289 results on '"Raivio T"'
Search Results
52. Comparison of a novel whole blood transglutaminase-based ELISA with a whole blood rapid antibody test and established conventional serological celiac disease assays.
- Author
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Raivio T, Korponay-Szabó IR, Paajanen T, Ashorn M, Iltanen S, Collin P, Laurila K, Nemes E, Kovács JB, Carrard G, Saramäki M, Mäki M, Kaukinen K, Raivio, Tiina, Korponay-Szabó, Ilma R, Paajanen, Tuula, Ashorn, Merja, Iltanen, Sari, Collin, Pekka, and Laurila, Kaija
- Published
- 2008
53. Circulating glucocorticoid bioactivity during peroral glucocorticoid treatment in children and adolescents with inflammatory bowel disease.
- Author
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Vihinen MK, Raivio T, Verkasalo M, Jänne OA, and Kolho KL
- Published
- 2008
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54. Reversal of idiopathic hypogonadotropic hypogonadism.
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Raivio T, Falardeau J, Dwyer A, Quinton R, Hayes FJ, Hughes VA, Cole LW, Pearce SH, Lee H, Boepple P, Crowley WF Jr., Pitteloud N, Raivio, Taneli, Falardeau, John, Dwyer, Andrew, Quinton, Richard, Hayes, Frances J, Hughes, Virginia A, Cole, Lindsay W, and Pearce, Simon H
- Abstract
Background: Idiopathic hypogonadotropic hypogonadism, which may be associated with anosmia (the Kallmann syndrome) or with a normal sense of smell, is a treatable form of male infertility caused by a congenital defect in the secretion or action of gonadotropin-releasing hormone (GnRH). Patients have absent or incomplete sexual maturation by the age of 18. Idiopathic hypogonadotropic hypogonadism was previously thought to require lifelong therapy. We describe 15 men in whom reversal of idiopathic hypogonadotropic hypogonadism was sustained after discontinuation of hormonal therapy.Methods: We defined the sustained reversal of idiopathic hypogonadotropic hypogonadism as the presence of normal adult testosterone levels after hormonal therapy was discontinued.Results: Ten sustained reversals were identified retrospectively. Five sustained reversals were identified prospectively among 50 men with idiopathic hypogonadotropic hypogonadism after a mean (+/-SD) duration of treatment interruption of 6+/-3 weeks. Of the 15 men who had a sustained reversal, 4 had anosmia. At initial evaluation, 6 men had absent puberty, 9 had partial puberty, and all had abnormal secretion of GnRH-induced luteinizing hormone. All 15 men had received previous hormonal therapy to induce virilization, fertility, or both. Among those whose hypogonadism was reversed, the mean serum level of endogenous testosterone increased from 55+/-29 ng per deciliter (1.9+/-1.0 nmol per liter) to 386+/-91 ng per deciliter (13.4+/-3.2 nmol per liter, P<0.001), the luteinizing hormone level increased from 2.7+/-2.0 to 8.5+/-4.6 IU per liter (P<0.001), the level of follicle-stimulating hormone increased from 2.5+/-1.7 to 9.5+/-12.2 IU per liter (P<0.01), and testicular volume increased from 8+/-5 to 16+/-7 ml (P<0.001). Pulsatile luteinizing hormone secretion and spermatogenesis were documented.Conclusions: Sustained reversal of normosmic idiopathic hypogonadotropic hypogonadism and the Kallmann syndrome was noted after discontinuation of treatment in about 10% of patients with either absent or partial puberty. Therefore, brief discontinuation of hormonal therapy to assess reversibility of hypogonadotropic hypogonadism is reasonable. (ClinicalTrials.gov number, NCT00392756 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]- Published
- 2007
55. Mutations That Impact the Enteropathogenic Escherichia coliCpx Envelope Stress Response Attenuate Virulence in Galleria mellonella
- Author
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Leuko, S. and Raivio, T. L.
- Abstract
ABSTRACTIn this paper, we show that the larvae of the greater wax moth, Galleria mellonella, can be used as a model to study enteropathogenic Escherichia coli(EPEC) virulence. G. mellonellalarvae are killed after infection with EPEC type strain E2348/69 but not by an attenuated derivative that expresses diminished levels of the major virulence determinants or by a mutant specifically defective in type III secretion (T3S). Infecting EPEC inhabit the larval hemocoel only briefly and then become localized to melanized capsules, where they remain extracellular. Previously, it was shown that mutations affecting the Cpx envelope stress response lead to diminished expression of the bundle-forming pilus (BFP) and the type III secretion system (T3SS). We demonstrate that mutations that activate the Cpx pathway have a dramatic effect on the ability of the bacterium to establish a lethal infection, and this is correlated with an inability to grow in vivo. Infection with all E. colistrains led to increased expression of the antimicrobial peptides (AMPs) gloverin and cecropin, although strain- and AMP-specific differences were observed, suggesting that the G. mellonellahost perceives attenuated strains and Cpx mutants in unique manners. Overall, this study shows that G. mellonellais an economical, alternative infection model for the preliminary study of EPEC host-pathogen interactions, and that induction of the Cpx envelope stress response leads to defects in virulence.
- Published
- 2012
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56. Circulating adiponectin as a marker for glucocorticoid-related side effects in children and adolescents with inflammatory bowel disease.
- Author
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Vihinen MK, Kolho KL, Jänne OA, Andersson S, and Raivio T
- Published
- 2009
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57. Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations
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Villanueva C, Jacobson-Dickman E, Xu C, ManouvrierS, DwyerA, Sykiotis GP, Beenken A, Liu Y, Tommiska J, Hu Y, Tiosano D, Gerard M, Leger J, Drouin-Garraud V, Lefebvre H, Polak M, Carel J, Phan-Hug F, Hauschild M, Raivio T, Bouloux P, Sidis Y, Mohammadi M, de Roux N, and Pitteloud N
- Abstract
Purpose:Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two.Methods:We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence and structure based predictions and/or functional assays.Results:We identified eight probands with CHH with (n = 3; Kallmann syndrome) or without anosmia (n = 5) and SHFM seven of whom (88) harbor FGFR1 mutations. Of these seven one individual is homozygous for p.V429E and six individuals are heterozygous for p.G348R p.G485R p.Q594 p.E670A p.V688L or p.L712P. All mutations were predicted by in silico analysis to cause loss of function. Probands with FGFR1 mutations have severe gonadotropin releasing hormone deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was observed only in the patient with the homozygous p.V429E mutation; V429 maps to the fibroblast growth factor receptor substrate 2a binding domain of FGFR1 and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of fibroblast growth factor receptor substrate 2a to FGFR1 thereby resulting in reduced mitogen activated protein kinase signaling.Conclusion:FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM because the likelihood of a mutation increases from 10 in the general CHH population to 88 in these patients.Genet Med advance online publication 13 November 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.166.
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58. VIATO-visual interactive aircraft trajectory optimization
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Virtanen, K., primary, Ehtamo, H., additional, Raivio, T., additional, and Hamalainen, R.P., additional
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59. LIN28B, LIN28A, KISS1, and KISS1R in idiopathic central precocious puberty
- Author
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Koivu Rosanna, Aksglaede Lise, Sørensen Kaspar, Tommiska Johanna, Puhakka Lea, Juul Anders, and Raivio Taneli
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LIN28B ,LIN28A ,KISS1 ,KISS1R ,idiopathic central precocious puberty ,timing of puberty ,Medicine ,Biology (General) ,QH301-705.5 ,Science (General) ,Q1-390 - Abstract
Abstract Background Pubertal timing is a strongly heritable trait, but no single puberty gene has been identified. Thus, the genetic background of idiopathic central precocious puberty (ICPP) is poorly understood. Overall, the genetic modulation of pubertal onset most likely arises from the additive effect of multiple genes, but also monogenic causes of ICPP probably exist, as cases of familial ICPP have been reported. Mutations in KISS1 and KISSR, coding for kisspeptin and its receptor, involved in GnRH secretion and puberty onset, have been suggested causative for monogenic ICPP. Variation in LIN28B was associated with timing of puberty in genome-wide association (GWA) studies. LIN28B is a human ortholog of the gene that controls, through microRNAs, developmental timing in C. elegans. In addition, Lin28a transgenic mice manifest the puberty phenotypes identified in the human GWAS. Thus, both LIN28B and LIN28A may have a role in pubertal development and are good candidate genes for monogenic ICPP. Methods Thirty girls with ICPP were included in the study. ICPP was defined by pubertal onset before 8 yrs of age, and a pubertal LH response to GnRH testing. The coding regions of LIN28B, LIN28A, KISS1, and KISS1R were sequenced. The missense change in LIN28B was also screened in 132 control subjects. Results No rare variants were detected in KISS1 or KISS1R in the 30 subjects with ICPP. In LIN28B, one missense change, His199Arg, was found in one subject with ICPP. However, this variant was also detected in one of the 132 controls. No variation in LIN28A was found. Conclusions We did not find any evidence that mutations in LIN28B or LIN28A would underlie ICPP. In addition, we confirmed that mutations in KISS1 and KISS1R are not a common cause for ICPP.
