Bad Reception: Unlocking a Confounding Enigma Behind Monogenic Obesity in Children

When two very different pediatric patients with obesity presented with unusually high leptin levels, endocrine researchers took notice and discovered that leptin was not adequately binding with receptors. When the young patients’ familial history was considered, solutions were finally forthcoming.

About three years ago, a 19-month-old girl presented to Sidra Medicine – a women’s and children’s hospital, medical education and biomedical research center located in Doha, Qatar  – with severe obesity, the signs of which began developing at just three months of age.

Khalid Hussain, MD, division chief of Endocrinology at Sidra, which is a member of Qatar Foundation, and his team took on the case of this child who weighed almost 60 pounds before reaching the age of two. Hussain says the child could hardly walk or even breathe, so she also came under the care of a respiratory team since the physicians thought her asthma may be related to the obesity as well.

“I became very interested,” Hussain says. “I wanted to understand why she had such severe obesity at this age. We did some tests in Qatar, and I think the family at some stage went to the UK, as well. To cut a very long story short, between the UK, Qatar, and Germany, we found that this child had a genetic cause for the obesity — a defect in the hormone called leptin, which regulates your feeding satiety.”

Monogenic obesity is a rare early-onset, and severe form of obesity resulting from a mutation or deficiency of a single gene, e.g. of leptin.

But this case was unusual in that children who have problems with leptin have a deficiency; this child had very high levels of leptin. After running some tests at the University Medical Center in Ulm, Germany Germany, Hussain and his team were able to show that the child was producing leptin, but it wasn’t working as well in the body, not activating the leptin receptor as it should.

An Increase in Pediatric Leptin Deficiency

In June 2023, Hussain and his colleagues and co-authors published a paper in The New England Journal of Medicine, detailing the case of the above patient (Patient B) and another unrelated adolescent, a 14-year-old boy (Patient A), who also had characteristics of leptin dysfunction including intense hyperphagia, impaired satiety, and severe, early-onset obesity. The authors point out that Patient A is of European descent, while Patient B is of Arab descent.

Martin Wabitsch, MD, PhD, head of the Division of Pediatric Endocrinology and Diabetes at the  University Medical Center in Ulm, Germany and senior author of the NEJM paper tells Endocrine News that after the first description of congenital leptin deficiency by Stephen O’Rahilly and Sadaf Farooqi most experts agreed that leptin deficiency was only found in consanguineous families from Pakistan, Turkey and possibly some Arabic countries.

But then an adolescent girl from a family in Austria without known consanguinity with severe, early-onset obesity and leptin deficiency presented to the clinic in Ulm. Wabitsch runs a lab that focuses on children and adolescents with genetic obesity and leptin deficiency. He and his team tested this girl’s adipose tissue derived stem cells and differentiated adipocytes and found proof that the patient did indeed have adipocytes which do not secrete leptin. Congenital leptin deficiency in this girl has been shown to bedue to a biallelic variant in the leptin gene. 

“The phenotype was different to the Pakistani patients,” Wabitsch says, “no Immunological phenotype at all, and the weight was much lower than that of the published patients. We treated the patient with metreleptin, which was very difficult to get a the time.”

Wabitsch says that from that point on, they had several new patients with congenital leptin deficiency. Then in 2015, a two-year-old patient from Germany presented with the classical phenotype of leptin deficiency – severe obesity, hyperphagia – so the team measured serum  leptin levels, but this time found the patient had high levels of leptin, in the 40s. “After excluding other forms of genetic obesity We said, ‘We don’t know what this patient has,’” he says.

Around that time, another colleague of Wabitsch’s did leptin sequencing in this child (which Wabitsch admits he wouldn’t have done because the leptin levels were so high) and detected a biallelic variant in the leptin gene. “I was reminded of Kowarski syndrome,” Wabitsch says, “growth hormone deficiency with high growth hormone levels due to a defect in the binding of the growth hormone, so bio-inactive growth hormone. And then I said, ‘It seems to me that we have congenital leptin deficiency with high leptin levels due to bio-inactive leptin.’”

A “Eureka!” Moment

Wabitsch marks 2015 as a milestone – the time they found that even though high levels of leptin are secreted in the body, but there’s a defect in binding. They also found that these patients could be treated with metreleptin as well. These results were also published in NEJM in 2015. Wabitsch and his team screened more patients and found several further patients with bio-inactive leptin.

Wabitsch explains that bio-inactive hormones have been known to endocrinologists for a while, from the aforementioned growth hormone to luteinizing hormone to thyroid-stimulating hormone. But this was new for leptin, and it told the researchers that leptin measurements are not enough – gene sequencing to exclude leptin was also required.

