Guideline sources The following summarized guidelines for the evaluation and management of congenital adrenal hyperplasia (CAH) are prepared by our editorial team based on guidelines from the Japanese Society for Neonatal Screening (JSNS/JSPU/JES/JSPE 2022) and the Endocrine Society (ES 2018). 1 2 3 Calculator Prader staging for virilization of f Guidelines 1. Screening and diagnosis https://web.pathway.md/diseases/recGcZVhXIHbbw5tv 1/7 6/23/23, 3:35 AM Congenital adrenal hyperplasia Pathway Neonatal screening: As per JSNS 2022 guidelines, include screening for 21-hydroxylase deficiency in the neonatal mass screening programs. E Show 2 more As per ES 2018 guidelines, incorporate screening for CAH due to 21-hydroxylase deficiency in all newborn screening programs. B Show 2 more Screening for non-classic CAH: Consider obtaining early morning 17-hydroxyprogesterone levels in the follicular phase (or on a random day) to screen for nonclassical CAH due to 21-hydroxylase deficiency in patients with hyperandrogenemia and amenorrhea or infrequent menses. C Consider obtaining early morning 17-hydroxyprogesterone levels to screen for nonclassical CAH due to 21-hydroxylase deficiency in patients with hirsutism at high risk of CAH (positive family history, member of a high-risk ethnic group), even if serum total and free testosterone are normal. C 2. Diagnostic investigations Clinical assessment: assess for symptoms of adrenal insufficiency (including poor feeding, weight loss, and vomiting) for the diagnosis of 21-hydroxylase deficiency. Initiate corticosteroid treatment before confirmation of the diagnosis if symptoms of adrenal insufficiency or biochemical abnormalities occur, including hyponatremia, hyperkalemia, or metabolic acidosis. E 17-hydroxyprogesterone: obtain an early-morning (before 8 AM) baseline serum 17- hydroxyprogesterone measurement by liquid chromatography-tandem mass spectrometry in symptomatic patients past infancy. B Cosyntropin stimulation test: obtain cosyntropin stimulation testing as needed in infants with positive newborn screening results. B Complete adrenocortical profile: As per JSNS 2022 guidelines: Obtain a detailed endocrinological evaluation in neonates with 17-hydroxyprogesterone levels above the cut-off value for an immediate work-up in neonatal mass screening, regardless of the presence or absence of clinical symptoms, such as atypical external genitalia, hyperpigmentation of the skin, or symptoms or signs of adrenal insufficiency. E Obtain a detailed endocrinological evaluation in neonates with 17-hydroxyprogesterone levels remaining above the cut-off value for the repeated test, regardless of the presence or absence of clinical symptoms. E As per ES 2018 guidelines, obtain a complete adrenocortical profile after a cosyntropin stimulation test in patients with borderline 17-hydroxyprogesterone levels, in order to differentiate 21-hydroxylase deficiency from other enzyme defects. B https://web.pathway.md/diseases/recGcZVhXIHbbw5tv 2/7 6/23/23, 3:35 AM Congenital adrenal hyperplasia Pathway Genetic testing: consider obtaining genotyping in patients with CAH only when results of the adrenocortical profile after a cosyntropin stimulation test are equivocal, or cosyntropin stimulation test cannot be accurately obtained (patient receiving corticosteroids), or for purposes of genetic counseling. C Adrenal imaging: do not obtain routine adrenal imaging in adult patients with classic CAH. D 3. Medical management Prenatal treatment: As per JSNS 2022 guidelines, offer prenatal diagnosis and treatment at institutions with experts, after genetic counseling and approval from the institutional ethics committee. B Avoid offering prenatal diagnosis and treatment in institutions with no long-term follow-up system for safety or ethical approval of clinical studies. B As per ES 2018 guidelines, regard prenatal therapy as experimental. Insufficient evidence to recommend specific treatment protocols. E Show 2 more Management of classic CAH, initiation of treatment: As per JSPE/JES/JSPU/JSNS 2022 guidelines: Initiate corticosteroid treatment before confirmation of the diagnosis if symptoms of adrenal insufficiency or biochemical abnormalities occur, including hyponatremia, hyperkalemia, or metabolic acidosis. E Consider initiating high-dose corticosteroids as initial therapy during the neonatal period to rapidly suppress excessive adrenal androgen production in patients with classic 21- hydroxylase deficiency. C As per ES 2018 guidelines, initiate maintenance