A novel mutation in the proopiomelanocortin (POMC) gene of a Hispanic child: metformin treatment shows a beneficial impact on the body mass index
-
Mark A. Hilado
Abstract
Background
Proopiomelanocortin (POMC) is a complex polypeptide that produces a variety of biologically active substances via cleavage in a tissue-specific manner [Challis BG, Millington GW. Proopiomelanocortin deficiency. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle, 1993–2018], yielding several products including adrenocorticotrophic (ACTH) and melanocyte stimulating hormones (MSH). These peptides have roles in the regulation of food intake, energy homeostasis, adrenal steroidogenesis, melanocyte stimulation and immune modulation. Rare mutations in the POMC gene can lead to ACTH deficiency and thus isolated hypocortisolism. The first cases of POMC mutation were documented by Krude et al. in 1998 [Krude H, Biebermann H, Luck W, Horn R, Brabant G, et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998;19:155–7]. Mutations in the POMC gene were linked with a clinical phenotype of adrenal insufficiency, red hair pigmentation, early onset and rapidly progressive obesity, early onset type 2 diabetes, hypothyroidism, hypogonadism and growth hormone deficiency.
Case presentation
We describe a prepubertal Hispanic boy with a novel homozygous POMC mutation with severe obesity, hypothyroidism, adrenal insufficiency and abnormal reddish hair pigmentation. The patient presented as a 2-year-old with exponential weight gain, abnormal thyroid labs and speech delay. Laboratory testing demonstrated central adrenal insufficiency and genetic testing confirmed a homozygous mutation (nucleotide change c.20_21ins25) in exon 3 of the POMC gene. Replacement therapy with thyroid hormone and hydrocortisone was coupled to a slight decrease in the rate of weight gain, although hyperphagia persisted. Parent-directed nutrition and activity education as well as attempts to restrict access to food resulted in a plateau of the body mass index (BMI). At 4 years of age, metformin treatment was initiated with the patient showing evolving signs of insulin resistance and failure of lifestyle/dietary intervention to adequately decrease the BMI. Over a 3-year metformin treatment span, the BMI decreased from 34.9 kg/m2 to 32.9 kg/m2.
Conclusions
We demonstrate a possible role for metformin in stemming progressive weight gain, thereby impacting the early onset obesity due to hyperphagia.
References
1. Yeo GS, Farooqi IS, Challis BG, Jackson RS, O’Rahilly S. The role of melanocortin signalling in the control of body weight: evidence from human and murine genetic models. Q J Med 2000;93:7–14.10.1093/qjmed/93.1.7Search in Google Scholar PubMed
2. Krude H, Biebermann H, Schnabel D, Tansk MZ, Theunissen P, et al. Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4–10. J Clin Endocrinol Metabol 2003;88:4633–40.10.1210/jc.2003-030502Search in Google Scholar PubMed
3. Challis BG, Millington GW. Proopiomelanocortin deficiency. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle, 1993–2018.Search in Google Scholar
4. Krude H, Biebermann H, Luck W, Horn R, Brabant G, et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998;19:155–7.10.1038/509Search in Google Scholar PubMed
5. Al-hussaini A, Almutairi A, Mursi A, Alghofely M, Asery A. Isolated cortisol deficiency: a rare cause of neonatal cholestasis. Saudi J Gastroenterol 2012;18:339–41.10.4103/1319-3767.101137Search in Google Scholar PubMed PubMed Central
6. Mendriatta MS, Yang Y, Balazs AE, Willis AS, Eng CM, et al. Early onset obesity and adrenal insufficiency associated with a homozygous POMC mutation. Int J Pediatr Endocrinol 2011;2011:5.10.1186/1687-9856-2011-5Search in Google Scholar PubMed PubMed Central
7. Mencarelli M, Zulian A, Cancello R, Alberti L, Gilardini L, et al. A novel missense mutation in the signal peptide of the human POMC gene: a possible additional link between early-onset type 2 diabetes and obesity. Eur J Hum Genet 2012;20:1290–4.10.1038/ejhg.2012.103Search in Google Scholar PubMed PubMed Central
8. Clément K, Dubern B, Mencarelli M, Czernichow P, Ito S, et al. Unexpected endocrine features and normal pigmentation in a young adult patient carrying a novel homozygous mutation in the POMC gene. J Clin Endocrinol Metab 2008;93:4955–62.10.1210/jc.2008-1164Search in Google Scholar PubMed PubMed Central
9. Hung CN, Poon WT, Lee CY, Law CY, Chan AY. A case of early-onset obesity, hypocortisolism, and skin pigmentation problem due to a novel homozygous mutation in the proopiomelanocortin (POMC) gene in an Indian boy. J Pediatr Endocrinol Metab 2012;25:175–9.10.1515/jpem-2011-0437Search in Google Scholar PubMed
