Band 36, Heft 11

Objectives Infantile hypercalcemia-1 (HCINF1) is a rare disease caused by pathogenic variants in the CYP24A1 gene, resulting in the inability to metabolize active vitamin D. This leads to hypercalcemia and severe complications. Content On December 8th, 2022, a systematic literature search was conducted in PubMed, Wanfang, and CNKI using the keywords “hypercalcemia” and “ CYP24A1 ”. Data extraction included patient demographics, clinical presentation, treatment medications, and outcomes. The findings were synthesized to identify common patterns and variations among cases and to assess the efficacy of different therapies in reducing serum calcium. Our findings revealed two distinct peaks in the incidence of HCINF1 caused by CYP24A1 pathogenic variant. Kidney stones or renal calcifications were the most common clinical manifestations of the disease, followed by polyuria and developmental delay. Laboratory investigations showed hypercalcemia, elevated vitamin D levels, hypercalciuria, and low parathyroid hormone. Genetic analysis remains the only reliable diagnostic tool. Although there is no definitive cure for HCINF1, multiple drugs, including bisphosphonates, calcitonin, and rifampicin, have been used to control its symptoms. Blocking the production and intake of vitamin D is the preferred treatment option. Summary and outlook Our review highlights the basic clinical and biochemical features of HCINF1 and suggests that targeted diagnostic and therapeutic strategies are needed to address the clinical heterogeneity of the disease. The insights gained from this study may facilitate the development of innovative treatments for HCINF1.

Objectives Impaired linear growth is a known complication of pediatric inflammatory bowel disease (IBD), but the use of growth hormone (GH) in this population is not well-described. The primary aim of this study is to determine whether growth hormone use in pediatric IBD leads to improved height outcomes. Methods This was a retrospective chart review of patients with IBD aged 0–21 years followed at a single center between 2018 and 2021 treated with at least 1 year of GH. Records collected included demographics, IBD phenotype, IBD disease activity scores, medications, weight z-score, height z-score, bone age, and details of GH therapy including testing for GH deficiency. The primary outcome measure was change in height z-score after 1 year of GH treatment. Results Forty-six patients were identified and 18 were excluded. Of the 28 patients included (7 female; 25.0 %), 26 (92.9 %) had a diagnosis of Crohn’s disease (CD) and 2 (7.1 %) had ulcerative colitis (UC). The mean (SD) age at GH initiation was 9.6 (3.4) years. Among all participants, there was a significant mean difference in height z-score from baseline to 1 year on therapy (−2.25 vs. −1.50, respectively; difference, 0.75; 95 % CI, 0.56 to 0.94; p<0.001). Among the 19 subjects that completed GH therapy there was a significant mean difference between baseline and final height z-scores (−2.41 vs. −0.77, respectively; difference, 1.64; 95 % CI, 1.30 to 1.98; p<0.001). Conclusions GH use was associated with improved height outcomes. The pediatric IBD patients in this cohort had significant improvements in height z-scores both after one year on therapy and at completion of GH therapy.

Objectives The objective of this study was to compare the diurnal variations in cortisol and cortisone concentrations in serum and saliva among extremely preterm (EPT), very preterm (VPT), and full-term (FT) children, all born appropriate for gestational age (AGA). Methods EPT, VPT, and FT children, all born AGA, were recruited from two healthcare centers. Cortisol and cortisone concentrations in serum and saliva were measured by liquid chromatography-mass spectrometry (LC‒MS). Statistical analysis was performed using nonparametric tests. Results A total of 101 children (5.0–8.9 years old) were included in this study: EPT=18, VPT=43 and FT=40. All groups had similar distributions in terms of age, birth weight standard deviation score (SDS) and BMI (SDS), showing no differences in serum ACTH, cortisol, or cortisone levels. Additionally, salivary cortisol and cortisone concentrations decreased significantly throughout the day (p-values<0.0001). Salivary cortisol concentrations were below the limit of detection (0.55 nmol/L) before dinner and before bedtime in approximately one-third and two-thirds of all children, respectively. Salivary cortisone was detectable in all but one sample. Conclusions The diurnal cortisol rhythm was preserved in all preterm children, regardless of their gestational age, and no differences in cortisol concentrations among the groups were found. This may have significant implications for the clinical management and follow-up of preterm individuals.

