Next Article in Journal
Factors Deciding Conservative or Intervention Treatment for Prostate Abscess: A Retrospective Case-Control Study
Previous Article in Journal
Cuproptosis Depicts Immunophenotype and Predicts Immunotherapy Response in Lung Adenocarcinoma
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JPM
Volume 13
Issue 3
10.3390/jpm13030483
jpm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

A Gender-Based Point of View in Pediatric Neurology

by
Pierluigi Diana
and
Susanna Esposito
*
Pediatric Clinic, Department of Medicine and Surgery, University Hospital of Parma, 43126 Parma, Italy
*
Author to whom correspondence should be addressed.
J. Pers. Med. 2023, 13(3), 483; https://doi.org/10.3390/jpm13030483
Submission received: 15 February 2023 / Revised: 1 March 2023 / Accepted: 5 March 2023 / Published: 8 March 2023
(This article belongs to the Section Clinical Medicine, Cell, and Organism Physiology)
Versions Notes

Abstract

:
While the significance of gender has only recently been recognized, gender assigned at birth has long been understood to have a significant influence on a number of illnesses. Due to the paucity of data in this regard in pediatrics, the purpose of this narrative review is to frame the most recent knowledge about the role of gender assigned at birth in the neurological development and neuropsychiatric disorders among young people. Literature analysis showed that gender disparities exist in neurologic and neuropsychiatric disorders among the pediatric population and supported the fact that new guidelines should take this into account. However, there is an urgent need for specific studies focused on gender role among children and adolescents in order to better understand how this can relate to diagnosis, development and treatment of different neurologic and neuropsychiatric diseases. Moreover, further efforts should be directed to identify unique risks linked to gender disorders and gender dysphoria as well as taking into account a gender point of view when approaching a pediatric patient.

1. Background

Physical aspects of gender, such as the appearance of external genitalia or secondary gender characteristics, are referred to as “gender assigned at birth”. Gender includes social gender in the sense of gender presentation, expression and role as well as psychological gender in the sense of gender identity [1,2]. Data on the formation of gender identity are still lacking, but prior research has shown that it appears to be a complicated phenomenon in which epigenetic, biochemical and prenatal variables (including genes and hormones) may all play a role [3,4,5]. According to a very recent review, gender identity and sexual orientation are likely programmed in the brain during early development: during the intrauterine phase in the second half of pregnancy, a surge in testosterone masculinizes the developing male brain; in the absence of this surge, a female brain will develop [6]. While the significance of gender has only recently been recognized, gender assigned at birth has long been understood to have a significant influence on a number of illnesses. Nowadays, medicine is moving towards an individualized approach to the patient that must include both biological sex and gender. Even if the examples of such applications in pediatrics are fewer, it has been shown in other medicinal areas how gender can actually affect the human pathology. As reported by Biskup et al., several studies conducted among adult patients have reported a strong association between gender and neuropsychiatric disorders (such as Alzheimer disease, schizophrenia and depression) [7]. The purpose of this review is to frame the most recent knowledge about the role of gender assigned at birth on the neurological development and neuropsychiatric disorders among young people.

2. Methods

This is a narrative review of literature focusing on neurological and neuropsychiatric gender medicine in pediatrics. This review was carried out by the Pediatric Clinic in the University of Parma, Parma, Italy. Systematic searches were performed using PubMed up to January 2023. Language was restricted to English. Search terms included gender, transgender, gender nonconforming, health, neuropsychiatric and neurodevelopment in combination with adolescents, children and/or youth. Original research studies, review articles, letters to the editor and cohort studies published between 2012 and 2023 were included. Data from earlier studies were taken into account if relevant to the scope of this review. All relevant articles were then evaluated, and pertinent articles were included in this review. In this review, we will refer to the terms male, female, boys and girls always in the sense of assigned gender at birth, unless specified differently.

3. Brain Development

The human brain is a complex structure that goes through deep remodeling during childhood and adolescence, especially under the hormonal pressure that marks this critical part of youth [8,9,10,11]. This is when several neuropsychiatric symptoms emerge, suggesting that brain development disorders may lead to specific neuropsychiatric conditions. Furthermore, it has been shown that there is a difference in their prevalence between adolescents being assigned as male at birth (AMAB) and assigned as female at birth (AFAB) [12,13,14,15]. Remarkable differences in the central nervous system development among AMAB and AFAB people have been reported. Young and adult AMAB people are shown to have brain sizes about 9–12% larger compared to AFAB people [16,17,18,19,20,21], with both total gray matter volume and gray matter mass greater in an AMAB than in an AFAB [18]. It has also been reported that cortical gray matter positively grows in the pre-adolescent period, then decreases faster in males than in females later in life [17,22,23]; conversely, white matter volume shows a linear increase from childhood to young adulthood [17,22,24]. While an AMAB shows larger white and gray matter, an AFAB shows a greater ratio of gray to white matter [20,25,26,27] and a greater gray matter density across the cortex [20,28]. This has not been confirmed in females younger than 8 years old in other studies [18]. Moreover, a 2011 study performed among children from 6 to 10 years old has reported that older assigned females at birth have greater cortical thickness then their male peers in the right insula and sensory area [29]. Disparities based on gender assigned at birth on white matter development are likely due to different hormonal impacts as seen by Herting et al.; higher testosterone exposition in AMAB youths predicts greater fractional anisotropy in their white matter tracts compared to AFAB youths [30].
Some differences based on gender have been also reported in structural variability. Two studies underlined how assigned males at birth show a greater variance in the hippocampus, pallidum and putamen compared to assigned females at birth [21,31].
As previously reported, there are even disparities based on biological gender of cerebral blood flow in both adults and youths [32,33,34,35,36]. It has been shown that an AMAB youth has lower blood flow in the posterior cingulate and experiences a linear decline in cerebral blood flow from age 8 to 22 years, as opposed to an AFAB [37,38]. Moreover, it has been reported how cerebral blood flow levels seem to be equivalent among early pubescent boys and girls, but then diverge around mid-puberty [38].

4. Febrile Seizures

Febrile seizures (FSs) are the most common neurological disorder during childhood. FSs occur in association with a central temperature of 38 °C or higher and in the absence of a history of prior afebrile seizures and without evidence of central nervous system infection [39]. Several risk factors are known to be associated with FSs, such as age <1 year old, a family history of epilepsy or FS, presence of seizures with low fever and AMAB [40]. In a recent study, Kazemi et al. reported a male predominance of FSs, as Mahyar et al. found previously by observing a prevalence of 66% among males [41]. In accordance with those findings, Renda et al. showed a male/female ratio varying between 1.2:1 and 1.7:1. Moreover, a difference in the age of onset between an AMAB and AFAB has been observed, with the most frequent age being around 6–12 months in females and 36 months in males [42]. Table 1 summarizes the available evidence on the relationship between FSs and gender.

