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Frontiers in Endocrinology 2023Noonan syndrome (NS) is a genetic multisystem disorder characterised by variable clinical manifestations including dysmorphic facial features, short stature, congenital...
BACKGROUND
Noonan syndrome (NS) is a genetic multisystem disorder characterised by variable clinical manifestations including dysmorphic facial features, short stature, congenital heart disease, renal anomalies, lymphatic malformations, chest deformities, cryptorchidism in males.
METHODS
In this narrative review, we summarized the available data on puberty and gonadal function in NS subjects and the role of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway in fertility. In addition, we have reported our personal experience on pubertal development and vertical transmission in NS.
CONCLUSIONS
According to the literature and to our experience, NS patients seem to have a delay in puberty onset compared to the physiological timing reported in healthy children. Males with NS seem to be at risk of gonadal dysfunction secondary not only to cryptorchidism but also to other underlying developmental factors including the MAP/MAPK pathway and genetics. Long-term data on a large cohort of males and females with NS are needed to better understand the impact of delayed puberty on adult height, metabolic profile and well-being. The role of genetic counselling and fertility related-issues is crucial.
Topics: Male; Child; Adult; Female; Humans; Noonan Syndrome; Cryptorchidism; Gonads; Puberty; Mitogen-Activated Protein Kinases
PubMed: 37576960
DOI: 10.3389/fendo.2023.1213098 -
Clinical and Translational Allergy Nov 2022Several risk factors for asthma have been proposed; however, the causality of these associations is sometimes unclear. Mendelian randomization is a powerful... (Review)
Review
BACKGROUND
Several risk factors for asthma have been proposed; however, the causality of these associations is sometimes unclear. Mendelian randomization is a powerful epidemiological approach that can help elucidate the causality of risk factors. The aim of the present study was to identify causal risk factors for asthma through Mendelian Randomization studies.
METHODS
A systematic search of PubMed and EMBASE was conducted, to identify studies investigating risk factors for asthma or respiratory allergies through Mendelian Randomization. When two or more studies investigated the same risk factor a meta-analysis was conducted. Of 239 studies initially identified, 41 were included.
RESULTS
A causal association between adiposity and adult asthma risk was found in 10 out of 12 studies with a summary risk ratio of 1.05 per kg/m increase in BMI (95% CI: 1.03-1.07). Puberty timing (n = 3), alcohol (n = 2), and linoleic acid (n = 1) had causal effects on asthma risk, while vitamins/minerals (n = 6) showed no consistent effect on asthma. The effect of smoking on adult asthma conflicted between studies. Several of the significant associations of asthma with immune related proteins (n = 5) and depression (n = 2) investigated through multiple traits analyses could generally benefit from replications in independent datasets.
CONCLUSION
This systematic review and meta-analysis found evidence for causal effects of adiposity, puberty timing, linoleic acid, alcohol, immune related proteins, and depression on risk of asthma.
PubMed: 36434743
DOI: 10.1002/clt2.12207 -
Journal of the Endocrine Society May 2019mutations represent the most common genetic cause of central precocious puberty (CPP) but associations between genotype and clinical features have not been extensively...
mutations represent the most common genetic cause of central precocious puberty (CPP) but associations between genotype and clinical features have not been extensively explored. This systematic review and meta-analysis investigated genotype-phenotype associations and prevalence of mutations in CPP. The search was conducted in seven electronic databases (Cochrane, EMBASE, LILACS, LIVIVO, PubMed, Scopus, and Web of Science) for articles published until 4 September 2018. Studies evaluating mutations in patients with CPP were considered eligible. A total of 22 studies, studying 880 subjects with CPP, fulfilled the inclusion criteria. Eighty-nine subjects (76 girls) were identified as harboring mutations. Girls, compared with boys, exhibited earlier age at pubertal onset (median, 6.0 years; range, 3.0 to 7.0 8.5 years; range, 5.9 to 9.0; < 0.001), and higher basal FSH levels (median, 4.3 IU/L; range, 0.7 to 13.94 IU/L 2.45 IU/L; range, 0.8 to 13.70 IU/L; = 0.003), and bone age advancement (BA; median, 2.3 years; range, -0.9 to 5.2 1.2 years; range, 0.0 to 2.3; = 0.01). Additional dysmorphisms were uncommon. A total of 14 studies evaluating 857 patients were included for quantitative analysis, with a pooled overall mutation prevalence of 9.0% (95% CI, 0.04 to 0.15). Subgroup analysis showed that prevalence estimates were higher in males, familial cases, and in non-Asian countries. In conclusion, mutations are associated with nonsyndromic CPP and manifest in a sex-dimorphic manner, with girls being affected earlier. They represent a common cause of CPP in western countries, especially in boys and familial cases.
