Endocrine

Ambiguous Genitalia

Background

  •  A disorder of sex development (DSD) occurs when there is incongruence between a child’s external genitalia, gonads (ovaries or testes) and chromosomal sex (XX – female or XY – male). This incongruence can often manifest as external genitalia that are neither overtly male nor female, termed ambiguous genitalia.
  • The term DSD has replaced outdated phrases such as hermaphrodite or pseudohermaphrodite based on a 2006 Consensus Statement on the Management of Intersex disorders.
  • Clinical management of DSD includes the following principles:

1.     The child should not be assigned a gender until a thorough evaluation by an expert has been performed.

2.     The child should have long-term management performed at a center with a multidisciplinary team. This is critical, as these children require expertise in endocrinology, urological surgery, psychiatry, genetics, neonatology and social work.

3.     The child must eventually receive a gender assignment, not only for future management, but also for parental comfort.

4.     Open communication, shared decision making, patience and confidence are imperative

  • While gender assignment previously hinged on the capacity for adequate reproductive potential in adulthood, this paradigm has been recently questioned due to a more nuanced understanding of psychosexual development. Gender assignment, therefore, should take into account what adult gender identity is most likely in addition to sexual function. 

 

Development of External Genitalia

  • During development the genitals are initially indifferent, as male and female morphology is not evident until the seventh week.
  • The sex-determining region on the Y (SRY) gene located on the Y chromosome establishes the male phenotype. The gene product is testis-determining factor (TDF), which induces formation of the male testis.
  • Testosterone produced by the testis causes masculinization of the indifferent external genitalia. This includes elongation of the genital tubercle to form the glans penis, fusing of labioscrotal swellings to become a scrotum, and midline fusion of the urethral folds to create an enclosed urethra within the penis.
  •  If the Y chromosome, SRY gene and TDF are absent (XX female), then the lack of testosterone and presence of maternal estrogens stimulate the development of female external genitalia. The genital tubercle becomes the clitoris, the unfused urethral folds become the labium minus, and the unfused labioscrotal swellings become the labium majus.
  • It is interesting to note that the only difference between the glans penis and clitoris is the presence of an enclosed urethra!

 

500px-Gray1119.png

Development of external genitalia. A: common development. C, E: male development. B, D, F: female development. 
From https://en.wikipedia.org/wiki/Development_of_the_reproductive_system

Indications for Evaluation

  • Family history of DSD, such as complete androgen insensitivity syndrome.
  • Discordance between genital appearance and a prenatal karyotype.
  • Apparent female genitalia with an enlarged clitoris and posterior labial fusion, an inguinal/labial mass.
  • Apparent male genitalia with bilateral undescended testes, a microphallus, proximal hypospadias or distal or mid-shaft hypospadias with undescended testis.

 

History

  • Family History – parental consanguinity and relatives with ambiguous genitalia, primary amenorrhea, early death, medical issues.  Autosomal recessive pattern may suggest altered steroidogenesis.  X-linked recessive pattern may suggest androgen insensitivity syndrome.
  • Maternal history – medications (androgens-progesterones, danazol, testosterone or endocrine disrupters- phenytoin, aminoglutethimide), virilization before or during pregnancy, prenatal test results.

 

Physical Exam

  • General Exam.
    • Dysmorphic features
    • Midline defects
    • Hydration
    • Blood pressure
  • Penile/Clitoral length and diameter. A normal stretched penile length is at least 2 cm.
  • Gonads – present/absent, size, location. Federmans rule – a gonad felt below the inguinal ligament is a testicle until proven otherwise
  • Urethral opening – hypospadias, epispadias, virilized urogenital sinus
  • Rectal inspection. Anogenital ratio (distance between anus and posterior fourchette divided by the distance between the anus and the base of the clitoris) of >0.5 suggests virilization with some posterior labial fusion.