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- 2011
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60. Incidence, Phenotypic Features and Molecular Genetics of Kallmann Syndrome in Finland
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Tommiska Johanna, Vaaralahti Kirsi, Laitinen Eeva-Maria, Eklund Elina, Tervaniemi Mari, Valanne Leena, and Raivio Taneli
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Medicine - Abstract
Abstract Background Kallmann syndrome (KS), comprised of congenital hypogonadotropic hypogonadism (HH) and anosmia, is a clinically and genetically heterogeneous disorder. Its exact incidence is currently unknown, and a mutation in one of the identified KS genes has only been found in ~30% of the patients. Methods Herein, we investigated epidemiological, clinical, and genetic features of KS in Finland. Results The minimal incidence estimate of KS in Finland was 1:48 000, with clear difference between males (1:30 000) and females (1:125 000) (p = 0.02). The reproductive phenotype of 30 probands (25 men; 5 women) ranged from severe HH to partial puberty. Comprehensive mutation analysis of all 7 known KS genes (KAL1, FGFR1, FGF8, PROK2, PROKR2, CHD7, and WDR11) in these 30 well-phenotyped probands revealed mutations in KAL1 (3 men) and FGFR1 (all 5 women vs. 4/25 men), but not in other genes. Conclusions Our results suggest that Finnish KS men harbor mutations in gene(s) yet-to-be discovered with sex-dependent penetrance of the disease phenotype. In addition, some KS patients without CHD7 mutations display CHARGE-syndrome associated phenotypic features (e.g. ear or eye anomalies), possibly implying that, in addition to CHD7, there may be other genes associated with phenotypes ranging from KS to CHARGE.
- Published
- 2011
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61. Generation of a restriction minus enteropathogenic Escherichia coli E2348/69 strain that is efficiently transformed with large, low copy plasmids
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Ward Jordan D, Price Nancy L, Hobson Neil, and Raivio Tracy L
- Subjects
Microbiology ,QR1-502 - Abstract
Abstract Background Many microbes possess restriction-modification systems that protect them from parasitic DNA molecules. Unfortunately, the presence of a restriction-modification system in a given microbe also hampers genetic analysis. Although plasmids can be successfully conjugated into the enteropathogenic Escherichia coli strain E2348/69 and optimized protocols for competent cell preparation have been developed, we found that a large, low copy (~15) bioluminescent reporter plasmid, pJW15, that we modified for use in EPEC, was exceedingly difficult to transform into E2348/69. We reasoned that a restriction-modification system could be responsible for the low transformation efficiency of E2348/69 and sought to identify and inactivate the responsible gene(s), with the goal of creating an easily transformable strain of EPEC that could complement existing protocols for genetic manipulation of this important pathogen. Results Using bioinformatics, we identified genes in the unfinished enteropathogenic Escherichia coli (EPEC) strain E2348/69 genome whose predicted products bear homology to the HsdM methyltransferases, HsdS specificity subunits, and HsdR restriction endonucleases of type I restriction-modification systems. We constructed a strain carrying a deletion of the conserved enzymatic domain of the EPEC HsdR homologue, NH4, and showed that its transformation efficiency was up to four orders of magnitude higher than that of the parent strain. Further, the modification capacity of NH4 remained intact, since plasmids that were normally recalcitrant to transformation into E2348/69 could be transformed upon passage through NH4. NH4 was unaffected in virulence factor production, since bundle forming pilus (BFP) subunits and type III secreted (T3S) proteins were present at equivalent levels to those seen in E2348/69. Further, NH4 was indistinguishable from E2348/69 in tissue culture infection model assays of localized adherence and T3S. Conclusion We have shown that EPEC strain E2348/69 utilizes a type I restriction-modification system to limit entry of new DNA. This restriction-modification system does not appear to be involved in virulence determinant expression or infection phenotypes. The hsdR mutant strain should prove useful in genetic analysis of the important diarrheal pathogen EPEC.
- Published
- 2008
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62. VIATO-visual interactive aircraft trajectory optimization.
- Author
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Virtanen, K., Ehtamo, H., Raivio, T., and Hamalainen, R.P.
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- 1997
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63. Circulating antimüllerian hormone levels in boys decline during early puberty and correlate with inhibin B.
- Author
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Hero M, Tommiska J, Vaaralahti K, Laitinen EM, Sipilä I, Puhakka L, Dunkel L, and Raivio T
- Published
- 2012
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64. Perspectives of preimplantation genetic testing patients in Belgium on the ethics of polygenic embryo screening.
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Siermann M, Vermeesch JR, Raivio T, Vanhie A, Peeraer K, Tšuiko O, and Borry P
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- Humans, Female, Belgium, Adult, Male, Multifactorial Inheritance, Pregnancy, Preimplantation Diagnosis ethics, Preimplantation Diagnosis psychology, Genetic Testing ethics
- Abstract
Research Question: What are the perspectives of preimplantation genetic testing (PGT) patients in Belgium on the ethics of PGT for polygenic risk scoring (PGT-P)?, Design: In-depth interviews (18 in total, 10 couples, 8 women, n = 28) were performed with patients who had undergone treatment with PGT for monogenic/single-gene defects (PGT-M) or chromosomal structural rearrangements (PGT-SR) between 2017 and 2019 in Belgium. Participants were asked about their own experiences with PGT-M/SR and about their viewpoints on PGT-P, including their own interest and their ideas on its desirability, scope and consequences. Inductive content analysis was used to analyse the interviews., Results: Participants stated that their experiences with PGT-M/SR had been physically, psychologically and practically difficult. Most participants stated that, partly because of these difficulties, they did not see the added value of knowing the risk scores of embryos via PGT-P. Many participants worried that PGT-P could lead to additional anxieties, responsibilities and complex choices in reproduction and parenthood. They argued that not everything should be controlled and felt that PGT-P, especially non-medical and broad screening, was going too far. With regards to the clinical implementation of PGT-P, participants in general preferred PGT-P to be limited to people with a serious polygenic family history and wanted embryo selection decisions to be made by healthcare professionals., Conclusions: This study shows that individuals with experience of PGT-M/SR saw PGT-P as different from PGT-M/SR. They had various ethical concerns with regards to PGT-P, especially regarding broadly offering PGT-P. These stakeholder viewpoints need to be considered regarding potential PGT-P implementation and guidelines., (Copyright © 2024 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2024
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65. Prenatal, newborn and childhood factors and the timing of puberty in boys and girls.
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Suutela M, Hero M, Kosola S, Miettinen PJ, and Raivio T
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- Humans, Female, Male, Pregnancy, Infant, Newborn, Child, Prenatal Exposure Delayed Effects, Smoking adverse effects, Age Factors, Linear Models, Puberty, Birth Weight, Body Mass Index, Gestational Age, Body Height
- Abstract
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/m
2 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., (© 2024. The Author(s).)- Published
- 2024
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66. Polygenic embryo screening: quo vadis?
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Siermann M, Vermeesch JR, Raivio T, Tšuiko O, and Borry P
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- Humans, Female, Multifactorial Inheritance genetics, Pregnancy, Decision Making ethics, Preimplantation Diagnosis ethics, Preimplantation Diagnosis methods, Genetic Testing ethics, Genetic Testing methods, Genetic Testing trends
- Abstract
Recently, the use of polygenic risk scores in embryo screening (PGT-P) has been introduced on the premise of reducing polygenic disease risk through embryo selection. However, it has been met with extensive critique: considered "technology-driven" rather than "evidence-based", concerns exist about its validity, utility, ethics, and societal effects. Its scientific foundations and criticisms thus need to be carefully considered. However, seeing as PGT-P is already offered in some settings, further questions need to be addressed, in order to give due diligence to various aspects of PGT-P. By examining the complexities of clinical introduction of PGT-P, we discuss whether PGT-P could be responsibly implemented in the first place, what elements need to be addressed if PGT-P is clinically implemented, and subsequently how counselling and decision-making of its users could be envisaged. By dissecting these elements, we provide an overview of important practical questions of PGT-P and emphasize elements of PGT-P that we think have yet to be given sufficient attention. These questions and elements are for example related to the potential target group, scope, and decision-making possibilities of PGT-P. The aspects we raise are crucial to consider by the scientific community and policy makers for the development of guidelines and/or an ethical framework for PGT-P., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2024
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67. A splice site variant in MADD affects hormone expression in pancreatic β cells and pituitary gonadotropes.
