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17α-Hydroxylase deficiency; a rare cause of chronic hypertension
The Netherlands
JOUFWAL OF M E D ICINE ELSEVIER
NetherlandsJournal of Medicine 49 (1996) 205-208
Brief report
17wHydroxylase deficiency; a rare cause of chronic hypertension P.E. Spronk a,* , F. Bergkamp b, R.W. ten Kate a ’ Department of Internal Medicine, Kennemer Gasthuis (EGI. Boerhaauelaan 22,2035 RC Haarlem, Netherlands b Department of Clinical Chemistry, Kennemer Gasthuis (EGJ, Boerhaacelaan 22, 2035 RC Haarlem. Netherlands
Received 11 April 1996; revised 26 June 1996; accepted10 July 1996
AiMact We demonstrate a case with 17cx-hydroxylase deficiency that presented in an unusual way. The steroid metabolism and diagnostic procedures are discussed. Keywords: 17cx-Hydroxylasedeficiency; Hypertension
1. Introduction The presence of 17cx-hydroxylase deficiency is characterized by hypertension, hypokalaemia, and an excess of mineralocorticoids. Other clinical signs include primary amenorrhoea and the absence of secondary sex characteristics [ 1,2]. This enzymatic deficiency is a rare cause of congenital adrenal hyperplasia. Recognition of this syndrome is important in view of the differences in treatment when compared with other causes of hypertension.
2. Case description A woman 34 years old was seen in the outpatient clinic because of scheduled surgery on her mandibula. At the age of 18 she had visited the gynaecologist because of the persistent absence of menses and secondary sex characteristics. Regular menstruation was ensured after starting oral contraceptive medica* Correspondingauthor. Fax ( + 3 l-23) 5350627.
tion. Hypertension was also present. Renal arteriography was performed. As it proved to be normal, the patient was treated with antihypertensive medication for several years. In the subsequent period she was not willing to take any medication, until her present visit to our outpatient clinic. At presentation there were no complaints. Besides oral contraceptive medication she did not use any drugs (i.e., no diuretics were used). Physical examination revealed a pulse of 80 beats/min and a blood pressure of 185/115 mmHg. Examination of eye fundi showed hypertensive retinopathy grade II. Bruits over the renal artery were not present. Other clinical findings were normal. Laboratory analysis showed hypokalaemia (2.8 mmol/l) and alkalosis (bicarbonate 33.4 mmol/l) (Table 1). Plasma prorenin levels were markedly decreased (8 nmol/l; normal range 99-247 nmol/l). Urinary aldosterone secretion was normal (14 nmo1/24 h, normal range 1 l-55 nmo1/24 h). Hence, primary hyperaldosteronism could be excluded (Fig. I), and plasma levels of several steroid metabolites were measured (Fig. 2, Table 1). Results indicated deficiency of 17cw-hy-
0300-2977/96/:El5.00 Copyright 0 1996 Elsevier Science B.V. All rights reserved. I’II SO300-29’77(96)00047-2
ACTH
pregnenolone + low Potassium [no diuretics)
progesterone : *+
plasma renin \ /
ll-Dot c
tow
high
I
corttcosterone
I
k.renalis stenosis? high I primary aldosteronism
I normal I tow K Intake (rare)
dehydroepi ondrosterone
6~zEe-
rZ+LZE
andro$tenediOne j
1 I cleoxy co(tisoI 4
testosterone
cortisol 1
urine aldosterone /
+$-+
1 \
oestrad~ol
i aldosterone
low I hydroxyiation deficiency (17 alfa/beta 01 beta] DOC producing tumor cortisol resistency excessive liquorice
Fig. 1. Description of several possibilities if endocrine hypertension is suspected.
Fig. 2. Description of the steroid biosynthesis pathway, regulated (in part) by pituitary production of ACTH. The crosses indicate enzymatic blocks due to l7cu-hydroxylase deficiency. Das@d lines indicate some intermediate metabolites of which no plasma levels were available. DOC = desoxycorticosterone; OH = hydroxy. Metabolites found in particularly high levels due to enzymatic blocking are indicated in bold lettering.
