Hormone Research in Paediatrics最新文献

{"title":"Sex Differences in Pediatric and Adolescent Endocrinology: What Are the Origins?","authors":"Gerhard Binder, Desiree Dunstheimer, Bettina Gohlke, Sabine Heger, Thomas Reinehr, Annette Richter-Unruh, Joachim Woelfle, Achim Wüsthof","doi":"10.1159/000552184","DOIUrl":"10.1159/000552184","url":null,"abstract":"<p><strong>Background: </strong>Endocrine disorders appear to be unevenly distributed between females and males in pediatric endocrinology.</p><p><strong>Summary: </strong>This narrative review collects causes from nurture and nature that may contribute to these differences in prevalence. For this purpose, the scientific literature from 1990 to 2025 was evaluated using the keywords sex-specific difference, gender-specific difference, sex difference, gender difference in combination with the endocrine disorder being treated.</p><p><strong>Key messages: </strong>One identified reason for sex differences in pediatric and adolescent endocrinology is arbitrary thresholds regarding the timing of puberty, which may favor the diagnosis of precocious puberty in females. Another reason for sex differences appears to be the different severity of psychosocial stress, which may contribute to sex differences, with males more frequently diagnosed with delayed puberty and growth hormone deficiency (GHD). Possibly contributing biological factors include the different regulation of endocrine processes in both sexes, which imply lower or higher homeostatic stability. Such sex dimorphism of biology has been described for the regulation of GH and LH/FSH. Therefore, nature may have an additional impact on sex disparities in GHD and precocious puberty. Less convincing data on the influence of nature were available for delayed puberty. This review can aid physicians to critically review their individual clinical practice and refrain from prematurely diagnosing and treating healthy children when therapeutic interventions are not truly warranted.</p>","PeriodicalId":13025,"journal":{"name":"Hormone Research in Paediatrics","volume":" ","pages":"1-7"},"PeriodicalIF":3.8,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147769726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Does Carbohydrate Counting from Diabetes Onset Make a Difference to Glycemic Outcomes? A Swedish Registry Study.","authors":"Elisabeth Jelleryd, Carmel E Smart, Hans Järnbert-Petterson, Ulrika Käck, Anna-Lena Brorsson, Anna Lindholm-Olinder","doi":"10.1159/000552151","DOIUrl":"10.1159/000552151","url":null,"abstract":"<p><strong>Introduction: </strong>Carbohydrate counting (CC) for calculating insulin for meals is recommended in type 1 diabetes to optimize the postprandial glycemic response. Few studies have studied the effect of CC on glycemic outcomes when introduced from diabetes diagnosis. Our aim was to investigate if CC effects metabolic outcomes over time between individuals taught CC from diabetes onset and those who were not. A secondary aim was to examine if use of CC was associated with glycemic outcomes at 8 years diabetes duration.</p><p><strong>Methods: </strong>This was a cohort study analyzing pediatric data from the Swedish Diabetes Registry (NDR), comparing two groups with diabetes onset 2011-2013, where one was taught CC from diagnosis and the other group used fixed doses. HbA1c data were analyzed from first year of diabetes up to 8 years. A cross-sectional analysis at 8 years diabetes duration, compared groups with reported use of CC to the NDR to examine the association with glycemic outcomes.</p><p><strong>Results: </strong>There was no difference in HbA1c over time between the group taught CC from diagnosis (n = 253) and those that were not (n = 221) after adjusting for gender, age, and insulin regimen (difference fixed CC: 1.0; 95% confidence interval: -0.8 to 2.9; p = 0.27). The group using CC after 8 years duration had significantly lower HbA1c than those not using CC (56.2 mmol/L vs. 64.8 mmol/L, p = <0.001).</p><p><strong>Conclusion: </strong>The results suggest that CC can be effective in achieving target glycemic outcomes over time and support its introduction at any time in the life course to improve metabolic outcomes.