Viivästynyt murrosikä : etiologia, ennustekijät ja kasvuvaikutukset

During puberty, adolescents achieve reproductive capability and attain adult height. An intact hypothalamic-pituitary-gonadal (HPG) axis is crucial for the normal onset of puberty. Pubertal timing is influenced by genetic and environmental factors, but the exact mechanisms that trigger puberty remain elusive. A finding of a paternally-inherited loss-of-function mutation in makorin ring finger protein 3 (MKRN3) gene in patients who were diagnosed with central precocious puberty suggests that key genes regulate the central restrain on the HPG axis during childhood, and that the loosening of the restrain precedes the onset of puberty. A variety of diseases can delay puberty, but it is particularly important to early identify the patients who suffer from acquired or congenital hypogonadotropic hypogonadism (CHH) which results from the absent or impaired functions of gonadotropin-releasing hormone. This congenital sex steroid deficiency predisposes to long-term consequences, but very little is known about its role in the modulation of growth during early infancy and its impact on health-related quality of life (HRQoL) in adulthood. In the first study, circulating MKRN3 levels were measured in boys with idiopathic short stature before and after the onset of puberty. In boys, serum levels of MKRN3 declined faster before than after the clinical onset of puberty. In the second study, the diagnoses that underlie delayed puberty (DP) were investigated in a large series of patients with delayed puberty examined at the Helsinki University Central Hospital between 2004 and 2014. A multitude of different diagnoses were found to cause DP, albeit constitutional delay of growth puberty (CDGP) was the most common cause in both sexes. Annual growth velocity, a history of prior cryptorchidism, and a positive family history of DP appeared to be useful in the differential diagnosis of DP. The third study consisted of growth charts of 42 patients with CHH, and evaluated the influence of congenital sex steroid deficiency on growth from birth length to adult height. The boys with CHH experienced a length deflection during the first six months of life (i.e. minipuberty), which was likely to result from deficient testosterone surge during the same period. In the fourth study, the HRQoL was measured in men with CHH with the generic 15D questionnaire. The men with CHH experienced an impaired HRQoL, especially in the dimensions of depression and distress. The age of diagnosis correlated negatively with HRQoL scores, which emphasize the timely diagnosis of CHH. In summary, sex steroids modulate growth from early infancy to adulthood. In boys, circulating MKRN3 levels decline before the clinical onset of puberty which supports the current view that MKRN3 is a key regulator of pubertal onset. Many diseases can delay pubertal maturation, but CDGP is the most common cause in Finland. In men, the timely diagnosis of CHH is crucial to avoid the long-term adverse effects of sex steroid deficiency on HRQoL.Murrosiässä nuori siirtyy lapsuudesta aikuisuuteen saavuttaen sukukypsyyden ja aikuispituuden. Murrosiän käynnistymisen ja etenemisen edellytyksenä on normaalisti toimiva hypotalamus-aivolisäke-sukupuolirauhanen-järjestelmä. Sitä, mikä varsinaisesti käynnistää murrosiän, ei kuitenkaan tiedetä. Äskettäin julkaistu havainto, että isältä peritty MKRN3-geenin mutaatio altistaa ennenaikaiselle murrosiälle viittaa siihen, että lapsuusiän keskushermoston estovaikutus murrosiän käynnistymiseen johtuu osin puberteettia säätelevien geenien ilmentymisestä. Tällä hetkellä vain murrosiän käynnistymisen välillisiä vaikutuksia voidaan mitata verenkierrosta, muttei käytössä ole merkkiainetta, joka mittaisi suoraan keskushermoston estovaikutusta murrosiän käynnistymiseen. Monet eri sairaudet voivat viivästyttää murrosikää, mutta erityisen tärkeää olisi löytää ajoissa potilaat, joilla viivästyneen puberteetin syynä on synnynnäinen hypogonadotrooppinen hypogonadismi (HH) eli aivolisäkkeen erittämien gonadotropiinien puutteesta johtuva sukupuolirauhasten vajaatoiminta. HH:n sukupuolihormonivaje altistaa pitkäaikaisille haittavaikutuksille, mutta sen vaikutuksista imeväisiän ja lapsuuden kasvuun sekä terveyteen liittyvään elämänlaatuun aikuisena tiedetään hyvin vähän. Tämän väitöskirjan osatyössä raportoitiin ensimmäistä kertaa, että seerumin MKRN3-tasot laskevat pojilla murrosiän käynnistyessä sopien keskushermoston murrosiän estovaikutuksen määrän vähenemiseen. Lisäksi kartoitettiin viivästyneen puberteetin syyt Helsingin yliopistollisen keskussairaalan lastenendokrinologian vastaanotolla vuosien 2004 2014 aikana. Murrosiän viivästymisen taustalta löytyi 30 eri syytä. Työssä havaittiin, että tarkka selvitys aiemmasta sairaushistoriasta, kasvunopeuden arviointi ja kattava kliininen tutkiminen auttavat puberteetin viivästymisen syyn tunnistamisessa. Kolmas väitöskirjan kohdealue oli selvittää sukupuolihormonien vaikutusta kasvuun syntymästä alkaen. Tarkasteltaessa HH-poikien kasvukäyriä havaittiin heidän kasvun hidastuvan jo minipuberteetin eli ensimmäisen puolen vuoden aikana viitaten siihen, että sukupuolihormonit säätelevät kasvua jo imeväisiästä alkaen. Aikuisena HH-miehillä oli heikentynyt terveyteen liittyvä elämänlaatu, joka assosioitui korkeampaan HH:n diagnoosi-ikään. Väitöskirjan osatöiden perusteella todetaan, että HH:n tunnistaminen viivästyneen murrosiän taustalta on tärkeää, koska viivästynyt diagnoosi heikentää terveyteen liittyvää elämänlaatua jopa aikuisikään saakka. Lisäksi tulokset painottavat esitietojen ja kliinisen tutkimuksen tärkeyttä selvitettäessä murrosiän viivästymisen syitä, ja tuovat myös uusia työkaluja potilastyöhön

