We present two cases of 17-alpha hydroxylase deficiency (17OHD), a rare cause of congenital adrenal hyperplasia (1%); our patients are first cousins (their fathers are brothers). Genetically female patients with congenital adrenal hyperplasia due to 17OHD represent with sexual infantilism, hypertension, while genetically male patients represent with male pseudohermaphroditisim and, hypertension at pubertal age. The cousins presented to our Endocrinology and Metabolism Department with primary amenorrhea and hypertension at different times at age of 18 and 22 and their karyotypes were 46, XX and 46, XY, respectively. 17OHD was diagnosed with clinical findings and laboratory investigations. Blood pressure was improved with glucocorticoid therapy and the development of secondary sexual characteristics was enhanced with estrogen therapy.Turk Jem 2010; 14: 73-5
Key words: 17- Alpha Hydroxylase, adrenal
17 alfa hidroksilaz eksikliği konjenital adrenal hiperplazilerin nadir görülen bir formudur. Bu enzim defektine sahip genetiği kız olan olgular pubertal dönemde seksüel infantilizm ve hipertansiyon, genetiği erkek olan olgular ise erkek psödohermafroditizm ve hipertansiyon ile ortaya çıkabilirler. Tüm konjenital adrenal hiperplazililerin %1 ini oluşturan 17 alfa hidroksilaz eksikliği olan bu olgular nadir görülmesi ve amca çocukları olmaları nedeniyle sunulmuştur. Gaziantep Üniversitesi Tıp Fakültesi Endokrinoloji ve Metabolizma Polikliniği ne primer amenore ve hipertansiyon nedeniyle değişik zamanlarda başvuran 18 ve 22 yaşlarında amca kızı olan, karyotipleri sırası ile 46,XX ve 46,XY olan iki olguda klinik ve laboratuar bulgular ile 17 alfa hidroksilaz eksikliği tanısı konuldu. Replasman tedavileri ile kan basıncında düzelme ve sekonder seksüel karakterlerde gelişme sağlandı. Türk Jem 2010; 14: 73-5
Anahtar kelimeler: 17- Alfa Hidroksilaz, adrenal
Congenital adrenal hyperplasia (CAH) resulting from 17-alpha hydroxylase deficiency (17OHD) is a rare autosomal recessive disorder with an estimated incidence of about 1:50.000- 1:100.00 in newborns (1). 17OHD accounts for approximately 1% of all forms of CAH. The classic syndrome caused by 17OHD is characterized by hypertension, hypokalemia and suppression of sexual hormones resulting in sexual infantilism. In the adrenals, testosterone and cortisol production pathways are blocked because of 17OHD. In addition to this, adrenocorticotropic hormone arises and the levels of mineralocorticoids - except aldosterone - become much higher causing hypertension and hypokalemia. In the gonads, 17OHD leads to suppressed sex steroids followed by an increase in gonadotropin levels and development of hypergonadotropic hypogonadism in these patients. In patients with XY karyotype, male pseudohermaphroditism occurs as a result of absent adrenal and gonadal androgen production. In XX karyotype patients, sexual infantilism and primary amenorrhea occur as a result of absent estrogen production in the ovaries. 17OHD has an autosomal recessive heritage and cytochrome P450c17 enzyme gene locus is 10q24-q25. This gene expresses in the adrenal glands and gonads (2,3). Nearly 50 mutations were described for this gene (3,4). 17OHD can be diagnosed with genetic analysis additional to clinical and laboratory findings. Therapy begins with replacement of glucocorticoids. Multidisciplinary approach must be adopted to determine secondary sexual characteristics. We present here two cousins (their fathers are brothers) with 17OHD, one of them is genetically female and the other genetically male.
An unmarried 18-year-old female patient visited the Department of Endocrinology and Metabolism in 2009 because of hypertension (140-160/100-110 mmHg) lasting for 2 years and primary amenorrhea. We learned that her elder sister and her cousins had similar complaints. Physical examination showed that her height was 160 cm, weight 60 kg and blood pressure was 150/100 mmHg. Tanner stage I breast development, absent axillary and absent pubic hair and external genitalia were the infantile female characteristics.
