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`C L I N I C A L
`
`P R A C T I C E G U I D E L I N E
`
`Congenital Adrenal Hyperplasia Due to Steroid
`21-Hydroxylase Deficiency: An Endocrine
`Society* Clinical Practice Guideline
`
`Phyllis W. Speiser,1,2 Wiebke Arlt,3 Richard J. Auchus,4 Laurence S. Baskin,5
`Gerard S. Conway,6 Deborah P. Merke,7,8 Heino F. L. Meyer-Bahlburg,9
`Walter L. Miller,5 M. Hassan Murad,10 Sharon E. Oberfield,11 and Perrin C. White12
`
`1Cohen Children’s Medical Center of New York, New York, New York 11040; 2Zucker School of Medicine at
`Hofstra/Northwell, Hempstead, New York 11549; 3University of Birmingham, Birmingham B15 2TT, United
`Kingdom; 4University of Michigan, Ann Arbor, Michigan 48109; 5University of California San Francisco, San
`Francisco, California 94143; 6University College London Hospitals, London NW1 2BU, United Kingdom;
`7National Institutes of Health Clinical Center, Bethesda, Maryland, 20892; 8Eunice Kennedy Shriver National
`Institute of Child Health and Human Development, Bethesda, Maryland 20892; 9New York State Psychiatric
`Institute, Vagelos College of Physicians & Surgeons of Columbia University, New York, New York 10032;
`10Mayo Clinic’s Evidence-Based Practice Center, Rochester, Minnesota 55905; 11NewYork–Presbyterian,
`Columbia University Medical Center, New York, New York 10032; and 12University of Texas Southwestern
`Medical Center, Dallas, Texas 75390
`
`ORCiD numbers: 0000-0002-0565-8325 (P. W. Speiser).
`
`*Cosponsoring Associations: CARES Foundation, European Society of
`Endocrinology, European Society for Paediatric Endocrinology, Socie-
`ties for Pediatric Urology, and Pediatric Endocrine Society.
`
`Objective: To update the congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency
`clinical practice guideline published by the Endocrine Society in 2010.
`
`Conclusions: The writing committee presents updated best practice guidelines for the clinical
`management of congenital adrenal hyperplasia based on published evidence and expert opinion
`with added considerations for patient safety, quality of life, cost, and utilization. (J Clin Endocrinol
`Metab 103: 4043–4088, 2018)
`
`List of Recommendations
`
`Newborn screening
`
`Cost-effectiveness
`
`1.1 We recommend that all newborn screening programs
`incorporate screening for congenital adrenal hyper-
`plasia due to 21-hydroxylase deficiency. (1|s)
`1.2 We recommend that first-tier screens use 17-
`hydroxyprogesterone assays standardized to a
`
`ISSN Print 0021-972X ISSN Online 1945-7197
`Printed in USA
`Copyright © 2018 Endocrine Society
`Received 27 August 2018. Accepted 27 August 2018.
`First Published Online 27 September 2018
`
`common technology with norms stratified by
`gestational age. (1|s)
`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.
`1.3 We recommend that screening laboratories employ
`a second-tier screen by liquid chromatography–
`tandem mass spectrometry in preference to all other
`
`Abbreviations: 17OHP, 17-hydroxyprogesterone; 21OHD, 21-hydroxylase deficiency;
`BMI, body mass index; BMD, bone mineral density; CAH, congenital adrenal hyperplasia
`(both classic and nonclassic); Dex, dexamethasone; DSD, disorders of sex development;
`GC, glucocorticoid; LC-MS/MS, liquid chromatography–tandem mass spectrometry; MC,
`mineralocorticoid; NCCAH, nonclassic congenital adrenal hyperplasia; PRA, plasma renin
`activity; QOL, quality of life; SDS, SD score; TART, testicular adrenal rest tumor.
`
`doi: 10.1210/jc.2018-01865
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`Guidelines on Congenital Adrenal Hyperplasia
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`J Clin Endocrinol Metab, November 2018, 103(11):4043–4088
`
`methods (e.g., genotyping) to improve the positive
`predictive value of congenital adrenal hyperplasia
`screening. (1|ss)
`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.
