Background: Pancreas transcription factor-1 alpha (PTF1A), encoded by the PTF1A gene, is a beta helix loop(bHLH) protein which involved in the development of the pancreas and cerebellar neurogenesis. Although mutations of PTF1A cause permanent neonatal diabetes(PNDM), pancreas agenesis and cerebellar agenesis, PTF1A enhancer mutations reported causing PNDM and isolated pancreas agenesis. In the present study, we evaluate the phenotype-genotype characteristics and long-term follow up of 17 patients with PNDM and isolated pancreas agenesis due to PTF1A distal enhancer mutation.
Patients and Method: NDM was defined as diabetes presented within the first 6 months of life. Presenting clinical and biochemical characteristics were reviewed from the hospital files. Molecular genetic analysis was performed for all patients and parents. The latest growth, developmental milestones and metabolic characteristics were re-evaluated.
Results: Presenting and follow-up characteristics are summarized in Table 1. Majority of cases had severe IUGR and birth weight was negatively correlated with gestational age(r=0.827;P=0.000). All patients had clinical signs of exocrine pancreas insufficiency and pancreas agenesis/hypoplasia in imaging. Low faecal elastase was measured in 8 out of 9 patients. Insulin therapy and pancreas enzyme replacement were introduced to all patients. A transient, but markedly elevated ferritin level was detected in all patients who ferritin levels had been measured at the neonatal period. In the molecular genetics analysis, the most common mutation was PTF1A distal enhancer g.23508437A>G which was detected in 12 cases. PTF1A distal enhancer g.23508363A>G and g.23508365A>G in 2 cases and g.23508336G>T in a single case.
Conclusion: In this series of 17 cases with PNDM due to homozygous distal enhancer PTF1A mutations, severe IUGR, isolated pancreas agenesis/hypoplasia and exocrine pancreas insufficiency in all cases suggested a good phenotype-genotype correlation. Although was not measured in all subjects, markedly elevated ferritin level and its role in the phenotype of patients remain unknown and require to be further elucidated. Although all were replaced using pancreas enzyme, majority of cases failed to catch-up growth. This can be attributed to poor compliance, but, requires further investigations to clarify the exact mechanism.
|Age of diagnosis (day)||6.5||1-60|
|Gestational age (week)||36||28-40|
|Latest height (SDS)||-2.52||-4.17-(-0.99)|
|Curent insulin dose (U/kg/day)||0.8||0.5-1.0|
|Latest HbA1c (%)||9.9||8.0-12.1|
19 - 21 Sep 2019
European Society for Paediatric Endocrinology