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Obesity due to prohormone convertase I deficiency

MedGen UID:
318777
Concept ID:
C1833053
Disease or Syndrome
Synonyms: OBESITY AND ENDOCRINOPATHY DUE TO IMPAIRED PROCESSING OF PROHORMONES; Proprotein convertase 1/3 deficiency; Proprotein Convertase-1 Deficiency
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): PCSK1 (5q15)
 
Monarch Initiative: MONDO:0010961
OMIM®: 600955
Orphanet: ORPHA71528

Definition

Proprotein convertase-1/3 deficiency is an autosomal recessive disorder characterized by neonatal severe generalized malabsorptive diarrhea and failure to thrive. As the disease progresses, additional endocrine abnormalities develop, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency, and hypothyroidism (summary by Wilschanski et al., 2014). [from OMIM]

Clinical features

From HPO
Primary amenorrhea
MedGen UID:
115918
Concept ID:
C0232939
Disease or Syndrome
Abnormally late or absent menarche in a female with normal secondary sexual characteristics.
Obesity
MedGen UID:
18127
Concept ID:
C0028754
Disease or Syndrome
Accumulation of substantial excess body fat.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Villous atrophy
MedGen UID:
154306
Concept ID:
C0554101
Finding
The enteric villi are atrophic or absent.
Malabsorption
MedGen UID:
811453
Concept ID:
C3714745
Finding
Impaired ability to absorb one or more nutrients from the intestine.
Reactive hypoglycemia
MedGen UID:
124409
Concept ID:
C0271710
Disease or Syndrome
Hypoglycermia following a meal (or more generally, after intake of glucose).
Hypogonadotropic hypogonadism
MedGen UID:
82883
Concept ID:
C0271623
Disease or Syndrome
Hypogonadotropic hypogonadism is characterized by reduced function of the gonads (testes in males or ovaries in females) and results from the absence of the gonadal stimulating pituitary hormones
Decreased circulating cortisol level
MedGen UID:
322961
Concept ID:
C1836623
Finding
Abnormally reduced concentration of cortisol in the blood.
Hypoinsulinemia
MedGen UID:
852189
Concept ID:
C2748055
Disease or Syndrome
A decreased concentration of insulin in the blood.
Elevated circulating proinsulin concentration
MedGen UID:
1053011
Concept ID:
CN377015
Finding
The concentration of proinsulin in the blood circulation is above the upper limit of normal.

Term Hierarchy

Follow this link to review classifications for Obesity due to prohormone convertase I deficiency in Orphanet.

Professional guidelines

PubMed

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

Recent clinical studies

Etiology

Szarek M, Reijnders E, Jukema JW, Bhatt DL, Bittner VA, Diaz R, Fazio S, Garon G, Goodman SG, Harrington RA, Ruhaak LR, Schwertfeger M, Tsimikas S, White HD, Steg PG, Cobbaert C, Schwartz GG; ODYSSEY OUTCOMES Investigators
Circulation 2024 Jan 16;149(3):192-203. Epub 2023 Aug 26 doi: 10.1161/CIRCULATIONAHA.123.066398. PMID: 37632469Free PMC Article
Van Dijck E, Beckers S, Diels S, Huybrechts T, Verrijken A, Van Hoorenbeeck K, Verhulst S, Massa G, Van Gaal L, Van Hul W
Genes (Basel) 2022 Sep 27;13(10) doi: 10.3390/genes13101746. PMID: 36292633Free PMC Article
Ramos-Molina B, Martin MG, Lindberg I
Prog Mol Biol Transl Sci 2016;140:47-74. Epub 2016 Jan 29 doi: 10.1016/bs.pmbts.2015.12.001. PMID: 27288825Free PMC Article
Creemers JW, Choquet H, Stijnen P, Vatin V, Pigeyre M, Beckers S, Meulemans S, Than ME, Yengo L, Tauber M, Balkau B, Elliott P, Jarvelin MR, Van Hul W, Van Gaal L, Horber F, Pattou F, Froguel P, Meyre D
Diabetes 2012 Feb;61(2):383-90. Epub 2011 Dec 30 doi: 10.2337/db11-0305. PMID: 22210313Free PMC Article
Farooqi IS
Best Pract Res Clin Endocrinol Metab 2005 Sep;19(3):359-74. doi: 10.1016/j.beem.2005.04.004. PMID: 16150380

Diagnosis

Szarek M, Reijnders E, Jukema JW, Bhatt DL, Bittner VA, Diaz R, Fazio S, Garon G, Goodman SG, Harrington RA, Ruhaak LR, Schwertfeger M, Tsimikas S, White HD, Steg PG, Cobbaert C, Schwartz GG; ODYSSEY OUTCOMES Investigators
Circulation 2024 Jan 16;149(3):192-203. Epub 2023 Aug 26 doi: 10.1161/CIRCULATIONAHA.123.066398. PMID: 37632469Free PMC Article
Kostopoulou E, Spilioti DX, Pantzaris ND, Spiliotis BE
Eur Rev Med Pharmacol Sci 2022 Apr;26(7):2437-2442. doi: 10.26355/eurrev_202204_28478. PMID: 35442499
Pépin L, Colin E, Tessarech M, Rouleau S, Bouhours-Nouet N, Bonneau D, Coutant R
J Clin Endocrinol Metab 2019 Apr 1;104(4):985-993. doi: 10.1210/jc.2018-01854. PMID: 30383237
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
Ramos-Molina B, Martin MG, Lindberg I
Prog Mol Biol Transl Sci 2016;140:47-74. Epub 2016 Jan 29 doi: 10.1016/bs.pmbts.2015.12.001. PMID: 27288825Free PMC Article

Therapy

Szarek M, Reijnders E, Jukema JW, Bhatt DL, Bittner VA, Diaz R, Fazio S, Garon G, Goodman SG, Harrington RA, Ruhaak LR, Schwertfeger M, Tsimikas S, White HD, Steg PG, Cobbaert C, Schwartz GG; ODYSSEY OUTCOMES Investigators
Circulation 2024 Jan 16;149(3):192-203. Epub 2023 Aug 26 doi: 10.1161/CIRCULATIONAHA.123.066398. PMID: 37632469Free PMC Article
Agarwal H, Tinsley B, Sarecha AK, Ozcan L
Curr Atheroscler Rep 2023 Dec;25(12):931-937. Epub 2023 Nov 18 doi: 10.1007/s11883-023-01162-7. PMID: 37979063
Farooqi IS
Front Horm Res 2008;36:1-11. doi: 10.1159/000115333. PMID: 18230891
Farooqi IS
Best Pract Res Clin Endocrinol Metab 2005 Sep;19(3):359-74. doi: 10.1016/j.beem.2005.04.004. PMID: 16150380
Farooqi IS, O'Rahilly S
Recent Prog Horm Res 2004;59:409-24. doi: 10.1210/rp.59.1.409. PMID: 14749512

Prognosis

Szarek M, Reijnders E, Jukema JW, Bhatt DL, Bittner VA, Diaz R, Fazio S, Garon G, Goodman SG, Harrington RA, Ruhaak LR, Schwertfeger M, Tsimikas S, White HD, Steg PG, Cobbaert C, Schwartz GG; ODYSSEY OUTCOMES Investigators
Circulation 2024 Jan 16;149(3):192-203. Epub 2023 Aug 26 doi: 10.1161/CIRCULATIONAHA.123.066398. PMID: 37632469Free PMC Article
Van Dijck E, Beckers S, Diels S, Huybrechts T, Verrijken A, Van Hoorenbeeck K, Verhulst S, Massa G, Van Gaal L, Van Hul W
Genes (Basel) 2022 Sep 27;13(10) doi: 10.3390/genes13101746. PMID: 36292633Free PMC Article
He Y, Ren L, Zhang Q, Zhang M, Shi J, Hu W, Peng H
Postgrad Med J 2021 Apr;97(1146):234-238. Epub 2020 Feb 29 doi: 10.1136/postgradmedj-2019-137422. PMID: 32114491
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
Bandsma RH, Sokollik C, Chami R, Cutz E, Brubaker PL, Hamilton JK, Perlman K, Zlotkin S, Sigalet DL, Sherman PM, Martin MG, Avitzur Y
J Clin Gastroenterol 2013 Nov-Dec;47(10):834-43. doi: 10.1097/MCG.0b013e3182a89fc8. PMID: 24135795Free PMC Article

Clinical prediction guides

Meier DT, Rachid L, Wiedemann SJ, Traub S, Trimigliozzi K, Stawiski M, Sauteur L, Winter DV, Le Foll C, Brégère C, Guzman R, Odermatt A, Böni-Schnetzler M, Donath MY
Nat Commun 2022 Aug 13;13(1):4761. doi: 10.1038/s41467-022-32509-4. PMID: 35963866Free PMC Article
Lindberg I, Fricker LD
Endocrinology 2021 Dec 1;162(12) doi: 10.1210/endocr/bqab155. PMID: 34333593Free PMC Article
Stijnen P, Ramos-Molina B, O'Rahilly S, Creemers JW
Endocr Rev 2016 Aug;37(4):347-71. Epub 2016 May 17 doi: 10.1210/er.2015-1117. PMID: 27187081
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

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