{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T07:49:13Z","timestamp":1782460153531,"version":"3.54.5"},"reference-count":63,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Obesity"],"published-print":{"date-parts":[[2026,6]]},"abstract":"ABSTRACT<\/jats:title>\n \n Objective<\/jats:title>\n Non\u2010syndromic monogenic obesity, caused by defects in the leptin\u2010melanocortin pathway, presents with early\u2010onset severe obesity and hyperphagia, but genotype\u2013phenotype and metabolic correlations across different genetic forms remain unclear.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n In this multicentre retrospective cohort study, individuals with biallelic (likely) pathogenic variants in\n LEP, LEPR, POMC, PCSK1, MC4R, ADCY3<\/jats:italic>\n , and monoallelic (likely) pathogenic\n MC4R<\/jats:italic>\n variants were recruited from 23 paediatric endocrinology centres across T\u00fcrkiye. Anthropometric, clinical, metabolic data, including HOMA\u2010IR and SPISE index, systematically applied across different monogenic obesity subtypes, were collected using a standardised case record form.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A total of 130 individuals (49% female; median age 10.0\u2009years) were included. Biallelic\n LEPR<\/jats:italic>\n (\n n<\/jats:italic>\n \u2009=\u200947) and monoallelic\n MC4R<\/jats:italic>\n (\n n<\/jats:italic>\n \u2009=\u200949) variants were the most frequent causes, followed by biallelic\n POMC<\/jats:italic>\n (\n n<\/jats:italic>\n \u2009=\u200913) and\n MC4R<\/jats:italic>\n (\n n<\/jats:italic>\n \u2009=\u200911) variants. Individuals with\n LEP, LEPR<\/jats:italic>\n , and biallelic\n MC4R<\/jats:italic>\n variants had higher BMI\u2010SDS than those with\n POMC<\/jats:italic>\n and monoallelic\n MC4R<\/jats:italic>\n variants (\n p\u2009<<\/jats:italic>\n \u20090.0001). SPISE index differed across groups (\n p\u2009=<\/jats:italic>\n \u20090.0051), with lower values in biallelic LEPR and MC4R compared with monoallelic\n MC4R<\/jats:italic>\n variants. Within\n LEPR,<\/jats:italic>\n individuals carrying \u2018double homozygous\u2019 missense variants showed poorer metabolic outcomes independent of BMI\u2010SDS (\n p\u2009<<\/jats:italic>\n \u20090.05). POMC deficiency showed a similar phenotype to monoallelic\n MC4R,<\/jats:italic>\n with later obesity onset, lower BMI\u2010SDS, and a more favourable metabolic profile. Bone age was advanced in\n LEPR<\/jats:italic>\n compared to\n POMC, biallelic<\/jats:italic>\n and monoallelic\n MC4R<\/jats:italic>\n variants (\n p\u2009=<\/jats:italic>\n \u20090.013) and bone age\u2010adjusted height\u2010SDS was lower than non\u2010adjusted height\u2010SDS (\n p\u2009=<\/jats:italic>\n \u20090.004), indicating impaired growth when adjusted for skeletal maturation.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Biallelic\n LEPR, particularly<\/jats:italic>\n those with double homozygous missense variants, and\n MC4R<\/jats:italic>\n variants represent the most metabolically adverse forms of monogenic obesity, extending current evidence beyond BMI\u2010based risk stratification. In\n LEPR, advanced<\/jats:italic>\n bone age may contribute to impaired growth. These data provide a comprehensive genotype\u2013phenotype characterisation in a genetically homogeneous population and emphasise the importance of early diagnosis for risk stratification.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/ijpo.70121","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T04:30:03Z","timestamp":1780029003000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genotype\u2013Phenotype Spectrum of Non\u2010Syndromic Monogenic Obesity in a National Paediatric Cohort"],"prefix":"10.1111","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7627-1996","authenticated-orcid":false,"given":"Ahmet","family":"Kahveci","sequence":"first","affiliation":[{"name":"Department of Paediatric Endocrinology Marmara University Faculty of Medicine Istanbul T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Selin 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