PubMed: 31041429
DOI: 10.1210/js.2019-00041 -
BMJ Clinical Evidence Jan 2009Depression may affect 2-8% of children and adolescents, with a peak incidence around puberty. It may be self-limiting, but about 40% of affected children experience a... (Review)
Review
INTRODUCTION
Depression may affect 2-8% of children and adolescents, with a peak incidence around puberty. It may be self-limiting, but about 40% of affected children experience a recurrent attack, a third of affected children will make a suicide attempt, and 3-4% will die from suicide.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of pharmacological, psychological, combination, and complementary treatments for depression in children and adolescents? What are the effects of treatments for refractory depression in children and adolescents? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 18 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review we present information relating to the effectiveness and safety of the following interventions: citalopram, cognitive behavioural therapy (CBT) (individual or group, to prevent relapse), escitalopram, electroconvulsive therapy, family therapy, fluoxetine (alone or with cognitive therapy or CBT), fluvoxamine, group therapeutic support (other than CBT), guided self-help, individual psychodynamic psychotherapy, interpersonal therapy, lithium, mirtazapine, monoamine oxidase inhibitors (MAOIs), omega-3 polyunsaturated fatty acids, paroxetine, sertraline (alone or with CBT), St John's Wort (Hypericum perforatum), tricyclic antidepressants, and venlafaxine.
Topics: Adolescent; Child; Depression; Depressive Disorder; Fluoxetine; Humans; Incidence; Psychotherapy, Psychodynamic; Sexual Maturation
PubMed: 19445770
DOI: No ID Found -
Journal of Pediatric Endocrinology &... Jul 2018Background Some pediatric endocrinologists recommend that girls with central precocious puberty (CPP) have cranial magnetic resonance imaging (MRI) performed only if... (Meta-Analysis)
Meta-Analysis Review
Background Some pediatric endocrinologists recommend that girls with central precocious puberty (CPP) have cranial magnetic resonance imaging (MRI) performed only if they are younger than 6 years of age. However, no practice guidelines exist. The objective of this review was to assess the frequency of intracranial lesions in girls with CPP. Content We searched six electronic databases (PubMed, Cochrane, Web of Science, SCOPUS, ProQuest, and Dissertation & Theses) from 1990 through December 2015. We included studies on girls with CPP and MRI data. Case reports, case series, studies from the same author/group with the same patient population, and studies with conditions predisposing to CPP were excluded. Two physicians independently reviewed the search results and extracted data. A random-effects model was used to obtain pooled prevalence of positive MRI's across studies. Heterogeneity among studies was evaluated with the Q-statistic. Publication bias was assessed with funnel plots and Egger's test. Pooled prevalence was computed by age group. A linear regression assessed the relationship between intracranial lesion prevalence and healthcare availability. We included 15 studies with a total of 1853 girls <8 year old evaluated for CPP. Summary The pooled prevalence from all studies was 0.09 [95% confidence interval (CI) 0.06-0.12]. There was a significant heterogeneity, indicating the appropriateness of a random effects model in computing pooled prevalence. In the few studies stratified by age group, pooled prevalence was 25% in girls <6 years vs. 3% in girls 6-8 of age. Outlook Our results support that the benefit of routine MRIs in girls with CPP older than 6 years of age without any neurological concerns is not clear-cut.
Topics: Brain Diseases; Child; Female; Humans; Magnetic Resonance Imaging; Prevalence; Prognosis; Puberty, Precocious
PubMed: 29902155
DOI: 10.1515/jpem-2018-0052 -
Dermatology and Therapy Feb 2022Hidradenitis suppurativa (HS) is a chronic, inflammatory, recurrent disease, usually presenting after puberty with inflammatory lesions that mainly affect the apocrine... (Review)
Review
INTRODUCTION
Hidradenitis suppurativa (HS) is a chronic, inflammatory, recurrent disease, usually presenting after puberty with inflammatory lesions that mainly affect the apocrine gland-bearing areas of the body, most commonly the axillary, inguinal and anogenital regions. The treatment of HS is associated with certain challenges due to intrinsic resistance to various treatments and the presence of comorbidities and complications. The antibiotic dapsone is an established treatment for HS, but the current evidence base is limited. The aim of this review is to systematically review the literature on the efficacy of dapsone in the treatment of HS.
METHODS
The Cochrane, PubMed and CINAHL databases were searched for relevant articles to be included in the systematic review.