5. Depression and Anxiety

Anxiety is one of the most common psychiatric disorders, with an estimated lifetime prevalence near to 25% [12,43,44]. It usually breaks up in childhood, increasing in the adolescence period. It is well accepted that an anxiety diagnosis is two times more frequent in an AFAB than in an AMAB, especially during pubertal development [45]. While it is not well documented whether anxiety is associated with brain structural abnormalities or not [46,47], a more consistent relationship with cerebral blood flow has been shown. Several studies have indeed reported a positive association between anxiety symptoms and greater regional cerebral blood flow in the insula and amygdala prefrontal/temporal cortices [48,49,50,51], which may explain why females frequently present more symptoms during puberty when they show an increased cerebral blow flood [52]. Moreover, a study conducted on adults has showed how males and females react differently to a given stressful condition: on the one hand, cerebral blood flow increases in the right prefrontal cortex in an AMAB, with a reduced flow in the left orbital cortex; on the other hand, an AFAB showed an increased flow in the ventral striatum, putamen, insula and cingulate cortex [53].
Furthermore, an AFAB experiences more severe depressive symptoms than an AMAB, starting from adolescence and with a prevalence of major depressive episodes being two times higher in an AFAB than in an AMAB [45]. Moreover, the female biological gender appears to be associated with internalizing symptoms and a higher rate of suicide attempts, while the opposite sex with greater aggressive symptoms, drug abuse, risk-taking behaviors and completed suicide [54,55]. However, it is still not clear how depressive manifestations differ between AMAB and AFAB people. Wise et al. reported smaller prefrontal cortex volumes in females with major depressive disorder [56]. Whittle et al. underlined an association between depression and greater amygdala growth in females; furthermore, they focused on the link between depressive symptoms and smaller nucleus accumbens volumes in girls [57].
Table 2 summarizes the available evidence on the relationship between anxiety/depression and gender.

6. Autism Spectrum Disorders and Attention Deficit/Hyperactivity Disorders

Autism spectrum disorder (ASD) is associated with impairments in social and communication skills, repetitive interests and peculiarities in sensitive perception; however, it is well established that they must be considered as a heterogeneous group of conditions [58]. Studies suggest a major role is genetic factors in ASD etiology [59] and show that up to 1% of the population is affected by ASD, mainly prevalent in assigned males at birth [60].
AMAB predominance is a well-established fact in ASD, with a male–female ratio reported in many studies in the range of 3–4:1 [60,61]. Nevertheless, in recent research, the prevalence of ASD in AFAB people compared with AMAB people in several known ASD-related neurological phenotypes has been examined [62]. A significant female representation has been related to microcephaly, developmental regression, neurological dysfunction and seizure frequency, suggesting that abnormal neurological phenotypes are consistently associated with female gender. Some of these findings are in accordance with previous studies. Miles et al. reported a higher rate of microcephaly among AFAB people with ASD [63], and a greater frequency of seizures in AFAB people with ASD has been observed by Bolton et al. [64]. According to Levy et al., AFAB people might be more protected than AMAB people from idiopathic ASD, showing on the other hand a higher prevalence of ASD as a secondary manifestation of other disorders [65].
It is widely reported that also attention-deficit/hyperactivity disorder (ADHD) is much more represented among young AMAB people than in AFAB people (2.4 times greater) and also into adolescence [66]. On the other hand, since the higher rate of misdiagnosis is in girls, it has been described a “gender paradox” which results in more impairment and worse outcomes in AFAB people with ADHD than in AMAB people [67]. Concerning the reasons behind the ADHD sexual disparity, we still have a lack of data in this regard. A reduced gray matter volume in the left lateral promotor cortex has been described in young females with ADHD, in opposition to reduced white matter volume in the prefrontal cortex in AMAB people [68]. Moreover, Dirlikov et al. reported an association between reduced surface area of the prefrontal cortex and the female biological gender, while in young AMAB people, the reduction was restricted to the right cingulate and left medial prefrontal cortex [69]. These data are in contrast with other studies where no differences between male and female youths diagnosed with ADHD have been found [70,71].
Table 3 summarizes the available evidence on the relationship between ASD/ADHD and gender.

7. Multiple Sclerosis

Multiple sclerosis (MS) affects the central nervous system and consists in a demyelinating condition due to autoimmune inflammation. Even if its prevalence among adults is higher, it is estimated that a rate between 2.7 and 5.4% of patients develop the disease before 18 years old [72]. In a recent study, two peaks of disease onset have been reported in youths: one at around 4 years of age and another one later at around 15 years [72].
It is well known that MS risk is related to gender assigned at birth: AFAB adults present a higher prevalence of MS, earlier disease onset and slower disability progression [73,74]. Similar data have been recently shown among young patients; after a similar incidence between males and females until the age of 9 years, a strong female predominance appears afterwards, with a peak in the age range 12–17 years, which may suggest a role of sex hormones on the onset of the condition during adolescence [72]. The importance of the hormonal modulation on the age of MS onset has been supported by Lulu et al. by observing how the MS onset in young females peaked 2 years after menarche, with a slightly higher age at onset in girls compared to boys [72,75].
Available evidence on the relationship between multiple sclerosis (MS) and gender is reported in Table 4.

8. Primary Eating Disorders

The last ten years have shown increasing attention on the role of gender regarding the development of primary eating disorders (EDs). Among them, anorexia nervosa (AN) and bulimia nervosa (BN) are considered the most common ones both in the adult and young population [76]. Basically, both conditions are characterized by excessive attention to one’s weight, shape and attempts to manage weight: people who have AN are underweight in relation to their age and assigned gender at birth, engaging in actions to prevent weight growth. Patients with BN are characterized by multiple binge eating episodes and subsequent various weight compensatory behaviors, such as the use of diuretics or laxatives, high intensity physical exercise, fasting or self-induced vomiting [76]. As reviewed by Timko et al., recent literature shows how the proportion of males with EDs has increased, becoming much higher than previously considered; the female to male ratios reported in the last 10 years goes from 1:1 to 1:10 [13,77]. This has led to recent changes to the DSM-5 in order to make ED diagnostic criteria less gender specific (e.g., elimination of amenorrhea) [13]. Several studies agreed on the role of puberty in the development of EDs and attribute sex hormones as playing a significant role in this process: in this particular age, estrogen is described to worsen the risk in AFAB people [78,79]. Conversely, testosterone exposure during prenatal development seems to be a protective factor later in adolescence [80,81,82]. Moreover, some differences have been reported in the pattern of motives for restriction and food intake disorder: for instance, AMAB people tend to be more concerned with muscularity and shape than they are with body image or the desire to be thin [83,84]. Therefore, while they exercise more frequently to develop their muscles [85,86], AFAB people appear to more frequently express a wish to lose weight and look skinnier [87]. In addition to this, adolescent females with extreme EDs tend to also express suicidal thoughts and plans, while suicide attempts seem to be more frequent in their male peers [88].
Table 5 summarizes the available evidence on the relationship between EDs and gender.

