The prevalence of pathogenic LEPR
mutations in our subjects with hyperphagia and severe early-onset obesity was 3%. The prevalence of LEPR
mutations in this highly selected cohort is unlikely to reflect that in unrelated populations of obese subjects or in populations in which the age at the onset of obesity is more heterogeneous.24,25
Six of the probands were from consanguineous families, but two probands (including the compound heterozygote) were whites in the United Kingdom whose parents were not known to be related. Although the prevalence of LEPR
mutations is likely to be higher in ethnic groups in which consanguinity is common, LEPR
deficiency should be considered in all patients with hyperphagic obesity of early onset.
None of the subjects with LEPR
mutations characterized in this study, including those with nonsense mutations that were predicted to result in the loss of all isoforms, had disproportionately elevated serum leptin levels. Thus, serum leptin levels are not a generally useful marker of leptin-receptor deficiency — contrary to a previous suggestion.13
Congenital leptin-receptor deficiency is characterized by severe, early-onset obesity associated with selective deposition of fat mass, as seen in subjects with leptin deficiency.9
All of our subjects had hyperphagia from an early age, and we demonstrated that the ad libitum energy intake was greatly increased in children with leptin-receptor deficiency, with no evidence of a major deficit in basal energy expenditure.
Children with leptin-receptor deficiency had normal linear growth during childhood and had normal IGF-1 levels. However, because of the lack of a pubertal growth spurt, the final height of adult subjects was reduced. In the one previously described family, short stature and abnormal serum growth hormone levels and IGF-binding protein 3 levels were noted in childhood.5
However, assessment of the growth hormone–IGF axis is difficult in obese children and adults, since obesity is itself associated with abnormal results of basal and of dynamic tests of this axis.26,27
We conclude that impaired linear growth does not appear to be a common characteristic of patients with this disease.
Adults with leptin-receptor deficiency have hypogonadotropic hypogonadism and do not undergo puberty. Irregular menses developed in the third and fourth decades in the three oldest women in our study, as reported previously for one woman with leptin deficiency.28
It is plausible that the excess mass of adipose tissue leads to the production of sufficient estrogen (owing to the action of aromatase) to result in uterine development and irregular menses in the absence of fully developed secondary sexual characteristics. However, this may not be the only explanation, since luteinizing hormone and follicle-stimulating hormone levels in these three subjects were within the normal range for the follicular phase of the menstrual cycle, suggesting that even in the absence of leptin activity, some activation of the hypothalamic–pituitary–gonadal axis is possible, albeit temporally delayed.
Subjects with LEPR
mutations tended to have a lower CD4+ T-cell count and a significantly greater compensatory B-cell count than age-matched control subjects — findings that are consistent with the known effects of leptin on immune function.29
Lymphocytes in the affected subjects showed decreased proliferation and altered cytokine release in response to nonspecific and antigen-specific stimuli. In two families, very obese children died after an infection in the first decade of life. It is likely that this immune dysfunction, perhaps together with impaired respiratory reserve as a result of severe obesity, contributed to these early deaths.
Heterozygotes who were leptin-receptor-deficient but not obese had an increased fat mass, a finding consistent with our observation that heterozygote carriers of a leptin mutation had 23% more fat than was predicted with anthropometric methods.17
These findings are consistent with those of Chung et al., who found an increase in the fat mass of mice that were heterozygous for deletion of leptin or of the leptin receptor (ob+/−
Our data suggest that several phenotypic features seen in subjects with leptin-receptor deficiency are not as severe as those in subjects with leptin deficiency.9,11
This is surprising, given the fact that the LEPR
protein product is the only known receptor for leptin and given the phenotypic similarity between mice lacking leptin (ob/ob
) and mice lacking the leptin receptor (db/db
) that share the same genetic background.31
The differences seen between the two groups of subjects may relate to the fact that our leptin-receptor–deficient subjects were, on average, older than the leptin-deficient subjects we studied previously.9
Also, the leptin-deficient subjects were of Pakistani origin, whereas the leptin-receptor–deficient subjects were from various ethnic groups. However, the differences between these two groups are striking in magnitude and consistency and raise the possibility that in humans, the canonical leptin receptor may not be the only receptor that mediates the actions of leptin, at least when serum leptin levels are high.
Congenital leptin-receptor deficiency cannot be ruled out by measuring serum leptin levels, and this diagnosis should be considered in all patients with severe obesity and hyperphagia in the absence of developmental delay and dysmorphic features. This diagnosis has implications for the care of these patients, both in terms of genetic counseling of the affected families and in terms of future prospects for treatment, since these patients would be predicted to have a favorable response to drugs targeted at pathways downstream of the leptin receptor.