RFX6 haploinsufficiency predisposes to diabetes through impaired beta cell function.

AIMS/HYPOTHESIS: Regulatory factor X 6 (RFX6) is crucial for pancreatic endocrine development and differentiation. The RFX6 variant p.His293LeufsTer7 is significantly enriched in the Finnish population, with almost 1:250 individuals as a carrier. Importantly, the FinnGen study indicates a high predisposition for heterozygous carriers to develop type 2 and gestational diabetes. However, the precise mechanism of this predisposition remains unknown. METHODS: To understand the role of this variant in beta cell development and function, we used CRISPR technology to generate allelic series of pluripotent stem cells. We created two isogenic stem cell models: a human embryonic stem cell model; and a patient-derived stem cell model. Both were differentiated into pancreatic islet lineages (stem-cell-derived islets, SC-islets), followed by implantation in immunocompromised NOD-SCID-Gamma mice. RESULTS: Stem cell models of the homozygous variant RFX6-/- predictably failed to generate insulin-secreting pancreatic beta cells, mirroring the phenotype observed in Mitchell-Riley syndrome. Notably, at the pancreatic endocrine stage, there was an upregulation of precursor markers NEUROG3 and SOX9, accompanied by increased apoptosis. Intriguingly, heterozygous RFX6+/- SC-islets exhibited RFX6 haploinsufficiency (54.2% reduction in protein expression), associated with reduced beta cell maturation markers, altered calcium signalling and impaired insulin secretion (62% and 54% reduction in basal and high glucose conditions, respectively). However, RFX6 haploinsufficiency did not have an impact on beta cell number or insulin content. The reduced insulin secretion persisted after in vivo implantation in mice, aligning with the increased risk of variant carriers to develop diabetes. CONCLUSIONS/INTERPRETATION: Our allelic series isogenic SC-islet models represent a powerful tool to elucidate specific aetiologies of diabetes in humans, enabling the sensitive detection of aberrations in both beta cell development and function. We highlight the critical role of RFX6 in augmenting and maintaining the pancreatic progenitor pool, with an endocrine roadblock and increased cell death upon its loss. We demonstrate that RFX6 haploinsufficiency does not affect beta cell number or insulin content but does impair function, predisposing heterozygous carriers of loss-of-function variants to diabetes. DATA AVAILABILITY: Ultra-deep bulk RNA-seq data for pancreatic differentiation stages 3, 5 and 7 of H1 RFX6 genotypes are deposited in the Gene Expression Omnibus database with accession code GSE234289. Original western blot images are deposited at Mendeley ( https://data.mendeley.com/datasets/g75drr3mgw/2 ).

Prenatal, newborn and childhood factors and the timing of puberty in boys and girls.

BACKGROUND: Our aim was to determine if prenatal factors, gestational age, birth weight and length, and childhood body mass index (BMI) are associated with the timing of puberty. METHODS: Our population-based study comprised 4826 girls and 5112 boys born between 1997 and 2002. Multiple linear regression modeled the relationships between the maternal and child predictors and the age at peak height velocity (PHV). RESULTS: Maternal smoking throughout pregnancy was associated with earlier age at PHV (-1.8 months in girls, 95%CI = -3.2 to -0.3, p = 0.015 and -1.7 months in boys, 95%CI = -3.1 to -0.3, p = 0.016). Older gestational age predicted later age at PHV in boys. One SDS increase in birth weight led to 1.7 months later age at PHV in girls (95%CI = 1.2 to 2.2, p < 0.001) and 0.8 months in boys (95%CI = 0.2 to 1.3, p = 0.005). At the age of 9 years, each increment of BMI by 1 kg/m2 was associated with 1.7 months (95%CI = -1.9 to -1.6, p < 0.001) and 1.3 months (95%CI = -1.4 to -1.1, p < 0.001) earlier age at PHV in girls and boys, respectively. CONCLUSIONS: Fetal exposure to smoking can potentially exert enduring effects on pubertal timing. Birth weight and childhood nutritional status are significant determinants of pubertal timing in both sexes. IMPACT: Maternal smoking was associated with earlier timing of puberty and greater birth weight with later timing of puberty in both girls and boys. Most previous studies have focused on girls and used surveys to assess pubertal development, but we studied both sexes and used the same objective measure (age at peak height velocity) for the timing of puberty. Our study increases knowledge especially regarding factors associated with the timing of puberty among boys.

During an 18-month course of automated insulin delivery treatment, children aged 2 to 6 years achieve and maintain a higher time in tight range.

