aim of the study is to explore the role of the deficiency of vitamin B12, folic acid and homocysteine in children with Turner syndrome. Methods The study included 78 children with Turner syndrome and 67 healthy age and sex matched children. Karyotype was implemented for all patients. The serum levels of vitamin B12, folic acid and serum homocysteine were assessed. The prevalence of the deficiency of vitamin B12 and folic acid was estimated to study its correlation to hyperhomocysteinemia in Turner syndrome children. Results The karyotype analysis showed 45,X (monosomy X) in the 78 patients. Vitamin B12 and folic acid were significantly decreased in children with Turner syndrome in 65–73% of the patients, respectively, while the serum level of homocysteine significantly increased to 48.7% compared to healthy controls. Homocysteine level negatively correlated with vitamin B12 and folic acid. The deficiency of vitamin B12 and folic acid increased the risk of hyperhomocysteinemia in children with Turner syndrome (OR 2.49 and 2.36, respectively). Conclusions This report highlights that hyperhomocyste-inemia in children with Turner syndrome may be related to the deficiency vitamin B12 and folic acid.

Objectives Vitamin D dependent rickets type 1A (VDDR1A) is a rare autosomal recessive condition due to inactivating mutation of CYP27B1 . It mimics clinically, biochemically and rediologically to nutritional and hypophosphatemic rickets. In developing countries like Pakistan, VDDR1A is often misdiagnosed as nutritional rickets or hypophosphatemic rickets due lack of free access to 1,25 (OH) 2 D level and genetic testing. This study was aimed to determine the clinical spectrum and diagnostic challenges of VDDR1A due to CYP27B1 mutation in developing countries. Methods Retrospective review of all cases of VDDR1A due to CYP27B1 mutation over a period of two years presenting in the Pediatric Endocrine clinic of Hameed Latif Hospital, Lahore, Pakistan. Results Six cases of VDDR1A (4 males) were identified. Mean age of clinical manifestation was 14 (9–24) months. Mean age of presentation to endocrine department was 5.5 (1.5–11.8) years. Growth failure and bony deformities were the most common presentation (n=6), followed by repeated diarrheas and abdominal distension (n=3) and recurrent fractures (n=1). All cases shared same biochemical profile of low/normal calcium, hypophosphatemia, raised alkaline phosphatase, raised PTH, normal/high 25(OH)D and tubular reabsorption of phosphate (TRP) <85%. Patients treated with calcitriol showed rapid healing as compared to those treated with 1-alfacalcidol. Conclusions We should have a high index of suspicion of VDDR1A in rickets not responding to cholecalciferol therapy.

Objectives Adaptation processes in body of schoolchildren, along with study load and social factors, are determined by influence of climatic and geographical factors of residence region. This research has been undertaken to study the morphofunctional characteristics of schoolchildren at the age of 7–17 years. Methods The research involved 880 schoolchildren of both sexes in age from 7 to 17 years, studying in secondary school №22 in Pavlodar (Kazakhstan) and secondary school №7 in Kyzylorda (Kazakhstan). The Quetelet index of northern schoolchildren was within the norm but higher compared to southern peers. Results The Quetelet index was within the normal range for all schoolchildren, but higher among northerners. The indicator of the life index in the boys of the south was higher up to 10 years, then the adaptive possibilities of breathing decreased; in the girls in the north this indicator was higher in all periods, except for 8–9 years. The physical performance index (PWC170/kg) was higher in children from the southern region. Conclusions This study revealed significant geographical differences in the morphofunctional development of children. The obtained data served allowed establishing the “Electronic map of schoolchildren’s health” and indicated the need for systematic accounting of schoolchildren’s health indicators for effective development of differentiated prevention programs.