The serum levels of estradiol (E2), testosterone (T), dehydroepiandrosterone-sulfate (DHEA-S), potassium (K), cortisol were reduced, while the serum levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), progesterone (P), ACTH were increased (for details see Table I). Pelvic MR revealed band- like atrofic uterus and nodulary developments of 11X17 mm in the left and 14X13 mm in the right adnexial area suggestive for ovaries. Cortisol, DHEAS and 17OHP showed no response to ACTH stimulation test. The patient had normal female karyotype (46,XX). This case who was sexually infantile, had hypertension and hypergonadotrophic hypogonadism, was diagnosed with 17OHD. Prednisolone was initiated at a dose of 5 milligrams a day. Cyclic estrogen and progesterone therapy was given with glucocorticoid for maturation of secondary sexual characteristics. After the first month of therapy, blood pressure normalized.
An unmarried 22-year-old female patient visited the Department of Endocrinology and Metabolism in 2002 because of hypertension (140-150/100-110 mmHg) lasting for 4 years and primary amenorrhea. We learned that she was taller than her girlfriends at the same age since she was seven years old. One of her sisters died twenty seven days after birth and the other one died at nine months old; her cousin had similar complaints. Physical examination showed that her height was 180 cm, weight -71 kg, and blood pressure was 150/100 mmHg. Tanner stage I breast development, absent axillary and pubic hair and external genitalia were the infantile female characteristic.
The serum levels of E2, T, DHEA-S, K, and cortisol were reduced, while serum levels of LH, FSH, P, ACTH were increased (for details see Table 2). Pelvic US showed hypoplastic uterus and, very small ovaries. Cortisol, DHEAS and 17OHP did not respond to ACTH stimulation test. Her karyotype was 46,XY. This case who was sexually infantile, had hypergonadotrophic hypogonadism with male pseudohermaphroditism and hypokalemic hypertension was diagnosed as having 17OHD. Prednisolone was initiated at a dose of 5 milligrams a day. Vaginoplasty was performed because she wanted to live as a female fort he rest of her life. Gonadectomy was made due to probability of malignancy development; pathology report revealed atrophic testis. Cyclic estrogen and progesterone therapy was given with glucocorticoid for maturation of secondary sexual characteristics. After - the first month of therapy, blood pressure normalized. At later follow-up visit, it was seen that breast development started as well as, axillary and pubic hair development.
The classical clinical presentation of 17OHD is hypertension, hypokalemia, and infantilism of secondary sexual characteristics. All of these findings existed in case 2 and, except for hypokaelemia, in case 1. The effected genetically male individuals may have absolutely female fenotype or rarely ambiguous genitalia (3,5). The degree of impaired masculinization is related to fetal testosterone levels depending on the amount of 17-alpha hydroxylation blockade. Analysis of enzymatic activity has shown that more than 25% of normal activity is necessary for normal fetal masculinization of the external genitalia (1,6). Although case 2 was genetically male, her fenotype was absolutely female; we had no facility to evaluate the enzymatic activity of our patient.
In 17OHD, decreased cortisol secretion causes increased ACTH production, which results in overproduction of 17-deoxysteroids (DOC, corticosterone and 18-hydroxycorticosterone) by the adrenal cortex. 18-hydroxycorticosterone levels were normal in our patients, while serum progesterone, one of the 17a-hydroxylase substrates and a useful marker in the diagnosis of 17OHD, was elevated in both of our patients.
Most patients with 17OHD have very low or subnormal production of aldosterone (8,9). Overproduction of DOC suppresses renin-angiotensin system and inhibits aldosterone production. Aldosterone levels were normal in our patients. The last level to diagnose 17OHD in these patients, being relatives, was genetic analysis, which could not be done because of limited facilities. Nearly 50 different mutations in CYP17 have been reported since 1988 (8).
Hypertension can be improved in 17OHD patients by glucocorticoid therapy (9). Additive therapy with a mineralocorticoid antagonist like spironolactone can provide better blood pressure control. If blood pressure can not be controlled with inhibition of mineralocorticoid production/effect, calcium channel blockers can be added to the therapy (7). The other target of therapy in these patients is to help the development of secondary sexual characters. Estrogen replacement therapy can be used for this aim and, with this therapy, the final height can be reduced (10). Prophylactic gonadectomy must be performed to genetically male patients because of malign transformation. Female sex assignment was continued in our chromosomally male patient due to established psychosexual development and identity. Estrogen replacement therapy was given for induction of female secondary sex characteristics. Since 17OHD is a rare condition, we intended to present two interesting cases of cousins having this rare disorder. 17OHD must be considered in patients with hypokaelemic hypertension and sexual infantilism.
Address for Correspondence: Müge Özsan MD, University of Gaziantep, Endocrinology and Metabolism, Gaziantep, Turkey E-mail: email@example.com Recevied: 30.09.2010 Accepted: 23.11.2010
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