Montague et al. (1997) described 2 morbidly obese cousins, an 8-year-old girl and a 2-year-old boy, from an inbred Pakistani kindred. Although of normal weight at birth, both children suffered from severe, intractable obesity from an early age. ... Montague et al. (1997) described 2 morbidly obese cousins, an 8-year-old girl and a 2-year-old boy, from an inbred Pakistani kindred. Although of normal weight at birth, both children suffered from severe, intractable obesity from an early age. The children had no additional clinical features to suggest that they might have a pleiotropic genetic syndrome associated with obesity. Montague et al. (1997) found that serum leptin levels in both patients were very low despite their markedly elevated fat mass. The female patient weighed 86 kg at the age of 8 years, with 57% body fat and height of 137 cm. Her birth weight had been normal, but she gained weight rapidly in the early postnatal period and was clearly outside the normal range by 4 months of age. As the result of her obesity she developed abnormalities of growth in the long bones of the legs, resulting in the need for corrective orthopedic surgery. She underwent liposuction of lower limb fat at the age of 6 years in an attempt to improve her mobility. Her affected cousin, a male aged 2 years, had a weight of 29 kg, with 54% body fat. He had difficulty in walking because of extreme obesity. He likewise was of normal weight at birth but rapidly became obese, deviating far above the normal range by 3 months of age. Both children had a clear history of marked hyperphagia, being noted from early infancy to be constantly hungry, demanding food continuously, and eating considerably more than their sibs. Thus, in both mice and humans, congenital leptin deficiency is associated with normal birth weight followed by rapid development of severe obesity associated with hyperphagia and impaired satiety. Detailed assessment of energy expenditure in these children had not been performed, although their mean body temperatures were within the normal range. Since they were prepubertal, it was impossible to determine whether they would show hypogonadotropic hypogonadism with sterility, which is found in ob/ob mice; serum concentrations of luteinizing hormone, follicle-stimulating hormone, estradiol, and testosterone were at prepubertal levels. In contrast to ob/ob mice, which are markedly hypercortisolemic, plasma cortisol levels in both children were within the reference range. Fasting plasma glucose was normal in both children, but fasting insulin levels were elevated in the older child, consistent with the hyperinsulinemia and insulin resistance seen in ob/ob mice. None of the 4 heterozygous parents nor the one heterozygous sib was morbidly obese, a finding consistent with the absence of severe obesity in the murine heterozygotes. Farooqi et al. (1999) followed up on the older of the 2 cousins described by Montague et al. (1997), then 9 years of age. She had marked hyperphagia, was constantly hungry, demanded food continually, and was disruptive when denied food. As a result of her severe obesity, valgus deformities of the legs developed, for which she required bilateral proximal tibial osteotomies. When she was 6 years old, liposuction was performed to remove fat from her legs. Although there were no normative data for a child of this weight, there was no evidence of substantial impairment in her basal or total energy expenditure, and her body temperature was normal, which is not the case in ob/ob mice, whose oxygen consumption, energy expenditure, and body temperature are low (Trayhurn et al., 1977). Thus, leptin may be less central to the regulation of energy expenditure in humans than in mice. Another difference in all humans with either leptin or leptin receptor mutations is the consistently normal glucocorticoid concentrations, in contrast to the marked excess in ob/ob mice. Farooqi et al. (2002) described a third child with leptin deficiency, from a consanguineous family of Pakistani origin living in the United Kingdom. Leptin deficiency was associated with reduced numbers of circulating CD4+ T cells and impaired T cell proliferation and cytokine release, all of which were reversed by recombinant human leptin administration. Gibson et al. (2004) reported a child of consanguineous Pakistani parents in Canada who presented with severe hyperphagia and obesity. The family originated from the same area of Pakistan as the 2 United Kingdom families reported by Montague et al. (1997) and Farooqi et al. (2002), but was not known to be related over 4 generations. Four years of therapy with subcutaneous injections of recombinant leptin had dramatically beneficial effects on weight, appetite, metabolism, and neuroendocrine phenotypes and was associated with clinical improvement in asthma and recurrent infections. Biochemical hypothyroidism, which was persistent before treatment, was completely reversed by leptin therapy. Infertility due to hypothalamic-pituitary hormone insufficiency is a feature of leptin-deficient ob/ob mice. Two of the homozygous individuals in the Turkish kindred of Strobel et al. (1998) were adults. One had primary amenorrhea; the male homozygote never entered puberty and had clinical features of hypogonadism: no beard, scanty pubic and axillary hair, bilateral gynecomastia, and small penis and testes. Testosterone rose after administration of human chorionic gonadotropin (see 118860) in the latter patient, and normal responses to gonadotropin-releasing hormone (152760) were also demonstrated. As in ob/ob mice, a sympathetic system dysfunction (low sympathetic tone) was observed in the propositus. The cold pressor test elicited an abnormally small response in systolic and diastolic blood pressures, and orthostatic hypotension was demonstrated. The phenotype of these adult patients suggested that leptin not only controls body mass but also is a necessary signal for the initiation of human puberty.