AIMS: To investigate whether the positive effects on glycaemic outcomes of 3-month automated insulin delivery (AID) achieved in 2- to 6-year-old children endure over an extended duration and how AID treatment affects time in tight range (TITR), defined as 3.9-7.8 mmol/L. RESEARCH DESIGN AND METHODS: We analysed 18 months of follow-up data from a non-randomized, prospective, single-arm clinical trial (n = 35) conducted between 2021 and 2023. The main outcome measures were changes in time in range (TIR), glycated haemoglobin (HbA1c), time above range (TAR), TITR, and mean sensor glucose (SG) value during follow-up visits (at 0, 6, 12 and 18 months). The MiniMed 780G AID system in SmartGuard Mode was used for 18 months. Parental diabetes distress was evaluated at 3 and 18 months with the validated Problem Areas in Diabetes-Parent, revised (PAID-PR) survey. RESULTS: Between 0 and 6 months, TIR and TITR increased, and HbA1c, mean SG value and TAR decreased significantly (p < 0.001); the favourable effect persisted through 18 months of follow-up. Between 3 and 18 months, PAID-PR score declined significantly (0 months: mean score 37.5; 3 months: mean score 28.6 [p = 0.06]; 18 months: mean score 24.6 [p < 0.001]). CONCLUSIONS: Treatment with AID significantly increased TITR and TIR in young children. The positive effect of AID on glycaemic control observed after 6 months persisted throughout the 18 months of follow-up. Similarly, parental diabetes distress remained reduced during 18 months follow-up. These findings are reassuring and suggest that AID treatment improves glycaemic control and reduces parental diabetes distress in young children over an extended 18-month follow-up.

Health-related quality of life and self-reported health status in adolescents with chronic health conditions before transfer of care to adult health care: an international cohort study.

BACKGROUND: Heath-related quality of life (HRQoL) is lower in adolescents with chronic health conditions compared to healthy peers. While there is evidence of some differences according to the underlying condition and gender, differences by measure and country are poorly understood. In this study we focus on the differences in HRQoL in adolescents with various chronic medical conditions in the year before transfer of care to adult health services. We also study the associations of two different HRQoL measurements to each other and to self-reported health. METHODS: We recruited 538 adolescents from New Children`s Hospital, Helsinki, Finland, and the Royal Children`s Hospital, Melbourne, Australia in 2017-2020. We used two validated HRQoL measurement instruments, Pediatric Quality of Life Inventory (PedsQL) and 16D, and a visual analog scale (VAS) for self-reported health status. RESULTS: In total, 512 adolescents (50.4% female, mean age 17.8 [SD 1.2] years), completed the survey measures. Higher HRQoL was reported in males than females in both countries (PedsQL 79.4 vs. 74.1; 16D 0.888 vs. 0.846), and in adolescents from Finland than Australia (80.6 vs. 72.2 and 0.905 vs. 0.825, p < 0.001 for all). Adolescents with diabetes, rheumatological, nephrological conditions and/or organ transplants had higher HRQoL than adolescents with neurological conditions or other disease syndromes (p < 0.001). PedsQL and 16D scores showed a strong correlation to each other (Spearman correlation coefficient r = 0.81). Using the 7-point VAS (1-7), 52% (248 of 479) considered their health status to be good (6-7) and 10% (48 of 479) rated it poor (1-2). Better self-reported health was associated with higher HRQoL. CONCLUSIONS: The HRQoL of transition aged adolescents varies between genders, diagnostic groups, and countries of residence. The association between self-reported health and HRQoL suggests that brief assessment using the VAS could identify adolescents who may benefit from in-depth HRQoL evaluation. TRIAL REGISTRATION: Trial registration name The Bridge and registration number NCT04631965 ( https://clinicaltrials.gov/ct2/show/NCT04631965 ).

Central precocious puberty in boys: secular trend and clinical features.