Table I Levels of electrolytes and steroid metabolites in plasma and urine before and after treatment with dexamethasone in a patient with 17ol-hydroxylase deficiency
Ekwoljm Nat
K. Bicarbonate Urea Creatinine PH
After therapy
135-145 mmol/l
142 2.6
140 4.3 99.8 27.3 7.3 8s 7.37
98.5 33.4
5.1 66 7.44
(plasma)
ACTH Pregnenolone 1 i-Deoxycorticosterone (DOC) I &Deoxycorticosterone Corticosterone Aldosterone 17.Hydroxypregnenolone Dehydrepiandrosterone 11-Deoxycortisol Cortisol Testosterone 17P-Oestrogens NA = not available.
Before therapy
3.5-4.5 mmol/l 89-98 mmol/l 22-27 mmol/l 3.5-7.8 mmol/l 64- 118 pmol/l 7.38-7.42
Cl
Steroid nzrtuholism
Normal range
IO-100 rig/l 1.3-20.8 nmol/l 0.2-0.5 nmol/l 0.03-1.00 nmol/l 15-45 nmol/l O-O.35 nmol/l O-35 nmol/l 9-46 pmol/l 3-10 nmol/l 100-500 mnol/l I-10 pmol/l 0.1-0.9 nmol/l
132 14 9.0
10 5.6
11
NA
720 0.09 0.2
20 1.10 0.4 0.2 < 0.1
0.1 2.9 10
1.2
NA < 0.1
P.E. Spr-onk et al./Nether-lands Journal of Medicine 49 (1996) 205-208
droxylase, an inborn error of adrenal metabolism. Treatment with dexamethasone 1 mg once daily resulted in normalisation of ACTH, levels of mineralocorticoid hormones, hypokalaemia, and alkalosis (Table 1). Six months after starting therapy with dexamethasone, registration of blood pressure during 24 h revealed mean values of 150/90 mmHg. Hypertensive retinopathy had disappeared. Additional information regarding her family could not be obtained, but her sister might have been treated elsewhere for infertility.
3. Discussion Deficiency of 17o-hydroxylase is a rare cause of congenital adrenal hyperplasia, comprising only 1% of all possible causes [3]. Changes in the so-called CYP17 gene, encoding mitochondrial cytochrome P450 with both 17o-hydroxylase and 17,20-lyase activity, result in decreased levels of both these enzymes. A number of mutations in this particular gene have been described resulting in cases with homozygous single mutations as well as cases that are heterozygous for two mutations [4]. Transcription takes place in testes and adrenal glands [51. Deficiency of 17or-hydroxylase results in low levels of cortisol. Concomitant deficiency of 17,20-lyase blocks normal production of androgens and oestrogens (Fig. 2). Due to these low levels of cortisol and sex hormones, a specific clinical picture emerges. Low levels of cortisol stimulate the production of high levels Iof ACTH by the pituitary gland with subsequent adrenal hyperplasia. High levels of mineralocorticoid steroids like desoxycorticosterone (DOC) and corticosterone result in sodium retention, renal loss of potassium and subsequent severe hypertension (Fig. 2). The presence of 1‘lo-hydroxylase deficiency should be considered in the case of hypertension with concomitant low levels of potassium and renin. Despite the absence of enzymatic blocking, it should be noted that levels of aldosterone are frequently decreased due to the DOC-induced hypertension, suppression of renin production, and hypokalaemia. This hypokalaemia can be life-threatening. Villabona et al. described a patient with 17o-hydroxylase deficiency who developed a tetraparesis due to severe
207
hypokalaemia requiring mechanical ventilation. Rapid improvement was seen after treatment with dexamethasone and potassium [6]. As mentioned above, deficiency of 17a-hydroxylase also leads to disturbances in sexual development. Testosterone is almost absent in males, resulting in incomplete masculinisation and frequent designation to the female sex. Surgical construction of a vagina may be necessary, while undescended testes should be removed because of the risk of developing testicular tumours [7]. Affected females may be undetected at birth since primary sex characteristics are normal. In puberty, however, female patients do not develop secondary sex characteristics and have primary amenorrhoea [7]. Treatment should be started with glucocorticoids (like dexamethasone) to restore adequate regulatory feedback to the pituitary gland. In addition, sex steroids, depending on the sex of rearing, should be started in puberty to ensure the development of secondary sex characteristics. As demonstrated in this case, this combination therapy normalizes levels of mineralocorticoids and potassium, blood pressure and the menstrual cycle. However, in a long-term study in 3 siblings with 17ct-hydroxylase deficiency who were treated with chronic (8 years) low-dose glucocorticoids, electrolyte disorders were corrected, but blood pressure normalized in 2 cases whereas it was only reduced in the third [8]. We have demonstrated a classic disturbance of steroid metabolism. In young female patients with hypertension, low potassium levels and the absence of secondary sex characteristics the presence of 17a-hydroxylase deficiency should be suspected. The recognition of this rare disease entity is important because treatment with glucocorticoids instead of antihypertensive medication is required. Although endocrine causes of hypertension are rare, this case illustrates the surprising way in which these patients may present at the outclinic.