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Pulli K, Saarimäki-Vire J, Ahonen P, Liu X, Ibrahim H, Chandra V, Santambrogio A, Wang Y, Vaaralahti K, Iivonen AP, Känsäkoski J, Tommiska J, Kemkem Y, Varjosalo M, Vuoristo S, Andoniadou CL, Otonkoski T, and Raivio T
- Subjects
- Humans, Animals, Mice, Male, Gonadotrophs metabolism, Female, RNA Splice Sites genetics, Cell Line, Insulin metabolism, Siblings, Exons genetics, rab3 GTP-Binding Proteins metabolism, rab3 GTP-Binding Proteins genetics, Hypogonadism genetics, Hypogonadism metabolism, Hypogonadism pathology, Insulin-Secreting Cells metabolism
- Abstract
MAPK activating death domain (MADD) is a multifunctional protein regulating small GTPases RAB3 and RAB27, MAPK signaling, and cell survival. Polymorphisms in the MADD locus are associated with glycemic traits, but patients with biallelic variants in MADD manifest a complex syndrome affecting nervous, endocrine, exocrine, and hematological systems. We identified a homozygous splice site variant in MADD in 2 siblings with developmental delay, diabetes, congenital hypogonadotropic hypogonadism, and growth hormone deficiency. This variant led to skipping of exon 30 and in-frame deletion of 36 amino acids. To elucidate how this mutation causes pleiotropic endocrine phenotypes, we generated relevant cellular models with deletion of MADD exon 30 (dex30). We observed reduced numbers of β cells, decreased insulin content, and increased proinsulin-to-insulin ratio in dex30 human embryonic stem cell-derived pancreatic islets. Concordantly, dex30 led to decreased insulin expression in human β cell line EndoC-βH1. Furthermore, dex30 resulted in decreased luteinizing hormone expression in mouse pituitary gonadotrope cell line LβT2 but did not affect ontogeny of stem cell-derived GnRH neurons. Protein-protein interactions of wild-type and dex30 MADD revealed changes affecting multiple signaling pathways, while the GDP/GTP exchange activity of dex30 MADD remained intact. Our results suggest MADD-specific processes regulate hormone expression in pancreatic β cells and pituitary gonadotropes.
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- 2024
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68. Classes and predictors of reversal in male patients with congenital hypogonadotropic hypogonadism: a cross-sectional study of six international referral centres.
- Author
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Dwyer AA, McDonald IR, Cangiano B, Giovanelli L, Maione L, Silveira LFG, Raivio T, Latronico AC, Young J, Quinton R, Bonomi M, Persani L, Seminara SB, and Lee CS
- Subjects
- United States, Child, Adult, Humans, Male, Adolescent, Cross-Sectional Studies, Follicle Stimulating Hormone therapeutic use, Hypogonadism genetics, Hypogonadism drug therapy, Genital Diseases, Male, Penis abnormalities
- Abstract
Background: Although some male patients with congenital hypogonadotropic hypogonadism (CHH) undergo spontaneous reversal following treatment, predictors of reversal remain elusive. We aimed to assemble the largest cohort of male patients with CHH reversal to date and identify distinct classes of reversal., Methods: This multicentre cross-sectional study was conducted in six international CHH referral centres in Brazil, Finland, France, Italy, the UK, and the USA. Adult men with CHH (ie, absent or incomplete spontaneous puberty by age 18 years, low serum testosterone concentrations, and no identifiable cause of hypothalamic-pituitary-gonadal [HPG] axis dysfunction) were eligible for inclusion. CHH reversal was defined as spontaneous recovery of HPG axis function off treatment. Centres provided common data elements on patient phenotype, clinical assessment, and genetics using a structured, harmonised data collection form developed by COST Action BM1105. Latent class mixture modelling (LCMM) was applied to establish whether at least two distinct classes of reversal could be identified and differentially predicted, and results were compared with a cohort of patients without CHH reversal to identify potential predictors of reversal. The primary outcome was the presence of at least two distinct classes of reversal., Findings: A total of 87 male patients with CHH reversal and 108 without CHH reversal were included in the analyses. LCMM identified two distinct reversal classes (75 [86%] in class 1 and 12 [14%] in class 2) on the basis of mean testicular volume, micropenis, and serum follicle-stimulating hormone (FSH) concentration. Classification probabilities were robust (0·998 for class 1 and 0·838 for class 2) and modelling uncertainty was low (entropy 0·90). Compared with class 1, patients in class 2 had significantly larger testicular volume (p<0·0001), no micropenis, and higher serum FSH concentrations (p=0·041), consistent with the Pasqualini syndrome (fertile eunuch) subtype of CHH. Patients without CHH reversal were more likely to have anosmia (p=0·016), cryptorchidism (p=0·0012), complete absence of puberty (testicular volume <4 cm³; p=0·0016), and two or more rare genetic variants (ie, oligogenicity; p=0·0001). Among patients who underwent genetic testing, no patients (of 75) with CHH reversal had a rare pathogenic ANOS1 variant compared with ten (11%) of 95 patients without CHH reversal. Individuals with CHH reversal had a significantly higher rate of rare variants in GNRHR than did those without reversal (nine [12%] of 75 vs three [3%] of 95; p=0·025)., Interpretation: Applying LCMM to a large cohort of male patients with CHH reversal uncovered two distinct classes of reversal. Genetic investigation combined with careful clinical phenotyping could help surveillance of reversal after withdrawing treatment, representing the first tailored management approach for male patients with this rare endocrine disorder., Funding: National Institutes of Health National Center for Advancing Translational Sciences; Ministry of Health, Rome, Italy; Ministry of University, Rome, Italy; National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development; and the Josiah Macy Jr Foundation., Translation: For the Italian translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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69. Central precocious puberty in boys: secular trend and clinical features.
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Huttunen H, Kärkinen J, Varimo T, Miettinen PJ, Raivio T, and Hero M
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- Humans, Male, Follicle Stimulating Hormone, Retrospective Studies, Testosterone, Gonadotropin-Releasing Hormone, Luteinizing Hormone, Puberty, Precocious diagnosis, Puberty, Precocious epidemiology
- Abstract
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., Competing Interests: Conflict of interest: The authors have no conflict of interest to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
- Published
- 2024
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70. HiHo-AID2: boosting homozygous knock-in efficiency enables robust generation of human auxin-inducible degron cells.
- Author
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Li S, Wang Y, van der Stoel M, Zhou X, Madhusudan S, Kanerva K, Nguyen VD, Eskici N, Olkkonen VM, Zhou Y, Raivio T, and Ikonen E
- Subjects
- Humans, Proteins metabolism, Cell Line, Proteolysis, Indoleacetic Acids pharmacology, Indoleacetic Acids metabolism, Degrons
- Abstract
Recent developments in auxin-inducible degron (AID) technology have increased its popularity for chemogenetic control of proteolysis. However, generation of human AID cell lines is challenging, especially in human embryonic stem cells (hESCs). Here, we develop HiHo-AID2, a streamlined procedure for rapid, one-step generation of human cancer and hESC lines with high homozygous degron-tagging efficiency based on an optimized AID2 system and homology-directed repair enhancers. We demonstrate its application for rapid and inducible functional inactivation of twelve endogenous target proteins in five cell lines, including targets with diverse expression levels and functions in hESCs and cells differentiated from hESCs., (© 2024. The Author(s).)
- Published
- 2024
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71. "Are we not going too far?": Socio-ethical considerations of preimplantation genetic testing using polygenic risk scores according to healthcare professionals.
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Siermann M, Valcke O, Vermeesch JR, Raivio T, Tšuiko O, and Borry P
- Subjects
- Pregnancy, Female, Child, Humans, Genetic Risk Score, Genetic Testing, Health Personnel, Delivery of Health Care, Preimplantation Diagnosis
- Abstract
The recent introduction of polygenic risk scores within preimplantation genetic testing (PGT-P) has been met with many concerns. To get more insights into the perspectives of relevant stakeholders on the socio-ethical aspects of PGT-P, an interview study with 31 healthcare professionals involved in reproductive medicine and genetics in Europe and North-America was performed. Healthcare professionals in our study were concerned that PGT-P was going too far in terms of selection, with regards to both medical conditions and non-medical traits. Healthcare professionals were worried about the ethical 'slippery slope' of PGT-P, the increasing medicalization of reproductive health, the commercial context of PGT-P, and potential stigmatization and discrimination. There were also concerns that the availability and the 'technological imperative' of PGT-P could lead to pressure and a sense of responsibility for parents to use PGT-P. Additionally, it could cause new anxieties about the child's health before the child has even been born. Since PGT-P provides polygenic risk scores before birth, the autonomy of the child has to be considered. These socio-ethical concerns heighten existing debates regarding reproductive genetic technologies and show that the specifics of PGT-P make this screening option especially ethically controversial., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
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- 2024
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72. Limitations, concerns and potential: attitudes of healthcare professionals toward preimplantation genetic testing using polygenic risk scores.