</p>","PeriodicalId":13025,"journal":{"name":"Hormone Research in Paediatrics","volume":" ","pages":"1-11"},"PeriodicalIF":3.8,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13322686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adrenocortical Tumors in Pediatrics beyond the Classic Presentation: A Case Series.","authors":"Elsa Dieterlen, Carine Villanueva, Sara Cabet, Grégoire Schneider, Cécile Picard, Marc Nicolino, Cecile Faure-Conter, Kevin Perge","doi":"10.1159/000552155","DOIUrl":"10.1159/000552155","url":null,"abstract":"<p><strong>Introduction: </strong>Adrenocortical tumors (ACTs) are rare pediatric malignancies, typically presenting with signs of virilization or hypercortisolism. However, nonclassical presentations may delay diagnosis and complicate management. Our study aimed to illustrate the diagnostic and therapeutic challenges posed by atypical forms of pediatric ACTs through a series of five diverse clinical cases.</p><p><strong>Cases presentation: </strong>We report five cases of pediatric ACTs with unusual features: bilateral tumors, acute stroke due to hypertensive crisis, incidental discovery after trauma, misleading hormonal workup, or gradual onset of premature pubarche, and hemorrhagic lesion. In two cases, the diagnosis was delayed due to initial absence of endocrine evaluation. One patient experienced tumor rupture following biopsy, leading to metastasis and death despite intensive treatment. Histopathological scoring (Wieneke score) was heterogeneous and did not always correlate with outcome. Two patients had underlying cancer predisposition syndromes (Li-Fraumeni and Beckwith-Wiedemann).</p><p><strong>Conclusion: </strong>This case series highlights the wide phenotypic variability of pediatric ACTs, which may mimic benign or unrelated conditions. Early recognition, systematic hormonal evaluation, and avoidance of biopsy are critical for improving prognosis. Multidisciplinary management is essential, and genetic screening should be systematically considered, even in the absence of suggestive personal or familial history.</p>","PeriodicalId":13025,"journal":{"name":"Hormone Research in Paediatrics","volume":" ","pages":"1-9"},"PeriodicalIF":3.8,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13309078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147769967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preferences for (Dis)Continuing Growth Hormone Treatment at Mid-Puberty in Patients with Transient Idiopathic Isolated Growth Hormone Deficiency: A Qualitative Analysis.","authors":"Joeri Vliegenthart, Iris Vernooij, Eric J E van der Hijden, Stefan Schuiling, Edmond H H M Rings, Erica L T van den Akker, Danielle C M van der Kaay","doi":"10.1159/000552013","DOIUrl":"10.1159/000552013","url":null,"abstract":"<p><strong>Introduction: </strong>The SEENEZ GH trial found no difference in near adult height (NAH) between patients with isolated idiopathic growth hormone deficiency (IIGHD) who continued or discontinued recombinant human growth hormone (rhGH) at mid-puberty after a sufficient GH retest. These findings support revision of the current guideline to recommend rhGH discontinuation for patients with a sufficient mid-pubertal retest result. To enable successful adaptation, insight into stakeholder preferences, perceived (dis)advantages, and factors influencing guideline implementation is crucial.</p><p><strong>Methods: </strong>A qualitative study was conducted based on 25 interviews involving 26 participants, including patients with transient IIGHD, their parents, healthcare professionals, and organizational stakeholders. Participants were asked to assume there was no clinical difference between (dis)continuing rhGH. Interviews combined a structured impact analysis tool with open-ended questions.</p><p><strong>Results: </strong>Patients and parents generally preferred rhGH continuation, mainly for reassurance and reduced uncertainty. Patients valued discontinuation for reducing injection-related pain, whereas continuation aligned with personal treatment goals. Parents perceived rhGH continuation as reducing uncertainty. Healthcare professionals and organizational stakeholders favored discontinuation, citing cost-effectiveness, reduced workload, and ethical concerns about overtreatment; lower healthcare costs were the main perceived advantage. Facilitators for guideline revision included positive communication, clear and timely information, and sufficient implementation resources. Barriers included old habits among clinicians, limited awareness of new evidence among stakeholders, and a lack of strong drivers for change.</p><p><strong>Conclusion: </strong>Patients and parents favored continuing rhGH, whereas professionals and organizational stakeholders preferred discontinuation. Given comparable NAH outcomes after a sufficient mid-pubertal GH retest, successful guideline revision requires clear communication, adequate resources, and involvement of patients and parents.