References [I] Goldsmith 0, Solomon DH, Horton R. Hypogonadism and mineralocorticoid excess. The 17-hydroxylase deficiency syndrome. N Engl J Med 1967;277:673-677. [2] Birkenhager WH, Reid JL, eds. Handbook of hypertension. Amsterdam: Elsevier. 1992: 15:420-460.
[3] Kater CE, Biglieri EG. Disorders of steroid 17.alpha-hydrox ylase deficiency. Endocrinol Metab Clin N Am lY94;23:341357. [4] New MI, White PC. Steroid hormone synthesis and metabolism. Bailhere’s Clin Endocrinol Metabol 1995:9:525S 554. [5] Chung BC, Picado-Leonard J, Hainu M, et al. Cytochrome P45Oc17 (steroid 17.alpha-hydroxylase/ 17,20-lyase): cloning of human adrenal testis cDNA indicates the same gene is expressed in both tissues. Proc Nat1 Acad Sci USA lYX7;84:407.
[6] Villabona C, Kodriguez P, Joven J, et al. Potassium disturbance\ as a cause of metabolic neuromyopathy. Intens Care Med 1Y87: 13:20X-2 IO. [7] New Ml. Male pwudohermaphroditism due to 17.alpha-hydroxylase deficiency. J Clin Invest 1970;49: I Y30- 194 I. [g] Scaroni C. Biason A, Carpenc G, et al. 17.Alpha-hydroxylase deficiency in three siblings: short- and long-term studies. J Endocrind Inve\t I YY I : 14:YY 108.
JOUFWAL OF M E D ICINE ELSEVIER
NetherlandsJournal of Medicine 49 (1996) 205-208
Brief report
17wHydroxylase deficiency; a rare cause of chronic hypertension P.E. Spronk a,* , F. Bergkamp b, R.W. ten Kate a ’ Department of Internal Medicine, Kennemer Gasthuis (EGI. Boerhaauelaan 22,2035 RC Haarlem, Netherlands b Department of Clinical Chemistry, Kennemer Gasthuis (EGJ, Boerhaacelaan 22, 2035 RC Haarlem. Netherlands
Received 11 April 1996; revised 26 June 1996; accepted10 July 1996
AiMact We demonstrate a case with 17cx-hydroxylase deficiency that presented in an unusual way. The steroid metabolism and diagnostic procedures are discussed. Keywords: 17cx-Hydroxylasedeficiency; Hypertension
1. Introduction The presence of 17cx-hydroxylase deficiency is characterized by hypertension, hypokalaemia, and an excess of mineralocorticoids. Other clinical signs include primary amenorrhoea and the absence of secondary sex characteristics [ 1,2]. This enzymatic deficiency is a rare cause of congenital adrenal hyperplasia. Recognition of this syndrome is important in view of the differences in treatment when compared with other causes of hypertension.
2. Case description A woman 34 years old was seen in the outpatient clinic because of scheduled surgery on her mandibula. At the age of 18 she had visited the gynaecologist because of the persistent absence of menses and secondary sex characteristics. Regular menstruation was ensured after starting oral contraceptive medica* Correspondingauthor. Fax ( + 3 l-23) 5350627.
