1 Department of Obstetrics and Gynaecology and 2 Department of Clinical Chemistry and Haematology, Amphia Hospital Langendijk, Breda and 3 Department of Internal Medicine, Section of Endocrinology, Erasmus MC, Rotterdam, The Netherlands
4 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Amphia Hospital Langendijk, 3019 EV Breda, The Netherlands. e-mail: mtkate{at}amphia.nl
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: gene mutation/17,20-lyase deficiency/ovarian cysts/P450c17
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
![]() |
Case report |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
Confirmation of the enzyme defect
Based on hormone data from the index case and the enzyme deficiency in her sister, a defective CYP17 gene was expected in the index patient, causing isolated defective 17,20-lyase activity (Figure 1). In order to confirm a genetic disorder, DNA from blood lymphocytes from both the index patient and her mother was analysed for mutations in this gene using methods described previously (Van den Akker et al., 2002). The index patient was shown to be compound heterozygote for the same combination of two mutations in the CYP17 gene found earlier in her sister: a missense R347C (CGT
TGT) point mutation and a 25-base pair (bp) deletion in exon 1 (nucleotides 204228 of the coding sequence). The 25 bp deletion was demonstrated in the DNA of the mother, making it likely that the children had inherited the R347C mutation from their father.
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
The steroid levels in the samples of cyst fluid reflected the enzyme defect: relatively normal levels of progesterone and 17-OHP were accompanied by strongly suppressed levels of androstenedione, testosterone and estradiol. The ratio between the sum of the mean concentrations of these three hormones on the one hand and 17OHP on the other was at least 500-fold lower compared with data reported elsewhere (diZerega et al., 1983).
The majority of cases with either combined or isolated 17-hydroxylase/17,20-lyase deficiencies described so far have been male pseudohermaphrodites with ambiguous or female external genitalia (Zachmann et al., 1982
; Oei et al., 1995
). One group (Biglieri et al., 1966
) were the first to describe 17
-hydroxylase deficiency in a female individual with primary amenorrhoea, and a case study was subsequently reported (Mallin, 1969
) concerning two sisters with amenorrhoea, hypokalaemia, hypertension and cystic ovaries, based on 17
-hydroxylase deficiency. An absence of the enzyme led to a deficient sex steroid synthesis on the one hand and a reduced cortisol synthesis on the other hand. Another group (Pertzeran et al., 1981
) described a 15-year-old girl with an absence of sexual development, polycystic ovaries and hypertension due to 17
-hydroxylase deficiency. Finally, a report was made about a female individual with hypergonadotrophic hypogonadism due to 17,20-lyase deficiency (Larrea et al., 1983
), while others (Pellicer et al., 1991
) described a female patient with 17,20-lyase deficiency in combination with hypogonadotrophic hypogonadism.
The hyperstimulated ovaries with cysts in the present patient presumably resulted from elevated FSH and LH levels secondary to the lack of estrogens. These high levels of FSH and LH may have caused the stimulation of growth of follicles in the ovaries and therefore the increased serum levels of progesterone and 17-OHP. Initially, the girl was treated with an oral contraceptive to suppress gonadotrophins, but within a few weeks after the laparoscopy she had suffered again from episodic abdominal pain caused by enlarged ovarian cysts, probably because the estrogen dose was inadequate to suppress the gonadotrophin levels. As a higher estrogen dose might have created a risk to the girls final body height, she was further treated with a GnRH antagonist in order to suppress the cysts rapidly. Later, treatment was switched to a GnRH agonist in combination with estrogens in order to initiate sexual development. After suppression of the gonadotrophins with the GnRH-agonist, concentrations of progesterone and 17-OHP were each reduced to levels comparable with those in the gonadectomized sister. If the girl had not developed enlarged ovaries, she would most likely have been referred some years later with primary amenorrhoea and an absence of any signs of puberty.
In the present patient, the synthesis of cortisol was not (or was only slightly) impaired under basal circumstances, because of residual 17-hydroxylase activity. An ACTH stimulation test showed a low to normal basal level of cortisol, which did not respond to ACTH (Table II), and this was suggestive of a partial 17
-hydroxylase deficiency. It is questionable whether this could be regarded as a mild form of glucocorticoid insufficiency, as the adrenal glands should be able to produce corticosterone, which also has glucocorticoid activity.
Questions remain about the girls chances of future pregnancy, however. Based on the results of a previous study (Schoot et al., 1994), it was apparent that ovarian stimulation with recombinant FSH in hypogonadotrophic women resulted in ovarian follicle development to the pre-ovulatory stage, with no or only a minor increase in estradiol concentrations. Others (Rabinovici et al., 1989
; Pellicer et al., 1991
) described successful IVF after oocyte retrieval from women with combined 17
-hydroxylase/17,20-lyase and 17,20-lyase deficiency respectively. Hence, it cannot be taken for granted that a lack of endogenous estrogen production automatically leads to a failure of follicular maturation. An important point here is how to deal with the ethical dilemmas related to the inheritance of a disease in case of reproduction.