OBJECTIVE: Recent studies suggest that boys enter puberty at a younger age, and the incidence of male central precocious puberty (CPP) is increasing. In this study, we explore the incidence of male CPP and identify key clinical and auxological indicators for organic CPP (OCPP). DESIGN: A retrospective registry-based study. METHODS: The medical records of 43 boys treated with CPP at the Helsinki University Hospital between 1985 and 2014 were reviewed. Clinical, auxological, and endocrine data of the CPP patients were included in the analyses. RESULTS: Based on brain MRI, 26% of patients had OCPP. Between 2010 and 2014, the CPP incidence in boys was 0.34 per 10 000 (95% CI 0.20-0.60). Between 1990 and 2014, the male CPP incidence increased (incidence rate ratio [IRR] 1.10, P = .001). This increase was driven by rising idiopathic CPP (ICPP) incidence (IRR 1.11, 95% CI 1.05-1.19, P < .001), while OCPP incidence remained stable (P = .41). Compared with the patients with ICPP, the patients with OCPP were younger (P = .006), were shorter (P = .003), and had higher basal serum testosterone levels (P = .038). Combining 2 to 4 of these readily available clinical cues resulted in good to excellent (all, area under the curve 0.84-0.97, P < .001) overall performance, differentiating organic etiology from idiopathic. CONCLUSIONS: The estimated incidence of CPP in boys was 0.34 per 10 000, with 26% of cases associated with intracranial pathology. The increase in CPP incidence was driven by rising ICPP rates. Patients with OCPP were characterized by shorter stature, younger age, and higher basal testosterone levels, providing valuable cues for differentiation in addition to brain MRI. Utilizing multiple cues could guide diagnostic decision-making.

Mechanisms of thyrotropin receptor-mediated phenotype variability deciphered by gene mutations and M453T-knockin model.

The clinical spectrum of thyrotropin receptor-mediated (TSHR-mediated) diseases varies from loss-of-function mutations causing congenital hypothyroidism to constitutively active mutations (CAMs) leading to nonautoimmune hyperthyroidism (NAH). Variation at the TSHR locus has also been associated with altered lipid and bone metabolism and autoimmune thyroid diseases. However, the extrathyroidal roles of TSHR and the mechanisms underlying phenotypic variability among TSHR-mediated diseases remain unclear. Here we identified and characterized TSHR variants and factors involved in phenotypic variability in different patient cohorts, the FinnGen database, and a mouse model. TSHR CAMs were found in all 16 patients with NAH, with 1 CAM in an unexpected location in the extracellular leucine-rich repeat domain (p.S237N) and another in the transmembrane domain (p.I640V) in 2 families with distinct hyperthyroid phenotypes. In addition, screening of the FinnGen database revealed rare functional variants as well as distinct common noncoding TSHR SNPs significantly associated with thyroid phenotypes, but there was no other significant association between TSHR variants and more than 2,000 nonthyroid disease endpoints. Finally, our TSHR M453T-knockin model revealed that the phenotype was dependent on the mutation's signaling properties and was ameliorated by increased iodine intake. In summary, our data show that TSHR-mediated disease risk can be modified by variants at the TSHR locus both inside and outside the coding region as well as by altered TSHR-signaling and dietary iodine, supporting the need for personalized treatment strategies.

Congenital hypogonadotropic hypogonadism in a patient with a de novo POGZ mutation.

OBJECTIVE: Congenital hypogonadotropic hypogonadism (CHH) is a rare, genetically heterogeneous reproductive disorder caused by gonadotropin-releasing hormone (GnRH) deficiency. Approximately half of CHH patients also have decreased or absent sense of smell, that is, Kallmann syndrome (KS). We describe a patient with White-Sutton syndrome (developmental delay and autism spectrum disorder) and KS due to a heterozygous de novo mutation in POGZ (c.2857C>T, p.(Gln953*)), a gene encoding pogo transposable element derived with zinc finger domain, which acts as a transcriptomic regulator of neuronal networks. DESIGN AND METHODS: We modeled the role of POGZ in CHH by generating 2 clonal human pluripotent stem cell lines with CRISPR/Cas9, carrying either the heterozygous patient mutation (H11 line) or a homozygous mutation (c.2803-2906del; p.E935Kfs*7 encoding a truncated POGZ protein; F6del line). RESULTS: During the differentiation to GnRH neurons, neural progenitors derived from F6del line displayed severe proliferation defect, delayed wound-healing capacity, downregulation of intermediate progenitor neuron genes TBR1 and TBR2, and immature neuron markers PAX6 and TUBB3 and gave rise to fewer neurons with shorter neurites and less neurite branch points compared to the WT and H11 lines (P < .005). Both lines, however, could be successfully differentiated to GnRH neurons. CONCLUSIONS: In conclusion, this is the first report on the overlap between White-Sutton syndrome and CHH. POGZ mutations do not hinder GnRH neuron formation but may cause CHH/KS by affecting the size and motility of the anterior neural progenitor pool and neurite outgrowth.

Residual insulin secretion in individuals with type 1 diabetes in Finland: longitudinal and cross-sectional analyses.

