Continuing Education Activity

Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive disorders caused by a deficiency in one of the enzymes required for steroid biosynthesis in the adrenal glands. The most common cause of CAH is 21-hydroxylase (21-OH) deficiency, resulting from mutations or deletions of the CYP21A2 gene, which accounts for over 90% of CAH cases. In contrast, 17-hydroxylase (17-OH) deficiency is a rare form of CAH, accounting for about 1% of cases. This condition results from biallelic mutations in the CYP17A1 gene, leading to impaired cortisol and sex steroid biosynthesis. Notably, 17-OH deficiency is not detected by newborn screening and is typically identified around puberty due to symptoms such as ambiguous genitalia, delayed sexual maturation, hypertension, or hypokalemia.

In general, 17-OH deficiency presents as sexual infantilism in individuals with both 46,XX and 46,XY chromosomes, along with hypertension and hypokalemia. In cases of partial deficiency, 46,XY individuals may also present with ambiguous genitalia. Diagnosis involves hormonal evaluation, genetic testing, and imaging. Management involves lifelong glucocorticoid replacement to suppress excess adrenocorticotropic hormone and control mineralocorticoid excess, with antihypertensives if necessary. This activity provides a comprehensive review of the etiology, epidemiology, pathophysiology, clinical features, evaluation, and treatment of 17-OH deficiency. This activity also highlights the importance of collaboration among interprofessional healthcare providers in ensuring early diagnosis, prompt management, and a thorough understanding of the prognosis and potential complications to rate patients with this rare genetic disorder.

Objectives:

• Identify the clinical manifestations of 17-hydroxylase deficiency, including hypertension, hypokalemia, and lack of secondary sexual development.

• Implement appropriate glucocorticoid and sex hormone replacement therapy to manage adrenal insufficiency and promote normal sexual development.

• Assess the need for antihypertensive therapy and adrenocorticotropic hormone stimulation tests in patients who do not achieve adequate blood pressure control with glucocorticoid replacement alone.

• Collaborate with the interprofessional healthcare team to optimize patient outcomes and manage long-term reproductive health concerns in individuals with 17-hydroxylase deficiency.

Introduction

Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive disorders caused by a deficiency in one of the enzymes required for steroid biosynthesis in the adrenal glands. The most common cause of CAH is 21-hydroxylase (21-OH) deficiency, resulting from mutations or deletions of the CYP21A2 gene, which accounts for over 90% of CAH cases. In contrast, 17-hydroxylase (17-OH) deficiency is a rare form of CAH caused by biallelic mutations in the CYP17A1 gene, accounting for approximately 1% of cases.[1] Please see StatPearls' companion resource, "Congenital Adrenal Hyperplasia," for further information.

Among the CAH disorders, the resulting phenotype depends on the individual's genotypic sex, the type of enzyme deficiency, and the severity of the genetic mutation. Unlike 21-OH deficiency, 17-OH deficiency is not detected by newborn screening and is typically identified later due to symptoms such as ambiguous genitalia, delayed sexual maturation, hypertension, or hypokalemia. Generally, 17-OH deficiency presents as sexual infantilism in individuals with both 46,XX and 46,XY chromosomes, hypertension and hypokalemia, and ambiguous genitalia in 46,XY individuals with partial deficiency.[1][2]

Etiology

CAH is a group of autosomal recessive disorders caused by deficiencies in one of several enzymes involved in steroid biosynthesis. Specifically, 17-OH deficiency is a rare cause of CAH, resulting from loss-of-function mutations in the CYP17A1 gene located on chromosome 10q24-q25.[2][3] These mutations typically lead to the loss of both 17-hydroxylase and 17,20-lyase activities, which are essential enzymes crucial for 3 key steps in cortisol and sex steroid biosynthesis.

In particular, 17-hydroxylase mediates the synthesis of 17-hydroxypregnenolone from pregnenolone, 17-hydroxyprogesterone from progesterone, and dehydroepiandrosterone (DHEA) from 17-hydroxypregnenolone. The latter step, mediated by 17,20-lyase, is crucial as DHEA serves as the precursor to steroid sex hormones. While isolated 17,20-lyase deficiency is known, it is extremely rare. This condition is not classified as part of CAH because steroid biosynthesis remains normal; instead, it is considered an androgen and sex-steroid biosynthetic defect.

