294
9.2 Stepwise Analysis
The index patient presented with primary amenorrhea, poor development of second-
ary sexual characteristics, genital ambiguity, and bilateral palpable gonads. The dif-
ferential diagnosis to be considered with this presentation includes androgen
biosynthetic defect, ovotesticular DSD, partial 46,XY gonadal dysgenesis, and par-
tial androgen insensitivity syndrome. The possibility of androgen biosynthetic
defect is considered in view of peripubertal onset of virilization and feminization,
absence of uterus, and bilateral palpable gonads with 46,XY karyotype. The diag-
nosis of ovotesticular DSD should also be considered as she experienced some
degree of virilization as well as feminization during peripubertal period. Bilateral
palpable gonads are usually not a feature of ovotesticular DSD, unless there are
bilateral ovotestes or testis and ovotestis on either side. This was further confi rmed
by the presence of bilateral testicular tissue on histology. 46,XY partial gonadal
dysgenesis is usually associated with varying degree of genital ambiguity and lack
of uterus as seen in the index patient; however, the palpable gonads in the labioscro-
tal folds do not favor this diagnosis, as dysgenetic testes usually do not descend to
the scrotum. This diagnosis was further denied by high serum androstenedione
level. The diagnosis of partial androgen insensitivity (PAIS) is less likely in view of
poor breast development with markedly undervirilized genitalia. Further, low serum
testosterone excluded this possibility as well. The androgen biosynthetic defects
due to 17α-hydroxylase, 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3),
and 5α-reductase defi ciency are the contenders for the differential diagnosis in the
index patient. 17α-hydroxylase defi ciency in 46,XY DSD is usually associated with
tall stature with eunuchoidal proportions, hypertension and female external genita-
lia, and undetectable or low serum androstenedione (A) and testosterone (T) level.
Patients with 5α-reductase defi ciency are usually associated with normal body pro-
portions, varying degree of genital ambiguity with palpable gonads, absence of
gynecomastia, virilization during peripubertal period, and high serum testosterone
and low dihydrotestosterone (DHT) levels. Therefore, the possibilities of these two
biosynthetic defects are excluded as she had high androstenedione and low testos-
terone levels. Patients with 17β-HSD3 defi ciency usually have female external geni-
talia with palpable gonads, eunuchoidal proportions, peripubertal virilization, and
varying degree of gynecomastia. Low testosterone, high androstenedione, and ele-
vated gonadotropins and hCG stimulated low T/A ratio (<0.8) confi rmed the diag-
nosis of 17β-HSD3 defi ciency in the index patient. The T/A ratio is confi rmatory for
the diagnosis of 17β-HSD3 defi ciency only in the presence of high levels of andro-
stenedione. Further, hCG stimulation test is only required in prepubertal children, as
during peripubertal period endogenous LH drive is suffi cient to stimulate the Leydig
cell for unmasking the respective enzyme defi ciency as was observed in the index
patient who had modest ∆ rise in T/A ratio after hCG stimulation. High gonadotro-
pins, both LH and FSH, are also a feature of 17 β-HSD3 defi ciency as was seen in
the index patient. High LH is attributed to decreased negative feedback by low tes-
tosterone, and elevated FSH is the result of decreased inhibin B which occurs due to
low intratesticular testosterone-mediated inhibition of spermatogenesis and