BACKGROUND: Contrary to the presumption that type 1 diabetes leads to an absolute insulin deficiency, many individuals with type 1 diabetes have circulating C-peptide years after the diagnosis. We studied factors affecting random serum C-peptide concentration in individuals with type 1 diabetes and the association with diabetic complications. METHODS: Our longitudinal analysis included individuals newly diagnosed with type 1 diabetes from Helsinki University Hospital (Helsinki, Finland) with repeated random serum C-peptide and concomitant glucose measurements from within 3 months of diagnosis and at least once later. The long-term cross-sectional analysis included data from participants from 57 centres in Finland who had type 1 diabetes diagnosed after 5 years of age, initiation of insulin treatment within 1 year from diagnosis, and a C-peptide concentration of less than 1·0 nmol/L (FinnDiane study) and patients with type 1 diabetes from the DIREVA study. We tested the association of random serum C-peptide concentrations and polygenic risk scores with one-way ANOVA, and association of random serum C-peptide concentrations, polygenic risk scores, and clinical factors with logistic regression. FINDINGS: The longitudinal analysis included 847 participants younger than 16 years and 110 aged 16 years or older. In the longitudinal analysis, age at diagnosis strongly correlated with the decline in C-peptide secretion. The cross-sectional analysis included 3984 participants from FinnDiane and 645 from DIREVA. In the cross-sectional analysis, at a median duration of 21·6 years (IQR 12·5-31·2), 776 (19·4%) of 3984 FinnDiane participants had residual random serum C-peptide secretion (>0·02 nmol/L), which was associated with lower type 1 diabetes polygenic risk compared with participants without random serum C-peptide (p<0·0001). Random serum C-peptide was inversely associated with hypertension, HbA1c, and cholesterol, but also independently with microvascular complications (adjusted OR 0·61 [95% CI 0·38-0·96], p=0·033, for nephropathy; 0·55 [0·34-0·89], p=0·014, for retinopathy). INTERPRETATION: Although children with multiple autoantibodies and HLA risk genotypes progressed to absolute insulin deficiency rapidly, many adolescents and adults had residual random serum C-peptide decades after the diagnosis. Polygenic risk of type 1 and type 2 diabetes affected residual random serum C-peptide. Even low residual random serum C-peptide concentrations seemed to be associated with a beneficial complications profile. FUNDING: Folkhälsan Research Foundation; Academy of Finland; University of Helsinki and Helsinki University Hospital; Medical Society of Finland; the Sigrid Juselius Foundation; the "Liv and Hälsa" Society; Novo Nordisk Foundation; and State Research Funding via the Helsinki University Hospital, the Vasa Hospital District, Turku University Hospital, Vasa Central Hospital, Jakobstadsnejdens Heart Foundation, and the Medical Foundation of Vaasa.

Pancreatic imaging in MEN1-comparison of conventional and somatostatin receptor positron emission tomography/computed tomography imaging in real-life setting.

OBJECTIVE: Pancreatic neuroendocrine tumors (panNETs) are the leading cause of death in patients with multiple endocrine neoplasia type 1 (MEN1). The role of somatostatin receptor positron emission tomography/computed tomography (SSTR PET/CT) in MEN1 has not been established. The aim was to assess pancreatic imaging in MEN1 in a real-life setting. DESIGN: Fifty-eight patients with MEN1 [median age 40 (range 16-72) years] underwent SSTR PET/CT imaging; either as a screening tool regardless of disease stage (n = 47) or to further characterize known panNETs (n = 11). SSTR PET/CT and matched conventional imaging were blindly analyzed. We assessed the findings and the impact of SSTR PET/CT during a median follow-up of 47 months. RESULTS: SSTR PET/CT detected three times as many panNETs as conventional imaging (P < .001). SSTR PET/CT altered the management of 27 patients (47%). Seven patients (12%) were referred for surgery, and five (9%) received systemic treatment. In 15/25 (60%) patients with no previous panNET (n = 22) or in remission after surgery (n = 3), SSTR PET/CT identified a panNET (n = 14) or recurrence (n = 1). In eight patients, SSTR PET/CT revealed a panNET not immediately visible on conventional imaging. During a median follow-up of 47 months, three became visible on conventional imaging, but none required intervention. When SSTR PET/CT was negative, no panNETs were identified on conventional imaging during 38 months of follow-up. CONCLUSIONS: SSTR PET/CT demonstrates high accuracy in the detection of panNETs and alters the clinical management in nearly half of the MEN1-patients. SSTR PET/CT enables timely diagnosis and staging of MEN1-related panNETs.

