Hormone Research in Paediatrics最新文献

Introduction: Individuals with differences of sex development (DSD) experience complex, often competing, medical and psychosocial challenges surrounding fertility. The study aimed to characterize how "success" in fertility-related care is conceptualized and attained among individuals with a DSD, their parents or caregivers, healthcare providers, and other stakeholders.

Methods: As part of a larger study, DSD stakeholders (n = 110) participated in semi-structured interviews covering the clinical care of patients with DSD. Primary questions included "What is a successful outcome in DSD care?" and "How do you achieve it?" with fertility as either a spontaneous or suggested topic of discussion. Transcripts were analyzed utilizing a phenomenological approach. This analysis focuses on the extracted themes related to fertility.

Results: Fertility was discussed by 19/24 individuals with DSD, 12/19 parents or caregivers, 35/37 healthcare providers, and 19/30 other stakeholders. Components of successful fertility-related care included (1) specific discussions surrounding the relationship between DSD and fertility potential, options for fertility preservation, and options for non-biologic parenthood; (2) early and repeated introduction of these topics; and (3) consideration of age, developmental maturity, and cultural context on decisions around fertility. Challenges included the lack of fertility outcome data in this population and the irreversibility of gonadectomy. Trade-offs identified included anatomic typicality versus function, fertility preservation versus cancer risk reduction, and balancing the different priorities of stakeholders.

Discussion/conclusions: A wide range of DSD stakeholders highlighted the importance of addressing fertility concerns in achieving favorable outcomes for individuals with DSD. These stakeholder perspectives should inform fertility-related education, shared decision-making processes, and clinical care.

Introduction: Most children with adrenocortical tumors (ACTs) present with accelerated growth and skeletal maturation at diagnosis, which potentially compromises their adult heights (AHs). Knowledge about growth and pubertal patterns after ACT resection is scarce. This study presents the pubertal and auxological development of patients treated for ACT and followed up at a single pediatric endocrinology service in Brazil.

Methods: Retrospective cohort study including 63 patients (47 girls) followed up between 1966 and 2021. Pubertal and auxological data from ACT diagnosis to AH were analyzed.

Results: At diagnosis, the patients had median values of bone age (BA) more advanced than chronological age (CA), height standard deviation score greater than target height (TH-SDS), and predicted adult height (PAH-SDS) lower than TH-SDS. The difference between BA and CA decreased gradually during follow-up and the PAH-SDS moved closer to the TH-SDS 7 years after tumor resection. Puberty started at a median CA of 9.3 (8.3-11.3) years in girls and 9.9 (9.2-13.6) years in boys. Nine patients (6 girls) developed central precocious puberty (CPP), which was influenced by a CA >4 years at diagnosis. The difference between AH-SDS and TH-SDS was not significant (p = 0.3). The factors independently associated with AH below TH were CA >4 years at diagnosis, time between clinical manifestation and diagnosis >1 year, and development of CPP.

Conclusion: Most patients treated for ACT during childhood attained AH within the TH despite presenting with advanced skeletal maturation at diagnosis. Development of CPP was not infrequent.

Introduction: Pseudohypoparathyroidism, newly classified as inactivating PTH/PTHrP signaling disorder (iPPSD) type 2 or type 3, is a rare disease caused by defects in the GNAS imprinted gene that encodes Gsα. The most common phenotype comprises resistance to hormones binding to G protein-coupled receptors such as PTH, PTHrP, or TSH, subcutaneous ossifications, short stature, brachydactyly, and early onset obesity. Uncommon features have been described including sleep apnea, asthma, and resistance to calcitonin. At the national French reference center for rare calcium and phosphate metabolism diseases, a large cohort of patients with iPPSD type 2 and type 3 is followed. Interestingly, digestive manifestations and in particular intractable constipation were regularly reported by families of children with iPPSD type 2 or type 3.

Objective: The aim of our study was therefore to specify the frequency and characteristics of digestive manifestations in children followed up for iPPSD2 or iPPSD3 in our reference center.

Material and methods: Thirty-six patients aged between 2 and 18 years (32 followed up for iPPSD2 and 4 for iPPSD3) were included. Parents completed a specific questionnaire to assess any digestive disorders in their child. The diagnosis of constipation was established using the Bristol visual scale in the event of a score of less than 2 according to stool appearance.