More than 150 mutations in the CYP17A1 gene have been identified, with most resulting in a complete loss of both enzymatic activities.[1][4] Compound heterozygous cases have also been reported. However, genotype-phenotype correlation remains uncertain, as disease severity can vary even among individuals with the same mutation. Molecular genetic testing of the CYP17A1 gene is available to detect known mutations. Regional variations should be considered when conducting molecular genetic analysis. For example, 2 recent studies from China identified exon 6 as a hotspot in the Chinese population, indicating that testing for common variants can be more efficient and expedite the diagnostic process.[5][6]

Epidemiology

CAH due to 17-OH deficiency accounts for only 1% of worldwide CAH cases. Although the exact incidence of 17-OH deficiency is not well established, it is estimated to be approximately 1 per 50,000 births.[1][4] The disease prevalence is higher in certain countries such as Brazil, China, and Japan, where it is the second leading cause of CAH. Recent studies from Türkiye also reported a significant number of affected individuals.[1][7][8] The higher incidence in these regions is likely due to the founder effect, although additional studies are needed to determine the frequency of mutations across different populations.

Pathophysiology

Steroid 17-hydroxylase is a cytochrome P450 enzyme that hydroxylates pregnenolone and progesterone, which are precursors to aldosterone, to form 17-hydroxypregnenolone and 17-hydroxyprogesterone, which are precursors to cortisol.[9][10] Additionally, 17-hydroxypregnenolone and 17-hydroxyprogesterone are precursors to DHEA and androstenedione, respectively. Patients with 17-OH deficiency are unable to synthesize cortisol or sex hormones effectively. The cortisol deficiency disrupts the feedback loop to the hypothalamic-pituitary axis, leading to the overproduction of adrenocorticotropic hormone (ACTH) and subsequent adrenal cortex hyperplasia. Adrenal insufficiency and adrenal crisis are rare or absent in this condition, as excess corticosterone compensates for the lack of cortisol by acting similarly to cortisol.[9]

The inability to effectively synthesize sex hormones leads to delayed or absent sexual maturation. This results in an excess of 11-deoxycorticosterone and corticosterone due to elevated ACTH levels and the preferential diversion of the reaction cascade towards the mineralocorticoid pathway. The excessive mineralocorticoid activity of these precursors causes hypertension, hypokalemia, and metabolic alkalosis. Aldosterone levels may vary, ranging from low to high. As previously mentioned, the enzyme may have either complete (more common) or partial defects. Approximately 90% of individuals had the complete form in a recent large series.[1] 

The clinical phenotype, androgens, and cortisol levels have been used to define partial and complete forms of 17-OH deficiency, although there are no universally accepted definitions. Furthermore, a mutation in the CYP17A1 gene can differentially affect the 2 enzyme functions, 17-hydroxylase and 17,20-lyase.[11] As elevated precursor levels lead to increased mineralocorticoid activity, this type of CAH does not present with salt wasting.

Sex steroid synthesis is affected by the severity of the 17,20-lyase defect, which can range from complete female genitalia in 46,XY individuals to varying degrees of hypospadias. Similarly, depending on the extent of enzyme blockade, there are varying degrees of mineralocorticoid precursor accumulation, leading to different levels of hypertension, which can present from early childhood to adulthood.[1] 

Inadequate sex steroid production, resulting in hypogonadism, and severely impaired gametogenesis (along with an immature uterus in 46,XX individuals) frequently lead to infertility in both sexes.[11][12] In 46,XX individuals, additional factors such as inadequate disease control and high progesterone levels can make the endometrium unsuitable for implantation.[12][13]

History and Physical

As mentioned earlier, patients with 17-OH deficiency do not exhibit signs or symptoms of adrenal crisis, unlike those with classical CAH due to 21-OH deficiency. As a result, patients with 17-OH deficiency typically present later than those with 21-OH deficiency, who often show signs of adrenal crisis early in life. Another key distinction is that individuals with 17-OH deficiency usually have complete enzyme defects, leading to severely impaired androgen production, which causes complete female genitalia in 46,XY individuals. In contrast, 46,XX individuals may experience virilization at birth, allowing early diagnosis. Patients with 17-OH deficiency are generally diagnosed early only if they present with severe hypertension and/or hypokalemia in the prepubertal years or when an astute clinician suspects the condition while evaluating secondary hypertension.