A case of congenital tuberculosis with a favorable outcome in a full term neonate

This case of congenital tuberculosis (TB) emphasizes that TB should be suspected in newborns whose parents are from areas with high incidence of TB or who present with symptoms of an infection unresponsive to wide-spectrum antibiotics.Peer reviewe

Circulating miR-30b levels increase during male puberty

Objective: The role of miRNA as endocrine regulators is emerging, and microRNA mir-30b has been reported to repress Mkrn3. However, the expression of miR-30b during male puberty has not been studied. Design and methods: Circulating relative miR-30b expression was assessed in sera of 26 boys with constitutional delay of growth and puberty (CDGP), treated with low-dose testosterone (T) (n =11) or aromatase inhibitor letrozole (Lz) (n =15) for 6 months and followed up to 12 months (NCT01797718). The associations between the relative expression of miR-30b and hormonal markers of puberty were evaluated. Results: During the 12 months of the study, circulating miR-30b expression increased 2.4 +/- 2.5 (s.D.) fold (P = 0.008) in all boys, but this change did not correlate with corresponding changes in LH, testosterone, inhibin B, FSH, or testicular volume (P = 0.25-0.96). Lz-induced activation of the hypothalamic-pituitary-gonadal (HPG) axis was associated with more variable miR-30b responses at 3 months (P <0.05), whereas those treated with T exhibited significant changes in relative miR-30b levels in the course the study (P <0.01-0.05). Conclusions: Circulating miR-30b expression in boys with CDGP increases in the course of puberty, and appears to be related to the activity of the HPG axis.Peer reviewe

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

Background Between March 18(th) and May 13(th) 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.Peer reviewe

First year on commercial hybrid closed-loop system - experience on 111 children and adolescents with type 1 diabetes

Objective The hybrid close-loop system (HCL) is a rapidly emerging treatment method for type 1 diabetes (T1D), but the long-term effectiveness of the system remains unclear. This study investigates the influence of the HCL on glycemic control in children and adolescents with T1D in a real-life setting during the first year on HCL. Research design and methods This retrospective study included all the patients (n = 111) aged 3 to 16 years with T1D who initiated the HCL system between 1st of December 2018 and 1st of December 2019 in the Helsinki University Hospital. Time in range (TIR), HbA1c, mean sensor glucose (SG) value, time below range (TBR), and SG coefficient of variance (CV) were measured at 0, 1, 3, 6, and 12 month. The changes over time were analyzed with a repeated mixed model adjusted with baseline glycemic control. Results After the initiation of HCL, all measures of glycemic control, except HbA1c, improved and the effect lasted throughout the study period. Between 0 and 12 month, TIR increased (beta = -2.5 [95%CI: -3.6 - (-1.3)], p < 0.001), whereas mean SG values (beta = -0.7 [95%CI: -0.9 - (-0.4)]), TBR (beta = -2.5 [95%CI: -3.6 - (-1.3)]), and SG CV (beta = -4.5 [95%CI: -6.3 - [-2.8]) decreased significantly (p < 0.001). Importantly, the changes occurred regardless of the age of the patient. Conclusions Measurements of glycemic control, except HbA1c, improved significantly after the initiation of the HCL system and the favorable effect lasted throughout the follow-up. These results support the view that HCL is an efficacious treatment modality for children and adolescents with T1D of all ages.Peer reviewe

