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Cited by 1,484Sexual Differentiation and DisordersAdrenal Hormones and DisordersMetabolism and Genetic Disorders

Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society Clinical Practice Guideline.

Open access
Speiser, Phyllis W., Azziz, Ricardo, Baskin, Laurence S., Ghizzoni, Lucia, Hensle, Terry W., Merke, Deborah P., Meyer-Bahlburg, Heino F. L., Miller, Walter L. +4 more·2010·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2009-2631PMC PMC2936060
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Abstract

OBJECTIVE: We developed clinical practice guidelines for congenital adrenal hyperplasia (CAH). PARTICIPANTS: The Task Force included a chair, selected by The Endocrine Society Clinical Guidelines Subcommittee (CGS), ten additional clinicians experienced in treating CAH, a methodologist, and a medical writer. Additional experts were also consulted. The authors received no corporate funding or remuneration. CONSENSUS PROCESS: Consensus was guided by systematic reviews of evidence and discussions. The guidelines were reviewed and approved sequentially by The Endocrine Society's CGS and Clinical Affairs Core Committee, members responding to a web posting, and The Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments. CONCLUSIONS: We recommend universal newborn screening for severe steroid 21-hydroxylase deficiency followed by confirmatory tests. We recommend that prenatal treatment of CAH continue to be regarded as experimental. The diagnosis rests on clinical and hormonal data; genotyping is reserved for equivocal cases and genetic counseling. Glucocorticoid dosage should be minimized to avoid iatrogenic Cushing's syndrome. Mineralocorticoids and, in infants, supplemental sodium are recommended in classic CAH patients. We recommend against the routine use of experimental therapies to promote growth and delay puberty; we suggest patients avoid adrenalectomy. Surgical guidelines emphasize early single-stage genital repair for severely virilized girls, performed by experienced surgeons. Clinicians should consider patients' quality of life, consulting mental health professionals as appropriate. At the transition to adulthood, we recommend monitoring for potential complications of CAH. Finally, we recommend judicious use of medication during pregnancy and in symptomatic patients with nonclassic CAH.

Integrity signals

Registry

Crossref · 10.1210/jc.2009-2631

Cites

353 of 353 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 331 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Retrospective analysis of sudden infant death in the Czech Republic and Austria identified three genotype-proven cases of classic congenital adrenal hyperplasia among 242 samples screened.

    “Indeed, retrospective analysis of sudden infant death in the Czech Republic and Austria identified three genotype-proven cases of classic CAH among 242 samples screened (23).”
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  • Findingcitation

    Females outnumber males in some but not all retrospective studies in which congenital adrenal hyperplasia was diagnosed clinically.

    “In fact, females outnumber males in some (1,24,25) but not all (26) retrospective studies in which CAH was diagnosed clinically.”
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  • Findingcitation

    Screening markedly reduces the time to diagnosis of infants with congenital adrenal hyperplasia.

    “Screening markedly reduces the time to diagnosis of infants with CAH (19 -22).”
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  • Findingcitation

    The delay before correct sex assignment of severely virilized females is markedly reduced by screening.

    “Although salt-wasting males would seem to derive the greatest benefit from screening programs, the delay before correct sex assignment of severely virilized females is also markedly reduced (22,31).”
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  • Findingcitation

    In The Netherlands and Switzerland, adopting gestational age criteria improved the positive predictive value of screening.

    “Indeed, in The Netherlands and Switzerland, adopting gestational age criteria improved the positive predictive value of screening (29,39).”
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    Findingcitation

    Antenatal corticosteroid treatment might reduce 17-hydroxyprogesterone levels, but inconsistent effects have been observed in practice.

    “Finally, antenatal corticosteroid treatment (as used to induce lung maturation in fetuses at risk for premature birth) might reduce 17-OHP levels, but inconsistent effects have been observed in practice (40,41).”
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    Findingcitation

    A single approach to prenatal treatment has been studied, but optimal dosing and duration of treatment have not been determined.

    “A single approach to prenatal treatment has been studied (57,58), but optimal dosing and duration of treatment have not been determined.”
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    Findingcitation

    There are no universally accepted standards for stratifying infants, but most U.S. laboratories use a series of birth weight-adjusted cutoffs.

    “There are no universally accepted standards for stratifying infants, but most U.S. laboratories use a series of birth weight-adjusted cutoffs (9,36,37).”
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    Findingcitation

    Both RIAs and ELISAs have been almost completely supplanted by automated time-resolved dissociation-enhanced lanthanide fluoroimmunoassay (DELFIA) in at least 45 states and most European countries.

    “Both RIAs and ELISAs have been almost completely supplanted (9) (in at least 45 states and most European countries) by automated time-resolved dissociation-enhanced lanthanide fluoroimmunoassay (DELFIA) (35).”
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    Findingcitation

    Several studies of genotyping of samples from screening programs have suggested that this is a potentially useful adjunct to hormonal measurements, but no large-scale study of efficacy has been reported as a second-tier screen in actual use.

    “Several studies of genotyping of samples from screening programs have suggested that this is a potentially useful adjunct to hormonal measurements (48 -51), but no large-scale study of efficacy has been reported as a second-tier screen in actual use.”
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    Findingcitation

    Calculations of costs per life-year saved are sensitive to the assumed death rate, and recent estimates have ranged widely from $20,000 to $250,000-300,000.

    “Calculations of costs per lifeyear saved are sensitive to the assumed death rate, and recent estimates have ranged widely from $20,000 (32) to $250,000 -300,000 (33).”
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    Findingcitation

    The data suggested greatest risk for exposure between 1-8 weeks, but the numbers were small (odds ratio = 7.3; 95% confidence interval = 1.8-29.4).

    “The data suggested greatest risk for exposure between 1-8 weeks, but the numbers were small (odds ratio ϭ 7.3; 95% confidence interval ϭ 1.8 -29.4) (83).”
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    Findingcitation

    Those never treated were most virilized, averaging 3.75.

    “Those never treated were most virilized, averaging 3.75.”
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    Findingcitation

    Among 118 women treated to term who responded to a mailed questionnaire, the mean pregnancy-associated weight gain was 7.1 lbs (3.2 kg) greater than that experienced by untreated women (P<0.005); these women also reported increased striae (P=0.01) and increased edema (P=0.02) but no reported increase in hypertension or gestational diabetes.

    “Among 118 women treated to term who responded to a mailed questionnaire, the mean pregnancy-associated weight gain was 7.1 lbs (3.2 kg) greater than that experienced by untreated women (P Ͻ 0.005); these women also reported increased striae (P ϭ 0.01) and increased edema (P ϭ 0.02) but no reported increase in hypertension or gestational diabetes (58).”
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    Findingcitation

    In the largest single series, among 25 CAH-affected females receiving dexamethasone before the ninth week of pregnancy, 11 had normal female genitalia, 11 had minimal virilization (Prader stages 1-2), and three were virilized (Prader stage 3); the mean Prader score for this group was 1.0.

    “Among 25 CAH-affected females receiving dexamethasone before the ninth week of pregnancy, 11 had normal female genitalia, 11 had minimal virilization (Prader stages 1-2), and three were virilized (Prader stage 3); the mean Prader score for this group was 1.0.”
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    Findingcitation

    One year after prenatal exposure of nonhuman primates to 120 g/kg dexamethasone, there were reduced pancreatic β-cell numbers, impaired glucose tolerance, increased systolic and diastolic blood pressure, and reduced postnatal growth despite normal birth weight.

    “One year after prenatal exposure of nonhuman primates to 120 g/kg dexamethasone, there were reduced pancreatic ␤-cell numbers, impaired glucose tolerance, increased systolic and diastolic blood pressure, and reduced postnatal growth despite normal birth weight (92).”
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    Findingcitation

    In response to a questionnaire, compared with untreated controls, treated women reported increased appetite (P<0.01), rapid weight gain (P<0.02), and edema (P=0.04), and 30 of the 44 women indicated they would decline prenatal treatment of a subsequent pregnancy.