Objectives Maple syrup urine disease (MSUD) is an inborn metabolic disease. The nutritional treatment with restricted intake of branched chain amino acids and prevention of leucine toxicity are crucially important for a favorable outcome. The aim of this study is to analyze the relation of blood leucine levels at diagnosis with future leucine tolerances, to determine whether any prediction about the future leucine tolerances or plasma leucine levels is possible by evaluating blood leucine levels at diagnosis. Methods The study group consisted of 45 MSUD patients. Leucine levels at diagnosis were compared with age at diagnosis, leucine tolerances, maximum leucine levels/ages, and average blood leucine levels. Results The mean plasma leucine level at diagnosis was 2,355.47 ± 1,251.7 μmol/L (ref: 55–164 μmol/L). The median age at diagnosis was 17 days. Leucine tolerances per kg body weight declined until the age of 8 years and stabilized subsequently. The average age of maximum leucine level during follow-up was 3.14 ± 1.92 years, and the mean maximum lifetime plasma leucine level on follow-up was 1,452.13 ± 621.38 μmol/L. The leucine levels at diagnosis did not have any significant relationship with lifetime leucine tolerances, maximum plasma leucine levels or mean plasma leucine levels. Conclusions The plasma leucine levels at diagnosis did not have a predictive value for later leucine tolerances or plasma leucine levels. The maximum lifetime leucine level is likely to happen within the first 3 years of life, underlining the importance of good metabolic control and compliance to dietary treatment at early ages.

Objectives Diabetic ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes. Our objective was to determine if children with severe DKA without alteration in mental status can be managed safely on a general children’s medical unit. Methods Single center retrospective study of 191 patient encounters among 168 children admitted to the children’s medical unit (CMU) at Primary Children’s Hospital between 2007 and 2017 with severe DKA (pH <7.1 and/or bicarbonate <5 mmol/L). Chart review identified complications including death, transfer to the intensive care unit (ICU), incidence of cerebral edema, and hypoglycemia. We compared patients requiring ICU transfer with those who did not with respect to demographics, laboratory findings at presentation, therapeutic interventions, length of stay, and cost. Results Of 191 patient encounters, there were 0 deaths (0%, 95% CI 0–2.4%), 22 episodes of alteration of mental status concerning for developing cerebral edema (11.5%, 95% CI 7.7–16.9%), 19 ICU transfers (10%, 95% CI 6.4–15.1%), and 7 episodes of hypoglycemia (3.7%, 95% CI 1.6–7.5%). ICU transfer was associated lower initial pH (7.03 ± 0.06 vs. 7.07 ± 0.07, p<0.05), increased length of stay (3.0 ± 0.8 vs. 2.2 ± 0.9 days, p<0.05), and increased cost of hospitalization (mean ± SD $8,073 ± 2,042 vs. $5,217 ± 1,697, p<0.05). Conclusions The majority of children with severe DKA without alteration in mental status can be managed safely on a medical unit. Implementing a pH cutoff may identify high-risk patients that require ICU level of care.

Objectives There is a lack of information regarding thiamine status in children with diabetic ketoacidosis (DKA). This study was designed to assess the thiamine status upon admission and 24 h after treatment initiation of DKA, whether newly diagnosed children or with established T1DM diagnosis, who presented with DKA. Methods We enrolled 90 children (mean age, 9.8 ± 2.6 years; 58 females and 32 males) with type 1 diabetes mellitus (T1DM), whether newly diagnosed or with an established T1DM diagnosis (from 1 to 5.2 years ago), who presented with DKA. We observed the initial Glasgow Coma Scale (GCS) and recovery time. The whole blood thiamine diphosphate levels were measured upon admission (baseline point) and 24 h after initiation of the DKA treatment (second-time point). Results The mean blood thiamine levels at the second-time point (90.11 ± 15.76 nmol/L) significantly decreased compared with their levels at baseline (108.8 ± 17.6 nmol/L) (p<0.001). We compared thiamine levels with the initial GCS, patient’s age, and recovery time. Thiamine levels at the second-time point were positively correlated with baseline thiamine levels (r=0.86, p=0.0001) and the initial GCS (r=0.68, p=0.001) but were negatively correlated with patient’s age (r=−0.61, p=0.001) and recovery time (r=−0.724, p=0.001). Based on multiple regression analysis, thiamine levels at the second-time point were directly related to the initial GCS and inversely related to the patient’s age. Conclusions The current study indicates that blood thiamine diphosphate levels significantly decreased after 24 h of DKA treatment initiation compared to pre-treatment levels. After 24 h of treatment initiation, blood thiamine levels are directly related to the initial GCS and inversely related to the patient’s age.