Results: Parents reported constipation through the questionnaires in 22/36 (over 60%) of the children. It was the most frequently reported digestive disorder. Among these 22 children, 19 (87%) had a Bristol score for stool shape and texture between 1 and 2 on a scale of 7, confirming constipation. Dedicated treatment had been initiated for 10 (55%) of them, yet only 3 families (16%) considered this treatment effective. Neonatal vomiting and eating disorders, such as lack of satiety or food selectivity, were also noted in 18 (50%) of patients, as was gastroesophageal reflux present in the neonatal period in 14 (40%) of children. There were no significant differences according to the type of iPPSD or patient age.

Conclusion: Our work shows for the first time that digestive manifestations, including constipation, occur frequently in children followed for iPPSD, suggesting a potential role of Gsα and G protein receptors in the digestive tract. It is well known that constipation and digestive symptoms alter quality of life. Early management is therefore essential to improve the quality of life of children followed for iPPSD. Our data need to be confirmed on a larger cohort.

Introduction: Cushing's syndrome (CS) constitutes one of the most challenging diagnostic assessments for paediatric endocrinologists. The clinical presentation of some children with exogenous obesity overlaps with those observed in hypercortisolism states. Accurate, non-invasive first-line tests are necessary to avoid false-positive results in the obese. We aimed to evaluate the diagnostic accuracy of salivary cortisol to assess endogenous hypercortisolism in children with obesity and clinical overlapping signs of CS.

Methods: Case-control study that included children aged 2-18 years, BMI-SDS ≥2.0 and a follow-up >2 years. Patients were assigned to three categories: group A, features strongly indicative of paediatric CS (growth failure combined with increasing weight); group B, features suggestive of CS (e.g., moon face and striae); and group C, less specific features overlapping with CS (e.g., hypertension, hirsutism, insulin resistance). Children in categories A and B formed the control group. Ten patients with confirmed CS were the case group. All children collected saliva samples on the same day in the morning between 7 and 8:00 a.m. (morning salivary cortisol: mSC) and at 11 p.m. (nocturnal salivary cortisol: nSC). The mSC and nSC results were used to calculate the percentage decrease of cortisol at night (%D). Main outcomes by receiver operating characteristic for nSC and the %D were sensitivity, specificity, positive (P) and negative (N) predictive values (PV) and their corresponding 95% CI. Salivary cortisol was measured by electrochemiluminescence assay (lower limit of quantification: 2.0 nmol/L).

Results: 75/112 children met the inclusion criteria, whereas 22/75 children were eligible for the control group. Only controls decreased nSC (median and interquartile range: 2.0 [2.0-2.5] nmol/L) compared to mSC (6.9 [4.8-10.4] nmol/L), p < 0.0001. A cut-off for nSC ≥8 nmol/L confirmed CS within a sensitivity: 1.0 (0.69-1.0), specificity: 1.0 (0.85-1.0), PPV: 1.0 (0.69-0.99), and NPV: 1.0(0.85-0.99), achieving a diagnostic efficiency of 100%. The cut-off obtained for %D was 50%. No child with CS had a %D ≥50%, but 6/22 children in the control group had a %D below the cut-off, resulting in a lower overall diagnostic accuracy of 81% compared to nSC.

Conclusion: Salivary cortisol at 11 p.m. is an accurate, feasible, and non-invasive first-line test to assess endogenous hypercortisolism in children with obesity and clinical suspicion of CS. The nSC was also useful in showing that the circadian rhythm of cortisol was preserved in children with exogenous obesity. In patients with nSC ≥8.0 nmol/L, other biochemical assessments and imaging studies are needed to further confirm the aetiology.

Background: Hypophosphatasia (HPP) is a rare genetic disorder caused by loss-of-function variants in the ALPL gene, leading to deficient tissue-nonspecific alkaline phosphatase (ALP) activity. This results in a distinctive biochemical profile marked by low serum ALP levels and elevated pyridoxal-5-phosphate (PLP). The clinical spectrum of HPP ranges from perinatal lethality to asymptomatic cases, presenting significant diagnostic and therapeutic challenges.

Summary: Diagnosis of HPP relies on identifying the characteristic biochemical signature (low ALP, high PLP), concomitant with skeletal (osteomalacia, rickets, pseudofracture) or extraskeletal (muscle weakness, musculoskeletal pain, dental) manifestations. Current diagnostic frameworks lack uniformity, highlighting the imperative for a standardized diagnostic approach. Molecular genetic testing plays a pivotal role in making the diagnosis of HPP, but difficulties persist in diagnosing milder cases and correlating genotypes with phenotypes. Comprehensive multidisciplinary care is indispensable, with enzyme replacement therapy (ERT) proving efficacious in severe cases and more nuanced management approaches for milder presentations. Overcoming challenges in ERT initiation, treatment response assessment, dose titrations, and long-term surveillance necessitates further refinement of management guidelines.