    “However, in response to a questionnaire, compared with untreated controls, treated women reported increased appetite (P Ͻ 0.01), rapid weight gain (P Ͻ 0.02), and edema (P ϭ 0.04), and 30 of the 44 women indicated they would decline prenatal treatment of a subsequent pregnancy (72).”
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    Findingcitation

    A carefully controlled study of 44 women receiving prenatal dexamethasone (only six to term) found increased weight gain in mothers treated during the first trimester, but this difference was absent at term; there were no differences in maternal blood pressure, glycosuria, proteinuria, length of gestation, or placental weight.

    “A carefully controlled study of 44 women receiving prenatal dexamethasone (only six to term) found increased weight gain in mothers treated during the first trimester, but this difference was absent at term.There were no differences in maternal blood pressure, glycosuria, proteinuria, length of gestation, or placental weight.”
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    Findingcitation

    A review lacking a control group indicated that 9-30% of treated women complained of mild gastric distress, weight gain, mood swings, pedal edema, and mild hypertension and that only 1.5% of 253 treated women had serious complications including striae, large weight gain, hypertension, preeclampsia, and gestational diabetes.

    “A review lacking a control group indicated that 9 -30% of treated women complained of mild gastric distress, weight gain, mood swings, pedal edema, and mild hypertension and that only 1.5% of 253 treated women had serious complications including striae, large weight gain, hypertension, preeclampsia, and gestational diabetes (57).”
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    Findingcitation

    Follow-up reports of prenatally treated children have reported birth weights in the normal range but are nevertheless reduced by about 0.4-0.6 kg in the largest studies.

    “Follow-up reports of prenatally treated children have reported birth weights in the normal range (56,57,71,72) but are nevertheless reduced by about 0.4 -0.6 kg in the largest studies (58).”
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  • May combine two claims.

    Findingcitation

    No teratogenic effects have been identified with high-dose glucocorticoids administered during gestation; however, these studies concerned steroids that are inactivated by placental 11β-HSD2 and as such do not affect the fetus.

    “No teratogenic effects have been identified with high-dose GCs administered during gestation; however, these studies concerned steroids that are inactivated by placental 11␤-HSD2 and as such do not affect the fetus (80,81).”
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    Findingcitation

    The prevalence of testicular adrenal rests in boys with classic CAH aged 2-18 years varies from 21-28%; there have been no such studies in NCCAH males.

    “The prevalence of testicular adrenal rests in boys with classic CAH aged 2-18 yr varies from 21-28% (154 -156); there have been no such studies in NCCAH males.”
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  • May combine two claims.

    Findingcitation

    Heterozygotes have slightly elevated 17-OHP levels after ACTH stimulation, but there is overlap with unaffected subjects.

    “Heterozygotes have slightly elevated 17-OHP levels after ACTH stimulation, but there is overlap with unaffected subjects (115).”
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    Findingcitation

    Testicular masses in boys with classic CAH are usually bilateral and smaller than 2 cm in diameter and therefore not palpable but detectable by ultrasound.

    “Testicular masses in boys with classic CAH are usually bilateral and smaller than 2 cm in diameter and therefore not palpable but detectable by ultrasound (US) (154 -156).”
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    Findingcitation

    The estimated growth-suppressive effect of prednisolone is about 15-fold more potent than hydrocortisone, and dexamethasone is 70- to 80-fold more potent.

    “In one trial, the estimated growth-suppressive effect of prednisolone was about 15-fold more potent than HC (119); dexamethasone is 70-to 80-fold more potent (120).”
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    Findingcitation

    The parents of the prenatally treated children described them as being more sociable than controls (P=0.042); there were no differences in psychopathology, behavioral problems, or adaptive functioning.

    “The parents of the prenatally treated children described them as being more sociable than controls (P ϭ 0.042); there were no differences in psychopathology, behavioral problems, or adaptive functioning (105).”
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    Findingcitation

    Hydrocortisone suspension and hydrocortisone tablets are not bioequivalent, and hydrocortisone oral suspension may be inadequate to control CAH in children due to uneven distribution of the drug in liquid.

    “HC suspension and HC tablets are not bioequivalent, and HC oral suspension may be inadequate to control CAH in children (121) due to uneven distribution of the drug in liquid.”
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    Findingcitation

    Sensitivity to mineralocorticoids may vary over time, and recovery from salt wasting has been described in some patients, most probably secondary to extraadrenal 21-hydroxylation.

    “Sensitivity to MCs may vary over time, and recovery from salt wasting has been described in some patients, most probably secondary to extraadrenal 21-hydroxylation (132, 133).”
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    Findingcitation

    CAH-unaffected children prenatally treated short term had poorer verbal working memory, rated lower on self-perception of scholastic competence (both P=0.003), and had increased self-rated social anxiety (P=0.026).

    “However, CAH-unaffected children prenatally treated short term had poorer verbal working memory, rated lower on self-perception of scholastic competence (both P ϭ 0.003), and had increased self-rated social anxiety (P ϭ 0.026) (104).”
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    The prevalence of adrenal masses in autopsy samples increases with age, being 0.2% in young adults and 7% in subjects older than 70 years.

    “Their prevalence in autopsy samples increases with age, being 0.2% in young adults and 7% in subjects older than 70 yr (149).”
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    Findingcitation

    Subclinical aldosterone deficiency is present in all forms of 21-hydroxylase deficiency and can be best evaluated by the aldosterone to PRA ratio.

    “Although the aldosterone biosynthetic defect is clinically apparent only in the salt-wasting form, subclinical aldosterone deficiency is present in all forms of 21-hydroxylase deficiency (112, 130, 275) and can be best evaluated by the aldosterone to PRA ratio.”
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    Findingcitation

    A small but rigorous study using a standardized treatment protocol, questionnaires, and standardized neuropsychological tests compared prenatally treated children and a control group matched for age and sex; no differences were found in intelligence, handedness, or long-term memory.

    “A small but rigorous study, using a standardized treatment protocol, questionnaires, and standardized neuropsychological tests administered by a clinical psychologist, compared prenatally treated children and a control group matched for age and sex.No differences were found in intelligence, handedness, or long-term memory.”
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    Findingcitation

    Adult height of CAH patients correlates negatively with the dose of glucocorticoid administered in early puberty; patients treated with less than 20 mg hydrocortisone/m2 per day at start of puberty are significantly taller than those given higher hydrocortisone doses.

    “Adult height of CAH patients correlates negatively with the dose of GC administered in early puberty; patients treated with less than 20 mg HC/m 2 ⅐ d at start of puberty are significantly taller than those who were given higher HC doses.”
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    Findingcitation

    Adrenal carcinomas have rarely been reported in adults and in only two pediatric patients with CAH.

    “Adrenal carcinomas have rarely been reported in adults (151) and in only two pediatric patients with CAH (152,153).”
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    Findingcitation

    Studies in pediatric patients showed that approximately half are overweight, and 16-25% are obese.

    “Studies in pediatric patients showed that approximately half are overweight, and 16 -25% are obese (170 -172).”
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    Findingcitation

    Inconsistent data have been reported on triglyceride levels, with one study reporting higher levels in a group of prepubertal patients on glucocorticoid treatment compared with age-matched controls and another showing a lipid profile in CAH children similar to that of controls.

    “Inconsistent data have been reported on triglyceride levels, with one study reporting higher levels in a group of prepubertal patients on GC treatment compared with agematched controls (175) and another showing a lipid profile in CAH children similar to that of controls (176).”
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  • May combine two claims.

    Findingcitation

    Subtle insulin resistance can be detected in untreated NCCAH, but frankly impaired glucose tolerance is uncommon.

    “Whereas subtle insulin resistance can be detected in untreated NCCAH (274), frankly impaired glucose tolerance is uncommon.”
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    • cites [274]

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  • May combine two claims.