</p>","PeriodicalId":13025,"journal":{"name":"Hormone Research in Paediatrics","volume":" ","pages":"1-8"},"PeriodicalIF":3.8,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13309073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147769677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diabetic Kidney Disease Screening and Management Practices among North American Pediatric Endocrinologists Caring for Youth with Type 2 Diabetes.","authors":"Paul M Ryan, Jill Hamilton, Elizabeth A C Sellers, Edgar Delbert, Melissa Del Vecchio, Carrie Costello, Kalie L Tommerdahl, Petter Bjornstad, Allison Dart, Brandy Wicklow","doi":"10.1159/000552027","DOIUrl":"10.1159/000552027","url":null,"abstract":"<p><strong>Introduction: </strong>Assess current diabetic kidney disease (DKD) screening practices in adolescents with type 2 diabetes (T2D), identify the comfort level of pediatric endocrinologists in interpreting and treating kidney dysfunction, and investigate barriers and facilitators to implementation of estimated glomerular filtration rate (eGFR) as an adjunctive surveillance metric.</p><p><strong>Methods: </strong>An anonymous survey was distributed via email to North American pediatric endocrinologists.</p><p><strong>Results: </strong>A total of 115 pediatric endocrinologists (Canada, n = 40, USA, n = 75) with mean 12.4 (SD 10.3) years in practice, largely from tertiary care centers, completed the survey. Most respondents screen for DKD at T2D diagnosis and annually thereafter. Exposure to an electronic medical record screening prompt was associated with complete adherence. Random urine albumin-to-creatinine ratio was the most common test, while most respondents never ordered an eGFR for DKD surveillance. Discomfort with eGFR interpretation was common, with only one-quarter recognizing hyperfiltration as a clinical concern. Respondents would be more likely to use eGFR if it was externally validated, endorsed by a major society, or incorporated into clinical practice guidelines, with automated electronic medical record reporting as the preferred implementation method.</p><p><strong>Conclusion: </strong>Pediatric endocrinologists demonstrate fidelity to pediatric T2D DKD screening clinical practice guidelines; however, comfort with eGFR interpretation in this setting remains limited.</p>","PeriodicalId":13025,"journal":{"name":"Hormone Research in Paediatrics","volume":" ","pages":"1-9"},"PeriodicalIF":3.8,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147716724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glucagon-Like Peptide-1 Receptor Agonists in the Management of Mitochondrial Diabetes in an Adolescent: A Case Report.","authors":"Eadaoin Hayes, Ann Nillsen, Peter W Rowe, Aris Siafarikas, Mary B Abraham","doi":"10.1159/000552014","DOIUrl":"10.1159/000552014","url":null,"abstract":"<p><strong>Introduction: </strong>Mitochondrial diabetes is rare and typically treated with dietary intervention and oral hypoglycaemic agents. Most require insulin. Novel treatments are available but are not well characterised.</p><p><strong>Case presentation: </strong>A 16-year-old adolescent girl with a genetically confirmed diagnosis of MELAS due to an m.3243A>G variant presented with clinical and biochemical features of diabetes. She was successfully transitioned from subcutaneous insulin therapy to weekly GLP-1RA monotherapy shortly after diagnosis of diabetes. Treatment with 0.25 mg semaglutide SC weekly led to a reduction in HbA1c from 13.7% (126 mmol/mol) to 5.6% (38 mmol/mol) over a 7-month period. Insulin was completely ceased within 5 days of starting semaglutide. CGM data from a 11 months follow-up period are presented, which demonstrate CGM data meeting glycaemic targets.</p><p><strong>Conclusion: </strong>Low-dose semaglutide 0.25 mg sc weekly was efficacious and well tolerated without lactic acidosis. Use of GLP-1RA could be considered a novel and effective treatment in the pharmacological management of paediatric mitochondrial diabetes.</p>","PeriodicalId":13025,"journal":{"name":"Hormone Research in Paediatrics","volume":" ","pages":"1-9"},"PeriodicalIF":3.8,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147716727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early-Onset Monogenic Obesity due to Leptin Receptor Deficiency: Fatal Outcome in Childhood in the Era of Precision Therapy.","authors":"Ummahan Tercan, Tugce Kandemir, Asli Derya Kardelen, Nilay Bas Ikizoglu, Sukran Poyrazoglu, Feyza Darendeliler, Firdevs Bas, Melek Yildiz","doi":"10.1159/000551903","DOIUrl":"10.1159/000551903","url":null,"abstract":"<p><strong>Introduction: </strong>Early-onset monogenic obesity due to leptin receptor (LEPR) deficiency is characterized by severe hyperphagia, rapid weight gain, and obesity-related comorbidities, including obstructive sleep apnea syndrome (OSAS). Setmelanotide, a melanocortin-4 receptor agonist, is an approved targeted treatment for patients with LEPR deficiency. However, access to this treatment remains limited in many countries.