Hormone Research in Paediatrics最新文献

Introduction: Growth patterns in Noonan syndrome (NS) remain relatively unknown. The objective of this study was to provide growth reference curves for patients with NS and identify correlations between their growth, genotype, and clinical features.

Methods: This was a 15-year-long, monocentric, observational, retrospective, non-interventional study. Children with NS followed up between 2005 and 2022 at "Bambino Gesù" Children's Hospital, Italy, were included and excluded if they had received growth hormone treatment. Comparison of growth curves of participants with NS versus the general Italian population and further genotypic analyses were performed.

Results: Overall, 190 eligible participants with NS were identified, with median (interquartile range) age of 14.01 (9.05-19.25) years (55.8% male). Cardiovascular anomalies were present in 85.3% of participants, most commonly pulmonary stenosis (52.6%) and atrial septal defects (36.8%); 48.1% of male participants had cryptorchidism. The most frequently detected mutations were in PTPN11 (66.3%) and SOS1 (13.9%). NS sex-specific centile curves for height, weight, body mass index, and height velocity were produced. For both sexes, the 50th percentile of height and weight for participants with NS overlapped with the 3rd percentile for the general Italian population. Both sexes with a PTPN11 mutation had a significantly lower height and weight than those with "other mutations" at 5 years old. No significant associations were observed between cardiac anomalies and PTPN11 mutation status.

Conclusion: We present longitudinal data describing growth curves and trends, the natural history, and genotypes of the NS population, which provide a useful tool for clinicians in the management of NS.

Introduction: Childhood hypophosphatemia is a rare condition and may be caused by malabsorption, malignancies, or genetic factors. Prolonged hypophosphatemia leads to impaired growth and radiographic signs of rickets.

Methods: We performed a detailed clinical and genetic evaluation of an adolescent boy with repeatedly low plasma phosphate concentrations (below 0.60 mmol/L) and growth failure.

Results: At 14 years, the patient presented with decelerating growth and delayed puberty. Biochemistry showed hypophosphatemia due to increased urinary phosphate loss; kidney function and vitamin D status were normal. Radiographs showed mild metaphyseal changes. A gene panel for known genetic hypophosphatemia was negative. Trio exome analysis followed by Sanger sequencing identified a pathogenic heterozygous de novo stop-gain variant in PRPF8 gene, c.5548C>T p.(Arg1850*), in the conserved RNase H homology domain. PRPF8 encodes the pre-RNA protein 8, which has a role in RNA processing. Heterozygous PRPF8 variants have been associated with retinitis pigmentosa and neurodevelopmental disorders but not with phosphate metabolism. The patient underwent growth hormone (GH) stimulation tests which confirmed GH deficiency. Head MRI indicated partially empty sella. GH treatment was started at 15 years. Surprisingly, phosphate metabolism normalized during GH treatment, suggesting that hypophosphatemia was at least partly secondary to GH deficiency.

Conclusion: The evaluation of an adolescent with profound long-term hypophosphatemia revealed a pituitary developmental defect associated with a stop-gain variant in PRPF8. Hypophosphatemia alleviated with GH treatment. The pathological PRPF8 variant may contribute to abnormal pituitary development; however, its role in phosphate metabolism remains uncertain.

Introduction: While the influence of various factors on classical androgen synthesis in children and adolescents and its impact on puberty has been widely investigated, there appear to be gaps and contradictory findings regarding the association of overweight and obesity with the synthesis of adrenal-derived 11-oxygenated androgen (11-OA) serum levels. With this study, we aimed to examine how overweight and obesity affect 11-OA serum levels during puberty in a large cohort of children and adolescents.

Methods: Our cohort comprised 1,054 healthy children aged 6-19 years providing serum samples at a total of 1,734 visits. Liquid chromatography-tandem mass spectrometry was used to quantify 11-ketotestosterone (11-KT), 11-ketoandrostendione (11-KA4), 11-β-hydroxytestosterone (11-OHT), 11-β-hydroxyandrostendione (11-OHA4), testosterone, androstenedione, and DHEAS. In addition, we assessed BMI-SDSs, skinfold thicknesses, and Tanner stages. The significance level α was set to α = 0.05.