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Siermann M, Valcke O, Vermeesch JR, Raivio T, Tšuiko O, and Borry P
- Subjects
- Pregnancy, Female, Humans, Prospective Studies, Genetic Testing, Attitude, Delivery of Health Care, Aneuploidy, Preimplantation Diagnosis
- Abstract
Preimplantation genetic testing using polygenic risk scores (PGT-P) has recently been introduced. However, PGT-P has been met with many ethical concerns. It is therefore important to get insights into the perspectives of stakeholders regarding PGT-P. We performed a qualitative interview study on the views of healthcare professionals toward PGT-P. We conducted in-depth semi-structured interviews with 31 healthcare professionals working in the field of preimplantation genetic testing. The interviews explored the attitudes of healthcare professionals toward the technology of PGT-P, e.g., the validity, utility, limitations and potential benefits of PGT-P. We found that most healthcare professionals were concerned about the prematurity of introducing PGT-P into clinical practice. They had various ethical considerations, such as concerns related to validity and utility of PGT-P, limited embryos and options, and difficulties for prospective parents regarding comprehension and informed decision-making. Positive aspects were also identified, e.g., regarding reproductive autonomy and potential health benefits. Overall, most healthcare professionals considered that clinical implementation of PGT-P is premature. More comprehensive, longitudinal and inclusive studies are needed first, though these might not improve PGT-P enough to responsibly implement it. Healthcare professionals were also concerned that PGT-P could cause anxiety and create difficult choices for prospective parents. These perspectives and ethical considerations are crucial to consider for future guidelines and recommendations regarding PGT-P., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)
- Published
- 2023
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73. Congenital hypogonadotropic hypogonadism in a patient with a de novo POGZ mutation.
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Eskici N, Madhusudan S, Vaaralahti K, Yellapragada V, Gomez-Sanchez C, Kärkinen J, Almusa H, Brandstack N, Miettinen PJ, Wang Y, and Raivio T
- Subjects
- Humans, Neurons, Gonadotropin-Releasing Hormone, Mutation genetics, Autism Spectrum Disorder, Kallmann Syndrome genetics
- Abstract
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., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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74. Deciphering the Transcriptional Landscape of Human Pluripotent Stem Cell-Derived GnRH Neurons: The Role of Wnt Signaling in Patterning the Neural Fate.
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Wang Y, Madhusudan S, Cotellessa L, Kvist J, Eskici N, Yellapragada V, Pulli K, Lund C, Vaaralahti K, Tuuri T, Giacobini P, and Raivio T
- Subjects
- Humans, Wnt Signaling Pathway genetics, Neurons metabolism, Cell Differentiation genetics, Gonadotropin-Releasing Hormone genetics, Gonadotropin-Releasing Hormone metabolism, Pluripotent Stem Cells metabolism
- Abstract
Hypothalamic gonadotropin-releasing hormone (GnRH) neurons lay the foundation for human development and reproduction; however, the critical cell populations and the entangled mechanisms underlying the development of human GnRH neurons remain poorly understood. Here, by using our established human pluripotent stem cell-derived GnRH neuron model, we decoded the cellular heterogeneity and differentiation trajectories at the single-cell level. We found that a glutamatergic neuron population, which generated together with GnRH neurons, showed similar transcriptomic properties with olfactory sensory neuron and provided the migratory path for GnRH neurons. Through trajectory analysis, we identified a specific gene module activated along the GnRH neuron differentiation lineage, and we examined one of the transcription factors, DLX5, expression in human fetal GnRH neurons. Furthermore, we found that Wnt inhibition could increase DLX5 expression and improve the GnRH neuron differentiation efficiency through promoting neurogenesis and switching the differentiation fates of neural progenitors into glutamatergic neurons/GnRH neurons. Our research comprehensively reveals the dynamic cell population transition and gene regulatory network during GnRH neuron differentiation., (© The Author(s) 2022. Published by Oxford University Press.)
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- 2022
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75. Health-related quality of life in boys with constitutional delay of growth and puberty.
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Kariola L, Varimo T, Huopio H, Tenhola S, Voutilainen R, Kosola S, Toppari J, Sintonen H, Miettinen PJ, Raivio T, and Hero M
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- Adolescent, Child, Humans, Male, Letrozole, Quality of Life, Puberty, Testosterone therapeutic use, Puberty, Delayed drug therapy, Puberty, Delayed diagnosis
- Abstract
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., Competing Interests: HS is one of the developers of the 16D. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2022 Kariola, Varimo, Huopio, Tenhola, Voutilainen, Kosola, Toppari, Sintonen, Miettinen, Raivio and Hero.)- Published
- 2022
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76. Simulated Colonic Fluid Replicates the In Vivo Growth Capabilities of Citrobacter rodentium cpxRA Mutants and Uncovers Additive Effects of Cpx-Regulated Genes on Fitness.
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Gilliland A, Gavino C, Gruenheid S, and Raivio T
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- Animals, Bacterial Proteins genetics, Bacterial Proteins metabolism, Bile Acids and Salts, Mice, Regulon, Virulence genetics, Citrobacter rodentium genetics, Enterobacteriaceae Infections microbiology
- Abstract
Citrobacter rodentium is an attaching and effacing (A/E) pathogen used to model enteropathogenic and enterohemorrhagic Escherichia coli infections in mice. During colonization, C. rodentium must adapt to stresses in the gastrointestinal tract, such as antimicrobial peptides, pH changes, and bile salts. The Cpx envelope stress response (ESR) is a two-component system used by some bacteria to remediate stress by modulating gene expression, and it is necessary for C. rodentium pathogenesis in mice. Here, we utilized simulated colonic fluid (SCF) to mimic the gastrointestinal environment, which we show strongly induces the Cpx ESR and highlights a fitness defect specific to the Δ cpxRA mutant. While investigating genes in the Cpx regulon that may contribute to C. rodentium pathogenesis, we found that the absence of the Cpx ESR resulted in higher expression of the locus of enterocyte effacement (LEE) master regulator, ler , and that the genes yebE , ygiB , bssR , and htpX relied on CpxRA for proper expression. We then determined that CpxRA and select gene mutants were essential for proper growth in SCF when in the presence of extraneous stressors and in competition. Although none of the Cpx-regulated gene mutants exhibited marked virulence phenotypes in vivo , the Δ cpxRA mutant had reduced colonization and attenuated virulence, as previously determined, which replicated the in vitro growth phenotypes specific to SCF. Overall, these results indicate that the Δ cpxRA virulence defect is not due to any single Cpx regulon gene examined. Instead, attenuation may be the result of defective growth in the colonic environment resulting from the collective impact of multiple Cpx-regulated genes.
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- 2022
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77. Timing of puberty and school performance: A population-based study.
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Suutela M, Miettinen PJ, Kosola S, Rahkonen O, Varimo T, Tarkkanen A, Hero M, and Raivio T
- Subjects
- Child, Female, Humans, Male, Body Height, Puberty
- Abstract
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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Suutela, Miettinen, Kosola, Rahkonen, Varimo, Tarkkanen, Hero and Raivio.)
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- 2022
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78. FGF8-FGFR1 signaling regulates human GnRH neuron differentiation in a time- and dose-dependent manner.
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Yellapragada V, Eskici N, Wang Y, Madhusudan S, Vaaralahti K, Tuuri T, and Raivio T
- Subjects
- Fibroblast Growth Factor 8 metabolism, Fibroblast Growth Factor 8 pharmacology, Forkhead Transcription Factors metabolism, Humans, Intracellular Signaling Peptides and Proteins metabolism, Membrane Proteins metabolism, Nerve Tissue Proteins metabolism, Neurogenesis, Neurons metabolism, Gonadotropin-Releasing Hormone metabolism, Gonadotropin-Releasing Hormone pharmacology, Receptor, Fibroblast Growth Factor, Type 1 genetics, Receptor, Fibroblast Growth Factor, Type 1 metabolism
- Abstract
Fibroblast growth factor 8 (FGF8), acting through the fibroblast growth factor receptor 1 (FGFR1), has an important role in the development of gonadotropin-releasing hormone-expressing neurons (GnRH neurons). We hypothesized that FGF8 regulates differentiation of human GnRH neurons in a time- and dose-dependent manner via FGFR1. To investigate this further, human pluripotent stem cells were differentiated during 10 days of dual-SMAD inhibition into neural progenitor cells, followed either by treatment with FGF8 at different concentrations (25 ng/ml, 50 ng/ml or 100 ng/ml) for 10 days or by treatment with 100 ng/ml FGF8 for different durations (2, 4, 6 or 10 days); cells were then matured through DAPT-induced inhibition of Notch signaling for 5 days into GnRH neurons. FGF8 induced expression of GNRH1 in a dose-dependent fashion and the duration of FGF8 exposure correlated positively with gene expression of GNRH1 (P<0.05, Rs=0.49). However, cells treated with 100 ng/ml FGF8 for 2 days induced the expression of genes, such as FOXG1, ETV5 and SPRY2, and continued FGF8 treatment induced the dynamic expression of several other genes. Moreover, during exposure to FGF8, FGFR1 localized to the cell surface and its specific inhibition with the FGFR1 inhibitor PD166866 reduced expression of GNRH1 (P<0.05). In neurons, FGFR1 also localized to the nucleus. Our results suggest that dose- and time-dependent FGF8 signaling via FGFR1 is indispensable for human GnRH neuron ontogeny. This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)
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- 2022
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79. Presentation and diagnosis of childhood-onset combined pituitary hormone deficiency: A single center experience from over 30 years.
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Hietamäki J, Kärkinen J, Iivonen AP, Vaaralahti K, Tarkkanen A, Almusa H, Huopio H, Hero M, Miettinen PJ, and Raivio T
- Abstract
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., Competing Interests: The authors have nothing to disclose., (© 2022 The Authors.)
