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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 10 4633-4640
Copyright © 2003 by The Endocrine Society

Obesity Due to Proopiomelanocortin Deficiency: Three New Cases and Treatment Trials with Thyroid Hormone and ACTH4–10

Heiko Krude, Heike Biebermann, Dirk Schnabel, Mojca Zerjav Tansek, Pierre Theunissen, Primus E. Mullis and Annette Grüters

Institute of Pediatric Endocrinology (H.K., H.B., D.S., A.G.), University Children’s Hospital, Charite, Humboldt-University Berlin, D-13353 Berlin, Germany; Medical Center Ljubljana University Children’s Hospital (M.Z.T.), SL-61104 Ljubljana, Slovenia; Atrium Medisch Centrum (P.T.), NL-6401 Heerlen, The Netherlands; and University Children’s Hospital (P.E.M.), Inselspital, CH-3010 Bern, Switzerland

Address correspondence and reprint requests to: Dr. Heiko Krude, Institute of Pediatric Endocrinology, Humboldt-University, Augustenburgerplatz 1, D-13353 Berlin. E-mail: heiko.krude{at}charite.de.


   Abstract
Top
 Abstract
Introduction
 Case Reports
 Materials and Methods
 Results
 Discussion
 References
 
The symptoms of severe early-onset obesity, adrenal insufficiency, and red hair define the proopiomelanocortin (POMC) deficiency syndrome as described so far in two children with complete loss-of-function mutations of the human POMC gene. In POMC deficiency, obesity reflects the lack of POMC-derived peptides as ligands at the melanocortin (MC) MC4 and MC3 receptors, which are expressed in the hypothalamic leptin-melanocortin pathway of body weight regulation. Hypocortisolism and alteration of pigmentation are caused by the lack of POMC-derived peptides at the adrenal MC2 receptor and the skin MC1 receptor, respectively. Here we describe three new cases of complete loss-of-function mutations of the POMC gene. Patients were diagnosed based on the clinical trials of red hair, adrenal insufficiency, and early-onset severe obesity. One previously described translation initiation mutation (C3804A) as well as one new nonsense (A6851T) and two new frame-shift mutations (6996del and 7100 + 2G) were found in homozygosity or compound heterozygosity. The heterozygous parents were found to have high normal or mildly elevated body weight, suggesting a dosage effect of the POMC gene product on weight regulation. To compensate for the lack of hypothalamic melanocortin function, we initiated a trial in the two previously published patients with intranasal ACTH4–10, a melanocortin fragment for which an anorexic effect has been described recently. During 3 months with increasing doses of ACTH4–10, no change of body weight or metabolic rate was observed, suggesting that at least in these two POMC-deficient patients ACTH4–10 is without any compensatory effect. In the same two patients, further investigation revealed a mildly elevated TSH. However, a 1-yr treatment with thyroid hormone did not result in a significant reduction of body weight.


   Introduction
Top
 Abstract
 Introduction
Case Reports
 Materials and Methods
 Results
 Discussion
 References
 
THE GENE CODING for the multiple-hormone precursor proopiomelanocortin (POMC) (1) was cloned more than 20 yr ago (2, 3). Subsequently it was shown that it contains three exons and is located on human chromosome 2 (4). Sequences coding for the biological active melanocortin peptides ACTH, {alpha}-MSH, ß-MSH, and {gamma}-MSH identified so far as well as ß-endorphin are highly conserved among different species (5). Differential expression of the prohormone convertase (PC) 1 and PC2 enzymes leads to the generation of these different melanocortin peptides in POMC-expressing tissues (6). Although the single expression of PC1 in the pituitary generates the longer cleavage product ACTH, the coexpression of PC1 and PC2 in the hypothalamus and skin results in the generation of the smaller fragments {alpha}-MSH, ß-MSH, and {gamma}-MSH as well as the opioid-receptor ligand ß-endorphin in equimolar concentrations (6).

POMC-derived melanocortin peptides bind with different affinity and specificity to a set of five homologous melanocortin receptors (MCRs), which belong to the large family of G protein-coupled receptors (7, 8). Hypothalamic MSH peptides are involved in regulation of body weight via activation of the MC3R and MC4R (9). Pituitary-derived ACTH regulates cortisol secretion via binding to the adrenal MC2-receptor (10), and, as paracrine ligands, MSH peptides bind to the MC1 receptor in the skin to influence pigmentation (11). Accordingly, inactivating mutations of the MC2-receptor were shown to result in ACTH resistance leading to congenital hypocortisolism (10), and mutations of the MC1 receptor were shown to be the most frequent molecular change in red-haired and light-skinned individuals (11). Mutations in the MC4R reflect the most common monogenetic cause of obesity so far described, affecting at least 3% of extremely obese individuals (12). Therefore, complete loss-of-function mutations of the POMC gene could have been expected to influence adrenal function as well as skin pigmentation in addition to obesity. Accordingly, the first two patients with complete loss of POMC gene function were diagnosed on the basis of the clinical trials of secondary hypocortisolism, red hair, and early-onset and extreme obesity (13). Subsequently, the same association of altered fur color, adrenal insufficiency, and obesity was observed in mice with targeted deletion of the POMC gene (14).

In contrast to the first syndromic obese patients with complete loss-of-function POMC gene mutations, several mutation-screening studies in normal obese populations did not reveal complete loss-of-function mutations but identified few heterozygous mutations with functional relevance so far mainly not clarified (15, 16, 17, 18). Therefore, the contribution of POMC gene mutations to the pathogenesis of normal obesity remains unclear.

Since our first description of complete loss-of-function mutations in the POMC gene in two children in 1998 (13), we became aware of three additional children with severe early-onset obesity, red hair, and secondary hypocortisolism. Herein we report about the mutational studies in these three children who are homozygous or compound heterozygous for complete loss-of-function mutations of the POMC gene. In addition, we investigated the thyroid function of the two initially identified patients with POMC deficiency to assess the link between the hypothalamic melanocortin pathway and the pituitary-thyroid axes (19, 20). Furthermore, we report about a treatment trial with ACTH 4–10, a melanocortin fragment that has been shown recently to reduce body weight in normal-weight probands after intranasal application (21).


   Case Reports
Top
 Abstract
 Introduction
 Case Reports
Materials and Methods
 Results
 Discussion
 References
 
Because of the same clinical spectrum of early-onset obesity, red hair, and hypocortisolism, compared with the two previously published patients with POMC deficiency, DNA of three European children was sent to our center for mutation analysis of the POMC gene. The male patient from Ljubljana, Slovenia, was diagnosed in the first weeks of life because of hypoglycemia and convulsions. An abdominal ultrasound revealed a decreased size of the adrenal glands. Serum cortisol concentrations and ACTH levels were extremely low. The male patient from Heerlen, The Netherlands, was found to have low serum glucose levels on the second day of life, which resolved after oral glucose administration. At an age of 4 wk, generalized convulsions appeared. Additional conjugated hyperbilirubinemia with normal liver function ultimately led to the diagnosis of central hypocortisolism. The neonatal period of the female patient from Bern, Switzerland, was uneventful, but convulsions in the sixth month of life resulted in the diagnosis of hypoglycemia because of isolated ACTH deficiency.

All three patients were substituted with hydrocortisone with low doses of 8–10 mg/m2 body surface area per day. Combined pituitary hormone deficiencies were excluded in all children by multiple pituitary hormone stimulation tests. Normal aldosterone levels and normal serum electrolytes indicated a normal function of the zona glomerulosa of the adrenal gland in these three children.

In contrast to other family members, the hair color of all three children was red or red-brown and the skin was pale. Interestingly, in the patients from The Netherlands and Switzerland, the hair color changed to brown in the second and third year of life.

Despite low dosage of hydrocortisone, the three children developed extreme obesity already within the first year of life. A concomitant acceleration of growth excluded an iatrogenic hypercortisolism as the underlying cause for overweight. Although birth weights had been normal in all children, all parents reported that their children had been hyperphagic from the first weeks of life and that their behavior was always determined by their search for food. Mental development was normal in all, and mild delay in motor skills can most likely be explained by their extreme obesity.


   Materials and Methods
Top
 Abstract
 Introduction
 Case Reports
 Materials and Methods
Results
 Discussion
 References
 
All genetic and treatment studies were performed with the informed consent of all parents and were approved by the local ethic committee. Genomic DNA was prepared from peripheral white blood cells using a commercial kit (blood amp kit, QIAGEN, Hilden, Germany). After informed consent exons 2 and 3 of the POMC gene were amplified and sequenced in all patients and family members using the BigDye Terminator cycle sequencing ready reaction kit (Perkin-Elmer, Weiterstadt, Germany) and an automatic sequencer (ABI 373, Applied Biosystems, Foster City, CA). Primers used to amplify the POMC gene are identical to Ref.13 .

Restriction enzyme analyses of POMC exon 2 with SphI and for exon 3 with NheI and BsshII were performed at 37 C for 2 h (enzymes are from New England Biolabs, Frankfurt a.M., Germany). Fragments were separated on a 2% agarose gel.

Body weight of all individuals was calculated as body BMI-SDSLMS based on the French reference data published by Rolland-Cachera et al. (22).

Measurement of serum TSH, total T4, and total T3 was according to the instructions of the time-resolved fluoroimmunoassay (Delfia, Wallac, Freiburg, Germany). TRH test was performed with iv administration of 100 µg/m2 body surface of Protirelin (Hoechst, Frankfurt, Germany).

Basal metabolic rate was assessed by indirect calorimetry for 30 min as previously described (23). A computerized open-circuit system was employed to measure gas exchange across a 25-L-canopy (MBM-200, DeltatracII, Datex Instruments, Helsinki, Finland). Basal metabolic rate was determined from carbon dioxide production and oxygen consumption by use of the equation of Weir (24). Patients were tested between 0800 and 0900 h after an overnight fast and before medication (hydrocortisone). The initial 10 min of calorimetry were used for acclimatization, and the calculations represent the mean values of 30 measurements performed at 1-min intervals. Results were compared with normative data according to the Shofield equation, which takes into account age, weight, and height in obese children (25).

For intranasal treatment (ACTH 4–10 intranasal preparation administration from Bachem Biochemica, Heidelberg, Germany), the treatment and substance were identical to the recently published procedure (21). After sterile filtration and solving in 0.9% NaCl, aliquots were stored at -20 C, and one aliquot for use was thawed at the beginning of each treatment week and stored thereafter at 4 C. One puff in each nostril was administered three times a day with a nasal spray atomizer. Intranasal application was tolerated well and no local irritation occurred. The dosage per day was calculated per kilogram body weight corresponding to the study in normal-weight probands (21) with a daily dose approximately two times higher in the overweight children at the beginning of the trial (1 mg/d) escalated up to a dose 10 times higher (5 mg/d), compared with the normal-weight probands in the study of Fehm et al. (21); during the trial the body weight of the treated children was 56 kg and 46 kg.


   Results
Top
 Abstract
 Introduction
 Case Reports
 Materials and Methods
 Results
Discussion
 References
 
Mutation studies

Direct sequencing of the POMC coding region revealed homozygous or compound heterozygous mutations in all three children (Fig. 1AGo). Parents were found to be heterozygous for the respective POMC gene mutations. Because all mutations introduce a premature stop codon or a frameshift a truncation of the POMC gene product, N-terminal to the region containing {alpha}-MSH and ACTH can be predicted according to the position of each mutation (Fig. 1BGo). Besides three new nonsense and frame-shift mutations (A6851T, 6996del, 7100ins2G), a previously described mutation in exon 2 (C3804A) was identified again in two families. This mutation introduces an additional out-of-frame 5' start codon within a favorable region for translation initiation (so-called Kozak region) (26), which would lead to the translation of a completely different non-POMC-related protein. Carriers of these most frequently identified C3804A mutation are from a circumscribed geographical region in Europe (The Netherlands, Switzerland, and Germany), which suggests a founder effect. However, the family histories did not reveal any obvious relationship in the last several generations.



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  		FIG. 1. Complete loss-of-function POMC gene mutations in three newly identified patients with complete POMC deficiency. A, Results of mutation studies are shown for each family. The patient from family 1 is compound heterozygous for two new mutations, e.g. A6851T and 6996del. Both mutations are shown as sequencing profiles, and both parents are heterozygous. In family 2 the previously described mutation C3804A is found in homozygosity in the affected child and in heterozygosity in both parents, but the brother carries only the wild-type allele. The C3804A mutation is shown by restriction enzyme analysis with Sph1. In the third family, the affected child is compound heterozygous for the C3804A mutation and a new 2-bp insertion mutation (7100insGG). The C3804A mutation, which is also present in heterozygosity in the mother and the brother, is shown again by restriction with Sph1. The new mutation, 7100insGG, is shown as sequencing profiles after cloning of PCR products and subsequent sequencing of the two different alleles. The father is a heterozygous carrier of the new 7100insGG mutation. B, Peptides of the POMC precursor protein are shown in terms of sequential cleavage by prohormone convertases 1 and 2 together with the predicted protein structure of each loss-of-function POMC mutation identified so far. Positions of sequential cleavage are shown by small numbers. Altered protein sequences by frame-shift mutations are shown in gray gene product bars. The numbers indicate the position of the mutated codon. The numbering of POMC gene nucleotides and POMC amino acid residues corresponds to Refs. 50 and 2 , respectively.

 
Genotype-phenotype correlation of obesity

To compare the obese phenotype of the different POMC gene mutation carriers, we calculated the maximum lifetime BMI-SDSLMS values of all heterozygous and homozygous or compound heterozygous individuals (Fig. 2Go). All homozygous or compound heterozygous children were in the extreme obesity range of BMI-SDSLMS. Interestingly, none of the heterozygous parents has a low normal BMI value; instead body weight in heterozygous mutation carriers was shifted to the high normal +1 BMI-SDSLMS, or even overweight range of +2 BMI-SDSLMS.



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  		FIG. 2. Body weight of all POMC gene mutation carriers diagnosed so far and POMC-deficient patients are shown as BMI-SDSLMS values. The heterozygous parents are represented as white bars. The homozygous and compound heterozygous affected children are represented as gray bars. The genotype is indicated below each individual bar.

 
Treatment with ACTH4–10 and metabolic rate

Based on the molecular diagnosis of POMC deficiency, we initiated a trial to treat the extreme obesity by substituting the hypothalamic lack of melanocortin peptides. We tested the effect of the peptide fragment ACTH 4–10, which contains the amino acids 4–10 of ACTH, which are identical in {alpha}-MSH. This fragment contains the MCR-binding core sequence of melanocortin peptides (HFRW) and has been shown to exert binding affinity to MCRs, albeit with very low affinity (27). We chose this component because it had already been administered to a large number of probands in several pharmacological studies without side effects, and more importantly, it had recently been shown to be efficient in reducing body weight in normal-weight individuals after intranasal administration (21). Therefore, in a 3-month treatment trial, we administered intranasal ACTH4–10, with doses increasing from 1–5 mg/d, to the two previously published patients. Beside monitoring body weight and body composition, we measured the resting metabolic rate and asked the parents for any changes in the hyperphagic behavior of their children. Even after the last interval of the maximum dose of 5 mg, no reduction of body weight or increase of basal metabolic rate (Fig. 3Go) and change of body composition (data not shown) could be measured, and the parents did not report any changes in eating behavior.



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  		FIG. 3. Results of a 3-month intranasal treatment with ACTH4–10 in the two previously published patients with POMC deficiency. After the first 6-wk course of 1 mg/d, and after the second 6-wk course of 5 mg/d, body weight and basal metabolic rate were measured and are expressed for the female (B1) and male (B2) patient. Basal metabolic rate is shown as the ratio of the measured kilocalorie per day to the predicted kilocalorie per day values according to the Schofield equation for obese children. A normal basal metabolic rate would reach a ratio of 1. Both children are hypometabolic as shown in the ratios lower than 1 (range 0.73–0.83).

 
Thyroid function

A retrospective summary of thyroid function tests in the same two previously published patients revealed repeatedly elevated TSH and sometimes borderline reduced total T4 values, but total T3 was in the normal range (Fig. 4Go). In TRH stimulation tests, at least at two time points, a 10-times stimulation of TSH was documented (Fig. 4Go). At the same time, normal thyroid volume and negative thyroid autoantibodies were found in both patients (data not shown). Together these data suggested a subclinical hypothyroid situation most likely of central origin.



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  		FIG. 4. Thyroid function in the two previously published children with POMC deficiency. All available data of TSH, total T4, and total T3 are shown for the female (B1) and male (B2) patient. The respective normal ranges are highlighted in gray. The numbers in brackets represent the measured TSH values 30 min after TRH stimulation (normal > 30). The treatment periods with the respective levothyroxine doses are indicated as dark gray horizontal bars. Patient B2 was temporally treated with a low dose of 25 µg LT4 before.

 
To optimize thyroid hormone values in both patients and overcome the potential contribution of reduced thyroid function, we treated both children in a prospective 1-yr trial with increasing doses of levothyroxine. The treatment resulted in normal T4 values and low normal or even suppressed TSH (Fig. 4Go). Because we observed accelerated growth in both children, we calculated all weight and height values as BMI-SDSLMS to better assess the observed weight changes during thyroxin treatment (Fig. 5Go). As outlined by BMI-SDSLMS values, the course of obesity in both children was characterized by a rapid and extreme gain of weight during the first 4 yr of life followed by a stable phase of constant BMI-SDSLMS. Interestingly, in the male patient, BMI-SDSLMS subsequently declined even without therapy, which resulted from a reduced rate of weight gain and an accelerated growth. In both patients the course of BMI-SDSLMS did not change after initiation of treatment with T4. The ratio of measured to predicted metabolic rate was also not changed during the treatment period with T4 (data not shown).



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  		FIG. 5. Course of obesity in the two oldest patients with POMC deficiency. Weight curves are shown relative to the normal ranges indicated as the 97th and 3rd percentiles (according to Ref.22 ). BMI-SDSLMS of all available weight and height measurements of both children were calculated (22 ). The normal range +2 to -2 is highlighted in gray. The time periods of levothyroxine treatment are indicated as black horizontal bars in the BMI-SDSLMS graphs.

 

   Discussion
Top
 Abstract
 Introduction
 Case Reports
 Materials and Methods
 Results
 Discussion
References
 
The four different melanocortin peptides and their respective five MCRs constitute one of the most complex functional networks within the endocrine system. The role of melanocortin peptides in skin pigmentation and adrenal cortisol secretion was already described in the 1950s (28). In contrast, further impact of the melanocortin system on central nervous system (CNS) function as suggested by numerous pharmacological studies (29) remained mainly controversial until the first CNS-expressed MCRs were cloned (30, 31). The finding of expression of the MCR3 and MCR4 in the CNS and particularly the targeted inactivation of these two receptors conclusively demonstrated the role of melanocortin peptides in the CNS to regulate body weight (32). In accordance with these diverse functions of POMC-derived peptides, the two first patients with a POMC gene defect were shown to be affected by adrenal insufficiency, red hair, and severe early-onset obesity (13).

The identification of POMC gene mutations in three additional cases presented here confirms this distinct clinical syndrome of POMC deficiency in humans. This spectrum of obesity, red hair, and hypocortisolism clearly reflects the lack of activation of central MC4-R and MC3-R, the skin MC1-R, and the adrenal MC2-R, respectively (33).

Based on the clinical experience with five children with POMC deficiency so far, it appears that the earliest and most life-threatening symptoms can be recognized during the neonatal period and are due to secondary congenital hypocortisolism. Hypoglycemic seizures as well as hyperbilirubinemia and cholestasis, as described already for other cases of neonatal hypocortisolism (11, 34, 35), were found in POMC-deficient neonates and can develop into lethal hepatic failure if hydrocortisone substitution is not being initiated promptly. Because of these neonatal complications and the fatal episodes later during infancy of hypocortisolism in severe infections, most patients with POMC deficiency may not survive. This fatal course occurred in the first-born son of the first published family with POMC deficiency (13), who died because of hepatic failure before the diagnosis of hypocortisolism was established. In a neonatal screening paper specimen, the same compound heterozygous loss-of-function POMC gene mutation as in his sister could have been demonstrated (33). In this boy postmortem studies were performed, which revealed adrenal hypoplasia because of the absence of the zona fasciculata and reticularis, but the zona glomerulosa and adrenal medulla were intact (33). These histological findings correspond with the normal level of aldosterone and the lack of symptoms of aldosterone deficiency in the five patients with POMC deficiency identified so far. In contrast to these findings in human POMC deficiency, it has been shown that mice with complete POMC deficiency lack any adrenal gland tissue and are aldosterone deficient (14). Therefore, a clear difference in POMC function on adrenal growth and function seems to exist in mice and humans.

Already during the neonatal period, the second sign of POMC deficiency, e.g. red hair and pale skin, could be observed in all five patients identified so far. Red hair in POMC deficiency clearly reflects the lack of melanocortin peptides at the skin MC1R, a situation that resembles homozygous or compound heterozygous loss-of-function mutations of the MC1R, which were identified in red-haired individuals so far (11). Interestingly, the initially deep red hair color of the affected children tends to change over time to brown. Patients with reduced pigmentation of the skin because of POMC deficiency will have most likely the same increased risk to develop skin cancer as already described for patients with pale skin because of MC1R mutations (11) and a careful skin protection against sunlight seems to be mandatory. So far no additional dermatological diseases occurred in the described patients with POMC deficiency. Because of the young age of patients identified so far, the lack of further dermatological symptoms has only a limited impact for the question of the overall importance of the skin melanocortin system, e.g. skin immunology (36).

Obesity in patients with POMC deficiency reflects an interruption of the hypothalamic signaling cascade of weight regulation because the CNS cannot adequately respond to increased leptin and insulin levels in terms of activation of the MC4 receptor and MC3 receptor (37). The clinical consequence of this central leptin and insulin insensitivity already occurs during the first year of life because all parents of POMC-deficient children reported an obvious hyperphagic behavior in the first month of life and the body weight of all children increased dramatically during the first year of life. These observations implicate that in POMC deficiency obesity seems to be caused mainly by hyperphagia. Whether in addition obesity might also be the consequence of inadequately low metabolic responses relative to an increased body weight needs further investigation because normative data for metabolic rates in early-onset and extremely obese children are not sufficiently available.

Recently it has been shown that melanocortin peptides stimulate the hypothalamic pituitary thyroid axis (19) via axons contacting TRH-expressing cells of the nucleus paraventricularis (20). Therefore, in POMC deficiency the lack of melanocortin function might cause a state of relative TRH deficiency with the consequence of a biological inactive and elevated TSH as has been shown for clinical examples (38) and experimental models of TRH deficiency (39). In the two previously published POMC-deficient patients, elevated TSH and normal or low normal total T4 values are compatible with this proposed state of mild central hypothyroidism because of low TRH release. Nevertheless, a currently unrecognized direct influence of POMC-derived peptides on the maturation of the hypothalamic-pituitary-thyroid axis might exist, which would result in a developmental rather than functional alteration of the regulation of thyroid function in POMC deficiency. However, during the treatment period with thyroid hormone that was initiated to optimize the subclinical hypothyroidism in both children, no improvement of obesity could be achieved. These observations suggest that altered thyroid function in POMC deficiency does not critically contribute in the pathophysiology of obesity and that other regulatory deficits like a lower sympathetic outflow (40) might be present in POMC deficiency, which has to be determined.

Based on the molecular defect and the resulting lack of melanocortin function, it seems reasonable to treat obesity in POMC deficiency by administration of compounds with melanocortin activity. In two recent studies, a comparable approach has been shown for the successful substitution with recombinant leptin in patients with genetic leptin deficiency (41, 42). In contrast to leptin substitution, in which the lack of the peripheral hormone can be compensated within the natural compartment by subcutaneus administration, hypothalamic melanocortin deficiency cannot as easily be substituted because of the difficulty of a stable transfer of melanocortin peptides through the blood-brain barrier (43). Therefore, it was promising that an intranasal administration of the melanocortin peptide ACTH 4–10 was reported to result in relevant levels of cerebrospinal fluid concentrations (44) and that the intranasal administration of ACTH 4–10 in normal-weight probands induced a significant weight reduction (21). During a 3-month trial with increasing doses of ACTH 4–10, no effect on body weight, metabolic rate, or body composition was observed. These results strongly suggest that intranasal ACTH 4–10 in the dosage used is not sufficient to act as a hypothalamic melanocortin substitution therapy in completely POMC-deficient patients. The 1000-times lower affinity of ACTH 4–10 at the MC4R, compared with {alpha}-MSH (27), might be one important reason for this lack of activity.

So far, other melanocortin peptides with high MC4R affinity and selectivity are available. One of these compounds, MTII, has been extensively used in rodent obesity models and was shown to reduce body weight (45). However, an additional stimulatory effect on sexual behavior was recently described for MTII, which led to initial trials of sc treatment with MTII for erectile dysfunction (46). Subsequent studies in MC4R knockout mice confirmed this role of the melanocortin pathway in the regulation of sexual function (47). Unfortunately, because of these additional effects on sexual function, MTII or equivalent compounds with high affinity at the MC4R will not represent a therapeutic option to treat obesity in POMC-deficient children.

In addition to obesity, hypocortisolism, and red hair, no further clinical signs or symptoms were observed in the five patients with complete POMC deficiency identified so far. No obvious alterations in pain sensation was reported, although not formally tested because of ethical reasons, which implicates that the lack of the C-terminal POMC fragment ß-endorphin, which binds to opioid receptors and was expected to play a role in the endogenous analgetic system, can be compensated by other components like the enkephalins (48). Because of the young age of the patients diagnosed so far, it cannot be excluded that further defects not apparent so far may appear in postpubertal and adult life.

The POMC deficiency syndrome is inherited as a recessive trait because all heterozygous mutation carriers identified so far are not extremely obese, do not have red hair, and were shown to have normal cortisol secretion. However, the increased number of identified patients allowed the estimate of the influence of POMC haploinsufficiency on the individual body weight in heterozygous mutation carriers. According to the maximum lifetime BMI-SDSLMS values of all 10 heterozygous parents and implicated by the fact that all heterozygous parents are under diet restriction, POMC haploinsufficiency seems to have an impact on the individual eating behavior and may shift the individual body weight to higher normal or even mildly obese levels. Although these observations need further confirmation by more detailed studies, these findings are in accordance with obesity in MC4R mutation carriers. So far, most of the identified MC4R mutation carriers are heterozygous for loss-of-function mutations, suggesting a dosage effect of the MC4R gene (12). This finding is paralleled by the observation of elevated body weight in heterozygous MC4R knockout mice (49). In agreement with these observations in heterozygous MC4R +/- mice, targeted inactivation of the POMC gene could result in increased body weight in heterozygous mice dependent on the genetic background (M. Low, personal communication). Together these data implicate that both components of the POMC/MC4R signaling pathway might contribute in a dose-dependent manner to the individual set point of body weight. Subtle changes in expression of these genes because of mutations in regulatory regions might therefore play a role in the multigenic susceptibility for obesity. Therefore, it might turn out that findings in the very rare condition of POMC deficiency as described here will further help to also better understand common obesity.


   Acknowledgments
 
The peptide preparation of ACTH 4–10 was kindly provided by Professor Born and Professor Fehm, University Lübeck, Germany. We thank Dr. A. Dannenberg for help in BMI-SDSLMS calculations.


   Footnotes
 
This work was supported by the Deutsche Forschungsgemeinschaft (SFB 577-B3) and Swiss Science Foundation (PEM 32-53714.98).

Abbreviations: BMI-SDSLMS, Body mass index SDscore according to the least mean square method; CNS, Central nervous system; MCR, melanocortin receptor; PC, prohormone convertase; POMC, proopiomelanocortin.

Received March 21, 2003.

Accepted June 27, 2003.


   References
Top
 Abstract
 Introduction
 Case Reports
 Materials and Methods
 Results
 Discussion
 References
 

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