10. Aslan IR, Ranadive SA, Valle I, Kollipara S, Noble JA, et al. The melanocortin system and insulin resistance in humans: insights from a patient with complete POMC deficiency and type 1 diabetes mellitus. Int J Obes (Lond) 2014;38:148–51.10.1038/ijo.2013.53Search in Google Scholar PubMed PubMed Central
11. Doulla M, McIntyre AD, Hegele RA, Gallego PH. A novel MC4R mutation associated with childhood-onset obesity: a case report. Paediatr Child Health 2014;19:515–8.10.1093/pch/19.10.515Search in Google Scholar PubMed PubMed Central
12. Kühnen P, Clément K, Wiegand S, Blankenstein O, Gottesdiener K. Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist. N Engl J Med 2016;375:240–6.10.1056/NEJMoa1512693Search in Google Scholar PubMed
13. Park MH, Kinra S, Ward KJ, White B, Viner RM. Metformin for obesity in children and adolescents: a systematic review. Diabetes Care 2009;32:1743–5.10.2337/dc09-0258Search in Google Scholar PubMed PubMed Central
©2018 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Review
- Prevalence of cranial MRI findings in girls with central precocious puberty: a systematic review and meta-analysis
- Original Articles
- Can having a sibling with type 1 diabetes cause disordered eating behaviors?
- Wrist circumference as a novel predictor of obesity in children and adolescents: the CASPIAN-IV study
- Evaluation of Mn-superoxide dismutase and catalase gene expression in childhood obesity: its association with insulin resistance
- Impact of a group-based treatment program on adipocytokines, oxidative status, inflammatory cytokines and arterial stiffness in obese children and adolescents
- Clinical management of childhood hyperthyroidism with and without Down syndrome: a longitudinal study at a single center
- Detection of distant metastasis at the time of ablation in children with differentiated thyroid cancer: the value of pre-ablation stimulated thyroglobulin
- Random serum free cortisol and total cortisol measurements in pediatric septic shock
- Self-assessment of pubertal development in a puberty cohort
- Growth, the Mediterranean diet and the buying power of adolescents in Greece
- Clinical and molecular genetic characterization of two patients with mutations in the phosphoglucomutase 1 (PGM1) gene
- Genetic analysis of three families with X-linked dominant hypophosphatemic rickets
- Clinical heterogeneity and molecular profile of triple A syndrome: a study of seven cases
- No central adrenal insufficiency found in patients with Prader-Willi syndrome with an overnight metyrapone test
- Case Reports
- A novel mutation in the proopiomelanocortin (POMC) gene of a Hispanic child: metformin treatment shows a beneficial impact on the body mass index
- Hypertriglyceridemia thalassemia syndrome
- Severe consumptive hypothyroidism caused by multiple infantile hepatic haemangiomas
Articles in the same Issue
- Frontmatter
- Review
- Prevalence of cranial MRI findings in girls with central precocious puberty: a systematic review and meta-analysis
- Original Articles
- Can having a sibling with type 1 diabetes cause disordered eating behaviors?
- Wrist circumference as a novel predictor of obesity in children and adolescents: the CASPIAN-IV study
- Evaluation of Mn-superoxide dismutase and catalase gene expression in childhood obesity: its association with insulin resistance
- Impact of a group-based treatment program on adipocytokines, oxidative status, inflammatory cytokines and arterial stiffness in obese children and adolescents
- Clinical management of childhood hyperthyroidism with and without Down syndrome: a longitudinal study at a single center
- Detection of distant metastasis at the time of ablation in children with differentiated thyroid cancer: the value of pre-ablation stimulated thyroglobulin
- Random serum free cortisol and total cortisol measurements in pediatric septic shock
- Self-assessment of pubertal development in a puberty cohort
- Growth, the Mediterranean diet and the buying power of adolescents in Greece
- Clinical and molecular genetic characterization of two patients with mutations in the phosphoglucomutase 1 (PGM1) gene
- Genetic analysis of three families with X-linked dominant hypophosphatemic rickets
- Clinical heterogeneity and molecular profile of triple A syndrome: a study of seven cases
- No central adrenal insufficiency found in patients with Prader-Willi syndrome with an overnight metyrapone test
- Case Reports
- A novel mutation in the proopiomelanocortin (POMC) gene of a Hispanic child: metformin treatment shows a beneficial impact on the body mass index
- Hypertriglyceridemia thalassemia syndrome
- Severe consumptive hypothyroidism caused by multiple infantile hepatic haemangiomas