therapy with hydrocortisone in growing patients with classic CAH. B Management of classic CAH, choice of agent: As per JSPE/JES/JSPU/JSNS 2022 guidelines, initiate hydrocortisone for maintenance therapy in pediatric patients with classic 21-hydroxylase deficiency. B Show 3 more As per ES 2018 guidelines, do not use oral hydrocortisone suspension and chronic long-acting potent corticosteroids in growing patients with CAH. D Show 2 more Management of classic CAH, dose adjustments: As per JSPE/JES/JSPU/JSNS 2022 guidelines, individualize the dosage of corticosteroids during maintenance therapy to avoid undertreatment or overtreatment. E Show 2 more As per ES 2018 guidelines, do not suppress endogenous adrenal corticosteroid secretion completely to prevent adverse effects of overtreatment in adult patients with CAH. D https://web.pathway.md/diseases/recGcZVhXIHbbw5tv 3/7 6/23/23, 3:35 AM Congenital adrenal hyperplasia Pathway Show 2 more Management of non-classic CAH, initiation of treatment: As per JSPE/JES/JSPU/JSNS 2022 guidelines, consider initiating maintenance therapy in patients with non-classic 21-hydroxylase deficiency with symptoms of adrenal hyperandrogenism, such as an increase in growth velocity, advancement of bone age, virilization of female external genitalia, and irregular menstruation. C Show 4 more As per ES 2018 guidelines, consider initiating corticosteroid treatment of non-classic CAH in pediatric and adolescent patients with inappropriately early onset and rapid progression of pubarche or bone age and in adolescent patients with overt virilization. C Show 3 more Management of non-classic CAH, stress dosing: As per JSPE/JES/JSPU/JSNS 2022 guidelines, administer a stress dose of corticosteroids during maintenance therapy or when cortisol levels fall below the borderline (15-18 mg/dL) after the ACTH stimulation test in the following situations: febrile illness (> 38.5 C), gastroenteritis with possible dehydration, surgery under general anesthesia, major trauma, or childbirth. B As per ES 2018 guidelines, consider administering hydrocortisone stress dosing for major surgery, trauma, or childbirth in patients with non-classic CAH if the cortisol response to cosyntropin or iatrogenic adrenal suppression is suboptimal (< 14-18 g/dL, < 400-500 nmol/L). C Management of non-classic CAH, discontinuation of treatment: As per JSPE/JES/JSPU/JSNS 2022 guidelines, consider discontinuing treatment when adult height is reached or when symptoms disappear in patients with non-classic 21-hydroxylase deficiency treated with corticosteroids since childhood. C As per ES 2018 guidelines, consider discontinuing treatment when adult height is attained or other symptoms resolve in previously treated patients with non-classic CAH. C Emergency self-injection kit: As per JSNS 2022 guidelines, consider prescribing a corticosteroid self-injection kit for emergency use and providing instructions for self-injection in patients with 21-hydroxylase deficiency or their parents (or guardians). C As per ES 2018 guidelines, equip all patients with CAH with a corticosteroid injection kit for emergency use and provide education on parenteral self-administration (young adult and older) or lay administration (parent or guardian) of emergency corticosteroids. B 4. Nonpharmacologic interventions Psychological support: offer behavioral/mental health consultation and evaluation to address any concerns related to CAH in patients with CAH and their parents. B https://web.pathway.md/diseases/recGcZVhXIHbbw5tv 4/7 6/23/23, 3:35 AM Congenital adrenal hyperplasia Pathway 5. Surgical interventions Indications for surgery: As per JSNS 2022 guidelines, discuss the advantages and disadvantages of surgery in each individual case through shared decision-making with a multidisciplinary team. E Show 3 more As per ES 2018 guidelines, inform parents of all pediatric patients with CAH, particularly minimally virilized girls, about surgical options, including delaying surgery and/or observation until the child is older. E Show 4 more 6. Specific circumstances Pregnant patients: As per JSNS 2022 guidelines, choose corticosteroid preparations with low placental transfer for maintenance therapy in adult female patients wishing to conceive. B As per ES 2018 guidelines, initiate corticosteroids not traversing the placenta in patients with non-classic CAH in case of infertility or a history of prior miscarriage. B Show 4 more 7. Patient education General counseling: Educate patients with CAH and their guardians