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Pediatric Endocrinology |
Division of Paediatric Endocrinology, University Children’s Hospital (P.E.M., B.K.) and Policlinic of Medicine, University Hospital (K.L., P.J.), 3010 Bern, Switzerland; and Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University (N.Y., N.H.),Toyake, Aichi, Japan
Address all correspondence and requests for reprints to: P.E. Mullis, Paediatric Endocrinology, University Children’s Hospital, Inselspital, CH-3010 Bern, Switzerland. E-mail: primus.mullis{at}insel.unibe.ch
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Abstract |
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Aromatase deficiency was already suspected because of the marked virilization occurring prepartum in the mother, and the diagnosis was confirmed shortly after birth. Extremely low levels of serum estrogens were found in contrast to high levels of androgens. Ultrasonographic follow-up studies revealed persistently enlarged ovaries (19.5–22 mL) during early childhood (2 to 4 yr) which contained numerous large cysts up to 4.8 x 3.7 cm and normal-appearing large tertiary follicles already at the age of 2 yr. In addition, both basal and GnRH-induced FSH levels remained consistently strikingly elevated. Low-dose estradiol (E2) (0.4 mg/day) given for 50 days at the age of 36/12 yr resulted in normalization of serum gonadotropin levels, regression of ovarian size, and increase of whole body and lumbar spine (L1-L4) bone mineral density. The FSH concentration and ovarian size returned to pretreatment levels shortly (150 days) after cessation of E2 therapy. Therefore, we recommend that affected females be treated with low-dose E2 in amounts sufficient to result in physiological prepubertal E2 concentrations using an ultrasensitive estrogen assay. However, E2 replacement needs to be adjusted throughout childhood and puberty to ensure normal skeletal maturation and adequate adolescent growth spurt, normal accretion of bone mineral density, and, at the appropriate age, female secondary sex maturation.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Aromatization of fetal adrenal androgens is essential for production of
estrogens during pregnancy by the human placenta (10). Therefore, a
placental defect in aromatization results in low estrogen production
during pregnancy. During gestation, placental P450arom
converts androstenedione (
4A) and testosterone (T)
derived from fetal and maternal adrenal dehydroepiandrosterone sulfate
(DHEA-S) to estrone (E1) and estradiol (E2),
whereas 16-
OH-androstenedione (16-OH-4A) derived
from fetal 16- OH-dehydroepiandrosterone sulfate (16-OH-DHEA-S) is
converted to estriol (E3) (10). Thus, the principal
products of placental aromatase activity are E3,
E1, and E2 (10).
Aromatase deficiencies are rare, and five well-documented cases have been described so far (11, 12, 13, 14, 15, 16, 17). The first reported female was homozygous for a consensus 5'-splice donor sequence mutation from GT-GC, resulting in the use of a cryptic splice donor site further downstream in intron 6 and, therefore, in a protein with an insert of 87 bp encoding 29 amino acids (12). By transient expression in COS-7 cells, the aromatase complementary DNA of this patient was found to produce a protein with traces of activity (<0.3%) (12). Ito et al. (13, 15) reported a compound heterozygote female patient who had two missense mutations, one at position 1303 bp (C->T; R435C) and the other at 1310 bp (G->A; C437Y) in exon 10. Assays of the expressed mutated proteins showed that R435C mutant had 1.1% the activity of the wild-type P450arom enzyme, whereas the C437Y mutant demonstrated no activity (15). The two siblings reported by Morishima et al. (16) demonstrated a single base change at bp 1123 (C->T), a highly conserved region, that resulted in a cysteine instead of an arginine at position 375 (R375C) in exon 9. The expression of the mutant cDNA in COS-1 cells revealed an activity of 0.2% when compared with the wild type (16). Most recently, Portrat-Doyan et al. (17) reported a female with a homozygous mutation R457X, resulting in a stop codon in exon 10.
