Clinical manifestations of Johanson-Blizzard syndrome in a patient with nucleotide variants in the UBR1 gene

  • Danijela Jojkić-Pavkov University of Novi Sad, Faculty of Medicine, Novi Sad, Serbia; Institute for Child and Youth Health Care of Vojvodina, Department of Gastroenterology, Hepatology, and Nutrition, Novi Sad, Serbia
  • Jela Tošić University of Novi Sad, Faculty of Medicine, Novi Sad, Serbia; Institute for Child and Youth Health Care of Vojvodina, Department of Gastroenterology, Hepatology, and Nutrition, Novi Sad, Serbia
  • Ivana Kavečan University of Novi Sad, Faculty of Medicine, Novi Sad, Serbia; Institute for Child and Youth Health Care of Vojvodina, Department of Gastroenterology, Hepatology, and Nutrition, Novi Sad, Serbia
  • Milica Plazačić Institute for Child and Youth Health Care of Vojvodina, Department of Gastroenterology, Hepatology, and Nutrition, Novi Sad, Serbia
Keywords: exocrine pancreatic insufficiency;, genes;, hypothyroidism;, johanson-blizzard syndrome;, mutation;, ubr1 protein, human

Abstract


Introduction. Johanson-Blizzard syndrome (JBS) is a very rare genetic disorder caused by a mutation of the ubiquitin protein ligase E3 component N-recognin 1 (UBR1) gene. Clinical diagnosis is based on the pathognomonic combination of congenital exocrine pancreatic insufficiency and characteristic signs of facial dysmorphology (nasal wing hypoplasia/aplasia and oligodontia of permanent teeth). Diagnosis is confirmed by genetic screening of the UBR1 gene. The aim of this case report was to emphasize that nucleotide variants in the UBR1 gene, described as benign or unclassified, should still be considered a genetic cause of the clinical characteristics in patients with JBS. Case report. We present an 8-month-old child, with clinical features of JBS, who was admitted to our hospital due to poor weight gain and loose stools. Upon admission, signs of protein-energy malnutrition, facial dysmorphology, and other anomalies were observed. The child had hypotonia and convergent strabismus. A laboratory examination confirmed exocrine pancreatic insufficiency and hypothyroidism. Genetic testing confirmed two single nucleotide variants in the UBR1 gene – chromosome 15q15.2: NM_174916.3:c.4700+12A>G (intron 42) and NM_174916.3 UBR1:c.862-18C>T (intron 07). A pancreatic enzyme replacement therapy with liposoluble vitamin supplementation and adequate nutrition was conducted. Conclusion. Recognizing the clinical features of JBS and confirming it with genetic analysis is essential, especially in patients with idiopathic pancreatic insufficiency. Even when genetic confirmation is not possible, adequate treatment is necessary for normal growth and development of the child.

Author Biography

Ivana Kavečan, University of Novi Sad, Faculty of Medicine, Novi Sad, Serbia; Institute for Child and Youth Health Care of Vojvodina, Department of Gastroenterology, Hepatology, and Nutrition, Novi Sad, Serbia
 

 

References

Orphanet. Johanson-Blizzard syndrome [Internet]. Available from: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=2315 [ac-cessed on: 2023 October 19]

Sukalo M, Fiedler A, Guzmán C, Spranger S, Addor MC, McHeik JN, et al. Mutations in the human UBR1 gene and the associ-ated phenotypic spectrum. Hum Mutat 2014; 35(5): 521‒31.

Almashraki N, Abdulnabee MZ, Sukalo M, Alrajoudi A, Shara-fadeen I, Zenker M. Johanson-Blizzard syndrome. World J Gas-troenterol 2011; 17(37): 4247‒50.

Atik T, Karakoyun M, Sukalo M, Zenker M, Ozkinay F, Aydoğdu S. Two novel UBR1 gene mutations ın a patient with Johan-son Blizzard Syndrome: A mild phenotype without mental re-tardation. Gene 2015; 570(1): 153‒5.

Alkhouri N, Kaplan B, Kay M, Shealy A, Crowe C, Bauhuber S, et al. Johanson-Blizzard syndrome with mild phenotypic features confirmed by UBR1 gene testing. World J Gastroenterol 2008; 14(44): 6863‒6.

Rezaei N, Sabbaghian M, Liu Z, Zenker M. Eponym: Johanson-Blizzard syndrome. Eur J Pediatr 2011; 170(2): 179‒83.

Demir D, Kendir Demirkol Y, Gerenli N, Aktaş Karabay E. Johanson-Blizzard's Syndrome with a Novel UBR1 Mutation. J Pediatr Genet 2020; 11(2): 147‒50.

Liu S, Wang Z, Jiang J, Luo X, Hong Q, Zhang Y, et al. Severe forms of Johanson-Blizzard syndrome caused by two novel compound heterozygous variants in UBR1: Clinical manifesta-tions, imaging findings and molecular genetics. Pancreatology 2020; 20(3): 562‒8.

Lee JK, Enns R. Review of idiopathic pancreatitis. World J Gastroenterol 2007; 13(47): 6296‒313.

Kunovský L, Dítě P, Jabandžiev P, Eid M, Poredská K, Vaculová J, et al. Causes of Exocrine Pancreatic Insufficiency Other Than Chronic Pancreatitis. J Clin Med 2021; 10(24): 5779.

Zenker M, Mayerle J, Lerch MM, Tagariello A, Zerres K, Durie PR, et al. Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome). Nat Genet 2005; 37(12): 1345‒50.

Ellery KM, Erdman SH. Johanson-Blizzard syndrome: expand-ing the phenotype of exocrine pancreatic insufficiency. JOP 2014; 15(4): 388‒90.

Sukalo M, Schäflein E, Schanze I, Everman DB, Rezaei N, Argente J, et al. Expanding the mutational spectrum in Johanson-Blizzard syndrome: identification of whole exon deletions and duplications in the UBR1 gene by multiplex ligation-dependent probe amplification analysis. Mol Genet Genomic Med 2017; 5(6): 774‒80.

Published
2023/11/02
Section
Case report