Academic Journal
Genotype-Phenotype Spectrum of Non-Syndromic Monogenic Obesity in a National Paediatric Cohort.
| Τίτλος: | Genotype-Phenotype Spectrum of Non-Syndromic Monogenic Obesity in a National Paediatric Cohort. |
|---|---|
| Συγγραφείς: | Kahveci A; Department of Paediatric Endocrinology, Marmara University Faculty of Medicine, Istanbul, Türkiye., Karauzum SU; Department of Paediatric Endocrinology, Ege University Faculty of Medicine, Izmir, Türkiye., Manyas H; Department of Paediatric Endocrinology, Sanliurfa Eyyubiye Training and Research Hospital, Sanliurfa, Türkiye., Ozdemir BS; Department of Paediatric Endocrinology, Ankara Etlik City Hospital, Ankara, Türkiye., Orbak Z; Department of Paediatric Endocrinology, Ataturk University Faculty of Medicine, Erzurum, Türkiye., Tercan U; Department of Paediatric Endocrinology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye., Yildirim R; Department of Paediatric Endocrinology, Diyarbakir Children Hospital, Diyarbakir, Türkiye., Hatipoglu N; Department of Paediatric Endocrinology, Erciyes University Faculty of Medicine, Kayseri, Türkiye., Kilci F; Department of Paediatric Endocrinology, Kocaeli City Hospital, Kocaeli, Türkiye., Nursoy H; Department of Paediatric Endocrinology, Uludag University Faculty of Medicine, Bursa, Türkiye., Ozalkak S; Department of Paediatric Endocrinology, Diyarbakir Children Hospital, Diyarbakir, Türkiye., Kolbasi B; Department of Paediatric Endocrinology, Dicle University Faculty of Medicine, Diyarbakir, Türkiye., Cetinkaya S; Department of Paediatric Endocrinology, Dr. Sami Ulus Training and Research Hospital, Ankara, Türkiye., Ozdemir HC; Department of Paediatric Endocrinology, Antalya Training and Research Hospital, Antalya, Türkiye., Parlak M; Department of Paediatric Endocrinology, Akdeniz University Faculty of Medicine, Antalya, Türkiye., Kokenli FT; Department of Paediatric Endocrinology, Trakya University Faculty of Medicine, Edirne, Türkiye., Camtosun E; Department of Paediatric Endocrinology, Inonu University Faculty of Medicine, Malatya, Türkiye., Dibeklioglu SE; Department of Paediatric Endocrinology, Konya City Hospital, Konya, Türkiye., Buyukyilmaz G; Department of Paediatric Endocrinology, Ankara Bilkent City Hospital, Ankara, Türkiye., Bulus AD; Department of Paediatric Endocrinology, Ankara Ataturk Sanatory Education and Research Hospital, Ankara, Türkiye., Balki HG; Department of Paediatric Endocrinology, Necip Fazil City Hospital, Kahramanmaras, Türkiye., Ozden A; Department of Paediatric Endocrinology, Ataturk University Faculty of Medicine, Erzurum, Türkiye., Gonc EN; Department of Paediatric Endocrinology, Hacettepe University Faculty of Medicine, Ankara, Türkiye., Ozsu E; Department of Paediatric Endocrinology, Ankara University Faculty of Medicine, Ankara, Türkiye., Demirbilek H; Department of Paediatric Endocrinology, Hacettepe University Faculty of Medicine, Ankara, Türkiye., Yildiz M; Department of Paediatric Endocrinology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye., Ozen S; Department of Paediatric Endocrinology, Ege University Faculty of Medicine, Izmir, Türkiye., Bereket A; Department of Paediatric Endocrinology, Marmara University Faculty of Medicine, Istanbul, Türkiye., Haliloglu B; Department of Paediatric Endocrinology, Marmara University Faculty of Medicine, Istanbul, Türkiye. |
| Πηγή: | Pediatric obesity [Pediatr Obes] 2026 Jun; Vol. 21 (6), pp. e70121. |
| Τύπος έκδοσης: | Journal Article; Multicenter Study |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Wiley-Blackwell for the International Association for the Study of Obesity Country of Publication: England NLM ID: 101572033 Publication Model: Print Cited Medium: Internet ISSN: 2047-6310 (Electronic) Linking ISSN: 20476302 NLM ISO Abbreviation: Pediatr Obes Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Oxford, UK : Wiley-Blackwell for the International Association for the Study of Obesity |
