RESUMEN
Objective: The safety and impact of the advanced hybrid closed-loop (AHCL) system on glycemic outcome in 2- to 6-year-old children with type 1 diabetes and the diabetes distress of caregivers were evaluated. Research Design and Methods: This was an open-label prospective study (n = 35) with historical controls matched by treatment unit, diabetes duration, age, gender, and baseline treatment modality. The inclusion criteria were (1) type 1 diabetes diagnosis >6 months, (2) total daily dose of insulin ≥8 U/day, (3) HbA1c <10% (85 mmol/mol), and (4) capability to use insulin pump and continuous glucose monitoring. The MiniMed 780G™ AHCL in SmartGuard™ Mode was used for 12 weeks. Parental diabetes distress was evaluated with a validated Problem Areas In Diabetes-Parent, revised (PAID-PR) survey. Results: No events of diabetic ketoacidosis or severe hypoglycemia occurred. Between 0 and 12 weeks, HbA1c (mean change = -2.7 mmol/mol [standard deviation 5.7], P = 0.010), mean sensor glucose value (SG) (-0.8 mmol/L [1.0], P < 0.001), and time above range (TAR) (-8.6% [9.5], P < 0.001) decreased and time in range (TIR) (8.3% [9.3], P < 0.001) increased significantly, whereas no significant change in time below range (TBR) was observed. At the same time, PAID-PR score decreased from 37.5 (18.2) to 27.5 (14.8) (P = 0.006). Conclusions: MiniMed 780G™ AHCL is a safe system and 12-week use was associated with improvements in glycemic control in 2- to 6-year-old children with type 1 diabetes. In addition, AHCL is associated with a reduction in parental diabetes distress after 12-week use. ClinicalTrials.gov registration number: NCT04949022.
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Diabetes Mellitus Tipo 1 , Niño , Humanos , Glucemia , Automonitorización de la Glucosa Sanguínea , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/complicaciones , Hemoglobina Glucada , Hipoglucemiantes/uso terapéutico , Insulina/efectos adversos , Sistemas de Infusión de Insulina , Estudios Prospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: It has been suggested that adverse early life exposures increase the risk of developing polycystic ovary syndrome (PCOS) in later life. We hypothesized that women born preterm would have more biochemical and clinical signs of PCOS than women born at term. DESIGN: The ESTER Preterm Birth Study participants were born in Northern Finland and identified from the Northern Finland Birth Cohort and the Finnish Medical Birth Register. Altogether, 74 women born very or moderately preterm (<34 gestational weeks, VMPT), 127 born late preterm (at 34-36 weeks, LPT), and 184 born full term (≥37 weeks, controls) were included in the analysis (mean age: 23.2 years). METHODS: We measured serum total testosterone and sex hormone-binding globulin (SHBG) and calculated the free androgen index (FAI). PCOS according to the clinical and biochemical signs was defined either as hirsutism and oligoamenorrhea (via questionnaire) or as oligoamenorrhea and elevated testosterone levels (>2.4 nmol/L). RESULTS: Women born VMPT/LPT exhibited 33.0% (8.7, 62.8)/16.4% (-2.0, 38.1) higher testosterone, 28.5% (5.3, 45.9)/24.1% (5.6, 38.9) lower SHBG levels, and 64.6% (19.4, 127.1)/42.5% (11.1, 82.9) higher FAI than controls after adjusting for age and recruitment cohort, maternal BMI, smoking, and pregnancy disorders, parental education, history of hypertension, diabetes, myocardial infarction or stroke, and subject's birth weight s.d. Odds ratios for having PCOS were 1.67 (0.44, 6.23)/3.11 (1.26, 7.70). CONCLUSIONS: Women born preterm have a more hyperandrogenic hormonal profile, and those born LPT are approximately three times more likely at risk to have PCOS compared to women born at term.
