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From diarrhea to obesity in prohormone convertase 1/3 deficiency: age-dependent clinical, pathologic, and
Robert H J Bandsma1, Christiane Sokollik, Rose Chami
1Divisions of *Gastroenterology, Hepatology and Nutrition †Pathology §Endocrinology, The Hospital for Sick Children ‡Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON ∥Alberta Children's Hospital Intestinal Rehabilitation Program, Alberta Children's Hospital and University of Calgary, Calgary, AB, Canada ¶Department of Pediatrics, Mattel Children's Hospital, David Geffen School of Medicine at the University of California, Los Angeles, CA.
Insights
Prohormone convertase 1/3 (PC1/3) deficiency in children causes severe diarrhea and malabsorption, later leading to hyperphagia and weight gain. Proinsulin levels can effectively screen for this rare enteroendocrine disorder.
Area of Science:
- Endocrinology
- Gastroenterology
- Genetics
Background:
- Prohormone convertases are crucial for activating hormones.
- Congenital enteroendocrine (EE) axis defects, like PC1/3 deficiency, are rare with unknown mechanisms.
Purpose of the Study:
- To detail the clinical, pathologic, and EE features of PC1/3 deficiency in children.
- To investigate the pathophysiological mechanisms of PC1/3 deficiency.
Main Methods:
- Evaluated EE function and pathology in 4 boys with PC1/3 deficiency.
- Utilized clinical course analysis, immunohistochemistry (PC1/3, PC2, GLP-1), electron microscopy, and EE function tests (GLP-1, GLP-2, OGTT).
Main Results:
- All patients presented with congenital severe diarrhea and malabsorption, improving with age.
- Hyperphagia and excessive weight gain became prominent in older children.
- Elevated proinsulin, low GLP-2, and impaired insulin/GLP-1 secretion were observed; PC1/3 and PC2 immunostaining was reduced.
Conclusions:
- PC1/3 deficiency presents an age-dependent phenotype due to intestinal and EE dysfunction.
- Serum proinsulin levels serve as an effective screening tool for PC1/3 deficiency.
Goals:
The aim of this report is to delineate the clinical, pathologic, and enteroendocrine (EE) features of prohormone convertase 1/3 (PC1/3) deficiency in children.
Background:
Prohormone convertases play a pivotal role in the activation of biologically inactive hormones. Congenital defects in the EE axis, such as PC1/3 deficiency, have been rarely reported and their pathophysiological mechanisms are largely unknown.
Study:
EE function and pathology was evaluated in 4 males (1, 2, 7, and 10 y old) from 2 families with PC1/3 deficiency at a university children's hospital. Clinical course, pathology analysis including immunohistochemistry for PC1/3, PC2, and glucagon-like peptide 1 (GLP-1) and electron microscopy, as well as EE function tests (GLP-1, GLP-2, oral glucose tolerance test) were performed.
Results:
All (n=4) suffered from congenital severe diarrhea associated with malabsorption. The diarrhea improved during the first year of life and hyperphagia with excessive weight gain (BMI>97th percentile) became the predominant phenotype at an older age. Analysis of the enteroendocrine axis revealed high proinsulin levels (57 to 1116 pmol/L) in all patients, low serum GLP-2 levels, and impaired insulin and GLP-1 secretion after an oral glucose tolerance test at a young age, with improvement in 1 older child tested. Electron microscopy showed normal ultrastructure of enterocytes and EE cells. Immunohistochemistry revealed normal expression of chromogranin A, a marker of EE cells but markedly reduced immunostaining for PC1/3 and PC2 in all patients.
Conclusions:
PC1/3 deficiency is associated with an age dependent, variable clinical phenotype caused by severe abnormalities in intestinal and EE functions. Serum level of proinsulin can be used as an effective screening tool.
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