Objectives Prader–Willi syndrome (PWS) is characterized by obesity, growth hormone deficiency, hypogonadism, and a high prevalence of premature adrenarche despite reported hypothalamic–pituitary–adrenal axis dysfunction. While idiopathic premature adrenarche is associated with accelerated pre-pubertal growth and advanced bone age, the consequences of elevated adrenal androgens on growth and bone maturation in PWS remain unknown. This study therefore sought to describe age-related changes in dehydroepiandrosterone sulfate (DHEAS) and their effects on growth and bone maturation in PWS. Methods This retrospective observational study included 62 children with PWS. Simple and multiple regression models were constructed to relate age and BMI-SDS with DHEAS levels. Height velocity was compared to age and sex-based norms with t-tests and two-way ANOVA. Patterns in bone age Z-score were examined with two-way ANOVA, and the contributions of age, BMI-SDS, and DHEAS to bone age Z-score were analyzed with multiple regression. Results DHEAS levels rose earlier and were less strongly correlated with age in males and females with PWS (R 2 =0.12 and 0.30) compared to healthy controls (R 2 =0.89 and 0.88) in a pattern unrelated to BMI-SDS (adjusted R 2 =0.076, p=0.10 for age, and 0.29 for BMI-SDS). Mid-childhood height velocity was increased in males and preserved in females with PWS before declining at the age of expected puberty (p<0.0001). Peri-adrenarchal bone age was advanced in a manner associated with DHEAS but not BMI-SDS (p<0.0001; adjusted R 2 =0.48, p=0.0014 for DHEAS, and 0.78 for BMI-SDS). Conclusions An obesity-independent increase in adrenal androgens is associated with accelerated mid-childhood growth and bone maturation in PWS.

Objectives Adrenal insufficiency (AI) is a life-threatening condition where an accurate diagnosis is critical. While the ACTH stimulation test is the diagnostic test of choice, there remains uncertainty around its protocols and interpretation of results. In this context, the objective of this study was to understand practices of North American pediatric endocrinology providers on the diagnosis of AI in children. Methods An anonymous electronic survey was sent to members of the Pediatric Endocrine Society. Results A total of 221 participants were included. The majority practiced in academic centers (78%). All respondents ordered ACTH stimulation tests. While 85% used high-dose ACTH stimulation tests (HDST) to diagnose primary AI, there was less consistency in the choice of tests (HDST vs. low-dose ACTH stimulation test; LDST) when diagnosing secondary AI. When interpreting results, 95% used peak cortisol levels, 70% considered the clinical picture, and 49% used relative increase in cortisol levels. Median (IQR) cortisol cutoff level after ACTH stimulation test that was considered sufficient was 18 (15.5–18) μg/L [496 (428–496) nmol/L]; 17% used different cutoffs for LDST, and 18% used different cutoffs for newborns. Finally, 47% were unaware of the assay that was used in their institution for cortisol measurements. Conclusions Pediatric endocrinology providers use ACTH stimulation tests variably, including in the choice between HDST vs. LDST, test protocols, and interpretation of results.

Objectives Pituitary gigantism is a rare condition and it often has an identifiable genetic cause. In this article we report a case of a young girl with pituitary gigantism and two genetic changes. Case presentation A 15-year-old girl with primary amenorrhea was diagnosed with a growth hormone (GH) and prolactin (PRL)-producing tumor, needing surgery and medical treatment with octreotide in order to achieve disease control. The co-occurrence of an  AIP  mutation and a  MEN1  variant of uncertain significance was demonstrated in this patient. The germline mutation involving  AIP  was inherited from her father who at the age of 55 was unaffected and the  MEN1  variant was a  de novo  duplication of the region 11q13.1. The latter variant, not previously reported, is unlikely to be pathogenic. Nonetheless, screening for other components of multiple endocrine neoplasia type 1 (MEN1) was performed and proved negative. Conclusions The rare co-occurrence of an  AIP  mutation and a  MEN 1  variant of uncertain significance was demonstrated in this patient.