    Findingcitation

    Age at diagnosis, sex, type or dose of steroid, and age of onset of puberty did not significantly influence adult height; however, these subgroup analyses were inconclusive.

    “Age at diagnosis, sex, type or dose of steroid, and age of onset of puberty did not significantly influence adult height; however, these subgroup analyses were inconclusive.”
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    • cites [131]

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  • May combine two claims.

    Findingcitation

    In nonsystematic reviews, patients who were diagnosed late or were exposed to glucocorticoid doses higher than 15 mg/m2 per day had diminished height.

    “In nonsystematic reviews, patients who were diagnosed late or were exposed to GC doses higher than 15 mg/m 2 ⅐ d had diminished height (191,192).”
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    • cites [191]

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    Findingcitation

    Urinary incontinence and vaginal stenosis requiring dilation or reoperation remain a postoperative concern but have not been reported by either Peña or Rink.

    “Urinary incontinence and vaginal stenosis requiring dilation or reoperation remain a postoperative concern but have not been reported by either Pen ˜a (179) or Rink (180 -182).”
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    • cites [179]

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    • cites [182]

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  • May combine two claims.

    Findingcitation

    Hypertension is more prevalent in children with classic CAH than in the general population, and systolic blood pressure was related to body mass index independent of glucocorticoid or mineralocorticoid therapy.

    “Hypertension is more prevalent in children with classic CAH than in the general population, and systolic blood pressure was related to body mass index independent of GC or MC therapy (173, 174).”
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  • May combine two claims.

    Findingcitation

    A meta-analysis of data from 18 centers worldwide showed that the mean adult height of patients with classic CAH was 1.37 SD (10 cm) below the mean, and patients diagnosed before 1 year of age had increased adult height outcomes (0.54 SD).

    “A metaanalysis of data from 18 centers worldwide showed that the mean adult height of patients with classic CAH was 1.37 SD (10 cm) below the mean, and patients diagnosed before 1 yr of age had increased adult height outcomes (0.54 SD) (190).”
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  • May combine two claims.

    Findingnone given

    There are no randomized controlled studies on longterm follow-up of different modes of treatment of adults with classic CAH, and practice varies.

    “There are no randomized controlled studies on longterm follow-up of different modes of treatment of adults with classic CAH, and practice varies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Combined cortisol and epinephrine deficiency results in glucose, insulin, and leptin dysregulation, shown during short-term high-intensity exercise and long-term moderate-intensity exercise.

    “Combined cortisol and epinephrine deficiency results in glucose, insulin, and leptin dysregulation, shown during short-term high-intensity exercise (211, 212) and longterm moderate-intensity exercise (213).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [211]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [212]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [213]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingnone given

    There is no evidence of clinically significant cortisol deficiency or adrenal crisis in NCCAH.

    “There is no evidence of clinically significant cortisol deficiency or adrenal crisis in NCCAH, and we do not suggest that previously untreated adults with NCCAH be given substitution during severe stress, unless they have demonstrated a subnormal cortisol response during cosyntropin stimulation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Laparoscopic bilateral adrenalectomy in two women with classic salt-wasting CAH for difficult-to-suppress androgens resulted in weight loss and regular menstruation in both, and one had a successful pregnancy 3 years postoperatively.

    “Laparoscopic bilateral adrenalectomy was performed in two women (aged 22 and 28 yr) with classic salt-wasting CAH for difficult-to-suppress androgens, with amenorrhea, hirsutism, and acne (204).Weight loss and regular menstruation followed in both patients, and one had a successful pregnancy 3 yr postoperatively.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [204]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    One patient had mildly elevated adrenal steroid precursors, likely due to adrenal rest tissue.

    “One patient had mildly elevated adrenal steroid precursors, likely due to adrenal rest tissue.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [204]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation

    Three adult female patients with salt-wasting CAH underwent adrenalectomy for unsuppressible hyperandrogenism and worsening obesity; weight loss was achieved, but all three experienced pigmentation and adrenal crises during follow-up.

    “Three patients underwent adrenalectomy for unsuppressible hyperandrogenism and worsening obesity.Weight loss was achieved; however, all three patients experienced pigmentation and adrenal crises during follow-up.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [203]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingnone given

    Available studies report on small series, and different modes for monitoring treatment have not been studied systematically.

    “Available studies report on small series, and different modes for monitoring treatment have not been studied systematically.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    All patients reported subjective benefits after adrenalectomy, including the need for less frequent monitoring, weight loss, and fewer signs and symptoms of androgen excess.

    “All patients reported subjective benefits after surgery, including the need for less frequent monitoring, weight loss, and fewer signs and symptoms of androgen excess.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [202]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    A modified-release oral form of hydrocortisone is being developed.

    “A modified-release oral form of HC is being developed (209).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [209]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingnone given

    There are scant empiric data and no widely accepted recommendations for the management of GC doses in the pregnant CAH patient.

    “There are scant empiric data and no widely accepted recommendations for the management of GC doses in the pregnant CAH patient.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    Several reviews, but no controlled studies, describe how to transfer CAH patients from pediatric to adult care.

    “Several reviews, but no controlled studies, describe how to transfer CAH patients from pediatric to adult care.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    There is a mild nonclassic form of congenital adrenal hyperplasia that may show variable degrees of postnatal androgen excess but is sometimes asymptomatic.

    “In addition to the so-called classic salt-wasting and simple virilizing forms of CAH, there is also a mild nonclassic form, which may show variable degrees of postnatal androgen excess but is sometimes asymptomatic (10).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    More than 100 CYP21A2 mutations are known.

    “More than 100 CYP21A2 mutations are known (13),”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    Congenital adrenal hyperplasia is a disease suited to newborn screening because it is common and potentially fatal.

    “CAH is a disease suited to newborn screening because it is common and potentially fatal.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Nonclassic forms of congenital adrenal hyperplasia occur in approximately 0.1-0.2% of the general Caucasian population but in up to 1-2% among inbred populations such as Eastern European (Ashkenazi) Jews.

    “Nonclassic forms of CAH are more prevalent, occurring in approximately 0.1-0.2% in the general Caucasian population but in up to 1-2% among inbred populations, such as Eastern European (Ashkenazi) Jews (11).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The incidence of congenital adrenal hyperplasia ranges from 1:10,000 to 1:20,000 births.

    “The incidence ranges from 1:10,000 to 1:20,000 births (1)(2)(3)(4)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [2]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [3]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Congenital adrenal hyperplasia is more prevalent in some ethnic groups, particularly in remote geographic regions such as Alaskan Yupiks.

    “and is more prevalent in some ethnic groups, particularly in remote geographic regions (e.g.Alaskan Yupiks).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [2]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [3]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    These problems can be ameliorated by adopting screening methods with higher positive predictive values.

    “These problems can be ameliorated by adopting screening methods with higher positive predictive values.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Genotyping is focused on a single gene, CYP21A2, and will not be helpful in diagnosing other enzyme deficiencies causing congenital adrenal hyperplasia, as can be done with LC-MS/MS.

    “Additionally, it is focused on a single gene, i.e.CYP21A2, and will not be helpful in diagnosing other enzyme deficiencies causing CAH, as can be done with LC-MS/MS.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Only half of affected fetuses will be females; hence, treatment is potentially beneficial for only one in eight fetuses.

    “Furthermore, only half of the affected fetuses will be females; hence, treatment is potentially beneficial for only one in eight fetuses.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Because antenatally administered glucocorticoids are widely used to induce fetal lung development in the third trimester, many studies have addressed the effects of late-gestation, high-dose, short-term administration, but this may not be germane to prenatal treatment of congenital adrenal hyperplasia.

    “Because antenatally administered GCs are widely used to induce fetal lung development in the third trimester, many studies have addressed the effects of late-gestation, high-dose, shortterm administration, but this may not be germane to prenatal treatment of CAH.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Prenatal treatment does not change the need for lifelong hormonal replacement therapy, the need for careful medical monitoring, or the risk of life-threatening salt-losing crises if therapy is interrupted.

