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Congenital Leptin Deficiency Due to Homozygosity for the 133G Mutation: Report of Another Case and Evaluation of Response to Four Years of Leptin Therapy

University Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke’s Hospital (W.T.G., I.S.F., S.O.), Cambridge, United Kingdom CB2 2XY; Department of Pediatric Endocrinology, Alberta Children’s Hospital (M.M., R.A.T.), Calgary, Alberta, Canada T2T 5C7; and Amgen, Inc. (A.M.D., E.L.), Thousand Oaks, California 91320-1799

Address all correspondence and requests for reprints to: Dr. William T. Gibson, University Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge, United Kingdom CB2 2XY. E-mail: wtgibson{at}cmmt.ubc.ca (or sorahill{at}hgmp.mrc.ac.uk).

	Abstract

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Congenital leptin deficiency is a rare, but treatable, cause of severe early-onset obesity. To date, two United Kingdom families of Pakistani origin carrying a frameshift/premature stop mutation, c.398delG (133G), and one Turkish family carrying a missense mutation, c.313C>T (Arg¹⁰⁵Trp), have been described. Affected subjects are homozygotes and manifest severe obesity and hyperphagia accompanied by metabolic, neuroendocrine, and immune dysfunction. The effects of recombinant leptin therapy have been reported in three children with the 133G mutation, and in all cases this has led to a dramatic resolution of clinical and biochemical abnormalities. We now report a Canadian child, of Pakistani origin but unrelated to the previously reported subjects, presenting with severe hyperphagia and obesity, who was found to be homozygous for the 133G mutation. In this child, 4 yr of therapy with sc injections of recombinant leptin provided additional evidence for the sustained beneficial effects of leptin replacement on fat mass, hyperinsulinemia, and hyperlipidemia. In addition, leptin administration corrected abnormal thyroid biochemistry and allowed the withdrawal of T₄ treatment, providing additional support for the role of leptin in the regulation of the human hypothalamic-pituitary-thyroid axis.

	Introduction

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CONGENITAL LEPTIN DEFICIENCY is a rare human genetic syndrome resulting in severe hyperphagia and early-onset obesity. It was first reported in 1997 in two cousins of Pakistani origin living in the United Kingdom (1). Both were homozygous for a frameshift mutation in the ob gene that resulted in undetectable circulating leptin concentrations. A Turkish family was subsequently reported in which homozygotes for a missense mutation (Arg¹⁰⁵Trp) had a similar clinical phenotype (2). Farooqi et al. (3) reported the beneficial effects of recombinant leptin therapy in one of the original United Kingdom subjects and subsequently in two other subjects of Pakistani origin who also had the 133G mutation (4). Leptin therapy had dramatic effects on weight, fat mass, food intake, hyperinsulinemia, and lipid levels as well as on neuroendocrine and immune function in these children (4). Additional data on three adult patients with leptin deficiency treated over 18 months showed loss of fat mass, increased physical activity, improvement in insulin sensitivity and resolution of hypogonadism (5). These data established that leptin is a true bioactive hormone in humans and demonstrated that congenital leptin deficiency, albeit rare, was a form of human obesity that was dramatically responsive to hormone replacement therapy. We now report a fourth pediatric subject homozygous for the 133G mutation and provide additional evidence for the beneficial effects of leptin replacement therapy in this condition, including the reversal of biochemical hypothyroidism.

	Case History

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The patient was born of normal birth weight (3.2 kg; 50th percentile) to consanguineous Pakistani parents in Canada. After a period of difficulty with breastfeeding, the patient fed voraciously on infant formula and exceeded the 95th percentile for weight at 90 d of age. Rapid weight gain and hyperphagia continued, and by 5 yr of age she weighed 64.4 kg with a height of 121.8 cm, giving a body mass index of 43.4 and a body mass index SD score of 7.0. There were no additional clinical features suggestive of any recognized syndromic form of obesity. The patient had a history of recurrent urinary tract infections and perineal dermatitis, and on several occasions she had an elevated white cell count without obvious signs of infection. She developed asthma at age 2 yr, which was treated with bronchodilators and inhaled corticosteroids, and which required emergency treatment three or four times each winter between the ages of 2 and 5 yr.

