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46,XX Gonadal Dysgenesis

46,XX gonadal dysgenesis is a disorder present in individuals who are phenotypic females with normal karyotypes of 46,XX and who have streak gonads Gonads The gamete-producing glands, ovary or testis. Hormones: Overview and Types with no functional ovarian tissue. It is also called “pure gonadal dysgenesis Gonadal dysgenesis A number of syndromes with defective gonadal developments such as streak gonads and dysgenetic testes or ovaries. The spectrum of gonadal and sexual abnormalities is reflected in their varied sex chromosome (sex chromosomes) constitution as shown by the karyotypes of 45, X monosomy (Turner syndrome); 46, XX (gonadal dysgenesis, 46xx); 46, XY (gonadal dysgenesis, 46, xy); and sex chromosome mosaicism. Their phenotypes range from female, through ambiguous, to male. This concept includes gonadal agenesis. Wilms Tumor” to differentiate these patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship from those who present with the phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics of Turner's syndrome (webbed neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess, short stature, widely spaced nipples). Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship present with a normal development during childhood, primary amenorrhea Amenorrhea Absence of menstruation. Congenital Malformations of the Female Reproductive System, infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility, and a lack of secondary sexual characteristics Secondary Sexual Characteristics Precocious Puberty. Management includes hormone replacement therapy Hormone Replacement Therapy Hormone replacement therapy (HRT) is used to treat symptoms associated with female menopause and in combination to suppress ovulation. Risks and side effects include uterine bleeding, predisposition to cancer, breast tenderness, hyperpigmentation, migraine headaches, hypertension, bloating, and mood changes. Noncontraceptive Estrogen and Progestins and prophylactic gonadectomy.

Last updated: Feb 10, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Etiology and Pathophysiology

Synonyms

Epidemiology

  • Very rare
  • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency is thought to be < 1 case per 10,000 individuals

Etiology

  • Karyotype Karyotype The full set of chromosomes presented as a systematized array of metaphase chromosomes from a photomicrograph of a single cell nucleus arranged in pairs in descending order of size and according to the position of the centromere. Congenital Malformations of the Female Reproductive System of an individual with pure gonadal dysgenesis Gonadal dysgenesis A number of syndromes with defective gonadal developments such as streak gonads and dysgenetic testes or ovaries. The spectrum of gonadal and sexual abnormalities is reflected in their varied sex chromosome (sex chromosomes) constitution as shown by the karyotypes of 45, X monosomy (Turner syndrome); 46, XX (gonadal dysgenesis, 46xx); 46, XY (gonadal dysgenesis, 46, xy); and sex chromosome mosaicism. Their phenotypes range from female, through ambiguous, to male. This concept includes gonadal agenesis. Wilms Tumor is 46,XX
  • Caused by homozygous or compound heterozygous mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the gene-encoding follicle-stimulating hormone receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (FSHR) on chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 2p16
  • Various genetic defects are known:
    • Autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance mutations that inactivate the FSHR gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics 
    • X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) mutations in the BMP15 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
    • Autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance mutations in the NR5A1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics

Pathophysiology

Various mutations (especially point mutations that lead to FSH-resistant ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries: Anatomy) lead to interrupted ovarian development during embryogenesis OR premature Premature Childbirth before 37 weeks of pregnancy (259 days from the first day of the mother’s last menstrual period, or 245 days after fertilization). Necrotizing Enterocolitis depletion of ovarian follicles → impaired estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy secretion Secretion Coagulation Studies → undeveloped secondary sexual characteristics Secondary Sexual Characteristics Precocious Puberty.

Clinical Presentation

  •   Phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics:
    • Childhood: normal development of female genital organs
    • Puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty: undeveloped secondary sexual characteristics Secondary Sexual Characteristics Precocious Puberty
  • Cognition/intelligence: normal
  • Behavioral phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics: normal
  • Sex Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria development/fertility: 
  • Perrault syndrome: ovarian dysgenesis Ovarian Dysgenesis Congenital Malformations of the Female Reproductive System with sensorineural deafness
    • Hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss
    • Intellectual disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment
    • Ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia (difficulty with balance and coordination Coordination Cerebellar Disorders)
    • Peripheral neuropathy Peripheral Neuropathy Neurofibromatosis Type 2

Diagnosis and Management

Diagnosis

Diagnosis is mainly clinical, based on amenorrhea Amenorrhea Absence of menstruation. Congenital Malformations of the Female Reproductive System, undeveloped secondary sexual characteristics Secondary Sexual Characteristics Precocious Puberty, and a lack of the typical phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics of Turner’s syndrome.

  • Hormonal testing:
    • ↑ Gonadotropins
    • Estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy
  • Karyotype Karyotype The full set of chromosomes presented as a systematized array of metaphase chromosomes from a photomicrograph of a single cell nucleus arranged in pairs in descending order of size and according to the position of the centromere. Congenital Malformations of the Female Reproductive System testing: confirms 46,XX normal female karyotype Karyotype The full set of chromosomes presented as a systematized array of metaphase chromosomes from a photomicrograph of a single cell nucleus arranged in pairs in descending order of size and according to the position of the centromere. Congenital Malformations of the Female Reproductive System
  • Imaging of the pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 “hip” bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis: Anatomy shows presence of a normal or small uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Uterus, Cervix, and Fallopian Tubes: Anatomy and no ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries: Anatomy.

