Seminario 13 Diferenciacion sexual humana - Rodolfo Rey

Introduction to Human Sexual Differentiation

Overview of the Class

• Rodolfo Rey introduces the class on human sexual differentiation, focusing on genetic bases and anomalies related to sex chromosomes.

• The session will cover concepts of sex and gender, anatomy, physiology, and genetics involved in sexual differentiation during intrauterine life.

Genetic Aspects of Sexual Differentiation

• Discussion includes typical dimorphic characteristics in chromosomal sex (XX or XY), which account for over 99% of the population.

• The presentation will explore examples of genetic anomalies affecting sexual differentiation using the acronym CD (Congenital Disorders).

Dimorphism in Gonads and Genitals

Expression of Genes

• Chromosomal types are associated with female (46XX) or male (46XY), but this association is not absolute.

• Dimorphic gene expression is evident in gonads; certain genes are expressed more strongly in testes than ovaries and vice versa.

Variability Across Organs

• While there is significant dimorphism in gonadal expression, differences in other organs like the liver or brain are less pronounced.

• Notable anatomical distinctions exist between male and female genitalia, while variations in organ function may require sensitive techniques to detect.

Sex vs. Gender: Definitions and Implications

Biological vs. Psychosocial Perspectives

• "Sex" refers to biological aspects such as chromosomes and anatomy; "gender" encompasses psychosocial dimensions.

• Legal sex assignment at birth typically aligns with external genitalia but does not always match an individual's later gender identity.

Identity and Expression of Gender

• Gender identity reflects an individual's self-perception, which may differ from their assigned legal sex at birth.

Understanding Gender Expression and Chromosomal Sex

Gender Expression in Society

• The transcript discusses how societal norms associate certain activities with gender, such as boys playing with balls (masculine expression) and girls playing with dolls (feminine expression). This association is culturally variable and evolves over time.

Sexual Orientation Concepts

• It highlights the concept of sexual orientation, emphasizing that individuals can have sexual desires towards the same gender, another gender, both genders, or no gender at all. This diversity reflects a range of possibilities beyond traditional binary classifications.

Genetic Aspects of Sex Determination

• The focus shifts to genetic factors influencing sex determination, particularly chromosomal sex. It explains that an individual's chromosomal sex is primarily determined by the sperm's chromosome during fertilization.

Developmental Stages of Embryos

• At conception, embryos possess two pairs of chromosomes: 22 autosomes and one pair of sex chromosomes (XX or XY). The type of sperm (carrying X or Y chromosome) determines whether the resulting zygote will be XX (female) or XY (male).

Indifferent Stage in Sexual Development

• For approximately six weeks post-fertilization, human embryos are sexually indifferent. During this period, anatomical structures related to both male and female development are present but not yet differentiated.

Importance of Alfred Jost's Research

What Did the French Biologist Observe?

Gonadal Differentiation and Its Effects

• The French biologist observed that when gonads differentiate towards ovaries, the Wolffian ducts (mesonephric ducts) disappear while Müllerian ducts persist, forming parts of the uterus and upper vagina.

• In contrast, when gonads differentiate towards male, Müllerian ducts regress and Wolffian ducts develop into structures such as the epididymis, seminal vesicles, and prostate.

Experimental Insights on Gonadal Removal

• A significant experiment involved removing gonads from rabbit embryos before sexual differentiation (before the sixth week in humans), resulting in all newborn rabbits exhibiting female characteristics regardless of their genetic sex.

• This finding highlighted that without gonads, internal and external genitalia default to a female phenotype during early development stages.

Hormonal Influence on Sexual Differentiation

• To further investigate hormonal influence, an experiment was conducted where testes were implanted in embryos with ovaries. The results showed that even with ovaries present, if testes were implanted, male genital structures developed instead of female ones.

• This confirmed that the presence of testes is crucial for masculinization; if no testes are present (even with ovaries), genitalia will feminize.

Role of Testosterone and Anti-Müllerian Hormone

• It was established that testosterone is responsible for some aspects of masculinization while another hormone known as Anti-Müllerian Hormone (AMH) is responsible for regression of Müllerian ducts during embryonic development.

Chromosomal Influence on Gender Development

• By approximately 11 weeks into gestation, differences between embryos with functioning testes producing hormones versus those without become evident. By the end of the first trimester, clear differentiation into male or female genitalia occurs.