	Materials and Methods

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Trial of leptin therapy

In view of the safety and efficacy of leptin replacement in congenital leptin deficiency, we applied for and received approval for a clinical trial of leptin replacement from the Conjoint Health Research Ethics Board (Office of Biomedical Ethics, University of Calgary). Written informed consent was obtained from the child’s parents, and assent was obtained from the child herself. All procedures were conducted in accordance with the principles outlined in the Declaration of Helsinki. Recombinant methionyl human leptin was supplied by Amgen, Inc. (Thousand Oaks, CA). Dosage calculation and monitoring were conducted as previously reported (4) with leptin administered sc once daily at 0800 h.

Measurement of body composition

We measured body composition using dual energy x-ray absorptiometry scans (QDR-4500, Hologic, Waltham, MA). Fat mass, lean mass, and bone mineral content were determined every 2 months.

Laboratory analyses

Serum leptin was measured using a solid phase sandwich ELISA (Amgen Inc.) as previously described (4). The nucleotide sequence of the ob gene was analyzed in the proband and her parents by direct sequencing (1). Fasting insulin, glucose, cholesterol, triglycerides, uric acid, TSH, free T₄, FSH, LH, and estradiol were measured using standard protocols. Measurement of anti-recombinant met-human leptin antibodies was performed using published methods (4).

	Results

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Diagnosis of congenital leptin deficiency

Plasma leptin levels were undetectable in this child. Direct sequencing of the ob gene revealed the child to be homozygous for deletion of a single guanine nucleotide in codon 133 of the open reading frame (Fig. 1A). The deletion was present in the heterozygous state in both parents. This family originates from the same area of Pakistan as the two previously reported United Kingdom-based families, but they are not known to be related over four generations (Fig. 1B).

View larger version (20K): [in this window] [in a new window]   FIG. 1. Genotyping and family pedigree. A, Sequence traces at the site of the c.398delG (133) mutation are shown. B, The parents of the proband are double first cousins. The patient’s mother had systemic lupus erythematosus and hypothyroidism since her early twenties. Other relatives are affected with lupus, as indicated.

Weight loss began within 2 wk of therapy and continued with some episodes of relapse that required an increase in the leptin dose (Fig. 2). Total fat mass decreased from 34.3 kg at the start of the trial to 18.4 kg during the first 48 months of therapy; the percentage of body fat decreased from 53.4% to 38.1% (Fig. 2). Body mass index decreased from 43.4 to 24.2 kg/m² with dramatic clinical benefits (Fig. 3). In contrast to the reports of the three previously studied children, there was a small loss of fat-free mass acutely (29.7 to 27.3 kg after 6 months of treatment). The patient continued to gain height and accrue bone mass in keeping with predicted growth for age. Bone mineral content increased over the same period in keeping with age-related growth. Bone age was advanced at time of diagnosis (8 yr, 10 months at a chronological age of 5 yr), and remained advanced after 48 months of therapy (11 yr at a chronological age of 9 yr); however, the gap between bone age and chronological age had decreased significantly.

View larger version (16K): [in this window] [in a new window]   FIG. 2. Weight curve for the proband compared with normal percentiles for girls. Initiation of leptin therapy is marked by an arrow.

View larger version (94K): [in this window] [in a new window]   FIG. 3. Clinical photographs of the proband before initiation of therapy at age 5 yr (A) and after 48 months of leptin therapy at age 9 yr (B).

Within the first month of therapy, plasma triglycerides normalized from pretreatment levels that were more than twice the upper limit of normal (Table 1). This was accompanied by an increase in high density lipoprotein cholesterol levels. Low density lipoprotein cholesterol remained stable throughout the trial. Fasting glucose levels were normal before treatment and were unchanged throughout the trial, but hyperinsulinemia normalized by 6 months of treatment and remained within the normal range subsequently (Table 1).