tion. Hypertension was also present. Renal arteriography was performed. As it proved to be normal, the patient was treated with antihypertensive medication for several years. In the subsequent period she was not willing to take any medication, until her present visit to our outpatient clinic. At presentation there were no complaints. Besides oral contraceptive medication she did not use any drugs (i.e., no diuretics were used). Physical examination revealed a pulse of 80 beats/min and a blood pressure of 185/115 mmHg. Examination of eye fundi showed hypertensive retinopathy grade II. Bruits over the renal artery were not present. Other clinical findings were normal. Laboratory analysis showed hypokalaemia (2.8 mmol/l) and alkalosis (bicarbonate 33.4 mmol/l) (Table 1). Plasma prorenin levels were markedly decreased (8 nmol/l; normal range 99-247 nmol/l). Urinary aldosterone secretion was normal (14 nmo1/24 h, normal range 1 l-55 nmo1/24 h). Hence, primary hyperaldosteronism could be excluded (Fig. I), and plasma levels of several steroid metabolites were measured (Fig. 2, Table 1). Results indicated deficiency of 17cw-hy-
0300-2977/96/:El5.00 Copyright 0 1996 Elsevier Science B.V. All rights reserved. I’II SO300-29’77(96)00047-2
ACTH
pregnenolone + low Potassium [no diuretics)
progesterone : *+
plasma renin \ /
ll-Dot c
tow
high
I
corttcosterone
I
k.renalis stenosis? high I primary aldosteronism
I normal I tow K Intake (rare)
dehydroepi ondrosterone
6~zEe-
rZ+LZE
andro$tenediOne j
1 I cleoxy co(tisoI 4
testosterone
cortisol 1
urine aldosterone /
+$-+
1 \
oestrad~ol
i aldosterone
low I hydroxyiation deficiency (17 alfa/beta 01 beta] DOC producing tumor cortisol resistency excessive liquorice
Fig. 1. Description of several possibilities if endocrine hypertension is suspected.
Fig. 2. Description of the steroid biosynthesis pathway, regulated (in part) by pituitary production of ACTH. The crosses indicate enzymatic blocks due to l7cu-hydroxylase deficiency. Das@d lines indicate some intermediate metabolites of which no plasma levels were available. DOC = desoxycorticosterone; OH = hydroxy. Metabolites found in particularly high levels due to enzymatic blocking are indicated in bold lettering.
Table I Levels of electrolytes and steroid metabolites in plasma and urine before and after treatment with dexamethasone in a patient with 17ol-hydroxylase deficiency
Ekwoljm Nat
K. Bicarbonate Urea Creatinine PH
After therapy
135-145 mmol/l
142 2.6
140 4.3 99.8 27.3 7.3 8s 7.37
98.5 33.4
5.1 66 7.44
(plasma)
ACTH Pregnenolone 1 i-Deoxycorticosterone (DOC) I &Deoxycorticosterone Corticosterone Aldosterone 17.Hydroxypregnenolone Dehydrepiandrosterone 11-Deoxycortisol Cortisol Testosterone 17P-Oestrogens NA = not available.
Before therapy
3.5-4.5 mmol/l 89-98 mmol/l 22-27 mmol/l 3.5-7.8 mmol/l 64- 118 pmol/l 7.38-7.42
Cl
Steroid nzrtuholism
Normal range
IO-100 rig/l 1.3-20.8 nmol/l 0.2-0.5 nmol/l 0.03-1.00 nmol/l 15-45 nmol/l O-O.35 nmol/l O-35 nmol/l 9-46 pmol/l 3-10 nmol/l 100-500 mnol/l I-10 pmol/l 0.1-0.9 nmol/l
132 14 9.0
10 5.6
11
NA
720 0.09 0.2
20 1.10 0.4 0.2 < 0.1
0.1 2.9 10
1.2
NA < 0.1
P.E. Spr-onk et al./Nether-lands Journal of Medicine 49 (1996) 205-208
droxylase, an inborn error of adrenal metabolism. Treatment with dexamethasone 1 mg once daily resulted in normalisation of ACTH, levels of mineralocorticoid hormones, hypokalaemia, and alkalosis (Table 1). Six months after starting therapy with dexamethasone, registration of blood pressure during 24 h revealed mean values of 150/90 mmHg. Hypertensive retinopathy had disappeared. Additional information regarding her family could not be obtained, but her sister might have been treated elsewhere for infertility.