</p><p><strong>Case presentation: </strong>A 20-month-old boy born to first-degree consanguineous parents was referred for severe obesity and hyperphagia. At presentation, his weight was 23.4 kg (+5.3 standard deviation score [SDS]), with a BMI of 34.0 kg/m2 (+7.6 SDS). There were no dysmorphic features, developmental delay, or clinical findings suggestive of syndromic obesity. Targeted LEPR sequencing identified a homozygous splice-site variant (c.1603+2T>C), previously detected in his similarly affected sibling. Both parents were heterozygous carriers. At 2.5 years, BMI reached 39.3 kg/m2 (+6.7 SDS), and polysomnography confirmed severe OSAS. Adenoidectomy was deferred due to anesthesia-related risks associated with severe obesity and lack of an adequately equipped center. Following FDA approval of setmelanotide for children ≥2 years of age, a 6-month court-approved authorization for compassionate use was obtained. However, the drug was not yet available when the patient died suddenly during sleep at 3 years and 9 months of age, with presumed OSAS-related respiratory failure.</p><p><strong>Conclusion: </strong>This case highlights the fatal consequences of delayed access to precision therapy in rare monogenic forms of obesity, such as LEPR deficiency, despite early molecular diagnosis. It also provides insight into the natural history and long-term outcomes of affected patients.</p>","PeriodicalId":13025,"journal":{"name":"Hormone Research in Paediatrics","volume":" ","pages":"1-6"},"PeriodicalIF":3.8,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13286472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147716790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polish Recommendations for the Early Detection of Type 1 Diabetes in the Pediatric Population: A Position Statement of the Polish Society of Pediatric Endocrinology and Diabetology and the Pediatric Section of the Diabetes Poland 2026.","authors":"Agata Chobot, Artur Bossowski, Przemysława Jarosz-Chobot, Małgorzata Myśliwiec, Agnieszka Szadkowska, Agnieszka Szypowska, Mieczysław Walczak","doi":"10.1159/000551858","DOIUrl":"10.1159/000551858","url":null,"abstract":"<p><p>Recent advances in the understanding of the natural history of type 1 diabetes (T1D), together with the availability of disease-modifying therapies, have fundamentally changed the rationale for early detection of this disease. T1D is a common autoimmune disorder with rapidly increasing incidence among Polish children, particularly in the youngest age groups, and is still frequently diagnosed at the stage of diabetic ketoacidosis (DKA), which carries significant short- and long-term morbidity. The document summarizes current evidence supporting screening based on the detection of islet autoantibodies (GADA, IA-2A, ZnT8A, and IAA), reviews international and national screening programs, and outlines the clinical, psychological, and economic benefits of early identification, including a marked reduction in DKA at diagnosis. Definitions of T1D stages, diagnostic criteria, and risks of progression are described, along with practical algorithms for confirmatory testing, referral, and follow-up. Particular attention is given to screening strategies in both high-risk groups and the general pediatric population, recommended ages for screening, and principles of longitudinal monitoring. These recommendations, developed by national experts, are intended to support the implementation of structured early detection programs and to improve outcomes for children at risk of or living with preclinical T1D within the Polish healthcare system.</p>","PeriodicalId":13025,"journal":{"name":"Hormone Research in Paediatrics","volume":" ","pages":"1-13"},"PeriodicalIF":3.8,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13299132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147716730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural History of the Hyperinsulinism/Hyperammonemia Syndrome: A Retrospective Review Incorporating Patient-Centered Data.","authors":"Elizabeth Rosenfeld, Olivia Taylor, Lauren M Mitteer, Kara E Boodhansingh, Tai L S Pasquini, Julie Raskin, Deborah Rafferty, Paul S Thornton, Diva D De Leon","doi":"10.1159/000551535","DOIUrl":"10.1159/000551535","url":null,"abstract":"<p><strong>Introduction: </strong>The hyperinsulinism/hyperammonemia (HI/HA) syndrome manifests with fasting and protein-induced hypoglycemia, hyperammonemia, and neurodevelopmental features including epilepsy. There is a paucity of information describing the natural history of the HI/HA syndrome.