`
`Prenatal treatment of congenital
`adrenal hyperplasia
`
`2.1 We advise that clinicians continue to regard pre-
`natal therapy as experimental. Thus, we do not
`recommend specific treatment protocols.
`(Un-
`graded Good Practice Statement)
`2.2 In pregnant women at risk for carrying a fetus
`affected with congenital adrenal hyperplasia and
`who are considering prenatal treatment we rec-
`ommend 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|s)
`2.3 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.
`(Ungraded Good
`Practice Statement)
`
`3.4 In individuals with congenital adrenal hyperplasia,
`we suggest genotyping only when results of the
`adrenocortical profile after a cosyntropin stimu-
`lation test are equivocal, or cosyntropin stimula-
`tion cannot be accurately performed (i.e., patient
`receiving glucocorticoid), or for purposes of ge-
`netic counseling. (2|s)
`Technical remark: Genotyping at least one parent
`aids in the interpretation of genetic test results
`because of the complexity of the CYP21A2 locus.
`
`Treatment of classic congenital adrenal hyperplasia
`
`4.1 In growing individuals with classic congenital
`adrenal hyperplasia, we recommend maintenance
`therapy with hydrocortisone. (1|s)
`4.2 In growing individuals with congenital adrenal hy-
`perplasia, we recommend against the use of oral
`hydrocortisone suspension and against the chronic
`use of long-acting potent glucocorticoids. (1|s)
`4.3 In the newborn and in early infancy, we recom-
`mend using fludrocortisone and sodium chloride
`supplements to the treatment regimen. (1|s)
`4.4 In adults with classic congenital adrenal hyper-
`plasia, we recommend using daily hydrocortisone
`and/or long-acting glucocorticoids plus mineral-
`ocorticoids, as clinically indicated. (1|s)
`4.5 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|s)
`4.6 In all individuals with classic congenital adrenal hy-
`perplasia, we recommend monitoring for signs of
`mineralocorticoid deficiency or excess. (1|s)
`
`Diagnosis of congenital adrenal hyperplasia
`
`Stress dosing
`
`3.1 In infants with positive newborn screens for con-
`genital adrenal hyperplasia we recommend referral
`to pediatric endocrinologists (if regionally avail-
`able) and evaluation by cosyntropin stimulation
`testing as needed. (1|s)
`3.2 In symptomatic individuals past infancy, we rec-
`ommend screening with an early-morning (before
`8 AM) baseline serum 17-hydroxyprogesterone
`measurement by liquid chromatography–tandem
`mass spectrometry. (1|s)
`3.3 In individuals with borderline 17-hydroxyprogester-
`one levels, we recommend obtaining a complete
`adrenocortical profile after a cosyntropin stimulation
`test to differentiate 21-hydroxylase deficiency from
`other enzyme defects. (1|s)
`
`4.7 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 in-
`creasing the glucocorticoid dosage. (1|s)
`4.8 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 in-
`creased glucocorticoid doses. (1|ss)
`4.9 In patients with congenital adrenal hyperplasia who
`require treatment, we recommend always wearing
`or carrying medical identification indicating that
`they have adrenal insufficiency. (1|s)
`
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`Technical remark: Risks and benefits of gluco-
`corticoid therapy should be considered and dis-
`cussed with the patient’s family.
`5.2 In asymptomatic nonpregnant individuals with non-
`classic congenital adrenal hyperplasia we recommend
`against glucocorticoid treatment. (1|s)
`5.3 In previously treated patients with nonclassic con-
`genital adrenal hyperplasia we suggest giving the
`option of discontinuing therapy when adult height is
`attained or other symptoms resolve. (2|s)
`5.4 In adult women with nonclassic congenital
`adrenal hyperplasia who also have patient-important
`hyperandrogenism or infertility we suggest gluco-
`corticoid treatment. (2|ss)
`5.5 In most adult males with nonclassic congenital adrenal
`hyperplasia, we suggest that clinicians generally not
`prescribe daily glucocorticoid therapy. (2|sss)
`Technical remark: Exceptions include infertility,
`testicular adrenal rest tumors or adrenal tumors,
`and phenotypes that are intermediate between
`classic and nonclassic phenotypes.