• Most individuals with a 46XX karyotype typically develop female characteristics; however, questions arise about whether two X chromosomes are necessary for this or if one Y chromosome suffices for male differentiation.

Observations from Turner and Klinefelter Syndromes

• Studies from the late 1950s revealed women with Turner syndrome (45X karyotype) could still develop female characteristics despite lacking two X chromosomes. Conversely, men with Klinefelter syndrome (47XXY karyotype) exhibited male traits despite having an extra X chromosome.

Differentiation Sexual: El Papel del Cromosoma Y

Introducción a la Diferenciación Sexual

• La diferenciación sexual se inicia con la presencia de un cromosoma Y, que determina el desarrollo de testículos y la masculinización de genitales.

• Investigadores comenzaron a estudiar individuos con anomalías en el cromosoma para entender su papel en la diferenciación sexual, como el síndrome Turner, donde falta parte del cromosoma.

Estudios sobre Anomalías del Cromosoma

• Se examinaron individuos con diferentes configuraciones del cromosoma X e Y; incluso aquellos con partes faltantes seguían desarrollándose como mujeres.

• Se identificó el gen SRY (Sex-determining Region Y), crucial para la formación de testículos y masculinización, ubicado en el brazo corto del cromosoma Y.

Mecanismos Genéticos y Su Importancia

• En 1990, se creía que tener SRY era suficiente para desarrollar características masculinas; sin embargo, surgieron preguntas sobre su necesidad y mecanismo de acción.

• Se estudiaron casos de mujeres XY sin SRY, lo que llevó a investigar cómo este gen puede ser transferido entre los cromosomas durante la meiosis.

Intercambio Genético y Resultados Inesperados

• Durante la meiosis, si hay un intercambio anormal entre los cromosomas X e Y, puede resultar en un individuo XX con características masculinas si recibe SRY.

• Alternativamente, un embrión XX sin SRY resultará en una mujer con genitales femeninos. Este fenómeno plantea interrogantes sobre otros factores involucrados en la diferenciación sexual.

Conclusiones sobre Genes Implicados

• Aunque se comprende cómo algunos individuos pueden ser XX o XY dependiendo de la presencia o ausencia de SRY, esto no explica todos los casos observados.

Understanding Urogenital Development

Formation of the Urogenital Crest

• The urogenital crest is derived from intermediate and lateral mesoderm, which gives rise to the gonadal primordium or indifferent gonad. This structure contains numerous genes that can be expressed.

Testicular Differentiation

• When the R.I. gene is expressed, it influences genes related to testicular differentiation, leading to male gonadal development between weeks 7 and 9 of gestation. This results in a testicular phenotype.

Ovarian Differentiation

• In the absence of R.I., other genes (notably those marked in red) dominate, resulting in ovarian differentiation within the indifferent gonad for XX individuals. The presence of R.I. favors testicular development while its absence leads to ovarian formation.

Sexual Differentiation Process

• Following gonadal differentiation into either ovaries or testes, internal and external genitalia begin to develop between weeks 9 and 13 of gestation, marking significant sexual differentiation during early fetal development.

Hormonal Influence on Genital Development

• Testes produce two key hormones: testosterone (from Leydig cells) which promotes masculinization of internal and external genitalia, and anti-Müllerian hormone (AMH) from Sertoli cells that causes regression of Müllerian ducts in males; ovaries do not produce these hormones at this stage.

The Role of Steroidogenesis

Testosterone Synthesis

• Testosterone synthesis involves steroidogenesis, a complex process where cholesterol is converted into testosterone through various enzymatic transformations involving multiple intermediates before reaching final production. Understanding this pathway is crucial for grasping hormonal regulation during sexual differentiation.

Dihydrotestosterone Conversion

• Testosterone is further converted into dihydrotestosterone (DHT), a more potent androgen responsible for developing external genitalia via action on androgen receptors present in these tissues; this conversion occurs through the enzyme 5-alpha reductase.

Genetic Regulation in Sexual Development

Androgen Receptor Gene Location

• The androgen receptor gene (A-R) located on the X chromosome plays a critical role in mediating androgen effects on both internal and external genital structures despite common associations with female sex linked to X chromosomes; this highlights genetic complexity in sexual development processes.

AMH Functionality

Understanding the Role of MHR2 and Sox9 in Sexual Differentiation

The Specific Receptor for M H

• The specific receptor for M H is called M H R 2, which is encoded by a gene located on chromosome 12, not on the X or Y chromosomes.