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Biomarcadores , Síndrome del Ovario Poliquístico/diagnóstico , Síndrome del Ovario Poliquístico/epidemiología , Nacimiento Prematuro/epidemiología , Adulto , Hijos Adultos/estadística & datos numéricos , Andrógenos/sangre , Biomarcadores/análisis , Biomarcadores/sangre , Índice de Masa Corporal , Estudios de Casos y Controles , Femenino , Finlandia/epidemiología , Edad Gestacional , Hirsutismo/sangre , Hirsutismo/diagnóstico , Hirsutismo/epidemiología , Humanos , Recién Nacido , Síndrome del Ovario Poliquístico/sangre , Síndrome del Ovario Poliquístico/etiología , Embarazo , Complicaciones del Embarazo/epidemiología , Efectos Tardíos de la Exposición Prenatal/epidemiología , Efectos Tardíos de la Exposición Prenatal/etiología , Factores de Riesgo , Testosterona/sangre , Adulto JovenRESUMEN
A multicenter randomized controlled pilot trial investigated whether motivational interviewing (MI) by diabetes physicians improves glycemic control and variability in the context of follow-up for adolescent patients with poorly controlled type 1 diabetes. Patients (n = 47) aged 12 to 15.9 years who showed poor glycemic control (HbA1c >75 mmol/mol/9.0%) were randomized to standard education (SE) only or MI+SE, with study physicians randomized to employ MI+SE (N = 24 patients) or SE only (N = 23). For one year of follow-up, the main outcome measurements were obtained at three-month visits (HbA1c) or six-monthly: time in range (TIR) and glycemic variability (CV). Mean adjusted 12-month change in HbA1c was similar between the MI+SE and SE-only group (-3.6 vs. -1.0 mmol/mol), and no inter-group differences were visible in the mean adjusted 12-month change in TIR (-0.8 vs. 2.6%; P = 0.53) or CV (-0.5 vs. -6.2; P = 0.26). However, the order of entering the study correlated significantly with the 12-month change in HbA1c in the MI+SE group (r = -0.5; P = 0.006) and not in the SE-only group (r = 0.2; P = 0.4). No link was evident between MI and changes in quality of life. The authors conclude that MI's short-term use by diabetes physicians managing adolescents with poorly controlled type 1 diabetes was not superior to SE alone; however, improved skills in applying the MI method at the outpatient clinic may produce greater benefits in glycemic control.
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Glucemia/análisis , Diabetes Mellitus Tipo 1/psicología , Diabetes Mellitus Tipo 1/terapia , Entrevista Motivacional/métodos , Adolescente , Antropometría , Niño , Diabetes Mellitus Tipo 1/sangre , Femenino , Finlandia , Hemoglobina Glucada/biosíntesis , Humanos , Masculino , Pacientes Ambulatorios , Proyectos Piloto , Calidad de Vida , Reproducibilidad de los Resultados , Resultado del TratamientoRESUMEN
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.
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Mutación , Pubertad Precoz/genética , Ubiquitina-Proteína Ligasas/genética , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/uso terapéutico , Heterocigoto , Humanos , Masculino , Herencia Paterna , Linaje , Fenotipo , Pubertad Precoz/diagnóstico , Pubertad Precoz/tratamiento farmacológico , Resultado del TratamientoRESUMEN
The initiation of puberty is driven by an upsurge in hypothalamic gonadotropin-releasing hormone (GnRH) secretion. In turn, GnRH secretion upsurge depends on the development of a complex GnRH neuroendocrine network during embryonic life. Although delayed puberty (DP) affects up to 2% of the population, is highly heritable, and is associated with adverse health outcomes, the genes underlying DP remain largely unknown. We aimed to discover regulators by whole-exome sequencing of 160 individuals of 67 multigenerational families in our large, accurately phenotyped DP cohort. LGR4 was the only gene remaining after analysis that was significantly enriched for potentially pathogenic, rare variants in 6 probands. Expression analysis identified specific Lgr4 expression at the site of GnRH neuron development. LGR4 mutant proteins showed impaired Wnt/ß-catenin signaling, owing to defective protein expression, trafficking, and degradation. Mice deficient in Lgr4 had significantly delayed onset of puberty and fewer GnRH neurons compared with WT, whereas lgr4 knockdown in zebrafish embryos prevented formation and migration of GnRH neurons. Further, genetic lineage tracing showed strong Lgr4-mediated Wnt/ß-catenin signaling pathway activation during GnRH neuron development. In conclusion, our results show that LGR4 deficiency impairs Wnt/ß-catenin signaling with observed defects in GnRH neuron development, resulting in a DP phenotype.