Results: Increases in 11-KT, 11-KA4, 11-OHT, and 11-OHA4 levels were observed in boys and girls during puberty. 11-KT (β = 0.2, p < 0.001), 11-KA4 (β = 0.16, p < 0.001), and 11-OHA4 (β = 0.12, p = 0.003) were positively correlated with BMI in boys aged 13 years and under. 11-KT (β = 0.1, p = 0.047) was positively correlated with BMI in girls aged 11 years and under. 11-OHT was positively correlated with BMI independent of age (boys 13 years and under: β = 0.17, p < 0.001; over 13 years: β = 0.14, p = 0.001; girls 11 years and under: β = 0.17, p < 0.001; over 11 years: β = 0.18, p < 0.001).

Conclusion: We found increasing 11-OA serum levels throughout all Tanner stages. 11-OAs were observed to be associated with BMI and skinfold thickness, suggesting that overweight and obesity may be associated with pubertal alterations in 11-OA serum levels.

Introduction: Thyroid dyshormonogenesis (TDH) is a subgroup of congenital hypothyroidism with recessive inheritance resulting from disease-causing variants in thyroid hormone biosynthesis pathway genes, like DUOX2, TG, TPO, SLC5A5, SLC26A4, IYD, DUOXA2, and SLC26A7. Thyroid peroxidase (TPO) is a crucial enzyme involved in thyroid hormone biosynthesis and is one of the frequently mutated genes in patients with TDH. The purpose of the study was to describe the in silico and functional characterization of novel variants in TPO gene identified in patients with TDH.

Methods: We performed exome sequencing in Indian patients with TDH. In the current study, we describe the results of patients with TPO gene mutations. Exome sequencing results were further analysed by Sanger sequencing, computational studies, and in vitro functional studies such as immunofluorescence and enzyme assay.

Results: We identified nine biallelic disease-causing variants in the TPO gene in 12 patients from nine unrelated Indian families. Eight of the nine variants were novel. No recurrent variants were identified. Computational analysis of six missense variants showed that these amino acid substitutions caused changes in non-covalent interactions with the adjacent residues that may affect the TPO protein structure and function. In vitro experimental data using immunofluorescence assay showed that these variants did not affect the plasma membrane localization of the TPO protein but caused a significant loss of TPO enzymatic activity compared to the wild type.

Conclusion: Our study revealed multiple novel pathogenic variants in TPO gene in Indian patients, thereby expanding the genotype spectrum. Functional studies helped us to reveal the pathogenicity of the missense variants.

Introduction: In this article, the importance of holistic care is highlighted trough the case of a 10-year-old female with diabetes type 1 presenting with recurrent severe hypoglycemia.

Case presentation: A 10-year-old female, with type 1 diabetes mellitus for 2 years, was hospitalized because of persistent hypoglycemia. At time of presentation, the patient was getting her insulin through an automated insulin delivery device. She came to the emergency room because of severe hypoglycemia despite adequate administration of glucagon intranasal and oral sugar solutions. The patient was hospitalized to resolve the hypoglycemia and to investigate the cause of the persistent hypoglycemia. Extensive further investigation was performed without result.

Conclusion: After several conversations with psychologists, the patient admitted having manipulated the insulin pump resulting in auto-induced persistent and recurrent life-threatening hypoglycemia. Through camera monitoring, the team was able to confirm the manipulation.

Introduction: The clinical features of bi-allelic IGF1 defects are well established, i.e., severe growth failure and microcephaly, delayed psychomotor development, and sensorineural deafness. However, information on clinical and endocrine consequences of heterozygous IGF1 variants and treatment options is scarce. We aimed at extending the knowledge base of the clinical presentation and growth response to recombinant human growth hormone (rhGH) of patients carrying such variants.

Methods: Retrospective case series of patients with pathogenic heterozygous IGF1 variants.

Results: Nine patients from six families were included, harbouring five whole or partial gene deletions and one frameshift variant resulting in a premature stop codon (three de novo, one unknown inheritance). In the other two families, variants segregated with short stature. Mean (SD) birth length was -1.9 (1.3) SDS (n = 7), height -3.8 (0.6) SDS, head circumference -2.5 (0.6) SDS, serum IGF-I -1.9 (0.7) SDS, serum IGFBP-3 1.1 (0.4) SDS (n = 7), and GH peak range 5-31 μg/L (n = 4). Five patients showed feeding problems in infancy. Average height increased after 1 and 2 years of rhGH treatment by 0.8 SDS (range 0.3-1.3 SDS) and 1.3 SDS (range 0.5-2.0 SDS), respectively. Adult height in 2 patients was -2.8 and -1.3 SDS, which was, respectively, 1.3 and 2.9 SDS taller than predicted before start of treatment.