Disease control and psychiatric comorbidity among adolescents with chronic medical conditions: a single-centre retrospective study.

BACKGROUND: To investigate disease control, psychiatric comorbidity, substance use and their possible associations in adolescents with chronic medical conditions before transfer to adult healthcare. METHODS: We collected clinical data from the year preceding transfer of care and psychiatric data from the records of the paediatric hospital in Helsinki, Finland (population base 1.7 million). Participants were grouped into three disease and/or adherence control categories (good, some evidence of concern, poor) based on clinical data from the medical records of the year preceding the transfer of care. Participants completed the Adolescent's Substance Use Measurement Questionnaire before transfer of care and were divided into four risk subgroups accordingly. RESULTS: In total, 253 adolescents (mean age 17.3 years, SD 1.2) from six paediatric subspecialties participated in this study. Disease control and/or adherence were rated as good in 28% (n=70), moderate in 42% (n=105) and poor in 30% (n=76) in the year before participants transferred to adult health services. A quarter of participants had at least one psychiatric diagnosis during adolescence. Adolescents with concomitant psychiatric diagnoses more often had poor disease control of their chronic medical condition than adolescents with only a medical condition (44% vs 26%; n=25 of 59 vs 51 of 194, respectively). More than half of adolescents (56%) were abstinent or used substances infrequently; 10% (n=26) reported hazardous substance use. CONCLUSIONS: Psychiatric comorbidity in adolescents with chronic medical conditions is common. Its negative association with disease control and possible substance use should be considered in the transition process to adult health services.

MiniMed 780G™ in 2- to 6-Year-Old Children: Safety and Clinical Outcomes After the First 12 Weeks.

Objective: The safety and impact of the advanced hybrid closed-loop (AHCL) system on glycemic outcome in 2- to 6-year-old children with type 1 diabetes and the diabetes distress of caregivers were evaluated. Research Design and Methods: This was an open-label prospective study (n = 35) with historical controls matched by treatment unit, diabetes duration, age, gender, and baseline treatment modality. The inclusion criteria were (1) type 1 diabetes diagnosis >6 months, (2) total daily dose of insulin ≥8 U/day, (3) HbA1c <10% (85 mmol/mol), and (4) capability to use insulin pump and continuous glucose monitoring. The MiniMed 780G™ AHCL in SmartGuard™ Mode was used for 12 weeks. Parental diabetes distress was evaluated with a validated Problem Areas In Diabetes-Parent, revised (PAID-PR) survey. Results: No events of diabetic ketoacidosis or severe hypoglycemia occurred. Between 0 and 12 weeks, HbA1c (mean change = -2.7 mmol/mol [standard deviation 5.7], P = 0.010), mean sensor glucose value (SG) (-0.8 mmol/L [1.0], P < 0.001), and time above range (TAR) (-8.6% [9.5], P < 0.001) decreased and time in range (TIR) (8.3% [9.3], P < 0.001) increased significantly, whereas no significant change in time below range (TBR) was observed. At the same time, PAID-PR score decreased from 37.5 (18.2) to 27.5 (14.8) (P = 0.006). Conclusions: MiniMed 780G™ AHCL is a safe system and 12-week use was associated with improvements in glycemic control in 2- to 6-year-old children with type 1 diabetes. In addition, AHCL is associated with a reduction in parental diabetes distress after 12-week use. ClinicalTrials.gov registration number: NCT04949022.

Identification of monogenic variants in more than ten per cent of children without type 1 diabetes-related autoantibodies at diagnosis in the Finnish Pediatric Diabetes Register.