The present case describes the clinical entity of female pseudohermaphroditism at birth and hypergonadotropic hypogonadism secondary to total aromatase deficiency. Molecular biological studies revealed compound heterozygosity for a point mutation/deletion resulting in two stop codons. One is a one base (C) deletion occurring at P408 (CCC; exon 9), which corresponds to the aromatic consensus region of the aromatase enzyme and results in a frameshift and nonsense codon 111 bp (37 aa) downstream in the aromatase transcripts. The other is a point mutation G->A at the splicing site (canonical GT-> mutational AT) between exon 3 and intron 3 yielding a stop codon 3 bp downstream.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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OH
progesterone, free T and DHEA and DHEA-S, were determined by
commercially available RIA kits (Diagnostic Systems Labs., Diagnostic
Products Corp., Los Angeles, CA). The conversion factors are as
follows: E3, serum: pmol/L = 3.67 x pg/mL;
E2, serum: pmol/L = 3.67 x pg/mL; DHEA-S, serum:
µmol/L = 0.0027 x ng/mL; DHEA, serum: nmol/L =
3.467 x µg/L; free T, serum: pmol/L = 3.467 x pg/mL;
4A, serum: pmol/L = 0.028 x ng/dL; cortisol,
serum: nmol/L = 27.6 x µg/dL; LH, plasma: IU/L: 1.0
x mIU/mL; and FSH, plasma: IU/L = 1.0 x mIU/mL. Dual energy x-ray absorptiometry (DEXA)
Whole body and lumbar spine bone mineral density (BMD) was measured three times using DEXA (Hologic QDR 4500, Hologic, Waltham, MA) as previously described (18). To take into account the influence of vertebral growth between each measurement, the lumbar spine BMD (g/cm2) was corrected using a simple mathematical method (19). Briefly, volume density (d) of the lumbar spine, approximately a cylinder of height (h), and diameter (A; A and h are obtained from DEXA analysis), was expressed in g/cm3.
The equation we used was: d = 4/
x h x BMD/A (19). The
volume related BMD (d) was a constant value of 0.255 ± 0.015
g/cm3 (19).
DNA isolation
Genomic DNA was isolated from peripheral leukocytes of the affected subjects and relatives, as previously described (20). The concentration of each sample was determined by measuring the optical density of the purified DNA at 260 and 280 nm.
Amplification, subcloning, and sequencing of genomic DNA
Each exon of the CYP19 gene, including the 5'-flanking regions,
were amplified using the primers as shown in Table 1
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Placenta-specific exon 1, exons 2–9, and their boundary intron and
promoter regions were amplified by PCR of genomic DNA using a pair of
Pro-1F and In-1R, In-1F and In-2R, In-2F and In-3R, In-3F and In-4R,
In-4F and In-5R, In-5F and In-6R, In-6F and In-7R, In-7F and In-8R, and
In-8F and In-9R, respectively. Exon 10 and the intron 9-exon 10
junctions were divided into three portions, and they were amplified by
PCR using a pair of In-9F and Ex-10R1, Ex-10F1 and Ex-10R2, or Ex-10R3.
The PCR was performed in a total volume of 50 µL containing 2 ng
genomic DNA, 0.2 micromolar deoxynucleotide triphosphates, 50 pmol each
of PCR primers, 2 U recombinant Taq DNA polymerase XL (Perkin-Elmer,
Cetus, Norwalk, CT) for 38 cycles as follows: 94 C for 20 sec, 58 C for
30 sec, and 72 C for 30 sec. After an extra 10-min extension period at
72 C in the final cycle, PCR products were purified with QIAquick spin
column (QIAGEN Inc., Santa Clarita, CA) and subcloned into Bluescript
(Stratagene, La Jolla, CA). DNA sequences of at least 20 independent
clones for each PCR product were determined by dideoxy-chain terminator
method on a DNA sequencer 373A (Applied Biosystems, Foster City, CA).
Possible mutation sites in exon 3-intron 3 junction and exon 9 were
further confirmed by repeated DNA sequencing of at least 30 independent
clones from genomes DNAs of the patient and her family members.
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The history of this Swiss family was unremarkable, in particular there is no evidence of consanguinity. The patient is the second child of a 28-yr-old mother. The first child, a female as well, was born after a normal full-term pregnancy and has grown uneventfully. The affected female sibling was a 3.5-kg product of a full-term pregnancy. No medications were taken during the pregnancy. At about 12 weeks, the mother began to suffer from progressive virilization, including severe acne on her face, generalized pigmentation, lowering and breaking of her voice, hypertrophy of the clitoris, and masculinizing changes in her face. At about 20 weeks gestation, she was referred to a dermatologist for treatment of her severe acne. These virilizing signs worsened progressively until delivery.