    “prenatal treatment does not change the need for lifelong hormonal replacement therapy, the need for careful medical monitoring, or the risk of life-threatening salt-losing crises if therapy is interrupted.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Because treatment must be started at 6-7 weeks gestation, and genetic diagnosis by chorionic villous biopsy cannot be done until 10-12 weeks, all pregnancies at risk for congenital adrenal hyperplasia are treated, even though only one in four is affected.

    “Because treatment must be started at 6 -7 wk gestation, and genetic diagnosis by chorionic villous biopsy cannot be done until 10 -12 wk, all pregnancies at risk for CAH are treated, even though only one in four is affected.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Congenital adrenal hyperplasia is autosomal recessive; if a woman has previously had a child with congenital adrenal hyperplasia and again becomes pregnant via the same partner, her fetus will have a one in four chance of having congenital adrenal hyperplasia.

  • May combine two claims.

    Premisecitation

    Fetal cortisol levels are low in very early gestation, rise during weeks 8-12 while the external genitalia are differentiating, are only about 10% of maternal levels during midgestation, and then increase during the third trimester.

    “Fetal cortisol levels are low in very early gestation, rise during wk 8 -12 while the external genitalia are differentiating (59), are only about 10% of maternal levels during midgestation (60,61), and then increase during the third trimester.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [59]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [60]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [61]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Study design and conductcitation

    Reports from the group first describing prenatal treatment do not provide actual numbers describing their outcomes and did not include control groups of nontreated pregnancies.

    “However, these reports do not provide actual numbers describing their outcomes and did not include control groups of nontreated pregnancies.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Newborn birth weight correlates with adult incidences of ischemic heart disease and hypertension.

    “Because newborn birth weight correlates with adult incidences of ischemic heart disease and hypertension (84,85)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [84]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [85]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    The groups advocating and performing prenatal treatment appear to agree that it is effective in reducing and often eliminating virilization of female fetal genitalia and that the success rate is about 80-85%.

    “Thus, the groups advocating and performing prenatal treatment appear to agree that it is effective in reducing and often eliminating virilization of female fetal genitalia and that the success rate is about 80 -85%.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Moderately low-dose dexamethasone (100 g/kg) reduced birth weight and increased blood pressure in rats.

    “and because moderately low-dose dexamethasone (100 g/kg) reduced birth weight and increased blood pressure in rats (86),”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Prenatal dexamethasone alters postnatal renal structure and function and produces hypertension in rodents.

    “Prenatal dexamethasone alters postnatal renal structure and function and produces hypertension in rodents (90,91).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [90]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [91]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    Multiple studies indicate that prenatal treatment is associated with modest but manageable maternal complications that do not appear to pose a major risk to the mother.

    “Thus, multiple studies indicate that prenatal treatment is associated with modest but manageable maternal complications that do not appear to pose a major risk to the mother.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Many reports of teratogenic effects, especially orofacial clefts, produced by high doses of dexamethasone administered to pregnant animals and in human patients led the U.S. Food and Drug Administration to classify dexamethasone as a category B drug, whose safety in pregnancy is not established.

    “Many reports of teratogenic effects, especially orofacial clefts, produced by high doses of dexamethasone admin-istered to pregnant animals (74 -76) and in human patients (77)(78)(79) led the U.S. Food and Drug Administration to classify dexamethasone as a category B drug, whose safety in pregnancy is not established.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [74]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [75]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [76]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites (77)(78)(79)

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    In salt-wasting CAH patients, the sodium content of breast milk or infant formulas is insufficient, and sodium chloride supplements are necessary.

    “However, in saltwasting CAH patients, the sodium content of breast milk or infant formulas is insufficient, and sodium chloride supplements are necessary (129).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    Although prednisolone and dexamethasone are effective in suppressing adrenal androgens in children with CAH, these more potent drugs are more likely to impede statural growth and cannot be routinely recommended.

    “Thus, although prednisolone and dexamethasone treatment are effective in suppressing adrenal androgens in children with CAH, these more potent drugs are more likely to impede statural growth and cannot be routinely recommended.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Testicular adrenal rest tumors are benign, often related to suboptimal therapy, and usually decrease in size after optimization of glucocorticoid therapy.

    “These so-called testicular adrenal rest tumors are benign, often related to suboptimal therapy, and usually decrease in size after optimization of GC therapy (157).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Adrenal masses affect 1-4% of normal men and women.

    “Adrenal masses affect 1-4% of normal men and women (148).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [148]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    Patients with severe forms of 21-hydroxylase deficiency are unable to produce a sufficient cortisol response to physical stress, such as febrile illness, gastroenteritis with dehydration, surgery, or trauma, and therefore require increased doses of glucocorticoid during such episodes.

    “Patients with severe forms of 21-hydroxylase deficiency are unable to produce a sufficient cortisol response to physical stress, such as febrile illness, gastroenteritis with dehydration, surgery, or trauma, and therefore require increased doses of GC during such episodes (Table 3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 3

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    The concern is treating seven unaffected and/or male fetuses to treat one affected female in the context of inadequate data regarding the long-term risks of this therapy.

    “The concern is treating seven unaffected and/or male fetuses to treat one affected female in the context of inadequate data regarding the long-term risks of this ther-apy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Other analytes have been used as markers of heterozygosity, but genotyping is usually a superior method of heterozygote detection.

    “Other analytes have been used as markers of heterozygosity (116, 117), but genotyping is a usually superior method of heterozygote detection.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [116]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [117]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    Maintenance of sodium balance reduces vasopressin and ACTH levels, contributing to lower glucocorticoid doses, leading to better auxological outcomes.

    “Maintenance of sodium balance reduces vasopressin and ACTH levels, contributing to lower GC doses, leading to better auxological outcomes (108,123,131).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [108]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [123]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [131]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Elevated plasma renin activity (PRA) and a reduced ratio of aldosterone to PRA indicate impaired aldosterone synthesis and can differentiate salt wasters from simple virilizers after the newborn period.

    “Elevated plasma renin activity (PRA) and a reduced ratio of aldosterone to PRA indicate impaired aldosterone synthesis and can differentiate salt wasters from simple virilizers (112) after the newborn period.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    A polycystic ovary syndrome type of functional ovarian hyperandrogenism may cause irregular menses in women with well-controlled CAH; the hyperandrogenism and menstrual irregularity of such individuals benefits from additional therapy with second- or third-generation oral contraceptives.

    “A polycystic ovary syndrome type of functional ovarian hyperandrogenism may cause irregular menses in women with well-controlled CAH (163, 164); the hyperandrogenism and menstrual irregularity of such individuals benefits from additional therapy with secondor third-generation oral contraceptives.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [163]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [164]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    Overtreatment during infancy or treatment with long-acting, high-potency glucocorticoids may also reduce height.

    “Overtreatment during infancy (126,193) or treatment with long-acting, high-potency GCs may also reduce height (118).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [126]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [193]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [118]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationcitation

    The recommendation for neurovascular-sparing clitoroplasty and vaginoplasty using total or partial urogenital mobilization is based on the poor results of other forms of vaginoplasty and is consistent with the consensus statement on 21-hydroxylase deficiency.

    “This recommendation is based on the poor results of other forms of vaginoplasty (147, 183), including flap vaginoplasty for severe CAH and vaginal pull-through separating the urethra and vaginal components, and is consistent with the consensus statement on 21-hydroxylase deficiency from the Pediatric Endocrine Society (formerly known as Lawson Wilkins Pediatric Endocrine Society) and the European”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [147]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [183]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [107]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Administration of dexamethasone, 0.25 mg/d, can be effective in reducing acne and irregular menstruations within 3 months and hirsutism within 30 months.