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Neuronas , Pubertad Tardía , Receptores Acoplados a Proteínas G/deficiencia , Vía de Señalización Wnt , Animales , Femenino , Estudios de Seguimiento , Hormona Liberadora de Gonadotropina/genética , Hormona Liberadora de Gonadotropina/metabolismo , Humanos , Masculino , Ratones , Neuronas/metabolismo , Neuronas/patología , Pubertad Tardía/genética , Pubertad Tardía/metabolismo , Pubertad Tardía/patología , Receptores Acoplados a Proteínas G/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
CONTEXT: Maternal gestational diabetes mellitus (GDM) and prepregnancy overweight/obesity [body mass index (BMI) ≥25 kg/m2] might adversely affect offspring cardiometabolic health. OBJECTIVE: To assess the associations between maternal GDM and prepregnancy overweight/obesity with adult offspring cardiometabolic risk factors. DESIGN: Longitudinal cohort study (ESTER Maternal Pregnancy Disorders Study and the Arvo Ylppö Longitudinal Study). SETTING: Province of Uusimaa and Northern Finland. PARTICIPANTS: At a mean age of 24.1 ± 1.3 years, we classified offspring as offspring of mothers with GDM regardless of the prepregnancy BMI (OGDM; n = 193); normoglycemic mothers with prepregnancy overweight/obesity (ONO; n = 157); and normoglycemic mothers with prepregnancy BMI <25 kg/m2 (controls; n = 556). MAIN OUTCOME MEASURES: We assessed the cardiometabolic biomarkers from blood and measured the blood pressure at rest and heart rate. RESULTS: Compared with the controls, the OGDM and ONO groups had greater fasting glucose (1.6%; 95% CI, 0.1% to 3.1%; and 2.3%; 95% CI, 0.5% to 4.3%, respectively) and insulin (12.7%; 95% CI, 4.4% to 21.9%; and 8.7%; 95% CI, 0.2% to 17.8%). These differences attenuated to nonsignificance when adjusted for confounders and/or current offspring characteristics, including BMI or body fat percentage. The OGDM group had lower SHBG (men, -12.4%; 95% CI, -20.2% to -3.9%; women, -33.2%; 95% CI, -46.3% to -16.8%), high-density lipoprotein (-6.6%; 95% CI, -10.9% to -2.2%), and apolipoprotein A1 (-4.5%; 95% CI, -7.5% to -1.4%). These differences survived the adjustments. The heart rate and other biomarkers were similar among the groups. CONCLUSIONS: Adult offspring of mothers with GDM have increased markers of insulin resistance and a more atherogenic lipid profile. These were only partly explained by confounders or current offspring adiposity. Maternal prepregnancy overweight/obesity was associated with impaired offspring glucose regulation, which was explained by confounders and/or current adiposity.
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Enfermedades Cardiovasculares/metabolismo , Diabetes Gestacional/epidemiología , Síndrome Metabólico/metabolismo , Obesidad Materna/epidemiología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Adulto , Apolipoproteína A-I/metabolismo , Apolipoproteínas B/metabolismo , Biomarcadores , Glucemia/metabolismo , Presión Sanguínea , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Estudios de Cohortes , Femenino , Finlandia/epidemiología , Frecuencia Cardíaca , Humanos , Insulina/metabolismo , Resistencia a la Insulina , Estudios Longitudinales , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/epidemiología , Globulina de Unión a Hormona Sexual/metabolismo , Triglicéridos/metabolismo , Adulto JovenRESUMEN
The initiation of puberty is orchestrated by an augmentation of gonadotropin-releasing hormone (GnRH) secretion from a few thousand hypothalamic neurons. Recent findings have indicated that the neuroendocrine control of puberty may be regulated by a hierarchically organized network of transcriptional factors acting upstream of GnRH. These include enhanced at puberty 1 (EAP1), which contributes to the initiation of female puberty through transactivation of the GnRH promoter. However, no EAP1 mutations have been found in humans with disorders of pubertal timing. We performed whole-exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited delayed puberty (DP). Variants were analyzed for rare, potentially pathogenic variants enriched in case versus controls and relevant to the biological control of puberty. We identified one in-frame deletion (Ala221del) and one rare missense variant (Asn770His) in EAP1 in two unrelated families; these variants were highly conserved and potentially pathogenic. Expression studies revealed Eap1 mRNA abundance in peri-pubertal mouse hypothalamus. EAP1 binding to the GnRH1 promoter increased in monkey hypothalamus at the onset of puberty as determined by chromatin immunoprecipitation. Using a luciferase reporter assay, EAP1 mutants showed a reduced ability to trans-activate the GnRH promoter compared to wild-type EAP1, due to reduced protein levels caused by the Ala221del mutation and subcellular mislocation caused by the Asn770His mutation, as revealed by western blot and immunofluorescence, respectively. In conclusion, we have identified the first EAP1 mutations leading to reduced GnRH transcriptional activity resulting in a phenotype of self-limited DP.