`5.6 In patients with nonclassic congenital adrenal hy-
`perplasia, we suggest hydrocortisone stress dosing
`for major surgery, trauma, or childbirth only if a
`patient has a suboptimal (,14 to 18 mg/dL, ,400
`to 500 nmol/L) cortisol response to cosyntropin or
`iatrogenic adrenal suppression. (2|sss)
`Technical remark: A range is given for cortisol cut
`points due to greater specificity of newer cortisol
`assays (see below).
`
`Long-term management of patients with congenital
`adrenal hyperplasia
`
`Transition to adult care
`
`6.1 In adolescent patients with congenital adrenal hy-
`perplasia, we suggest that the transition to adult care
`begins several years prior to dismissal from pediatric
`endocrinology. (2|sss)
`Technical remark: We advise the use of joint clinics
`comprised of pediatric, reproductive, and adult en-
`docrinologists and urologist during this transition.
`6.2 In adolescent females with congenital adrenal
`hyperplasia, we suggest a gynecological history
`and examination to ensure functional
`female
`anatomy without vaginal stenosis or abnormali-
`ties in menstruation. (2|ss)
`
`Genetic counseling
`
`6.3 In children with congenital adrenal hyperplasia,
`adolescents transitioning to adult care, adults with
`
`4.10 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 min-
`eralocorticoid) during intercurrent illness. (1|s)
`4.11 We recommend equipping every patient with con-
`genital adrenal hyperplasia with a glucocorticoid
`injection kit for emergency use and providing ed-
`ucation on parenteral self-administration (young
`adult and older) or lay administration (parent or
`guardian) of emergency glucocorticoids. (1|s)
`
`Monitoring therapy
`
`4.12 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|ss)
`4.13 In pediatric patients with congenital adrenal hyper-
`plasia, we recommend conducting regular assess-
`ments 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|ss)
`4.14 In pediatric patients with congenital adrenal hy-
`perplasia under the age of 2 years, we advise annual
`bone age assessment until near-adult height is
`attained. (Ungraded Good Practice Statement)
`4.15 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|ss)
`4.16 In adults with congenital adrenal hyperplasia, we
`recommend monitoring treatment through con-
`sistently timed hormone measurements relative to
`medication schedule and time of day. (1|ss)
`4.17 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|s)
`
`Treatment of nonclassic congenital
`adrenal hyperplasia
`
`5.1 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 con-
`genital adrenal hyperplasia. (2|ss)
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`Guidelines on Congenital Adrenal Hyperplasia
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`J Clin Endocrinol Metab, November 2018, 103(11):4043–4088
`
`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|ss)
`
`Fertility counseling
`
`6.4 In individuals with congenital adrenal hyperplasia
`and impaired fertility we suggest referral to a
`reproductive endocrinologist and/or fertility spe-
`cialist. (2|ss)
`
`Management of congenital adrenal hyperplasia
`and nonclassic congenital adrenal hyperplasia
`during pregnancy
`
`6.5 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|ss)
`6.6 In women with congenital adrenal hyperplasia who
`are pregnant, we advise management by an endo-
`crinologist familiar with congenital adrenal hyper-
`plasia. (Ungraded Good Practice Statement)
`6.7 In women with congenital adrenal hyperplasia
`who become pregnant we recommend con-
`tinued prepregnancy doses of hydrocortisone/
`prednisolone and fludrocortisone therapy, with
`dosage adjustments if symptoms and signs of
`glucocorticoid insufficiency occur. (1|ss)
`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.
