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Obesity due to pro-opiomelanocortin deficiency(OBAIRH)

MedGen UID:
341863
Concept ID:
C1857854
Disease or Syndrome
Synonyms: Obesity, adrenal insufficiency, and red hair due to POMC deficiency; OBESITY, EARLY-ONSET, WITH ADRENAL INSUFFICIENCY AND RED HAIR; Proopiomelanocortin deficiency
SNOMED CT: Obesity, early-onset, adrenal insufficiency, and red hair (702949005); Proopiomelanocortin deficiency syndrome (702949005)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): POMC (2p23.3)
 
Monarch Initiative: MONDO:0012335
OMIM®: 609734
Orphanet: ORPHA71526

Definition

Early-onset obesity with adrenal insuficiency and red hair (OBAIRH) is an autosomal recessive endocrine disorder characterized by early-onset obesity due to severe hyperphagia, pigmentary abnormalities, mainly pale skin and red hair, and secondary hypocortisolism. In the neonatal period, affected individuals are prone to hypoglycemia, hyperbilirubinemia, and cholestasis that may result in death if not treated. The disorder results from mutation in the POMC gene, which encodes a preproprotein that is processed into a range of bioactive peptides, including alpha-melanocyte-stimulating hormone (MSH) and ACTH (summary by Kuhnen et al., 2016 and Clement et al., 2008). [from OMIM]

Additional description

From MedlinePlus Genetics
Proopiomelanocortin (POMC) deficiency causes severe obesity that begins at an early age. In addition to obesity, people with this condition have low levels of a hormone known as adrenocorticotropic hormone (ACTH) and tend to have red hair and pale skin.

Affected infants are usually a normal weight at birth, but they are constantly hungry, which leads to excessive feeding (hyperphagia). The babies continuously gain weight and are severely obese by age 1. Affected individuals experience excessive hunger and remain obese for life. It is unclear if these individuals are prone to weight-related conditions like cardiovascular disease or type 2 diabetes.

Low levels of ACTH lead to a condition called adrenal insufficiency, which occurs when the pair of small glands on top of the kidneys (the adrenal glands) do not produce enough hormones. Adrenal insufficiency often results in periods of severely low blood sugar (glucose), known as hypoglycemia. Adrenal insufficiency may also cause seizures, elevated levels of a toxic substance called bilirubin in the blood (hyperbilirubinemia), and a reduced ability to produce and release a digestive fluid called bile (cholestasis). Without early treatment, adrenal insufficiency can be fatal.

Pale skin that easily burns when exposed to the sun and red hair are common in POMC deficiency, although not everyone with the condition has these characteristics.  https://medlineplus.gov/genetics/condition/proopiomelanocortin-deficiency

Clinical features

From HPO
Obesity
MedGen UID:
18127
Concept ID:
C0028754
Disease or Syndrome
Accumulation of substantial excess body fat.
Cholestasis
MedGen UID:
925
Concept ID:
C0008370
Disease or Syndrome
Impairment of bile flow due to obstruction in bile ducts.
Polyphagia
MedGen UID:
9369
Concept ID:
C0020505
Finding
A neurological anomaly with gross overeating associated with an abnormally strong desire or need to eat.
Congenital isolated adrenocorticotropic hormone deficiency
MedGen UID:
137968
Concept ID:
C0342388
Disease or Syndrome
Congenital isolated adrenocorticotropic hormone deficiency (IAD) is characterized by severe hypoglycemia in the neonatal period, associated with seizures in about half of cases, prolonged cholestatic jaundice, and very low plasma ACTH levels with no significant response to corticotropin-releasing hormone (CRH; 122560). Plasma cortisol levels are also extremely low (Vallette-Kasic et al., 2005). TBX19 is required for initiation of transcription of the POMC gene (176830), which produces the precursor peptide from which ACTH is derived (Lamolet et al., 2001).
Hypoglycemic seizures
MedGen UID:
164079
Concept ID:
C0877056
Disease or Syndrome
Gonadotropin deficiency
MedGen UID:
1632671
Concept ID:
C4552011
Disease or Syndrome
A reduced ability to secrete gonadotropins, which are protein hormones secreted by gonadotrope cells of the anterior pituitary gland, including the hormones follitropin (FSH) and luteinizing hormone (LH).
Hyperbilirubinemia
MedGen UID:
86321
Concept ID:
C0311468
Finding
An increased amount of bilirubin in the blood.
Red hair
MedGen UID:
66796
Concept ID:
C0239803
Finding
Adrenal insufficiency
MedGen UID:
1351
Concept ID:
C0001623
Disease or Syndrome
Insufficient production of steroid hormones (primarily cortisol) by the adrenal glands.
Decreased circulating cortisol level
MedGen UID:
322961
Concept ID:
C1836623
Finding
Abnormally reduced concentration of cortisol in the blood.
Adrenal hypoplasia
MedGen UID:
337539
Concept ID:
C1846223
Pathologic Function
Developmental hypoplasia of the adrenal glands.
Decreased response to growth hormone stimulation test
MedGen UID:
1784655
Concept ID:
C5539399
Finding
Insufficient responses to growth hormone (GH) provocation tests. GH deficiency is defined as a serum peak GH concentration less than 10 ng/mL on provocation with a combination of at least two separate stimulation tests.
Decreased growth hormone responses to growth hormone-releasing hormone challenge
MedGen UID:
1778726
Concept ID:
C5539698
Finding
Insufficient growth hormone secretion following administration of growth hormone-releasing hormone.