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- 2022
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80. A review of normative documents on preimplantation genetic testing: Recommendations for PGT-P.
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Siermann M, Tšuiko O, Vermeesch JR, Raivio T, and Borry P
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- Aneuploidy, Female, Genetic Testing, Humans, Morals, Multifactorial Inheritance, Pregnancy, Preimplantation Diagnosis
- Abstract
Purpose: Recently, preimplantation genetic testing (PGT) for polygenic conditions (PGT-P) has been introduced commercially. In view of the lack of specific guidance on this development, we analyzed normative documents on PGT for monogenic conditions (PGT-M) to understand what we can learn from these documents for recommendations for PGT-P., Methods: We conducted a systematic review of normative guidelines and recommendations on PGT-M. The aim was to understand what the current consensus and disagreements are on ethical acceptability of PGT-M and how this compares with PGT-P., Results: We analyzed 38 documents by advisory committees at the national, European, and global level. In total, 2 themes were identified, which included the following: (1) what PGT is considered appropriate for and (2) who can make decisions regarding the use of PGT. Many aspects of PGT-M documents apply to PGT-P as well. Additional factors such as the fact that PGT-P screens for risk indications of multiple polygenic conditions increase ethical difficulties regarding severity, risk, autonomy, and informed decision-making., Conclusion: On the basis of PGT-M normative documents, we conclude that ethical acceptability for PGT-P is limited. Our findings present various factors that have to be considered for the development of guidelines and the appropriateness of PGT., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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81. Onset and progression of puberty in Klinefelter syndrome.
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Tanner M, Miettinen PJ, Hero M, Toppari J, and Raivio T
- Subjects
- Adolescent, Female, Humans, Luteinizing Hormone, Male, Puberty, Retrospective Studies, Testis, Testosterone therapeutic use, Klinefelter Syndrome drug therapy
- Abstract
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., (© 2021 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)
- Published
- 2022
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82. Circulating Liver-enriched Antimicrobial Peptide-2 Decreases During Male Puberty.
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Varimo T, Miettinen PJ, Vaaralahti K, Toppari J, Huopio H, Voutilainen R, Tenhola S, Hero M, and Raivio T
- Abstract
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 ( r
s = 0.48, P = .011), and negatively with growth velocity and estradiol levels ( rs = -0.43, 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 = -0.55, 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 Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)- Published
- 2022
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83. A systematic review of the views of healthcare professionals on the scope of preimplantation genetic testing.
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Siermann M, Claesen Z, Pasquier L, Raivio T, Tšuiko O, Vermeesch JR, and Borry P
- Abstract
Preimplantation genetic testing (PGT) involves testing embryos created through in vitro fertilization for the presence of hereditary genetic disorders and chromosome abnormalities. PGT for monogenic conditions (PGT-M) is generally performed for childhood-onset, lethal disorders, but is increasingly accepted for certain adult-onset conditions, conditions with available treatment options or conditions with lower penetrance. Furthermore, the development of PGT for polygenic conditions (PGT-P) makes ethical questions regarding PGT indications imperative. A systematic review was therefore performed to gather and analyse studies on the perspectives of healthcare professionals on the appropriate scope of PGT, with the aim of getting insights into the concerns about the scope of PGT now and in the near future. PRISMA guidelines were followed. Twelve qualitative articles were included. The main themes extracted were the scope of PGT and decision-making about PGT. Defining 'a serious genetic condition' was seen as complex, but severity, high penetrance and absence of treatability and patients' experience were seen as relevant indications to determine the appropriateness of PGT. In navigating the decision-making processes with patients, professionals experienced friction between setting limits and respecting patients' autonomy. Such friction and ethical dilemmas around seriousness, informed decision-making and preventative medicine show that while expanding the list of possible PGT indications and the development of PGT-P could augment patients' reproductive autonomy, it could also lead to an increased reproductive 'burden' for patients. These insights are crucial for establishing guidelines that help healthcare professionals navigate ethical tensions associated with PGT., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2022
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84. Gut microbiota develop towards an adult profile in a sex-specific manner during puberty.
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Korpela K, Kallio S, Salonen A, Hero M, Kukkonen AK, Miettinen PJ, Savilahti E, Kohva E, Kariola L, Suutela M, Tarkkanen A, de Vos WM, Raivio T, and Kuitunen M
- Subjects
- Adolescent, Clostridiaceae, Cohort Studies, Estrogens metabolism, Feces microbiology, Female, Finland, Humans, Male, Ruminococcus, Surveys and Questionnaires, Gastrointestinal Microbiome physiology, Gastrointestinal Tract microbiology, Puberty physiology, Sex Characteristics
- Abstract
Accumulating evidence indicates that gut microbiota may regulate sex-hormone levels in the host, with effects on reproductive health. Very little is known about the development of intestinal microbiota during puberty in humans. To assess the connection between pubertal timing and fecal microbiota, and to assess how fecal microbiota develop during puberty in comparison with adult microbiota, we utilized a Finnish allergy-prevention-trial cohort (Flora). Data collected at 13-year follow-up were compared with adult data from a different Finnish cohort. Among the 13-year-old participants we collected questionnaire information, growth data from school-health-system records and fecal samples from 148 participants. Reference adult fecal samples were received from the Health and Early Life Microbiota (HELMi) cohort (n = 840). Fecal microbiota were analyzed using 16S rRNA gene amplicon sequencing; the data were correlated with pubertal timing and compared with data on adult microbiota. Probiotic intervention in the allergy-prevention-trial cohort was considered as a confounding factor only. The main outcome was composition of the microbiota in relation to pubertal timing (time to/from peak growth velocity) in both sexes separately, and similarity to adult microbiota. In girls, fecal microbiota became more adult-like with pubertal progression (p = 0.009). No such development was observed in boys (p = 0.9). Both sexes showed a trend towards increasing relative abundance of estrogen-metabolizing Clostridia and decreasing Bacteroidia with pubertal development, but this was statistically significant in girls only (p = 0.03). In girls, pubertal timing was associated positively with exposure to cephalosporins prior to the age of 10. Our data support the hypothesis that gut microbiota, particularly members of Ruminococcaceae, may affect pubertal timing, possibly via regulating host sex-hormone levels.Trial registration The registration number for the allergy-prevention-trial cohort: ClinicalTrials.gov, NCT00298337, registered 1 March 2006-Retrospectively registered, https://clinicaltrials.gov/show/NCT00298337 . The adult-comparison cohort (HELMi) is NCT03996304., (© 2021. The Author(s).)
- Published
- 2021
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85. The aetiology of extreme tall stature in a screened Finnish paediatric population.
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Kärkinen J, Sorakunnas E, Miettinen PJ, Raivio T, and Hero M
- Abstract
Background: Extremely tall children (defined as height SDS (HSDS) ≥+3) are frequently referred to specialized healthcare for diagnostic work-up. However, no systematic studies focusing on such children currently exist. We investigated the aetiology, clinical features, and auxological clues indicative of syndromic tall stature in extremely tall children subject to population-wide growth monitoring and screening rules., Methods: Subjects with HSDS ≥+3 after three years of age born between 1990 and 2010 were identified from the Helsinki University Hospital district growth database. We comprehensively reviewed their medical records up to December 2020 and recorded underlying diagnoses, auxological data, and clinical features., Findings: We identified 424 subjects (214 girls and 210 boys) who fulfilled the inclusion criteria. Underlying growth disorder was diagnosed in 61 (14%) patients, in 36 (17%) girls and 25 (12%) boys, respectively (P=0•15). Secondary causes were diagnosed in 42 (10%) patients and the two most frequent secondary diagnoses, premature adrenarche, and central precocious puberty were more frequent in girls. Primary disorder, mainly Marfan or Sotos syndrome, was diagnosed in 19 (4%) patients. Molecular genetic studies were used as a part of diagnostic work-up in 120 subjects. However, array CGH or next-generation sequencing studies were seldom used. Idiopathic tall stature (ITS) was diagnosed in 363 (86%) subjects, and it was considered familial in two-thirds. Dysmorphic features or a neurodevelopmental disorder were recorded in 104 (29%) children with ITS. The probability of a monogenic primary growth disorder increased with the degree of tall stature and deviation from target height., Interpretation: A considerable proportion of extremely tall children have an underlying primary or secondary growth disorder, and their risk is associated with auxological parameters. Clinical features related to syndromic tall stature were surprisingly frequent in subjects with ITS, supporting the view that syndromic growth disorders with mild phenotypes may be underdiagnosed in extremely tall children. Our results lend support to comprehensive diagnostic work-up of extremely tall children., Funding: Päivikki and Sakari Sohlberg Foundation, Foundation for Pediatric Research, and Helsinki University Hospital research grants., Competing Interests: The authors have nothing to disclose., (© 2021 The Authors.)
- Published
- 2021
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86. Familial central precocious puberty: two novel MKRN3 mutations.
