Leptin Receptor Defects Rare but Important in Obesity

CAMBRIDGE, England, Jan. 17 -- Defects in the receptor for leptin are rare but should be considered when diagnosing obese patients with uncontrolled appetites, according to researchers here.

The diagnosis of a leptin-receptor defect, instead of leptin deficiency, would have implications for the treatment of such patients, Sadaf Farooqi, M.D., of Cambridge University, and colleagues, reported in the Jan. 18 issue of the New England Journal of Medicine.

For instance, drugs that have targets downstream of the leptin receptor would be expected to produce better results, Dr. Farooqi and colleagues wrote.

"Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism," the researchers concluded.

The recommendation arises from a cohort study of 300 volunteers with hyperphagia and severe early-onset obesity, including 90 from consanguineous families, Dr. Farooqi and colleagues reported.

The volunteers were part of a larger group, the Genetics of Obesity Study (GOOS) cohort, which includes 2,100 people with severe early-onset obesity - defined as being more than three standard deviations above the norm for the British population, the researchers said.

Genetic analysis showed that eight of the 300 volunteers (3%) had either missense or nonsense mutations in the gene for the leptin receptor. Seven had the same mutation on each allele of the gene, while the eighth had different mutations on each allele.

Six of the affected volunteers were from consanguineous families, and in three family groups further investigation found additional homozygous family members, all with severe early-onset obesity.

The effect of the mutations in most cases was to cause complete loss of signaling from the leptin receptors, although in one case there was some residual activity, the researchers said.

Affected volunteers were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty because of hypogonadotropic hypogonadism.

Although linear growth was normal in children with the defect, their final adult height was reduced because of the lack of a growth spurt at puberty.

However, serum leptin levels were normal, considering their elevated fat mass, and their clinical features were less severe than those of people with congenital leptin deficiency, Dr. Farooqi and colleagues said.

The researchers noted that the prevalence of leptin receptor defects in this group is not likely to be the same in unrelated populations of obese people or in groups where the age at the onset of obesity is more varied.