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Hormona Liberadora de Gonadotropina/fisiología , Pubertad Tardía/genética , Securina/genética , Adolescente , Adulto , Animales , Niño , Femenino , Regulación de la Expresión Génica/genética , Hormona Liberadora de Gonadotropina/genética , Humanos , Hipotálamo/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Neuronas/metabolismo , Regiones Promotoras Genéticas/genética , Pubertad/genética , Pubertad/fisiología , ARN Mensajero/genética , Securina/fisiología , Maduración Sexual/genética , Transactivadores/genética , Factores de Transcripción/genética , Secuenciación del Exoma , Adulto JovenRESUMEN
Context: Self-limited delayed puberty (DP) segregates in an autosomal-dominant pattern, but the genetic basis is largely unknown. Although DP is sometimes seen in relatives of patients with hypogonadotropic hypogonadism (HH), mutations in genes known to cause HH that segregate with the trait of familial self-limited DP have not yet been identified. Objective: To assess the contribution of mutations in genes known to cause HH to the phenotype of self-limited DP. Design, Patients, and Setting: We performed whole-exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited DP, validated the pathogenicity of the identified gene variant in vitro, and examined the tissue expression and functional requirement of the mouse homolog in vivo. Results: A potentially pathogenic gene variant segregating with DP was identified in 1 of 28 known HH genes examined. This pathogenic variant occurred in HS6ST1 in one pedigree and segregated with the trait in the six affected members with heterozygous transmission (P = 3.01 × 10-5). Biochemical analysis showed that this mutation reduced sulfotransferase activity in vitro. Hs6st1 mRNA was expressed in peripubertal wild-type mouse hypothalamus. GnRH neuron counts were similar in Hs6st1+/- and Hs6st1+/+ mice, but vaginal opening was delayed in Hs6st1+/- mice despite normal postnatal growth. Conclusions: We have linked a deleterious mutation in HS6ST1 to familial self-limited DP and show that heterozygous Hs6st1 loss causes DP in mice. In this study, the observed overlap in potentially pathogenic mutations contributing to the phenotypes of self-limited DP and HH was limited to this one gene.
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Hipogonadismo/genética , Pubertad Tardía/genética , Sulfotransferasas/deficiencia , Animales , Estudios de Cohortes , Femenino , Finlandia , Hormona Liberadora de Gonadotropina/genética , Heterocigoto , Humanos , Hipotálamo/metabolismo , Masculino , Ratones , Mutación , Linaje , Fenotipo , Sulfotransferasas/genética , Secuenciación del ExomaRESUMEN
Context: Self-limited delayed puberty (DP) is often associated with a delay in physical maturation, but although highly heritable the causal genetic factors remain elusive. Genome-wide association studies of the timing of puberty have identified multiple loci for age at menarche in females and voice break in males, particularly in pathways controlling energy balance. Objective/Main Outcome Measures: We sought to assess the contribution of rare variants in such genes to the phenotype of familial DP. Design/Patients: We performed whole-exome sequencing in 67 pedigrees (125 individuals with DP and 35 unaffected controls) from our unique cohort of familial self-limited DP. Using a whole-exome sequencing filtering pipeline one candidate gene [fat mass and obesity-associated gene (FTO)] was identified. In silico, in vitro, and mouse model studies were performed to investigate the pathogenicity of FTO variants and timing of puberty in FTO+/- mice. Results: We identified potentially pathogenic, rare variants in genes in linkage disequilibrium with genome-wide association studies of age at menarche loci in 283 genes. Of these, five genes were implicated in the control of body mass. After filtering for segregation with trait, one candidate, FTO, was retained. Two FTO variants, found in 14 affected individuals from three families, were also associated with leanness in these patients with DP. One variant (p.Leu44Val) demonstrated altered demethylation activity of the mutant protein in vitro. Fto+/- mice displayed a significantly delayed timing of pubertal onset (P < 0.05). Conclusions: Mutations in genes implicated in body mass and timing of puberty in the general population may contribute to the pathogenesis of self-limited DP.