• This receptor alone is insufficient; it must interact with another shared receptor (Type 1) involved in signaling other factors from the same family.

Interaction Between Receptors

• The interaction between the specific Type 2 receptor and the non-specific Type 1 receptor leads to signal transduction initiated by M H, resulting in the regression of Müllerian ducts.

• Other masculinizing factors exist beyond just SRY protein, including genes like DAX1 and SOX9 that play critical roles in sexual differentiation.

Impact of Gene Expression on Sexual Development

• In an XY fetus with a mutation affecting SRY expression, there can be a predominance of pathways leading to female differentiation due to improper expression of SOX9. This results in no testicular formation and consequently female genital development at birth.

• A similar outcome occurs when individuals have mutations in SOX9; despite having normal SRY, testicular development fails due to lack of androgen production. Thus, they may present as females externally.

Genetic Variations Affecting Gonadal Development

• An example includes individuals with duplications of SOX9 leading to increased expression levels that promote testicular differentiation even without functional SRY presence. This results in male characteristics developing despite genetic anomalies.

• Another case involves individuals who are XX but have duplications affecting DAX1 on their X chromosome, leading to overexpression that inhibits proper gonadal differentiation towards male characteristics despite having functional SRY present.

Importance of Gene Dosage

• Observations highlight how gene dosage impacts sexual differentiation: correct expression levels lead to typical testis or ovary formation while alterations can result in unexpected outcomes such as XX individuals developing testes or vice versa.

Additional Factors Influencing Sexual Differentiation

Understanding Genetic Expression in Sexual Differentiation

Mechanisms of Müllerian Hormone (MH) and Testicular Development

• Discussion on the development of Müllerian ducts, including potential outcomes such as the formation of a uterus or testes in XY individuals. The presence of specific gene doses like SOX9 and LH1 is highlighted.

• Explanation of pathogenic variants that affect MH expression, leading to atypical sexual differentiation, such as the formation of a uterus in males due to insufficient androgen production.

• Emphasis on how loss-of-function mutations can lead to female genital differentiation when androgens are absent during fetal development.

Gene Expression and Gonadal Differentiation

• Clarification that while certain alleles may be present, pathogenic variants can disrupt proper gene expression necessary for male differentiation.

• Inquiry into why XY embryos produce testosterone only from testicular cells despite having the SRY gene across all cells; highlights selective gene expression during embryonic development.

• Notable genes involved in gonadal differentiation are mentioned, with emphasis on their specific expressions at different developmental stages, particularly in the gonadal ridge.

Regulatory Factors Influencing Sexual Development

• Identification of key genes (e.g., SOX9, SF1, WT1) that must co-express for proper testicular differentiation; absence or misexpression leads to female phenotype development.

• Discussion on how certain tissues express SOX9 but lack other critical genes required for testis formation; underscores the importance of combinatorial gene expression for sexual differentiation.

Experimental Evidence from Mouse Models

• Presentation of mouse strains (FBB, Acaerne, Iarra), illustrating varying levels of SRY expression and its impact on testicular development and hormone production.

• FBB strain shows normal SRY expression timing correlating with typical testis formation; contrasts with Acaerne strain which has lower SRY levels leading to abnormal genital development.

Development of Testes and AMH Role

Importance of Gene Expression Timing

• The formation of testes is not solely dependent on the presence of genes but also on when these genes are expressed during development.

• Anti-Müllerian hormone (AMH) is produced by differentiated testes starting from the seventh week, while ovaries begin producing AMH only from the 26th fetal week.

AMH and Müllerian Duct Regression

• The expression of AMH receptors in Müllerian ducts occurs between weeks 7 to 9; after this period, receptor expression ceases. If AMH is absent during this time, Müllerian ducts do not regress as expected.

• By week 10, if AMH has been produced, regression of Müllerian ducts occurs due to the presence of both AMH and its receptors. Conversely, without early AMH production, a uterus forms despite later ovarian production of AMH.

Mechanisms Behind Sexual Development Disorders (DSD)

• Normal genital formation relies on timely gene expression; disruptions can lead to disorders known as DSD (Disorders of Sexual Development). This includes discrepancies between genetic sex and external genitalia.

• Examples include individuals with a 46XX karyotype exhibiting male or ambiguous external genitalia instead of female characteristics expected for their chromosomal makeup. Similarly, some with a 46XY karyotype may present with female or ambiguous genitalia.

