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17-Hydroxylase Deficiency

Editor: Maria Rosaria Muzio Updated: 1/3/2023 11:28:15 AM


Congenital adrenal hyperplasia (CAH) is a term covering a group of autosomal recessive disorders resulting from a deficiency of one of the required enzymes for steroid biosynthesis (cortisol, aldosterone, or both) in the adrenal glands. The most common etiology of CAH is a 21-hydroxylase deficiency due to mutations or deletions of CYP21A, which accounts for more than 90% of CAH cases. On the other hand, 17-hydroxylase deficiency is a rare cause of CAH, accounting for approximately 1% of cases.[1]

Among the CAH disorders, the particular phenotype that results depends on the sex of the individual, the type of deficit, and the severity of the deletion or genetic mutation. Unlike 21-hydroxylase deficiency, the 17-hydroxylase deficiency does not get identified by newborn screening and is typically identified later due to ambiguous genitalia, delayed sexual maturation, hypertension, or hypokalemia. In general, the 17-hydroxylase deficiency expresses as sexual infantilism in 46XX females and ambiguous genitalia in 46XY males.

This activity will focus on the etiology, epidemiology, and clinical features of this rare genetic disorder. Moreover, it will also cover the role of an interprofessional team for early diagnosis and prompt management.


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Congenital adrenal hyperplasia is an autosomal recessive disorder caused by one of several enzyme deficiencies. In particular, the 17-hydroxylase deficiency is a rare cause of CAH due to loss of function mutations in the CYP17A1 gene located on chromosome 10q24-q25.[2] Typically these mutations result in the loss of function of both 17-hydroxylase and 17,20-lyase activities. These activities mediate three key transformations in cortisol and sex steroid biosynthesis. In particular, 17-hydroxylase mediates the synthesis of 17-hydroxypregnenolone from pregnenolone, the 17-hydroxyprogesterone from progesterone, and the production of dehydroepiandrosterone (DHEA) from 17-hydroxypregnenolone. This latter step, mediated by 17,20-lyase, is of paramount importance since DHEA is considered the progenitor of steroid sex hormones.

Over 100 mutations in the CYP17A1 gene are known, with most resulting in complete loss of both enzymatic activities.[3] Researchers have also reported a partial loss of enzymatic activity and loss of either hydroxylase or lyase activity, but not both. Compound heterozygote patients also exist. Genotype and phenotype correlation remains uncertain with varying severity of disease even with the same mutation reported. Molecular genetic testing of the CYP17 gene is available for the detection of known mutations.


Congenital adrenal hyperplasia due to 17-hydroxylase deficiency represents only 1% of worldwide cases. The incidence of 17-hydroxylase deficiency is not well established but is estimated to be around 1 per 50000.[3] The disease prevalence is higher in certain countries such as Brazil, China, and Japan, where it is the second leading cause of CAH. This higher incidence is thought to be due to the founder effect though additional studies are required to establish the frequency of mutations in all populations.


Steroid 17-hydroxylase is a cytochrome p-450 enzyme.[4] It hydroxylates pregnenolone and progesterone, which are precursors to aldosterone, to form 17 OH pregnenolone and 17 OH progesterone, which are precursors to cortisol.[4]  17-OH pregnenolone and 17-OH progesterone are also precursors to DHEA and androstenedione, respectively.

Patients with a 17-hydroxylase deficiency cannot synthesize cortisol or sex hormones effectively. The deficiency in cortisol production results in a disruption of the feedback loop to the hypothalamic-pituitary axis and a resultant overproduction of adrenocorticotropic hormone (ACTH), which in turn leads to hyperplasia of the adrenal cortex. The inability to effectively synthesize sex hormones results in a range of defects in sexual maturation. There is a resultant excess in 11-deoxycorticosterone and corticosterone. Aldosterone levels may vary and can range from low to high.

History and Physical

Patients with a 17-hydroxylase deficiency do not present with signs and symptoms of adrenal crisis, as is seen with classical CAH due to 21-hydroxylase deficiency induced by the retained aldosterone synthesis pathway. As a result, patients will typically present later than those with CAH due to 21-hydroxylase deficiency, which in the classical form presents with adrenal crisis early in life or virilization of females at birth. In particular, patients with a 17-hydroxylase deficiency may present with hypertension and hypokalemia in childhood or adulthood due to the mineralocorticoid excess that develops in the presence of excess ACTH. The additional presenting features will differ based on genotypic sex and are associated with deficient sex hormone production, which will typically not manifest until puberty.

46XX Patients 

If genotypically female patients do not develop hypertension or hypokalemia before puberty, they will have no complaints or physical exam findings before the typical age of puberty when the deficiency in sex hormones becomes apparent.

They will generally present with complaints of delayed puberty, primary amenorrhea, and lack of secondary sexual characteristics. Female external and internal genitalia will be present and will show a prepubertal uterus and sometimes cystic ovaries but are otherwise normal on the exam.

46XY Patients

The presentation in male patients is typically under masculinization and can range from phenotypic females to ambiguous or small male genitalia.

Phenotypic female 46XY patients may present with a history of abdominal hernia or inguinal mass due to undescended testes. If undetected until puberty, they will present with similar complaints to 46XX patients of delayed puberty, amenorrhea, and lack of secondary sexual characteristics. On physical exam, they will have a blind pouch instead of a vagina and lack internal female genitalia. The testes are undescended or located in the inguinal canal on imaging studies.

Males with ambiguous or small male genitalia may present with undescended testes or other complaints related to lack of virilization at puberty. Gynecomastia has been reported in these patients as well.