A recent large nationwide study from Türkiye identified delayed secondary sexual characteristics as the most common presenting sign (approximately 50%) in both 46,XX and 46,XY individuals.[1] The study also found that although hypertension was present in nearly two-thirds of cases upon examination, only 3% of individuals initially sought medical attention due to hypertension. This finding highlights the importance of routine blood pressure monitoring in suspected individuals and family members of known cases. Another study from the same region emphasized that hypertension and/or hypokalemia serve as a critical clue for early diagnosis.[7] 

Patients with 17-OH deficiency may present with hypertension and hypokalemia in childhood or adulthood in both 46,XX and 46,XY individuals due to mineralocorticoid excess. This excess is primarily due to deoxycorticosterone, although corticosterone and its 5-alpha metabolites, as well as 11-oxygenated products of progesterone, also contribute. The mineralocorticoid excess develops in the presence of elevated ACTH levels.

Additional presenting features vary based on genotypic sex and result from deficient sex hormone production. In 46,XY individuals, this leads to genital ambiguity, while both 46,XX and 46,XY individuals may experience delayed or absent puberty, which often remains unrecognized until puberty. In the large series referenced earlier, approximately 60% of individuals had a 46,XY karyotype. The vast majority (>90%) were raised as females, a finding consistent with other large studies.[1][11]

Individuals With 46,XX Karyotype

In this case, genotypically female patients do not develop hypertension or hypokalemia before puberty. They may not present with any symptoms or physical examination findings until the typical age of puberty when sex hormone deficiency becomes evident. At that time, they often present with delayed puberty, primary amenorrhea, and absence of secondary sexual characteristics. Female external and internal genitalia will usually appear normal, although a prepubertal uterus and cystic, multilocular ovaries may be observed. 

Partial deficiency in 17-OH deficiency is uncommon but contributes to the varied presentation of this rare condition. Patients with partial enzymatic deficiency may undergo normal puberty and experience normal menarche with regular menstrual cycles. A recent series from China examining 46,XX patients with partial 17-OH deficiency demonstrated a diverse clinical presentation, including spontaneous thelarche, spontaneous menarche, irregular menses, oligomenorrhea, primary amenorrhea, sparse or absent axillary and pubic hair, infantile genitalia, and mild hypertension or hypokalemia. Infertility is common in these individuals; however, modern assisted reproductive techniques offer promising options.[13]

Individuals With 46,XY Karyotype

These individuals typically present with under-masculinization, ranging from a phenotypic female appearance to ambiguous genitalia. Complete enzyme defects result in a female genital appearance, with hypertension and/or hypokalemia as the only clues before puberty in sporadic cases. In some instances, patients may present in adulthood with infertility and gynecomastia despite having normal male genitalia.[11] 

Phenotypically 46,XY females may present with a history of abdominal hernia or an inguinal mass due to undescended testes. If undiagnosed until puberty, they typically exhibit delayed puberty, amenorrhea, and a lack of secondary sexual characteristics, similar to 46,XX patients. On physical examination, they have a blind vaginal pouch and lack internal female genitalia. Imaging studies often reveal undescended testes or testes located in the inguinal canal.

The most common presentation of 17-OH deficiency is a female with delayed puberty and low renin hypertension. Severe hypertension, a positive family history in both 46,XX and 46,XY individuals, and atypical genitalia in 46,XY (due to a partial 17-OH defect) are key factors that contribute to early diagnosis.[8] Less common presentations in both genotypic sexes include short stature, inguinal hernia, adrenal insufficiency, and hypoglycemia.