Term Hierarchy

Follow this link to review classifications for Obesity due to pro-opiomelanocortin deficiency in Orphanet.

Professional guidelines

PubMed

Wang S, Downing G, Olsen KF, Sawyer TK, Cone RD, Schwendeman SP
J Control Release 2023 Dec;364:589-600. Epub 2023 Nov 15 doi: 10.1016/j.jconrel.2023.09.015. PMID: 37678438
Wabitsch M, Fehnel S, Mallya UG, Sluga-O'Callaghan M, Richardson D, Price M, Kühnen P
Adv Ther 2022 Apr;39(4):1772-1783. Epub 2022 Feb 22 doi: 10.1007/s12325-022-02059-8. PMID: 35192151Free PMC Article
Hainerová IA, Lebl J
World Rev Nutr Diet 2013;106:105-12. Epub 2013 Feb 11 doi: 10.1159/000342556. PMID: 23428688

Recent clinical studies

Etiology

Wang S, Downing G, Olsen KF, Sawyer TK, Cone RD, Schwendeman SP
J Control Release 2023 Dec;364:589-600. Epub 2023 Nov 15 doi: 10.1016/j.jconrel.2023.09.015. PMID: 37678438
Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K, Farooqi IS, Gonneau-Lejeune J, Gordon G, Kohlsdorf K, Poitou C, Puder L, Swain J, Stewart M, Yuan G, Wabitsch M, Kühnen P; Setmelanotide POMC and LEPR Phase 3 Trial Investigators
Lancet Diabetes Endocrinol 2020 Dec;8(12):960-970. Epub 2020 Oct 30 doi: 10.1016/S2213-8587(20)30364-8. PMID: 33137293
Rose SR, Horne VE, Howell J, Lawson SA, Rutter MM, Trotman GE, Corathers SD
Nat Rev Endocrinol 2016 Jun;12(6):319-36. Epub 2016 Apr 1 doi: 10.1038/nrendo.2016.45. PMID: 27032982
Greenfield JR
J Neuroendocrinol 2011 Feb;23(2):186-93. doi: 10.1111/j.1365-2826.2010.02088.x. PMID: 21062377
Bray GA
Clin Cornerstone 1999;2(3):1-15. doi: 10.1016/s1098-3597(99)90001-7. PMID: 10696281

Diagnosis

Vitellius G, Lombes M
Eur J Endocrinol 2020 Feb 1;182(2):R15-R27. doi: 10.1530/EJE-19-0811. PMID: 31995340
Collet TH, Dubern B, Mokrosinski J, Connors H, Keogh JM, Mendes de Oliveira E, Henning E, Poitou-Bernert C, Oppert JM, Tounian P, Marchelli F, Alili R, Le Beyec J, Pépin D, Lacorte JM, Gottesdiener A, Bounds R, Sharma S, Folster C, Henderson B, O'Rahilly S, Stoner E, Gottesdiener K, Panaro BL, Cone RD, Clément K, Farooqi IS, Van der Ploeg LHT
Mol Metab 2017 Oct;6(10):1321-1329. Epub 2017 Jul 8 doi: 10.1016/j.molmet.2017.06.015. PMID: 29031731Free PMC Article
Rose SR, Horne VE, Howell J, Lawson SA, Rutter MM, Trotman GE, Corathers SD
Nat Rev Endocrinol 2016 Jun;12(6):319-36. Epub 2016 Apr 1 doi: 10.1038/nrendo.2016.45. PMID: 27032982
Babcock Gilbert S, Roth LW
Minerva Endocrinol 2015 Mar;40(1):61-70. Epub 2014 Nov 5 PMID: 25370939
Santini F, Maffei M, Pelosini C, Salvetti G, Scartabelli G, Pinchera A
Adv Clin Chem 2009;48:95-109. PMID: 19803416