In conclusion, the present case report illustrates the clinical expression of an identical rare genetic disorder in a female and a male proband. Both were compound heterozygotes for the same mutations in the CYP17, gene resulting in a 17,20-lyase deficiency, and as a consequence the circulating levels of sex steroids were either absent or extremely low. Although for both children this had medical and emotional implications, the clinical picture of the mutations was completely different. The boy was reared as a girl based on his female phenotype, whereas in the girl the increased gonadotrophin levels gave rise to formation of ovarian cysts, which necessitated permanent suppression of pituitary secretion of LH and FSH. At present, these patients with GnRH analogues can be treated and their ovaries preserved.
![]() |
Acknowledgements |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
Biason-Lauber A, Kempken B, Werder E, Forest MG, Einaudi S, Ranke MB, Matsuo N, Brunelli V, Schonli EJ and Zachmann M (2000) 17-Hydroxylase/17,20-lyase deficiency as a model to study enzymatic activity regulation: role of phosphorylation. J Clin Endocrinol Metab 85,12261231.
Biglieri EG, Herron MA and Brust N (1966) 17-Hydroxylation deficiency in man. J Clin Invest 45,19461954.[ISI][Medline]
diZerega GS, Campeau JD, Nakamura RN, Ujita EL, Lobo R and Marrs RP (1983) Activity of a human follicular fluid protein(s) in spontaneous and induced ovarian cycles. J Clin Endocrinol Metab 57,838846.[Abstract]
Geller DH, Auchus RJ and Miller WL (1999) P450c17 mutations R347H and R358Q selectively disrupt 17,20-lyase activity by disrupting interactions with P450 oxidoreductase and cytochrome b5. Mol Endocrinol 13,167174.
Goebelsmann U, Zachmann M, Davajan V, Israel R, Metsman IH and Mishell DR (1976) Male pseudohermaphroditism consistent with 17,20 desmolase deficiency. Gynecol Invest 7,138156.[ISI][Medline]
Katsumata N, Satof M, Mikami A, Mikami S and Nagashima-Miyokawa A (2001) New compound heterozygous mutation in the CYP17 gene in a 46,XY girl with 17-hydroxylase/17,20-lyase deficiency. Horm Res 55,141146.[CrossRef][ISI][Medline]
Larrea F, Lisker R, Banuelos R, Bermudez JA, Herrera J, Rasilla VN and Perez-Palacios G (1983) Hypergonadotrophic hypogonadism in an XX female subject due to 17,20 steroid desmolase deficiency. Acta Endocrinol (Kbh) 103,400405.
Mallin SR (1969) Congenital adrenal hyperplasia secondary to 17-hydroxylase deficiency: two sisters with amenorrhea, hypokalemia, hypertension, and cystic ovaries. Ann Intern Med 70,6972.[ISI][Medline]
Miller WL, Auchus RJ and Geller DH (1997) The regulation of 17,20 lyase activity. Steroids 62,133142.[CrossRef][ISI][Medline]
Oei SG, Derksen J, Weusten JJAM, Lentjes EGWM and Helmerhorst FM (1995) A case of 16-ene-synthetase deficiency in male pseudo hermaphroditism due to combined 17-hydroxylase/17,20-lyase deficiency. Eur J Endocrinol 132,281285.[ISI][Medline]
Pellicer A, Miro F, Sampaio M, Gomez E and Bonilla-Musoles FM (1991) In vitro fertilization as a diagnostic and therapeutic tool in a patient with partial 17,20-desmolase deficiency. Fertil Steril 55,970975.[ISI][Medline]
Pertzeran A, Kaufman H, Kraiem Z and Laron Z (1981) 17-hydroxylase deficiency in an adolescent girl. Acta Paediatr Belg 34,263267.
Rabinovici J, Blankstein J, Goldman B, Rudak E, Dor Y, Pariente C, Geier A, Lunenfeld B and Mashiach S (1989) In vitro fertilization and primary embryonic cleavage are possible in 17-hydroxylase deficiency despite extremely low intrafollicular 17
-estradiol. J Clin Endocrinol Metab 68,693697.[Abstract]
Schoot DC, Harlin J, Shoham Z, Mannaerts BMJL, Coelingh Bennink HJT and Fauser BCJM (1994) Recombinant human follicle-stimulating hormone and ovarian response in gonadotrophin-deficient women. Hum Reprod 9,12371242.[Abstract]
Speroff L, Glass RH and Kase NG (eds) (1999) Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins, Baltimore.
Van den Akker ELT, Koper JW, Boehmer ALM, Themmen APN, Verhoef-Post M, Timmerman MA, Otten BJ, Drop SLS and Jong de FH (2002) Differential inhibition of 17-hydroxylase and 17,20-lyase activities by three novel missense CYP17 mutations identified in patients with P450c17 deficiency. J Clin Endocrinol Metab 87,57145721.
Zachmann M, Vollmin JA, Hamilton W et al. (1972) Steroid 17,20 desmolase deficiency: a new cause of male pseudohermaphrodism. Clin Endocrinol 1,369385.[Medline]
Zachmann M, Werder EA and Prader A (1982) Two types of male pseudohermaphroditism due to 17,20 desmolase deficiency. J Clin Endocrinol Metab 55,487490.[Abstract]
Submitted on May 9, 2003; resubmitted on July 25, 2003; accepted on September 29, 2003.