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Varimo T, Iivonen AP, Känsäkoski J, Wehkalampi K, Hero M, Vaaralahti K, Miettinen PJ, Niedziela M, and Raivio T
- Subjects
- Child, Child, Preschool, Female, Genetic Predisposition to Disease, Gonadotropin-Releasing Hormone analogs & derivatives, Gonadotropin-Releasing Hormone therapeutic use, Heterozygote, Humans, Male, Paternal Inheritance, Pedigree, Phenotype, Puberty, Precocious diagnosis, Puberty, Precocious drug therapy, Treatment Outcome, Mutation, Puberty, Precocious genetics, Ubiquitin-Protein Ligases genetics
- Abstract
Background: Paternally inherited loss-of-function mutations in MKRN3 underlie central precocious puberty (CPP). We describe clinical and genetic features of CPP patients with paternally inherited MKRN3 mutations in two independent families., Methods: The single coding exon of MKRN3 was analyzed in three patients with CPP and their family members, followed by segregation analyses. Additionally, we report the patients' responses to GnRH analog treatment., Results: A paternally inherited novel heterozygous c.939C>G, p.(Ile313Met) missense mutation affecting the RING finger domain of MKRN3 was found in a Finnish girl with CPP (age at presentation 6 years). Two Polish siblings (a girl presenting with B2 at the age of 4 years and a boy with adult size testes at the age of 9 years) had inherited a novel heterozygous MKRN3 mutation c.1237_1252delGGAGACACATGCTTTT p.(Gly413Thrfs*63) from their father. The girls were treated with GnRH analogs, which exhibited suppression of the hypothalamic-pituitary-gonadal axis. In contrast, the male patient was not treated, yet he reached his target height., Conclusions: We describe two novel MKRN3 mutations in three CPP patients. The first long-term data on a boy with CPP due to an MKRN3 mutation questions the role of GnRH analog treatment in augmenting adult height in males with this condition., Impact: We describe the genetic cause for central precocious puberty (CPP) in two families. This report adds two novel MKRN3 mutations to the existing literature. One of the mutations, p.(Ile313Met) affects the RING finger domain of MKRN3, which has been shown to be important for repressing the promoter activity of KISS1 and TAC3. We describe the first long-term observation of a male patient with CPP due to a paternally inherited MKRN3 loss-of-function mutation. Without GnRH analog treatment, he achieved an adult height that was in accordance with his mid-parental target height., (© 2020. International Pediatric Research Foundation, Inc.)
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- 2021
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87. Bone structure assessed with pQCT in prepubertal males with delayed puberty or congenital hypogonadotropic hypogonadism.
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Varimo T, Miettinen PJ, Laine T, Salonen P, Tenhola S, Voutilainen R, Huopio H, Hero M, and Raivio T
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- Adolescent, Adult, Bone Density, Bone and Bones, Cross-Sectional Studies, Humans, Male, Radius diagnostic imaging, Tibia diagnostic imaging, Hypogonadism, Puberty, Delayed
- Abstract
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/mm3 ] vs. 181.2 mg/mm3 [172-192 mg/mm3 ], p = .002) and distal tibia (167.6 mg/mm3 [145-190 mg/mm3 ] vs. 207.2 mg/mm3 [187-227 mg/mm3 ], 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-naïve 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., (© 2021 John Wiley & Sons Ltd.)- Published
- 2021
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88. Bridge study protocol: an international, observational cohort study on the transition of healthcare for adolescents with chronic conditions.
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Kosola S, Culnane E, Loftus H, Tornivuori A, Kallio M, Telfer M, Miettinen PJ, Kolho KL, Aalto K, Raivio T, and Sawyer S
- Subjects
- Adolescent, Adult, Humans, Young Adult, Australia, Chronic Disease, Delivery of Health Care, Finland, Observational Studies as Topic, Prospective Studies, Women's Health, Child Health, Quality of Life
- Abstract
Introduction: More than 10% of adolescents live with a chronic disease or disability that requires regular medical follow-up as they mature into adulthood. During the first 2 years after adolescents with chronic conditions are transferred to adult hospitals, non-adherence rates approach 70% and emergency visits and hospitalisation rates significantly increase. The purpose of the Bridge study is to prospectively examine associations of transition readiness and care experiences with transition success: young patients' health, health-related quality of life (HRQoL) and adherence to medical appointments as well as costs of care. In addition, we will track patients' growing independence and educational and employment pathways during the transition process., Methods and Analysis: Bridge is an international, prospective, observational cohort study. Study participants are adolescents with a chronic health condition or disability and their parents/guardians who attended the New Children's Hospital in Helsinki, Finland, or the Royal Children's Hospital (RCH) in Melbourne, Australia. Baseline assessment took place approximately 6 months prior to the transfer of care and follow-up data will be collected 1 year and 2 years after the transfer of care. Data will be collected from patients' hospital records and from questionnaires completed by the patient and their parent/guardian at each time point. The primary outcomes of this study are adherence to medical appointments, clinical health status and HRQoL and costs of care. Secondary outcome measures are educational and employment outcomes., Ethics and Dissemination: The Ethics Committee for Women's and Children's Health and Psychiatry at the Helsinki University Hospital (HUS/1547/2017) and the RCH Human Research Ethics Committee (38035) have approved the Bridge study protocol. Results will be published in international peer-reviewed journals and summaries will be provided to the funders of the study as well as patients and their parents/guardians., Trial Registration Number: NCT04631965., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2021
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89. Kallmann syndrome in a patient with Weiss-Kruszka syndrome and a de novo deletion in 9q31.2.
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Iivonen AP, Kärkinen J, Yellapragada V, Sidoroff V, Almusa H, Vaaralahti K, and Raivio T
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- Adolescent, Basic Helix-Loop-Helix Transcription Factors genetics, Chromosomes, Human, Pair 9 genetics, Craniofacial Abnormalities complications, DNA Repair Enzymes genetics, Developmental Disabilities complications, Gene Deletion, Haploinsufficiency, Hearing Loss, Sensorineural complications, Heart Septal Defects complications, Humans, Ion Channels genetics, Kallmann Syndrome complications, Kruppel-Like Factor 4, Kruppel-Like Transcription Factors genetics, Male, Membrane Proteins metabolism, Neoplasm Proteins genetics, Sequence Analysis, RNA, Syndrome, Exome Sequencing, Craniofacial Abnormalities genetics, DNA-Binding Proteins genetics, Developmental Disabilities genetics, Hearing Loss, Sensorineural genetics, Heart Septal Defects genetics, Kallmann Syndrome genetics, Membrane Proteins genetics, Nerve Tissue Proteins genetics, Transcription Factors genetics
- Abstract
Patients with deletions on chromosome 9q31.2 may exhibit delayed puberty, craniofacial phenotype including cleft lip/palate, and olfactory bulb hypoplasia. We report a patient with congenital HH with anosmia (Kallmann syndrome, KS) and a de novo 2.38 Mb heterozygous deletion in 9q31.2. The deletion breakpoints (determined with whole-genome linked-read sequencing) were in the FKTN gene (9:108,331,353) and in a non-coding area (9:110,707,332) (hg19). The deletion encompassed six protein-coding genes (FKTN, ZNF462, TAL2, TMEM38B, RAD23B, and KLF4). ZNF462 haploinsufficiency was consistent with the patient's Weiss-Kruszka syndrome (craniofacial phenotype, developmental delay, and sensorineural hearing loss), but did not explain his KS. In further analyses, he did not carry rare sequence variants in 32 known KS genes in whole-exome sequencing and displayed no aberrant splicing of 15 KS genes that were expressed in peripheral blood leukocyte transcriptome. The deletion was 1.8 Mb upstream of a KS candidate gene locus (PALM2AKAP2) but did not suppress its expression. In conclusion, this is the first report of a patient with Weiss-Kruszka syndrome and KS. We suggest that patients carrying a microdeletion in 9q31.2 should be evaluated for the presence of KS and KS-related features.
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- 2021
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90. Circulating miR-30b levels increase during male puberty.
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Varimo T, Wang Y, Miettinen PJ, Vaaralahti K, Hero M, and Raivio T
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- Adolescent, Drug Therapy, Combination, Gonads drug effects, Gonads metabolism, Gonads physiology, Growth Disorders blood, Growth Disorders complications, Growth Disorders drug therapy, Hormone Replacement Therapy, Humans, Hypothalamo-Hypophyseal System drug effects, Hypothalamo-Hypophyseal System metabolism, Hypothalamo-Hypophyseal System physiology, Injections, Intramuscular, Letrozole administration & dosage, Letrozole pharmacology, Longitudinal Studies, Male, Puberty drug effects, Puberty genetics, Puberty, Delayed blood, Puberty, Delayed complications, Puberty, Delayed drug therapy, Testosterone administration & dosage, Testosterone pharmacology, Ubiquitin-Protein Ligases genetics, MicroRNAs blood, Puberty blood
- Abstract
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.
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- 2021
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91. Contribution of the Locus of Heat Resistance to Growth and Survival of Escherichia coli at Alkaline pH and at Alkaline pH in the Presence of Chlorine.
