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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-2067
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 5 2508-2511
Copyright © 2005 by The Endocrine Society

Subtle 17{alpha}-Hydroxylase/17,20-Lyase Deficiency with Homozygous Y201N Mutation in an Infertile Woman

Matsuo Taniyama, Makito Tanabe, Hiroshi Saito, Yoshio Ban, Hajime Nawata and Toshihiko Yanase

Division of Endocrinology and Metabolism, Departments of Internal Medicine (M.Tani) and Obstetrics and Gynecology (H.S.), Showa University Fujigaoka Hospital, Yokohama 227-8501, Japan; Third Department of Internal Medicine (M.Tani., Y.B.), Showa University School of Medicine, Tokyo 142-8666, Japan; and Third Department of Internal Medicine (M.Tana., H.N., T.Y.), Faculty of Medicine, Kyushu University, Fukuoka 818-8582, Japan

Address all correspondence and requests for reprints to: Matsuo Taniyama, M.D., Division of Endocrinology and Metabolism, Department of Internal Medicine, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba, Yokohama, Kanagawa 227-8501, Japan. E-mail: taniyama{at}showa-university-fujigaoka.gr.jp.


   Abstract
Top
 Abstract
Introduction
 Patient and Methods
 Results
 Discussion
 References
 
Steroid 17{alpha}-hydroxylase deficiency is characterized by failed sexual development and mineralocorticoid hypertension. Female patients usually exhibit primary amenorrhea. Some patients with partial deficiency are reported to have menses, yet they have hypertension and hypokalemia. We describe here a normotensive, infertile female patient with menses and minimal defects in secondary sex characteristics.

The patient experienced menarche at age 13, and her menstrual cycles were regular until age 18 and irregular thereafter. Pubic hair was present (Tanner stage 3), and breast maturation was within normal range (Tanner stage 5). The patient’s resting blood pressure was normal, and hypokalemia was not observed despite high blood corticosterone levels and reduced plasma renin activity. Analysis of the CYP17 gene revealed that the patient was homozygous for the Y201N mutation. In vitro expression of the mutated Y201N enzyme revealed reduced activities of both 17{alpha}-hydroxylase and 17,20-lyase; however, these reductions were less than those of the F53/54DEL mutation, which also shows mild clinical deficiency of 17{alpha}-hydroxylase/17,20-lyase. Thus, the 17{alpha}-hydroxylase/17,20-lyase deficiency in the present case is very mild both clinically and enzymatically. This case raises the possibility that there are infertile, menstruating women with undiagnosed 17{alpha}-hydroxylase deficiency.


   Introduction
Top
 Abstract
 Introduction
Patient and Methods
 Results
 Discussion
 References
 
STEROID 17{alpha}-HYDROXYLASE DEFICIENCY (17OHD) is an autosomal recessive disorder characterized by failure of sexual development and mineralocorticoid hypertension (1, 2, 3, 4). It is caused by a defect (5) in the steroidogenic enzyme cytochrome P450c17 gene (6), which has both 17{alpha}-hydroxylase and 17,20-lyase activities. Lack of sex steroids results in female external genitalia in genetically male individuals and the absence of sexual maturation, including primary amenorrhea, in genetically female individuals (7). Mineralocorticoid excess causes severe hypertension and hypokalemia. In a milder form of 17OHD, genetically male individuals exhibit ambiguous genitalia (8, 9, 10), and female patients sometimes menstruate (11, 12). Most patients with mild 17OHD have severe hypertension. When defects in the secondary sexual characteristics are minimal and severe hypertension is absent in female patients who menstruate, 17OHD may be overlooked.

We observed subtle 17OHD in a female patient with minimal defects in sexual maturation and detected a mutation in the CYP17 gene. This case suggests that there may be undiagnosed cases of mild 17OHD among normotensive menstruating women.


   Patient and Methods
Top
 Abstract
 Introduction
 Patient and Methods
Results
 Discussion
 References
 
Clinical features

The patient was a 38-yr-old Japanese woman who was evaluated for low plasma renin activity. She was an offspring of a consanguineous marriage. She had menarche at age 13, and her menstrual cycles were regular until age 18 and irregular thereafter. After marriage, she was found to be infertile and was under the care of an obstetric clinic for several years. She visited Showa University Hospital at age 34 because of atypical genital bleeding. Her blood pressure at that time was 130/84. On gynecological examination, hypoplastic uterus was observed. Plasma LH and FSH levels were 17 and 22 mU/ml, respectively. Serum progesterone was 2.2 ng/ml, and serum estradiol was 107 pg/ml.