AIMS/HYPOTHESIS: Monogenic forms of diabetes (MODY, neonatal diabetes mellitus and syndromic forms) are rare, and affected individuals may be misclassified and treated suboptimally. The prevalence of type 1 diabetes is high in Finnish children but systematic screening for monogenic diabetes has not been conducted. We assessed the prevalence and clinical manifestations of monogenic diabetes in children initially registered with type 1 diabetes in the Finnish Pediatric Diabetes Register (FPDR) but who had no type 1 diabetes-related autoantibodies (AABs) or had only low-titre islet cell autoantibodies (ICAs) at diagnosis. METHODS: The FPDR, covering approximately 90% of newly diagnosed diabetic individuals aged ≤15 years in Finland starting from 2002, includes data on diabetes-associated HLA genotypes and AAB data (ICA, and autoantibodies against insulin, GAD, islet antigen 2 and zinc transporter 8) at diagnosis. A next generation sequencing gene panel including 42 genes was used to identify monogenic diabetes. We interpreted the variants in HNF1A by using the gene-specific standardised criteria and reported pathogenic and likely pathogenic findings only. For other genes, we also reported variants of unknown significance if an individual's phenotype suggested monogenic diabetes. RESULTS: Out of 6482 participants, we sequenced DNA for 152 (2.3%) testing negative for all AABs and 49 (0.8%) positive only for low-titre ICAs (ICAlow). A monogenic form of diabetes was revealed in 19 (12.5%) of the AAB-negative patients (14 [9.2%] had pathogenic or likely pathogenic variants) and two (4.1%) of the ICAlow group. None had ketoacidosis at diagnosis or carried HLA genotypes conferring high risk for type 1 diabetes. The affected genes were GCK, HNF1A, HNF4A, HNF1B, INS, KCNJ11, RFX6, LMNA and WFS1. A switch from insulin to oral medication was successful in four of five patients with variants in HNF1A, HNF4A or KCNJ11. CONCLUSIONS/INTERPRETATION: More than 10% of AAB-negative children with newly diagnosed diabetes had a genetic finding associated with monogenic diabetes. Because the genetic diagnosis can lead to major changes in treatment, we recommend referring all AAB-negative paediatric patients with diabetes for genetic testing. Low-titre ICAs in the absence of other AABs does not always indicate a diagnosis of type 1 diabetes.

Health-related quality of life in boys with constitutional delay of growth and puberty.

Introduction: Constitutional delay of growth and puberty (CDGP) is the most common reason for delayed puberty in healthy male adolescents. The main indication for medical treatment for this condition is psychosocial burden. However, to the best of our knowledge, no previous study has addressed the impact of puberty-promoting treatment on health-related quality of life (HRQoL) among boys with CDGP. Methods: We investigated HRQoL in 22 boys with CDGP, who participated in a randomized controlled trial in four Finnish pediatric endocrinology outpatient clinics between 2013 and 2017. The boys were randomized to receive either aromatase inhibitor letrozole (2.5mg/day; n=11) or intramuscular testosterone (1mg/kg/every 4 weeks; n=11) for 6 months and followed up to 12 months. HRQoL was assessed with a generic self-assessment 16D© instrument developed and validated for adolescents aged 12 to 15 years. The 16D includes 16 dimensions (vitality, sight, breathing, distress, hearing, sleeping, eating, discomfort and symptoms, speech, physical appearance, school and hobbies, mobility, friends, mental function, excretion and depression). The results were compared with an age-matched reference population that included 163 boys from the Finnish capital-city area. The study protocol is registered to ClinicalTrials.gov (registration number: NCT01797718). Results: At baseline, the mean 16D score of the CDGP boys was similar to the age-matched reference population (0.95 vs 0.96, p=0.838). However, the physical appearance score (satisfaction with general appearance, height and weight) was significantly lower in the CDGP boys (0.75 vs 0.92, p=0.004) than their peers. Twelve months after treatment, Appearance had improved significantly (0.75 vs 0.87, p=0.004) and no HRQoL dimension was inferior compared to the age-matched reference population. Discussion: In terms of HRQoL, the main impact of delayed puberty was dissatisfaction with physical appearance. Puberty promoting therapy was associated with a positive change in perceived appearance, with no clear difference between low-dose testosterone and letrozole treatments.

Timing of puberty and school performance: A population-based study.

Objective: To determine whether the timing of puberty associates with school performance. Methods: Growth data on 13,183 children born between 1997 and 2002, were collected from child health clinics and school healthcare and school performance data from school records. Age at peak height velocity (PHV) marked pubertal timing. The relationships between age at PHV and average grades in mathematics, native language, English, and physical education from school years 6 (end of elementary school; age 11-12 years), 7 (start of middle school; 12-13 years), and 9 (end of middle school; 14-15 years) were modeled using generalized estimating equations and linear mixed models, adjusted for the month of birth and annual income and education levels in school catchment areas. Results: The mean (SD) age at PHV was 13.54 (1.17) years in boys and 11.43 (1.18) years in girls. In girls, age at PHV was associated with grades in mathematics (ß=0.041-0.062, p<0.005) and physical education (ß=0.077-0.107, p<0.001) across the study years, and in school year 9, also with grades in English (ß=-0.047, 95%CI -0.072 to -0.021, p<0.001). Among boys, only the grades in physical education were related to age at PHV across the study years (ß=0.026-0.073, p<0.01) and in middle school the grades in mathematics decreased dramatically. Conclusions: In both sexes, the timing of puberty was associated with the grades in physical education, and in girls, with academic achievement. The decrease in boys' mathematics grades and sex difference in academic achievement were unexplained by the timing of puberty.