9. Gender Diverse People and Neuropsychiatric Conditions

In the field of gender-based medicine, it should also be important to take care of gender nonconforming youths. Transgender (TG) is a term used to include people who cross define categories of gender based on the sex they were assigned at birth [89,90,91,92]; TG people may experience gender dysphoria (GD), which is defined as the discomfort that may come with the incongruence between one’s experienced gender and one’s assigned sex [91]. Recently, an American national survey has estimated that almost 0.73% of 13–17 year-old adolescents identify as TG [93].
Due to the onset of puberty and the possibility of experiencing significant psychological distress, adolescence is a particularly critical period for transgender youth. For example, a transgender male may experience breast development and menstruation, while a transgender female may experience voice changes, morning erections and hair growth [94]. The general assessment and specific medical care of youths with GD are driven by the World Professional Association for Transgender Health (WPATH), which has recently provided upgraded guidelines [2].
GnRH analogues (GnRHa), often known as puberty blockers, are frequently advised in the early stages of puberty to avoid or reduce dysphoria by preventing lasting changes to the body that misalign with recognized gender. A Tanner stage 2 of puberty is recommended in order to start pubertal suppression therapy: defined by the occurrence of breast budding in an assigned female at birth and by the attainment of a testicular volume of at least 4 mL in an assigned male at birth [2,95].
Gender-affirming hormone therapy (i.e., testosterone or estrogen) may follow GnRHa or not, with the target of producing physical transformations consistent with the identified gender. Studies reported that the correct management of TG adolescents within a multidisciplinary healthcare setting and timely treatment are associated with similar mental health outcomes observed in the general population [96]. A decrease in depressive symptoms, emotional problems and general functioning improvement were seen [97]. Moreover, Olson et al. highlighted similar mental health outcomes between socially transitioned prepubertal TG children and cisgender peers [98]
Recent studies have reported increased rates of gender diversity in the population of children and adolescents diagnosed with ASD compared to non-ASD peers (4–5.4% vs. 0.7%) [89,90,91,92,99]. Other studies conducted among children, adolescents and adults have identified a positive association between GD and ASD in a rate between 4.8 and 26% [100,101,102,103,104]. This may be due to the lower attitude to conform to societal norms frequently shown by individuals with ASD [105]. As reported by Butler et al., around 35% of young people referring to the Gender Identity Development Service of London present with moderate to severe ASD traits [106]. Nevertheless, as Warrier et al. have also highlighted in their review study, TG and gender diverse individuals do not necessary experience GD; therefore, it is likely a different rate of ASD incidence in GD youths compared to non-GD ones. Moreover, a high rate of ADHD, bipolar disorders, depression, learning disorders and schizophrenia is reported among TG and gender diverse individuals compared to cisgenders. In a recent study conducted among TG adolescents, 35% of youths reported suffering depression (11% in the severe-to-extreme range), 51% had presented suicidal thoughts and 30% of them had attempted suicide at least once [107]. In accordance with these results, it has been reported that TG teenagers who are subjected to bullying or physical or verbal abuse at school are more likely to suffer from anxiety problems and commit suicide [108]. These results are also supported by two other studies focused on depression, anxiety and substance abuse rates in TG people compared to cisgender people [109,110].
Regarding Eds, there is still lack of data, but as reported by Ferrucci et al., 5.6% of transgender people in a population of adolescents aged 12–15 years old received an eating disorder diagnosis [111]. This aligns with previous studies. Gender nonconforming youths are at higher risk of being exposed to social rejection, having unsupportive families and a lack of timely treatment or referral to specific care; it has been shown how this may contribute to the escalation of maladaptive behaviors, such as EDs [112]. It is notable that an eating disorder may also be the presenting symptom in adolescents with gender dysphoria demonstrating the value of addressing gender identity in youths with eating disorders [113].
Lately, it has been suggested that prenatal mechanisms involved in brain development, such as sex steroid hormone influence, may contribute to both neurodevelopmental conditions and gender role behavior, but further studies are still needed [114,115,116].

10. Conclusions

There is substantial evidence that gender disparities exist in neurologic and neuropsychiatric disorders among the pediatric population as already reported in adults [7]. Our literature analysis supports the fact that new guidelines should take this into account because there are still important gaps in the sector that need to be filled. Our findings suggest the need for specific studies focused on gender role among children and adolescents in order to better understand how this can relate to diagnosis, development and treatment of different neurologic and neuropsychiatric diseases.
There is still a lack of data regarding the establishment of gender identity, but previous studies have highlighted how it seems to be a complex phenomenon in which epigenetic, biological and prenatal factors (including genes and hormones) could be involved [3,4,5]. Pediatric providers should consider the individual’s perception of being a male or female youth. As reported in a very recent review, sexual orientation is likely to be programmed into the brain during early development: a spike in testosterone masculinizes the unborn male brain during the intrauterine phase in the second half of pregnancy; in the absence of such a testosterone rush, a feminine brain will develop. Due to the fact that sexual differentiation of the genitals occurs far earlier in development than sexual differentiation of the brain, these two processes can be affected separately leading to gender dysphoria [4]. Moreover, no proof was observed that a person’s postnatal social environment has a significant influence on how they identify with one gender over another or with one sexual orientation [6]. All these considerations are urging us to direct further efforts in order to identify unique risks linked to gender disorders and gender dysphoria. A gender point of view should be taken into account when approaching a pediatric patient; this should include collecting information on gender identity in order to provide the best possible tailored heath care.

Author Contributions

P.D. wrote the first draft of the manuscript and performed the literature review; S.E. supervised the project, gave a scientific contribution and critically revised the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

The study received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interests.

