A Case of Disorder of Sexual Differentiation

Original Case by

Filippa Pritsini,1,2 Georgios A. Kanakis,1,2 Ioannis Kyrgios,1 Eleni P.Kotanidou,1 Eleni Litou,1 Konstantina Mouzaki,1 AggelikiKleisarchaki,1 Dimitrios G. Goulis,2 and Assimina Galli-Tsinopoulou1

A girl of 11 years and 3 months was referred to our unit due to enlargement of the clitoris associated with obstructive symptoms at micturition. According to her prenatal history, amniocentesis was conducted due to advanced maternal age, revealing a 46, XY karyotype. Pregnancy was otherwise uncomplicated. Cesarean section was performed at the gestational age of 40 weeks and 3 days due to cephalopelvic disproportion and failure to progress. The newborn was a healthy full-term baby, without electrolyte imbalance, presenting with an inadvertent female phenotype. In order to assess the discordance between chromosomal and phenotypical gender, the SRY gene was examined and found to be present, while imaging of the brain, hypothalamus, and pituitary gland was normal. At that time-point, the family decided to take no further action.

Q What are cause of 46 XY with unambiguous female genitalia at birth ?

  • Complete androgen insensitivity syndrome (CAIS)
  • Complete gonadal dysgenesis  (CGD)
  • 17 alpha hydroxylase deficiency

Q How will you distinguish CAIS from Complete gonadal dysgenesis ?

  • CAIS will have absent Mullerian structures while Complete gonadal dysgenesis may have Mullerian structures present.
  • Gonads are not palpable in complete gonadal dysgenesis while they may be present in the inguinal region or labioscrotal region in CAIS
  • On measuring the Serum testosterone- CAIS will have testosterone in normal male range while CGD will have low testosterone.

Anthropometric characteristics at presentation were in the normal range for girls at the patient’s age, while physical examination revealed excessive clitoriomegaly resembling a phallus of 6 cm and a shallow vaginal orifice.

Q Would you plot the patient’s growth with a female growth chart or in the male growth chart ?

  • You will plot it in female growth chart only, however it is an area of debate.
  • However most studies done have plotted it on female growth chart

While physical examination revealed excessive clitoridomegaly resembling a phallus of 6 cm and a shallow vaginal orifice. No testes were palpable.

Q What do you think of the diagnosis now ?

  • It seems odd that the child had normal female genitalia at birth and now has significant clitoromegaly and ambiguous genitalia.
  • It is more likely the ambiguous genitalia was missed at birth which seems strange because they already knew that the child was 46 XY on amniocentesis !
  • However my DD now would be 1) 5 alpha reductase 2 defect b) 17 beta HSD3 c) PAIS d) partial gonadal dysgenesis

Pubertal maturation, pubic hair, breast, and axillary hair were of Tanner stage III, I, and II, respectively

Q The breast they say is Tanner stage I , what will you narrow down your DD do ?

  • With absent breast enlargement ,5 alpha reductase 2 appears to be a more appopriate diagnosis
  • However it is possible that the child has not reached puberty , hence it would be premature to judge

Imaging of the lower abdomen with ultrasound and MRI revealed bilateral testicular tissue at the intraperitoneal space near the inner inguinal ring, hypoplastic penile cavernous bodies within a sizable clitoris, and the presence of a rudimentary prostate along with seminal vesicles.

Q Are wolffian duct derivatives present in CAIS ?

  • No generally not
  • Even if they are present they are rudimentry

Q There are absent Mullerian structures, which differential seems less likely with this ?

  • The presence of testis and absent of Mullerian derivatives make the diagnosis of partial gonadal dysgenesis less likely.

Basal hormones assessment showed elevated T (84.0 ng/dl) in the male reference range for the given pubertal stage, accompanied by mildly elevated LH (2.11 mU/mL) and follicular stimulating hormone (FSH) concentrations (18.56 mU/mL). Estradiol (E2) on the other hand was inappropriately low (14.45 pg/mL).

The ratio of T to -androstenedione (Δ4A) was >0.8, excluding 17β-hydroxysteroid dehydrogenase-3 (17β-HSD-3) deficiency, while the ratio of T to dihydrotestosterone (DHT) was <20, excluding 5α-reductase deficiency. The high elevation of T concentration (ΔΤ) after the hCG stimulation (>100 ng/dl) indicated the presence of testicular tissue, excluded gonadal dysgenesis, and supported the diagnosis of AIS (Table 2). Imaging control revealed the presence of bilateral testicular tissue. The combination of almost female phenotype with minimal virilization and proper male gonadal function was supportive for the diagnosis of severe PAIS

Q Give a typical protocol for HCG stimulation test ?

  • There are various protocol for HCG stimulation test. We will discuss one protocol which we follow
  • Baseline Testosterone, DHT and Androstenedione are sent
  • HCG is given as a single dose of 5000 IU for an older child IM
  • The sample are repeated after 72 hours

Q What ratios suggest 5 alpha reductase 2 and 17 beta HSD 3 ?

  • Stimulated T:DHT ratio > 27:1  – suggest 5 alpha reductase 2 defect
  • T: A ratio <0.8 suggests 17 beta HSD 3 deficiency

Q What small care you must take while calculating the ratios of T:A in this case?

The values of androstenedione are in ng/ml. Hence when we calculate the ratio, we need to convert it to ng/dl

Q What would you do for further management of this case ?

  • This is a case of PAIS raised as a female.
  • Since the child is already raised as female it would be wise to continue the same gender assignment.
  • I would consider going a gonadectomy and replacing the child with estrogen replacement.
  • I would also consider doing appropriate genital reconstruction.

Q What is the risk of gonadoblastoma in this case ?

  • PAIS with non scortal gonad have high risk of gonadoblastoma.

Reasonably, the assignment of female gender was recommended, since the patient had already been raised as a girl and the relevant interventions would be minimal. In addition, the testes that were found during imaging studies had to be removed, as they were atrophic and of increased risk for malignant change. Interestingly, the parents suggested that the child itself should be fully informed and participate in the final decision, and therefore, from the very first beginning, the patient was involved in all discussions made with the attending physicians. It is noteworthy that, being aware of the condition, she stated: “It does not matter if I am female or male, most of all I am a human being and thus gender assignment will not play any significant role in my future life.” Eventually, female gender was preferred by both the patient and the parents, and gonadectomy as well as cosmetic surgery of the external genitalia were successfully performed.

Learning points

  1. Be careful while calculating the T:A and T:DHT ratios. The units of the numerator and denominator should be the same.
  2. PAIS with non scrotal gonad have a high risk of gonadoblastoma and  gonadectomy must be done , generally before puberty.
  3. Female sex assignment is not inappropriate for PAIS, especially if the child is raised as a female.