Four years later, when she visited the Division of Internal Medicine, her initial blood pressure was 156/80. It rose to 180/100 in the doctor’s presence and then dropped to 150/90 after several deep breaths. Self-monitoring of blood pressure at home showed her regular blood pressure to be 120–130/70–80; however, it did increase in response to stress. Thereafter, her blood pressure at each visit to the outpatient clinic was almost normal. Although her initial hypertension was thought to be a form of white-coat hypertension, laboratory tests revealed that both plasma renin activity and aldosterone concentration were low, which prompted further endocrinological evaluations. She was 157 cm tall and weighed 45 kg. Pubic hair was present but relatively scarce (Tanner stage 3). Axillary hair had been present but was almost absent at the time of examination. Breast maturation was within normal limits (Tanner stage 5). Her karyotype was 46XX. Serum potassium concentrations were always within normal range. The patient’s serum steroid hormone profile is shown in Table 1Go. A marked increase in corticosterone and a slight increase in deoxycorticosterone were observed. These steroid levels were markedly reduced with dexamethasone administration. Serum cortisol levels and plasma ACTH level were within normal limits, but the cortisol level did not respond well to ACTH load. Serum dehydroepiandrosterone sulfate was within the normal range, and serum androstenedione was low. Abdominal computed tomography revealed no adrenal tumor or hypertrophy of the adrenal glands.


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  		TABLE 1. Hormonal data

 
Sequence analysis

Genomic DNA was extracted from peripheral blood leukocytes. The coding regions of exons 1–8 of the CYP17 gene, including exon-intron boundaries, were amplified from 1 µg genomic DNA by PCR with a set of gene-specific primers as described previously (13). Nucleotide sequences of purified PCR products were determined by direct sequencing with an ABI Prism Dye Termination Cycle Sequencing Core Kit (Applied Biosystems, Foster City, CA).

PCR-restriction fragment length polymorphism (PCR-RFLP) analysis

The detected mutation eliminates a TspE1 restriction site. We performed PCR-RFLP analysis of genomic DNA from the patient and her parents. The mutated codon was amplified with primers 5'-GGCCACCCACAACGGACAGTC-3' and 5'-GACTAGGTCCACCAGGCTGTC-3'. PCR consisted of 33 cycles of 94 C for 1 min, 58 C for 1 min, and 72 C for 1 min. PCR products were purified by ethanol precipitation, digested with TspE1 at 65 C for 4 h, and separated by agarose gel.

Site-directed mutagenesis, transfection of COS1 cells, and enzyme assays

A detected mutation was created in a human P450c17 cDNA in Bluescript (pBSH 17{alpha}-1), which was produced previously by Yanase et al. (14). Site-directed mutagenesis was performed with a BD Transformer Site-Directed Mutagenesis Kit (BD Biosciences Clontech, Tokyo, Japan) with a primer designed for the nucleotide change. The full-length mutant cDNA was sequenced to confirm the mutation. The BamHI-HindIII fragment containing the full-length mutant cDNA was inserted into the pCMV expression vector at the BglII and HindIII sites.

Transfection of COS-1 cells and thin layer chromatography analysis of the catalytic properties of P450c17 were carried out as described previously (14). Enzyme activities were compared with those of wild-type enzyme, which was produced with pCMV17{alpha}-H, and another mutant with mild 17{alpha}-hydroxylase/17,20-lyase deficiency, F53/54DEL enzyme, which was produced with pCMVJG17{alpha}-H (14). Immunoblotting of cellular proteins with antibody raised against porcine testis P450c17 was carried out as previously described (14).


   Results
Top
 Abstract
 Introduction
 Patient and Methods
 Results
Discussion
 References
 
Sequence of the CYP17 gene

A homozygous T->A transversion at nucleotide position 2472 in exon 3 of CYP17 (amino acid change, Tyr201 to Asn:Y201N) was detected in the proband (Fig. 1Go).



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  		FIG. 1. Sequence analysis of the CYP17 gene revealed homozygous mutation of thymine to adenine at nucleotide position 2472 in exon 3, which causes amino acid substitution tyrosine 201 to asparagine (Y201N).

 
PCR-RFLP analysis

Because the T2472A mutation eliminates a TspE1 restriction site, we used PCR-RFLP analysis for genotyping (Fig. 2Go). The expected PCR product was 184 bp. Digestion of the wild-type allele with TspE1 yielded 127-bp and 57-bp fragments. The patient carried only the mutant allele, whereas both her parents were heterozygous for the mutant allele.



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  		FIG. 2. PCR-RFLP analysis. Y201N mutation eliminates a TspE1 restriction site. Cont, Control; Pt, patient; F, father; M, mother. Patient had two mutant alleles, whereas each parent had one normal allele and one mutant allele.

 
In vitro expression study

To determine the functional significance of the Y201N mutation, the mutant cDNA was cloned into a eukaryotic expression vector, pCMV, and expressed in nonsteroidogenic COS-1 cells. Cells expressing the mutant cDNA(Y201N) produced the same amount of immunodetectable P450c17 protein as cells expressing wild-type P450c17 cDNA or mutant P450c17 cDNA (F53/54DEL) (data not shown). Although there was a similar amount of immunodetectable P450c17 protein in the various transfectants, the activities of P450c17 (Y201N), including 17{alpha}-hydroxylation and 17,20-lyase activity, were reduced. Comparison of the initial kinetics with progesterone and 17{alpha}-hydroxypregnenolone as substrates revealed that the 17{alpha}-hydroxylase and 17,20-lyase activities of P450c17 (Y201N) were less than 33% and less than 35%, respectively, those of wild-type P450c17. The activities of P450c17 (F53/54DEL) were less than 22 and 5.2%, respectively, those of wild-type (Table 2Go). Thus, P450c17 (Y201N) had greater 17{alpha}-hydroxylase and 17,20-lyase activities than did P450c17 (F53/54DEL), and both were reduced in parallel in P450c17 (Y201N), whereas there was a much greater reduction of 17,20-lyase activity relative to 17{alpha}-hydroxylase activity in P450c17 (F53/54DEL), as previously observed (14).