Objectives This prospective study compares testosterone injection type and effects on biochemical changes, clinical effects, and quality of life amongst transgender and gender diverse (TGD) adolescents assigned female at birth (AFAB) over the first 6 months of subcutaneous (SQ) vs. intramuscular (IM) testosterone injections as part of their gender affirming care. Methods Subjects were testosterone-naïve transgender adolescents, AFAB, ages 14–18 years old. Subjects were either randomized to injection type or selected a preferred injection type. At enrollment, subjects completed baseline labs and PedsQL™ quality of life questionnaire. At 3 month and 6 month follow up, subjects completed peak and trough testosterone levels, PedsQL™, masculinizing effects, and medication experience questionnaires. Results Twenty-six subjects participated with a median age 15.5 years. By 6-month follow up, trough testosterone levels were comparable between the two groups. Peak testosterone levels were higher in the IM group at 3-month follow up. Mild adverse effects were rare (12 %, all in SQ subjects) and limited to skin reaction only. Self-reported masculinization effects and quality of life were not statistically different between injection groups. A total of 92 % of participants was self-injecting by 3-month follow up. Conclusions In this prospective study, clinical and biochemical effects are similar between SQ and IM testosterone injections for transgender adolescents. Subjects expressed preference for both injection types. Both SQ and IM injection modalities are safe and effective for TGD youth initiating testosterone and both options should be offered to patients.

Objectives Cardiovascular diseases are the main causes of death in the world. They are associated with the presence of risk factors such as obesity and dyslipidemia. Our objectives were to verify association between body mass index (BMI) and abnormalities in children’s lipid profile evaluated during well-child visits, seeking to identify the frequency of each disorder in this population. Methods A cross-sectional study examined anthropometric data and laboratory results of children aged 2 to 9 (n=363) at a pediatric clinic between 2014 and 2017. Logistic and linear regression models were employed to assess associations between variables. Results Mean age was 6.3 ± 2.2 years; 187 (51.5 %) were male; 253 (69.7 %) were aged between 5 and 9 years old. A total of 114 (31.4 %) presented excess body weight and 53 (14.6 %) had obesity/severe obesity. Dyslipidemia was detected in 114 (34.4 %) children. Triglycerides was the most frequently altered lipid fraction (18.5 %), followed by HDL-c (16.8 %) and LDL-c (9.1 %). There was an association between hypertriglyceridemia (p=0.013) and low HDL-c (p=0.028) with obesity. BMI z-score showed a positive correlation with triglycerides (p=0.011) and a negative correlation with HDL-c (p=0.039). No association was observed between LDL-c and BMI. Conclusions Excess body weight and dyslipidemia were seen in one-third of evaluated children. Elevations in triglycerides concentration were correlated with increased in BMI z-score. These findings point to the importance of monitoring nutritional status in well-child visits and performing universal screening for dyslipidemia in children, regardless of BMI.