| Ιατρικοί όροι (MeSH): | Receptors, Leptin*/genetics , Receptor, Melanocortin, Type 4*/genetics , Pediatric Obesity*/genetics , Pediatric Obesity*/epidemiology, Pro-Opiomelanocortin/genetics ; Leptin/genetics ; Turkey/epidemiology ; Proprotein Convertase 1/genetics ; Adenylyl Cyclases/genetics ; Humans ; Female ; Child ; Retrospective Studies ; Male ; Genetic Association Studies ; Phenotype ; Adolescent ; Genotype ; Child, Preschool ; Body Mass Index |
| Περίληψη: | Objective: Non-syndromic monogenic obesity, caused by defects in the leptin-melanocortin pathway, presents with early-onset severe obesity and hyperphagia, but genotype-phenotype and metabolic correlations across different genetic forms remain unclear. Methods: In this multicentre retrospective cohort study, individuals with biallelic (likely) pathogenic variants in LEP, LEPR, POMC, PCSK1, MC4R, ADCY3, and monoallelic (likely) pathogenic MC4R variants were recruited from 23 paediatric endocrinology centres across Türkiye. Anthropometric, clinical, metabolic data, including HOMA-IR and SPISE index, systematically applied across different monogenic obesity subtypes, were collected using a standardised case record form. Results: A total of 130 individuals (49% female; median age 10.0 years) were included. Biallelic LEPR (n = 47) and monoallelic MC4R (n = 49) variants were the most frequent causes, followed by biallelic POMC (n = 13) and MC4R (n = 11) variants. Individuals with LEP, LEPR, and biallelic MC4R variants had higher BMI-SDS than those with POMC and monoallelic MC4R variants (p < 0.0001). SPISE index differed across groups (p = 0.0051), with lower values in biallelic LEPR and MC4R compared with monoallelic MC4R variants. Within LEPR, individuals carrying 'double homozygous' missense variants showed poorer metabolic outcomes independent of BMI-SDS (p < 0.05). POMC deficiency showed a similar phenotype to monoallelic MC4R, with later obesity onset, lower BMI-SDS, and a more favourable metabolic profile. Bone age was advanced in LEPR compared to POMC, biallelic and monoallelic MC4R variants (p = 0.013) and bone age-adjusted height-SDS was lower than non-adjusted height-SDS (p = 0.004), indicating impaired growth when adjusted for skeletal maturation. Conclusion: Biallelic LEPR, particularly those with double homozygous missense variants, and MC4R variants represent the most metabolically adverse forms of monogenic obesity, extending current evidence beyond BMI-based risk stratification. In LEPR, advanced bone age may contribute to impaired growth. These data provide a comprehensive genotype-phenotype characterisation in a genetically homogeneous population and emphasise the importance of early diagnosis for risk stratification. (© 2026 The Author(s). Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.) |
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| Contributed Indexing: | Keywords: LEPR; MC4R; genotype–phenotype; monogenic obesity |
| Substance Nomenclature: | 0 (Receptors, Leptin) 0 (Receptor, Melanocortin, Type 4) 66796-54-1 (Pro-Opiomelanocortin) 0 (MC4R protein, human) 0 (Leptin) EC 3.4.21.93 (PCSK1 protein, human) EC 3.4.21.93 (Proprotein Convertase 1) 0 (LEPR protein, human) EC 4.6.1.1 (Adenylyl Cyclases) 0 (LEP protein, human) |
| Entry Date(s): | Date Created: 20260529 Date Completed: 20260529 Latest Revision: 20260608 |
| Update Code: | 20260609 |
| DOI: | 10.1111/ijpo.70121 |
| PMID: | 42210527 |
| Βάση Δεδομένων: | MEDLINE |
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