High morbidity and mortality in children with untreated congenital deficiency of leptin or its receptor

• DOI: 10.1016/j.xcrm.2023.101187
• Publication Date: 2023-09-01T14:27:16Z
• Authors: Sadia Saeed; Roohia Khanam; Qasim M. Janjua; Jaida Manzoor; Lijiao Ning; Sharoon Hanook; Mickaël Canouil; Muhammad Ali; Hina Ayesha; Waqas I. Khan; I. Sadaf Farooqi; Giles S.H. Yeo; Stephen O'Rahilly; Amélie Bonnefond; Taeed A. Butt; Muhammad Arslan; Philippe Froguel
• Keywords: Leptin; morbidity; age-related changes; mortality; 3. Good health; Obesity, Morbid; [SDV] Life Sciences [q-bio]; consanguinity; Cross-Sectional Studies; leptin-signaling deficiency; body growth; Report; oxidative stress; Humans; Morbidity; Child; metabolism; monogenic obesity; Retrospective Studies

ABSTRACTBACKGROUNDBiallelic pathogenic mutations inLEP, LEPRandMC4Rgenes controlling central leptin-melanocortin signalling cause early onset severe obesity. However, the long-term clinical outcomes of leptin signalling deficiency are unknown.DESIGN AND OBJECTIVESWe carried out a retrospective cross-sectional clinical investigation of a large cohort of children withLEP, LEPRorMC4Rdeficiency, to evaluate the progression of the disease and its impact on morbidity and mortality.PARTICIPANTSSeverely obese children from 454 consanguineous families of Pakistani origin were screened for mutations in the three genes using Sanger and exome sequencing. We identified 132 probands and 13 affected family members with homozygous pathogenic mutations inLEP, LEPRorMC4R.MAIN OUTCOME MEASURESWeight, height, and head circumference were measured by trained technicians using standardized protocols. WHO-anthro and anthroplus were used to assess BMI-standard deviation score. All affected individuals underwent detailed physical and clinical investigations by expert paediatric endocrinologist. Metabolic and oxidative stress biomarkers were measured in serum.RESULTSWe report a very high mortality in children withLEP(26%) andLEPR-deficiency (9%), mainly due to recurrent pulmonary and gastro-intestinal infections. In addition, 40% ofLEP- orLEPR-deficient surviving children experienced life-threatening episodes of pulmonary or gastro-intestinal infections. Oxidative stress as assessed by biomarkers, was significantly higher inLEPdeficiency compared to the other two mutant groups.CONCLUSIONSChildren with congenital deficiency of leptin or its receptor suffer a high mortality rate, and severe morbidity. Although effective therapies are available for both but as yet(orto-date) are not accessible in Pakistan. An appreciation of the severe impact of leptin or leptin receptor deficiency on educational attainment, morbidity and early mortality risks should spur efforts to deliver available life-saving drugs to these children as a matter of urgency.