Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency

Publication Date: September 27, 2018

Recommendations

Newborn screening

Cost-effectiveness

We recommend that all newborn screening programs incorporate screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency. (1-M)
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We recommend that first-tier screens use 17-hydroxyprogesterone assays standardized to a common technology with norms stratified by gestational age. (1-M)
Technical remark: Clinicians should be aware that immunoassays are still in use and remain a source of false-positive results. Specificity may be improved with organic extraction to remove cross-reacting substances.
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We recommend that screening laboratories employ a second-tier screen by liquid chromatography–tandem mass spectrometry in preference to all other methods (e.g., genotyping) to improve the positive predictive value of congenital adrenal hyperplasia screening. (1-L)
Technical remark: Laboratories utilizing liquid chromatography–tandem mass spectrometry should participate in an appropriate quality assurance program. Additionally, clinicians should realize that immunoassays lead to more false-positive results. Thus, if laboratory resources do not include liquid chromatography–tandem mass spectrometry, a cosyntropin stimulation test should be performed to confirm diagnosis prior to initiation of corticosteroid treatment.
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Prenatal treatment of congenital adrenal hyperplasia

We advise that clinicians continue to regard prenatal therapy as experimental. Thus, we do not recommend specific treatment protocols. (UGPS)
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In pregnant women at risk for carrying a fetus affected with congenital adrenal hyperplasia and who are considering prenatal treatment we recommend obtaining prenatal therapy only through protocols approved by Institutional Review Boards at centers capable of collecting outcomes from a sufficiently large number of patients, so that risks and benefits can be defined more precisely. (1-M)
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We advise that research protocols for prenatal therapy include genetic screening for Y-chromosomal DNA in maternal blood to exclude male fetuses from potential treatment groups. (UGPS)
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Diagnosis of congenital adrenal hyperplasia

In infants with positive newborn screens for congenital adrenal hyperplasia we recommend referral to pediatric endocrinologists (if regionally available) and evaluation by cosyntropin stimulation testing as needed. (1-M)
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In symptomatic individuals past infancy, we recommend screening with an early-morning (before 8 AM) baseline serum 17-hydroxyprogesterone measurement by liquid chromatography–tandem mass spectrometry. (1-M)
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In individuals with borderline 17-hydroxyprogesterone levels, we recommend obtaining a complete adrenocortical profile after a cosyntropin stimulation test to differentiate 21-hydroxylase deficiency from other enzyme defects. (1-M)
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In individuals with congenital adrenal hyperplasia, we suggest genotyping only when results of the adrenocortical profile after a cosyntropin stimulation test are equivocal, or cosyntropin stimulation cannot be accurately performed (i.e., patient receiving glucocorticoid), or for purposes of genetic counseling. (2-M)
Technical remark: Genotyping at least one parent aids in the interpretation of genetic test results because of the complexity of the CYP21A2 locus.
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Treatment of classic congenital adrenal hyperplasia

In growing individuals with classic congenital adrenal hyperplasia, we recommend maintenance therapy with hydrocortisone. (1-M)
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In growing individuals with congenital adrenal hyperplasia, we recommend against the use of oral hydrocortisone suspension and against the chronic use of long-acting potent glucocorticoids. (1-M)
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In the newborn and in early infancy, we recommend using fludrocortisone and sodium chloride supplements to the treatment regimen. (1-M)
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In adults with classic congenital adrenal hyperplasia, we recommend using daily hydrocortisone and/or long-acting glucocorticoids plus mineralocorticoids, as clinically indicated. (1-M)
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In all individuals with classic congenital adrenal hyperplasia, we recommend monitoring for signs of glucocorticoid excess, as well as for signs of inadequate androgen normalization, to optimize the adrenal steroid treatment profile. (1-M)
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Stress dosing

In all patients with congenital adrenal hyperplasia who require glucocorticoid treatment, for situations such as febrile illness (>38.5°C), gastroenteritis with dehydration, major surgery accompanied by general anesthesia, and major trauma we recommend increasing the glucocorticoid dosage. (1-M)
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In patients with congenital adrenal hyperplasia under everyday mental and emotional stress and minor illness and/or before routine physical exercise we recommend against the use of increased glucocorticoid doses. (1-L)
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In patients with congenital adrenal hyperplasia who require treatment, we recommend always wearing or carrying medical identification indicating that they have adrenal insufficiency. (1-M)
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In patients with congenital adrenal hyperplasia, we recommend educating patients and their guardians and close contacts on adrenal crisis prevention and increasing the dose of glucocorticoid (but not mineralocorticoid) during intercurrent illness. (1-M)
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We recommend equipping every patient with congenital adrenal hyperplasia with a glucocorticoid injection kit for emergency use and providing education on parenteral self-administration (young adult and older) or lay administration (parent or guardian) of emergency glucocorticoids. (1-M)
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Monitoring therapy

