ESPE Abstracts (2022) 95 P2-59

ESPE2022 Poster Category 2 Diabetes and Insulin (43 abstracts)

First case of Diabetes Mellitus Caused by compound heterozygous changes in the WFS1 and PTF1A Genes from Kazakhstan

Dariga Aralbayeva 1 , Kassiyet Bolatbek 1 , Aigerim Berikkan 1 , Svetlana Ten 2 , Amrit Bhangoo 3 & Akmaral Nurbekova 1

1Kazakh National Medical University, Almaty, Kazakhstan; 2Richmond University Medical Center, Staten Island, USA; 3Children's Hospital of Orange County, Orange, CA, USA

Background: We report the first case of Wolfram syndrome with heterozygous polymorphisms of WFS1 and PTF1A genes.

Case description: 16 years-old girl presented with diabetes mellitus at 12 years of age with HbA1c of 8.4 %. The IA-2, Islet cell, Insulin antibodies (Ab) were negative. GAD Ab were positive 26 U/ml (nl< 4). C-peptide level was normal 1.33 ng/ml (1.1-4.4 ng/ml) even after 4 years of diagnosis. She was initially treated with Metformin 500 mg twice a day and HbA1c increased to 12.1 %. Metformin was increased to 850 mg twice a day and Glibenclamid 3.5 mg once a day was added and HbA1c improved to 6.7%. Right side sensorineural hearing loss was diagnosed at 14 yrs. She has mild ataxia diagnosed at 16 yrs. and learning disability diagnosed at 12 yrs. MRI the brain and pancreas were normal. MGF and PGM had diagnosis of diabetes type 2.

Results: DNA analysis revealed a heterozygous polymorphism c.47C>T or p.Pro16Leu (rs34653805) in exon 2 of WFS1 gene. This sequence change replaces proline with leucine at codon 16 of the WFS1 protein. Another heterozygous polymorphism c.172C>T or p.His58Tyr (rs759962056) was identified in the PTF1A gene. The PTF1A gene is associated with pancreatic and cerebellar agenesis. This sequence change replaces histidine with tyrosine at codon 58 of the PTF1A protein. In our case it is of uncertain significance. No evidence of cerebellar or pancreatic hypoplasia.

Discussion: It is remarkable that heterozygous polymorphism in WFS1 presented with sensorineural hearing loss, learning disability, mild ataxia and progressing diabetes not yet requiring insulin. Rare heterozygous variants in WFS1 were described before in cases of hearing impairment, diabetes, impaired vision. C-peptide level was normal after 4 yrs. of diabetes, despite positive Gad Ab. Positive GAD Ab are uncommon in Wolfram syndrome but described in rare cases.

Conclusion: The genetic investigation of diabetes in case of negative islet cell AB, normal C-peptide results in a personalized treatment. In our case identification of heterozygous polymorphism in WFS1 helped in clincial investigation of hearing, neurological evaluation and understanding of diabetes.


1. Morikawa S et al. A novel heterozygous mutation of the WFS1 gene leading to constitutive endoplasmic reticulum stress is the cause of Wolfram syndrome. Pediatr Diabetes. 2017, 18:934-941.

2. A novel mutation of WFS1 gene in Japanese man of Wolfram syndrome with positive diabetes-related antibodies. Chikara Shimizu et al. Diabetes research and clinical practice. 2005,73, p215-217.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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