A team of researchers in Germany has identified two more children with a rare genetic condition that causes extreme early onset obesity due to a malfunctioning form of the hormone leptin.
Dr. Martin Wabitsch of University Medical Center in Ulm, Germany, and colleagues identified the first known case of severe early onset obesity due to bioinactive leptin, in a two-year-old boy, reporting their findings in the New England Journal of Medicine in January 2015.
In the new report, online July 14 in the Journal of Clinical Endicrinology & Metabolism, Dr. Wabitsch and his team describe two additional cases caused by a different mutation in the gene.
The first case of severe early onset obesity due to absence of leptin was reported in the 1990s, Dr. Wabitsch noted in a telephone interview with Reuters Health. The disease is extremely rare, he added, with only about 40 patients worldwide identified to date.
In the new report, the researchers describe a 9-year-old girl and a 6-year-old boy, born in Germany, who both exhibited extreme hyperphagia and rapid weight gain. Both children had high serum leptin levels. Sequencing of their leptin genes revealed that both had a base substitution causing them to secrete a mutant form of leptin, p.N103K. Lab studies confirmed that the mutant protein was inactive.
After treatment with subcutaneous leptin injections, both children showed rapid improvement. Previously, Dr. Wabitsch noted, the children had been focused only on searching for food, and had no interest in playing or being with other children. “This behavior changed and in addition they lose weight and their metabolic profile also gets healthy,” he added.
“Children gaining weight in the first years in a very rapid and extreme way, children who are hyperhpagic, always food-seeking, they should be investigated for leptin deficiency, which will mean lack of leptin in the circulation or the presence of biologically inactive leptin,” Dr. Wabitsch said. “Both diseases can be ruled out by sequencing the leptin gene.”
What Is Leptin, and Why Does It Matter?
Leptin is a hormone produced by fat cells that signals the brain when you’re full. When leptin is missing or biologically inactive this signal never reaches the brain. The result? Extreme hyperphagia (constant hunger) and rapid fat accumulation, often from early childhood.
New Cases Confirm a Different Genetic Mutation
In this new study, the researchers describe two German-born siblings: a 9-year-old girl and a 6 year old boy. Both exhibited:
- Severe weight gain in early life
- Uncontrollable hunger
- Very high leptin levels in blood
But despite high hormone levels, the children continued to gain weight. Genetic sequencing revealed both carried a mutation known as p.N103K in the leptin gene. This caused their bodies to produce a form of leptin that couldn’t bind properly to brain receptors—making it functionally useless.
The Treatment That Changed Everything
Once diagnosed, both children received subcutaneous injections of leptin essentially replacing the defective hormone with a functional version.
The results were striking:
- Their constant hunger dramatically decreased
- They began to lose weight
- Their overall metabolic health improved
- They became more socially engaged and active
“Before treatment, they were only focused on food and not interested in play,” Dr. Wabitsch told Reuters Health. “This behavior changed dramatically.”
Why This Matters
Although extremely rare—fewer than 50 cases have been identified globally—this research highlights how hormonal imbalances and genetic mutations can be behind some cases of early-onset obesity.
Dr. Wabitsch urges doctors and parents to consider genetic testing in cases where:
- A child gains weight rapidly in early years
- Exhibits uncontrollable food-seeking behavior
- Has unusually high leptin levels with no obvious cause
“Both leptin deficiency and bioinactive leptin can be diagnosed by sequencing the leptin gene,” he noted.
Quick Fact
Only 10–20% of body weight regulation is genetic, but when it is—like in these rare cases—hormone therapy can be life-changing.
Editor’s Note:
This research was originally published in 2015, and while still relevant in rare genetic obesity cases, newer studies may offer updated insights into leptin biology and hormone-based treatments. As of today, leptin replacement therapy remains a niche treatment, primarily for individuals with confirmed leptin mutations. Scientists continue to explore leptin’s role in broader metabolic health and how it may be influenced by lifestyle, inflammation, and gut health. This research was supported by individual grants and fellowships. The authors reported no disclosures.
For the most current research, explore resources at PubMed.gov or consult with a pediatric endocrinologist specializing in genetic obesity disorders.
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Additional Resources
- NIH: The Biology of Leptin
- Reuters Health Original Report References: Reuters Health
James Van Der Berg
James Van Der Berg is your go-to for all things tech-meets-wellness. He’s the guy who tries the gadgets first, reads the fine print, and tells it like it is. Equal parts sexy nerd and lifestyle minimalist, he makes smart living feel cool and doable.