In patients ≤18 months with congenital adrenal hyperplasia, we recommend close monitoring in the first 3 months of life and every 3 months thereafter. After 18 months, we recommend evaluation every 4 months. (1-L)
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In pediatric patients with congenital adrenal hyperplasia, we recommend conducting regular assessments of growth velocity, weight, blood pressure, as well as physical examinations in addition to obtaining biochemical measurements to assess the adequacy of glucocorticoid and mineralocorticoid. (1-L)
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In pediatric patients with congenital adrenal hyperplasia under the age of 2 years, we advise annual bone age assessment until near-adult height is attained. (UGPS)
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In adults with congenital adrenal hyperplasia, we recommend annual physical examinations, which include assessments of blood pressure, body mass index, and Cushingoid features in addition to obtaining biochemical measurements to assess the adequacy of glucocorticoid and mineralocorticoid replacement. (1-L)
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In adults with congenital adrenal hyperplasia, we recommend monitoring treatment through consistently timed hormone measurements relative to medication schedule and time of day. (1-L)
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In adults with congenital adrenal hyperplasia, we recommend that clinicians do not completely suppress endogenous adrenal steroid secretion to prevent adverse effects of over treatment. (1-M)
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Treatment of nonclassic congenital adrenal hyperplasia

In children and adolescents with inappropriately early onset and rapid progression of pubarche or bone age and in adolescent patients with overt virilization we suggest glucocorticoid treatment of nonclassic congenital adrenal hyperplasia. (2-L)
Technical remark: Risks and benefits of glucocorticoid therapy should be considered and discussed with the patient’s family.
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In asymptomatic nonpregnant individuals with nonclassic congenital adrenal hyperplasia we recommend against glucocorticoid treatment. (1-M)
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In previously treated patients with nonclassic congenital adrenal hyperplasia we suggest giving the option of discontinuing therapy when adult height is attained or other symptoms resolve. (2-M)
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In adult women with nonclassic congenital adrenal hyperplasia who also have patient-important hyperandrogenism or infertility we suggest glucocorticoid treatment. (2-L)
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In most adult males with nonclassic congenital adrenal hyperplasia, we suggest that clinicians generally not prescribe daily glucocorticoid therapy. (2-VL)
Technical remark: Exceptions include infertility, testicular adrenal rest tumors or adrenal tumors, and phenotypes that are intermediate between classic and nonclassic phenotypes.
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In patients with nonclassic congenital adrenal hyperplasia, we suggest hydrocortisone stress dosing for major surgery, trauma, or childbirth only if a patient has a suboptimal (<14 to 18 μg/dL, <400 to 500 nmol/L) cortisol response to cosyntropin or iatrogenic adrenal suppression. (2-VL)
Technical remark: A range is given for cortisol cut points due to greater specificity of newer cortisol assays.
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Long-term management of patients with congenital adrenal hyperplasia

Transition to adult care

In adolescent patients with congenital adrenal hyperplasia, we suggest that the transition to adult care begins several years prior to dismissal from pediatric endocrinology. (2-VL)
Technical remark: We advise the use of joint clinics comprised of pediatric, reproductive, and adult endocrinologists and urologist during this transition.
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In adolescent females with congenital adrenal hyperplasia, we suggest a gynecological history and examination to ensure functional female anatomy without vaginal stenosis or abnormalities in menstruation. (2-L)
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Genetic counseling

In children with congenital adrenal hyperplasia, adolescents transitioning to adult care, adults with nonclassic congenital adrenal hyperplasia upon diagnosis, and partners of patients with congenital adrenal hyperplasia who are planning a pregnancy, we recommend that medical professionals familiar with congenital adrenal hyperplasia provide genetic counseling. (1-L)
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Fertility counseling

In individuals with congenital adrenal hyperplasia and impaired fertility we suggest referral to a reproductive endocrinologist and/or fertility specialist. (2-L)
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Management of congenital adrenal hyperplasia and nonclassic congenital adrenal hyperplasia during pregnancy

In women with nonclassic congenital adrenal hyperplasia who are infertile or have a history of prior miscarriage, we recommend treatment with a glucocorticoid that does not traverse the placenta. (1-L)
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In women with congenital adrenal hyperplasia who are pregnant, we advise management by an endocrinologist familiar with congenital adrenal hyperplasia. (UGPS)
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In women with congenital adrenal hyperplasia who become pregnant we recommend continued prepregnancy doses of hydrocortisone/prednisolone and fludrocortisone therapy, with dosage adjustments if symptoms and signs of glucocorticoid insufficiency occur. (1-L)
Technical remark: Clinicians should evaluate the need for an increase in glucocorticoid during the second or third trimester and administer stress doses of glucocorticoids during labor and delivery.
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In women with congenital adrenal hyperplasia who are pregnant, or trying to become pregnant, we recommend against using glucocorticoids that traverse the placenta, such as dexamethasone. (1-L)
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In women with congenital adrenal hyperplasia who are pregnant, we advise that the birthing plan includes an obstetric specialist. (UGPS)
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Surveillance for long-term complications of congenital adrenal hyperplasia and its treatment