Management

  • Lifelong hormonal therapy of estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries: Anatomy and progesterone Progesterone The major progestational steroid that is secreted primarily by the corpus luteum and the placenta. Progesterone acts on the uterus, the mammary glands and the brain. It is required in embryo implantation; pregnancy maintenance, and the development of mammary tissue for milk production. Progesterone, converted from pregnenolone, also serves as an intermediate in the biosynthesis of gonadal steroid hormones and adrenal corticosteroids. Gonadal Hormones substitution:
    • Primarily indicated to stimulate the development of secondary sexual characteristics Secondary Sexual Characteristics Precocious Puberty and restore a regular Regular Insulin menstrual cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation 
    • Cannot prevent infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility, since it has no effect on the FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing responsible for premature Premature Childbirth before 37 weeks of pregnancy (259 days from the first day of the mother’s last menstrual period, or 245 days after fertilization). Necrotizing Enterocolitis ovarian failure
  • Fertility treatment: oocyte donation Oocyte donation Transfer of preovulatory oocytes from donor to a suitable host. Oocytes are collected, fertilized in vitro, and transferred to a host that can be human or animal. Reproductive Ethical Issues and hormonal therapy

Differential Diagnosis

The following conditions are differential diagnoses for pure gonadal dysgenesis Gonadal dysgenesis A number of syndromes with defective gonadal developments such as streak gonads and dysgenetic testes or ovaries. The spectrum of gonadal and sexual abnormalities is reflected in their varied sex chromosome (sex chromosomes) constitution as shown by the karyotypes of 45, X monosomy (Turner syndrome); 46, XX (gonadal dysgenesis, 46xx); 46, XY (gonadal dysgenesis, 46, xy); and sex chromosome mosaicism. Their phenotypes range from female, through ambiguous, to male. This concept includes gonadal agenesis. Wilms Tumor.

  • Turner syndrome Turner syndrome Turner syndrome is a genetic condition affecting women, in which 1 X chromosome is partly or completely missing. The classic result is the karyotype 45,XO with a female phenotype. Turner syndrome is associated with decreased sex hormone levels and is the most common cause of primary amenorrhea. Turner Syndrome: a gonosomal monosomy Monosomy The condition in which one chromosome of a pair is missing. In a normally diploid cell it is represented symbolically as 2n-1. Types of Mutations of the X-chromosome, resulting in a karyotype Karyotype The full set of chromosomes presented as a systematized array of metaphase chromosomes from a photomicrograph of a single cell nucleus arranged in pairs in descending order of size and according to the position of the centromere. Congenital Malformations of the Female Reproductive System of 45,X0 and a female phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship usually present with amenorrhoea, webbed neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess, short stature, infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility, intellectual deficit, and wide-spaced nipples. 
  • Swyer syndrome Swyer syndrome Swyer syndrome is a disorder of sex development caused by a defect in the SRY gene on chromosome Y. The syndrome is characterized by complete testicular dysgenesis in an individual who has a 46,XY karyotype and is phenotypically female. Swyer Syndrome: a disorder of sex Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria development caused by a defect in the SRY gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics on chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics Y. Characterized by complete testicular dysgenesis in an individual who has a 46,XY karyotype Karyotype The full set of chromosomes presented as a systematized array of metaphase chromosomes from a photomicrograph of a single cell nucleus arranged in pairs in descending order of size and according to the position of the centromere. Congenital Malformations of the Female Reproductive System and is phenotypically female. Presents as a phenotypic female, taller than an individual with 46,XX gonadal dysgenesis Gonadal dysgenesis A number of syndromes with defective gonadal developments such as streak gonads and dysgenetic testes or ovaries. The spectrum of gonadal and sexual abnormalities is reflected in their varied sex chromosome (sex chromosomes) constitution as shown by the karyotypes of 45, X monosomy (Turner syndrome); 46, XX (gonadal dysgenesis, 46xx); 46, XY (gonadal dysgenesis, 46, xy); and sex chromosome mosaicism. Their phenotypes range from female, through ambiguous, to male. This concept includes gonadal agenesis. Wilms Tumor, with a normal childhood and development until puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty, which is characterized by primary amenorrhea Amenorrhea Absence of menstruation. Congenital Malformations of the Female Reproductive System and no development of secondary sexual characteristics Secondary Sexual Characteristics Precocious Puberty.

References

  1. O’Neill MJF. Ovarian Dysgenesis 1. (2018). Online Mendelian Inheritance in Man, An Online Catalog of Human Genes and Genetic Disorders. https://www.omim.org/entry/233300#
  2. O’Neill MJF, Bocchini CA. (Last edit:  August 2019). 46,XY Gonadal Dysgenesis, Complete, Sry-Related. Online Mendelian Inheritance in Man, An Online Catalog of Human Genes and Genetic Disorders. https://www.omim.org/entry/400044?search=swyer&highlight=swyer
  3. Moshiri M, Chapman T, Fechner PY. (2012). Evaluation and Management of Disorders of Sex Development: Multidisciplinary Approach to a Complex Diagnosis. RadioGraphics 2012; 32:1599–1618. DOI: 10.1148/rg.326125507.
  4. Orphanet. 46,XX gonadal dysgenesis. Retrieved on August 15, 2020 from https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=1011&MISSING%20CONTENT=46-XX-gonadal-dysgenesis&search=Disease_Search_Simple&title=46,XX%20gonadal%20dysgenesis

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