Study reveals alarming mortality risk in children with extreme genetic obesity

A new study reveals the dramatic short-term health & education consequences of untreated severe childhood obesity due to leptin signalling deficiency.

Led by Imperial's Professor Philippe Froguel, an international team of researchers from the University of Cambridge, France, and Pakistan has conducted an investigation into the health of the world's largest cohort of severely obese children with genetic mutations in three crucial appetite-regulating genes: Leptin (LEP), leptin receptor (LEPR), and melanocortin 4 receptor (MC4R).

The study involved an extensive analysis of children's clinical state, and for the first time determined child mortality and serious disease rates, their physical activity and social behaviour, including school attendance. The research underscores the immediate perils to health and education stemming from untreated severe childhood obesity due to leptin signalling deficiency, and it urgently calls for the implementation of existing effective treatments.

Published in Cell Reports Medicine, the article titled "High Morbidity and Mortality in Children with Untreated Congenital Deficiency of Leptin or Its Receptor" provides a comprehensive evaluation of a distinctive and sizable group of severely obese children from consanguineous Pakistani families, forming the Severe Obesity in Pakistani Population (SOPP) study. This cohort, afflicted by LEP, LEPR, or MC4R deficiencies, underwent an exhaustive retrospective examination, tracing disease progression and its impact on their overall well-being.

Striking findings

The study's findings are striking, revealing a disturbingly high mortality rate among young LEP (26%) and LEPR-deficient (9%) children, primarily due to severe pulmonary and gastrointestinal infections. Additionally, 40% of surviving children with LEP or LEPR deficiencies faced life-threatening lung or gastrointestinal infections, pinpointed as leading causes of death.

Speaking about the findings, Professor Froguel, Chair in Genomic Medicine in the Department of Metabolism, Digestion and Reproduction, said: "We are urgently appealing to the medical community and relevant organisations to expedite the distribution of life-saving drugs already accessible for LEP and LEPR deficiencies among these children."

This research marks a significant stride in comprehending the prolonged clinical ramifications of severe obesity linked to leptin signalling deficits in children. The hope is that these revelations will galvanise further research and drive immediate actions to address this pressing healthcare imperative. Moreover, within the same cohort of severely obese children, the research team recently identified a novel manifestation of syndromic obesity named P4HTM. This discovery emphasises the life-threatening nature of certain genetic forms of childhood obesity, further underscoring the critical necessity for intervention.

High Morbidity and Mortality in Children with Untreated Congenital Deficiency of Leptin or Its Receptor. 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. Cell Reports Medicine. Sept 2023.