    “However, administration of dexamethasone, 0.25 mg/d, can be effective in reducing acne and irregular menstruations within 3 months and hirsutism within 30 months (223).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [223]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    The need for MCs decreases with age, because serum aldosterone is high and renal MC receptor mRNA is low at birth.

    “The need for MCs decreases with age, because serum aldosterone is high and renal MC receptor mRNA is low at birth (229), and the degree of MC and/or salt supplementation must be monitored by blood pressure and renin measurements in blood.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [229]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Among European pediatric endocrinologists, 36% said they used HC (mean dose 13.75 mg/m2), 14% used prednisolone (4.75 mg/d), and 33% used dexamethasone (0.5 mg/d) as the primary form of GC for substitution in adults with CAH.

    “Among European pediatric endocrinologists, 36% said they used HC (mean dose 13.75 mg/m 2 ), 14% used prednisolone (4.75 mg/d), and 33% used dexamethasone (0.5 mg/d) as the primary form of GC for substitution in adults with CAH (226).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [226]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    The occurrence and severity of osteopenia/osteoporosis was not related to CAH genotype or phenotype but probably was due to overtreatment with GCs.

    “The occurrence and the severity of osteopenia/osteoporosis was not related to CAH genotype or phenotype but probably was due to overtreatment with GCs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [227]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Falhammar et al. found that CAH patients over 30 yr of age had a higher waist to hip ratio than age-matched controls, fat mass was similar, and few CAH patients had hypertension, cardiovascular disease, or diabetes.

    “Although Falhammar et al. (228) found that CAH patients over 30 yr of age had a higher waist to hip ratio than age-matched controls, fat mass was similar, and few CAH patients had hypertension, cardiovascular disease, or diabetes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [228]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    Patients with classic CAH have adrenomedullary insufficiency because glucocorticoids play essential roles in the development and regulation of the adrenal medulla.

    “Patients with classic CAH have adrenomedullary insufficiency because GCs play essential roles in the development and regulation of the adrenal medulla (198,210).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [198]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [210]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Overtreatment with GCs may lead to osteoporosis, as noted in retrospective studies of 62 adult women with CAH, accompanied by an increased incidence of fractures as compared with healthy controls.

    “Overtreatment with GCs may lead to osteoporosis, as noted in retrospective studies of 62 adult women with CAH, accompanied by an increased incidence of fractures as compared with healthy controls (227).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [227]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Baseline follicular-phase early-morning 17-OHP levels can be used to detect CAH, but the normal cutoff varies between 200 and 400 ng/dl, depending on the assay.

    “Baseline follicular-phase early-morning 17-OHP levels can be used to detect CAH, but the normal cutoff varies between 200 and 400 ng/dl, depending on the assay (6 and 13 nmol/liter) (167, 218 -220).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [167]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [218]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [219]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [220]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Gestational diabetes was increased among CAH women vs. controls but without other metabolic or cardiovascular abnormalities.

    “Gestational diabetes was increased among CAH women vs. controls but without other metabolic or cardiovascular abnormalities (228).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [228]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Existing clinical guidelines recommend interdisciplinary teams involving mental health staff with expertise in managing psychosocial problems specific to disorders of sexual development (DSD).

    “Existing clinical guidelines (107, 246 -250) recommend interdisciplinary teams involving mental health staff with expertise in managing psychosocial problems specific to disorders of sexual development (DSD).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [107]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [246]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [247]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [248]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [249]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [250]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Among 33 46,XX CAH patients raised as males, four identified themselves as female, and three were gender dysphoric.

    “Among 33 46,XX CAH patients raised as males, four identified themselves as female, and three were gender dysphoric (251).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [251]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    A Finnish study found a better health-related QoL in both male and female patients with CAH than in the general Finnish population, despite numerous medical complications; however, 45% of eligible patients did not participate.

    “A Finnish study found a better health-related QoL in both male and female patients with CAH than in the general Finnish population, despite numerous medical complications; however, 45% of eligible patients did not participate (241).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [241]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Among 45 German women with CAH, the overall QoL of the CAH women did not differ from controls, but significant impairments were found concerning body image and attitudes toward sexuality, and CAH women were more often single and fewer of them had children than did controls.

    “Among 45 German women with CAH (260), the overall QoL of the CAH women did not differ from controls, but significant impairments were found concerning body image and atti-tudes toward sexuality, and CAH women were more often single and fewer of them had children than did controls.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [260]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    In an Australian study, most of the DSD patients including XX women with CAH had positive psychosocial and psychosexual outcomes, although there were some problems with sexual activity.

    “In an Australian study, most of the DSD patients including XX women with CAH had positive psychosocial and psychosexual outcomes, although there were some problems with sexual activity ( 258).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [258]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hagenfeldt et al. summarized this literature, finding an unexplained 2:1 female to male ratio for offspring of CAH women.

    “Hagenfeldt et al. (160) summarized this literature, finding an unexplained 2:1 female to male ratio for offspring of CAH women.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [160]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Bidet et al. found a combined incidence of mild and severe mutations in 8% of partners of French NCCAH patients, suggesting a much higher risk for offspring to have CAH of any form.

    “Bidet et al. (219) found a combined incidence of mild and severe mutations in 8% of partners of French NCCAH patients, suggesting a much higher risk for offspring to have CAH of any form.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [219]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    One study reported normal fertility, but others reported substantially reduced fertility.

    “One study reported normal fertility (188), but others reported substantially reduced fertility (243).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [188]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [243]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Recent reports of long-term follow-up studies show variable outcomes including impaired cosmesis and sexual functioning, and even nonsurgical procedures such as vaginal dilatation can be problematic.

    “Recent reports of long-term follow-up studies show variable outcomes including impaired cosmesis and sexual functioning (264 -267), and even nonsurgical procedures such as vaginal dilatation can be problematic (268).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [264]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [265]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [266]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [267]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [268]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Psychosocial factors may also play a role, because fewer men with CAH had steady heterosexual relationships than did age-matched controls.

    “Psychosocial factors may also play a role, because fewer men with CAH had steady heterosexual relationships than did age-matched controls (241).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [241]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    The cosmetic results are variably evaluated by patients, who tend to be more critical than their physicians.

    “The cosmetic results are variably evaluated by patients, who tend to be more critical than their physicians (184, 185).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [184]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [185]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Obstetricians should be aware that despite an apparent normal pregnancy rate of about 90%, classic CAH women have low fecundity (0.25 live births per woman vs. 1.8 in the general population).

    “Obstetricians should be aware that despite an apparent normal pregnancy rate of about 90%, classic CAH women have low fecundity (0.25 live births per woman vs. 1.8 in the general population) (239).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [239]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CAH is one specific subtype under the rubric of DSD.

    “CAH is one specific subtype under the rubric of DSD (250) but should not be equated with other forms of DSD in which outcomes are less well defined.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [250]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    Tools to assess health-related QoL were not designed for issues related to DSD or CAH; hence, the results of the few studies of QoL in CAH women are somewhat variable.

    “Tools to assess health-related QoL were not designed for issues related to DSD or CAH (255); hence, the results of the few studies of QoL in CAH women are somewhat variable.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [255]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

103 of 103

  • The paper relies on this without support.

    21-hydroxylase deficiency accounts for approximately 95% of congenital adrenal hyperplasia.

    “Because this enzyme deficiency accounts for approximately 95% of CAH, we will discuss only 21-hydroxylase deficiency here.”

  • The paper relies on this without support.

    Disease severity correlates with CYP21A2 allelic variation.

    “Disease severity correlates with CYP21A2 allelic variation.”

  • The paper relies on this without support.

    A nonconservative amino substitution in exon 4 (Ile172Asn) that preserves approximately 1-2% of enzyme function is associated with simple virilizing classic congenital adrenal hyperplasia.

    “A nonconservative amino substitution in exon 4 (Ile172Asn) that preserves approximately 1-2% of enzyme function is associated with simple virilizing classic CAH.”

  • The paper relies on this without support.