The evaluation of suspected 17-hydroxylase should include:[5]

  • ACTH level will be elevated.
  • Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels in postpubertal patients will be elevated.
  • ACTH stimulation test with adrenal hormone profile including 17-hydroxyprogesterone, cortisol, deoxycorticosterone, 17-hydroxypregnenolone, dehydroepiandrosterone, and androstenedione to evaluate adrenal function and to identify the potential enzymatic defect.
  • Aldosterone and plasma renin levels may be useful though levels vary across patients.
  • Basic metabolic panel to evaluate for hypokalemia and metabolic alkalosis.
  • Karyotype may be useful in individual phenotypically female patients.
  • Genetic testing may be useful to identify specific gene mutations.
  • Imaging studies such as pelvic ultrasound to evaluate internal genitalia to establish if phenotypically female patients have female reproductive organs or potentially undescended testes in genotypic males.

Treatment / Management

Medical management of CAH due to 17-hydroxylase deficiency focuses on glucocorticoid and sex steroid hormone replacement. 

Glucocorticoids such as dexamethasone (0.25 to 1.0 mg/day) or prednisone (2 to 5 mg/day) are given to suppress excess ACTH and 11-deoxycorticosterone production; this will reduce the mineralocorticoid excess and lead to improved blood pressure and serum electrolyte levels. Glucocorticoid replacement should continue throughout life at the lowest possible dose that suppresses ACTH levels. If blood pressure control is not achievable by glucocorticoids alone, then appropriate antihypertensives should also be administered. Spironolactone or other mineralocorticoid antagonists are often the antihypertensives of choice as the underlying cause is the mineralocorticoid excess; however, other antihypertensives may be options.[6]

46XY patients who are phenotypically male require testosterone replacement at the onset of puberty to promote secondary sex characteristics.

46XY patients who are phenotypically female require estrogen/progesterone therapy to induce secondary sex characteristics

46XX patients require estrogen/progesterone replacement to induce secondary sex characteristics and for uterus development. Cyclic therapy in patients with amenorrhea is necessary to induce cyclic withdrawal bleeding and prevent endometrial hyperplasia.

Appropriate sex hormone replacement does not typically include DHEA but instead relies on testosterone and estrogen/progesterone therapy.

Surgical management in patients who are 46XY but phenotypically female may be required to remove undescended testes, which present a risk for neoplasia and vaginoplasty to create typical female sexual anatomy.[7]

Additional treatment may be considered by reproductive medicine for fertility as these patients often are unable to conceive.

Differential Diagnosis

The differential diagnosis is often complex and must be broad, with a wide range of disorders.

  • CAH due to other enzyme deficiencies
    • 21-hydroxylase deficiency
    • 11-beta hydroxylase deficiency
    • 3 beta-hydroxysteroid dehydrogenase deficiency
  • Androgen insensitivity syndrome
  • 5-alpha reductase deficiency
  • Disorders of gender development


The prognosis for both male and female patients is excellent with appropriate glucocorticoid and sex hormone replacement therapy. Unlike other types of CAH, these patients very rarely have serious problems, especially without the adrenal crisis and associated morbidity related to difficulty with stress, infections, and surgery. There is no virilization, as seen in other forms of CAH, and the patient typically achieves appropriate secondary sexual characteristics with therapy. Furthermore, individuals with 17-hydroxylase deficiency do not have the risk of some cognitive impairment as those affected by the classic 21-hydroxylase deficiency.[8]

Potential psychosocial difficulty due to a lack of sexual maturation and ambiguous genitalia is a significant concern in the long term for patients if the condition is not identified and treated with appropriate medical or potentially surgical intervention. Additionally, fertility is a major long-term issue for these patients as, depending on the severity of the disease, they may be unable to conceive. They may require extensive reproductive health consults if they desire children. Furthermore, in the long term and with appropriate management, there is normal development and health otherwise.


Complications due to 17-hydroxylase deficiency vary depending on disease severity and therapy. Severely affected patients may have hypertension and hypokalemia even with glucocorticoid therapy and require additional therapy. If excess glucocorticoid therapy is received, the patient can develop symptoms such as obesity, abdominal striae, hyperglycemia, and other findings similar to Cushing disease.[9][10]

Deterrence and Patient Education

Patient education for a 17-hydroxylase deficiency depends on the severity of the patient's phenotype. Therapy compliance and surgical options should be subject to a thorough review with patients. Fertility counseling may be appropriate for many patients. Genetic counseling may also be appropriate for patients.

Enhancing Healthcare Team Outcomes

Congenital adrenal hyperplasia due to 17-hydroxylase deficiency is a rare form of CAH that presents differently than other forms of the disease and, if untreated, can cause significant morbidity. The condition is best diagnosed and managed by an interprofessional team, including pediatricians, nurses, endocrinologists, reproductive health, geneticists, surgeons, and mental health providers. Early diagnosis and treatment, indeed, allow for the prevention of morbidity associated with hypertension, electrolyte abnormalities, and sexual development impairment.  Since newborn screening programs that identify the most common form of CAH do not detect 17-hydroxylase deficiency, provider awareness and consideration of this condition are imperative for appropriate diagnosis.

Treatment, whether medical or surgical, also requires an interprofessional team approach. The physicians, including specialists, will dictate the therapeutic direction in conjunction with the patient and the family. For medical treatment, the pharmacist should assist the physician with steroid/hormone therapy management, verify dosing, and check for drug-drug interactions. Nursing often is best positioned to assess the effectiveness or failure of treatment, monitor for adverse drug reactions, counsel the patient, and assess for compliance. Both the pharmacist and nurse should report immediately to the physician any concerns or changes they encounter. This interprofessional approach will best ensure that patients receive an accurate diagnosis and the proper therapy they need for a successful outcome. [Level V]



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