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Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Peso Corporal/genética , Polimorfismo de Nucleótido Simple , Pubertad Tardía/genética , Pubertad/genética , Adolescente , Animales , Índice de Masa Corporal , Estudios de Casos y Controles , Niño , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Ratones , Ratones Noqueados , Linaje , Fenotipo , Factores de TiempoAsunto(s)
Glycyrrhiza , Estrés Psicológico , Niño , Cognición , Femenino , Humanos , Embarazo , Efectos Tardíos de la Exposición PrenatalRESUMEN
Earlier puberty, especially in girls, is associated with physical and mental disorders. Prenatal glucocorticoid exposure influences the timing of puberty in animal models, but the human relevance of those findings is unknown. We studied whether voluntary consumption of licorice, which contains glycyrrhizin (a potent inhibitor of placental 11ß-hydroxysteroid dehydrogenase type 2, the "barrier" to maternal glucocorticoids), by pregnant women was associated with pubertal maturation (height, weight, body mass index for age, difference between current and expected adult height, Tanner staging, score on the Pubertal Development Scale), neuroendocrine function (diurnal salivary cortisol, dexamethasone suppression), cognition (neuropsychological tests), and psychiatric problems (as measured by the Child Behavior Checklist) in their offspring. The children were born in 1998 in Helsinki, Finland, and examined during 2009-2011 (mean age = 12.5 (standard deviation (SD), 0.4) years; n = 378). Girls exposed to high maternal glycyrrhizin consumption (≥500 mg/week) were taller (mean difference (MD) = 0.4 SD, 95% confidence interval (CI): 0.1, 0.8), were heavier (MD = 0.6 SD, 95% CI: 0.2, 1.9), and had higher body mass index for age (MD = 0.6 SD, 95% CI: 0.2, 0.9). They were also 0.5 standard deviations (95% CI: 0.2, 0.8) closer to adult height and reported more advanced pubertal development (P < 0.04). Girls and boys exposed to high maternal glycyrrhizin consumption scored 7 (95% CI: 3.1, 11.2) points lower on tests of intelligence quotient, had poorer memory (P < 0.04), and had 3.3-fold (95% CI: 1.4, 7.7) higher odds of attention deficit/hyperactivity disorder problems compared with children whose mothers consumed little to no glycyrrhizin (≤249 mg/week). No differences in cortisol levels were found. Licorice consumption during pregnancy may be associated with harm for the developing offspring.
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Trastorno por Déficit de Atención con Hiperactividad/inducido químicamente , Glycyrrhiza/efectos adversos , Ácido Glicirrínico/farmacología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Inteligencia/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal , Maduración Sexual/efectos de los fármacos , Adolescente , Antiinflamatorios/efectos adversos , Antiinflamatorios/farmacología , Índice de Masa Corporal , Niño , Factores de Confusión Epidemiológicos , Dexametasona/administración & dosificación , Dexametasona/farmacología , Femenino , Finlandia , Estudios de Seguimiento , Ácido Glicirrínico/efectos adversos , Humanos , Masculino , Embarazo , Saliva/química , Distribución por SexoRESUMEN
OBJECTIVE: Previous studies have suggested that people born preterm have increased rates of eating disorders (ED). However, a recent study suggested lower levels of ED-related symptoms in the extreme group of adults born preterm with very low birth weight (<1,500 g). We examined symptoms related to EDs in adults born early (<34 weeks of gestational age) or late (34 to <37 weeks of gestational age) preterm. METHODS: We studied young adults (mean age 24.1 years) from two birth cohorts: ESTER (Northern Finland 1985-1989) and AYLS (Uusimaa, Finland, 1985-1986). Of the participants, 185 were born early preterm, 348 late preterm, and 637 were term-born controls (N = 1,170). They completed three subscales of the Eating Disorder Inventory (EDI)-2, including Drive for Thinness (DT), Body Dissatisfaction (BD), and Bulimia (B). Group differences were examined by linear regression. RESULTS: Young women born early preterm scored 4.1 points (95% CI -8.0, -0.2, P =.04) lower in summed EDI subscale scores than women born at term, when adjusted for age and cohort. This difference was observed also in DT and BD but not for B subscales. The differences persisted after adjustments for current, pre- and neonatal characteristics. We did not observe differences in EDI scores among men or women born late preterm when compared to controls. DISCUSSION: Women born early preterm have significantly fewer symptoms related to EDs in early adulthood when compared to their peers born at term, which may protect from developing an ED. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:572-580).
