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

BACKGROUND Biallelic pathogenic mutations in LEP, LEPR and MC4R genes controlling central leptin-melanocortin signalling cause early onset severe obesity. However, the long-term clinical outcomes of leptin signalling deficiency are unknown. DESIGN AND OBJECTIVES We carried out a retrospective cross-sectional clinical investigation of a large cohort of children with LEP, LEPR or MC4R deficiency, to evaluate the progression of the disease and its impact on morbidity and mortality. PARTICIPANTS Severely 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 in LEP, LEPR or MC4R . MAIN OUTCOME MEASURES Weight, 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. RESULTS We report a very high mortality in children with LEP (26%) and LEPR -deficiency (9%), mainly due to recurrent pulmonary and gastro-intestinal infections. In addition, 40% of LEP - or LEPR -deficient surviving children experienced life-threatening episodes of pulmonary or gastro-intestinal infections. Oxidative stress as assessed by biomarkers, was significantly higher in LEP deficiency compared to the other two mutant groups. CONCLUSIONS Children 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 (or to-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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by Imperial College London. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study involves human participants and was approved by the Children's Hospital and Institute of Child Health (now Children's Hospital and UCHS) Ethical approval letter no. 5178/PH. Participants gave informed consent to participate in the study before taking part. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript.