Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4-10.
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.
Krude
Heiko
H
Institute of Pediatric Endocrinology, University Children's Hospital, Charite, Humboldt-University Berlin, D-13353 Berlin, Germany. heiko.krude@charite.de
Biebermann
Heike
H
Schnabel
Dirk
D
Tansek
Mojca Zerjav
MZ
Theunissen
Pierre
P
Mullis
Primus E
PE
Grüters
Annette
A
D000324:Adrenocorticotropic Hormone / Q000008:administration & dosage*; D001481:Basal Metabolism; D001835:Body Weight / Q000187:drug effects; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005838:Genotype; D006200:Hair Color; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009765:Obesity / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage*; D010641:Phenotype; D011333:Pro-Opiomelanocortin / Q000172:deficiency / Q000235:genetics*; D013961:Thyroid Gland / Q000502:physiology; D013963:Thyroid Hormones / Q000008:administration & dosage*
D010446:Peptide Fragments; D013963:Thyroid Hormones; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; C011394:ACTH (4-10)