Evaluation

The evaluation of suspected 17-OH deficiency should include:

• Elevated ACTH levels with low basal and stimulated cortisol levels.
• Elevated follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, which are typically present in almost all children at the pubertal age. These elevated levels may be observed as early as age 4, but are usually evident by the onset of puberty.[7][8][11]
• An ACTH stimulation test along with an adrenal hormone profile, including cortisol, 17-hydroxyprogesterone, progesterone, 17-hydroxypregnenolone, pregnenolone, deoxycorticosterone, corticosterone, DHEA, and androstenedione. This test assesses adrenal function and identifies potential enzymatic defects.
  • In this test, samples are collected immediately before and 60 minutes after administering 0.25 mg of cosyntropin, a synthetic ACTH.
  • Cosyntropin stimulates the adrenal glands pharmacologically, optimizing hormone secretion.
• Elevated progesterone levels in nearly all individuals with this condition. Basal progesterone and the ratio of progesterone to other metabolites are useful diagnostic tools.[11][14]
• Suppressed renin levels, with varying levels of aldosterone.
• Serum electrolytes and blood gas analysis may reveal hypokalemia and alkalosis.
• Karyotyping to determine genotypic sex, as up to 90% of individuals with a 46,XY karyotype are raised as females.[1][11]
• Genetic testing to identify specific gene mutations. Exon 1-6 deletion studies (multiplex ligation-dependent probe amplification) have been suggested as the initial molecular test in a Turkish series, as these deletions were the most common underlying causes in their cohort.[1] 
  • Chinese studies have identified a hotspot in exon 6, recommending analysis of this region first.[5][6] 
  • Molecular testing priorities may be tailored according to region-specific data.
  • Approximately 150 mutations have been reported so far, but genotype-phenotype correlation remains poor, as the same mutation can present with varying clinical manifestations, even within the same family.
• Imaging studies, such as pelvic ultrasound, should be conducted to evaluate internal genitalia and determine whether phenotypically female patients have female reproductive organs or, in genotypic men, undescended testes.[15]

Treatment / Management

The medical management of CAH due to 17-OH deficiency focuses on glucocorticoid and sex steroid hormone replacement. Glucocorticoids such as hydrocortisone, prednisone, or dexamethasone are used to suppress excess ACTH and 11-deoxycorticosterone production. This reduces mineralocorticoid excess, which in turn improves blood pressure and serum electrolyte levels. Although glucocorticoid replacement should physiologically control hypertension, a significant number of patients may still require antihypertensive medications, though typically at lower doses.[7]

The permanent effects of uncontrolled hypertension on blood vessels may contribute to ongoing complications. Glucocorticoid replacement therapy should be continued throughout life at the lowest effective dose to suppress excess ACTH levels. Typically, replacement or near-replacement doses of steroids are sufficient, as hyperandrogenism—commonly observed in 21-OH deficiency—is not an issue in these patients. Additionally, adrenal insufficiency is not a concern, as excess corticosterone helps mitigate this risk.

If blood pressure cannot be controlled with glucocorticoids alone, appropriate antihypertensive treatment should be introduced to patients. Spironolactone or other mineralocorticoid antagonists are typically the preferred options due to the underlying mineralocorticoid excess; however, other antihypertensives may also be considered.[16] Often, potassium levels normalize after steroid therapy. In cases where hypokalemia persists, potassium supplements or potassium-sparing diuretics such as amiloride can help correct hypokalemia. However, amiloride is less effective than spironolactone in controlling blood pressure.[7] 

Moreover, as most individuals are raised as female, common issues such as gynecomastia and erectile dysfunction are not typically a concern. Therefore, spironolactone (50-100 mg/d q 12 h) remains the treatment of choice for hypertension. Plasma renin activity and potassium levels can help guide the titration of therapy. Renin levels may take months or even years to increase following the initiation of glucocorticoid therapy due to chronic suppression. As anticipated, a significant number of children with this condition achieve a final height within the normal range, as there is no excess of sex steroids.

Management of Sex Hormone Replacement and Surgical Interventions in 46,XY Patients

Treatment of 46,XY individuals with 17-OH deficiency involves appropriate sex hormone replacement and, when necessary, surgical interventions to promote normal sexual development and address potential complications.