The white blood cell count doubled within the first month of therapy and remained elevated for the first 3 months. There was no evidence of concomitant infection at the time. Lymphocytes, neutrophils, and monocytes all increased, with the appearance of reactive lymphocytes and immature band forms. The recurrent perineal dermatitis disappeared during the first year of therapy. Symptoms of asthma initially worsened, but improved in the second year of therapy. The patient had required emergency treatment for bronchospasm on several occasions before the trial; she has not required hospital visits for asthma since month 12 of leptin therapy.

Neuroendocrine effects of leptin

FSH and LH remained at prepubertal levels throughout the first 4 yr of the trial. Clinically, there was no evidence of premature pubertal development. Before the start of leptin therapy, plasma free T₄ concentrations were persistently within the normal range. However, elevated TSH was detected on several independent occasions and rose to 16.4 µU/ml at 53 months of age during a trial off thyroid replacement. Antimicrosomal antibodies were detected at low titer (1:1600). T₄ therapy was started at age 35 months with no obvious effects on phenotype. At the start of the trial, the patient was receiving 50 µg T₄ daily. TSH and free T₄ levels were monitored throughout the course of the trial. After 12 months of therapy, her free T₄ level was found to be above the upper limit of the reference range (see Table 2), and her T₄ was decreased to 37.5 µg/d. To examine whether leptin therapy might have normalized the preexisting abnormal thyroid function, T₄ was withdrawn after 34 months of therapy. Two months later, the patient’s hypothalamic-pituitary-thyroid axis showed a normal TSH response to TRH (Table 2, inset). After withdrawal of T₄, plasma TSH and free T₄ have remained within the respective normal ranges over 14 months of follow-up.

	Discussion

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In common with the three previously treated patients (4), this child showed a rapid and sustained reduction in weight and body mass index. Although this was largely due to a reduction in fat mass, there was also a small decrease in lean mass acutely, which was regained over time. We speculate that this might be related to the concomitant therapy with T₄ that only occurred in this patient, although significant loss of lean mass was reported when the adult patients were treated (5). No detailed measurements of food intake or energy expenditure were undertaken in this child; however, her parents met regularly with a pediatric dietician and consistently reported a significant decrease in her appetite as well as a significant increase in her level of physical activity. These effects began within the first 2 wk of treatment, a phenomenon consistent with previous reports (4).

The improvement in plasma insulin, triglyceride, and high density lipoprotein levels seen here is consistent with those reported in the previous studies (4) and with the effects of leptin replacement in ob/ob mice. It is possible that the triglyceride-lowering effect may involve the effects of leptin on the expression of stearoyl coenyzme A desaturase 1 recently described (6), although this has not been measured directly in humans. The effects of leptin could also have been mediated indirectly through changes in weight and/or activity level.

There was also an improvement in asthma symptoms and a reduction in hospital admissions due to asthma after initiation of leptin therapy in this child. This effect has also been seen in the three other leptin-deficient subjects we have studied. Leptin has profound effects on the immune system in mice and humans (4, 7, 8). One of these effects is to promote T helper cell type 1 (Th1)-mediated responses at the expense of Th2-mediated responses. Asthma is typically associated with an enhanced Th2 response, so hypoleptinemia might be expected to promote this. The improvement in this child’s asthma is probably attributable to leptin’s effects on relative Th1/Th2 activity, although this was not directly addressed in this patient. With respect to the immune response to infection, it is notable that before therapy, this patient often had elevated white cell counts without apparent cause. After leptin therapy, her white cell count initially doubled, then returned to normal within several weeks. Clinically, the number of urinary tract infections and episodes of perineal dermatitis reduced markedly after therapy.

This patient remains clinically and biochemically prepubertal, so the effect of leptin on the hypothalamic-pituitary-gonadal axis cannot be assessed in her case. Nevertheless, our oldest patient showed gonadotropin pulsatility after 12 months of leptin replacement (3); both she and the three adult patients treated by other investigators have shown correction of menstrual irregularities or onset of puberty (4, 5), providing evidence of a permissive role for leptin in the human reproductive axis.

