Case Study # 26

Ambiguous genitalia
-Dana Rice GWU-SOM 2008

Learning Objectives :

By then end of this case report readers will be able to:

• Define and discuss the incidence and prevalence of ambiguous genitalia
• Recognize the common clinical presentations, causes and diagnostic criteria for ambiguous genitalia
• Implement an effective clinical management strategy to differentiate between life-threatening presentations of ambiguous genitalia and non-emergent management.
• Discuss the theories of gender assignment, surgical and psychological impacts

Pretest Questions :

1. 5 weeks
2. 7 weeks
3. 9 weeks
4. 11 weeks
5. 13 weeks

2.  What is the most common cause of ambiguous genitalia?

1. Prenatal androgen exposure
2. Congenital adrenal hyperplasia (CAH)
3. Abnormal androgen response
4. Abnormal androgen synthesis
5. Placental aromatase deficiency

3. Gender decisions should be made:

1. Immediately, based on which genital type the baby most resembles
2. Within in the shortest time frame possible once a the karyotype has been determined
3. Within the shortest time frame possible once the medical teams have determined which sexual genitalia would be most functional for the patient long-term following genital reconstructive surgery.
4. Within the shortest time frame possible once the parents and medical team determine which sexual genitalia would be most functional for the patient long-term following genital reconstructive surgery with the least psychological repercussions
5. Due to lack of evidence based research there is no clear consensus to timing and approach of genital reconstruction.

1. C, 2. B, 3. E

Case Study :

You are a third year medical student on a pediatrics rotation in NICU and asked to evaluate a baby with ambiguous genitalia. The infant's vital signs are stable and physical exam is unremarkable except for the genitalia findings consistent with the picture below. The baby was born via NSVD @ 40 weeks following an uncomplicated pregnancy. The baby is eating well, within normal weight limits and APGAR scores were 9 and 9 at 1 and 5 minutes. There is no significant family history of nulliparous females. Both parents are anxious to know the sex of their child and how soon the infant will be able to go home.

Questions:

• What is ambiguous genitalia?
• What is the incidence and prevalence?
• What are the clinical presentations that should lead a physician to consider the diagnosis of ambiguous genitalia?
• What is the most common cause of ambiguous genitalia?
• What are the 3 diagnostic categories for ambiguous genitalia?
• What is the differential diagnosis for each diagnostic category?
• What is the initial concern for management of patients with ambiguous genitalia?
• What is included in the initial evaluation for ambiguous genitalia?
• Discuss the traditional approach to gender decisions versus current approaches.

1. What is ambiguous genitalia?
Ambiguous genitalia is the term used to describe an individuals genitalia which can not be determined by general appearance.

2. What is the incidence and prevalence?
The incidence and prevalence of ambiguous genitalia has not been as well documented as some other medical conditions because of the numerous varying etiologies. Research on CAH has been fairly well documented and is estimated to affect 1 in 5,000 live births. (McKusick, 1986). Historically there have been large variations in this number. For instance in, in Switzerland the estimate remains 1 in 5,000 while in Maryland the estimated case rate for ambiguous genitalia is 1 in 67,000 births.

One study following 120 pediatric patients found CAH was the underlying cause of ambiguous genitalia in 41 of 63 patients with ambiguity due to endocrine causes. In 57 patients, ambiguous genitalia were due to congenital developmental defects. The most common endocrine case of ambiguous genitalia was 21-OH deficiency. Seven patients were classified as idiopathic with six showing the 46,XY and one the 46,XX karyotype. (McKusick, 1986).

3. What are the clinical presentations that should lead a physician to consider the diagnosis of ambiguous genitalia?

1. Bilateral nonpalpable testes
2. Microphallus
3. Perineal hypospadias with bifid scrotum
4. Clitoromegaly
5. Posterior labial fusion
6. Gonads palable in labioscrotal folds
7. Discordant genitalia and sex chromosomes

4. What is the most common cause of ambiguous genitalia?
The most common cause of ambiguous genitalia is congenital adrenal hyperplasia. This is due to the fact that CAH can be caused by multiple metabolic deficiencies. CAH can lead to XX virilization via multiple enzyme deficiencies such as, 21-alpha-hydroxylase deficiency, 11-beta-hydroxylase deficiency and 3-beta-hydroxysteroid dehydrogenase deficiency. In cases of undervirilized XY, the most common deficiencies are StAR protein deficiency, 3-beta-hydroxysteroid dehydrogenase deficiency and 17-alpha-hydroxylase deficiency.

5. What are the 3 diagnositic catogories for ambiguous genitalia?

1. XX virilization
2. XY undervirilization
3. Mixed sex chromosome pattern

6. What is the differential diagnois for each diagnostic category?

1. XX virilization
   i.CAH
   ii.Gestational hyperandrogenism
   iii.SYR translocation
   iv.SOX9 duplication
   v. “True hermaphroditism”
2. XY undervirilization
   i.CAH
   ii.Abnormal testicular activity
   iii.Abnormal androgen synthesis
   iv.Abnormal response androgen
   v.Abnormal adrenal function
3. Mixed sex chromosome pattern
   i.True hermaphroditism
   ii.Mixed gonadal dysgenesis

7.  What is the initial concern for management of patients with ambiguous genitalia?
The initial step in management of ambiguous genitalia is determining stability of the patient. The salt wasting form of CAH can present with life-threatening medical consequences due to vomiting, diarrhea, hypovolemia, hyponatremia with hyperkalemia, hypoglycemia, and cardiovascular collapse. It is important to prevent these symptoms of adrenal crisis. Evaluation of serum electroytes and urinary excretion of sodium and potassium should be obtained daily until salt-wasting CAH can be ruled in or out. Administration of stress doses of glucocorticoids should be considered in all infants with questionable salt wasting form of CAH.

8. What is included in the initial evaluation for ambiguous genitalia?
The initial evaluation of ambiguous genitalia should include a detailed history and physical exam, assessment of adrenal steroid secretion, internal anatomic evaluation via ultrasound, peripheral blood karyotype to determine sex chromosomes, serum electrolytes and urinary excretion of sodium and potassium daily until salt-wasting CAH is ruled out. The history for these patients should include questions detailing prenatal androgen exposures or endocrine disrupters, maternal virilization in pregnancy, family tree with females who are childless or amemorrheac, family history of unexplained infant death and consanguity.

9. Discuss the traditional approach to gender decisions versus current approaches.
The traditional approach to gender decision is that gender is impossible. It was thought that the primary goal for XX babies was maintaining fertility followed by sexual function, while XY patients' primary focus was adequate sexual function. Finally, it was thought that adequate cosmetic result would lead to adult adaptation and satisfaction. There is a lack of supportive evidence from long-term studies for these theories.

On the other hand, recently proposed theories suggest gender assignment and sex of rearing be based upon the most probably adult gender identity and potential for adult function. The factors to be considered are diagnosis, degree of virilization as a marker of prenatal androgen exposure, capacity to respond to exogenous androgen. It is also thought that surgeries for cosmetic reasons be delayed or withheld unless a decision has been made by the intersex patient themselves. An exception to the delay in surgical intervention according to these guideline is 21-hydroxylase deficiency, which is recommended for surgically correction early to enable the patient to be raised in the female gender role.

Support Groups:

Ambiguous Genitalia Support Network
The intersex society of North America 's webpage introduces parents for pen-pal support. http://www.isna.org/node/531

AIS Support Group Australia Inc.
The Androgen Insensitivity Syndrome (AIS) Support Group Australia Inc. is a peer support, information and advocacy group for people affected by AIS and/or related intersex conditions, and their families.http://home.vicnet.net.au/~aissg/

Androgen Insensitivity Syndrome Support Group (AISSG)
This site provides information and support to young people, adults and families affected by complete and partial Androgen Insensitivity Syndrome (AIS) as well as a multitude of other related conditions.http://www.medhelp.org/www/ais/

Educational Resources:

References:

Al-Mutair, A, Iqbal, MA, Sakati, N and Ashwal, A. (2004) Cytogenetics and etiology of ambiguous genitalia in 120 pediatric patients. Ann. Saudi Med. Sep-Oct; 24 (5): 368-72.

Ambiguous genitalia. Picture retrieved November 17, 2005 from Google Images: http://www.medstudentdirect.com/slidelibrary/viewSlide.asp?pid=465.

Houk, CP. And Levitsky, LL. (2004 ) Evaluation of the infant with ambiguous genitalia. Retrieved from Up to date online on October 31, 2005.

Houk, CP. And Levitsky, LL. (2004 ) Management of the infant with ambiguous genitalia. Retrieved from Up to date online on October 31, 2005.

McKusick , VA (1986) MIM +201910 Adrenal Hyperplasia, Congenital, Due To 21-Hydroxylase Deficiency. Retrieved from Online Mendelian Inheritance in Man (OMIN) on Novemeber 2, 2005.