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Anorexia Nerviosa/psicología , Trastorno Dismórfico Corporal/psicología , Bulimia Nerviosa/psicología , Recien Nacido Prematuro/psicología , Adulto , Anorexia Nerviosa/epidemiología , Imagen Corporal/psicología , Bulimia Nerviosa/epidemiología , Conducta Alimentaria/psicología , Femenino , Desarrollo Fetal/fisiología , Finlandia/epidemiología , Edad Gestacional , Humanos , Recién Nacido , Masculino , Embarazo , Complicaciones del Embarazo/epidemiología , Embarazo Múltiple , Efectos Tardíos de la Exposición Prenatal , Ajuste Social , Delgadez/epidemiología , Delgadez/psicología , Adulto JovenRESUMEN
Early or late pubertal onset affects up to 5% of adolescents and is associated with adverse health and psychosocial outcomes. Self-limited delayed puberty (DP) segregates predominantly in an autosomal dominant pattern, but the underlying genetic background is unknown. Using exome and candidate gene sequencing, we have identified rare mutations in IGSF10 in 6 unrelated families, which resulted in intracellular retention with failure in the secretion of mutant proteins. IGSF10 mRNA was strongly expressed in embryonic nasal mesenchyme, during gonadotropin-releasing hormone (GnRH) neuronal migration to the hypothalamus. IGSF10 knockdown caused a reduced migration of immature GnRH neurons in vitro, and perturbed migration and extension of GnRH neurons in a gnrh3:EGFP zebrafish model. Additionally, loss-of-function mutations in IGSF10 were identified in hypothalamic amenorrhea patients. Our evidence strongly suggests that mutations in IGSF10 cause DP in humans, and points to a common genetic basis for conditions of functional hypogonadotropic hypogonadism (HH). While dysregulation of GnRH neuronal migration is known to cause permanent HH, this is the first time that this has been demonstrated as a causal mechanism in DP.
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Movimiento Celular , Inmunoglobulinas/genética , Proteínas Mutantes/genética , Neuronas/fisiología , Pubertad Tardía/fisiopatología , Adolescente , Animales , Análisis Mutacional de ADN , Femenino , Hormona Liberadora de Gonadotropina/metabolismo , Humanos , Hipotálamo/citología , Masculino , Modelos Animales , Neuronas/metabolismo , Análisis de Secuencia de ADN , Pez CebraRESUMEN
BACKGROUND AND OBJECTIVES: Lung function attained in young adulthood is 1 of the strongest predictors of obstructive airways disease in later life. Adults born preterm at very low birth weight (VLBW; <1500 g) who have experienced bronchopulmonary dysplasia (BPD) have reduced lung function. We studied the association of lung function in young adulthood with preterm birth at VLBW and with BPD and other prenatal and neonatal conditions. METHODS: We performed spirometry for 160 VLBW subjects (29 with BPD according to Northway criteria) aged 18 to 27 years and 162 term control subjects group-matched for gender, age, and birth hospital. Lung function was expressed as z scores according to the Global Lung Function Initiative standards. RESULTS: Forced expiratory volume in 1 second z score was 1.41 units (95% confidence interval [CI]: 0.89 to 1.94) lower in BPD-VLBW subjects and 0.39 units (95% CI: 0.08 to 0.69) in non-BPD VLBW subjects compared with control subjects. Corresponding differences for forced expiratory volume in 1 second/forced vital capacity were 1.52 (95% CI: 0.99 to 2.05) and 0.51 (95% CI: 0.21 to 0.81), respectively. Maternal smoking in pregnancy predicted poorer airflow in all groups; this finding was strongest in the BPD-VLBW group. Lung function was unrelated to fetal or postnatal growth or to neonatal respiratory distress syndrome. CONCLUSIONS: Young adults born at VLBW have reduced airflow. The outcome is stronger in those who have a history of BPD but is present among those with no such history. This finding suggests an increased risk of later obstructive airways disease in adults born at VLBW.