</p><p><strong>Methods: </strong>A retrospective review of patients with HI/HA syndrome evaluated at the Congenital Hyperinsulinism Centers at the Children's Hospital of Philadelphia or Cook Children's Medical Center or who contributed to the Congenital Hyperinsulinism International HI Global Registry (HIGR) was conducted to describe the natural history of the HI/HA syndrome with particular focus on treatment and neurodevelopmental outcomes.</p><p><strong>Results: </strong>A total of 66 patients (36 female) from the medical record review and 15 patients (7 female, 3 sex not reported) from HIGR were included. Median age at last follow-up was 13.1 years (IQR, 6.8-19.0 years) in the medical record cohort and median age at survey completion was 11.6 years (IQR, 5.5-18.0 years) among HIGR participants. Eighty percent of the medical record cohort and 82% of HIGR participants were treated with diazoxide and most continued treatment over the follow-up period. Epilepsy (29% of medical record cohort, 33% HIGR participants) and neurodevelopmental issues (64% medical record cohort, 73% HIGR participants) were common.</p><p><strong>Conclusion: </strong>Our findings underscore the importance of longitudinal endocrine and neuropsychological follow-up for patients with HI/HA syndrome and demonstrate the potential value of patient-driven registry data to address persistent knowledge gaps in the natural history of rare diseases.</p>","PeriodicalId":13025,"journal":{"name":"Hormone Research in Paediatrics","volume":" ","pages":"1-11"},"PeriodicalIF":3.8,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13173416/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147689553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<italic>MKRN3</italic> Variants in Central Precocious Puberty as an Example of the Complexity to Classify Missense Variants in Imprinted Genes as Pathogenic.","authors":"Clémence Delcour, Carole Harbulot, Leila Drira, Kathy Wagner Malher, Delphine Zenaty, George Gelwane, Dominique Simon, Mélanie Amouyal, Maryse Cartigny Maciejewski, Hélène Bony, Axelle Cauliez, Aurélie Donzeau, Rachel Reynaud, Catherine Brue Fabre, Isam Al-Amir Ahmad, Juliane Léger, Jean-Claude Carel, Nicolas de Roux","doi":"10.1159/000551859","DOIUrl":"10.1159/000551859","url":null,"abstract":"<p><strong>Introduction: </strong>Makorin ring-finger protein 3 (MKRN3) is a maternally imprinted gene, and variants of this gene have been associated with central precocious puberty (CPP). To date, the biochemical function of MKRN3 is still uncertain. The aim of this study was to assess American College of Medical Genetics and Genomics (ACMG) criteria for pathogenic classification of missense variants of MKRN3 and to propose specific ACMG criteria for this gene.</p><p><strong>Methods: </strong>MKRN3 missense variants from our cohort of CPP or the HGMD (considered pathogenic) and gnomAD (considered benign) databases were annotated by diverse in silico analysis tools. Performance of these tools was assessed by determining sensitivity, specificity, and positive and negative predictive values. We then assessed the relevance of using amino acid conservation between MKRN family proteins and the population constraint as additional criteria to annotate missense variants.</p><p><strong>Results: </strong>Usual in silico tools showed limited ability to distinguish the deleterious effect of pathogenic from benign variants. Analyses of amino acid conservation between MKRN family proteins and population constraints facilitated characterization of the damaging effect of MKRN3 missense variants. Revised ACMG criteria expanding familial segregation, conservation within the MKRN protein family, and population constraint allowed reclassification of several uncertain significant variants to likely pathogenic.</p><p><strong>Conclusion: </strong>This study highlights the challenge involved in the classification of missense variants of a maternally imprinted gene. Expanding familial segregation over three generations, protein-family conservation, and population constraint improve the accuracy of MKRN3 variant annotation in CPP.</p>","PeriodicalId":13025,"journal":{"name":"Hormone Research in Paediatrics","volume":" ","pages":"1-11"},"PeriodicalIF":3.8,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13275053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147638660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}