Chromosomal Anomalies in DSD

• Chromosomal DSD refers to sexual differentiation anomalies caused by chromosomal irregularities such as mosaicism or chimerism—where different cells within an individual have varying karyotypes (e.g., some cells being 46XX while others are 45X).

• Mosaicism can occur when one cell loses a chromosome early in development, leading to a mix of cell types within an individual that affects sexual differentiation outcomes. Chimerism results from the fusion of two embryos at an early stage.

Anomalies During Differentiation Phases

• Various mechanisms can lead to abnormal sexual differentiation during critical phases: undifferentiated phase, gonadal differentiation phase, and genital differentiation phase may all experience anomalies affecting normal development pathways.

Understanding Genital Development and Anomalies

Isolated Genesis Defects

• The transcript discusses isolated defects in genital development, specifically the absence of phallic formation leading to agenesis. While the scrotum and testes are masculinized, the penis does not form correctly.

Morphogenetic Disorders

• Various syndromes or conditions arise from defects in the morphogenetic system affecting internal ducts or external genitalia. These issues stem from pathogenic variants in genes predominantly located on autosomes rather than sex chromosomes.

Genetic Databases for Conditions

• A recommendation is made to familiarize with a genetic disease database that provides clinical characteristics and genetic details for various conditions identified by specific codes.

Hormonal Production and Gonadal Differentiation

• The discussion transitions to cases where gonads differentiate incorrectly despite initial proper formation. This leads to disorders of sexual differentiation (DSD), particularly when testicular or ovarian structures do not develop as expected.

Consequences of Testicular Dysgenesis

• In individuals with XY chromosomes, improper testicular formation results in insufficient hormone production, impacting both internal and external genital masculinization. This can lead to ambiguous genitalia if there is partial testicular development.

Pathogenic Variants Affecting Sexual Differentiation

• The presence of pathogenic variants in genes responsible for testicular differentiation can result in female phenotypes due to lack of androgen exposure during critical developmental stages.

Ambiguous Genitalia Cases

• When there is partial testis formation, individuals may exhibit ambiguous genitalia due to inadequate hormonal levels necessary for complete male or female differentiation.

Syndromes Related to Gonadal Dysgenesis

• Several syndromes characterized solely by gonadal dysgenesis exist without other anomalies. These cases highlight how certain gene variants affect only gonadal expression while leaving other systems unaffected.

Neurological Implications of Genetic Variants

• Some genetic variants not only impact gonadal development but also lead to neurological delays or neuropathies, indicating a broader spectrum of effects beyond just sexual differentiation.

Complex Intersex Conditions

• There are instances where individuals present with both ovarian and testicular tissue due to mutations affecting multiple genes involved in sexual development, complicating diagnosis and treatment options.

Understanding Disorders of Sexual Development

Overview of Disorders

• The discussion focuses on disorders limited to the final stage of sexual development, where gonads form correctly but hormonal production or action is abnormal.

• These conditions are termed "non-dysgenetic syndromes" because there is no dysgenesis; gonads develop, but steroid hormone production (like testosterone) may be defective or ineffective.

Examples of Conditions

• An example includes Leydig cell mutations affecting testosterone synthesis, leading to hypogonadism and insufficient androgen levels for proper masculinization.

• In cases of severe hypogonadism, individuals may present as females without a uterus despite having testes due to normal Müllerian hormone (MH) function causing regression of Müllerian ducts.

Variability in Androgen Sensitivity

• Less severe forms can result in ambiguous genitalia when some testosterone is produced but not enough for complete masculinization.

• Individuals with 46 XY karyotype may have ambiguous external genitalia due to inadequate testosterone levels during development.

Receptor Insensitivity Issues

• If androgens are produced normally but there’s a pathogenic variant in the androgen receptor, individuals may appear female externally while lacking a uterus.

• Partial insensitivity leads to ambiguous genitalia; if androgen receptor activity is completely absent, individuals will have fully female external genitalia.

Persistence of Müllerian Duct Syndrome

• In cases where testicular and androgen production is normal but MH action fails (due to resistance), individuals can develop male characteristics alongside a uterus.

• This condition arises from anomalies in the MH gene or its receptor type 2, leading to persistence of Müllerian structures despite male phenotype.

Summary Table Insights

• A summary table illustrates various genetic anomalies related to androgen sensitivity and synthesis that lead to sexual differentiation disorders.