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Displasia Broncopulmonar/fisiopatología , Adolescente , Adulto , Displasia Broncopulmonar/complicaciones , Femenino , Humanos , Recién Nacido , Recién Nacido de muy Bajo Peso , Masculino , Pruebas de Función Respiratoria , Adulto JovenRESUMEN
Constitutional delay of growth and puberty (CDGP) is the most common cause of pubertal delay. CDGP is defined as the proportion of the normal population who experience pubertal onset at least 2 SD later than the population mean, representing 2.3% of all adolescents. While adolescents with CDGP spontaneously enter puberty, they are at risk for short stature, decreased bone mineral density, and psychosocial problems. Genetic factors contribute heavily to the timing of puberty, but the vast majority of CDGP cases remain biologically unexplained, and there is no definitive test to distinguish CDGP from pathological absence of puberty during adolescence. Recently, we published a study identifying significant linkage between a locus at the pericentromeric region of chromosome 2 (chr 2) and CDGP in Finnish families. To investigate this region for causal variation, we sequenced chr 2 between the genomic coordinates of 79-124 Mb (genome build GRCh37) in the proband and affected parent of the 13 families contributing most to this linkage signal. One gene, DNAH6, harbored 6 protein-altering low-frequency variants (< 6% in the Finnish population) in 10 of the CDGP probands. We sequenced an additional 135 unrelated Finnish CDGP subjects and utilized the unique Sequencing Initiative Suomi (SISu) population reference exome set to show that while 5 of these variants were present in the CDGP set, they were also present in the Finnish population at similar frequencies. Additional variants in the targeted region could not be prioritized for follow-up, possibly due to gaps in sequencing coverage or lack of functional knowledge of non-genic genomic regions. Thus, despite having a well-characterized sample collection from a genetically homogeneous population with a large population-based reference sequence dataset, we were unable to pinpoint variation in the linked region predisposing delayed puberty. This study highlights the difficulties of detecting genetic variants under linkage regions for complex traits and suggests that advancements in annotation of gene function and regulatory regions of the genome will be critical for solving the genetic background of complex phenotypes like CDGP.
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Centrómero , Cromosomas Humanos Par 2 , Crecimiento/genética , Pubertad/genética , Adolescente , Exoma , Femenino , Genoma Humano , Humanos , Masculino , Linaje , Análisis de Secuencia de ADNRESUMEN
Adults who were born preterm with a very low birth weight have higher blood pressure and impaired glucose regulation later in life compared with those born at term. We investigated cardiometabolic risk factors in young adults who were born at any degree of prematurity in the Preterm Birth and Early Life Programming of Adult Health and Disease (ESTER) Study, a population-based cohort study of individuals born in 1985-1989 in Northern Finland. In 2009-2011, 3 groups underwent clinical examination: 134 participants born at less than 34 gestational weeks (early preterm), 242 born at 34-36 weeks (late preterm), and 344 born at 37 weeks or later (controls). Compared with controls, adults who were born preterm had higher body fat percentages (after adjustment for sex, age, and cohort (1985-1986 or 1987-1989), for those born early preterm, difference = 6.2%, 95% confidence interval (CI): 0.4, 13.2; for those born late preterm, difference = 8.0%, 95% CI: 2.4, 13.8), waist circumferences, blood pressure (for those born early preterm, difference = 3.0 mm Hg, 95% CI: 0.9, 5.1; for those born late preterm, difference = 1.7, 95% CI: -0.1, 3.4), plasma uric acid levels (for those born early preterm, difference = 20.1%, 95% CI: 7.9, 32.3; for those born late preterm, difference = 20.2%, 95% CI: 10.7, 30.5), alanine aminotransferase levels, and aspartate transaminase levels. They were also more likely to have metabolic syndrome (for those born early preterm, odds ratio = 3.7, 95% CI: 1.6, 8.2; for those born late preterm, odds ratio = 2.5, 95% CI: 1.2, 5.3). Elevated levels of conventional and emerging risk factors suggest a higher risk of cardiometabolic disease later in life. These risk factors are also present in the large group of adults born late preterm.