`6.8 In women with congenital adrenal hyperplasia
`who are pregnant, or trying to become preg-
`nant, we recommend against using glucocorti-
`coids
`that
`traverse the placenta,
`such as
`dexamethasone. (1|ss)
`6.9 In women with congenital adrenal hyperplasia
`who are pregnant, we advise that the birthing plan
`includes an obstetric specialist. (Ungraded Good
`Practice Statement)
`
`Surveillance for long-term complications of
`congenital adrenal hyperplasia and its treatment
`
`6.10 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 met-
`abolic syndrome and related sequelae. (2|sss)
`6.11 In adult patients with congenital adrenal hyper-
`plasia, 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|sss)
`6.12 In adults with classic congenital adrenal hyper-
`plasia, we recommend against routine adrenal
`imaging. (1|sss)
`Technical remark: Reserve adrenal imaging for
`individuals with classic congenital adrenal hy-
`perplasia 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.
`6.13 In males with classic congenital adrenal hyper-
`plasia, we recommend periodic testicular ultra-
`sound to assess for the development of testicular
`adrenal rest tumors. (1|ss)
`6.14 In patients with congenital adrenal hyperplasia, we
`recommend against routine evaluation for cardiac
`and metabolic disease beyond that recommended
`for the general population. (1|ss)
`Technical remark: Clinicians should use their own
`judgment for the above procedures.
`
`Restoring functional anatomy by surgery in
`individuals with congenital adrenal hyperplasia
`
`7.1 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 ob-
`servation until the child is older. (Ungraded Good
`Practice Statement)
`Technical remark: Surgeries should be performed
`only in centers with experienced pediatric surgeons/
`urologists, pediatric endocrinologists, pediatric
`anesthesiologists, behavioral/mental health pro-
`fessionals, 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.
`7.2 In severely virilized females, we advise discussion
`about early surgery to repair the urogenital sinus.
`(Ungraded Good Practice Statement)
`7.3 In the treatment of minors with congenital adrenal
`hyperplasia, we advise that all surgical decisions
`remain the prerogative of families (i.e., parents
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`CAH continues to be serum 17-hydroxyprogesterone
`(17OHP) measurements, most often with cosyntropin
`stimulation. The advent of commercially available serum
`21-deoxycortisol measurements may simplify identifi-
`cation of CAH carriers. The use of this analyte, or of
`steroid profiling to monitor treatment, has yet to be
`tested.
`New human and animal data convey further concerns
`regarding prenatal dexamethasone (Dex) treatment. No
`international registry has yet been established for long-
`term outcomes of individuals treated prenatally with
`Dex. Although noninvasive prenatal diagnosis of fetal
`sex is now commonly performed, CAH genotype has
`been reported only in a proof-of-concept study and is not
`routinely available. This guideline now includes more
`detailed protocols for adults, especially pregnant women.
`We suggest more moderate use of stress dosing during
`minor illness or minor surgery in patients with CAH.
`Over time, the approach to genital reconstructive
`surgery has changed, incorporating more shared decision-
`making among parents, patients, surgeons, endocrinolo-
`gists, mental health providers, and support groups. A
`systematic review and meta-analysis of published lit-
`erature on surgery for females with CAH through early
`2017 could not identify enough scientifically rigorous
`studies delineating a favorable benefit-to-risk ratio for
`either early or late elective genital reconstructive sur-
`gery for females with CAH. We maintain that CAH
`should not be equated with other, rarer 46,XX or XY
`disorders of sex development (DSD) in formulating
`treatment guidelines and policies. Our goals have been
`consistently directed at preserving functional anatomy
`and fertility.
`In another new meta-analysis, investigators found no
`direct well-controlled evidence of cardiovascular or
`metabolic morbidity and mortality associated with CAH.
`Thus, we recommend that individuals with CAH should
`be monitored according to conventional guidelines for
`monitoring CAH-unaffected children, adolescents, and
`adults. Retaining patients with CAH after “graduation”
`from pediatric care is an important goal, and we have
`stressed the need for improved mental health monitoring.
`Finally,
`in this guideline, we discuss potential new
`therapies and future ways to improve quality of life
`(QOL) for individuals with CAH.
`
`Definition, pathophysiology, and morbidities
`of CAH
`CAH is a group of autosomal recessive disorders
`characterized by impaired cortisol synthesis. Based
`on neonatal screening and national case registries,
`the worldwide incidence in most studies ranges from
`;1:14,000 to 1:18,000 births, but the condition is more
`
`and assent from older children) in joint decision-
`making with experienced surgical consultants.