• 46,XY patients raised as males require testosterone replacement at the onset of puberty to promote the development of secondary sex characteristics.
• 46,XY patients raised as females require estrogen or progesterone therapy to induce secondary sex characteristics and support uterine development with normal menstrual cycles.
• Cyclic therapy is necessary in patients with amenorrhea to induce withdrawal bleeding and prevent endometrial hyperplasia. Transient intensification of steroid therapy might be needed every 1 to 3 months to mitigate the risk of endometrial hyperplasia.
• The standard approach for sex hormone replacement typically includes testosterone for males and estrogen or progesterone for females rather than DHEA.
• Surgical management may be necessary for 46,XY individuals raised as females to remove undescended testes, which carry a risk for neoplasia, and to perform vaginoplasty to create typical female sexual anatomy.[17]
• Reproductive medicine specialists may consider additional treatment options for fertility, as many of these patients are unable to conceive. Historically, live births in these patients have been rare, but recent cases of successful live births have increased, primarily through assisted reproductive techniques and, in very rare instances, spontaneously after adequate disease control. These successful cases have utilized various protocols, including progesterone-primed ovarian stimulation, long-acting gonadotropin-releasing hormone (GnRH) agonist/dexamethasone or prednisolone, short-acting GnRH agonist/dexamethasone, prednisolone, and ultra-long GnRH agonists.[12][13]

Differential Diagnosis

The differential diagnosis is often complex and requires a broad approach, considering a wide range of disorders, as mentioned below.

• CAH subtypes: CAH due to other enzyme deficiencies, particularly P450 oxidoreductase deficiency (PORD), presents with high progesterone levels similar to 17-OH deficiency, but low 17-hydroxyprogesterone and very high deoxycorticosterone, which distinguishes it from PORD. The other hypertensive form of CAH, 11-hydroxylase deficiency, is due to deoxycorticosterone accumulation. In contrast, 11-deoxycortisol is low in 17-OH deficiency and elevated in 11-hydroxylase deficiency. Androgen levels are elevated in 11-hydroxylase deficiency but low in 17-OH deficiency.

• Disorders of sex development: This is also known as differences of sex development or DSD. When XY individuals present during the neonatal or infancy period, the differential diagnosis should include androgen insensitivity syndrome, 5-α-reductase deficiency, and other XY DSD conditions, such as gonadal dysgenesis spectrum or 17-β-hydroxysteroid dehydrogenase type-3 deficiency.

• Gonadal dysgenesis in adolescents: In adolescent girls with pubertal failure, primary amenorrhea, high gonadotropins, and low-sex steroids, gonadal dysgenesis is a more common diagnosis. Individuals with a 46,XY karyotype typically lack a uterus and may have testes located in the inguinal region or abdomen. Considering this condition is crucial, along with assessing blood pressure, blood gas, and electrolyte levels for signs of hypertension, alkalosis, and hypokalemia. A steroid profile, both at baseline and after cosyntropin stimulation, should be evaluated as outlined in the Evaluation section.

• Isolated 17,20 lyase deficiency: An isolated 17,20 lyase deficiency may present as undervirilized XY DSD in infancy, resembling gonadal dysgenesis on hormonal evaluation. This rare condition should be suspected when there is a high 17-hydroxyprogesterone to androstenedione ratio (typically >50) at baseline or after hCG stimulation. Another diagnostic clue in early infancy is a low DHEA level.[9] 

Prognosis

The prognosis for patients with 17-OH deficiency is excellent with appropriate glucocorticoid and sex hormone replacement therapy. Unlike other forms of CAH, these patients rarely experience adrenal crises or the associated morbidity related to stress, infections, or surgery. Virilization, commonly seen in other types of CAH, does not occur, and patients typically develop appropriate secondary sexual characteristics with therapy. Gender dysphoria is extremely rare and was not reported in any patients in two large recent studies.[1][11] This may be due to the severe androgen synthetic defect in the fetus, which leads to little or no androgen imprinting.

Potential psychosocial challenges, including issues related to delayed sexual maturation and ambiguous genitalia, are significant long-term concerns for patients if the condition is not identified and managed with appropriate medical or, in some cases, surgical intervention. Furthermore, fertility is a major long-term issue for these patients, and spontaneous conception is unlikely without help from the fertility team.

Complications

Complications due to 17-OH deficiency vary depending on disease severity and treatment. Severely affected patients may experience hypertension and hypokalemia despite glucocorticoid therapy, often requiring additional interventions. Long-standing undiagnosed or poorly controlled hypertension can lead to end-organ damage, similar to other causes of severe hypertension. Excess glucocorticoid therapy can lead to symptoms such as obesity, abdominal striae, hyperglycemia, and other features resembling Cushing disease.[18] 

Reproductive complications have also been reported, including arrested puberty, irregular menstruation, and multilocular ovaries. A recent series from China found that all 8 affected females had multilocular or polycystic ovaries, with 6 undergoing cystectomy before a definitive diagnosis. These multilocular ovaries responded well to oral contraceptives, suggesting that timely diagnosis could have prevented unnecessary surgery.[6]

Testicular adrenal rest tumors (TART), malignancy, and adrenal myelolipoma are rare. A recent review of gonadectomy data from 62 individuals with a 46,XY karyotype raised as females found no cases of TART or malignancy.[11] The modest elevation of ACTH may contribute to the rarity of TART and adrenal myelolipoma, likely due to elevated corticosterone compensating for cortisol deficiency.

