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HLA-DR/DQ haplotypes largely define genetic susceptibility to type 1 diabetes (T1D). The DQB1*06:02-positive haplotype (DR15-DQ602) common in individuals of European ancestry is very rare among children with T1D. Among 4,490 children with T1D in the Finnish Pediatric Diabetes Register, 57 (1.3%) case patients with DQB1*06:02 were identified, in comparison with 26.1% of affected family-based association control participants. There were no differences between DQB1*06:02-positive and -negative children with T1D regarding sex, age, islet autoantibody distribution, or autoantibody levels, but significant differences were seen in the frequency of second class II HLA haplotypes. The most prevalent haplotype present with DQB1*06:02 was DRB1*04:04-DQA1*03-DQB1*03:02, which was found in 27 (47.4%) of 57 children, compared with only 797 (18.0%) of 4,433 among DQB1*06:02-negative case patients (P < 0.001 by χ2 test). The other common risk-associated haplotypes, DRB1*04:01-DQA1*03-DQB1*03:02 and (DR3)-DQA1*05-DQB1*02, were less prevalent in DQB1*06:02-positive versus DQB1*06:02-negative children (P < 0.001). HLA-B allele frequencies did not differ by DQB1*06:02 haplotype between children with T1D and control participants or by DRB1*04:04-DQA1*03-DQB1*03:02 haplotype between DQB1*06:02-positive and -negative children with T1D. The increased frequency of the DRB1*04:04 allele among DQB1*06:02-positive case patients may indicate a preferential ability of the DR404 molecule to present islet antigen epitopes despite competition by DQ602. Article Highlights: The common HLA-DQB1*06:02 allele is strongly protective against type 1 diabetes (T1D), although few DQB1*06:02-positive individuals have been found. We compared the distribution of the second class II haplotypes in DQB1*06:02-positive children with T1D with the distribution of haplotypes found in in other children with T1D. HLA-DRB1*04:04-DQA1*03-DQB1*03:02 was the most common second haplotype in DQB1*06:02-positive children with T1D, whereas DRB1*04:01-DQA1*03-DQB1*03:02 was most frequent in other children with T1D. This finding suggests that the islet-specific epitopes presented by DRB1*04:04 can more efficiently avoid binding to DQB1*06:02 than epitopes presented by other risk-associated haplotypes. [ABSTRACT FROM AUTHOR]

Introduction: Newborn screening of congenital hypothyroidism (CH) has enabled early treatment with levothyroxine (LT4), ensuring normal growth and development. The initial LT4 dose recommendation has increased over decades. We evaluated whether the increased LT4 dosing influenced thyroid-stimulating hormone (TSH) and thyroxine (fT4) concentrations, growth, or treatment-related symptoms. Methods: LT4 doses, TSH, fT4, anthropometrics, and treatment-related symptoms until age 2 years were evaluated in 172 Finnish CH patients born between 1980 and 2018. The patients were grouped according to birth decade: 1980s (n = 19, mean LT4 starting dose 6.8 μg/kg/day), 1990s (n = 50, 7.4 μg/kg/day), 2000s (n = 59, 9.7 μg/kg/day), and 2010s (n = 44, 10.8 μg/kg/day). Results: TSH concentrations were higher during the first 2 years of life in children born in the 1980s compared to children born later. TSH concentrations were often subnormal in children receiving higher LT4 doses (children born in the 2000s and 2010s). However, symptoms of overtreatment were uncommon. Linear or head growth showed no differences between the groups during the first 2 years of life. Although growth was within the normal spectrum, children in all groups were shorter than their target length at 2 years and their weight-for-length was above the mean through the first 2 years of life. Discussion: Current treatment practice with higher LT4 dose normalizes TSH rapidly without significant increase in side effects. However, irrespective of initial LT4 dose, children were shorter than expected at 2 years of age. Effects of different initial LT4 dose on cognitive development urges further investigation. [ABSTRACT FROM AUTHOR]