For patients with congenital adrenal hyperplasia, we suggest introducing counseling regarding healthy lifestyle choices at an early age to maintain body mass index within the normal range to avoid metabolic syndrome and related sequelae. (2-VL)
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In adult patients with congenital adrenal hyperplasia, we suggest screening of bone mineral density in anyone subjected to a prolonged period of higher-than-average glucocorticoid dosing, or who has suffered a nontraumatic fracture. (2-VL)
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In adults with classic congenital adrenal hyperplasia, we recommend against routine adrenal imaging. (1-VL)
Technical remark: Reserve adrenal imaging for individuals with classic congenital adrenal hyperplasia who have clinical evidence of an adrenal mass, poor disease control, a lapse in treatment of several years, or lack of response to intensified therapy.
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In males with classic congenital adrenal hyperplasia, we recommend periodic testicular ultrasound to assess for the development of testicular adrenal rest tumors. (1-L)
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In patients with congenital adrenal hyperplasia, we recommend against routine evaluation for cardiac and metabolic disease beyond that recommended for the general population. (1-L)

Technical remark: Clinicians should use their own judgment for the above procedures.

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Restoring functional anatomy by surgery in individuals with congenital adrenal hyperplasia

In all pediatric patients with congenital adrenal hyperplasia, particularly minimally virilized girls, we advise that parents be informed about surgical options, including delaying surgery and/or observation until the child is older. (UGPS)
Technical remark: Surgeries should be performed only in centers with experienced pediatric surgeons/urologists, pediatric endocrinologists, pediatric anesthesiologists, behavioral/mental health professionals, and social work services. Extensive discussions regarding risks and benefits, shared decision-making, review of potential complications, and fully informed consent need to occur prior to surgery. The option to forgo surgery should be considered.
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In severely virilized females, we advise discussion about early surgery to repair the urogenital sinus. (UGPS)
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In the treatment of minors with congenital adrenal hyperplasia, we advise that all surgical decisions remain the prerogative of families (i.e., parents and assent from older children) in joint decision-making with experienced surgical consultants. (UGPS)
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In female patients with congenital adrenal hyperplasia for whom surgery is chosen, we suggest vaginoplasty using urogenital mobilization and, when chosen, neurovascular-sparing clitoroplasty for severe clitoromegaly. (2-VL)
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Experimental therapies and future directions

General considerations and unmet clinical needs

In patients with congenital adrenal hyperplasia, we advise against using experimental treatment approaches outside of formally approved clinical trials. (UGPS)
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Adrenalectomy

In patients with congenital adrenal hyperplasia, we suggest that bilateral adrenalectomy not be performed. (2-VL)
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Mental health

For individuals with congenital adrenal hyperplasia and their parents, we recommend behavioral/mental health consultation and evaluation to address any concerns related to congenital adrenal hyperplasia. (1-L)

Technical remark: Clinicians should be aware that individuals with congenital adrenal hyperplasia may be at risk for developing mental health problems and should have a low threshold for referral to psychological or psychiatric treatment. Mental health practitioners should have specialized expertise in assessing and managing congenital adrenal hyperplasia–related psychosocial problems.

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Recommendation Grading

Disclaimer

Overview

Title

Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency

Authoring Organization

Publication Month/Year

September 27, 2018

Document Type

Guideline

External Publication Status

Published

Country of Publication

US

Inclusion Criteria

Female, Male, Adolescent, Adult, Child, Infant

Health Care Settings

Ambulatory

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Counseling, Assessment and screening, Management, Treatment

Diseases/Conditions (MeSH)

D000312 - Adrenal Hyperplasia, Congenital

Keywords

congenital adrenal hyperplasia (CAH), Congenital Adrenal Hyperplasia

Source Citation

Phyllis W Speiser, Wiebke Arlt, Richard J Auchus, Laurence S Baskin, Gerard S Conway, Deborah P Merke, Heino F L Meyer-Bahlburg, Walter L Miller, M Hassan Murad, Sharon E Oberfield, Perrin C White, Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 103, Issue 11, November 2018, Pages 4043–4088, https://doi.org/10.1210/jc.2018-01865

Supplemental Methodology Resources

Systematic Review Document, Systematic Review Document