    17-hydroxyprogesterone levels are normally high at birth and decrease rapidly during the first few postnatal days.

    “In interpreting these tests, it must be remembered that 17-OHP levels are normally high at birth and decrease rapidly during the first few postnatal days.”

  • The paper relies on this without support.

    17-hydroxyprogesterone levels increase with time in infants affected with congenital adrenal hyperplasia.

    “In contrast, 17-OHP levels increase with time in infants affected with CAH.”

  • The paper relies on this without support.

    Premature, sick, or stressed infants typically have higher levels of 17-hydroxyprogesterone than term infants and generate many false positives unless higher cutoffs are used.

    “Additionally, premature, sick, or stressed infants typically have higher levels of 17-OHP than term infants and generate many false positives unless higher cutoffs are used.”

  • The paper relies on this without support.

    To obtain adequate sensitivity, cutoff levels for 17-hydroxyprogesterone are typically set low enough that approximately 1% of all tests are reported as positive.

    “To obtain adequate sensitivity, the cutoff levels for 17-OHP are typically set low enough that approximately 1% of all tests are reported as positive.”

  • The paper relies on this without support.

    Limitations of immunoassays for 17-hydroxyprogesterone include true elevations in levels in premature, sick, or stressed infants and lack of specificity of some antibodies for 17-hydroxyprogesterone.

    “Limitations of immunoassays for 17-OHP include true elevations in levels in premature, sick, or stressed infants and lack of specificity of some antibodies for 17-OHP.”

  • The paper relies on this without support.

    Immunoassay specificity can be increased by organic solvent extraction; this is currently mandated as a second screen in four states.

    “Immunoassay specificity can be increased by organic solvent extraction; this is currently mandated as a second screen in four states.”

  • The paper relies on this without support.

    CYP21A2 mutations can be detected in DNA extracted from the same dried blood spots that are used for hormonal screening.

    “CYP21A2 mutations can be detected in DNA extracted from the same dried blood spots that are used for hormonal screening.”

  • The paper relies on this without support.

    Genotyping is more costly than LC-MS/MS on a per-sample basis.

    “Genotyping is more costly than LC-MS/MS on a per-sample basis.”

  • The paper relies on this without support.

    Congenital adrenal hyperplasia is autosomal recessive; if a woman has previously had a child with congenital adrenal hyperplasia and again becomes pregnant via the same partner, her fetus will have a one in four chance of having congenital adrenal hyperplasia.

    “CAH is autosomal recessive; if a woman has previously had a child with CAH and again becomes pregnant via the same partner, her fetus will have a one in four chance of having CAH.”

  • The paper relies on this without support.

    Obtaining fetal DNA at chorionic villous biopsy reduces the length of time between instituting treatment and obtaining a genetic diagnosis.

    “Obtaining fetal DNA at chorionic villous biopsy reduces the length of time between instituting treatment and obtaining a genetic diagnosis.”

  • The paper relies on this without support.

    Knowing the specific mutations carried by each parent substantially increases the efficiency and speed of genetic diagnosis.

    “Knowing the specific mutations carried by each parent substantially increases the efficiency and speed of genetic diagnosis.”

  • The paper relies on this without support.

    Prescription of dexamethasone for prenatal treatment of congenital adrenal hyperplasia is an off-label use in the United States and European Union.

    “Prescription of dexamethasone for prenatal treatment of CAH is an offlabel use in the United States and European Union.”

  • The paper relies on this without support.

    The diagnosis of 21-hydroxylase deficiency is based on measuring 17-OHP and excluding 11-hydroxylase and P450 oxidoreductase deficiencies, in which 17-OHP may also be elevated.

    “The diagnosis of 21-hydroxylase deficiency is based on measuring 17-OHP, the enzyme's principal substrate, and excluding 11-hydroxylase and P450 oxidoreductase deficiencies, in which 17-OHP may also be elevated.”

  • The paper relies on this without support.

    Other steroids whose levels are usually elevated include 21-deoxycortisol, androstenedione, and testosterone.

    “Other steroids whose levels are usually elevated include 21-deoxycortisol, androstenedione, and testosterone.”

  • The paper relies on this without support.

    The severity of hormonal abnormalities depends on the degree of the enzymatic impairment, which depends on the genotype.

    “The severity of hormonal abnormalities depends on the degree of the enzymatic impairment, which depends on the genotype.”

  • The paper relies on this without support.

    A genetic test cannot detect salt wasting; this requires careful clinical evaluation.

    “A genetic test cannot detect salt wasting; this requires careful clinical evaluation.”

  • The paper relies on this without support.

    Compound heterozygotes for two different CYP21A2 mutations usually have a phenotype compatible with the milder mutation.

    “Compound heterozygotes for two different CYP21A2 mutations usually have a phenotype compatible with the milder mutation.”

  • The paper relies on this without support.

    Proper treatment with glucocorticoids prevents adrenal crisis and virilization, allowing normal growth and development.

    “Proper treatment with GCs prevents adrenal crisis and virilization, allowing normal growth and development.”

  • The paper relies on this without support.

    Undertreatment carries the risk of adrenal crisis and allows increased adrenal androgen production, with accelerated bone age and loss of growth potential; overtreatment may suppress growth, increase blood pressure, and cause iatrogenic Cushing's syndrome.

    “Undertreatment carries the risk of adrenal crisis and allows increased adrenal androgen production, with accelerated bone age and loss of growth potential; overtreatment may suppress growth, increase blood pressure, and cause iatrogenic Cushing's syndrome.”

  • The paper relies on this without support.

    Attempts to completely normalize 17-OHP levels typically result in overtreatment.

    “Attempts to completely normalize 17-OHP levels typically result in overtreatment.”

  • The paper relies on this without support.

    Infants with salt-wasting 21-hydroxylase deficiency require mineralocorticoids in addition to glucocorticoid treatment as well as supplemental sodium chloride.

    “Infants with salt-wasting 21-hydroxylase deficiency require MCs in addition to GC treatment as well as supplemental sodium chloride.”

  • The paper relies on this without support.

    The requirement for sodium in normally growing infants is approximately 1 mmol/kg per day, the amount provided by human milk.

    “The requirement for sodium in normally growing infants is approximately 1 mmol/kg ⅐ d, the amount provided by human milk.”

  • The paper relies on this without support.

    When pharmacological doses of hydrocortisone are given, mineralocorticoids are not needed because hydrocortisone can activate mineralocorticoid receptors.

    “When pharmacological doses of HC are given, MCs are not needed because HC can activate MC receptors.”

  • The paper relies on this without support.

    Either a reduced or an accelerated height velocity, signs of virilization, and delayed or premature bone maturation usually occur after protracted under- or overtreatment.

    “Either a reduced or an accelerated height velocity, signs of virilization, and delayed or premature bone maturation usually occur after protracted under-or overtreatment.”

  • The paper relies on this without support.

    17-OHP, androstenedione, and testosterone are the best indicators of the adequacy of glucocorticoid treatment.

    “17-OHP, androstenedione, and testosterone are the best indicators of the adequacy of GC treatment.”

  • The paper relies on this without support.

    Normal levels of 17-OHP and the other steroids are not a treatment goal but instead indicate overtreatment.

    “Normal levels of 17-OHP and the other steroids are not a treatment goal but instead indicate overtreatment.”

  • The paper relies on this without support.

    ACTH measurements are not useful for a diagnostic or therapeutic profile in CAH patients.

    “ACTH measurements are not useful for a diagnostic or therapeutic profile in CAH patients.”

  • The paper relies on this without support.

    Acceptably treated CAH patients generally have mildly elevated steroid levels when measured in a consistent manner, and dose adjustments should be made in the context of the overall clinical picture and not solely based on a single 17-OHP measurement.

    “Acceptably treated CAH patients generally have mildly elevated steroid levels when measured in a consistent manner, and dose adjustments should be made in the context of the overall clinical picture and not solely based on a single 17-OHP measurement.”

