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

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.This article is available to RD&E staff via NHS OpenAthens (subject to any publisher embargo). Click on the Publisher URL, and log in with NHS OpenAthens if prompted.Genetic testing for neonatal diabetes was funded through a Wellcome Trust Senior Investigator award (grant number: 098395/Z/12/Z). EDF is a Diabetes UK RD Law rence Fellow (19/005971), and SEF has a Sir Henry Dale Fellow ship jointly funded by the Wellcome Trust and the Royal Society (105636/Z/14/Z).published version, accepted version (12 month embargo), submitted versio

Hypogonadism in Systemic Diseases

Serum testosterone is often lower than normal in patients with acute or chronic systemic diseases. The underlying mechanisms involved in the reduced testosterone secretion depend on the type of systemic disease; thus, many pathogenetic mechanisms might be involved. These mechanisms involve the hypothalamus and the pituitary (secondary hypogonadism), the testis (primary hypogonadism), or both. The resulting low-serum testosterone could be reversible or not depending on the pathogenetic mechanism. Furthermore, the relationships between hypogonadism and the systemic disease are complex since these two clinical conditions may interact with each other in a bidirectional interplay. How to interpret low-serum testosterone in systemic diseases is not easy and univocal. Biochemical hypogonadism should be differentiated into overt clinical hypogonadism and functional hypogonadism, and testosterone treatment should be offered taking into account the primary systemic disease and the possible beneficial or harmful effect on it, as well as the presence of signs and symptoms of hypogonadism. In this chapter the main systemic illnesses associated with hypogonadism will be discussed together with their underlying pathogenetic mechanisms, clinical significance, relevance, and clinical and practical implications