3. Discussion Deficiency of 17o-hydroxylase is a rare cause of congenital adrenal hyperplasia, comprising only 1% of all possible causes [3]. Changes in the so-called CYP17 gene, encoding mitochondrial cytochrome P450 with both 17o-hydroxylase and 17,20-lyase activity, result in decreased levels of both these enzymes. A number of mutations in this particular gene have been described resulting in cases with homozygous single mutations as well as cases that are heterozygous for two mutations [4]. Transcription takes place in testes and adrenal glands [51. Deficiency of 17or-hydroxylase results in low levels of cortisol. Concomitant deficiency of 17,20-lyase blocks normal production of androgens and oestrogens (Fig. 2). Due to these low levels of cortisol and sex hormones, a specific clinical picture emerges. Low levels of cortisol stimulate the production of high levels Iof ACTH by the pituitary gland with subsequent adrenal hyperplasia. High levels of mineralocorticoid steroids like desoxycorticosterone (DOC) and corticosterone result in sodium retention, renal loss of potassium and subsequent severe hypertension (Fig. 2). The presence of 1‘lo-hydroxylase deficiency should be considered in the case of hypertension with concomitant low levels of potassium and renin. Despite the absence of enzymatic blocking, it should be noted that levels of aldosterone are frequently decreased due to the DOC-induced hypertension, suppression of renin production, and hypokalaemia. This hypokalaemia can be life-threatening. Villabona et al. described a patient with 17o-hydroxylase deficiency who developed a tetraparesis due to severe
207
hypokalaemia requiring mechanical ventilation. Rapid improvement was seen after treatment with dexamethasone and potassium [6]. As mentioned above, deficiency of 17a-hydroxylase also leads to disturbances in sexual development. Testosterone is almost absent in males, resulting in incomplete masculinisation and frequent designation to the female sex. Surgical construction of a vagina may be necessary, while undescended testes should be removed because of the risk of developing testicular tumours [7]. Affected females may be undetected at birth since primary sex characteristics are normal. In puberty, however, female patients do not develop secondary sex characteristics and have primary amenorrhoea [7]. Treatment should be started with glucocorticoids (like dexamethasone) to restore adequate regulatory feedback to the pituitary gland. In addition, sex steroids, depending on the sex of rearing, should be started in puberty to ensure the development of secondary sex characteristics. As demonstrated in this case, this combination therapy normalizes levels of mineralocorticoids and potassium, blood pressure and the menstrual cycle. However, in a long-term study in 3 siblings with 17ct-hydroxylase deficiency who were treated with chronic (8 years) low-dose glucocorticoids, electrolyte disorders were corrected, but blood pressure normalized in 2 cases whereas it was only reduced in the third [8]. We have demonstrated a classic disturbance of steroid metabolism. In young female patients with hypertension, low potassium levels and the absence of secondary sex characteristics the presence of 17a-hydroxylase deficiency should be suspected. The recognition of this rare disease entity is important because treatment with glucocorticoids instead of antihypertensive medication is required. Although endocrine causes of hypertension are rare, this case illustrates the surprising way in which these patients may present at the outclinic.
References [I] Goldsmith 0, Solomon DH, Horton R. Hypogonadism and mineralocorticoid excess. The 17-hydroxylase deficiency syndrome. N Engl J Med 1967;277:673-677. [2] Birkenhager WH, Reid JL, eds. Handbook of hypertension. Amsterdam: Elsevier. 1992: 15:420-460.
[3] Kater CE, Biglieri EG. Disorders of steroid 17.alpha-hydrox ylase deficiency. Endocrinol Metab Clin N Am lY94;23:341357. [4] New MI, White PC. Steroid hormone synthesis and metabolism. Bailhere’s Clin Endocrinol Metabol 1995:9:525S 554. [5] Chung BC, Picado-Leonard J, Hainu M, et al. Cytochrome P45Oc17 (steroid 17.alpha-hydroxylase/ 17,20-lyase): cloning of human adrenal testis cDNA indicates the same gene is expressed in both tissues. Proc Nat1 Acad Sci USA lYX7;84:407.
[6] Villabona C, Kodriguez P, Joven J, et al. Potassium disturbance\ as a cause of metabolic neuromyopathy. Intens Care Med 1Y87: 13:20X-2 IO. [7] New Ml. Male pwudohermaphroditism due to 17.alpha-hydroxylase deficiency. J Clin Invest 1970;49: I Y30- 194 I. [g] Scaroni C. Biason A, Carpenc G, et al. 17.Alpha-hydroxylase deficiency in three siblings: short- and long-term studies. J Endocrind Inve\t I YY I : 14:YY 108.