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  Partial Gonadal Dysgenesis
 
Authors: Claude Migeon, M.D., Amy Wisniewski, Ph.D. Last modified: October 11, 2001
DIAGNOSTIC CRITERIA

  EPIDEMIOLOGY

  • Gonadal Dysgenesis (GD) refers to the condition in which the gonads do not develop normally during fetal life.
  • Early in fetal life several transcription factors (such as LIM-1, SOX-9, SF-1, DAX-1 and WT-1) are necessary for gonads formation.
  • The SRY gene is also needed for testes formation. Mutations of SRY or any of the factors mentioned above will result in GD. DAX-1 gene duplication also results in GD.
  • GD in 46,XY individuals exists in both complete (CGD or Swyer Syndrome) and partial (PGD) forms.
  • Characteristically, GD impairs the two main functions of the testes: secretion of testosterone by Leydig cells and Mullerian Inhibiting Substance (MIS) by Sertoli cells.
  • Decreased testosterone secretion results in under-masculinization of the external genitalia and poor development of male ducts.
  • Decreased MIS secretion results in the failure to suppress female duct development.

  RISK FACTORS

  • Presence of a uterus and utriculo-vaginal pouch in patients reared male.
  • Gonadal tumors.
  • SF-1 mutations can result in adrenal insufficiency and CNS abnormalities.
  • WT-1 mutations are associated with Wilms tumors.
  • SOX-9 mutations are associated with camptomelic dysplasia.
  • DAX-1 mutations are associated with adrenal insufficiency and hypogonadotropic hypogonadism.
  • Turner stigmata in cases with hidden 45,XO/46,XY mosaicism.

  SIGNS AND SYMPTOMS

  • At birth, infants present with varying degrees of under-masculinized genitalia (ranging from almost completely female to almost completely male).
  • In patients reared male, a small penis with cryptochordism or small testes.
  • Infertility.

  DIFFERENTIAL DIAGNOSIS

  • At birth a full work-up for ambiguous genitalia must be obtained.
  • Monitor electrolytes daily.
  • At Day 1 or 2 of life, obtain a karyotype, plasma androstenedione, testosterone and dihydrotestosterone.
  • At Day 3 or 4, measure plasma 17-hydroxyprogesterone and 17-hydroxypregnenolone.
  • At Day 5, obtain a genitogram.
  • At Day 6 to 7, measure MIS and obtain blood for DNA studies.
  • At Day 8 to 9, repeat androstenedione, testosterone, dihydrotestosterone and 17-hydroxyprogesterone.
  • If the karyotype is 46,XY, Mullerian structures are seen on the genitogram and androstendione, testosterone, dihydrotestosterone and MIS are low, a presumptive diagnosis of GD can be made.
  • Both 17-hydroxyprogesterone and 17-hydroxypregnenolone should be normal except in cases of SF-1 or DAX-1 mutations.
  • Once a presumptive diagnosis of GD has been made, this can be confirmed by DNA studies. However these are difficult to have done and the exact mutation cannot always be identified.
  • Congenital Adrenal Hyperplasia (CAH) due to 3B-hydroxysteroid dehydrogenase deficiency
  • 5alpha-reductase deficiency
  • Partial Androgen Insensitivity Syndrome (PAIS)
  • Steroidogenic enzyme defect associated with testosterone production
  • Leydig cell hypoplasia
  • Timing defect
  • True hermaphroditism

  LABORATORY FINDINGS

  • 46,XY karyotype
  • Androstendione, testosterone and dihydrotestosterone concentrations are below normal.
  • MIS concentration is below normal.
  • 17-hydroxyprogesterone and 17-hydroxypregnenolone concentrations are decreased in cases of SF-1 and DAX-1 mutations.
  • A genitogram reveals the presence of Mullerian structures such as a uterus or utriculo-vaginal pouch.
 
TREATMENT
SEX OF REARING
  • At birth, consideration for raising the infant as female is made if the stretched penile length is equal to or less than 1.9 cm (mean - 2.5 SDs) and perineo-scrotal hypospadias exists.
  • If a uterus is present female rearing is considered because in such cases pregnancy is possible with invitro fertilization.
  • In less severe cases of genital ambiguity, male rearing can be successful.
  • When deciding on sex of rearing, parents must be completely informed about sex differentiation and abnormalities that can occur (www.hopkinsmedicine.org/pediatricendocrinology/intersex/).
  • Parents and patients should have realistic expectations for the difficulties and outcome of medical and surgical treatments offered to them regardless of sex of rearing.
TESTOSTERONE TREATMENT TO OPTIMIZE MASCULINIZATION
  • Patients with PGD reared male do not produce adequate amounts of testicular androgens. Testosterone treatment is needed to optimize masculinization.
SURGICAL RECONSTRUCTION IN PATIENTS REARED MALE
  • Under-masculinized genitalia requires surgical correction for hypospadias and removal of the utriculo-vaginal pouch.
  • If a uterus or other Mullerian structures are present, a hysterectomy is required.
  • If the testes were removed due to the inability to correct cryptochordism or gonadal tumor, implantation of prosthetic testes is recommended.
EDUCATION AND COUNSELING TO COPE WITH PROBLEMS OF INFERTILITY AND SEXUAL DYSFUNCTION
  • Patients benefit greatly from education and counseling regarding their condition. Education allows for patients and parents to make informed medical and surgical choices.
  • Many men and women with PGD benefit from counseling when dealing with infertility, sexual dysfunction and genital surgery.
 
IMPORTANT POINTS/RECOMMENDATIONS
  • It is important that people affected by PGD seek medical, surgical and psychological care from those who have experience treating this condition.
  • In patients with marked genital ambiguity, female sex of rearing may be optimal. This is particularly true in individuals with a well-formed uterus as they can carry pregnancies.
 
REFERENCES
  1. Migeon CJ, Wisniewski AB and Gearhart JP ;  Syndrome of Abnormal Sex Differentiation: A Guide for Patients and Their Families ;  www.hopkinsmedicine.org/pediatricendocrinology/intersex/

    Comment:
    This online guide explains gonadal dysgenesis (GD) within the context of male sex differentiation.

  2. Berkovitz GD, Fechner PY, Zacur HW et al ;  Clinical and Pathologic Spectrum of 46,XY Gonadal Dysgenesis: Its Relevance to the Understanding of Sex Differentiation. ;  Medicine; 70:375, 1991.

  3. Nachtigal MW, Hirokawa Y, Enyeart-Van Houten DL et al ;  Wilms tumor 1 and DAX-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression. ;  Cell; 93:445, 1998.

  4. Koopman P ;  Sry and Sox-9: Mammalian testis-determining genes. ;  Cell Mol Life Sci; 55:839, 1999.

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