Objectives Gonadotropin-releasing hormone agonist (GnRHa) has been used for central precocious puberty (CPP) or early and fast puberty. It was aimed to assess changes in body mass index (BMI), polycystic ovary syndrome (PCOS) frequency, and anti-Müllerian hormone (AMH) in girls who had been treated with GnRHa. Methods Fifty-eight adolescent girls treated with GnRHa for CPP or early and fast puberty (3.75 mg/28 days), between 2011 and 2015, were re-evaluated in 2020–2022 at least 2 years after menstruation. Hormonal analyses were compared with 51 healthy adolescents. Results In the GnRHa-treated group, a statistically significant increase was observed when the BMI standard deviation score (SDS) at the beginning of the treatment was compared with the BMI SDS at the end of the treatment (p=0.038). A statistically significant decrease was observed when the BMI SDS at the end of the treatment was compared with the BMI SDS in late adolescence (p=0.012). When the BMI SDS at the beginning of the treatment was compared with the BMI SDS in late adolescence, it was observed that there was no statistically significant difference (p=0.196). Of the 58 girls in the GnRHa-treated group, 8 (14 %) had PCOS. Serum AMH levels did not differ between the GnRHa-treated and the control group. Conclusions GnRHa treatment causes no adverse effect on BMI, at least in late adolescence. Girls treated with GnRHa were not found to be prone to developing PCOS. AMH levels were similar in the GnRHa-treated group as in the control group.

Objectives Disorders of pubertal development are enlisted as associated conditions in children and adolescents with type-1 diabetes (T1D). We conducted this study with objective (1) To estimate the median age at onset of puberty and luteinizing hormone (LH) and sex-steroid concentrations in Indian adolescents with T1D and (2) To assess the impact of puberty on glycemic control and insulin resistance (IR). Methods This cross-sectional study included 399 children and youth aged 6–23 years with T1D. Demographic, anthropometric, biochemical and pelvic ultrasound data were collected using standard protocols. IR was calculated using estimated glucose disposal rate and puberty was assessed using Tanner staging. Results Median age at onset of thelarche, pubarche and menarche were 11.3, 11.4 and 12.8 years in girls and that of gonadarche and pubarche were 10.6 and 12.7 years for boys. The mean LH and sex-steroid concentrations of subjects with T1D were similar to healthy subjects at each stage of puberty. The cut-offs of LH and sex-steroids derived from healthy Indian children yielded high sensitivity and specificity in determining pubertal onset. The prevalence of precocity, delayed puberty, ovarian cysts and polycystic ovaries was 0.9 , 5.1, 5.1 and 8.6 %, respectively. Glycaemic control and insulin sensitivity was poor in pubertal subjects. Conclusions The age at onset of puberty, LH, and sex-steroid concentrations in subjects with T1D were like otherwise healthy Indian children with poor glycemic control and IR in pubertal subjects. Although most complications of T1D are associated with poor glycemic control, pubertal disorders were significantly low despite the less-than-optimal glycemic control.

Objectives In the present study, we aimed to evaluate the genotype-phenotype relation in patients with biotinidase enzyme deficiency based on repeated biotinidase enzyme measurements. Methods The hospital file information of patients with biotinidase, enzyme deficiency was assessed retrospectively, and the relationship between the BTD gene mutations analysis results and biotinidase enzyme activity following the first and repeated enzyme activity assessments was analyzed. Results One-hundred-ten patients were included. In the first enzyme evaluation, profound biotinidase enzyme deficiency was identified in 15 (13.6 %), partial biotinidase enzyme deficiency in 63 (57.3 %), and heterozygous biotinidase enzyme deficiency in 32 (29.1 %) of the patients. The BTD genetic analysis revealed 42 (38.2 %) homozygous, 42 (38.2 %) heterozygous, and 26 (23.6 %) compound heterozygous variants. The most common homozygous variant, p.Asp444His, was evaluated with 130 repeated enzyme measurements and was consistent with a partial biotinidase enzyme deficiency in 55.4 % of cases, heterozygous biotinidase enzyme deficiency in 43.8 % of cases, and profound biotinidase enzyme deficiency in one (0.8 %) case. Clinical symptoms developed in 17 patients during follow-up, of which 70.6 % were related to neurodevelopment. The most common variant was homozygous p.Asp444His (29.4 %) among the patients who developed symptoms. Conclusions This is the first study to date to evaluate the genotype-phenotype relationship in patients with biotinidase deficiency through repeated measurements of biotinidase enzyme activity. The study reveals that biotinidase enzyme activity alone is inadequate for diagnosing biotinidase enzyme deficiency or evaluating disease severity, as genetic investigations are also required for a definitive diagnosis of biotinidase enzyme deficiency.

