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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). Autosomal recessive inheritance (Orphanet)

Gene (location): Gene(s) directly associated with this condition or phenotype.	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.

See: Feature record | Search on this feature

Obesity

MedGen UID:: 18127
•Concept ID:: C0028754
•: Disease or Syndrome

Accumulation of substantial excess body fat.

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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.

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Villous atrophy

MedGen UID:: 154306
•Concept ID:: C0554101
•: Finding

The enteric villi are atrophic or absent.

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Malabsorption

MedGen UID:: 811453
•Concept ID:: C3714745
•: Finding

Impaired ability to absorb one or more nutrients from the intestine.

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Reactive hypoglycemia

MedGen UID:: 124409
•Concept ID:: C0271710
•: Disease or Syndrome

Hypoglycermia following a meal (or more generally, after intake of glucose).

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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

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Decreased circulating cortisol level

MedGen UID:: 322961
•Concept ID:: C1836623
•: Finding

Abnormally reduced concentration of cortisol in the blood.

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Hypoinsulinemia

MedGen UID:: 852189
•Concept ID:: C2748055
•: Disease or Syndrome

A decreased concentration of insulin in the blood.

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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.

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Abnormality of metabolism/homeostasis
- Reactive hypoglycemia
Abnormality of the digestive system
Abnormality of the endocrine system
Abnormality of the genitourinary system
- Primary amenorrhea
Growth abnormality
- Obesity

Term Hierarchy

GTR
MeSH
Orphanet

CClinical test, RResearch test, OOMIM, GGeneReviews, VClinVar

CROGVMonogenic Non-Syndromic Obesity, Autosomal Recessive
- CROGVObesity due to congenital leptin deficiency
- CROGVObesity due to leptin receptor gene deficiency
- CROGVObesity due to pro-opiomelanocortin deficiency
- CROGVObesity due to prohormone convertase I deficiency

Hypogonadotropic hypogonadism associated with other endocrinopathies
- Obesity due to prohormone convertase I deficiency

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

Professional guidelines

PubMed

Melanocortin 4 Receptor Pathway Dysfunction in Obesity: Patient Stratification Aimed at MC4R Agonist Treatment.

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: 29726959 Free PMC Article

See all (1)

Recent clinical studies

Etiology

Relating Lipoprotein(a) Concentrations to Cardiovascular Event Risk After Acute Coronary Syndrome: A Comparison of 3 Tests.

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: 37632469 Free PMC Article

Rare Heterozygous PCSK1 Variants in Human Obesity: The Contribution of the p.Y181H Variant and a Literature Review.

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: 36292633 Free PMC Article

Role of PAI-1 in hepatic steatosis and dyslipidemia.

Levine JA, Oleaga C, Eren M, Amaral AP, Shang M, Lux E, Khan SS, Shah SJ, Omura Y, Pamir N, Hay J, Barish G, Miyata T, Tavori H, Fazio S, Vaughan DE
Sci Rep 2021 Jan 11;11(1):430. doi: 10.1038/s41598-020-79948-x. PMID: 33432099 Free PMC Article

PCSK1 Variants and Human Obesity.

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: 27288825 Free PMC Article

Heterozygous mutations causing partial prohormone convertase 1 deficiency contribute to human obesity.

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: 22210313 Free PMC Article

See all (18)

Diagnosis

Relating Lipoprotein(a) Concentrations to Cardiovascular Event Risk After Acute Coronary Syndrome: A Comparison of 3 Tests.

Prader-Willi Syndrome and PCSK1 mutation: a novel presentation of combined syndromic and monogenic obesity.

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

A New Case of PCSK1 Pathogenic Variant With Congenital Proprotein Convertase 1/3 Deficiency and Literature Review.

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

Melanocortin 4 Receptor Pathway Dysfunction in Obesity: Patient Stratification Aimed at MC4R Agonist Treatment.

PCSK1 Variants and Human Obesity.

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: 27288825 Free PMC Article

See all (10)

Therapy

Relating Lipoprotein(a) Concentrations to Cardiovascular Event Risk After Acute Coronary Syndrome: A Comparison of 3 Tests.

Rap1 in the Context of PCSK9, Atherosclerosis, and Diabetes.

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

Monogenic human obesity.

Farooqi IS
Front Horm Res 2008;36:1-11. doi: 10.1159/000115333. PMID: 18230891

Genetic and hereditary aspects of childhood obesity.

Farooqi IS
Best Pract Res Clin Endocrinol Metab 2005 Sep;19(3):359-74. doi: 10.1016/j.beem.2005.04.004. PMID: 16150380

Monogenic human obesity syndromes.

Farooqi IS, O'Rahilly S
Recent Prog Horm Res 2004;59:409-24. doi: 10.1210/rp.59.1.409. PMID: 14749512

See all (9)

Prognosis

Relating Lipoprotein(a) Concentrations to Cardiovascular Event Risk After Acute Coronary Syndrome: A Comparison of 3 Tests.

Rare Heterozygous PCSK1 Variants in Human Obesity: The Contribution of the p.Y181H Variant and a Literature Review.

Deficient serum furin predicts risk of abdominal obesity: findings from a prospective cohort of Chinese adults.

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

Melanocortin 4 Receptor Pathway Dysfunction in Obesity: Patient Stratification Aimed at MC4R Agonist Treatment.

From diarrhea to obesity in prohormone convertase 1/3 deficiency: age-dependent clinical, pathologic, and enteroendocrine characteristics.

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: 24135795 Free PMC Article

See all (10)

Clinical prediction guides

Relating Lipoprotein(a) Concentrations to Cardiovascular Event Risk After Acute Coronary Syndrome: A Comparison of 3 Tests.

Prohormone convertase 1/3 deficiency causes obesity due to impaired proinsulin processing.

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: 35963866 Free PMC Article

Obesity, POMC, and POMC-processing Enzymes: Surprising Results From Animal Models.

Lindberg I, Fricker LD
Endocrinology 2021 Dec 1;162(12) doi: 10.1210/endocr/bqab155. PMID: 34333593 Free PMC Article

PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders.

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

Monogenic human obesity syndromes.

Farooqi IS, O'Rahilly S
Recent Prog Horm Res 2004;59:409-24. doi: 10.1210/rp.59.1.409. PMID: 14749512

See all (18)