References

  1. HRC Foundation. Glossary of Terms. Available online: https://www.hrc.org/resources/glossary-of-terms (accessed on 14 February 2023).
  2. Coleman, E.; Radix, A.E.; Bouman, W.P.; Brown, G.R.; de Vries, A.L.C.; Deutsch, M.B.; Ettner, R.; Fraser, L.; Goodman, M.; Green, J.; et al. Standards of Care for the Health of Transgender and Gender Diverse People, Version 8. Int. J. Transgender Health 2022, 23 (Suppl. S1), S1–S259. [Google Scholar] [CrossRef] [PubMed]
  3. Lippa, R.A. Gender, Nature and Nuture; Psychology Press: New York, NY, USA, 2014. [Google Scholar]
  4. Swaab, D.F. Sexual differentiation of the brain and behavior. Best Pr. Res. Clin. Endocrinol. Metab. 2007, 21, 431–444. [Google Scholar] [CrossRef] [PubMed]
  5. Savic, I.; Garcia-Falgueras, A.; Swaab, D.F. Sexual differentiation of the human brain in relation to gender identity and sexual orientation. Prog. Brain Res. 2010, 186, 41–62. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Swaab, D.F.; Wolff, S.E.; Bao, A.-M. Sexual differentiation of the human hypothalamus: Relationship to gender identity and sexual orientation. Handb. Clin. Neurol. 2021, 181, 427–443. [Google Scholar] [CrossRef]
  7. Biskup, E.; Martinkova, J.; Ferretti, M.T. Gender medicine: Towards a gender-specific treatment of neuropsychiatric disorders. Handb. Clin. Neurol. 2020, 175, 437–448. [Google Scholar] [CrossRef]
  8. Schulz, K.M.; Sisk, C.L. The organizing actions of adolescent gonadal steroid hormones on brain and behavioral development. Neurosci. Biobehav. Rev. 2016, 70, 148–158. [Google Scholar] [CrossRef] [Green Version]
  9. Sisk, C.L.; Zehr, J.L. Pubertal hormones organize the adolescent brain and behavior. Front. Neuroendocr. 2005, 26, 163–174. [Google Scholar] [CrossRef]
  10. Goddings, A.-L.; Mills, K.L.; Clasen, L.S.; Giedd, J.N.; Viner, R.M.; Blakemore, S.-J. The influence of puberty on subcortical brain development. Neuroimage 2013, 88, 242–251. [Google Scholar] [CrossRef] [Green Version]
  11. Herting, M.M.; Gautam, P.; Spielberg, J.M.; Kan, E.; Dahl, R.E.; Sowell, E.R. The role of testosterone and estradiol in brain volume changes across adolescence: A longitudinal structural MRI study. Hum. Brain Mapp. 2014, 35, 5633–5645. [Google Scholar] [CrossRef] [Green Version]
  12. Remes, O.; Brayne, C.; van der Linde, R.; Lafortune, L. A systematic review of reviews on the prevalence of anxiety disorders in adult populations. Brain Behav. 2016, 6, e00497. [Google Scholar] [CrossRef]
  13. Smink, F.R.; van Hoeken, D.; Oldehinkel, A.J.; Hoek, H.W. Prevalence and severity of DSM-5 eating disorders in a community cohort of adolescents. Int. J. Eat. Disord. 2014, 47, 610–619. [Google Scholar] [CrossRef] [PubMed]
  14. Beesdo, K.; Knappe, S.; Pine, D.S. Anxiety and Anxiety Disorders in Children and Adolescents: Developmental Issues and Implications for DSM-V. Psychiatr. Clin. N. Am. 2009, 32, 483–524. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Albert, P.R. Why is depression more prevalent in women? J. Psychiatry Neurosci. 2015, 40, 219–221. [Google Scholar] [CrossRef] [PubMed]
  16. Sowell, E.R.; Peterson, B.S.; Kan, E.; Woods, R.P.; Yoshii, J.; Bansal, R.; Xu, D.; Zhu, H.; Thompson, P.M.; Toga, A.W. Sex Differences in Cortical Thickness Mapped in 176 Healthy Individuals between 7 and 87 Years of Age. Cereb. Cortex 2007, 17, 1550–1560. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. De Bellis, M.D.; Keshavan, M.S.; Beers, S.R.; Hall, J.; Frustaci, K.; Masalehdan, A. Sex differences in brain maturation during childhood and adolescence. Cereb. Cortex 2001, 11, 552–557. [Google Scholar] [CrossRef] [PubMed]
  18. Gennatas, E.D.; Avants, B.B.; Wolf, D.H.; Satterthwaite, T.D.; Ruparel, K.; Ciric, R.; Hakonarson, H.; Gur, R.E.; Gur, R.C. Age-Related Effects and Sex Differences in Gray Matter Density, Volume, Mass, and Cortical Thickness from Childhood to Young Adulthood. J. Neurosci. 2017, 37, 5065–5073. [Google Scholar] [CrossRef] [Green Version]
  19. Bramen, J.E.; Hranilovich, J.A.; Dahl, R.E.; Forbes, E.E.; Chen, J.; Toga, A.W.; Dinov, I.D.; Worthman, C.M.; Sowell, E.R. Puberty Influences Medial Temporal Lobe and Cortical Gray Matter Maturation Differently in Boys Than Girls Matched for Sexual Maturity. Cereb. Cortex 2011, 21, 636–646. [Google Scholar] [CrossRef] [Green Version]
  20. Luders, E.; Narr, K.; Thompson, P.; Woods, R.; Rex, D.; Jancke, L.; Steinmetz, H.; Toga, A. Mapping cortical gray matter in the young adult brain: Effects of gender. Neuroimage 2005, 26, 493–501. [Google Scholar] [CrossRef]
  21. Ritchie, S.J.; Cox, S.R.; Shen, X.; Lombardo, M.V.; Reus, L.M.; Alloza, C. Sex differences in the adult human brain: Evidence from 5216 UK Biobank participants. Cereb. Cortex 2018, 28, 2959–2975. [Google Scholar] [CrossRef]
  22. Giedd, J.N.; Blumenthal, J.; Jeffries, N.O.; Castellanos, F.; Liu, H.; Zijdenbos, A.; Paus, T.; Evans, A.C.; Rapoport, J.L. Brain development during childhood and adolescence: A longitudinal MRI study. Nat. Neurosci. 1999, 2, 861–863. [Google Scholar] [CrossRef]
  23. Gogtay, N.; Giedd, J.N.; Lusk, L.; Hayashi, K.M.; Greenstein, D.; Vaituzis, A.C.; Nugent, T.F.; Herman, D.H.; Clasen, L.S.; Toga, A.W.; et al. Dynamic mapping of human cortical development during childhood through early adulthood. Proc. Natl. Acad. Sci. USA 2004, 101, 8174–8179. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Thompson, P.M.; Giedd, J.N.; Woods, R.P.; MacDonald, D.; Evans, A.C.; Toga, A.W. Growth patterns in the developing brain detected by using continuum mechanical tensor maps. Nature 2000, 404, 190–193. [Google Scholar] [CrossRef] [PubMed]
  25. Allen, J.S.; Damasio, H.; Grabowski, T.J.; Bruss, J.; Zhang, W. Sexual dimorphism and asymmetries in the gray–white composition of the human cerebrum. Neuroimage 2003, 18, 880–894. [Google Scholar] [CrossRef]
  26. Goldstein, J.M.; Seidman, L.J.; Horton, N.; Makris, N.; Kennedy, D.N.; Caviness, V.S.; Faraone, S.; Tsuang, M.T. Normal Sexual Dimorphism of the Adult Human Brain Assessed by In Vivo Magnetic Resonance Imaging. Cereb. Cortex 2001, 11, 490–497. [Google Scholar] [CrossRef] [PubMed]
  27. Gur, R.C.; Turetsky, B.I.; Matsui, M.; Yan, M.; Bilker, W.; Hughett, P.; Gur, R.E. Sex Differences in Brain Gray and White Matter in Healthy Young Adults: Correlations with Cognitive Performance. J. Neurosci. 1999, 19, 4065–4072. [Google Scholar] [CrossRef] [PubMed]