RESULTS
A total of seven studies, with a cumulative patient population of 135 patients, were included. Of these 135 patients, 62.2% demonstrated various degrees of improvement following treatment. However, as only three of the seven studies used dapsone monotherapy it is difficult to assess the effectiveness of dapsone because the benefits observed may be due to concurrently administered treatment.
CONCLUSION
Overall, the quality of evidence supporting the use of dapsone is weak. However, it is a well established treatment recommended in current, various national guidelines. There is a crucial need for well-designed randomized controlled trials to support its usage.
PubMed: 34997914
DOI: 10.1007/s13555-021-00674-x -
Journal of Clinical Research in... Jun 2022No meta-analysis is available which has analysed the role of letrozole in constitutional delay in growth and puberty (CDGP). Electronic databases were searched for... (Meta-Analysis)
Meta-Analysis
No meta-analysis is available which has analysed the role of letrozole in constitutional delay in growth and puberty (CDGP). Electronic databases were searched for randomized controlled trials (RCTs) involving children with CDGP receiving letrozole. Primary outcomes were changes in predicted adult height (PAH) and pubertal progression. Secondary outcomes were alterations in bone age (BA), hormonal markers of puberty, bone mineral density and side-effects. One hundred-thirty articles were reviewed, from which seven RCTs which fulfilled all criteria were analysed. Letrozole was superior to placebo [mean difference (MD) 4.63 cm (95% confidence interval (CI): 3.90-5.36); p<0.01; I=0%] but not testosterone [MD: 2.21 cm (95% CI: -1.71-6.16); p=0.27; I=98%] with regards to improvement in PAH after 12-months use. Letrozole was superior to both placebo [MD: 4.80 mL (95% CI: 0.57-9.03); p=0.03] and testosterone [MD: 3.36 mL (95% CI: 0.58-6.75); p=0.02; I=0%] with regards to improvement in testicular volume after 12-months use. Letrozole tended to be superior to testosterone [MD: -0.84 years (95% CI: 2.83-8.18); p=0.06; I=0%] with regards to slowing in BA progression after 12-months use. Serum luteinizing hormone, follicle stimulating hormone, testosterone and inhibin-B were significantly higher after 6-months letrozole use compared to active as well as passive controls. No increased occurrence of adverse events, including spinal deformities, were noted with letrozole. Letrozole is safe and effective for improving height and pubertal outcomes in CDGP, and is better than testosterone with regards to improvement in testicular volume and may be better at delaying bone-age progression.
Topics: Body Height; Child; Growth Disorders; Humans; Letrozole; Luteinizing Hormone; Puberty; Puberty, Delayed; Testosterone
PubMed: 34477355
DOI: 10.4274/jcrpe.galenos.2021.2021.0169 -
The Journal of Clinical Endocrinology... Jan 2022Anti-Mullerian hormone (AMH) was originally described in the context of sexual differentiation in the male fetus but has gained prominence now as a marker of ovarian...
CONTEXT
Anti-Mullerian hormone (AMH) was originally described in the context of sexual differentiation in the male fetus but has gained prominence now as a marker of ovarian reserve and fertility in females. In this mini-review, we offer an updated synopsis on AMH and its clinical utility in pediatric patients.
DESIGN AND RESULTS
A systematic search was undertaken for studies related to the physiology of AMH, normative data, and clinical role in pediatrics. In males, AMH, secreted by Sertoli cells, is found at high levels prenatally and throughout childhood and declines with progression through puberty to overlap with levels in females. Thus, serum AMH has clinical utility as a marker of testicular tissue in males with differences in sexual development and cryptorchidism and in the evaluation of persistent Mullerian duct syndrome. In females, serum AMH has been used as a predictive marker of ovarian reserve and fertility, but prepubertal and adolescent AMH assessments need to be interpreted cautiously. AMH is also a marker of tumor burden, progression, and recurrence in germ cell tumors of the ovary.
CONCLUSIONS
AMH has widespread clinical diagnostic utility in pediatrics but interpretation is often challenging and should be undertaken in the context of not only age and sex but also developmental and pubertal stage of the child. Nonstandardized assays necessitate the need for assay-specific normative data. The recognition of the role of AMH beyond gonadal development and maturation may usher in novel diagnostic and therapeutic applications that would further expand its utility in pediatric care.
