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Aromatase Deficiency Caused by a Novel P450_arom Gene Mutation: Impact of Absent Estrogen Production on Serum Gonadotropin Concentration in a Boy¹

Division of Pediatric Endocrinology, University Children’s Hospital (J.D., C.F., P.E.M.) 3010 Bern, Switzerland; the Department of Biochemistry, School of Medicine Fujita Health University (N.Y., N.H.), Toyoake, Aichi 470-1192, Japan; and the Department of Endocrinology, Universitaire Ziekenhuizen Gasthuisberg (M.B.), 3000 Leuven, Belgium

Address all correspondence and requests for reprints to: Prof. Dr. Primus E. Mullis, Pediatric Endocrinology, University Children’s Hospital, Inselspital, CH-3010 Bern, Switzerland. E-mail: primus.mullis{at}insel.ch

	Abstract

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We identified a new point mutation in the CYP19 gene responsible for aromatase (P450_arom) deficiency in a 46,XY male infant with unremarkable clinical findings at birth. This boy is homozygote for a 1-bp (C) deletion in exon 5 of the aromatase gene causing a frame-shift mutation. The frame-shift results in a prematurely terminated protein that is inactive due to the absence of the functional regions of the enzyme.

Aromatase deficiency was suspected prenatally because of the severe virilization of the mother during the early pregnancy, and the diagnosis was confirmed shortly after birth. Four weeks after birth, the baby boy showed extremely low levels of serum estrogens, but had a normal level of serum free testosterone; in comparison with the high serum concentration of androstenedione at birth, a striking decrease occurred by 4 weeks postnatally. We previously reported elevated basal and stimulated FSH levels in a female infant with aromatase deficiency in the first year of life. In contrast, in the male infant, basal FSH and peak FSH levels after standard GnRH stimulation tests were normal. This finding suggests that the contribution of estrogen to the hypothalamic-pituitary gonadotropin-gonadal feedback mechanism is different in boys and girls during infancy and early childhood. In normal girls, serum estradiol concentrations strongly correlate with circulating inhibin levels, and thus, low inhibin levels may contribute to the striking elevation of FSH in young girls with aromatase deficiency. In contrast, estradiol levels are physiologically about a 7-fold lower in boys than in girls, and serum inhibin levels remain elevated even though levels of FSH, LH, and testosterone are decreased.

	Introduction

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CONVERSION of C₁₉ steroids to estrogens is catalyzed by the aromatase enzyme (P450_arom), which belongs to the cytochrome P-450 superfamily (1). P450_arom is encoded by the CYP19 gene localized on chromosome 15p21.1 (2). The enzyme is located in the endoplasmic reticulum of estrogen-producing cells and is expressed in a variety of tissues, including ovarian granulosa cells (3), placenta (4), testicular Sertoli (5) and Leydig cells (6), as well as adipose tissue (7) and various parts of the brain, including hypothalamus, amygdala, and hippocampus (8, 9).

Aromatization of fetal adrenal androgens is essential for the production of estrogens by the human placenta during pregnancy (10). Hence, a placental defect in aromatization results in low estrogen production during pregnancy. During gestation, placental P450_arom converts androstenedione (⁴A), testosterone, and 16-hydroxyandrostenedione (16-OH-⁴A) to estrone (E₁), estradiol (E₂), and estriol (E₃), respectively (10).

Due to the rarity of aromatase deficiency only eight well documented cases have been described to date (11, 12, 13, 14, 15, 16, 17, 18, 19). There are reports of two adult males (11, 12, 13) and six girls (11, 14, 15, 16, 17, 18, 19). In the two males, the first remarkable clinical findings were described only in adulthood. These men were tall and presented a continued linear growth with still unfused epiphysis in their midtwenties. Further clinical signs were decreased bone density as well as macroorchidism but normal sexual activity (11–13; for review, see Ref. 20). In the patient reported by Morishima et al. (11, 13), evidence for a role of estrogen in the normal feedback mechanism in the adult male was obtained. In females, however, the common clinical findings were virilized external genitalia at birth caused by hyperandrogenism with combined hypoestrogenism. Later in life the affected girls presented with sexual infantilism, primary amenorrhea, eunuchoid proportion, and tall stature. The low or lacking estrogen levels resulted in high circulating FSH concentrations that led to multicystic ovaries not only in the adolescent girls (11, 16) but in one case in infancy and childhood (19). Hormonal studies in the latter baby girl revealed that low levels of E₂ are essential as a component of the restraint of FSH and LH secretion during infancy (19) and later in childhood (16, 19).

Aromatase deficiency has not been described previously in an infant boy. We report a new mutation in the CYP19 gene as a cause of the disorder and the clinical impact of aromatase deficiency on gonadotropin in a male infant. Molecular biological studies revealed homozygosity for a C base deletion in exon 5 of the aromatase gene, causing a frame-shift mutation. This frame shift produced a stop codon after 21 codons. The resulting nascent peptide is completely inactive, because it does not contain the substrate binding pocket (I-helix), the electron-accepting site, or the heme-binding site (21).