and close contacts on adrenal crisis prevention and increasing the dose of corticosteroids (but not mineralocorticoids) during intercurrent illness. B Consider providing counseling regarding healthy lifestyle choices at an early age to maintain a BMI within the normal range to avoid metabolic syndrome and related sequelae. C Genetic counseling: Provide genetic counseling by medical professionals familiar with CAH in: pediatric patients with CAH adolescent patients transitioning to adult care adult patients with non-classic CAH upon diagnosis partners of patients with CAH planning a pregnancy. B 8. Follow-up and surveillance Indications for referral: Refer infants with positive newborn screening results to a pediatric endocrinologist, if regionally available. B https://web.pathway.md/diseases/recGcZVhXIHbbw5tv 5/7 6/23/23, 3:35 AM Congenital adrenal hyperplasia Pathway Consider referring patients with CAH and impaired fertility to a reproductive endocrinologist and/or fertility specialist. C Serial clinical assessment: obtain monitoring for signs of mineralocorticoid deficiency or excess in all patients with classic CAH. B Show 3 more Assessment of treatment response: As per JSNS 2022 guidelines, obtain comprehensive monitoring of treatment using growth velocity, pubertal stage, and bone advancement, in addition to endocrinological data, in pediatric patients with 21-hydroxylase deficiency. E Show 3 more As per ES 2018 guidelines, monitor for signs of corticosteroid excess and inadequate androgen normalization in all patients with classic CAH, in order to optimize the corticosteroid treatment profile. B Show 3 more Surveillance for treatment-related complications: As per JSNS 2022 guidelines, obtain regular monitoring (including physical examinations and endocrinological evaluations) whether corticosteroids are prescribed alone or in combination with mineralocorticoids. B Show 3 more As per ES 2018 guidelines, monitor bone mineral density in adult patients with CAH subjected to a prolonged period of higher-than-average corticosteroid dosing or experiencing a non-traumatic fracture. B Surveillance for testicular tumor: As per JSNS 2022 guidelines, obtain regular ultrasound screening for testicular adrenal rest tumors in > 10 years old male patients with classic CAH. B As per ES 2018 guidelines, obtain periodic testicular ultrasound to assess for the development of testicular adrenal rest tumors in male patients with classic CAH. B Transition from pediatric to adult care: As per JSNS 2022 guidelines, ensure a planned, systematic transition medicine from pediatric to adult healthcare service. E As per ES 2018 guidelines: Consider beginning the transition of adolescent patients with CAH to adult care several years before dismissal from pediatric endocrinology. C Consider eliciting gynecological history and performing examination to ensure functional female anatomy without vaginal stenosis or abnormalities in menstruation in adolescent female patients with CAH. C 9. Quality improvement https://web.pathway.md/diseases/recGcZVhXIHbbw5tv 6/7 6/23/23, 3:35 AM Congenital adrenal hyperplasia Pathway Gender assignment: assign gender as female at birth in 46, XX cases with classic 21- hydroxylase deficiency. Provide continuous psychosocial support and education regarding gender identity by a multidisciplinary team. E Medical alert bracelet: As per JSNS 2022 guidelines, advise patients with 21-hydroxylase deficiency to always wear or carry a medical identification card indicating adrenal insufficiency. B As per ES 2018 guidelines, advise patients with CAH requiring treatment to always wear or carry medical identification indicating that they have adrenal insufficiency. B References 1. Phyllis W Speiser, Wiebke Arlt, Richard J Auchus et al. Congenital Adrenal Hyperplasia Due to Steroid 21 Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018 Nov 1;103 11 4043 4088. Open 2. Tomohiro Ishii, Kenichi Kashimada, Naoko Amano et al. Clinical guidelines for the diagnosis and treatment of 21-hydroxylase deficiency 2021 revision). Clin Pediatr Endocrinol. 2022;31 3 116 143. Open 3. Martin KA, Anderson RR, Chang RJ et al. Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018 Apr 1;103 4 1233 1257. Open 4. A PRADER, H P GURTNER. The syndrome of male pseudohermaphrodism in congenital adrenocortical hyperplasia without overproduction of androgens (adrenal male pseudohermaphrodism)]. Helv Paediatr Acta. 1955 Aug;10 4 397 412. Open https://web.pathway.md/diseases/recGcZVhXIHbbw5tv 7/7