Presentation and diagnosis of childhood-onset combined pituitary hormone deficiency: A single center experience from over 30 years.

Background: Childhood-onset combined pituitary hormone deficiency (CPHD) has a wide spectrum of etiologies and genetic causes for congenital disease. We aimed to describe the clinical spectrum and genetic etiologies of CPHD in a single tertiary center and estimate the population-level incidence of congenital CPHD. Methods: The retrospective clinical cohort comprised 124 CPHD patients (48 with congenital CPHD) treated at the Helsinki University Hospital (HUH) Children's Hospital between 1985 and 2018. Clinical data were collected from the patient charts. Whole exome sequencing was performed in 21 patients with congenital CPHD of unknown etiology. Findings: The majority (61%;76/124) of the patients had acquired CPHD, most frequently due to craniopharyngiomas and gliomas. The estimated incidence of congenital CPHD was 1/16 000 (95%CI, 1/11 000-1/24 000). The clinical presentation of congenital CPHD in infancy included prolonged/severe neonatal hypoglycaemia, prolonged jaundice, and/or micropenis/bilateral cryptorchidism in 23 (66%) patients; despite these clinical cues, only 76% of them were referred to endocrine investigations during the first year of life. The median delay between the first violation of the growth screening rules and the initiation of GH Rx treatment among all congenital CPHD patients was 2·2 years, interquartile range 1·2-3·7 years. Seven patients harbored pathogenic variants in PROP1, SOX3, TBC1D32, OTX2, and SOX2, and one patient carried a likely pathogenic variant in SHH (c.676G>A, p.(Ala226Thr)). Interpretation: Our study suggests that congenital CPHD can occur in 1/16 000 children, and that patients frequently exhibit neonatal cues of hypopituitarism and early height growth deflection. These results need to be corroborated in future studies and might inform clinical practice. Funding: Päivikki and Sakari Sohlberg Foundation, Biomedicum Helsinki Foundation, and Emil Aaltonen Foundation research grants.

Circulating Liver-enriched Antimicrobial Peptide-2 Decreases During Male Puberty.

CONTEXT: Circulating levels of liver-enriched antimicrobial peptide 2 (LEAP2), a ghrelin receptor antagonist, decrease under caloric restriction and increase in obesity. The role of LEAP2 in male puberty, a phase with accelerated energy demand, is unclear. OBJECTIVE: This work aimed to investigate whether circulating LEAP2 levels are downregulated in boys following the onset of puberty to respond to the energy need required for growth. METHODS: We determined circulating LEAP2 levels in 28 boys with constitutional delay of growth and puberty (CDGP) who participated in a randomized controlled trial (NCT01797718), and were treated with letrozole (n = 15) or intramuscular low-dose testosterone (T) (n = 13) for 6 months. Blood sampling and dual-energy x-ray absorptiometry-measured body composition were performed at 0-, 6-, and 12-month visits. RESULTS: Serum LEAP2 levels decreased statistically significantly during pubertal progression (0-6 months: mean decrease -4.3 [10.3] ng/mL, P = .036 and 0-12 months: -3.9 [9.3] ng/mL, P = .033). Between 0 and 6 months, the changes in serum LEAP2 levels correlated positively with changes in percentage of body fat (rs = 0.48, P = .011), and negatively with growth velocity and estradiol levels (rs = -0.43, P = .022, rs = -0.55, P = .003, respectively). In the T group only, the changes in serum LEAP2 correlated negatively with changes in T and estradiol levels. Between 0 and 12 months, the change in LEAP2 levels correlated negatively with the change in high-density lipoprotein levels (rs = -0.44, P = .022) and positively with the change in insulin (rs = 0.50, P = .009) and HOMA-IR (rs = 0.51, P = .007) levels. CONCLUSION: Circulating LEAP2 levels decreased after induction of puberty reciprocally with increased growth rate and energy demand, reflecting the metabolic state of the adolescent. Further, the results suggest that estradiol levels may have a permissive role in downregulating circulating LEAP2 levels.

The effect of COVID-19 lockdown on the glycemic control of children with type 1 diabetes.