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Zhu T, Wang Z, McMullen LM, Raivio T, Simpson DJ, and Gänzle MG
- Abstract
The locus of heat resistance (LHR) confers resistance to extreme heat, chlorine and oxidative stress in Escherichia coli . This study aimed to determine the function of the LHR in maintaining bacterial cell envelope homeostasis, the regulation of the genes comprising the LHR and the contribution of the LHR to alkaline pH response. The presence of the LHR did not affect the activity of the Cpx two-component regulatory system in E. coli , which was measured to quantify cell envelope stress. The LHR did not alter E. coli MG1655 growth rate in the range of pH 6.9 to 9.2. However, RT-qPCR results indicated that the expression of the LHR was elevated at pH 8.0 when CpxR was absent. The LHR did not improve survival of E. coli MG1655 at extreme alkaline pH (pH = 11.0 to 11.2) but improved survival at pH 11.0 in the presence of chlorine. Therefore, we conclude that the LHR confers resistance to extreme alkaline pH in the presence of oxidizing agents. Resistance to alkaline pH is regulated by an endogenous mechanism, including the Cpx envelope stress response, whereas the LHR confers resistance to extreme alkaline pH only in the presence of additional stress such as chlorine.
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- 2021
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92. Etiology of severe short stature below -3 SDS in a screened Finnish population.
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Kärkinen J, Miettinen PJ, Raivio T, and Hero M
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- Adolescent, Body Height, Child, Child, Preschool, Databases, Factual, Dwarfism epidemiology, Female, Finland epidemiology, Growth Charts, Growth Disorders epidemiology, Humans, Male, Retrospective Studies, Syndrome, Dwarfism etiology, Growth Disorders etiology
- Abstract
Objective: To describe the etiology of severe short stature in the Helsinki University Hospital district covering a population of 1.2 million that is subject to frequent growth monitoring and screening rules during childhood., Design: Retrospective cohort study., Methods: We identified all subjects born 1990 or later with a height SD score <-3, after the age of 3 years, from the Helsinki University Hospital district growth database. A total of 785 subjects (376 females and 409 males) fulfilled our inclusion criteria; we reviewed their medical records and growth data and report their underlying diagnoses., Results: A pathological cause for short stature was diagnosed in 76% of the girls and 71% of the boys (P = NS). Syndromes were the most numerous pathological cause (n = 160; 20%), followed by organ disorders (n = 127; 16%), growth hormone deficiency (GHD, n = 94; 12%), SGA without catch-up growth (n = 73; 9%), and skeletal dysplasias (n = 57; 7%). Idiopathic short stature (ISS) was diagnosed in 210 (27%) subjects. The probability of growth-related pathology, particularly of a syndrome or skeletal dysplasia, increased with the shorter height SD score and the greater deviation from the target height. Sitting height to height SDS was increased in subjects with ISS, GHD, and SGA (all P < 0.01)., Conclusions: Height <-3 SDS after 3 years of age usually results from a pathological cause and should be thoroughly investigated in specialized health care. The chance of finding a specific etiology increased with the severity of short stature, and the mismatch with target height.
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- 2020
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93. Effect of Pediatric Testicular Torsion on Testicular Function in the Short Term.
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Taskinen S, Mäkelä E, and Raivio T
- Subjects
- Adolescent, Child, Humans, Male, Orchiectomy, Orchiopexy, Organ Sparing Treatments, Retrospective Studies, Treatment Outcome, Spermatic Cord Torsion physiopathology, Spermatic Cord Torsion surgery, Testis physiology, Testis surgery
- Abstract
Purpose: To evaluate short-term testicular outcome after torsion in children., Methods: Fifty-four children and adolescents were evaluated after 6 months of the operation for testicular torsion. Testicular volume was measured and circulating Inhibin B, FSH, LH and testosterone levels were checked., Results: Delay from the onset of symptoms to surgery was shorter in the orchidopexy group (n = 47), than in the orchiectomy group (n = 7, p = 0.001). In the orchidopexy group, the median volume of the affected testis was 83% (IQR 43-104) of the contralateral testis (p = 0.002). The plasma hormone levels in orchidopexy and orchiectomy groups were: 148 ng/l (IQR 108-208) vs. 129 ng/l (IQR, 123-138, p = 0.269) for Inhibin B; 4.5 IU/L (IQR2.6-6.9) vs. 11.7 IU/L (IQR 4.3-12.8, p = 0.037) for FSH; 2.9 IU/L (IQR 1.3-3.7) vs. 4.8 (IQR 3.0-5.6, p = 0.066) for LH; and 13.6 nM (IQR 6.5-18.0) vs. 14.5 nM (IQR 6.7-15.9, p = 0.834) for testosterone. The association between FSH, LH as well as testosterone levels was most clear with the volume of the contralateral testis (Rho = 0.574, p < 0.001, Rho = 0.621, p = 0.001 and Rho 0.718, p < 0.001 respectively)., Conclusions: Testicular function is mainly dependent on the volume of contralateral testicle after testicular torsion. However, testis preserving surgery tends to maintain better function than orchiectomy., Type of Study: Retrospective review., Level of Evidence: III., (Copyright © 2019 Elsevier Inc. All rights reserved.)
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- 2020
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94. Characterization of the human GnRH neuron developmental transcriptome using a GNRH1 -TdTomato reporter line in human pluripotent stem cells.
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Lund C, Yellapragada V, Vuoristo S, Balboa D, Trova S, Allet C, Eskici N, Pulli K, Giacobini P, Tuuri T, and Raivio T
- Subjects
- CRISPR-Associated Protein 9 metabolism, CRISPR-Cas Systems genetics, Cell Line, Fetus cytology, Fibroblast Growth Factor 8 pharmacology, Humans, Hypogonadism genetics, LIM-Homeodomain Proteins metabolism, Neurons drug effects, Pluripotent Stem Cells drug effects, RNA, Messenger genetics, RNA, Messenger metabolism, Transcription Factors metabolism, Up-Regulation drug effects, Up-Regulation genetics, Genes, Reporter, Gonadotropin-Releasing Hormone metabolism, Neurons metabolism, Pluripotent Stem Cells metabolism, Transcriptome genetics
- Abstract
Gonadotropin-releasing hormone (GnRH) neurons provide a fundamental signal for the onset of puberty and subsequent reproductive functions by secretion of gonadotropin-releasing hormone. Their disrupted development or function leads to congenital hypogonadotropic hypogonadism (CHH). To model the development of human GnRH neurons, we generated a stable GNRH1 -TdTomato reporter cell line in human pluripotent stem cells (hPSCs) using CRISPR-Cas9 genome editing. RNA-sequencing of the reporter clone, differentiated into GnRH neurons by dual SMAD inhibition and FGF8 treatment, revealed 6461 differentially expressed genes between progenitors and GnRH neurons. Expression of the transcription factor ISL1 , one of the top 50 most upregulated genes in the TdTomato-expressing GnRH neurons, was confirmed in 10.5 gestational week-old human fetal GnRH neurons. Among the differentially expressed genes, we detected 15 genes that are implicated in CHH and several genes that are implicated in human puberty timing. Finally, FGF8 treatment in the neuronal progenitor pool led to upregulation of 37 genes expressed both in progenitors and in TdTomato-expressing GnRH neurons, which suggests upstream regulation of these genes by FGF8 signaling during GnRH neuron differentiation. These results illustrate how hPSC-derived human GnRH neuron transcriptomic analysis can be utilized to dissect signaling pathways and gene regulatory networks involved in human GnRH neuron development.This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)
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- 2020
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95. Neuron-Derived Neurotrophic Factor Is Mutated in Congenital Hypogonadotropic Hypogonadism.
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Messina A, Pulli K, Santini S, Acierno J, Känsäkoski J, Cassatella D, Xu C, Casoni F, Malone SA, Ternier G, Conte D, Sidis Y, Tommiska J, Vaaralahti K, Dwyer A, Gothilf Y, Merlo GR, Santoni F, Niederländer NJ, Giacobini P, Raivio T, and Pitteloud N
- Subjects
- Adolescent, Animals, Cohort Studies, Female, Heterozygote, Humans, Hypogonadism pathology, Male, Mice, Mice, Knockout, Nerve Growth Factors physiology, Neurons metabolism, Pedigree, Zebrafish, Cell Movement, Hypogonadism congenital, Hypogonadism genetics, Mutation, Nerve Growth Factors genetics, Neurons pathology
- Abstract
Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by infertility and the absence of puberty. Defects in GnRH neuron migration or altered GnRH secretion and/or action lead to a severe gonadotropin-releasing hormone (GnRH) deficiency. Given the close developmental association of GnRH neurons with the olfactory primary axons, CHH is often associated with anosmia or hyposmia, in which case it is defined as Kallmann syndrome (KS). The genetics of CHH are heterogeneous, and >40 genes are involved either alone or in combination. Several CHH-related genes controlling GnRH ontogeny encode proteins containing fibronectin-3 (FN3) domains, which are important for brain and neural development. Therefore, we hypothesized that defects in other FN3-superfamily genes would underlie CHH. Next-generation sequencing was performed for 240 CHH unrelated probands and filtered for rare, protein-truncating variants (PTVs) in FN3-superfamily genes. Compared to gnomAD controls the CHH cohort was statistically enriched for PTVs in neuron-derived neurotrophic factor (NDNF) (p = 1.40 × 10
-6 ). Three heterozygous PTVs (p.Lys62∗ , p.Tyr128Thrfs∗ 55, and p.Trp469∗ , all absent from the gnomAD database) and an additional heterozygous missense mutation (p.Thr201Ser) were found in four KS probands. Notably, NDNF is expressed along the GnRH neuron migratory route in both mouse embryos and human fetuses and enhances GnRH neuron migration. Further, knock down of the zebrafish ortholog of NDNF resulted in altered GnRH migration. Finally, mice lacking Ndnf showed delayed GnRH neuron migration and altered olfactory axonal projections to the olfactory bulb; both results are consistent with a role of NDNF in GnRH neuron development. Altogether, our results highlight NDNF as a gene involved in the GnRH neuron migration implicated in KS., (Copyright © 2019. Published by Elsevier Inc.)- Published
- 2020
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96. Constitutional delay of puberty versus congenital hypogonadotropic hypogonadism: Genetics, management and updates.