`(Ungraded Good Practice Statement)
`7.4 In female patients with congenital adrenal hy-
`perplasia for whom surgery is chosen, we suggest
`vaginoplasty using urogenital mobilization and,
`when chosen, neurovascular-sparing clitoroplasty
`for severe clitoromegaly. (2|sss)
`
`Experimental therapies and future directions
`
`General considerations and unmet clinical needs
`
`8.1 In patients with congenital adrenal hyperplasia, we
`advise against using experimental treatment ap-
`proaches outside of formally approved clinical
`trials. (Ungraded Good Practice Statement)
`
`Adrenalectomy
`
`8.2 In patients with congenital adrenal hyperplasia, we
`suggest that bilateral adrenalectomy not be per-
`formed. (2|sss)
`
`Mental health
`
`9.1 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|ss)
`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 special-
`ized expertise in assessing and managing con-
`genital adrenal hyperplasia–related psychosocial
`problems.
`
`Introduction
`
`Summary of changes in 2018 congenital adrenal
`hyperplasia guidelines
`Since the publication of the 2010 Endocrine Society
`clinical practice guideline for congenital adrenal hyper-
`plasia [CAH (1)], there have been several changes.
`Neonatal diagnosis methods have been refined to use
`gestational age in addition to birth weight for cut-point
`interpretation or to employ liquid chromatography–
`tandem mass spectrometry (LC-MS/MS) as a secondary
`screening test. The standard for confirming a diagnosis of
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`Guidelines on Congenital Adrenal Hyperplasia
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`
`prevalent in small, genetically isolated groups with a smaller
`gene pool, particularly in remote geographic regions [e.g.,
`Alaskan Yupiks, among others; Table 1 (2–23)]. CAH is
`caused in ;95% of cases by mutations in CYP21A2, the
`gene encoding adrenal steroid 21-hydroxylase (P450c21)
`(24, 25). This enzyme converts 17OHP to 11-deoxycortisol
`and progesterone to deoxycorticosterone, with these
`products being precursors for cortisol and aldosterone.
`The blockage of cortisol synthesis leads to cortico-
`tropin stimulation of the adrenal cortex, with accu-
`mulation of cortisol precursors that are diverted to sex
`hormone biosynthesis (Fig. 1). A cardinal feature of
`classic or severe virilizing CAH in newborn females is
`abnormal development of the external genitalia with
`variable extent of virilization. Evaluation for CAH
`needs to be considered for infants found to have
`bilateral nonpalpable gonads. In 75% of cases with
`severe enzyme deficiency,
`inadequate aldosterone
`production causes salt wasting, failure to thrive, and
`potentially fatal hypovolemia and shock. Distinctions
`between various CAH phenotypes are detailed in White
`and Speiser (27). Newborn screening, now universal in
`the United States (28) and in many other developed
`countries (19), can mitigate these complications. Missed
`diagnosis of salt-losing CAH is associated with increased
`risk for early neonatal morbidity and mortality. If simple
`
`virilizing CAH is not recognized and treated, both girls
`and boys may undergo rapid postnatal growth and
`virilization.
`In addition to the “classic salt-wasting” and “simple
`virilizing” forms of CAH diagnosed in infancy, there is
`also a mild or “nonclassic” form, which features variable
`degrees of postnatal androgen excess but is sometimes
`asymptomatic (29). The mild subclinical impairment of
`cortisol synthesis in nonclassic CAH (NCCAH) generally
`does not lead to Addisonian crises. Based on haplotype
`association studies, nonclassic forms of CAH were es-
`timated to have a prevalence of 1:500 to 1:1000 in the
`general white population but up to 1:50 to 1:100 among
`populations with high rates of consanguineous marriages
`(30). More recent CYP21A2 genotype analysis indicates
`that NCCAH has an overall frequency of ;1:200 (95%
`confidence level, 1:100 to 1:280)
`in the US pop-
`ulation (31).
