Disorders of Sexual Develpment

Pediatric Surgery
An interactive discussion about disorders of sexual development between Todd Ponsky, MD and Kathy Graziano, MD.

Dr. Graziano is the director of the Reproductive Anomalies/Disorders of Sexual Development at Phoenix Children’s Hospital and is also the Director of the Arizona Fetal Care Network (AZFCN).

Intro track is adapted from "I dunno" by grapes, featuring J Lang, Morusque.
Artist URL: ccmixter.org/files/grapes/16626
License: creativecommons.org/licenses/by/3.0/

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Disorders of Sexual Development (Kathleen Graziano, MD)

What is a disorder of sexual development (DSD)?

 

  • A mismatch in a patient’s genetic sex and anatomic sex (i.e. a difference in genotype and phenotype)
  • AKA "difference of sexual development”, and is a replacement for older terms such as "hermaphrodite” and "intersex”
  • Diagnoses included in DSD:
    • Congenital adrenal hyperplasia (CAH)
    • Mayer-Rokitansky-Küster-Hauser syndrome (MRKH, or vaginal agenesis)
    • Severe hypospadias
    • Ambiguous genitalia

 

Coordination of care

  • Many babies will carry a prenatal or neonatal diagnosis.
  • The DSD team/clinic includes specialists from endocrinology, genetics, pediatric surgery/urology/gynecology, psychology, and social work
  • DSD is rarely an emergency and focus should be directed away from assigning a gender and toward more urgent medical issues.
  • Families are counseled extensively and told that in some cases the question of gender will not be answered for months (depending on labs and other studies).
  • Due to the infrequency of DSD clinic, patients are usually initially seen as an inpatient by the DSD team.
  • The surgeon should be the last physician to see the patient, as they should be first evaluated by endocrinology and genetics.
  • While severe hypospadias is considered a urologic diagnosis (more than a disorder of sexual development), these patients can still strongly benefit from long-term care from a DSD clinic.
  • A helpful resource is the Disorders of Sex Development Translational Research Network (http://dsdtrn.genetics.ucla.edu/)

How to raise a gender-neutral child

  • Some advocate that patients do not necessarily need to be given a concrete gender assignment at birth.
  • These controversies should be explained very clearly to families.
  • All advocacy groups, however, state that it is acceptable to assign a gender. The DSD team will provide guidance, as needed.
  • Some families, given this information, elect to rear their child as gender-neutral for the first few years of life, thereby deferring the decision of gender assignment.
  • After the first few years of life, it is usually apparent with which gender the child identifies.
  • The trend appears to be toward deferring unnecessary surgery and assigning gender later in life in select patients. This decision-making may even take place in the patient’s teenage years.

Case: Infant born with ambiguous genitalia

  • Always manage other, life-threatening issues first. However, families will often only be concerned with the ambiguous genitalia.
  • First, a patient who is XX with CAH should be ruled out, as this is most common. Furthermore, undiagnosed salt-wasting CAH can be life-threatening.
    • These patients may have clitoromegaly or even the appearance of a phallus and scrotum. These patients, however, will not have testes on exam (as they should have ovaries).
  • Information regarding any prenatal diagnostic studies, such as karyotype, should be obtained.
  • Physical exam
    • The overall focus should be looking for symmetry.
    • How many "holes” are there? Are there separate urethral and vaginal openings, or is there a urogenital sinus? This can be difficult in a small baby. However, a hemostat or cotton-tipped applicator can be used to gently probe for separate openings/structures.
    • Presence of midline structures: micropenis, severe hypospadias, clitoromegaly, enlarged phallus, etc.
    • Differentiate (swollen) labia from empty scrotum, or even asymmetric scrotum (as can be seen in mixed gonadal dysgenesis).
    • Presence or absence of palpable gonads.
  • Labs
    • Elevated 17-hydroxyprogesterone is the most common lab abnormality in patients with CAH.
    • Families should be reminded that even a rapid fluorescence in situ hybridization (FISH) study will take 24-48 hours in most hospital.
  • Imaging
    • Ultrasound to look for Müllerian structures, such as a utuerus.
    • The resolution and operator dependency of US can lead to structures occasionally being missed.
    • If there is a need for higher resolution imaging, MR may be obtained.
  • Bottom line: Ambiguous genitalia is CAH until proven otherwise and this must be ruled out before the patient may be discharged. This diagnosis is made by XX genotype, virilization of the genitalia, and elevated 17-OH progesterone. These patients must be started on steroids prior to discharge.

