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 with no functional ovarian tissue. It is also called “pure gonadal dysgenesis” to differentiate these patients from those who present with the phenotype of Turner’s syndrome (webbed neck, short stature, widely spaced nipples). Patients present with a normal development during childhood, primary amenorrhea Primary Amenorrhea Primary amenorrhea is defined as the absence of menstruation in a girl by age 13 years in the absence of secondary sex characteristics or by the age of 15 years with the presence of secondary sex characteristics. Etiologies can originate in the hypothalamic-pituitary-ovarian (HPO) axis or from anatomic abnormalities in the uterus or vagina. Primary Amenorrhea, 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. Management includes hormone replacement therapy and prophylactic gonadectomy.

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Etiology and Pathophysiology

Synonyms

  • Ovarian dysgenesis 1 (ODG-1)
  • Hypergonadotropic ovarian dysgenesis
  • Pure gonadal dysgenesis
  • 46,XX ovarian dysgenesis
  • Hypergonadotropic ovarian failure

Epidemiology

  • Very rare
  • Incidence is thought to be < 1 case per 10,000 individuals

Etiology

  • Karyotype of an individual with pure gonadal dysgenesis 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 (FSHR) on chromosome 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 Inheritancemutations that inactivate the FSHR gene 
    • X-linked mutations in the BMP15 gene
    • 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

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) lead to interrupted ovarian development during embryogenesis OR premature depletion of ovarian follicles → impaired estrogen secretion → undeveloped secondary sexual characteristics.

Clinical Presentation

  •  Phenotype:
    • 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
  • Cognition/intelligence: normal
  • Behavioral phenotype: normal
  • Sex development/fertility: 
    • Infertility
    • Primary amenorrhea
  • Perrault syndrome: ovarian dysgenesis 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
    • Ataxia (difficulty with balance and coordination)
    • Peripheral neuropathy

Diagnosis and Management

Diagnosis

Diagnosis is mainly clinical, based on amenorrhea, undeveloped secondary sexual characteristics, and a lack of the typical phenotype of Turner’s syndrome.

  • Hormonal testing:
    • ↑ Gonadotropins
    • ↓ Estrogen
  • Karyotype testing: confirms 46,XX normal female karyotype
  • 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 shows presence of a normal or small uterus 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.

Management

  • Lifelong hormonal therapy of estrogen and progesterone substitution:
    • Primarily indicated to stimulate the development of secondary sexual characteristics and restore a regular menstrual cycle Menstrual cycle The menstrual cycle is the cyclic pattern of hormonal and tissular activity that prepares a suitable uterine environment for the fertilization and implantation of an ovum. The menstrual cycle involves both an endometrial and ovarian cycle that are dependent on one another for proper functioning. There are 2 phases of the ovarian cycle and 3 phases of the endometrial cycle. Menstrual Cycle 
    • 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 resistance responsible for premature ovarian failure
  • Fertility treatment: oocyte donation and hormonal therapy

Differential Diagnosis

The following conditions are differential diagnoses for pure gonadal dysgenesis.

  • 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 of the X-chromosome, resulting in a karyotype of 45,X0 and a female phenotype. Patients usually present with amenorrhoea, webbed neck, 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 development caused by a defect in the SRY gene on chromosome Y. Characterized by complete testicular dysgenesis in an individual who has a 46,XY karyotype and is phenotypically female. Presents as a phenotypic female, taller than an individual with 46,XX gonadal dysgenesis, with a normal childhood and development until puberty, which is characterized by primary amenorrhea Primary Amenorrhea Primary amenorrhea is defined as the absence of menstruation in a girl by age 13 years in the absence of secondary sex characteristics or by the age of 15 years with the presence of secondary sex characteristics. Etiologies can originate in the hypothalamic-pituitary-ovarian (HPO) axis or from anatomic abnormalities in the uterus or vagina. Primary Amenorrhea and no development of secondary sexual characteristics.

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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