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  		TABLE 2. Enzymatic activities of mutant enzymes

 

   Discussion
Top
 Abstract
 Introduction
 Patient and Methods
 Results
 Discussion
References
 
The degree of deficiency in 17{alpha}-hydroxylase and 17,20-lyase activities in the present case was very mild. The manifestations possibly related to the enzyme defect were lack of axillary hair, irregular menstruation, hypoplastic uterus, infertility, and occasional hypertension. However, biochemical analyses suggested that the patient had 17OHD. Plasma renin activity and aldosterone level were low, whereas plasma corticosterone was high and suppressed by dexamethasone. We were not sufficiently confident to diagnose 17OHD at that time because hypokalemia was absent and plasma cortisol and corticotropin levels were within normal limits. Because consanguinity supported recessive inheritance, we sequenced the CYP17 gene and found that the proband was homozygous for a novel missense mutation. Each parent carried one mutant allele. In vitro expression analysis revealed that the Y201N mutation partially reduces the activities of both 17{alpha}-hydroxylase and 17,20-lyase. The 17{alpha}-hydroxylase activity and 17,20-lyase activity of mutant P450c17 were less than 33% and less than 35%, respectively, those of wild-type P450c17. This finding is consistent with the patient’s clinical 17{alpha}-hydroxylase/17,20-lyase activities. It appears that a 17{alpha}-hydroxylase activity that is 30% of that of normal may be sufficient to maintain a normal blood pressure. The patient’s 17,20-lyase activity (30% of normal) was higher than a previously reported patient with the F53/54DEL mutation, whose 17,20-lyase activity was 5% of that of normal and with regular menstruation (14). Therefore, this mutant may allow for regular menstruation. Although Tyr201 is located in the F helix that forms the F-G loop, the structural and functional significance of this region of the molecule remains unclear (15).

The clinical manifestations of 17{alpha}-hydroxylase/17,20-lyase deficiency reflect the activities of the mutated enzymes. Mutations that result in complete loss of enzymatic activities yield the phenotypes associated with complete deficiency (16). Partial deficiency is related to mutations that only partially affect activities (10, 17). Isolated 17,20-lyase deficiency, in which only phenotypes related to sex hormone deficiency are present and those of mineralocorticoid excess are absent, is caused by specific mutations such as R347H and R358Q (18). These mutations cause only 17,20-lyase defects, and 17{alpha}-hydroxylase activity is essentially unaffected (19).

There are generally three opportunities for diagnosis of 17OHD. Ambiguous genitalia at birth give the opportunity to check for genetically male infants with partial deficiency. Genetically male individuals with severe deficiency and genetically female individuals are both phenotypically female, and sex hormone deficiencies are typically recognized at puberty. Primary amenorrhea and lack of female secondary sex characteristics, including breast development and pubic hair, may require evaluation. In other cases, the disease is detected during the course of evaluation of severe hypertension. Genetic females with 17OHD who menstruate are typically identified in this manner (11, 12). To date, approximately 10 patients with 17OHD and menstruation have been reported including three patients with homozygous F53/54DEL mutation (Refs.11 , 12 , 21 , 22 , and references in Ref.2). Although these patients menstruated, only three had pubic hair and mature breast development. Moreover, with the exception of the patient described herein, all had severe hypertension and hypokalemia. Cases of 17OHD without hypertension (Ref.23 and references in Ref.2) or with mild hypertension (7) have been reported; however, the patients had primary amenorrhea. Thus, our case appears to be very rare. However, mild cases may be overlooked because the patients are not evaluated for mineralocorticoid excess or sex hormone deficiencies. Such infertile patients with mild 17OHD have been reported (24). Some specific mutations are reported to be widespread in the particular geographic area (25). It is conceivable that undiagnosed patients with subtle 17OHD with mild deficiency of enzyme activities are present.

It was reported that administration of testosterone as an aromatizable substrate to a patient with 17OHD resulted in follicular maturation and ovulation (26). Thus, identification of 17OHD is essential not only for diagnosis of the cause of infertility but also for developing possible strategies to treat this type of infertility. It seems valuable to screen for 17OHD by plasma renin activity or by corticosterone or progesterone level (27) in infertile women with only minimal defects on sexual maturation.


   Footnotes
 
First Published Online February 15, 2005

Abbreviations: 17OHD, 17-Hydroxylase deficiency; RFLP, restriction fragment length polymorphism.

Received October 19, 2004.

Accepted February 4, 2005.


   References
Top
 Abstract
 Introduction
 Patient and Methods
 Results
 Discussion
 References
 

  1. Biglieri EG, Herron MA, Brust N 1966 17-Hydroxylation deficiency in man. J Clin Invest 45:1946–1954
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