Objectives Gender-affirming testosterone therapy is increasingly prescribed among transmasculine adolescents and has been associated with improved mental health outcomes. However, expected and perceived effects of testosterone have not previously been compared in this population. Methods We compared desired and reported effects of testosterone in all consecutive transmasculine adolescents followed at a large interdisciplinary gender diversity clinic in North America. Participants received a prescription for testosterone and were first seen between November 2016 and May 2021. Our study was a retrospective audit of case notes. We collected self-reported desired effects prior to initiation of testosterone and self-reported perceived effects from participants’ medical records up to 24 months after initiation. The masculinizing effects of testosterone considered in our study were increased body/facial hair, voice deepening/Adam’s apple growth, increased muscle mass, clitoromegaly, and body fat redistribution. Results There were 76 participants included in this study. Mean age at prescription of testosterone was 16.31 years (standard deviation: 0.99 years). The effects desired by the greatest proportion of participants prior to initiation were increased body/facial hair (69 %) and voice deepening/Adam’s apple growth (52 %). These same two effects were the most reported by participants, reaching 80 % report rates at 12 months, and increasing steadily across the 24-month follow-up period. Conclusions Our study shows that for most, but not all gender diverse adolescents undergoing testosterone therapy, the most expected physical changes were seen in the first year of gender-affirming treatment. More research and provider education are needed to offer optimal counseling for adolescents undergoing gender-affirming hormone therapy.

Objectives Subclinical hypothyroidism (SCH) is defined by elevated thyrotropin (TSH) and normal level of thyroxine (T4). The definition of SCH and the cutoff for TSH normality in pregnancy are debated. In the present study, we assess offspring perinatal outcome, anthropometrics and early development in relation to different TSH levels. Methods An observational study with 77 singleton-pregnant women included by thyroid screening before a planned cesarean section. Two TSH-cutoffs (3.0 and 3.7 mIU/L) defined euthyroid and SCH groups, and were applied to evaluate offspring anthropometrics, complication rates (maternal blood loss, Apgar-score, cord arterial-pH, admission to neonatal intensive care unit, perinatal hypoglycemia) and offspring development. Development was evaluated by Bayley-III test in a subsample at age 6 months (n=27) and 15 months (n=22). Results Prevalence of SCH was 31.2 % at TSH-cutoff 3.0 mIU/L, and 16.9 % at TSH-cutoff 3.7 mIU/L. No differences in complications and anthropometrics were observed. In Bayley-III tests, cognitive score was decreased at 6 months (p=0.012) and at 15 months (p=0.056) by applying TSH-cutoff 3.0 mIU/L. At cutoff 3.7 mIU/L, motor score was decreased at 15 months (p=0.020). Male offspring had significantly lower cognitive scores at age 6 and 15 months (TSH-cutoff 3.0 mIU/L), and motor scores at age 15 months (TSH-cutoff 3.7 mIU/L). Conclusions The importance of the definition of thyroid normality in pregnancy is underlined. This study suggests that a gender-effect might be present in maternal thyroid disease, and that developmental differences exist if TSH-cutoff is low. Further research is needed.