The hormonal studies revealed that in contrast to the affected adult male, basal and GnRH-stimulated FSH peak levels were within the normal control range despite low serum estrogen concentrations. These data suggest that the feedback mechanisms within the hypothalamic-pituitary-gonadal axis may be differently regulated during infancy and early childhood in males and females.

	Materials and Methods

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Plasma LH and FSH were measured by a fluorometric enzyme immunoassay using Stratus (DADE International, Inc., Miami, FL). Inhibin was measured in a double antibody enzyme immunometric assay (22). Serum estrone, E₂, E₃, 17-hydroxyprogesterone, free testosterone, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S) were determined by commercially available RIA kits (Diagnostics Systems Laboratories, Inc., Webster, TX). The conversion factors were 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 = 0.027 x µg/dL; DHEA, serum: pmol/L = 34.67 x ng/dL; free testosterone, 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.

DNA isolation

Genomic DNA was isolated from peripheral leukocytes of the affected subjects and relatives, as previously described (23).

Amplification, subcloning, and sequencing of genomic DNA

Each exon of the CYP19 gene, including the 5'-flanking regions, was amplified using the primers previously reported (19). The PCR was performed in a total volume of 50 µL containing 2 µg genomic DNA, 0.2 µmol/L dNTPs, 50 pmol each of PCR primers, 2 U recombinant Taq DNA polymerase XL DNA polymerase XL (Perkin-Elmer Corp./Cetus, Norwalk, CT) for 38 cycles as follows: 94 C for 20 s, 58 C for 30 s, and 72 C for 30 s. After an extra 10-min extension period at 72 C in the final cycle, PCR products were purified with QIAquick spin column (Qiagen, Chatsworth, CA) and subcloned into pBluescript (Stratagene, La Jolla, CA). DNA sequences of at least 20 independent clones for each PCR product were determined by the dideoxy-chain terminator method on a DNA sequencer 373A (PE Applied Biosystems, Foster City, CA).

Case report

The history of this Swiss family was unremarkable, except that the parents are second cousins. The patient is the second child of a 25-yr-old mother. The first child, a girl, was born after a normal full-term pregnancy and has grown and developed normally. The affected male sibling was a 3.2-kg product of a full-term pregnancy. No medication was taken during the pregnancy. At about 13 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 clitoris, and masculinizing changes in her face. 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 5 days, spontaneous onset of labor occurred 1 h after rupture of the membranes, and the baby was vaginally delivered 4 h later with Apgar scores of 9, 9, and 10 at 10 min after birth. The infant had normal male external genitalia (phallus 3.6 cm long and 1.1 cm wide). Both testes were descended in a normal scrotum.

The hormonal changes in the mother before and after delivery are reported in Table 1. Of note, by 5 months after delivery, the maternal manifestations of virilization had disappeared, except for a broken voice.

The hormonal changes in the male infant are shown in Table 2. Both basal and GnRH-induced FSH levels were normal 2 months after birth, in contrast to those in an affected female infant of the same age (19) (Table 3).

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

Genomic DNA was extracted, and the individual exons and flanking regions of the CYP19 gene were amplified by PCR. The DNA fragments were individually subcloned into pBluescript and separately sequenced. To exclude artifacts, both strands were sequenced. Comparison with the published sequence of the human CYP19 gene (24, 25, 26) revealed homozygosity for a C-base deletion in exon 5 causing a frame-shift mutation. The frame shift produced a stop codon after 21 codons. In the normal gene, the DNA (amino acid) sequence in exon 5 is 5'-GGC(Gly)CTT(Leu)GTT(Val)CGT(Arg)ATG(Met)GTC(Thr) ACA(Val)-3', whereas in this affected patient, it is 5'-GGC(Gly)-X-TTG(Leu)TTC(Phe) GTA(Val)TGG(Trp)TCA(Ser)-30 bases-TGG(Trp) ACA(Thr)GGT(Gly) TGG(Trp)AGG(Arg)AGG(Arg)TGA(stop)-3' (Fig. 1). The resulting nascent peptide is completely inactive, because it does not contain the substrate binding pocket (I-helix), the electron acceptor site, or the heme-binding site. The affected boy is homozygous, whereas both of the parents and the older girl are heterozygous for this mutation (Fig. 1).

View larger version (34K): [in this window] [in a new window]   Figure 1. Pedigree and nucleotide sequences of the patient and a normal control are shown. There is a C base deletion in exon 5 of the aromatase gene causing a frame-shift mutation. The frame shift produces a stop codon after 21 codons.