Objectives MEGDHEL [3-methylglutaconic aciduria (MEG), deafness (D), hepatopathy (H), encephalopathy (E), and Leigh-like disease (L)] syndrome is an autosomal recessive disorder caused by mutations in the serine active site-containing protein 1 ( SERAC1 ) gene. MEGDHEL syndrome is clinically characterized by sensorineural hearing loss, encephalopathy, hepatopathy, 3-methylglutaconic aciduria, and Leigh-like lesions on cranial magnetic resonance imaging. During the neonatal period, it has been reported to present with hypoglycemia, hyperammonemia, impaired liver functions, cholestasis, metabolic acidosis, and sepsis-like clinical findings. However, clinical findings in the neonatal period were reported as a result of the retrospective evaluation of patients diagnosed at an older age. Herein we reported two cases diagnosed as MEGDHEL syndrome during neonatal period in two different clinics with sepsis-like findings, impaired liver functions, and ammonia levels high enough to require dialysis. Case presentation One of the cases was born 37 weeks of gestation with a birth weight of 2,060 g and initially presented with respiratory distress and feeding difficulties. The other case admitted to the neonatal intensive care unit had fed problems together with respiratory distress and circulatory failure within the first 24 h after initiation of parenteral nutrition. Conclusions MEGDHEL syndrome should be suspected in patients with sepsis-like clinical features and hyperammonemia.

Objectives Congenital hyperinsulinism (HI) is a heterogeneous clinical disorder with great variability in its clinical phenotype, and to date, pathogenic variants in 23 genes have been recognized.  Hyperinsulinism-hyperammonemia syndrome (HI/HA) is the second most frequent cause of this disease that shows an autosomal dominant pattern and is caused by an activating mutation of the GLUD1 gene, which responds favorably to the use of diazoxide. HI/HA syndrome presents with fasting hypoglycemia; postprandial hypoglycemia, especially in those with a high protein content (leucine); and persistent mild hyperammonemia. Neurological abnormalities, in the form of epilepsy or neurodevelopmental delay, are observed in a high percentage of patients; therefore, timely diagnosis is crucial for proper management. Case presentation We report the clinical presentation of two Peruvian children that presented with epilepsy whose genetic analysis revealed a missense mutation in the GLUD1 gene, one within exon 11, at 22% mosaicism; and another within exon 7, as well as their response to diazoxide therapy. To the best of our knowledge, these are the first two cases of HI/HA syndrome reported in Peru. Conclusions HI/HA syndrome went unnoticed, because hypoglycemia was missed and were considered partially controlled epilepsies. A failure to recognize hypoglycemic seizures will delay diagnosis and adequate treatment, so a proper investigation could avoid irreversible neurological damage.

Objectives Liddle syndrome is an autosomal dominant hereditary disease caused by a single gene mutation. Typical clinical manifestations are early-onset hypertension and hypokalemia. Case presentation This report describes a 17-year-old male with hypertension and hypokalemia. We performed Captopril inhibition and postural stimulation test to diagnose and type primary aldosteronism. The plasma renin activity was consistently low, and aldosterone levels were high, hence the patient was initially diagnosed with primary aldosteronism. After genetic analysis, a diagnosis of Liddle syndrome was made due to the presence of a p. Pro617Ser mutation in the SCNN1B gene. After diagnosis, the patient was prescribed one tablet of amiloride twice a day. The patient’s blood pressure (average in 120–135/70–80 mmHg) and serum potassium levels (3.6–4.0 mmol/L) returned to normal and was well-controlled after treatment. Conclusions Adolescent hypertension may be secondary to underlying medical conditions affecting the heart, kidneys, or endocrine system or primary with no known underlying disease process. Although in an adolescent with hypertension, hyperaldosteronism, and low plasma renin activity, the initial diagnosis suggested primary hyperaldosteronism, the failure of aldosterone receptor antagonist’s therapy led to the diagnosis of Liddle syndrome. Increased aldosterone levels should always be evaluated with caution before a definitive diagnosis to prevent misdiagnosis. Genetic testing is the gold standard for the diagnosis of Liddle syndrome. Early diagnosis and early precise treatment can restore normal blood pressure and prevent severe sequelae of chronic hypertension in patients.

Objectives Hybrid closed loop systems (HCL) improve the management of type 1 diabetes (T1DM). T1DM adolescent patients represent a risk category also if they are in an automated insulin infusion delivery therapy. Case presentation We describe a series of four cases in which adolescent patients have adopted incorrect behaviours in the managing of HCL systems, challenging the algorithm skills. Two patients performed fabricated sensor calibrations. The other two did not perform pre-prandial insulin boluses correctly. Despite these behaviours, the algorithm corrected the glucose values in three out of four patients. Only in one case, where fabricated calibrations were too frequent, the automatic system failed to restore the glycemic balance. Conclusions Fabricated calibrations seem to be more important than uncorrected insulin boluses to challenge the HCL systems.