Letrozole Monotherapy in Pre- and Early-Pubertal Boys Does Not Increase Adult Height

Background: Aromatase inhibitors (Als) have been used in boys with idiopathic short stature (ISS) to promote growth despite the lack of actual data regarding treatment effect on adult height. In this study, we characterized adult heights and long-term follow-up in Al-treated boys with ISS. Methods: Adult heights and long-term follow-up data, including spine MRIs, of a randomized, double-blind, placebo-controlled trial of boys who were treated with letrozole (Lz) (2.5 mg/d) or placebo (PI) for 2 years during prepuberty and early puberty. The mean bone ages at treatment cessation were 10.2 and 10.8 years, respectively. Results: Adult heights were similar between the boys treated with Lz (n = 10) and those who received PI (n = 10) (164.8 +/- 4.0 vs. 163.7 +/- 3.7 cm, p = 0.49, respectively). In either group, the adult heights did not differ from predicted adult heights at start of the study [PI: 163.7 (3.7) cm vs. 166.9 (3.3), p = 0.06; Lz: 164.8 (4.0) cm vs. 167.6 (7.9), p = 0.20, respectively]. Long-term follow-up data showed that the frequency of subjects with a vertebral deformity was similar between the groups (Lz, 29% and PI, 22%, p = 0.20), and no single comorbidity was clearly enriched in either group. Conclusions: The Lz-treated boys had similar adult heights with the subjects who received PI for 2 years, which indicates that the treatment is not beneficial when given to pre- or early-pubertal boys. Previously observed vertebral deformities ameliorated during follow-up, which supports the skeletal safety of Lz therapy in children and adolescents.Peer reviewe

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

Publisher Copyright: Copyright © 2022 Suutela, Miettinen, Kosola, Rahkonen, Varimo, Tarkkanen, Hero and Raivio.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 (β=0.041–0.062, p<0.005) and physical education (β=0.077–0.107, p<0.001) across the study years, and in school year 9, also with grades in English (β=-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 (β=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.Peer reviewe

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 (NCT017977181, 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 19.31 ng/mL, P = .033). Between 0 and 6 months, the changes in serum LEAP2 levels correlated positively with changes in percentage of body fat (r(s) = 0.48, P = .011), and negatively with growth velocity and estradiol levels (r(s) = -0.43, P = .022, r(s) = -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 (r(s) = -0.44, P = .022) and positively with the change in insulin (r(s) = 0.50, P = .009) and HOMA-IR (r(s )= 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.Peer reviewe

Bone structure assessed with pQCT in prepubertal males with delayed puberty or congenital hypogonadotropic hypogonadism

Objective Congenital hypogonadotropic hypogonadism (CHH) is associated with impaired bone mineral density in adulthood, whereas the estimates on bone structure in adolescents with CHH has not been previously evaluated. This study describes bone structure in CHH patients and compares it to that in boys with constitutional delay of growth and puberty (CDGP). Design A cross-sectional study. Methods Peripheral quantitative computed tomography (pQCT) of non-dominant arm and left leg were performed. Volumetric bone mineral density (BMD), bone mineral content, and area in trabecular and cortical bone compartments were evaluated, and bone age-adjusted Z-scores for the bone parameters were determined. Results The participants with CHH had more advanced bone age and were older, taller and heavier than the CDGP boys, yet they had lower trabecular BMD in distal radius (147.7 mg/mm(3) [95% CI, 128-168 mg/mm(3)] vs. 181.2 mg/mm(3) [172-192 mg/mm(3)], p = .002) and distal tibia (167.6 mg/mm(3) [145-190 mg/mm(3)] vs. 207.2 mg/mm(3) [187-227 mg/mm(3)], p = .012), respectively. CHH males had lower cortical thickness at diaphyseal tibia than the participants with CDGP (p = .001). These between-group differences remained significant in corresponding Z-scores adjusted for bone age and height (p = .001). In CDGP group, serum testosterone correlated positively with trabecular BMD (r = 0.51, p = .013) at distal radius, and estradiol levels correlated positively with trabecular BMD at the distal site of tibia (r = 0.58, p = .004). Conclusions Five treatment-naive male patients with CHH exhibited poorer trabecular BMD than untreated males with CDGP. We speculate that timely low-dose sex steroid replacement in CHH males may benefit skeletal health in adulthood.Peer reviewe