Objective: The influence of androgens and oestrogens on growth is complex, and understanding their relative roles is important for optimising the treatment of children with various disorders of growth and puberty. Design: We examined the proportional roles of androgens and oestrogens in the regulation of pubertal growth in boys with constitutional delay of growth and puberty (CDGP). The study compared 6‐month low‐dose intramuscular testosterone treatment (1 mg/kg/month; n = 14) with per oral letrozole treatment (2.5 mg/day; n = 14) which inhibits conversion of androgens to oestrogen. Patients: Boys with CDGP were recruited to a randomized, controlled, open‐label trial between 2013 and 2017 (NCT01797718). Measurements: The patients were evaluated at 0‐, 3‐ and 6‐month visits, and morning blood samples were drawn. Linear regression models were used for data analyses. Results: In the testosterone group (T‐group), serum testosterone concentration correlated with serum oestradiol concentration at the beginning of the study and at 3 months, whereas in the letrozole group (Lz‐group) these sex steroids correlated only at baseline. Association between serum testosterone level and growth velocity differed between the T and Lz groups, as each nmol/L increase in serum testosterone increased growth velocity 2.7 times more in the former group. Serum testosterone was the best predictor of growth velocity in both treatment groups. In the Lz‐group, adding serum oestradiol to the model significantly improved the growth estimate. Only the boys with serum oestradiol above 10 pmol/L had a growth velocity above 8 cm/year. Conclusions: During puberty promoting treatment with testosterone or aromatase inhibitor letrozole, growth response is tightly correlated with serum testosterone level. A threshold level of oestrogen appears to be needed for an optimal growth rate that corresponds to normal male peak height velocity of puberty. Serum testosterone 1 week after the injection and serum testosterone and oestradiol 3 months after the onset of aromatase inhibitor treatment can be used as biomarkers for treatment response in terms of growth. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Shared aetiopathogenetic factors have been proposed in type 1 diabetes and type 2 diabetes and both diseases have been shown to cluster in families. Characteristics related to type 2 diabetes have been described in patients with type 1 diabetes with a positive family history of type 2 diabetes. We wanted to characterise the family history of type 2 diabetes and its possible effects on the phenotype and genotype of type 1 diabetes in affected children at diagnosis. Methods: A total of 4993 children under the age of 15 years with newly diagnosed type 1 diabetes from the Finnish Pediatric Diabetes Register were recruited (56.6% boys, median age of 8.2 years) for a cross-sectional, observational, population-based investigation. The family history of diabetes at diagnosis was determined by a structured questionnaire, and markers of metabolic derangement, autoantibodies and HLA class II genetics at diagnosis were analysed. Results: Two per cent of the children had an immediate family member and 36% had grandparents with type 2 diabetes. Fathers and grandfathers were affected by type 2 diabetes more often than mothers and grandmothers. The children with a positive family history for type 2 diabetes were older at the diagnosis of type 1 diabetes (p < 0.001), had higher BMI-for-age (p = 0.01) and more often tested negative for all diabetes-related autoantibodies (p = 0.02). Conclusions/interpretation: Features associated with type 2 diabetes, such as higher body weight, older age at diagnosis and autoantibody negativity, are more frequently already present at the diagnosis of type 1 diabetes in children with a positive family history of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: The incidence of type 1 diabetes has been rising for decades, particularly among young children. Between 2006 and 2011, the incidence rate (IR) reached a plateau in Finland. In this observational, register-based cohort study, we assess recent trends in the disease rate in Finnish children.Research Design and Methods: Based on data from the Finnish Pediatric Diabetes Register, we studied the incidence of type 1 diabetes among children younger than 15 years of age between 2003 and 2018. We assessed sex-specific IRs per 100,000 person-years (PY) by 4-year time periods in three age-groups (0.50-4.99, 5.00-9.99, and 10.00-14.99 years).Results: Among the 7,871 children with newly diagnosed type 1 diabetes, the median age at diagnosis increased from 7.88 to 8.33 years (P = 0.001), while the overall IR decreased from 57.9/100,000 PY in 2003-2006 to 52.2/100,000 PY in 2015-2018, yielding an IR ratio (IRR) of 0.90 (95% CI 0.85-0.96, P = 0.001). This decline was mainly due to the decrease in the youngest age-group (IRR 0.77 [95% CI 0.68-0.87]; P < 0.001), being significant both among boys and girls. In the middle age-group, a significant decrease was observed only among girls. No changes were observed in the oldest children.Conclusions: The incidence of type 1 diabetes decreased among young Finnish children between 2003 and 2018. Current findings imply that environmental factors driving the immune system toward islet autoimmunity are changing in young children. [ABSTRACT FROM AUTHOR]

Aim: To examine the hypoglycaemic effect on neurodevelopmental outcome in patients with transient and persistent congenital hyperinsulinism (CHI) born in the 21st century.Method: A cohort of 117 patients (66 males, 51 females) with CHI aged 5 to 16 years (mean age 8y 11mo, SD 2y 7mo) were selected from a Finnish nationwide registry to examine all the patients with similar methods. Neurodevelopment was first evaluated retrospectively. The 83 patients with no risk factors for neurological impairment other than hypoglycaemia were recruited and 44 participated (24 males, 20 females; mean age 9y 7mo, SD 3y 1mo) in neuropsychological assessment with the Wechsler Intelligence Scale for Children, Fourth Edition and the Finnish version of the Developmental Neuropsychological Assessment, Second Edition domains of attention, language, memory, sensorimotor, and visual functioning.Results: In retrospective analysis, transient and persistent CHI groups had similar prevalences of mild (22% and 18% respectively) or severe (5% and 7% respectively) neurodevelopmental difficulties. In clinical assessment, the neurocognitive profile was within the average range in both groups, but children with persistent CHI showed significant but restricted deficits in attention, memory, visual, and sensorimotor functions compared with the general population. The transient CHI group did not differ from the standardization samples.Interpretation: Besides the more apparent broader neurological deficits, children with persistent CHI have an increased risk for milder specific neurocognitive problems, which should be considered in the follow-up.What This Paper Adds: Children with persistent congenital hyperinsulinism showed deficits in attention, memory, visual, and sensorimotor functions. The deficits were potentially of hypoglycaemic origin. Children with transient hyperinsulinism did not differ from the general population. [ABSTRACT FROM AUTHOR]