Examination under anesthesia

  • The labia are more easily separated and urogenital sinus may be diagnosed or excluded.
  • Patients will ultimately require cystoscopy and vaginoscopy.

Case: Newborn with prenatal diagnosis of ambiguous genitalia and XY genotype

  • Medically stable.
  • Female-appearing external genitalia on physical exam (genotype and phenotype discordance). Normal perineum.
  • This patient is categorized as XY DSD. Differential diagnosis includes androgen insensitivity syndrome (AIS).
  • In patients with complete AIS, there are normal, functioning testes. However, the tissues are unresponsive to the testosterone. Genetic diagnosis seeks to find mutations in the androgen receptors.
  • Labs (typically ordered by endocrinology)
    • Testosterone, FSH, LH, cortisol levels
    • Androgen receptor mutation, if AIS is suspected

Differential diagnosis for ambiguous genitalia

  • CAH is most common (and is an XX DSD)
  • XY DSD
    • These patients most commonly present as teenagers. They tend to have normal-appearing female external genitalia and present with amenorrhea.
  • When in doubt, keep an open mind and send a rapid FISH for chromosomal analysis.

Differential for XX DSD (typically presents in infancy)

  • CAH
    • Order electrolytes and 17-OH progesterone.
    • Treat with IV fluids and steroids
  • Ovotesticular DSD
    • Very rare.
    • These patients have XX genotype and components of both male and female gonads. These patients will have asymmetry on exam.

Differential for XY DSD (typically presents in teenage years)

  • Typically involves a urologic diagnosis, and does not involve abnormal hormone levels or chromosomal abnormalities.
  • Partial androgen insensitivity may have abnormal appearing external genitalia. Patients with complete AIS will have normal appearing, female external genitalia.

Severe hypospadias

  • The degree of severity of the hypospadias correlates with the difficulty of surgical correction.
  • There is an entity known as "hypospadias cripple”, which represents patients who undergo many surgeries and are unable to reach a desirable outcome.

Mixed gonadal dysgenesis

  • Extremely rare
  • Can be asymmetric on physical exam.
  • Patients who have a symmetric appearance on physical exam can be confused for CAH.
  • Patients may benefit from ultrasound and/or diagnostic laparoscopy to aid in diagnosis.
  • Historically, these patients were reared as female, as this was felt to be a more surgically achievable goal. However, there is no long term follow up data on this practice.
  • These patients typically benefit most from a wait-and-see approach to surgery.
  • Must have very close follow up with DSD clinic.

CAH intervention

  • There is no indication for prenatal steroid treatment as prophylaxis against genital abnormalities, due to the risk of cognitive delays.
  • The urogenital sinus should be fixed, but timing is controversial.

Teenagers with DSD

  • Teenagers are a significant portion of the DSD population and benefit from the expertise of the pediatric surgeon.
  • Patients typically present to their pediatricians with amenorrhea.
  • Patients with complete AIS and MRKH often have a normal exam in the office.
  • MRKH (vaginal agenesis) is the most frequently encountered entities in teenagers with DSD. They are XX genotype.
    • Initial evaluation includes karyotype and ultrasound. MRI may be indicated if the ultrasound is unclear.
    • Many patients will require examination under anesthesia (EUA) with cystoscopy and possible diagnostic laparoscopy.
    • Vaginal dilation is the first-line therapy to create a vaginal canal, for the purpose of sexual activity. However, not all patients will require this as vaginal intercourse can lead to dilation in and of itself. This activity is often best delayed until the patient is ready to be sexually active.
    • These patients have normally ovaries but typically cannot bear children due to absent or small uterus.
    • Some patients will not be anatomically amenable to vaginal dilation, usual due to urethral position.
    • Most MRKH patients will be asymptomatic, as opposed to those with hydrocolpos (e.g. secondary to imperforate hymen).
  • Complete AIS is also commonly encountered, and it is an XY genotype.
    • Usually have normal appearing female external genitalia, but also possess male gonads.
    • Typically present in teenage years with amenorrhea.
    • Many complete AIS patients elect to keep their gonads as long as possible (as those who undergo gonadectomy will require hormone replacement).
    • There is incomplete data regarding surveillance of these gonads for malignancy.
    • These patients may present as infants with an inguinal hernia.
      • If a mass is found and it is thought to be a testis, it should not be removed! Biopsy is acceptable.
      • The purpose of biopsy is to examine for normal testiucal tissue (not malignancy).

Surgical options

  • Commonly used surgery is buccal mucosa graft for vaginal strictures, vaginal septums, and/or vaginoplasty.

Contact information for Dr. Graziano

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