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
Idiopathic hypogonadotropic hypogonadism (IHH) is a rare disease caused by defects in the secretion of gonadotropin releasing hormone (GnRH) or the action of GnRH on the pituitary gonadotrophes. KISS1R is one of the genes which, when mutated, cause IHH and mutations of this gene are responsible for about 2-5% of patients with normosmic IHH (NIHH). In this report, we present three siblings with NIHH due to a compound heterozygous KISS1R mutation. Genetic studies were carried out in the 14 year old index case with IHH and three siblings, two of whom were prepubertal. Genomic DNA was extracted from peripheral leukocytes and KISS1R gene was sequenced by using standard polymerase chain reaction amplification procedures. In molecular analysis of the index case, a compound heterozygous mutation was determined in KISS1R gene c.969C>A (p.Y323X) (known pathogenic) and c.170T>C (p.L57P) (novel). Mutation c.170T>C (p.L57P) was inherited from the mother while c.969C>A (p.Y323X) was inherited from the father. The same genotype was also found in two of the three siblings. A compound heterozygous mutation of the KISS1 gene, including one novel mutation, was found to cause NIHH and also incomplete puberty in a non-consanguineous family.
Objective:
The aim of this study was to evaluate the efficiency of a buccal spray form of vitamin D compared to single oral dose (stoss therapy) and oral drops therapy in the treatment of vitamin D deficiency.
Methods:
Ninety healthy children and adolescents (3-18 years) with vitamin D deficiency [serum level of 25-hydroxyvitamin D (25(OH) D) <12 ng/mL] were randomized to receive vitamin D3 buccal spray (2000 U, n=30, group 1) for six weeks, oral drops (2000 U, n=30, group 2) for six weeks and a single oral dose (300 000 U) vitamin D3 (n=30, group 3). Serum calcium, phosphorus, alkaline phosphatase, parathyroid hormone and 25(OH)D levels of the patients were measured at baseline and after the treatment on the 42
nd
day.
Results:
All three groups had a significant increase in serum 25(OH)D concentrations (p<0.001). In group 1, baseline mean 25(OH)D was 8.0±0.41 ng/mL, which rose to 22.1 (17.8-28.2) ng/mL after treatment with a mean increase of 15.6±1.3 ng/mL. Similarly in group 2, baseline, post-treatment and mean increase in 25(OH)D concentrations were 7.9±0.45 ng/mL, 24.4 (20.6-29.6) ng/mL and 17.3±1.1 ng/mL while for group 3 these values were 7.6±0.47 ng/mL, 40.3 (29.4-58.4) ng/mL and 34.3±3.2 ng/mL, respectively.
Conclusion:
We conclude that vitamin D3 supplementation with buccal spray and oral drops is equally effective in terms of raising vitamin D concentrations in short-term treatment of vitamin D deficiency.
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