Biophysical findings excluded fetal distress, and ultrasonographic examinations demonstrated that the size and the rate of growth of the fetus as well as placenta were appropriate for gestational age. No fetal abnormalities were diagnosed. At 39 weeks and 1 day, spontaneous onset of labor occurred 1 h after the rupture of the membranes, and the baby was vaginally delivered 2 h later with an Apgar score of 8, 8, and 9 at 10 min after birth. The infant had masculine-appearing external genitalia: a greatly enlarged phallus (2.9 cm long and 0.9 cm wide; Prader V), complete fusion of posterior scrotolabial folds, rugation of the scrotolabial folds as in a scrotum, and a single meatus on the top of a phallus. Unfortunately, the parents were told by the obstetrician and midwife that the baby was a boy. Following the examination by the family’s pediatrician, female pseudohermaphroditism was suspected, and a comprehensive workup was initiated.
The hormonal changes in the mother before and after delivery are
reported in Table 2. Importantly, 6 months after
delivery, the maternal manifestations of virilization disappeared
except for her broken voice. The karyotype of the patient was 46,XX. To
rule out the possibility of 46,XX true hermaphroditism, the infant was
given 1500 U human CG, im daily for 3 days. No rise in serum free T was
detected. Further, she was SRY negative, and the plasma concentration
of the anti-Müllerian hormone was less than the sensitivity of
the assay. These observations are consistent with the absence of
testicular tissue. A blood screening test for 21-hydroxylase deficiency
indicated normal concentration of 17--OH progesterone; a urine
steroid profile was normal, and no evidence for a virilizing form of
congenital adrenal hyperplasia was found. Accordingly, the diagnosis of
a nonadrenal form of female pseudohermaphroditism was made.
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. The
patient was reevaluated at the age of 12 months. Both basal and
GnRH-induced FSH levels were strikingly elevated (Table 4). A laparoscopy at the age of 2 yr identified enlarged
(3.8 x 2.7 x 3.1 cm; 15.9 mL) ovaries with several cysts,
the largest of which measured 4.8 x 3.7 cm; the fallopian tubes
and uterus were normal in appearance. Biopsies of both ovaries were
performed; histopathological examinations demonstrated many
normal-appearing large tertiary follicles with an oocyte within a
cumulus oophorus projecting into the antrum (Fig. 1).
The bone age rated according to the method described by Tanner et
al. (22) (TW2 RUS) was 16/12 yr (chronological age: 2 yr)
(22).
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). The bone age was delayed at 2 3/12 yrs (22). FSH
remained elevated at 24.5 IU/L, and GnRH testing showed a striking rise
in FSH and LH (Table 4). A repeat pelvic ultrasound examination again
revealed enlarged ovaries (4.1 x 2.6 x 3.2 cm; 17 mL).
Because low levels of serum E2 are detectable (23) in
prepubertal females, we chose to administer estrogens (E2:
0.4 mg/day for 2 months; 50 days) to study the effect of low levels of
serum E2 on the hypothalamo-pituitary feedback mechanisms.
Previously, informed consent for estrogen treatment was obtained from
both parents. The low-dose E2 substitution resulted in a
normalization of serum gonadotropin levels (Tables 4 and 5) and regression of the enlarged ovaries on pelvic
ultrasound examination (2.3 x 1.2 x 1.6 cm; 2.2 mL). BMD
increased drastically, whereas bone age did not advance accordingly
(26/12 yr; chronological age 38/12 yr) (Table 6, Fig. 2). Four months (150 days) after
cessation of the low-dose estrogen therapy, the child was reassessed.
Once again a rise of unstimulated and stimulated gonadotropin levels
was noted, and the ovaries had increased in size (3.1 x 1.8 x
2.2 cm; 6.1 mL) (Tables 4 and 5). In contrast, at the chronological age
of 4 yr bone age remained unchanged and retarded at 26/12 yrs
(22).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Genomic DNA was extracted, and the individual exons and flanking
regions of the CYP gene were amplified by PCR. The DNA fragments were
individually subcloned into Bluescript and separately sequenced. To
exclude artefacts both strands were sequenced. Comparison with the
published sequence of the human CYP19 gene (24, 25, 26) revealed compound
heterozygosity for a point mutation and deletion within the CYP19 gene.
The allele inherited from her mother (allele 2) presented a base pair
deletion (C) occurring in the Pro (P408; CCC, exon 9), which
corresponds to the consensus aromatic region of the aromatase enzyme.