`Disease severity correlates with CYP21A2 allelic
`variation. Genotyping individuals with CAH is fraught
`with error due to the complexity of gene duplications,
`deletions, and rearrangements within chromosome
`6p21.3 (32). Almost 300 CYP21A2 mutations are
`known (33), but large deletions and a splicing mutation
`(intron 2, IVS-13 A/C→G, 213 nucleotides from the
`splice acceptor site) that ablate enzyme activity comprise
`
`Table 1. Comparative Incidence of Classic CAH in Different Populations
`
`Country
`Argentina (Buenos Aires)
`Australia (Western Australia)a
`Australia (New South Wales)
`Australiaa
`Brazil
`Brazil (state of Goias)
`Brazil (state of Minas Gerais)
`Brazil (state of Rio Grande do Sul)
`China
`Croatia
`Cuba
`Czech Republic
`France
`Germany (Bavaria)
`India
`Japan (Sapporo)
`Japan (Tokyo)
`New Zealand
`Sweden
`United Kingdoma
`United Arab Emirates
`Uruguay
`
`Complete National
`Data?
`No
`No
`No
`Yes
`No
`No
`No
`No
`No
`Yes
`Yes
`Yes
`Yes
`No
`No
`No
`No
`Yes
`Yes
`Yes
`Yes
`Yes
`
`Sample Size
`80,436
`550,153
`185,854
`
`748,350
`82,603
`159,415
`108,409
`30,000
`532,942
`621,303
`545,026
`6,012,798
`1,420,102
`55,627
`498,147
`2,105,108
`1,175,988
`2,737,932
`
`750,365
`190,053
`
`1/Incidence
`8937
`14,869
`15,488
`18,034
`14,967
`10,325
`19,927
`13,551
`6084
`14,403
`15,931
`11,848
`15,699
`12,457
`6334
`20,756
`21,264
`26,727
`14,260
`18,248
`9030
`15,800
`
`PPV % (Term Infants
`or Overall)
`50
`N/A
`1.8
`N/A
`
`28.6
`2.1
`1.6
`
`0.3
`1.6
`2.3
`5
`
`8
`25.8
`
`25.1
`N/A
`
`Reference
`(2)
`(3)
`(4)
`(4)
`(5)
`(6)
`(7)
`(8)
`(9)
`(10)
`(11)
`(12)
`(13)
`(14)
`(15)
`(16)
`(17)
`(18)
`(19)
`(20)
`(21)
`(22)
`
`Data are from newborn screening except those designated as coming from national case registries. Data are from studies published in 2008 and later.
`Earlier studies are summarized by van der Kamp and Wit 2004 (23) and Gidlof et al. 2014 (19).
`Abbreviations: N/A, not available; PPV, positive predictive value (for newborn screening; see section 1).
`aData are from national case registries.
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`doi: 10.1210/jc.2018-01865
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`4049
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`haploinsufficiency of tenascin-X, encod-
`ed by the TNXB gene, which overlaps
`CYP21A2 (37).
`amino sub-
`A nonconservative
`stitution in exon 4 (p.Ile172Asn) that
`preserves ;1% to 2% of enzyme
`function is associated with simple vir-
`ilizing classic CAH (38). A point mu-
`tation in exon 7 (p.Val281Leu) that
`preserves 20% to 50% of enzyme
`function (38) accounts for most NCCAH
`alleles (31, 39, 40). Because many
`compound heterozygous patients carry
`more than one mutation on either or
`both CYP21A2 alleles, there is a wide
`spectrum of phenotypes (35).
`
`Commissioned
`Systematic Review
`
`The writing committee commissioned
`two systematic reviews: one concern-
`ing the cardiac and metabolic mor-
`bidities associated with CAH (41), and
`the second to determine whether and
`when clinicians should perform genital
`surgery (42).
`The first review (41) summarized 20
`observational
`studies and demon-
`strated small but significant increases
`in systolic and diastolic blood pressure,
`insulin resistance, and carotid intima
`thickness in individuals with CAH
`compared with non-CAH controls.
`The quality of evidence (i.e., certainty
`in these estimates) was low due to the
`observational nature of the evidence,
`risk of bias, and heterogeneity. Fur-
`thermore, population-based studies
`found higher prevalence of hyper-
`tension, hyperlipidemia, and type 2
`diabetes in adults with CAH than in
`non-CAH controls.