Infertility is common in both 46,XX and 46,XY individuals due to hypogonadism, poor control of the condition, antral arrest of follicles, and an immature uterus in 46,XX individuals.[12][13]

An increased frequency of osteoporosis is also observed in patients with 17-OH deficiency. The underlying causes are deficiency of sex steroids and corticosteroid treatment.[19]

Consultations

Pediatric endocrinologists manage hormonal imbalances and glucocorticoid therapy. Pediatric surgeons and urologists may address ambiguous genitalia, whereas gynecologists and fertility specialists focus on reproductive health and infertility. Urologists handle genital surgeries and TART-related issues, and adult endocrinologists ensure continuity of care. Radiologists assist in diagnostics, and medical geneticists provide genetic counseling. Psychologists support patients with emotional and psychological challenges. Effective consultation with these specialists ensures a holistic, patient-centered approach to managing CAH.

Deterrence and Patient Education

Effective deterrence and patient education are key components in managing CAH, ensuring that patients and their families are well-informed and prepared to handle the condition's challenges.

• Patient education for a 17-OH deficiency varies based on the severity of the patient's phenotype. Therapy compliance and surgical options should be thoroughly discussed with patients. Fertility counseling may be appropriate for many individuals, and genetic counseling should also be considered.

• Genetic counseling should be provided to children transitioning to adult care and to patients planning a pregnancy, focusing on inheritance patterns and the likelihood of recurrence in the next generation.

• Molecular genetic testing of the fetus, such as chorionic villus sampling around the 10th week of gestation, is available and can be offered in affected families.

• Newborn screening is usually not designed to diagnose rare forms of CAH, and it is uncommon for an infant with this condition to be diagnosed through newborn screening.

• Patient and family education on proper treatment, especially compliance with medical therapy, is crucial for patients with CAH. Both over- and undertreatment with glucocorticosteroids can have deleterious effects on the health of these patients. As patients grow older, caregivers and patients should be counseled on appropriate treatment and when to seek medical care.

• Although frank adrenal insufficiency is rare in this condition, it is crucial to provide guidance on stress dosing during illness or stress to prevent potential adrenal crisis. Hence, patients and caregivers must be educated on the proper technique for administering intramuscular glucocorticoid injections.

Enhancing Healthcare Team Outcomes

A high index of suspicion for severe hypertension and/or hypokalemia by a primary care physician can lead to early referral and timely diagnosis of 17-OH deficiency. Prompt referral to specialists and facilities offering medical therapy can prevent end-organ damage caused by severe hypertension. Timely surgical intervention, when necessary, improves overall outcomes and enhances the quality of life for affected individuals. In addition to medical management by pediatric endocrinologists and surgical care by pediatric urologists, psychologists and social workers play essential roles in addressing the psychosocial aspects of care. Transition clinics, comprising both pediatric and adult medical and surgical specialists, can facilitate trust-building and ensure a smooth transition from pediatric to adult care. 

Caregivers of children diagnosed with CAH must receive thorough education about treatment options and potential complications of the condition. Responsibilities within the interprofessional healthcare team should be clearly defined, with each member contributing their specialized knowledge and skills to optimize patient care. Effective communication within the healthcare team fosters a collaborative environment where information is shared, questions are welcomed, and concerns are addressed promptly.

Lastly, care coordination is essential for ensuring seamless and efficient patient care. Clinicians, advanced practitioners, pharmacists, and other healthcare providers must collaborate to streamline the patient’s journey—from diagnosis to treatment and follow-up. This coordination minimizes errors, reduces delays, and enhances patient safety, ultimately leading to improved outcomes and patient-centered care that prioritizes the well-being and satisfaction of individuals affected by this rare form of CAH.