Topics: Anti-Mullerian Hormone; Child; Child Development; Cryptorchidism; Disorder of Sex Development, 46,XY; Female; Gonads; Humans; Male; Ovarian Reserve; Sexual Maturation
PubMed: 34537849
DOI: 10.1210/clinem/dgab687 -
Nutrients Aug 2023In phenylketonuria (PKU), natural protein tolerance is defined as the maximum natural protein intake maintaining a blood phenylalanine (Phe) concentration within a... (Meta-Analysis)
Meta-Analysis Review
In phenylketonuria (PKU), natural protein tolerance is defined as the maximum natural protein intake maintaining a blood phenylalanine (Phe) concentration within a target therapeutic range. Tolerance is affected by several factors, and it may differ throughout a person's lifespan. Data on lifelong Phe/natural protein tolerance are limited and mostly reported in studies with low subject numbers. This systematic review aimed to investigate how Phe/natural protein tolerance changes from birth to adulthood in well-controlled patients with PKU on a Phe-restricted diet. Five electronic databases were searched for articles published until July 2020. From a total of 1334 results, 37 articles met the eligibility criteria ( = 2464 patients), and 18 were included in the meta-analysis. The mean Phe (mg/day) and natural protein (g/day) intake gradually increased from birth until 6 y (at the age of 6 months, the mean Phe intake was 267 mg/day, and natural protein intake was 5.4 g/day; at the age of 5 y, the mean Phe intake was 377 mg/day, and the natural protein intake was 8.9 g/day). However, an increase in Phe/natural protein tolerance was more apparent at the beginning of late childhood and was >1.5-fold that of the Phe tolerance in early childhood. During the pubertal growth spurt, the mean natural protein/Phe tolerance was approximately three times higher than in the first year of life, reaching a mean Phe intake of 709 mg/day and a mean natural protein intake of 18 g/day. Post adolescence, a pooled analysis could only be performed for natural protein intake. The mean natural protein tolerance reached its highest (32.4 g/day) point at the age of 17 y and remained consistent (31.6 g/day) in adulthood, but limited data were available. The results of the meta-analysis showed that Phe/natural protein tolerance (expressed as mg or g per day) increases with age, particularly at the beginning of puberty, and reaches its highest level at the end of adolescence. This needs to be interpreted with caution as limited data were available in adult patients. There was also a high degree of heterogeneity between studies due to differences in sample size, the severity of PKU, and target therapeutic levels for blood Phe control.
Topics: Child; Child, Preschool; Adolescent; Adult; Humans; Infant; Phenylalanine; Phenylketonurias; Databases, Factual; Immune Tolerance; Longevity
PubMed: 37630696
DOI: 10.3390/nu15163506 -
Journal of Assisted Reproduction and... Oct 2012Kisspeptins (Kps), were first found to regulate the hypothalamopituitary-gonadal axis (HPG) axis in 2003, when two groups-demonstrated that mutations of GPR54 causes... (Review)
Review
OBJECTIVE
Kisspeptins (Kps), were first found to regulate the hypothalamopituitary-gonadal axis (HPG) axis in 2003, when two groups-demonstrated that mutations of GPR54 causes idiopathic hypogonadotropic hypogonadism (IHH) characterized by delayed puberty. Objective of this review is to highlight both animal and human discoveries in KISS1/GPR54 system in last decade and extrapolate the therapeutic potential in humans from till date human studies.
DESIGN
A systematic review of international scientific literature by a search of PUBMED and the authors files was done for Kp in reproduction, metabolic control & signal transduction.
SETTING
None Patient(s): In human studies--normal subjects patients with HH, or HA.
MAIN OUTCOME MEASURES
Effects of Kp on puberty, brain sexual maturation, regulation of GnRH secretion, metabolic control of GnRH Neurons (N).
RESULTS
Kps/GPR54 are critical for brain sexual maturation, puberty and regulation of reproduction. Kps have been implicated in mediating signals to GnRH N--positive and negative feedback, metabolic input. Ability of Kp neurons to coordinate signals impinging on the HPG axis makes it one of most important regulators of reproductive axis since GnRH N's lack many receptors, with Kp neurons serving as upstream modulators.
CONCLUSIONS
Kps have proven as pivotal regulators of the reproduction, with the ability to integrate signals from both internal and external sources. Knowledge about signaling mechanisms involved in Kp stimulation of GnRH and with human studies has made it possible that therapeutically available Kp agonists/antagonists may be used for treatment of delayed puberty/HH, Hypothalamic amenorrhea and in prevention of spread of malignant ovarian/gonadal malignancies along with uses in some eating disorders.
Topics: Animals; Brain; Feedback, Physiological; Follicular Phase; Gonadotropin-Releasing Hormone; Humans; Hypogonadism; Hypothalamus; Kisspeptins; Male; Mutation; Neurons; Puberty; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Sexual Maturation
PubMed: 23015158
DOI: 10.1007/s10815-012-9856-1