  28. Good, C.D.; Johnsrude, I.; Ashburner, J.; Henson, R.N.; Friston, K.J.; Frackowiak, R.S. Cerebral Asymmetry and the Effects of Sex and Handedness on Brain Structure: A Voxel-Based Morphometric Analysis of 465 Normal Adult Human Brains. Neuroimage 2001, 14, 685–700. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Muftuler, L.T.; Davis, E.P.; Buss, C.; Head, K.; Hasso, A.N.; Sandman, C.A. Cortical and subcortical changes in typically developing preadolescent children. Brain Res. 2011, 1399, 15–24. [Google Scholar] [CrossRef] [Green Version]
  30. Herting, M.M.; Maxwell, E.C.; Irvine, C.; Nagel, B.J. The Impact of Sex, Puberty, and Hormones on White Matter Microstructure in Adolescents. Cereb. Cortex 2011, 22, 1979–1992. [Google Scholar] [CrossRef] [Green Version]
  31. Wierenga, L.M.; Sexton, J.A.; Laake, P.; Giedd, J.N.; Tamnes, C.K. A Key Characteristic of Sex Differences in the Developing Brain: Greater Variability in Brain Structure of Boys than Girls. Cereb. Cortex 2018, 28, 2741–2751. [Google Scholar] [CrossRef] [Green Version]
  32. Liu, Y.; Zhu, X.; Feinberg, D.; Guenther, M.; Gregori, J.; Weiner, M.W.; Schuff, N. Arterial spin labeling MRI study of age and gender effects on brain perfusion hemodynamics. Magn. Reson. Med. 2012, 68, 912–922. [Google Scholar] [CrossRef]
  33. Mathew, R.J.; Wilson, W.H.; Tant, S.R. Determinants of resting regional cerebral blood flow in normal subjects. Biol. Psychiatry 1986, 21, 907–914. [Google Scholar] [CrossRef] [PubMed]
  34. Rodriguez, G.; Warkentin, S.; Risberg, J.; Rosadini, G. Sex Differences in Regional Cerebral Blood Flow. J. Cereb. Blood Flow Metab. 1988, 8, 783–789. [Google Scholar] [CrossRef] [Green Version]
  35. Baxter, L.R.; Mazziotta, J.C.; Phelps, M.E.; Selin, C.E.; Guze, B.H.; Fairbanks, L. Cerebral glucose metabolic rates in normal human females versus normal males. Psychiatry Res. 1987, 21, 237–245. [Google Scholar] [CrossRef] [PubMed]
  36. Gur, R.C.; Gur, R.E.; Obrist, W.D.; Hungerbuhler, J.P.; Younkin, D.; Rosen, A.D.; Skolnick, B.E.; Reivich, M. Sex and Handedness Differences in Cerebral Blood Flow During Rest and Cognitive Activity. Science 1982, 217, 659–661. [Google Scholar] [CrossRef]
  37. Taki, Y.; Hashizume, H.; Sassa, Y.; Takeuchi, H.; Wu, K.; Asano, M.; Asano, K.; Fukuda, H.; Kawashima, R. Correlation between gray matter density-adjusted brain perfusion and age using brain MR images of 202 healthy children. Hum. Brain Mapp. 2011, 32, 1973–1985. [Google Scholar] [CrossRef] [PubMed]
  38. Satterthwaite, T.D.; Shinohara, R.T.; Wolf, D.H.; Hopson, R.D.; Elliott, M.A.; Vandekar, S.N.; Ruparel, K.; Calkins, M.E.; Roalf, D.R.; Gennatas, E.D.; et al. Impact of puberty on the evolution of cerebral perfusion during adolescence. Proc. Natl. Acad. Sci. USA 2014, 111, 8643–8648. [Google Scholar] [CrossRef] [Green Version]
  39. A Mikati, M.; Rahi, A.C. Febrile seizures. From molecular biology to clinical practice. Neurosciences 2005, 10, 14–22. [Google Scholar]
  40. Kazemi, A.; Badv, R.S.; Fallah, R.; Piri, A.; Tahernia, L.; Shahi, M.V. The first febrile seizure; predisposing factors and recurrence rate. Iran. J. Child Neurol. 2021, 15, 69–76. [Google Scholar] [CrossRef]
  41. Mahyar, A.; Ayazi, P.; Fallahi, M.; Javadi, A. Risk Factors of the First Febrile Seizures in Iranian Children. Int. J. Pediatr. 2010, 2010, 862897. [Google Scholar] [CrossRef] [Green Version]
  42. Renda, R.; Yüksel, D.; Gürer, Y.K.Y. Evaluation of Patients with Febrile Seizure: Risk Factors, Reccurence, Treatment and Prognosis. Pediatr. Emerg. Care 2020, 36, 173–177. [Google Scholar] [CrossRef]
  43. Roza, S.J.; Hofstra, M.B.; Van Der Ende, J.; Verhulst, F.C. Stable Prediction of Mood and Anxiety Disorders Based on Behavioral and Emotional Problems in Childhood: A 14-Year Follow-Up During Childhood, Adolescence, and Young Adulthood. Am. J. Psychiatry 2003, 160, 2116–2121. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Kessler, R.C.; Chiu, W.T.; Demler, O.; Walters, E.E. Prevalence, Severity, and Comorbidity of 12-Month DSM-IV Disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 2005, 62, 617–627. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Baxter, A.J.; Scott, K.M.; Ferrari, A.J.; Norman, R.E.; Vos, T.; Whiteford, H.A. Challenging the Myth of an “Epidemic” of Common Mental Disorders: Trends in the Global Prevalence of Anxiety and Depression between 1990 and 2010. Depress. Anxiety 2014, 31, 506–516. [Google Scholar] [CrossRef] [PubMed]
  46. Karl, A.; Schaefer, M.; Malta, L.S.; Dörfel, D.; Rohleder, N.; Werner, A. A meta-analysis of structural brain abnormalities in PTSD. Neurosci. Biobehav. Rev. 2006, 30, 1004–1031. [Google Scholar] [CrossRef] [PubMed]
  47. Liberzon, I.; Duval, E.; Javanbakht, A. Neural circuits in anxiety and stress disorders: A focused review. Ther. Clin. Risk Manag. 2015, 11, 115–126. [Google Scholar] [CrossRef] [Green Version]
  48. Andreescu, C.; Gross, J.J.; Lenze, E.; Edelman, K.D.; Snyder, S.; Tanase, C.; Aizenstein, H. Altered cerebral blood flow patterns associated with pathologic worry in the elderly. Depress. Anxiety 2011, 28, 202–209. [Google Scholar] [CrossRef] [Green Version]
  49. Schuff, N.; Zhang, Y.; Zhan, W.; Lenoci, M.; Ching, C.; Boreta, L.; Mueller, S.G.; Wang, Z.; Marmar, C.R.; Weiner, M.W.; et al. Patterns of altered cortical perfusion and diminished subcortical integrity in posttraumatic stress disorder: An MRI study. Neuroimage 2011, 54, S62–S68. [Google Scholar] [CrossRef] [Green Version]
  50. Wang, J.; Rao, H.; Wetmore, G.S.; Furlan, P.M.; Korczykowski, M.; Dinges, D.F.; Detre, J.A. Perfusion functional MRI reveals cerebral blood flow pattern under psychological stress. Proc. Natl. Acad. Sci. USA 2005, 102, 17804–17809. [Google Scholar] [CrossRef] [Green Version]
  51. Kaczkurkin, A.N.; Moore, T.M.; Ruparel, K.; Ciric, R.; Calkins, M.E.; Shinohara, R.T.; Elliott, M.A.; Hopson, R.; Roalf, D.R.; Vandekar, S.N.; et al. Elevated Amygdala Perfusion Mediates Developmental Sex Differences in Trait Anxiety. Biol. Psychiatry 2016, 80, 775–785. [Google Scholar] [CrossRef] [Green Version]
  52. Kaczkurkin, A.N.; Raznahan, A.; Satterthwaite, T.D. Sex differences in the developing brain: Insights from multimodal neuroimaging. Neuropsychopharmacology 2019, 44, 71–85. [Google Scholar] [CrossRef]
  53. Wang, J.; Korczykowski, M.; Rao, H.; Fan, Y.; Pluta, J.; Gur, R.C.; McEwen, B.S.; Detre, J.A. Gender difference in neural response to psychological stress. Soc. Cogn. Affect. Neurosci. 2007, 2, 227–239. [Google Scholar] [CrossRef] [PubMed]
