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

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 characterised Objective To evaluate phenotype and genotype characteristics and long-term follow-up of patients with PTF1A enhancer mutations Setting Twelve tertiary paediatric endocrine referral centres Patients 30 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 haemoglobin) characteristics, pancreas imaging, 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), anaemia (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

Neonatal Diabetes Due to a Mutation in the Distal PTF1A Enhancer: A Case Report and Literature Review

“…Also, previous functional analyses showed that a homozygous mutation could distrust enhancer activity and is likely to decrease in PTF1A expression during pancreatic development. This result confirms a diagnosis of neonatal diabetes and exocrine pancreatic insufficiency due to a recessive PTF1A mutation (11,12). Therefore, we evaluated sequencing the coding regions of ABCC8, KCNJ11, INS, and EIF2AK3 genes and also the PTF1A gene in our study.…”

Neonatal diabetes caused by disrupted pancreatic and β‐cell development

“…None of the patients had severe neurological features; however, additional features such as growth retardation, anaemia and cholestasis were common. 25 Isolated pancreatic agenesis has also been reported in two families who were homozygous for the PTF1A missense mutation, p.(Pro191Thr). In vitro studies suggested that this mutation is likely to result in partial loss of function, thus potentially explaining the absence of the severe neurological features caused by coding loss of function mutations.…”

Molecular mechanisms of β-cell dysfunction and death in monogenic forms of diabetes

“…Homozygous missense (hypomorphic) mutations in the same gene cause neonatal diabetes mellitus, associated with pancreatic aplasia/hypoplasia but without neurological manifestations (Houghton et al, 2016). In addition, biallelic mutations in PTF1A enhancer regions have been associated with pancreas agenesis without extra pancreatic or neurological manifestations (Weedon et al, 2014, Demirbilek et al, 2020. Indeed, an initial study showed that recessive mutations in a 400 bp distal PTF1A enhancer located 25 kb downstream PTF1A were causal of isolated pancreas agenesis in ten independent families (Weedon et al, 2014).…”

“…A recent genetic and phenotypic follow-up study performed in a very large cohort of patients with PTF1A enhancer mutations (30 cases) identified one additional recessive mutation associated with isolated pancreatic agenesis, and provided a very detailed analysis of the clinical characteristics of the patients identifying recurrent extrapancreatic features that accompany the pancreatic manifestations e.g. hyperferritinemia, anemia, transient mild to severe elevation in liver trans-aminases between others (Demirbilek et al, 2020).…”