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Proopiomelanocortin deficiency(OBAIRH)

MedGen UID:
341863
Concept ID:
C1857854
Disease or Syndrome
Synonyms: OBAIRH; Obesity, adrenal insufficiency, and red hair due to POMC deficiency; OBESITY, EARLY-ONSET, WITH ADRENAL INSUFFICIENCY AND RED HAIR
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
Sources: HPO, OMIM
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

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.\n\nAffected 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.\n\nLow 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 (hypoglycemia) in people with POMC deficiency, which can 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.\n\nPale 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
Adrenal insufficiency
MedGen UID:
1351
Concept ID:
C0001623
Disease or Syndrome
Conditions in which the production of adrenal CORTICOSTEROIDS falls below the requirement of the body. Adrenal insufficiency can be caused by defects in the ADRENAL GLANDS, the PITUITARY GLAND, or the HYPOTHALAMUS.
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.
Obesity
MedGen UID:
18127
Concept ID:
C0028754
Disease or Syndrome
Accumulation of substantial excess body fat.
Red hair
MedGen UID:
66796
Concept ID:
C0239803
Finding
Hyperbilirubinemia
MedGen UID:
86321
Concept ID:
C0311468
Finding
An increased amount of bilirubin in the blood.
Adrenocorticotropic hormone deficiency
MedGen UID:
137968
Concept ID:
C0342388
Disease or Syndrome
Congenital isolated adrenocorticotropic hormone deficiency 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 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
Adrenal hypoplasia
MedGen UID:
337539
Concept ID:
C1846223
Finding
Developmental hypoplasia of the adrenal glands.
Growth hormone deficiency
MedGen UID:
811475
Concept ID:
C3714796
Disease or Syndrome
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.
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).

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Proopiomelanocortin deficiency in Orphanet.

Recent clinical studies

Etiology

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

Diagnosis

Graves LE, Khouri JM, Kristidis P, Verge CF
J Paediatr Child Health 2021 Apr;57(4):484-490. Epub 2021 Mar 5 doi: 10.1111/jpc.15407. PMID: 33666293
Çetinkaya S, Güran T, Kurnaz E, Keskin M, Sağsak E, Savaş Erdeve S, Suntharalingham JP, Buonocore F, Achermann JC, Aycan Z
J Clin Res Pediatr Endocrinol 2018 Mar 1;10(1):68-73. Epub 2017 Jul 24 doi: 10.4274/jcrpe.4638. PMID: 28739551Free PMC Article
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
Anisimova AS, Rubtsov PM, Akulich KA, Dmitriev SE, Frolova E, Tiulpakov A
J Clin Endocrinol Metab 2017 Feb 1;102(2):359-362. doi: 10.1210/jc.2016-3318. PMID: 27906547
Krude H, Biebermann H, Schnabel D, Tansek MZ, Theunissen P, Mullis PE, Grüters A
J Clin Endocrinol Metab 2003 Oct;88(10):4633-40. doi: 10.1210/jc.2003-030502. PMID: 14557433

Therapy

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
Hilado MA, Randhawa RS
J Pediatr Endocrinol Metab 2018 Jul 26;31(7):815-819. doi: 10.1515/jpem-2017-0467. PMID: 29858905
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
Kühnen P, Clément K, Wiegand S, Blankenstein O, Gottesdiener K, Martini LL, Mai K, Blume-Peytavi U, Grüters A, Krude H
N Engl J Med 2016 Jul 21;375(3):240-6. doi: 10.1056/NEJMoa1512693. PMID: 27468060
Krude H, Biebermann H, Schnabel D, Tansek MZ, Theunissen P, Mullis PE, Grüters A
J Clin Endocrinol Metab 2003 Oct;88(10):4633-40. doi: 10.1210/jc.2003-030502. PMID: 14557433

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
Hilado MA, Randhawa RS
J Pediatr Endocrinol Metab 2018 Jul 26;31(7):815-819. doi: 10.1515/jpem-2017-0467. PMID: 29858905
Anisimova AS, Rubtsov PM, Akulich KA, Dmitriev SE, Frolova E, Tiulpakov A
J Clin Endocrinol Metab 2017 Feb 1;102(2):359-362. doi: 10.1210/jc.2016-3318. PMID: 27906547
Aldemir O, Ozen S, Sanlialp C, Ceylaner S
Prenat Diagn 2013 Dec;33(13):1297-8. Epub 2013 Sep 12 doi: 10.1002/pd.4226. PMID: 24027193
Ito S, Wakamatsu K
J Eur Acad Dermatol Venereol 2011 Dec;25(12):1369-80. doi: 10.1111/j.1468-3083.2011.04278.x. PMID: 22077870

Clinical prediction guides

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
Anisimova AS, Rubtsov PM, Akulich KA, Dmitriev SE, Frolova E, Tiulpakov A
J Clin Endocrinol Metab 2017 Feb 1;102(2):359-362. doi: 10.1210/jc.2016-3318. PMID: 27906547
Aldemir O, Ozen S, Sanlialp C, Ceylaner S
Prenat Diagn 2013 Dec;33(13):1297-8. Epub 2013 Sep 12 doi: 10.1002/pd.4226. PMID: 24027193
Ito S, Wakamatsu K
J Eur Acad Dermatol Venereol 2011 Dec;25(12):1369-80. doi: 10.1111/j.1468-3083.2011.04278.x. PMID: 22077870
Krude H, Biebermann H, Schnabel D, Tansek MZ, Theunissen P, Mullis PE, Grüters A
J Clin Endocrinol Metab 2003 Oct;88(10):4633-40. doi: 10.1210/jc.2003-030502. PMID: 14557433

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