  54. Marcus, S.M.; Kerber, K.B.; Rush, A.J.; Wisniewski, S.R.; Nierenberg, A.; Balasubramani, G.; Ritz, L.; Kornstein, S.; Young, E.A.; Trivedi, M.H. Sex differences in depression symptoms in treatment-seeking adults: Confirmatory analyses from the Sequenced Treatment Alternatives to Relieve Depression study. Compr. Psychiatry 2008, 49, 238–246. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Martin, L.A.; Neighbors, H.W.; Griffith, D.M. The experience of symptoms of depression in men vs women: Analysis of the national comorbidity survey replication. JAMA Psychiatry 2013, 70, 1100–1106. [Google Scholar] [CrossRef] [Green Version]
  56. Wise, T.; Radua, J.; Via, E.; Cardoner, N.; Abe, O.; Adams, T.M.; Amico, F.; Cheng, Y.; Cole, J.H.; de Azevedo Marques Périco, C.; et al. Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: Evidence from voxel-based meta-analysis. Mol. Psychiatry 2016, 22, 1455–1463. [Google Scholar] [CrossRef] [PubMed]
  57. Whittle, S.; Lichter, R.; Dennison, M.; Vijayakumar, N.; Schwartz, O.; Byrne, M.L. Structural brain development and depression onset during adolescence: A prospective longitudinal study. Am. J. Psychiatry 2014, 171, 564–571. [Google Scholar] [CrossRef] [PubMed]
  58. American Psychiatric Association DI. American Psychiatric Association and Task Force on DSM IV. Diagnostic and Statistical Manual of Mental Disorders, DSM IV; APA: Washinfton, DC, USA, 1994. [Google Scholar]
  59. Schaaf, C.P.; Zoghbi, H.Y. Solving the Autism Puzzle a Few Pieces at a Time. Neuron 2011, 70, 806–808. [Google Scholar] [CrossRef] [Green Version]
  60. Loomes, R.; Hull, L.; Mandy, W.P.L. What Is the Male-to-Female Ratio in Autism Spectrum Disorder? A Systematic Review and Meta-Analysis. J. Am. Acad. Child Adolesc. Psychiatry 2017, 56, 466–474. [Google Scholar] [CrossRef] [Green Version]
  61. Weintraub, K. The prevalence puzzle: Autism counts. Nature 2011, 479, 22–24. [Google Scholar] [CrossRef] [Green Version]
  62. Ben-Itzchak, E.; Ben-Shachar, S.; Zachor, D.A. Specific Neurological Phenotypes in Autism Spectrum Disorders Are Associated with Sex Representation. Autism Res. 2013, 6, 596–604. [Google Scholar] [CrossRef]
  63. Miles, J.; Takahashi, T.; Bagby, S.; Sahota, P.; Vaslow, D.; Wang, C.; Hillman, R.; Farmer, J. Essential versus complex autism: Definition of fundamental prognostic subtypes. Am. J. Med. Genet. Part A 2005, 135A, 171–180. [Google Scholar] [CrossRef]
  64. Bolton, P.F.; Carcani-Rathwell, I.; Hutton, J.; Goode, S.; Howlin, P.; Rutter, M. Epilepsy in autism: Features and correlates. Br. J. Psychiatry 2011, 198, 289–294. [Google Scholar] [CrossRef] [PubMed]
  65. Levy, D.; Ronemus, M.; Yamrom, B.; Lee, Y.-H.; Leotta, A.; Kendall, J.; Marks, S.; Lakshmi, B.; Pai, D.; Ye, K.; et al. Rare De Novo and Transmitted Copy-Number Variation in Autistic Spectrum Disorders. Neuron 2011, 70, 886–897. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Willcutt, E.G. The Prevalence of DSM-IV Attention-Deficit/Hyperactivity Disorder: A Meta-Analytic Review. Neurotherapeutics 2012, 9, 490–499. [Google Scholar] [CrossRef] [Green Version]
  67. Tung, I.; Li, J.J.; Meza, J.I.; Jezior, K.L.; Kianmahd, J.S.; Hentschel, P.G.; O’Neil, P.M.; Lee, S.S. Patterns of Comorbidity Among Girls With ADHD: A Meta-analysis. Pediatrics 2016, 138, e20160430. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Mahone, E.M.; Ranta, M.E.; Crocetti, D.; O’Brien, J.; Kaufmann, W.E.; Denckla, M.B.; Mostofsky, S.H. Comprehensive Examination of Frontal Regions in Boys and Girls with Attention-Deficit/Hyperactivity Disorder. J. Int. Neuropsychol. Soc. 2011, 17, 1047–1057. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Dirlikov, B.; Rosch, K.S.; Crocetti, D.; Denckla, M.B.; Mahone, E.M.; Mostofsky, S.H. Distinct frontal lobe morphology in girls and boys with ADHD. NeuroImage Clin. 2015, 7, 222–229. [Google Scholar] [CrossRef] [Green Version]
  70. Shaw, P.; Malek, M.; Watson, B.; Greenstein, D.; De Rossi, P.; Sharp, W. Trajectories of Cerebral Cortical Development in Childhood and Adolescence and Adult Attention-Deficit/Hyperactivity Disorder. Biol. Psychiatry 2013, 74, 599–606. [Google Scholar] [CrossRef] [Green Version]
  71. Castellanos, X.F.; Lee, P.P.; Sharp, W.; Jeffries, N.O.; Greenstein, D.K.; Clasen, L.S. Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder. JAMA 2002, 288, 1740–1748. [Google Scholar] [CrossRef] [Green Version]
  72. Belman, A.L.; Krupp, L.B.; Olsen, C.S.; Rose, J.W.; Aaen, G.; Benson, L.; Chitnis, T.; Gorman, M.; Graves, J.; Harris, Y.; et al. Characteristics of Children and Adolescents With Multiple Sclerosis. Pediatrics 2016, 138, e20160120. [Google Scholar] [CrossRef] [Green Version]
  73. Duquette, P.; Pleines, J.; Girard, M. The increased susceptibility of women to multiple sclerosis. Can. J. Neurol. Sci. 1992, 19, 466–471. [Google Scholar] [CrossRef] [Green Version]
  74. Confavreux, C.; Vukusic, S.; Adeleine, P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: An amnesic process. Brain 2003, 126, 770–782. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Lulu, S.; Graves, J.; Waubant, E. Menarche increases relapse risk in pediatric multiple sclerosis. Mult. Scler. J. 2016, 22, 193–200. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Timko, C.A.; DeFilipp, L.; Dakanalis, A. Sex Differences in Adolescent Anorexia and Bulimia Nervosa: Beyond the Signs and Symptoms. Curr. Psychiatry Rep. 2019, 21, 1. [Google Scholar] [CrossRef]
  77. Swanson, S.A. Prevalence and correlates of eating disorders in adolescents. Results from the national comorbidity survey replication adolescent supplement. Arch. Gen. Psychiatry 2011, 68, 714–723. [Google Scholar] [CrossRef] [Green Version]
  78. Klump, K.L. Puberty as a critical risk period for eating disorders: A review of human and animal studies. Horm. Behav. 2013, 64, 399–410. [Google Scholar] [CrossRef] [Green Version]
  79. Klump, K.L.; Culbert, K.M.; Slane, J.D.; Burt, S.A.; Sisk, C.L.; Nigg, J.T. The effects of puberty on genetic risk for disordered eating: Evidence for a sex difference. Psychol. Med. 2012, 42, 627–637. [Google Scholar] [CrossRef] [Green Version]