Objectives Glycogen storage disease (GSD) type 1b is a multisystemic disease in which immune and infectious complications are present, different from GSD type 1a. Treatment with granulocyte-colony stimulating factor (G-CSF) is often required in the management of neutropenia and inflammatory bowel disease. Recently, an alternative treatment option to G-CSF has been preferred, like empagliflozin. To report on the demographics, genotype, clinical presentation, management, and complications of pediatric patients with glycogen storage disease type 1b (GSD 1b). Methods A retrospective analysis of the clinical course of eight patients with GSD type 1b whose diagnosis was confirmed by molecular testing. Results The mean age at referral was four months. The diagnosis of GSD 1b was based on clinical and laboratory findings and supported by genetic studies. One patient presented with an atypical clinical finding in the form of hydrocephalus at the time of first admission. The first symptom was abscess formation on the scalp due to neutropenia in another patient. Other patients had hypoglycemia at the time of admission. All patients presented suffered from neutropenia, which was managed with G-CSF, except one. Hospitalizations for infections were frequent. One patient developed chronic diarrhea and severe infections, which have been brought under control with empagliflozin. Conclusions Neutropenia is an essential finding in GSD 1b and responsible for complications. The coexistence of hypoglycemia and neutropenia should bring to mind GSD 1b. Empagliflozin can be a treatment option for neutropenia, which is resistant to G-CSF treatment.

Objectives The childhood mortality rate for IMDs is approximately 25 % in populations with no expanded newborn screening program. Although the factors that increase mortality risk are known, an index predicting long-term survival has yet to be established. Methods Two hundred sixty patients who were hospitalized during the first month of their life were screened, and 94 patients diagnosed with IMDs were included in the study. Clinical and laboratory data were assessed to identify any independent prognostic factors for overall survival. Results Among the 38 patients with IMDs in the exitus group, the presence of dysmorphism, extremity abnormalities, respiratory distress, cyanosis, elevated transaminases, elevated INR, hypoglycemia, hypoalbuminemia, metabolic acidosis, electrolyte imbalance and anemia were associated with poorer survival. Elevated INR (Hazard Ratio [HR]: 0.17, 95 % CI: 0.03–0.87, p=0.034), hypoglycemia (HR: 0.48, 95 % CI: 0.25–0.91, p=0.026) and hypoalbuminemia (HR: 0.09, 95 % CI: 0.03–0.26, p<0.001) were the independent prognostic factors for survival after adjusting for confounding factors. For the prediction of survival, INR, glucose, and albumin were used to structure a novel index (IGAm = INR-Glucose-Albumin metabolic index). The median survival was shorter in the IGAm-high group (2 or 3 points) than in the IGAm-low group (p<0.001). Harrell’s c-index was 0.73 for the IGAm index. Conclusions The devised novel IGAm index can predict long-term survival in patients with IMDs, with a high IGAm index being associated with higher mortality in patients with IMDs.

Objectives Hypercalcemia has been reported as an uncommon complication of the ketogenic diet (KD). Here we present a toddler whose hypercalcemia persisted for 2 months after stopping the KD. Case presentation A 2 year 11-month-old child with global developmental delay, infantile spasms, neuromuscular weakness with limited mobility, tracheostomy and ventilator dependence, and oropharyngeal dysphagia with G-tube dependence presented with hypercalcemia in the setting of recurrent vomiting. At presentation, the patient was adherent to a KD and taking topiramate since infancy for intractable seizures. His laboratory parameters at presentation showed hypercalcemia (11.9 mg/dL), hypercalciuria, acute renal failure, low alkaline phosphatase (76 IU/L [110–302 IU/L]), parathyroid hormone (PTH) <6 pg/mL (18–80 pg/mL), normal thyroid function, cortisol and vitamin D level. The patient’s hypercalcemia persisted post-discontinuation of the KD and topiramate. PTH-related protein was mildly elevated at 15.3 pmol/L. Follow-up laboratory and imaging studies ruled out malignancy. He was managed with calcitonin 4 u/kg/dose Q12H × 1 day and 8 u/kg/dose Q8H × 1 day, hydration and low-calcium formula. Post-discontinuation of the KD, normalization of alkaline phosphatase levels preceded the normalization of calcium on day 55 and PTH on day 85. Conclusions Hypercalcemia may persist for an extended period after weaning from a KD; lab parameters may mimic that of hypophosphatasia as previously described in the literature. Normalization of alkaline phosphatase, a marker of bone turnover, indicates recovery from the adynamic state induced by the KD and typically precedes the normalization of calcium and PTH.