Severe virilization of the mother as early as the 13 week of gestation correlates with the expected total lack of aromatase activity in the patient. The physical examination of this baby boy was normal at birth. Aromatase deficiency was suspected in light of the maternal virilization and prepartum hormone levels (Table 1); the diagnosis was confirmed in the patient at birth by the hormone values (Table 2). At 4 weeks after birth, the E₂ levels were low, the androstenedione level was decreasing toward the normal level for age and sex, whereas the free testosterone level had already fallen to within the normal range. In contrast to the previously described findings in a female infant (19), the basal FSH and the GnRH-stimulated FSH levels were normal. In both infants the serum LH values and the LH response to GnRH were in the upper normal range. Inhibin B levels at 2 months were elevated in the affected boy, as normally described in boys of his age (27), whereas inhibin B was undetectable in the affected girl (Table 3).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
The affected boy is a homozygote for a newly described CYP19 (aromatase) null mutation. There is a C base deletion in exon 5 of the CYP19 gene, causing a frame-shift mutation leading to a premature stop codon 21 amino acids downstream. As a consequence, the translated protein does not possess critical functional regions. Importantly, the substrate binding pocket (I-helix), the electron-accepting site, and the heme-binding site are absent. In the absence of P450_arom, the androgenic steroid (⁴A, testosterone, and 16-OH-⁴A) 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 virilization of the mother during pregnancy as well masculinization of the external genitalia in girls. In a previous report we suggested that about 1% of placental aromatase activity of the wild-type P450_arom enzyme seemed sufficient to prevent virilization of the mother during pregnancy (19). This idea is supported by the clinical presentation of this mother, who virilized as early as 13 weeks gestation, as there was no placental aromatase activity. Furthermore, the lower the activity of the P450_arom enzyme, the greater the degree of masculinization of affected female fetuses (19). As our patient is a male, the impact of the increased androgen levels during gestation on the appearance of the external genitalia is of interest. The boy presented with normal external genitalia, with no phallic enlargement. The basal FSH, LH, and GnRH-induced gonadotropin responses in this male infant were normal, in contrast to the affected female infant, in whom the basal FSH levels and the FSH response to GnRH were strikingly elevated not only in infancy but in childhood as well. Aromatase activity was totally absent in both of the children. These observations suggest that in boys during infancy estrogen does not contribute to the inhibition of FSH secretion, in contrast to girls. Furthermore, it implies that in boys and girls the feedback mechanisms within the hypothalamic-pituitary-gonadal axis are differently regulated. Inhibin, a gonadal peptide, may play an important role in that gender-specific feedback regulation. In normal male infants serum levels of inhibin B, FSH, LH, and testosterone are elevated, whereas the hormonal pattern of these hormones is more complex in girls (27). Further, looking at normal E₂ and inhibin values determined in our laboratory, we found a strong correlation between the two variables, which also has been previously reported using a different assay (28). Therefore, early postnatal activation of the hypothalamo-pituitary-gonadal axis may involve inhibin as well as gonadal steroids and gonadotropins. The lack of E₂ production in aromatase deficiency may result in undetectable inhibin B levels and contribute to the elevated FSH levels. In boys, however, E₂ levels are physiologically about 7-fold lower than in girls (29), and serum inhibin levels remain elevated up to the age of 15 months, although FSH, LH, and testosterone decrease into the range observed later in childhood by the age of 6–9 months (27).

Later in life, however, estrogen plays an important part in the regulation of gonadotropin secretion in females as well as males. For instance, in a man with estrogen resistance caused by a mutation in the estrogen receptor gene and, therefore, with a physiological lack of estrogens, elevated gonadotropin, LH, and FSH levels were reported (30). Further, estrogen treatment of a young adult aromatase-deficient male normalized the elevated serum concentrations of LH and FSH (11, 13). This suggests that estrogen, in addition to testosterone and inhibin, has an important role in regulating the secretion of both gonadotropins in adult life. The follow-up of this boy will help to define the time when E₂ becomes an important regulatory factor of the gonadotropin-testicular axis.

In conclusion, we report a new CYP19 gene alteration resulting in P450_arom deficiency in a boy. The clinical and hormonal analyses suggest a different impact of estrogen levels on the feedback mechanism within the hypothalamic-pituitary-gonadal axis in boys and girls. Furthermore, bearing in mind the normal clinical appearance of that baby boy, an aromatase deficiency might be the underlying defect of any transient virilization of a mother during pregnancy that regresses postpartum.

	Acknowledgments

 
We express our thanks to Prof. Melvin Grumbach (University of California-San Francisco) for his kind and valuable advice while reviewing the manuscript.

	Footnotes

 
¹ This work was supported by a grant from the Swiss National Science Foundation (3200–53714.98).

Received April 27, 1999.

Revised July 7, 1999.

Accepted July 13, 1999.

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