  • The paper relies on this without support.

    In adolescents with irregular menses and acne, symptoms are usually reversed within 3 months of glucocorticoid treatment, whereas remission of hirsutism is more difficult to achieve with glucocorticoid monotherapy.

    “In adolescents with irregular menses and acne, symptoms are usually reversed within 3 months of GC treatment, whereas remission of hirsutism is more difficult to achieve with GC monotherapy.”

  • The paper relies on this without support.

    Prolonged steroid therapy may reduce bone mineral density.

    “Prolonged steroid therapy may reduce BMD.”

  • The paper relies on this without support.

    The implied surgical advantage of delayed reconstruction is that the risk of vaginal stenosis and the need for subsequent dilation is diminished.

    “The implied surgical advantage of delayed reconstruction is that the risk of vaginal stenosis and the need for subsequent dilation is diminished.”

  • The paper relies on this without support.

    In infants with severe virilization where clitoroplasty is being considered, the advantages of early complete reconstruction are that the phallic skin can also be used as part of the vaginal reconstruction and gives the surgeon much more flexibility.

    “In infants with severe virilization where clitoroplasty is being considered, the advantages of early complete reconstruction are that the phallic skin can also be used as part of the vaginal reconstruction and gives the surgeon much more flexibility.”

  • The paper relies on this without support.

    Significant postoperative complications may occur after early or late surgery, such as urethra-vaginal fistulae and vaginal stenosis.

    “Systematic long-term evaluation is lacking for both early and late surgery, for which significant postoperative complications may occur, such as urethra-vaginal fistulae and vaginal stenosis.”

  • The paper relies on this without support.

    The incidence of urogenital sinus anomalies associated with CAH has not decreased.

    “In contrast to other significant congenital abnormalities of the genitourinary system (bladder exstrophy, prune belly syndrome, and posterior urethral valves), the incidence of urogenital sinus anomalies associated with CAH has not decreased.”

  • The paper relies on this without support.

    The adult short stature of many CAH patients may be caused by hypercortisolism, hyperandrogenism, or both.

    “The adult short stature of many CAH patients may be caused by hypercortisolism, hyperandrogenism, or both.”

  • The paper relies on this without support.

    Patients with NCCAH can also have compromised adult height, but height deficit is less severe than with classic CAH.

    “Patients with NCCAH can also have compromised adult height, but height deficit is less severe than with classic CAH.”

  • The paper relies on this without support.

    Normal adult height can be achieved in CAH with judicious use of standard glucocorticoid and mineralocorticoid therapies.

    “Normal adult height can be achieved in CAH with judicious use of standard GC and MC therapies, and height-enhancing drugs are not recommended for individuals whose height is, or is expected to be, more than Ϫ2.25 SD.”

  • The paper relies on this without support.

    Bilateral adrenalectomy reduces the risk of virilization in females and allows for treatment with lower glucocorticoid doses.

    “Bilateral adrenalectomy reduces the risk of virilization in females and allows for treatment with lower GC doses.”

  • The paper relies on this without support.

    Objections to adrenalectomy are based on surgical risk, possible increased risk of adrenal crisis due to loss of protective residual adrenal function, and possible loss of hormones that may have beneficial effects such as epinephrine and DHEA.

    “Objections to adrenalectomy are based on surgical risk, possible increased risk of adrenal crisis due to loss of protective residual adrenal function, and possible loss of hormones that may have beneficial effects such as epinephrine and DHEA.”

  • The paper relies on this without support.

    Individuals with a history of noncompliance are poor candidates for adrenalectomy because postoperative noncompliance in an adrenalectomized patient could be fatal.

    “Individuals with a history of noncompliance are poor candidates for adrenalectomy because postoperative noncompliance in an adrenalectomized patient could be fatal.”

  • The paper relies on this without support.

    Existing glucocorticoid therapy is nonphysiological and may contribute to adverse outcomes.

    “Existing GC therapy is nonphysiological and may contribute to adverse outcomes.”

  • The paper relies on this without support.

    The clinical implications of epinephrine deficiency are not fully known, but it likely plays a role in the risk for hypoglycemia during febrile illnesses, especially in young children.

    “The clinical implications of epinephrine deficiency are not fully known, but it likely plays a role in the risk for hypoglycemia during febrile illnesses, especially in young children.”

  • The paper relies on this without support.

    Current GC therapy for CAH is suboptimal because supraphysiological doses are often needed to suppress adrenal androgens.

    “Current GC therapy for CAH is suboptimal because supraphysiological doses are often needed to suppress adrenal androgens.”

  • The paper relies on this without support.

    Excess GC places patients at risk for iatrogenic Cushing's syndrome.

    “Excess GC places patients at risk for iatrogenic Cushing's syndrome, and lower-dose GC leads to inadequately treated androgen excess.”

  • The paper relies on this without support.

    Lower-dose GC leads to inadequately treated androgen excess.

    “Excess GC places patients at risk for iatrogenic Cushing's syndrome, and lower-dose GC leads to inadequately treated androgen excess.”

  • The paper relies on this without support.

    NCCAH patients reach higher than 1000 ng/dl (33 nmol/liter) after ACTH stimulation.

    “ACTH stimulation is needed for patients with baseline 17-OHP around the cutoff; NCCAH patients reach higher than 1000 ng/dl (33 nmol/ liter).”

  • The paper relies on this without support.

    Testicular adrenal rest tumors are common in adults with classic CAH but seem to be rare in NCCAH.

    “Testicular adrenal rest tumors are common in adults with classic CAH but seem to be rare in NCCAH.”

  • The paper relies on this without support.

    Adults with classic CAH are treated to avoid symptoms of adrenocortical deficiency in both sexes; hyperandrogenism, voice changes, and infertility in women; and testicular tumors in men.

    “Adults with classic CAH are treated to avoid symptoms of adrenocortical deficiency in both sexes; hyperandrogenism, voice changes, and infertility in women; and testicular tumors in men.”

  • The paper relies on this without support.

    Overtreatment with GCs will cause Cushingoid features, and excess MCs will cause hypertension.

    “However, overtreatment with GCs will cause Cushingoid features, and excess MCs will cause hypertension.”

  • The paper relies on this without support.

    GC substitution in the adult CAH patient aims to suppress virilization and menstrual disturbance in women, alteration of gonadotropin secretion in both sexes, and testicular adrenal rest tumors in men.

    “GC substitution in the adult CAH patient aims to suppress virilization and menstrual disturbance in women, alteration of gonadotropin secretion in both sexes, and testicular adrenal rest tumors in men.”

  • The paper relies on this without support.

    GC overtreatment may cause Cushingoid symptoms, whereas undertreatment may cause Addisonian symptoms.

    “GC overtreatment may cause Cushingoid symptoms, whereas undertreatment may cause Addisonian symptoms.”

  • The paper relies on this without support.

    Overtreatment with MCs may cause hypertension; undertreatment may lead to low blood pressure, salt loss, fatigue, and increased requirements for GC replacement.

    “Overtreatment with MCs may cause hypertension; undertreatment may lead to low blood pressure, salt loss, fatigue, and increased requirements for GC replacement.”

  • The paper relies on this without support.

    The principles of monitoring GC treatment in adult CAH patients are similar to those employed in monitoring children.

    “The principles of monitoring GC treatment in adult CAH patients are similar to those employed in monitoring children.”

  • The paper relies on this without support.

    Testosterone levels in men normally reflect gonadal rather than adrenal function and therefore are not useful for monitoring therapy.

    “Optimal levels for 17-OHP and androstenedione have not been defined; testosterone levels in men normally reflect gonadal rather than adrenal function and therefore are not useful for monitoring therapy.”

  • The paper relies on this without support.

    17-OHP may be elevated at night, even when morning levels are acceptable.

    “17-OHP may be elevated at night, even when morning levels are acceptable.”

  • The paper relies on this without support.