“This is, from a biological point of view, a totally new idea, new finding, never been described before, that human nature can present a mutated protein which is acting as an antagonist. It’s not an antibody. It’s not an autoimmune antibody. It’s a naturally occurring protein working as antagonist when you treat the patient with wild-type leptin, then you will see that it’s blocking the receptor. And that’s what we saw also in the patients.” — Martin Wabitsch, MD, PhD, head, Division of Pediatric Endocrinology and Diabetes, Ulm University Medical Center, Ulm, Germany

The  team in Ulm also looked at the interaction between leptin and its receptor. There  are three binding sites with which leptin engages with its receptor. Wabitsch says that binding site one’s function is unclear, site two is for high-affinity binding of leptin to its receptor, and site three is for receptor activation. They theorized that a genetic variant could also affect the code for binding site three, and thus naturally occurring antagonist could be impacting the receptor.

Factoring in Family History

That brings us back to the most recent NEJM paper. Hussain, Wabitsch, and the co-authors of the paper found that while both Patient A and Patient B had high levels of leptin, they both had variants in binding site three. “That’s what we were waiting for, humans with variants in this binding site, and both of them, in our in vitro assessments, showed that these variants behaved as antagonists on the level of the leptin receptor,” Wabitsch says. “Guided by our in vitro characterization, we started treatment with metreleptin and performed dose escalation and tapering. and we needed much higher amounts of metreleptin to overcome the antagonism”, Wabitsch says and he adds “This is, from a biological point of view, a totally new finding, never been described before, that human nature can present a mutated protein which is acting as an antagonist. It’s not an autoimmune antibody. It’s a naturally occurring protein working as antagonist when you treat the patient with wild-type leptin, then you will see that it’s blocking the receptor. And that’s what we saw in the two patients.”

“We realized that we needed to treat the children with high dose exogenous metreleptin,” Hussain says. “We admitted [Patient B], and we followed a particular protocol by escalating the dose of metreleptin every few days. And eventually we noticed that her appetite was reduced, and over the next several weeks, the weight also started coming down. She’s down to about 18 or 19 kilos at the age of about four or five now.”

Hussain says that the girl’s asthma has disappeared, she’s walking normally and even dancing, with no medical issues at all. “It’s been absolutely revolutionary managing her and seeing her go from a child that couldn’t breathe in my clinic to someone who is starting to dance around,” he says.

The girl’s parents are delighted, and Hussain says that the interesting this was that there were three other aunts in this family who are adults and have severe obesity, so clinicians investigated them, and the aunts have the same genetic problem. “They’re being treated by my adult colleagues in the adult hospital here in Qatar,” he says. They’re responding very well, so it’s not just the child. We eventually managed to treat the rest of the family here, and they’re doing extremely well.”

“If they present extremely early, that’s mostly suggestive of a genetic cause. And they should either discuss this with a specialist, an endocrinologist, or a geneticist who has an interest in this area, because if you find the cause, you can actually make a complete difference to the child’s management.” — Khalid Hussain, MD, division chief of Endocrinology, Sidra Medicine, Doha, Qatar

Indeed, both patients experienced a return to normal weight, and Patient A reached mature Tanner stage at age 16.5. “After the two patients had extensive weight loss, which was presumably accompanied by reductions in the endogenous production of antagonizing leptin variants, we reduced the metreleptin dose in both patients step by step,” the NEJM paper authors write.

“Here, we provide in vitro and in vivo evidence for the existence of leptin variants that orthosterically bind to, but do not fully activate the leptin receptor, hence acting as competitive antagonists in the presence of non-variant leptin” says Wabitsch.

Overcoming the Antagonist

And again, these findings speak to the absolute complexity of a disease like obesity. If a child under the age of five has severe obesity and hyperphagia, it’s highly probable that the cause is genetic. The general tendency is to think the parents are over-feeding the child, but that tendency falls apart in the case of a 19-month-old.

“If they present extremely early, that’s mostly suggestive of a genetic cause.” Hussain says. “And they should either discuss this with a specialist, an endocrinologist or a geneticist who has an interest in this area, because if you find the cause, you can actually make a complete difference to the child’s management. If we had not discovered the cause, this poor child would continue to gain weight, suffer from asthma, not being able to walk and not being able to do any of her life activities.”

Bagley is the Senior Editor of Endocrine News. In the February issue, he spoke to Endocrine Society member Kemal Agbaht, MD, about how he managed to practice endocrinology in the wake of the 2023 earthquake that devastated portions of Turkey.