 

Initial Studies

  • Karyotype, including FISH with SRY probe. 
  • CAH screen: Serum electrolytes and serum 17 alpha hydroxyprogesterone (17-OHP)
    • Elevated in most common cause of CAH, 21-hydroxylase deficiency
    • Further measurement of other products of the steroid biosynthesis pathway may be indicated, including  11-deoxycortisol, cortisol, and DHEA.

      steroid-pathways.jpg

  • Ultrasound of the pelvis/abdomen to check for Mullerian structures
  • ACTH stimulation test, hCG stimulation test.
  • A gonadal biopsy may ultimately be necessary for the diagnosis.

 

Differential Diagnosis for the 46XY, Undervirilized Male

  • Environmental chemicals leading to hypospadias, undescended testes that may not meet full criteria for DSD
  • Congenital adrenal hyperplasia
    • Multiple enzyme deficiencies may cause this.  21 hydroxylase deficiency does not result in genital ambiguity in males, but can lead to death from salt wasting if unrecognized.
  • 5 alpha reductase deficiency
  • Androgen insensitivity syndrome or receptor defects (testicular feminization)
  • Gonadal dysgenesis
  • Testicular regression syndromes

 

Differential Diagnosis for the 46XX, Virilized Female

  • Congenital adrenal hyperplasia: single most common cause of ambiguous genitalia.
    • 21 alpha hydroxylase deficiency is the most severe and presents at about two weeks of age with salt wasting and are at risk for adrenal crisis.  21 alpha hydroxylase deficiency and 11 beta hydroxylase deficiency can be excluded with serum 17 hydroxyprogesterone.
  • Gestational androgen excess states such as maternal androgen use, oral contraceptives, polycystic ovarian syndrome, tamoxifen use and androgen secreting tumors
  • Aromatase deficiency leading to estrogen deficiency and androgen excess – may see double virilizing effect – on both mother and child during pregnancy

 

Gender Assignment and Surgical Management

  •  The family must be adequately informed on the diagnosis, and play an active role in the gender decision of the child. The ability to respond to exogenous androgens, genetic sex and cultural background and expectations should all be considered when making this crucial decision.
  • Adult psychosocial adaptation and sexual satisfaction, as opposed to pure preservation of fertility, are likely more important
  • Gender assignment decisions should be made soon, after the information is collected to make an appropriate diagnosis. While the child should be raised as a specific gender, he or she should play a significant role in gender identity during childhood and adolescence
  • In general, most individuals that are 46 XY DSD make up identify as males in adulthood, and should be raised as such. Exceptions include AIS and complete gonadal dysgenesis
  • 46 XX DSD females can be raised as females; those with extensive virilization may benefit from being raised as male
  • Surgery for purely cosmetic reasons should be deferred until the individual has the knowledge to make an educated decision on their gender identity and external genitalia.   
    • Vaginoplasty if the child is reared as female may be beneficial because of improved functional outcomes in adulthood if the surgery is performed early. Clitoroplasy can be delayed until the child can provide input, and often because the CAH improves as the child ages.
  • Long term support should be offered to all patients with DSD and their families

 

References

  1. AAP Committee on Genetics. (2000). Evaluation of the newborn with developmental abnormalities of the external genitalia. Pediatrics, 106(1), 138-142.
  2. Anhalt, H., et. al. (1996). Ambiguous genitalia. Pediatrics in Review, 17(6), 213-220.
  3. Cavanaugh, R.M. (2009). Screening for genitourinary abnormalities in adolescent males. Pediatrics in Review, 30(11) 431-438.
  4. Copeland, K.C. (2004). Management of infants with ambiguous genitalia reassessed. AAP News, 24(3), 119.
  5. Lee, P., et. al. (2006). Consensus statement on the management of intersex disorders. Pediatrics, 118(2), 488-500.
  6. Levy, D.J., et. al. (1982). Male pseudhermaphroditism. Pediatrics in Review, 3(9), 273-283.