C 17 Hydroxylase Deficiency


Article Author:
Dianna Chormanski


Article Editor:
Maria Rosaria Muzio


Editors In Chief:
David Wood
Andrew Wilt
Hajira Basit


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
9/1/2019 4:39:54 PM

Introduction

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 the 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, the 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, clinical features of this rare genetic disorder. Moreover, it will also cover the role of a multi-professional team for early diagnosis and prompt management.

Etiology

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 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 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.

Epidemiology

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.

Pathophysiology

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 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 female 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.

Evaluation

The evaluation of suspected 17-hydroxylase should include:

  • ACTH and 11-deoxycortisol levels which will be elevated.
  • FSH and LH levels, which 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-deoxycortisol 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.

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.

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 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

Prognosis

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 have not a risk of some cognitive impairment as compared to those affected by the classic 21-hydroxylase deficiency.[5]

Potential psychosocial difficulty due to a lack of sexual maturation and ambiguous genitalia is a significant concern in the long term for patient's 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 and 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

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.

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 the 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, and 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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C 17 Hydroxylase Deficiency - Questions

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A 3-year-old female child presents to the clinician for a follow-up. The child was born via a spontaneous vaginal delivery and had an unremarkable prenatal course with normal newborn screens. The mother states that she had taken her daughter to the emergency department a few weeks ago due to a high fever when the doctors told her that the child has bilateral inguinal masses. Further evaluation reveals bilateral undescended testicles and a karyotype of 46XY. The child is also found to have elevated adrenocorticotropin levels. Which of the following clinical findings may be observed in early childhood of this child?



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What is the first step in the treatment of patients with C-17 hydroxylase deficiency?



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A 15-year-old female patient presents with a complaint of never having menstruated. She is otherwise healthy. Her vitals are notable for a blood pressure of 145/85 mmHg. She is Tanner stage 1. Further workup reveals normal female genitalia, and routine labs show only hypokalemia. Further studies reveal elevated ACTH and 11-deoxycortisol. Cortisol, 17-hydroxyprogesterone, estrogen, and progesterone are low. What is the most likely enzyme deficiency in this patient?



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A 4-week old baby is brought to the emergency department for altered mental status. The baby has not been seen by a provider ever since she was born and the mother reports that she was born at home and has had poor feeding since birth. On examination, the baby is afebrile, hypotensive, lethargic, and has ambiguous genitalia. The basic metabolic panel returns with hypoglycemia, hyperkalemia, and hyponatremia. Sepsis workup is negative. What is the most likely enzyme defect in this patient?



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A 16-year-old girl presents to the clinic for evaluation of delayed puberty. She has never menstruated and exhibits Tanner stage 1 development. Further workup reveals absent internal female organs, bilateral enlarged adrenal gland, and bilateral inguinal masses. A karyotype is performed and returns as 46 XY. A diagnosis of androgen insensitivity syndrome (AIS) is made, and the patient undergoes gonadectomy and begins estrogen therapy for induction of female secondary sexual characteristics. She returns to the clinic in her mid-20s for follow-up and is found to be hypertensive and hypokalemic. The provider suspects an alternative diagnosis to AIS, and this is confirmed by laboratory workup. Which of the following is the most appropriate first-line treatment for this patient at this time?



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A 16-year-old female presents to the clinic for evaluation of delayed puberty. She reports never having menstruated but is otherwise healthy. Her vitals show a blood pressure of 140/90 mmHg, the pulse of 78/min, respiratory rate of 14/min and a temperature of 37 C. On physical examination, she is a thin young woman with tanner stage 1 breast development. She has normal female anatomy, and her routine labs are significant for hypokalemia. Which of the following set of lab values would be most likely seen in this patient?



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A phenotypically female patient who is 46XY is diagnosed with 17-hydroxylase deficiency and is found to have bilateral undescended testicles present. The patient is given appropriate medical management with normalization of her ACTH levels. Which of the following is the patient at the highest risk for without additional management?



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C 17 Hydroxylase Deficiency - References

References

Bulsari K,Maple-Brown L,Falhammar H, Two rare forms of congenital adrenal hyperplasia, 11β hydroxylase deficiency and 17-hydroxylase/17,20-lyase deficiency, presenting with novel mutations. Hormones (Athens, Greece). 2018 Mar;     [PubMed]
Breder ISS,Garmes HM,Mazzola TN,Maciel-Guerra AT,de Mello MP,Guerra-Júnior G, Three new Brazilian cases of 17α-hydroxylase deficiency: clinical, molecular, hormonal, and treatment features. Journal of pediatric endocrinology     [PubMed]
Kim SM,Rhee JH, A case of 17 alpha-hydroxylase deficiency. Clinical and experimental reproductive medicine. 2015 Jun;     [PubMed]
Auchus RJ, Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and pharmacologic. The Journal of steroid biochemistry and molecular biology. 2017 Jan;     [PubMed]
Amr NH,Baioumi AY,Serour MN,Khalifa A,Shaker NM, Cognitive functions in children with congenital adrenal hyperplasia. Archives of endocrinology and metabolism. 2019 Mar-Apr     [PubMed]

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