Therapy

Yeo GSH, Chao DHM, Siegert AM, Koerperich ZM, Ericson MD, Simonds SE, Larson CM, Luquet S, Clarke I, Sharma S, Clément K, Cowley MA, Haskell-Luevano C, Van Der Ploeg L, Adan RAH
Mol Metab 2021 Jun;48:101206. Epub 2021 Mar 6 doi: 10.1016/j.molmet.2021.101206. PMID: 33684608Free PMC Article
Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K, Farooqi IS, Gonneau-Lejeune J, Gordon G, Kohlsdorf K, Poitou C, Puder L, Swain J, Stewart M, Yuan G, Wabitsch M, Kühnen P; Setmelanotide POMC and LEPR Phase 3 Trial Investigators
Lancet Diabetes Endocrinol 2020 Dec;8(12):960-970. Epub 2020 Oct 30 doi: 10.1016/S2213-8587(20)30364-8. PMID: 33137293
Collet TH, Dubern B, Mokrosinski J, Connors H, Keogh JM, Mendes de Oliveira E, Henning E, Poitou-Bernert C, Oppert JM, Tounian P, Marchelli F, Alili R, Le Beyec J, Pépin D, Lacorte JM, Gottesdiener A, Bounds R, Sharma S, Folster C, Henderson B, O'Rahilly S, Stoner E, Gottesdiener K, Panaro BL, Cone RD, Clément K, Farooqi IS, Van der Ploeg LHT
Mol Metab 2017 Oct;6(10):1321-1329. Epub 2017 Jul 8 doi: 10.1016/j.molmet.2017.06.015. PMID: 29031731Free PMC Article
Babcock Gilbert S, Roth LW
Minerva Endocrinol 2015 Mar;40(1):61-70. Epub 2014 Nov 5 PMID: 25370939
Farooqi IS
Front Horm Res 2008;36:1-11. doi: 10.1159/000115333. PMID: 18230891

Prognosis

Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K, Farooqi IS, Gonneau-Lejeune J, Gordon G, Kohlsdorf K, Poitou C, Puder L, Swain J, Stewart M, Yuan G, Wabitsch M, Kühnen P; Setmelanotide POMC and LEPR Phase 3 Trial Investigators
Lancet Diabetes Endocrinol 2020 Dec;8(12):960-970. Epub 2020 Oct 30 doi: 10.1016/S2213-8587(20)30364-8. PMID: 33137293
Baxter J, Armijo PR, Flores L, Krause C, Samreen S, Tanner T
Obes Surg 2019 Dec;29(12):4077-4083. doi: 10.1007/s11695-019-04200-z. PMID: 31641982
Ayers KL, Glicksberg BS, Garfield AS, Longerich S, White JA, Yang P, Du L, Chittenden TW, Gulcher JR, Roy S, Fiedorek F, Gottesdiener K, Cohen S, North KE, Schadt EE, Li SD, Chen R, Van der Ploeg LHT
J Clin Endocrinol Metab 2018 Jul 1;103(7):2601-2612. doi: 10.1210/jc.2018-00258. PMID: 29726959Free PMC Article
Zemel MB, Shi H
Nutr Rev 2000 Jun;58(6):177-80. doi: 10.1111/j.1753-4887.2000.tb01857.x. PMID: 10885325
Bray GA
Clin Cornerstone 1999;2(3):1-15. doi: 10.1016/s1098-3597(99)90001-7. PMID: 10696281

Clinical prediction guides

Wang S, Downing G, Olsen KF, Sawyer TK, Cone RD, Schwendeman SP
J Control Release 2023 Dec;364:589-600. Epub 2023 Nov 15 doi: 10.1016/j.jconrel.2023.09.015. PMID: 37678438
Lindberg I, Fricker LD
Endocrinology 2021 Dec 1;162(12) doi: 10.1210/endocr/bqab155. PMID: 34333593Free PMC Article
Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K, Farooqi IS, Gonneau-Lejeune J, Gordon G, Kohlsdorf K, Poitou C, Puder L, Swain J, Stewart M, Yuan G, Wabitsch M, Kühnen P; Setmelanotide POMC and LEPR Phase 3 Trial Investigators
Lancet Diabetes Endocrinol 2020 Dec;8(12):960-970. Epub 2020 Oct 30 doi: 10.1016/S2213-8587(20)30364-8. PMID: 33137293
Farooqi IS, O'Rahilly S
Recent Prog Horm Res 2004;59:409-24. doi: 10.1210/rp.59.1.409. PMID: 14749512
Kokkoris P, Pi-Sunyer FX
Endocrinol Metab Clin North Am 2003 Dec;32(4):895-914. doi: 10.1016/s0889-8529(03)00078-1. PMID: 14711067

Recent systematic reviews

Gregoric N, Groselj U, Bratina N, Debeljak M, Zerjav Tansek M, Suput Omladic J, Kovac J, Battelino T, Kotnik P, Avbelj Stefanija M
Front Endocrinol (Lausanne) 2021;12:689387. Epub 2021 Jun 9 doi: 10.3389/fendo.2021.689387. PMID: 34177811Free PMC Article
Fani L, Bak S, Delhanty P, van Rossum EF, van den Akker EL
Int J Obes (Lond) 2014 Feb;38(2):163-9. Epub 2013 Jun 18 doi: 10.1038/ijo.2013.80. PMID: 23774329

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