Conclusion: Haploinsufficiency of IGF1 causes a variable phenotype of prenatal and postnatal growth failure, microcephaly, feeding difficulties, low/low-normal serum IGF-I values in contrast to serum IGFBP-3 in the upper-normal range. Treatment with rhGH increased growth in the first 2 years of treatment, and in 2 patients adult height after treatment was higher than predicted at treatment initiation.

Introduction: TBX19 mutations cause isolated ACTH-deficiency. While this classically results in severe hypocortisolism, potential consequences for mineralocorticoid biosynthesis have not been described to date. Liquid chromatography mass spectrometry (LC-MS/MS) and gas chromatography mass spectrometry (GC-MS) allow novel insights into the steroid metabolism of pediatric endocrine diseases.

Case presentation: Patient 1 (female) presented right after birth with hypoglycemia and hyponatremia (minimum sodium 126 mmol/L). She recovered under therapy with hydrocortisone, fludrocortisone and initial NaCl. Patient 2 (male) presented after birth with prolonged cholestatic jaundice. Only at the age of 3.5 months, repeated episodes of hypoglycemia occurred. Both patients showed severely reduced ACTH. LC-MS/MS analyses on plasma samples demonstrated combined reduced glucocorticoid- and mineralocorticoid biosynthesis confirmed by GC-MS analyses on spot urine. In contrast to patient 1, patient 2 (currently 8 years old) never suffered from hyponatremia. Both patients carry the same homozygous c.172A>G, p.(Thr58Ala) mutation in the TBX19 gene proving isolated ACTH-deficiency.

Conclusion: Isolated ACTH-deficiency can be associated with reduced mineralocorticoids and hyponatremia. We hypothesize that sufficient pituitary ACTH secretion is an important predisposition for regular adrenal mineralocorticoid biosynthesis.

Introduction: Celiac disease (CD) is among the diseases most commonly associated with type 1 diabetes (T1D). This study aimed to evaluate the worldwide practices and attitudes of physicians involved in pediatric diabetes care regarding diagnosing and managing CD in children with T1D.

Methods: The 30-item survey was conducted between July and December 2023 aimed at targeting pediatricians with special interest in T1D and CD. It was shared by the JENIOUS - young investigators group of the International Society of Pediatric and Adolescent Diabetes (ISPAD) - and the YES - early career group of the European Society for Pediatric Endocrinology (ESPE).

Results: Overall, 180 physicians (67.8% female) from 25 countries responded. Among respondents, 62.2% expected sustaining optimal glycemic control in children with T1D and CD (T1D + CD) to be more difficult than in children with T1D alone. Majority (81.1%) agreed that more specific guidelines are needed. The follow-up routine for patients with T1D + CD differed, and one-quarter of physicians scheduled more frequent follow-up checkups for these patients. Seventy percent agreed multidisciplinary outpatient clinics for their follow-up is needed. In the multivariate ordinal logistic regression model, a statistically significant predictor of a higher degree of practice according to ISPAD 2022 guidelines was a higher level of country income (OR = 3.34; p < 0.001).

Conclusions: These results showed variations in physicians' practices regarding managing CD in children with T1D, emphasizing the need for more specific guidelines and intensive education of physicians in managing this population, especially in lower-income countries. Our data also suggest the implementation of multidisciplinary outpatient clinics for their follow-up.

Background: Congenital hyperinsulinism (HI) is a rare pediatric disease and the most common cause of severe, persistent hypoglycemia in childhood. It is characterized by the dysregulation of insulin secretion from the pancreas and can lead to irreversible brain damage with lifelong neurodisability.

Summary: The global birth prevalence of HI is currently unknown. An evidence-based estimate of HI birth prevalence is essential to improve diagnosis and patient management, to drive clinical research and the development of new treatments, and to inform public policy. In order to estimate the birth prevalence of persistent HI, a targeted literature review of studies that report HI epidemiological data was undertaken, and the strengths and limitations of each study were analyzed. Overall, eight global studies were identified that reported independently determined HI epidemiological data.

Key messages: The best estimate for the birth prevalence of persistent HI in European-ancestry populations is 3.5 per 100,000 births. Local consanguinity patterns appear to have a considerable impact on the birth prevalence of persistent HI in each country, precluding the application of this figure to all global populations. More epidemiological studies with robust methodology are needed to enable a reliable approximation of the incidence and prevalence of HI in global populations.