PMM2-CDG is the most common congenital disorder of glycosylation (CDG) accounting for almost 65% of known CDG cases affecting N-glycosylation. Abnormalities in N-glycosylation could have a negative impact on many endocrine axes. There is very little known on the effect of impaired N-glycosylation on the hypothalamic-pituitary-adrenal axis function and whether CDG patients are at risk of secondary adrenal insufficiency and decreased adrenal cortisol production. Cortisol and ACTH concentrations were simultaneously measured between 7:44 am to 1 pm in forty-three subjects (20 female, median age 12.8 years, range 0.1 to 48.6 years) participating in an ongoing international, multi-center Natural History study for PMM2-CDG (ClinicalTrials.gov Identifier: NCT03173300). Of the 43 subjects, 11 (25.6%) had cortisol below 5 μg/dl and low to normal ACTH levels, suggestive of secondary adrenal insufficiency. Two of the 11 subjects have confirmed central adrenal insufficiency and are on hydrocortisone replacement and/or stress dosing during illness; 3 had normal and 1 had subnormal cortisol response to ACTH low-dose stimulation test but has not yet been started on therapy; the remaining 5 have upcoming stimulation testing planned. Our findings suggest that patients with PMM2-CDG may be at risk for adrenal insufficiency. Monitoring of morning cortisol and ACTH levels should be part of the standard care in patients with PMM2-CDG.

Center for Integrative Brain Research Seattle Children's Research Institute Seattle WA 98101 USA; Division of Genetic Medicine Department of Pediatrics University of Washington School of Medicine Seattle WA USA

Centro Hospitalar Universitário do Porto Porto Portugal

Child Neuropsychiatry Unit Department of Clinical and Experimental Medicine University of Catania Catania Italy

Department of Clinical Genomics Department of Laboratory Medicine and Pathology Mayo Clinic MN USA

Department of Inborn Errors of Metabolism and Paediatrics the Institute of Mother and Child Warsaw Poland

Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Dept of Pediatrics Divisions of Endocrinology and Genetics and Metabolism Dept of Experimental and Clinical Pharmacology University of Minnesota USA

Division of Human Genetics Department of Pediatrics Children's Hospital of Philadelphia USA

Glycomine Inc San Francisco CA USA; Department of Pediatrics University of Nebraska Medical Center Omaha NE USA

Metabolic Center Department of Pediatrics University Hospitals Leuven Herestraat 49 3000 Leuven Belgium

Necker Hospital APHP Reference Center for Inborn Errors of Metabolism University of Paris Paris France

Necker Hospital APHP Reference Center for Inborn Errors of Metabolism University of Paris Paris France; Inserm UMR_S1163 Institut Imagine Paris France

Pediatric Neurology Department Hospital Sant Joan de Déu Institut de Recerca Sant Joan de Déu Barcelona Spain; U 703 Centre for Biomedical Research on Rare Diseases Instituto de Salud Carlos 3 Spain

Radboud University Medical Centre Department of Internal Medicine Nijmegen the Netherlands

Zobrazit více v PubMed

Ferreira CR, Altassan R, Marques-Da-Silva D, Francisco R, Jaeken J, Morava E. Recognizable phenotypes in CDG. J Inherit Metab Dis. 41(3):541–553, 2018 PubMed PMC

Ondruskova N, Cechova A, Hansikova H, Honzik T, Jaeken J. Congenital disorders of glycosylation: Still “hot” in 2020. Biochim Biophys Acta Gen Subj 1865 (1) :129751, 2021 PubMed

Miller B and Freeze HH, New Disorders in Carbohydrate Metabolism: Congenital Disorders of Glycosylation and Their Impact on the Endocrine System, Reviews in Endocrine & Metabolic Disorders;4:103–113, 2003 PubMed

Altassan R, Peanne R, Jaeken J, et al. International clinical guidelines for the management of phosphomannomutase 2-congenital disorders of glycosylation: Diagnosis, treatment and follow up. J Inherit Metab Dis, 42(1):5–28, 2019. PubMed

Ceccato F, Scaroni C. Central adrenal insufficiency: open issues regarding diagnosis and glucocorticoid treatment. Clin Chem Lab Med. 26;57(8):1125–1135, 2019. PubMed

Hawley JM, Owen LJ, Lockhart SJ, Monaghan PJ, Armston A, Chadwick CA, Wilshaw H, Freire M, Perry L, Keevil BG. Serum Cortisol: An Up-To-Date Assessment of Routine Assay Performance. Clin Chem. ;62(9):1220–9, 2016. PubMed

Mackenzie SD, Gifford RM, Boyle LD, Crane MS, Strachan MWJ, Gibb FW. Validated criteria for the interpretation of a single measurement of serum cortisol in the investigation of suspected adrenal insufficiency. Clin Endocrinol (Oxf);91(5):608–615. doi: 10.1111/cen.14071. Epub 2019. Aug 14. PubMed DOI

Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, Husebye ES, Merke DP, Murad MH, Stratakis CA, Torpy DJ. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab;101(2):364–89, 2016. PubMed PMC

Chabre O, Goichot B, Zenaty D, Bertherat J. Group 1. Epidemiology of primary and secondary adrenal insufficiency: Prevalence and incidence, acute adrenal insufficiency, long-term morbidity and mortality. Ann Endocrinol (Paris). 78(6):490–494, 2017. PubMed

Assil IQ, Abou-Samra AB, N-glycosylation of CRF receptor type 1 is important for its ligand-specific interaction, Am J Physiol Endocrinol Metab, 281: E1015–E1021, 2001 PubMed

Roy S, et al., Role of Asparagine-Linked Glycosylation in Cell Surface Expression and Function of the Human Adrenocorticotropin Receptor (Melanocortin 2 Receptor) in 293/FRT Cells Endocrinology 151: 660–670, 2010 PubMed

Zandberg WF, et al., N-Glycosylation controls trafficking, zymogen activation and substrate processing of proprotein convertases PC1/3 and subtilisin kexin isozyme-1, Glycobiology 21, (10) :1290–1300, 2011 PubMed

Martín MG, et al., Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort. Gastroenterology;145(1):138–148 2013 PubMed PMC

Hill LA, et al. N-glycosylation influences human corticosteroid binding globulin measurements, Endocrine Connections 8, 1136–1148, 2019 PubMed PMC

Etiology of combined pituitary hormone deficiency: GNAO1 as a novel candidate gene

Zobrazit více v PubMed

ClinicalTrials.gov
NCT03173300