  80. Culbert, K.M.; Breedlove, S.M.; Sisk, C.L.; Burt, S.A.; Klump, K.L. The emergence of sex differences in risk for disordered eating attitudes during puberty: A role for prenatal testosterone exposure. J. Abnorm. Psychol. 2013, 122, 420–432. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  81. Klump, K.L.; Gobrogge, K.L.; Perkins, P.S.; Thorne, D.; Sisk, C.L.; Breedlove, S.M. Preliminary evidence that gonadal hormones organize and activate disordered eating. Psychol. Med. 2006, 36, 539–546. [Google Scholar] [CrossRef] [Green Version]
  82. Culbert, K.M. Age differences in prenatal testosterone’s protective effects on disordered eating symptoms: Developmental windows of expression? Behav. Neurosc. 2015, 129, 18. [Google Scholar] [CrossRef]
  83. Joiner, T.E.; Katz, J.; Heatherton, T.F. Personality features differentiate late adolescent females and males with chronic bulimic symptoms. Int. Eat. Dis. 2000, 27, 191–197. [Google Scholar] [CrossRef]
  84. Kjelsås, E.; Augestad, L.; Flanders, D. Screening of males with eating disorders. Eating and Weight Disorders-Studies on Anorexia. Bulim. Obes. 2003, 8, 304–310. [Google Scholar]
  85. Darcy, A.M.; Lin, I.H.-J. Are we asking the right questions? A review of assessment of males with eating disorders. Eat. Disord. 2012, 20, 416–426. [Google Scholar] [CrossRef] [PubMed]
  86. Murray, S.B.; Griffiths, S.; Mitchison, D.; Mond, J. The Transition From Thinness-Oriented to Muscularity-Oriented Disordered Eating in Adolescent Males: A Clinical Observation. J. Adolesc. Health 2018, 60, 353–355. [Google Scholar] [CrossRef]
  87. Núñez-Navarro, A.; Agüera, Z.; Krug, I.; Jiménez-Murcia, S.; Sanchez, I.; Araguz, N.; Gorwood, P.; Granero, R.; Penelo, E.; Karwautz, A.; et al. Do Men with Eating Disorders Differ from Women in Clinics, Psychopathology and Personality? Eur. Eat. Disord. Rev. 2012, 20, 23–31. [Google Scholar] [CrossRef]
  88. Brown, C.S.; Kola-Palmer, S.; Dhingra, K. Gender differences and correlates of extreme dieting behaviours in US adolescents. J. Health Psychol. 2015, 20, 569–579. [Google Scholar] [CrossRef] [Green Version]
  89. May, T.; Pang, K.; Williams, K. Gender variance in children and adolescents with autism spectrum disorder from the National Database for Autism Research. Int. J. Transgenderism 2016, 18, 7–15. [Google Scholar] [CrossRef]
  90. Strang, J.F.; Kenworthy, L.; Dominska, A.; Sokoloff, J.; Kenealy, L.E.; Berl, M.; Walsh, K.; Menvielle, E.; Slesaransky-Poe, G.; Kim, K.-E.; et al. Increased Gender Variance in Autism Spectrum Disorders and Attention Deficit Hyperactivity Disorder. Arch. Sex. Behav. 2014, 43, 1525–1533. [Google Scholar] [CrossRef]
  91. Hisle-Gorman, E.; Landis, C.A.; Susi, A.; Schvey, N.A.; Gorman, G.H.; Nylund, C.M.; Klein, D.A. Gender Dysphoria in Children with Autism Spectrum Disorder. LGBT Health 2019, 6, 95–100. [Google Scholar] [CrossRef]
  92. Nabbijohn, A.N.; van der Miesen, A.I.R.; Santarossa, A.; Peragine, D.; de Vries, A.L.C.; Popma, A.; Lai, M.-C.; VanderLaan, D.P. Gender Variance and the Autism Spectrum: An Examination of Children Ages 6–12 Years. J. Autism Dev. Disord. 2019, 49, 1570–1585. [Google Scholar] [CrossRef]
  93. Diana, P.; Esposito, S. LGBTQ+ Youth Health: An Unmet Need in Pediatrics. Children 2022, 9, 1027. [Google Scholar] [CrossRef]
  94. Nahata, L.; Quinn, G.P.; Caltabellotta, N.M.; Tishelman, A.C. Mental Health Concerns and Insurance Denials among Transgender Adolescents. LGBT Health 2017, 4, 188–193. [Google Scholar] [CrossRef] [PubMed]
  95. Roberts, S.A.; Kaiser, U.B. Genetics in endocrinology: Genetic etiologies of central precocious puberty and the role of imprinted genes. Eur. J. Endocrinol. 2020, 183, R107–R117. [Google Scholar] [CrossRef] [PubMed]
  96. De Vries, A.L.; McGuire, J.K.; Steensma, T.D.; Wagenaar, E.C.; Doreleijers, T.A.; Cohen-Kettenis, P.T. Young adult psychological outcomes after puberty suppression and gender reassignment. Pediatrics 2014, 134, 696–704. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. de Vries, A.L.; Steensma, T.D.; Doreleijers, T.A.; Cohen-Kettenis, P.T. Puberty suppression in adolescents with gender identity disorder: A prospective follow-up study. J. Sex. Med. 2011, 8, 2276–2283. [Google Scholar] [CrossRef] [PubMed]
  98. Olson, K.R.; Durwood, L.; DeMeules, M.; McLaughlin, K.A. Mental health of transgender children who are supported in their identities. Pediatrics 2016, 137, e20153223. [Google Scholar] [CrossRef] [Green Version]
  99. Janssen, A.; Huang, H.; Duncan, C. Gender Variance among Youth with Autism Spectrum Disorders: A Retrospective Chart Review. Transgender Health 2016, 1, 63–68. [Google Scholar] [CrossRef] [Green Version]
  100. de Vries, A.L.C.; Noens, I.L.J.; Cohen-Kettenis, P.T.; van Berckelaer-Onnes, I.A.; Doreleijers, T.A. Autism spectrum disorders in gender dysphoric children and adolescents. J. Autism. Dev. Disord. 2010, 40, 930–936. [Google Scholar] [CrossRef] [Green Version]
  101. Kaltiala-Heino, R.; Sumia, M.; Työläjärvi, M.; Lindberg, N. Two years of gender identity service for minors: Overrepresentation of natal girls with severe problems in adolescent development. Child Adolesc. Psychiatry Ment. Health 2015, 9, 9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Shumer, D.E.; Reisner, S.L.; Edwards-Leeper, L.; Tishelman, A. Evaluation of Asperger Syndrome in Youth Presenting to a Gender Dysphoria Clinic. LGBT Health 2016, 3, 387–390. [Google Scholar] [CrossRef] [Green Version]
  103. Heylens, G.; Aspeslagh, L.; Dierickx, J.; Baetens, K.; Van Hoorde, B.; De Cuypere, G.; Elaut, E. The Co-occurrence of Gender Dysphoria and Autism Spectrum Disorder in Adults: An Analysis of Cross-Sectional and Clinical Chart Data. J. Autism Dev. Disord. 2018, 48, 2217–2223. [Google Scholar] [CrossRef]
  104. Cheung, A.S.; Ooi, O.; Leemaqz, S.; Cundill, P.; Silberstein, N.; Bretherton, I.; Thrower, E.; Locke, P.; Grossmann, M.; Zajac, J.D. Sociodemographic and Clinical Characteristics of Transgender Adults in Australia. Transgender Health 2018, 3, 229–238. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Warrier, V.; Greenberg, D.M.; Weir, E.; Buckingham, C.; Smith, P.; Lai, M.C.; Allison, C.; Baron-Cohen, S. Elevated rates of autism, other neurodevelopmental and psychiatric diagnoses, and autistic traits in transgender and gender-diverse individuals. Nat. Commun. 2020, 11, 3959. [Google Scholar] [CrossRef] [PubMed]
  106. Butler, G.; De Graaf, N.; Wren, B.; Carmichael, P. Assessment and support of children and adolescents with gender dysphoria. Arch. Dis. Child. 2018, 103, 631–636. [Google Scholar] [CrossRef] [PubMed]