Asunto(s)
Hipertensión/epidemiología , Síndrome Metabólico/epidemiología , Obesidad/epidemiología , Nacimiento Prematuro/epidemiología , Adulto , Glucemia , Presión Sanguínea , Pesos y Medidas Corporales , Femenino , Finlandia , Edad Gestacional , Humanos , Recién Nacido , Resistencia a la Insulina , Lípidos/sangre , Masculino , Factores de RiesgoRESUMEN
Unimpaired adults born preterm at very low birth weight (<1500 g) consistently have lower conditioning physical activity than those born at term. We used wrist-worn accelerometers to measure objectively physical activity in 57 very low birth weight and 47 control subjects aged 25 years. We found no difference in any physical activity measures.
Asunto(s)
Acelerometría , Actividad Motora , Conducta Sedentaria , Femenino , Humanos , Recién Nacido , Recien Nacido Prematuro , Recién Nacido de muy Bajo Peso , Masculino , Adulto JovenRESUMEN
CONTEXT: Preterm birth is associated with an increased risk of type 2 diabetes in adult life. The mechanisms are poorly known. OBJECTIVE: We studied insulin sensitivity and secretion in adults born preterm at very low birth weight (VLBW; < 1500 g). DESIGN: Longitudinal Birth Cohort Study (Helsinki Study of Very Low Birth Weight Adults). SETTING: The study was conducted at Uusimaa, Finland. PARTICIPANTS: One hundred seven adults born at VLBW and 100 controls born at term not small for gestational age (SGA), group-matched for sex, age, and birth hospital. The mean age was 25.0 years. MAIN OUTCOME MEASURES: We performed a 14-sample intravenous glucose tolerance test and calculated insulin sensitivity (Si), insulin secretory response (AIR), and disposition index, by Minimal Model (Minmod Millennium®). RESULTS: Compared with controls, VLBW adults had lower Si (mean difference -11.9%, 95% CI -22.1 to -0.4%, adjusted for sex, age, and body mass index) and higher AIR (19.9%; 4.4-37.7%). The association with Si attenuated when further adjusted for height, parental diabetes, parental education, smoking, maternal smoking, hormonal contraception, and physical activity, but the association with AIR remained. Disposition index was similar. There was no difference between the 40 VLBW adults born SGA and the remaining VLBW adults. CONCLUSIONS: Adults born preterm at VLBW have lower insulin sensitivity than their term-born peers with a similar body size. In young adulthood, this remains compensated by higher insulin secretion. We suggest that this represents an early stage in the pathway leading to type 2 diabetes. Our results underline the importance of a healthy lifestyle and prompt vigilance in the screening of type 2 diabetes and impaired glucose tolerance in adults born preterm.
Asunto(s)
Diabetes Mellitus Tipo 2/etiología , Recién Nacido de muy Bajo Peso/metabolismo , Resistencia a la Insulina/fisiología , Adulto , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , MasculinoRESUMEN
UNLABELLED: The immunoglobulin superfamily member 1 (IGSF1) gene encodes a plasma membrane glycoprotein mainly expressed in pituitary and testes. Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism (CeH), macroorchidism, and delayed puberty (delayed rise of testosterone, but normal timing of testicular growth). As this syndrome was discovered in patients with CeH, it is unknown whether IGSF1 mutations might also cause delayed puberty without CeH. We therefore determined the prevalence of IGSF1 sequence variants in 30 patients with an apparent X-linked form of constitutional delay of growth and puberty (CDGP). In four families, we discovered three novel variants of unknown clinical significance (VUCSs), with possible pathogenicity predicted by in silico analysis. However, the genotype did not fully cosegregate with CDGP, all three VUCSs showed normal plasma membrane expression in transfected HEK293 cells, and no other features of the IGSF1 deficiency syndrome were observed in family members carrying the VUCSs. The observation of hyperprolactinemia in two carriers remains unexplained. CONCLUSION: There is insufficient evidence to conclude that the three observed VUCSs in IGSF1 are associated with CDGP, making it unlikely that IGSF1 mutations are a prevalent cause of CDGP.