Perhaps the most novel feature relating to this patient is the fact that she had subclinical hypothyroidism for which T₄ therapy had been started, yet her thyroid function completely normalized once leptin therapy was established, allowing withdrawal of T₄. Thus, it appears that leptin deficiency is a cause of reversible subclinical hypothyroidism. Interpretation is complicated by the presence of low titer antithyroid microsomal antibodies, which suggests the possibility of autoimmune thyroid disease, but the low titer of these and the complete reversibility of the biochemical dysfunction suggest that autoimmune thyroid destruction was unlikely to play a major role in the abnormal thyroid biochemistry.

Evidence from rodents suggests that leptin is necessary for the normal biosynthesis and secretion of TRH and that complete leptin deficiency is associated with a moderate degree of central hypothyroidism (8, 9, 10, 11). Evidence in humans comes from individuals congenitally deficient in leptin or its receptor (1, 12, 13) and from short-term studies of obese adult subjects to whom leptin has been administered (14). Before this report, thyroid biochemistry has been reported in seven subjects with congenital leptin deficiency, three children (1, 3, 4) and four adults (2, 5, 12). In all cases, plasma free T₄ concentrations were within the normal range, but four children had significantly elevated TSH levels. The pulsatility of TSH secretion was studied in a single subject with congenital leptin deficiency and demonstrated to have a markedly disorganized secretory pattern (14). Two subjects homozygous for a nonsense mutation in the leptin receptor have been reported; both were diagnosed as hypothyroid in childhood, and thyroid hormone replacement therapy commenced (13). Mantzoros and colleagues (15) recently examined the ability of leptin to influence the responses of the hypothalamic-pituitary-thyroidal axis to 3-d starvation. They showed that although leptin abrogated the effects of starvation on integrated TSH levels and on TSH pulsatility, the fasting-induced drop in plasma free T₃ was not altered by leptin. In contrast, Rosenbaum et al. (16) showed that low dose leptin replacement therapy prevented the drop in free T₄ and free T₃ resulting from a more chronic, but lesser degree, of caloric restriction. The latter study was conducted over a longer interval, which may explain the observed differences in the reported effects of leptin on the thyroid axis in these groups of patients subjected to caloric restriction.

If leptin has a significant effect in circulating thyroid hormone concentrations, at what level is this effect operating? On the basis of the high expression of leptin receptors in the arcuate nucleus, the known projection of the arcuate to the paraventricular nucleus where the cell bodies are located, and the demonstrated effects of leptin on TRH biosynthesis and release, a central role of leptin seems most likely. There is no evidence to date for leptin having a direct role on the pituitary thyrotroph. Thus, the bulk of evidence favors a role for leptin in the hypothalamic control of TRH release as the major mediator of its effects on thyroidal function.

In the three previously reported children there were small, but sustained, increases in free T₄, free T₃, and TSH that occurred within 1 month of leptin therapy (4). The above is fully consistent with a central effect of leptin. This patient had substantial elevation of TSH before treatment, such that T₄ therapy was commenced. One possible interpretation is that the absence of leptin directly impaired the function of the thyroid. However, a more likely explanation is that TRH is necessary not only for the release of TSH, but also for posttranslational processing of TSH from high mannose forms to low mannose forms. The high mannose (immature) forms have reduced bioactivity and longer circulating half-life (17). Thus, the raised TSH is most likely to reflect dysfunction of the central elements of the hypothalamic-pituitary-thyroidal axis.

In summary, we report the first North American case of congenital leptin deficiency occurring in a young female of Pakistani origin. She carries the same mutation that has been described in two other families. Leptin therapy had dramatically beneficial effects on weight, appetite, metabolism, and neuroendocrine phenotypes and was associated with a clinical improvement in asthma and recurrent infections. Finally, the biochemical hypothyroidism, which was persistent before treatment, was completely reversed by leptin therapy.

	Footnotes

 
Abbreviations: Th1, T Helper cell type 1; Th2, T helper cell type 2.

Received February 25, 2004.

Accepted June 30, 2004.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gibson, W. T. Articles by Trussell, R. A. Search for Related Content PubMed PubMed Citation Articles by Gibson, W. T. Articles by Trussell, R. A.