Genetic Basis of X-Linked Disorders

Overview of Androgen Receptor Genetics

• The discussion begins with the genetic perspective on X-linked diseases, specifically focusing on the androgen receptor gene located on the long arm of the X chromosome. Males typically have one copy (hemizygous) while females possess two copies (homozygous) of this gene.

• In males, having a single normal androgen receptor gene is crucial for typical development, as they lack a corresponding gene on the Y chromosome. Conversely, females can be carriers if one allele is mutated without significant impact due to the presence of a normal allele.

Carrier Status and Genetic Implications

• A female carrier may pass on an affected or unaffected X chromosome to her offspring. If she transmits an X chromosome with a mutated androgen receptor gene (R-minus), it can lead to conditions in male offspring who inherit this variant from their mother. This results in them being hemizygous for the mutation.

• The potential outcomes for children from such pairings include various combinations: affected females (X-Y with pathogenic variant), carrier females (X-Y carrier), normal males (X-Y normal), and homozygous normal females (two normal X chromosomes). Each combination has distinct phenotypic implications based on their genotype.

Excess Androgens and Their Effects

• The conversation shifts to cases where individuals with XX chromosomes experience excessive androgen production leading to masculinization, which is unexpected given their chromosomal makeup. This condition often arises from congenital adrenal hyperplasia, resulting in overproduction rather than underproduction of androgens during fetal development.

• An example discussed includes an embryo with 46 XX chromosomes that develops ovaries but experiences abnormal masculinization due to excess androgens produced by adrenal glands or other sources like tumors during pregnancy. Such conditions can lead to significant physical changes in genitalia at birth, necessitating surgical intervention and gender assignment considerations postnatally.

Genetic Factors in Disorders of Sexual Development

Genetic Diagnosis in Individuals: A Comprehensive Overview

Understanding Phenotyping and Genetic Analysis

• The initial step in genetic diagnosis involves phenotyping, which is the characterization of an individual's phenotype through physical examination, interviews, imaging studies, and hormonal laboratory tests.

• Standardized terms known as HPO (Human Phenotype Ontology) are increasingly used to describe anatomical anomalies and laboratory findings, providing a dictionary-like reference for consistency.

• Following phenotyping, genotypic analysis begins with karyotyping to assess chromosomal structure using various techniques that will be explored in future classes.

• If karyotyping does not yield sufficient information, DNA sequencing is performed. This often includes next-generation sequencing (NGS), allowing for simultaneous analysis of multiple genes.

Case Study: Delayed Puberty in a Female Adolescent

• An illustrative case involves a 14-year-old female presenting with delayed puberty; she has not developed breast tissue or menstruated by this age. The condition is coded as HPO00800823 for delayed puberty.

• Additional findings include absent breast development (also coded under HPO), leading to further genetic analysis focused on identifying the gene of interest.

• An abdominal-pelvic ultrasound reveals an infantile uterus and absence of ovaries. Hormonal tests show elevated FSH and LH levels but low estradiol and undetectable testosterone levels.

Diagnosis of Disorders of Sexual Development (DSD)

• A biopsy indicates complete gonadal dysgenesis (pure gonadal dysgenesis), confirming the patient’s karyotype as 46 XX without any testicular tissue present.

• The lack of estrogen production due to absent ovaries explains the underdeveloped internal genitalia. The adolescent's normality in other aspects suggests that the issue lies within the differentiation process during gonadal development.

Karyotyping Techniques

• Traditional karyotyping is performed using peripheral blood lymphocytes; cells are cultured, separated, and stained using banding techniques to visualize chromosomes clearly.

Comparative Genomic Hybridization and Genetic Analysis

Overview of CGH and Karyotyping

• The use of array Comparative Genomic Hybridization (CGH) is discussed, highlighting its dependency on economic conditions in certain countries. Array CGH is noted to be more accessible than traditional karyotyping, which requires extensive manual analysis of 50 cells.

Limitations of Traditional Karyotyping

• If no abnormalities are found through traditional karyotyping, it may indicate undetectable small DNA sequence gains or losses that could be identified using microarray techniques.

Functionality of Array CGH

• Array CGH allows for the identification of genomic material losses or gains by comparing an individual's genome with a reference genome. This technique utilizes peripheral blood DNA for analysis.