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Raivio T and Miettinen PJ
- Subjects
- Adolescent, Diagnosis, Differential, Female, Humans, Hypogonadism congenital, Hypogonadism diagnosis, Male, Puberty physiology, Puberty, Delayed diagnosis, Puberty, Delayed etiology, Puberty, Delayed genetics, Hypogonadism complications, Puberty, Delayed therapy
- Abstract
Delayed puberty (DP) affects approximately 2% of adolescents. In the vast majority of patients in both sexes, it is due to constitutional delay of growth and puberty (CDGP), a self-limited condition in which puberty starts later than usual but progresses normally. However, some CDGP patients may benefit from medical intervention with low-dose sex steroids or peroral aromatase inhibitor letrozole (only for boys). Other causes of DP include permanent hypogonadotropic hypogonadism, functional hypogonadotropic hypogonadism (due to chronic diseases and conditions), and gonadal failure. In this review we discuss these themes along with the latest achievements in the field of puberty research, and include a brief synopsis on the differential diagnosis and management of patients with CDGP and congenital hypogonadotropic hypogonadism., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2019
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97. Treatment of gonadotropin deficiency during the first year of life: long-term observation and outcome in five boys.
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Kohva E, Huopio H, Hietamäki J, Hero M, Miettinen PJ, and Raivio T
- Subjects
- Adolescent, Child, Child, Preschool, Drug Therapy, Combination methods, Follicle Stimulating Hormone, Human administration & dosage, Follow-Up Studies, Gonadotropins blood, Humans, Hypogonadism blood, Hypogonadism congenital, Hypogonadism diagnosis, Infant, Inhibins blood, Inhibins metabolism, Longitudinal Studies, Male, Puberty blood, Recombinant Proteins administration & dosage, Retrospective Studies, Sertoli Cells metabolism, Severity of Illness Index, Testosterone administration & dosage, Treatment Outcome, Gonadotropins deficiency, Hypogonadism drug therapy, Puberty drug effects, Sertoli Cells drug effects
- Abstract
Study Question: What is the peripubertal outcome of recombinant human FSH (r-hFSH) treatment during minipuberty in boys with congenital hypogonadotropic hypogonadism (CHH)?, Summary Answer: Sertoli-cell response to r-hFSH, given during the minipuberty of infancy, appears insufficient to maintain Sertoli cell function throughout childhood, as evaluated by inhibin B measurements., What Is Known Already: Severe CHH in boys can be diagnosed during the minipuberty of infancy. Combined gonadotropin treatment at that age is suggested to improve testicular endocrine function and future fertility, yet long-term evidence is lacking., Study Design, Size, Duration: In this retrospective cohort study, we describe five CHH boys treated with r-hFSH in Helsinki University Hospital or Kuopio University Hospital between 2004 and 2018. Immediate follow-up data (0.1-1.4 months after cessation of the gonadotropin therapy) was available for four boys and long-term observations (at the age of 10.0-12.8 years) was available for three boys. As a retrospective control cohort, we provide inhibin B values of eight untreated CHH boys at the age of 12.7-17.8 years., Participants/materials, Setting, Methods: Four patients had combined pituitary hormone deficiency, and one had CHARGE syndrome due to a CHD7 mutation. The patients were treated at the age of 0.7-4.2 months with r-hFSH (3.4 IU/kg-7.5 IU/kg per week in 2 or 3 s.c. doses for 3-4.5 months) combined with T (25 mg i.m. monthly for three months for the treatment of micropenis). Inhibin B was chosen as the primary outcome measure., Main Results and the Role of Chance: During the r-hFSH + T treatment, inhibin B increased from 76 ± 18 ng/l to 176 ± 80 ng/l (P = 0.04) and penile length increased by 81 ± 50% (P = 0.04). Unexpectedly, two boys with robust inhibin B responses in infancy demonstrated low inhibin B values in peripuberty: declining from 290 ng/l (4 months) to 16 ng/l (12.4 years), and from 207 ng/l (6 months) to 21 ng/l (12.8 years). All boys underwent orchiopexy at 2.0 ± 0.7 years of age. Inhibin B values in long-term follow-up, available for the three boys, did not significantly differ from the untreated CHH controls., Limitations, Reasons for Caution: Limitations of this retrospective study are the small number and heterogeneity of the patients and their treatment schemes., Wider Implications of the Findings: We describe the first long-term follow-up data on CHH boys treated with r-hFSH and T as infants. The results from this small patient series suggest that the effects of infant r-hFSH treatment may be transient, and further longitudinal studies are required to determine the efficacy of this treatment approach to optimise the fertility potential in this patient population., Study Funding/competing Interest(s): This work was supported by the Finnish foundation for Pediatric Research, the Academy of Finland and the Emil Aaltonen Foundation. The authors have no competing interests., Trial Registration Number: Non-applicable., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.)
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- 2019
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98. Screening for mutations in selected miRNA genes in hypogonadotropic hypogonadism patients.
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Iivonen AP, Känsäkoski J, Vaaralahti K, and Raivio T
- Abstract
In approximately half of congenital hypogonadotropic hypogonadism (cHH) patients, the genetic cause remains unidentified. Since the lack of certain miRNAs in animal models has led to cHH, we sequenced human miRNAs predicted to regulate cHH-related genes (MIR7-3, MIR141, MIR429 and MIR200A-C) in 24 cHH patients with Sanger sequencing. A heterozygous variant in MIR200A (rs202051309; general population frequency of 0.02) was found in one patient. Our results suggest that mutations in the studied miRNAs are unlikely causes of cHH. However, the complex interplay between miRNAs and their target genes in these diseases requires further investigations.
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- 2019
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99. Letrozole Monotherapy in Pre- and Early-Pubertal Boys Does Not Increase Adult Height.
- Author
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Varimo T, Toiviainen-Salo S, Raivio T, Kerttula L, Dunkel L, and Hero M
- Abstract
Background: Aromatase inhibitors (AIs) 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 AI-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 (Pl) 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 Pl ( 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 [Pl: 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 Pl, 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 Pl 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.
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- 2019
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100. Clinical Management of Congenital Hypogonadotropic Hypogonadism.
- Author
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Young J, Xu C, Papadakis GE, Acierno JS, Maione L, Hietamäki J, Raivio T, and Pitteloud N
- Subjects
- Adolescent, Adult, Female, Humans, Infant, Infant, Newborn, Male, Gonadotropin-Releasing Hormone administration & dosage, Gonadotropin-Releasing Hormone deficiency, Gonadotropin-Releasing Hormone metabolism, Gonadotropins administration & dosage, Hypogonadism congenital, Hypogonadism diagnosis, Hypogonadism drug therapy, Hypogonadism metabolism
- Abstract
The initiation and maintenance of reproductive capacity in humans is dependent on pulsatile secretion of the hypothalamic hormone GnRH. Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder that results from the failure of the normal episodic GnRH secretion, leading to delayed puberty and infertility. CHH can be associated with an absent sense of smell, also termed Kallmann syndrome, or with other anomalies. CHH is characterized by rich genetic heterogeneity, with mutations in >30 genes identified to date acting either alone or in combination. CHH can be challenging to diagnose, particularly in early adolescence where the clinical picture mirrors that of constitutional delay of growth and puberty. Timely diagnosis and treatment will induce puberty, leading to improved sexual, bone, metabolic, and psychological health. In most cases, patients require lifelong treatment, yet a notable portion of male patients (∼10% to 20%) exhibit a spontaneous recovery of their reproductive function. Finally, fertility can be induced with pulsatile GnRH treatment or gonadotropin regimens in most patients. In summary, this review is a comprehensive synthesis of the current literature available regarding the diagnosis, patient management, and genetic foundations of CHH relative to normal reproductive development., (Copyright © 2019 Endocrine Society.)
- Published
- 2019
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