`The second review (42) summarized
`29 observational studies evaluating pa-
`tients who had undergone surgery at a
`mean age of 3 years. The studies eval-
`uated various surgical techniques and
`reported good overall patient and sur-
`geon satisfaction with cosmetic and
`functional outcomes. The review also provided estimates of
`surgical complication rates and sexual function. Such evi-
`dence was also of low quality and carried a high risk of bias.
`
`Figure 1. (a) Normal fetal adrenal steroidogenesis. Because the fetal adrenal has low levels of
`3b-hydroxysteroid dehydrogenase, most steroidogenesis is directed toward dehydroepiandrosterone
`(DHEA) and thence to DHEA sulfate, but small amounts of steroids enter the pathways toward
`aldosterone and cortisol. The adrenal 21-hydroxylase P450c21 is essential in both pathways.
`The adrenal can synthesize small amounts of testosterone via 17bHSD5 (AKR1C3). Included to
`the lower right is the 11-oxyandrogen pathway, in which androstenedione is converted in the
`adrenal to 11b-hydroxyandrostenedione (11OHA4) and then in the adrenal and/or peripheral
`tissues to 11-ketoandrostenedione and ultimately 11-ketotestosterone (11KT). The production
`of 11OHA4 and 11KT is an important pathway in postnatal life and may also occur in the fetal
`adrenal. (b) In the absence of the 21-hydroxylase activity of P450c21, three pathways lead to
`androgens. First, the pathway from cholesterol to DHEA remains intact. Although much DHEA is
`inactivated to DHEA sulfate, the increased production of DHEA will lead to some DHEA being
`converted to testosterone and dihydrotestosterone (DHT). Second, although minimal amounts of
`17OHP are converted to androstenedione in the normal adrenal, the massive amounts of 17OHP
`produced in CAH permit some 17OHP to be converted to androstenedione and then to
`testosterone. Third, the alternative pathway depends on the 5a and 3a reduction of 17OHP to
`17OH-allopregnanolone. This steroid is readily converted to androstanediol, which can then be
`oxidized to DHT by an oxidative 3a-hydroxysteroid dehydrogenase (3aHSD) enzyme. The role of
`the alternative pathway in CAH is evidenced by increased levels of metabolites of its unique
`steroidal intermediates in the urine of infants, children, and adults with CAH (26).
`
`;50% of classic CAH alleles (34–36). Approximately
`5% to 10% of patients with salt-wasting CAH have the
`hypermobility form of Ehlers-Danlos syndrome due to
`
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`Speiser et al
`
`Guidelines on Congenital Adrenal Hyperplasia
`
`J Clin Endocrinol Metab, November 2018, 103(11):4043–4088
`
`1. Newborn Screening
`
`Cost-effectiveness
`
`1.1 We recommend that all newborn screening pro-
`grams incorporate screening for CAH due to
`21-hydroxylase deficiency (21OHD). (1|s)
`
`Evidence
`Early recognition and treatment of CAH can prevent
`serious morbidity and mortality. Currently, all 50 states
`in the United States, 35 other countries, and portions of
`17 additional countries screen for CAH. According to
`screening results, the incidence of classic CAH in most
`populations is ;1:14,000 to 1:18,000. Table 1 sum-
`marizes data from 2008 onward; data collected from
`1997 to 2007 are similar (23, 43, 44).
`Screening markedly reduces the time to diagnosis of
`infants with CAH (45–48), consequently reducing
`morbidity and mortality. A retrospective analysis of
`neonatal dried blood samples that were not screened for
`CAH from cases of sudden infant death in the Czech
`Republic and Austria identified three genotypically
`confirmed cases of classic CAH among 242 samples
`screened (49). In contrast, a large population-based study
`in the Manchester area of the United Kingdom found no
`CAH cases among 1198 dried blood samples from in-
`fants who had died between 5 days and 6 months of age
`(50). Males with salt-wasting CAH are more likely than
`fem