Key message: Mild forms of HPP and asymptomatic carriers of pathogenic ALPL variants pose substantial diagnosis and management challenges. Developing consensus-driven guidelines is crucial to enhance clinical outcomes and patient care.

Introduction: Growth acceleration during postnatal growth only occurs during puberty as a physiological event and during catch-up growth mediated by growth-promoting therapies in growth disorders. Here we report on novel observations of skeletal symptoms during treatment with erdafitinib, a tyrosine kinase inhibitor (TKI) prescribed on the basis of a compassionate-use program.

Methods: Analysis of anthropometric, biochemical, clinical, and radiographic data of patients with CNS tumors who revealed an unanticipated growth spurt with initiation of therapy with erdafitinib was performed retrospectively.

Results: Linear growth acceleration was independent of sex steroids and IGF1 levels, which is especially remarkable in the context of heavily pretreated pediatric neuro-oncology patients with severe growth impairment before initiation of therapy. Growth acceleration was accompanied by a distinct widening of the growth plate and enhanced metaphyseal mineralization shortly after the start of TKI therapy.

Conclusions: While targeted therapies including TKIs have become an essential part of adult cancer treatment, applications in children are still limited. Off-target effects specific to the pediatric population have been observed in various organ systems; however, knowledge about the effect of TKIs on the growing skeleton is scarce. Treatment with erdafitinib inhibits FGFR3-mediated effects and thus represents a very logical hypothetical framework of growth factor and sex steroid-independent growth acceleration.

Introduction: Achieving evidence-based, high-quality medical care is the overarching goal of healthcare quality management. Quality indicators (QIs) serve as proxies to show whether good quality is reached or not. This article describes the development of QI for the evaluation of healthcare quality in the area of differences of sex development (DSD).

Methods: Following the model of Donabedian, the aim was to develop QI to assess defined relevant aspects of the quality of structures, processes, and outcomes of care in DSD. Ten DSD clinical centres and two self-advocacy groups in Germany included in the DSDCare project were involved in the development of the QI and a benchmarking system. The development of the QI involved several structured steps: analysis of guidelines and recommendations, literature review, qualitative interviews with key stakeholders in the field of DSD, and patients or their carers. QIs were discussed in a multi-stage systematic consensus process and assessed in terms of their relevance, feasibility, and practicability.

Results: In a multi-stage systematic consensus process involving medical and psychological experts from a range of disciplines, people with DSD and their families, and representatives of self-advocacy groups, we have developed a set of 37 QIs (22 structure, seven process, and eight outcome quality). The QIs serve to evaluate care in the field of DSD and may add to the German criteria for certification of Centres for Rare Conditions formulated by the National Action League for People with Rare Diseases (NAMSE) in this area of expertise.

Conclusion: We have succeeded in developing and jointly adopting a set of QIs that consider a wide range of perspectives on the quality of care for people with DSD and their families. These QIs have been found to be relevant, feasible, and practicable, and they are now used for a yearly quality benchmarking in the participating DSD centres.

Background: Recent advances in insulin research open new avenues for treatment, both, for type 1 and type 2 diabetes. In developed countries, standardized "ultra-rapid-acting insulins" are now also used in addition to rapid-acting insulins. First- and second-generation basal analogs are available. Third-generation basal analogs, which only need to be applied once a week, are in the pipeline.

Summary: Second-generation "ultra-rapid-acting insulins" insulins with faster onset and offset of action may be particularly useful for multiple daily injections and automated insulin delivery systems. An improved time-action profile of bolus insulin would be able to cover the rapid increase in glucose after meals with a rapid fall thereafter to avoid postprandial hypoglycemia. The third-generation basal insulins allowing once-weekly dosing made major steps toward becoming a clinical reality. However, issues with insulin affordability and availability remain problematic even in more affluent countries. Biosimilar insulins products can provide people with additional safe, high-quality, and potentially cost-effective options for treating diabetes. Particularly in low-middle income countries insulin therapy is facing issues not only of access but also storage, lack of diabetes education, and stigma.

Key message: With the new bolus insulins, the physiological insulin secretion pattern can be mimicked better and better and hypoglycemia can be avoided. With the ever longer pharmacokinetic action profiles of the basal analogs, the injection frequency is reduced, which leads to better adherence and quality of life, but these insulins are not available for everyone who needs it worldwide.

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.