Thereafter, a frameshift occurs resulting in a nonsense codon 111 bp
(37 aa) further down in the aromatase gene (Fig. 3). The
allele inherited from her father (allele 1) showed a point mutation
from G->A at the splicing point (canonical GT to mutational AT)
between exon and intron 3 (24, 25, 26). This mutation ignores the splice
site, and a stop codon 3 bp downstream occurs. Namely,
ATCAGCAA/(splicing) GT–[Ile Ser Lys/splicing–] in normal is altered
to ATCAGCAA/ATGA–[Ile Ser Lys/stop] in this allele. As expected
there was no active transcript found.
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The total lack of aromatase activity in the patient caused severe
virilization of the mother as early as the 12th week of gestation. The
female patient had striking masculinization of the external genitalia
at birth. Aromatase deficiency was suspected in view of the prepartum
hormone levels in the mother (Table 2), and the diagnosis was confirmed
after birth in the patient following hormonal analysis (Tables 2 and 3). At that time, the very low levels of estrogens were in remarkable
contrast to the high levels of androgens. Results of further
clinical and hormonal investigations suggested a total absence of
aromatase activity and, therefore, a generalized defect. Furthermore,
ultrasonographic follow-up studies revealed persistently enlarged
ovaries (19.5–22 mL) in early childhood (age: 2–4 yr), which
contained normal-appearing large tertiary follicles and numerous large
cysts up to 4.8 x 3.7 cm by the age of 2 yr. Both basal and
GnRH-induced FSH levels were consistently strikingly elevated
throughout the childhood. Low-dose E2 (0.4 mg/day) given
for 50 days resulted in normalization of serum gonadotropin levels and
regression of the enlarged ovaries and ovarian cysts and in an increase
of whole body and lumbar spine BMD. The plasma FSH returned to
pretreatment levels, and ovarian size increased shortly after cessation
(150 days).
BMD
Absolute values of whole body and lumbar spine BMD are given in
Table 6. Figure 2 depicts the percentage change from baseline of values
determined immediately before the beginning of estrogen
(E2) substitution therapy. Although the pretreatment values
for whole body BMD were within the normal range for age-matched females
(Table 6) (19), the lumbar spine BMD (L1-L4), when corrected for the
volume (g/cm3) to integrate the vertebral growth, was lower
than in controls. Therefore, there was densitometric evidence of
osteoporosis already at the age of 36/12 yr, which normalized
with low-dose E2 treatment (Table 6).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the absence of P450arom, the androgenic steroids
(4A, T, and 16- OH4A) cannot be
converted to E3, E1, or E2 and,
therefore, large quantities of 4A and T are transferred
to the maternal and fetal circulation, which results in a virilization
of the mother during pregnancy, as well as masculinization of the
urogenital sinus and external genitalia of the female fetus.
About 1% placental aromatase activity of wild-type
P450arom enzyme seems to be enough to prevent virilization
of the mother during pregnancy (Table 7). In all
affected females reported so far, the exposure to an excess of
androgens resulted in a variable virilization of the mother and
masculinization of the external genitalia. Interestingly, the lower the
aromatase activity (Table 7), the greater was the degree of
masculinization of the external genitalia at birth. Our patient had an
extreme degree of female pseudohermaphroditism, and virilization of the
mother began as early as 12 weeks gestation, when fetal age
differentiation of the fetal genital groove is determined (27).
Additionally, in contrast to previously reported affected females, we
found elevated FSH levels and striking GnRH-induced gonadotropin
responses not only in infancy but in childhood as well. This suggests
that a minimal amount of estrogen is needed not only in infancy but
also during childhood to contribute to the inhibition of FSH secretion
in prepubertal females.
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In conclusion, we suggest that in females with a complete lack of aromatase activity, a minimal dose of exogenous E2 should be given in childhood. The dose of E2 needs to be adjusted by the use of an ultrasensitive estrogen assay, determination of plasma gonadotropins, and pelvic ultrasonography. The aim will be to administer an adequate dose of E2 throughout childhood and puberty to ensure a physiological skeletal maturation, a normal adolescent growth spurt, normal accretion of bone mineral, and, at appropriate age, female secondary sex maturation.
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Acknowledgments |
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Footnotes |
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Received December 5, 1996.
Revised February 6, 1997.
Accepted February 24, 1997.
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References |
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4-androstenedione in normal newborns: evidence for
testicular activity at birth. J Clin Endocrinol Metab. 41:977–980.[Abstract]
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