In an inbred Pakistani kindred, Montague et al. (1997) found that 2 morbidly obese cousins, an 8-year-old girl and a 2-year-old boy, had a deletion of a guanine nucleotide in the leptin gene: there were 5 rather than ... In an inbred Pakistani kindred, Montague et al. (1997) found that 2 morbidly obese cousins, an 8-year-old girl and a 2-year-old boy, had a deletion of a guanine nucleotide in the leptin gene: there were 5 rather than the expected 6 guanine nucleotides present between nucleotides 393 and 398 (164160.0001). The mutation disrupted the reading frame of the leptin gene, leading to the introduction of 14 aberrant amino acids after gly132 in the leptin polypeptide, followed by a premature stop codon. Farooqi et al. (2002) described a third child from a consanguineous family of Pakistani origin living in the United Kingdom homozygous for the guanine deletion in codon 133 of leptin (delta-G133). The family was not known to be related to the family identified by Montague et al. (1997) over at least 5 generations. In a child of consanguineous Pakistani parents in Canada who presented with severe hyperphagia and obesity, Gibson et al. (2004) found homozygosity for the delta-133G mutation in leptin. The family originated from the same area of Pakistan as the 2 United Kingdom families reported by Montague et al. (1997) and Farooqi et al. (2002), but was not known to be related over 4 generations. Four years of therapy with subcutaneous injections of recombinant leptin had dramatically beneficial effects on weight, appetite, metabolism, and neuroendocrine phenotypes and was associated with clinical improvement in asthma and recurrent infections. Biochemical hypothyroidism, which was persistent before treatment, was completely reversed by leptin therapy. In a Turkish patient with a body mass index (BMI) of 55.8 kg/m(2), Strobel et al. (1998) found very low serum leptin concentrations and, in the LEP gene, a C-to-T transition in the leptin gene which resulted in an arg105-to-trp amino acid replacement in the mature protein (164160.0002). Two other markedly obese individuals with low levels of serum leptin were homozygous for the mutation. All 3 homozygotes were markedly hyperphagic. Plasma insulin concentrations were elevated, and 1 of the 3 was hyperglycemic. All other members of this highly consanguineous kindred were either heterozygous for the mutation or homozygous for the wildtype allele and had normal body weight, serum leptin levels, fasting blood glucose, and plasma insulin levels, indicating a recessive mutation responsible for monogenic obesity. Farooqi et al. (2001) examined 13 subjects who were heterozygous for the frameshift mutation delta-G133 (164160.0001). Serum leptin levels and anthropometric measurements in these subjects were compared with those in 96 ethnically matched controls with a similar sex distribution and age. Serum leptin concentrations in heterozygotes for the mutation were markedly lower than in controls. These were positively correlated with BMI in control subjects and in wildtype relatives of the heterozygotes. In contrast there was no significant correlation between BMI and serum leptin in the delta-G133 heterozygotes. Lower leptin levels in the delta-G133 heterozygotes were accompanied by an increased prevalence of obesity, with 76% of heterozygotes having a BMI greater than 30 compared with 26% of controls. Dual energy x-ray absorptiometry in 12 of the heterozygotes and in 6 Pakistani subjects who were wildtype at the leptin locus indicated that the mean measured percentage of body fat was similar to the predicted value in wildtype subjects; however, in the heterozygotes it significantly exceeded the predicted proportion of body fat, with all 12 heterozygous individuals showing a deviation in the same direction. Farooqi et al. (2001) concluded that a relatively small drop in leptin production may be sensed by the homeostatic feedback system that controls energy balance, with fat mass being increased in an attempt to restore leptin levels to some 'set point.'