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

Author:

Demirbilek Huseyin12ORCID,Cayir Atilla3,Flanagan Sarah E4,Yıldırım Ruken2,Kor Yılmaz5,Gurbuz Fatih6,Haliloğlu Belma27,Yıldız Melek89,Baran Rıza Taner2,Akbas Emine Demet5,Demiral Meliha10,Ünal Edip10,Arslan Gulcin11,Vuralli Dogus1,Buyukyilmaz Gonul12,Al-Khawaga Sara13,Saeed Amira14,Al Maadheed Maryam14,Khalifa Amel13,Onal Hasan6,Yuksel Bilgin6,Ozbek Mehmet Nuri210,Bereket Abdullah15,Hattersley Andrew T4,Hussain Khalid14,De Franco Elisa4

Affiliation:

1. Hacettepe University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey

2. Diyarbakır Children’s Hospital, Clinics of Pediatric Endocrinology, Diyarbakir, Turkey

3. Erzurum Training and Research Hospital, Clinics of Pediatric Endocrinology, Erzurum, Turkey

4. Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK

5. Adana Training and Research Hospital, Clinics of Pediatric Endocrinology, Adana, Turkey

6. Cukurova University Faculty of Medicine, Department of Pediatric Endocrinology, Adana, Turkey

7. Yeditepe University School of Medicine, Department of Pediatric Endocrinology, Istanbul, Turkey

8. Kanuni Sultan Suleyman Training and Research Hospital, Clinics of Pediatric Endocrinology, Istanbul, Turkey

9. Istanbul University, Istanbul Faculty of Medicine, Department of Pediatric Endocrinology, Istanbul, Turkey

10. Gazi Yasargil Training and Research Hospital, Pediatric Endocrinology, Diyarbakır, Turkey

11. University of Health Science, Behcet Uz Training and Research Hospital, Department of Pediatric Endocrinology, Izmir, Turkey

12. Ankara City Hospital, Department of Pediatric Endocrinology, Ankara, Turkey

13. College of Health & Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar

14. Department of Pediatrics, Division of Endocrinology, Sidra Medicine, Doha, Qatar

15. Maramara University Faculty of Medicine, Department of Pediatric Endocrinology, Istanbul, Turkey

Abstract

Abstract Context 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. Objective To evaluate phenotype and genotype characteristics and long-term follow-up of patients with PTF1A enhancer mutations. Setting Twelve tertiary pediatric endocrine referral centers. Patients 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. Results 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. Conclusion 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.

Funder

Wellcome Trust Senior Investigator

Diabetes UK RD Lawrence Fellow

Wellcome Trust

Royal Society

Publisher

The Endocrine Society

Subject

Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

Reference31 articles.

1. Reduction of Ptf1a gene dosage causes pancreatic hypoplasia and diabetes in mice;Fukuda;Diabetes.,2008

2. Transcription factor Ptf1a in development, diseases and reprogramming;Jin;Cell Mol Life Sci.,2019

3. A Turkish newborn infant with cerebellar agenesis/neonatal diabetes mellitus and PTF1A mutation;Tutak;Genet Couns.,2009

4. Mutations in PTF1A cause pancreatic and cerebellar agenesis;Sellick;Nat Genet.,2004

5. A novel PTF1A mutation in a patient with severe pancreatic and cerebellar involvement;Al-Shammari;Clin Genet.,2011

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