BACKGROUND: Between March 18th and May 13th 2020, the COVID-19 pandemic outbreak in Finland resulted in the closure of schools and the limitation of daycare (i.e. lockdown). Social distancing changed the daily routines of children with type 1 diabetes (T1D). Healthcare professionals were forced to adapt to the pandemic by replacing physical outpatient visits with virtual visits. However, the influence of the lockdown on glycemic control in these patients remained unknown. METHODS: In this retrospective register study from a pediatric diabetes outpatient clinic, we analyzed the glycemic data of T1D patients (n = 245; aged 4 to 16 years) before and under the lockdown. All the participants used continuous glucose monitoring (rtCGM or iCGM), two-thirds were on insulin pumps (CSII), and one-third on multiple daily insulin injections (MDI) therapy. RESULTS: In our patient cohort, time in range (TIR, n = 209) and mean glucose levels (n = 214) were similar prior to and under the lockdown (mean change 0.44% [95%CI: -1.1-2.0], p = 0.56 and -0.13 mmol/mol [95%CI: -0.3-0.1], p = 0.17, respectively). However, children treated with CSII improved their glycemic control significantly during the lockdown: TIR improved on average 2.4% [0.6-4.2] (p = 0.010) and mean blood glucose level decreased -0.3 mmol/mol [-0.6-(-0.1)] (p = 0.008). The difference was more pronounced in girls, adolescents and patients using conventional insulin pumps. CONCLUSIONS: The glycemic control in T1D children did not deteriorate under the lockdown, and patients on CSII even improved their control, which suggests that social distancing might have allowed families to use the insulin pump more accurately as out-of-home activities were on hold.

New-onset type 1 diabetes in Finnish children during the COVID-19 pandemic.

BACKGROUND: Viral infections may trigger type 1 diabetes (T1D), and recent reports suggest an increased incidence of paediatric T1D and/or diabetic ketoacidosis (DKA) during the COVID-19 pandemic. OBJECTIVE: To study whether the number of children admitted to the paediatric intensive care unit (PICU) for DKA due to new-onset T1D increased during the COVID-19 pandemic, and whether SARS-CoV-2 infection plays a role. METHODS: This retrospective cohort study comprises two datasets: (1) children admitted to PICU due to new-onset T1D and (2) children diagnosed with new-onset T1D and registered to the Finnish Pediatric Diabetes Registry in the Helsinki University Hospital from 1 April to 31 October in 2016-2020. We compared the incidence, number and characteristics of children with newly diagnosed T1D between the prepandemic and pandemic periods. RESULTS: The number of children admitted to PICU due to new-onset T1D increased from an average of 6.25 admissions in 2016-2019 to 20 admissions in 2020 (incidence rate ratio [IRR] 3.24 [95% CI 1.80 to 5.83]; p=0.0001). On average, 57.75 children were registered to the FPDR in 2016-2019, as compared with 84 in 2020 (IRR 1.45; 95% CI 1.13 to 1.86; p=0.004). 33 of the children diagnosed in 2020 were analysed for SARS-CoV-2 antibodies, and all were negative. CONCLUSIONS: More children with T1D had severe DKA at diagnosis during the pandemic. This was not a consequence of SARS-CoV-2 infection. Instead, it probably stems from delays in diagnosis following changes in parental behaviour and healthcare accessibility.

Onset and progression of puberty in Klinefelter syndrome.

OBJECTIVE: Klinefelter syndrome (KS) (47,XXY and variants, KS) is the most common sex chromosome disorder in humans. However, little is known about the onset and progression of puberty in patients with KS. In this study, we describe the onset and progression of puberty in a large series of boys with KS in a single tertiary centre. DESIGN AND PATIENTS: Retrospective data (Tanner stages, testicular length, testosterone supplementation, levels of luteinizing hormone [LH] and testosterone) before possible testosterone treatment on 72 KS patients with 47,XXY karyotype were reviewed, and G (n = 59 patients) and P (n = 56 patients) stages were plotted on puberty nomograms. MEASUREMENTS AND RESULTS: One boy had a delayed onset of puberty, as he was at the G1 stage at the age of 13.8 years (-2.2 SDs). No observations of delay were made of boys at Stage G2. The progression of G stages was within normal limits in the majority of patients; only few boys were late at G3 (4.1%; 1 out of 24) and G4 (7.4%; 2 out of 27). Testosterone supplementation was started at the average age of 15.5 years to 35 boys (47%), 2 of whom were over 18 years old. LH level was on average 18.2 IU/L (SD: 6.3 IU/L) and testosterone 9.1 nmol/L (SD: 3.1 nmol/L) when testosterone supplementation was started. CONCLUSIONS: Our results suggest that puberty starts within the normal age limits in boys with KS, and testosterone supplementation is not needed for the initial pubertal progression in the majority of patients.