  107. Olson, J.; Schrager, S.M.; Belzer, M.; Simons, L.K.; Clark, L.F. Baseline Physiologic and Psychosocial Characteristics of Transgender Youth Seeking Care for Gender Dysphoria. J. Adolesc. Health 2015, 57, 374–380. [Google Scholar] [CrossRef] [Green Version]
  108. Grossman, A.H.; D’Augelli, A.R. Transgender youth and lifethreatening behaviors. Suicide Life Threat. Behav. 2007, 37, 527–537. [Google Scholar] [CrossRef]
  109. Reisner, S.L.; Poteat, T.; Keatley, J.; Cabral, M.; Mothopeng, T.; Dunham, E.; E Holland, C.; Max, R.; Baral, S.D. Global health burden and needs of transgender populations: A review. Lancet 2016, 388, 412–436. [Google Scholar] [CrossRef]
  110. Dhejne, C.; Van Vlerken, R.; Heylens, G.; Arcelus, J. Mental health and gender dysphoria: A review of the literature. Int. Rev. Psychiatry 2016, 28, 44–57. [Google Scholar] [CrossRef]
  111. Ferrucci, K.A.; Lapane, K.L.; Jesdale, B.M. Prevalence of diagnosed eating disorders in US transgender adults and youth in insurance claims. Int. J. Eat. Disord. 2022, 55, 801–809. [Google Scholar] [CrossRef]
  112. Donaldson, A.A.; Hall, A.; Neukirch, J.; Kasper, V.; Simones, S.; Gagnon, S.; Reich, S.; Forcier, M. Multidisciplinary care considerations for gender nonconforming adolescents with eating disorders: A case series. Int. J. Eat. Disord. 2018, 51, 475–479. [Google Scholar] [CrossRef]
  113. Strandjord, S.E.; Ng, H.; Rome, E.S. Effects of treating gender dysphoria and anorexia nervosa in a transgender adolescent: Lessons learned. Int. J. Eat. Disord. 2015, 48, 942–945. [Google Scholar] [CrossRef]
  114. Hines, M. Gender Development and the Human Brain. Annu. Rev. Neurosci. 2011, 34, 69–88. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Baron-Cohen, S.; Auyeung, B.; Norgaardpedersen, B.; Hougaard, D.M.; Abdallah, M.W.; Melgaard, L.; Cohen, A.S.; Chakrabarti, B.; Ruta, L.; Lombardo, M. Elevated fetal steroidogenic activity in autism. Mol. Psychiatry 2015, 20, 369–376. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Auyeung, B.; Baron-Cohen, S.; Ashwin, E.; Knickmeyer, R.; Taylor, K.; Hackett, G. Fetal testosterone and autistic traits. Br. J. Psychol. 2009, 100, 1–22. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Table
Table 1. Available evidence on the relationship between febrile seizures (FS) and gender.
Table 1. Available evidence on the relationship between febrile seizures (FS) and gender.
What is known
  • The prevalence of febrile seizure is significantly greater in AMAB people than AFAB (66% vs. 44%) [41,42].
  • The onset is earlier in AFAB people than in AMAB people (6–12 months vs. 36 months) [40].
What is still unknown
  • The neurobiological background of different gender-based prevalence of FS should be deeply investigated.
AFAB, assigned female at birth; AMAB, assigned male at birth.
Table
Table 2. Available evidence on the relationship between anxiety/depression and gender.
Table 2. Available evidence on the relationship between anxiety/depression and gender.
What is known
  • Anxiety is one of the most common psychiatric disorders with adolescence onset [12,43,44].
  • In adolescence, an anxiety diagnosis is two times greater in AFAB people than in AMAB people [45].
  • In the adult age, the prevalence of major depressive episodes is two times higher in AFAB people than in AMAB people [45,54,55].
What is still unknown
  • The association between anxiety and brain structure abnormalities needs further investigations.
  • It is not clear how the characteristics of depressive manifestations differ between AFAB and AMAB people.
AFAB, assigned female at birth; AMAB, assigned male at birth.
Table
Table 3. Available evidence on the relationship between autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD) and gender.
Table 3. Available evidence on the relationship between autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD) and gender.
What is known
  • The prevalence of ASD and ADHD is greater in AMAB people than in AFAB people (3–4 times and 2.4 times greater, respectively) [58,60,61,62,63,64,65,66].
  • Females show more serious symptoms related to ASD than males [65].
What is still unknown
  • ADHD sexual disparity factors are still uncertain.
  • Studies show discordant data on neurobiological differences between AFAB and AMAB people diagnosed with ADHD.
AFAB, assigned female at birth; AMAB, assigned male at birth.
Table
Table 4. Available evidence on the relationship between multiple sclerosis (MS) and gender.
Table 4. Available evidence on the relationship between multiple sclerosis (MS) and gender.
What is known
  • The prevalence of MS is greater in AFAB people than in AMAB people [73,74,75].
What is still unknown
  • The role of sex hormones has been suggested for the onset of MS during adolescence, but further studies are needed.
  • The relation between menarche and MS onset in young females must be deeply investigated.
AFAB, assigned female at birth; AMAB, assigned male at birth.
Table
Table 5. Available evidence on the relationship between eating disorders (EDs) and gender.
Table 5. Available evidence on the relationship between eating disorders (EDs) and gender.
What is known
  • Traditionally considered related to assigned female at birth, EDs are increasing among AMAB adolescents [13,77].
  • AMAB people tend to be more concerned about muscularity and AFAB people about losing weight. Suicide attempts are more frequent among AMAB people [83,84,85,86,87,88].
What is still unknown
  • The roles of puberty and of sex hormones seem to be critical to the onset of EDs but still need to be investigated.
  • There is still a paucity of data regarding EDs among assigned males at birth.
AFAB, assigned female at birth; AMAB, assigned male at birth.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Diana, P.; Esposito, S. A Gender-Based Point of View in Pediatric Neurology. J. Pers. Med. 2023, 13, 483. https://doi.org/10.3390/jpm13030483

AMA Style

Diana P, Esposito S. A Gender-Based Point of View in Pediatric Neurology. Journal of Personalized Medicine. 2023; 13(3):483. https://doi.org/10.3390/jpm13030483

Chicago/Turabian Style

Diana, Pierluigi, and Susanna Esposito. 2023. "A Gender-Based Point of View in Pediatric Neurology" Journal of Personalized Medicine 13, no. 3: 483. https://doi.org/10.3390/jpm13030483

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop