GONADAL DYSGENESIS
Gonadal dysgenesis is a developmental abnormality of patients who do not carry the stigmata of Turner syndrome but still suffer absent menarche because of chromosomal abnormalities and abnormal (streak) gonads. These patients are generally tall (150 cm), are more normal in appearance, and are a chromosomally heterogeneous group: 46, XX, 46, XY, or mosaic X/XY karyotypes. Classic Turner syndrome is caused by the absence of one X chromosome. Turner syndrome is a collection of stigmata that include edema of the hands and feet, webbing of the neck, short stature, left-sided heart or aortic anomalies, and gonadal dysgenesis resulting in primary amenorrhea and infertility.
Gonadal dysgenesis occurs in 1 of 2500 female births and Turner syndrome
is estimated to occur in 1 of 2700 female births. Most patients with Turner
syndrome have a sporadic loss of one X chromosome (45, XO, 60% of cases; others
partial losses: amenorrhea with long-arm loss; short stature with short-arm
loss). Ninety-eight percent of conceptuses with only one X chromosome abort in
early pregnancy. Gonadal dysgenesis can occur with other chromosomal
abnormalities including 46,XY gonadal dysgenesis (Swyer syndrome) and 46, XX q5
X chromosome long-arm deletion and with mixed or mosaic states.
The symptoms and stigmata expressed by these individuals depend on the
amount of chromatin that has been lost: primary amenorrhea and infertility (95%
to 98%) are the most common. (Gonadal dysgenesis is the most common cause of
failure to begin menstruation and in approximately 60% of women with primary
amenorrhea, an abnormality of gonadal differentiation or function has occurred
during the fetal or neonatal period.) These patients have early and accelerated
oocyte atresia resulting in few, if any, oocytes remaining in the ovarian cortex
at the time of normal puberty. (Germ cell involution occurs soon after they
migrate into the undifferentiated gonad. This results in fibrous streak gonads
that are hormonally inactive.) Those with complete loss of the X chromosome
generally are of short stature (150 cm) and have a short neck, high palate,
low hairline, and widely-spaced, hypoplastic nipples (80%). Seventy to
seventy-five percent have a broad (shield) chest, nail hypoplasia, lymphedema,
cubitus valgus, prominent anomalous ears, multiple nevi, and hearing
impairment. Two thirds of these patients have webbing of the neck and a short
fourth metacarpal. Renal and cardiac anomalies are also common. Gonadoblastomas
or virilization may occur if the individual is mosaic for 45, X/46,XY.
The diagnosis of gonadal dysgenesis or Turner syndrome is usually
established by karyotyping. (Forty percent of those thought to have Turner
syndrome have a mosaic karyotype or have an abnormal X or Y chromosome.)
Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels are high
in these individuals, but the elevation is nonspecific.
These individuals generally require hormone replacement therapy, and they may require growth hormone therapy if the diagnosis is established before age 10. When there is a mosaicism involving a Y chromosome, surgical extirpation of the gonads must be performed because of a 25% to 30% risk of malignant gonadal tumors. Timing of gonadal removal in patients with a Y chromosome is controversial: removal as soon as the diagnosis is made versus delaying removal until pubertal changes are complete. (The risk of cancer in XY gonadal dysgenesis is 3% at age 10, 10% at 13, and 75% at 26 years of age.) If hormonal replacement is undertaken, it must be done with care because adolescents are much more sensitive to the effects of estrogen than are postmenopausal women, allowing doses in the range of 0.3 mg of conjugated estrogen, 0.5 mg of estradiol, or their equivalent daily. After 6 to 12 months of therapy at this level, the dose should be doubled and a progestin should be added, or the patient’s therapy should be switched to combination oral contraceptives. This generally results in regular menstruation, and normal pubertal development proceeds on its own when the patient reaches a bone age of 13. Growth hormone may be effective if given before age 10.