Sensitivity and Resolution of Techniques

• The commercial platform used can detect genetic material changes exceeding 100 kilobases. Smaller changes below this threshold may not be detected, emphasizing the limitations in identifying significant genetic alterations.

Results from Array CGH Analysis

• No significant genomic material loss or gain was detected in the analyzed sample. The results indicated normal karyotype findings with specific chromosome presence (46 chromosomes including X and Y).

Further Investigations into Gene Variants

• Despite normal findings from both karyotype and array CGH, there is suspicion regarding smaller gene variants that might not have been detected. A potential deletion in the GNR gene is highlighted as being less than 100 kilobases.

PCR Amplification for Gene Detection

• A PCR test was conducted to amplify the GNR gene using the same peripheral blood DNA sample. Controls were included to ensure accuracy in detecting gene presence.

Findings from PCR Testing

• The amplification results showed that both the SREI gene and a control gene were present in the patient’s sample, indicating that while SREI exists, it does not rule out possible mutations affecting amplification.

Next Steps: Whole Exome Sequencing (WES)

• To further investigate potential genetic variants, a whole exome sequencing (WES) approach was employed to analyze all genes within an individual’s exome comprehensively.

Comparison with Reference Exomes

• When comparing an individual's exome with a reference exome, numerous variants were identified; however, these do not necessarily correlate with disease causation due to natural genetic diversity among individuals.

Filtering Genetic Variants

Genetic Variants and Their Implications in Disease

Identification of Pathogenic Variants

• The American College of Medical Genetics (ACMG) provides criteria for analyzing genetic variants. A specific variant in the M gene was identified as a candidate for pathogenicity based on these criteria.

• This variant introduces a stop codon at position 322, with sequencing revealing it present in a heterozygous state—157 reads showed this variant, indicating its significance.

• The identified variant is rare in population databases, suggesting that its rarity may correlate with being disease-causing, as common variants are less likely to be pathogenic.

Scoring and Classification of Variants

• Following ACMG guidelines, the variant received a score of 9 points; variants scoring 6 or more are considered probably pathogenic, while those with 10 or more are deemed certainly pathogenic.

• The study using Next Generation Sequencing (NGS) confirmed the presence of this pathogenic variant in the MIRF gene located on chromosome 11.

Parental Analysis and Mutation Origin

• Genetic testing revealed that neither parent carried the MIRF variant, indicating it likely arose during gametogenesis from either an oocyte or spermatozoid mutation.

• This suggests that the mutation occurred during meiosis, leading to one gamete carrying the variant while others did not transmit it.

Phenotypic Correlation and Clinical Findings

• The phenotype associated with this genetic variant includes characteristics of cardiourogenital syndrome. Specific anomalies such as heart positioning and pulmonary return issues were investigated.

• Upon examination, only one anomaly—a right-sided heart orientation—was found in the patient. This condition was referred to cardiology for monitoring but had no significant clinical repercussions.

Broader Implications and Genetic Insights

• The variability in phenotypic expression among individuals highlights how different patients can exhibit diverse symptoms despite having similar genetic mutations.

• Data from Brazilian cohorts indicated that certain genes like androgen receptor genes were frequently implicated in DCD cases. Understanding these patterns integrates genetics with anatomy and molecular biology principles crucial for diagnosis and treatment strategies.

Differentiation Sexual y Hormonas

Influencia de los Conductos en la Diferenciación Sexual

• Los conductos de Bolf son unipotenciales, produciendo únicamente derivados masculinos, mientras que los conductos de Miuller generan solo derivados femeninos. La diferenciación sexual depende principalmente del testículo.

• Aunque los ovarios están presentes, no influyen en la diferenciación sexual inicial; su efecto se manifiesta más tarde durante la adolescencia y en la vida adulta.

Hormonas Involucradas en la Diferenciación Sexual

• Los testículos producen dos hormonas clave para la diferenciación sexual: andrógenos y hormona antimülleriana (AMH). Estas hormonas son fundamentales para el desarrollo adecuado de las características sexuales.

Anomalías Genéticas y su Impacto

• Las anomalías pueden ser malformativas y no afectar directamente la producción o acción hormonal. Sin embargo, pueden resultar de deficiencias en andrógenos o AMH, causando discordancias entre el cariotipo y los genitales.

• Las anomalías genéticas pueden surgir por alteraciones en la expresión génica, ya sea insuficiente o excesiva. No siempre hay una relación directa entre genotipo y fenotipo.

Métodos de Estudio de Anomalías