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Clinical Characteristics and Long-term Follow-up of Patients with Diabetes Due To PTF1A Enhancer Mutations

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submitted on 2024-06-04, 09:41 and posted on 2024-06-09, 11:20 authored by Huseyin Demirbilek, Atilla Cayir, Sarah E Flanagan, Ruken Yıldırım, Yılmaz Kor, Fatih Gurbuz, Belma Haliloğlu, Melek Yıldız, Rıza Taner Baran, Emine Demet Akbas, Meliha Demiral, Edip Ünal, Gulcin Arslan, Dogus Vuralli, Gonul Buyukyilmaz, Sara Al-Khawaga, Amira Saeed, Maryam Al Maadheed, Amel Khalifa, Hasan Onal, Bilgin Yuksel, Mehmet Nuri Ozbek, Abdullah Bereket, Andrew T Hattersley, Khalid Hussain, Elisa De Franco


Biallelic mutations in the PTF1A enhancer are the commonest cause of isolated pancreatic agenesis. These patients do not have severe neurological features associated with loss-of-function PTF1A mutations. Their clinical phenotype and disease progression have not been well characterized.


To evaluate phenotype and genotype characteristics and long-term follow-up of patients with PTF1A enhancer mutations.


Twelve tertiary pediatric endocrine referral centers.


Thirty patients with diabetes caused by PTF1A enhancer mutations. Median follow-up duration was 4 years.

Main Outcome Measures

Presenting and follow-up clinical (birthweight, gestational age, symptoms, auxology) and biochemical (pancreatic endocrine and exocrine functions, liver function, glycated hemoglobin) characteristics, pancreas imaging, and genetic analysis.


Five different homozygous mutations affecting conserved nucleotides in the PTF1A distal enhancer were identified. The commonest was the Chr10:g.23508437A>G mutation (n = 18). Two patients were homozygous for the novel Chr10:g.23508336A>G mutation. Birthweight was often low (median SDS = –3.4). The majority of patients presented with diabetes soon after birth (median age of diagnosis: 5 days). Only 2/30 presented after 6 months of age. All patients had exocrine pancreatic insufficiency. Five had developmental delay (4 mild) on long-term follow-up. Previously undescribed common features in our cohort were transiently elevated ferritin level (n = 12/12 tested), anemia (19/25), and cholestasis (14/24). Postnatal growth was impaired (median height SDS: –2.35, median BMI SDS: –0.52 SDS) with 20/29 (69%) cases having growth retardation.


We report the largest series of patients with diabetes caused by PTF1A enhancer mutations. Our results expand the disease phenotype, identifying recurrent extrapancreatic features which likely reflect long-term intestinal malabsorption.

Other Information

Published in: The Journal of Clinical Endocrinology & Metabolism
See article on publisher's website:


Wellcome Trust (098395/Z/12/Z), New insights from Neonatal Diabetes.

EDF is a Diabetes UK RD Lawrence Fellow (19/005971).

Wellcome Trust (105636/Z/14/Z), Applying the power of genetics to increase knowledge of underlying mechanisms of recessively inherited congenital hyperinsulinism.



  • English


Endocrine Society

Publication Year

  • 2020

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Hamad Bin Khalifa University
  • College of Health and Life Sciences - HBKU
  • Sidra Medicine