    Women with CAH are often overweight, with high blood pressure and hyperinsulinemia, and have risk factors for cardiovascular disease.

    “Women with CAH are often overweight, with high blood pressure and hyperinsulinemia, and have risk factors for cardiovascular disease.”

  • The paper relies on this without support.

    CAH is autosomal recessive.

    “CAH is autosomal recessive.”

  • The paper relies on this without support.

    The genotype and phenotype correlate well; siblings with CAH generally, but not always, have similar symptoms and degrees of female virilization.

    “The genotype and phenotype correlate well; siblings with CAH generally, but not always, have similar symptoms and degrees of female virilization.”

  • The paper relies on this without support.

    For NCCAH, about two thirds of patients are compound heterozygotes, carrying one allele that causes classic CAH and one that causes NCCAH.

    “For NCCAH, about two thirds of patients are compound heterozygotes, carrying one allele that causes classic CAH and one that causes NCCAH.”

  • The paper relies on this without support.

    Adult women with CAH often remember childhood visits to their physician as highly intrusive.

    “Adult women with CAH often remember childhood visits to their physician as highly intrusive.”

  • The paper relies on this without support.

    Pediatric endocrine care is usually transferred to an adult endocrinologist at the end of adolescence, usually coinciding with the completion of secondary school, i.e. typically at age 18.

    “Pediatric endocrine care is usually transferred to an adult endocrinologist at the end of adolescence, usually coinciding with the completion of secondary school, i.e. typically at age 18.”

  • The paper relies on this without support.

    Testicular adrenal rest tumors increase with age in CAH, impairing fertility.

    “Testicular adrenal rest tumors increase with age in CAH, impairing fertility.”

  • The paper relies on this without support.

    Undetected adrenal rest tumors may obstruct the seminiferous tubules, causing secondary gonadal dysfunction and infertility.

    “Undetected adrenal rest tumors may obstruct the seminiferous tubules, causing secondary go-nadal dysfunction and infertility.”

  • The paper relies on this without support.

    Higher binding globulins and placental aromatization typically protect the fetus from the potential virilizing effects of maternal androgens.

    “However, higher binding globulins and placental aromatization typically protect the fetus from the potential virilizing effects of maternal androgens.”

  • The paper relies on this without support.

    Maternal 17-OHP is elevated in normal pregnancy and hence cannot be used to monitor GC treatment.

    “Maternal 17-OHP is elevated in normal pregnancy and hence cannot be used to monitor GC treatment.”

  • The paper relies on this without support.

    Symptoms of adrenal insufficiency, including postural hypotension, may rarely develop in pregnant women with classic CAH.

    “Symptoms of adrenal insufficiency, including postural hypotension, may rarely develop in pregnant women with classic CAH.”

  • The paper relies on this without support.

    Patients with CAH may experience psychosocial and psychiatric problems that are not specific to CAH.

    “Patients with CAH may experience psychosocial and psychiatric problems that are not specific to CAH.”

  • The paper relies on this without support.

    These can usually be managed by standard mental health clinicians.

    “These can usually be managed by standard mental health clinicians.”

  • The paper relies on this without support.

    The 46,XX patients with CAH may also have to cope with problems that are more specific to DSD, such as parent/family medical education, gender assignment, decisions on genital surgery, and referral for psychological gender evaluation.

    “The 46,XX patients with CAH may also have to cope with problems that are more specific to DSD, such as 1) parent/family medical education, parent/family counseling regarding psychosocial prognosis, and managing parents' distress; 2) gender assignment at birth in cases of marked genital virilization; 3) decisions on gender-confirming (not medically necessitated) genital surgery in infancy and early”

  • The paper relies on this without support.

    Apart from urinary tract malformations in a minority of CAH girls, genital ambiguity usually does not require urgent surgical intervention.

    “Apart from urinary tract malformations in a minority of CAH girls, genital ambiguity usually does not require urgent surgical intervention.”

  • The paper relies on this without support.

    Severely virilized cases may initially be assigned as males, and once such assignment has been made, it may be difficult to reverse, thereby sacrificing fertility.

    “Severely virilized cases may initially be assigned as males, and once such assignment has been made, it may be difficult to reverse, thereby sacrificing fertility.”

  • The paper relies on this without support.

    In markedly virilized female-raised children, surgical intervention can facilitate heterosexual intercourse and conception, if desired.

    “In markedly virilized female-raised children, surgical intervention can facilitate heterosexual intercourse and conception, if desired.”

  • The paper relies on this without support.

    Fertility and fecundity, although reduced, remain feasible.

    “Fertility and fecundity, although reduced, remain feasible.”

  • The paper relies on this without support.

    Because the fetal adrenal has low levels of 3β-HSD, most steroidogenesis is directed toward DHEA, but small amounts of steroid enter the pathways toward aldosterone and cortisol.

    “Because the fetal adrenal has low levels of 3␤-HSD, most steroidogenesis is directed toward DHEA (and thence to DHEA-sulfate), but small amounts of steroid enter the pathways toward aldosterone and cortisol.”

  • The paper relies on this without support.

    The adrenal 21-hydroxylase, P450c21, is essential in both pathways.

    “The adrenal 21-hydroxylase, P450c21, is essential in both pathways.”

  • The paper relies on this without support.

    The adrenal can make small amounts of testosterone via 17β-HSD.

    “The adrenal can make small amounts of testosterone via 17␤-HSD.”

  • The paper relies on this without support.

    In the absence of the 21-hydroxylase activity of P450c21, three pathways lead to androgens.

    “In the absence of the 21-hydroxylase activity of P450c21, three pathways lead to androgens.”

  • The paper relies on this without support.

    Randomly measured 17-OHP levels can be normal in NCCAH; hence, a screening 17-OHP level should be measured in the early morning (before 0800 h).

    “Note that randomly measured 17-OHP levels can be normal in NCCAH; hence, a screening 17-OHP level should be measured in the early morning (before 0800 h).”

  • The paper relies on this without support.

    Steroid measurements may differ with the assay employed.

    “Steroid measurements may differ with the assay employed.”
82 of 82

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • CAH due to 21-hydroxylase deficiency is the most common cause of adrenal insufficiency in infancy.

    “CAH due to 21-hydroxylase deficiency is the most common cause of adrenal insufficiency in infancy (14).”

    From Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline (2016) · cites this paper as [14]

    The Definition, Pathophysiology, and Morbidities section says 21-hydroxylase deficiency accounts for approximately 95% of CAH and describes cortisol deficiency and potentially fatal salt loss in newborns. The 1.3 Remarks section also discusses adrenal insufficiency in infants with positive CAH screens. Neither passage establishes that it is the most common cause of adrenal insufficiency in infancy relative to other causes. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • A 17-OHprogesterone level >1000 ng/dL is diagnostic for 21-OH deficiency.

    “a 17-OHprogesterone Ͼ1000 ng/dL is diagnostic for 21-OH deficiency (14).”

    From Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline (2016) · cites this paper as [14]

    The guideline’s 9.1 Evidence section says that patients with nonclassical congenital adrenal hyperplasia reach 17-OHP levels above 1000 ng/dL after ACTH stimulation. It does not say that any 17-OHP result above that threshold is diagnostic of 21-hydroxylase deficiency; the 3.1–3.3 Evidence section notes that other enzyme deficiencies can also elevate 17-OHP. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • 21-Hydroxylase deficiency, caused by mutations in P450c21, is the most common form of CAH and one of the most common inborn errors of metabolism.

    “21-Hydroxylase deficiency, caused by mutations in P450c21, is the most common form of CAH and one of the most common inborn errors of metabolism.”

    From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [410]

    The Definition, Pathophysiology, and Morbidities section says that mutations in CYP21A2, the gene encoding P450c21, cause the most common form of CAH, accounting for approximately 95% of cases. The guideline calls CAH common in its newborn-screening evidence section, but does not establish that it is one of the most common inborn errors of metabolism. No page numbers are available in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • After appropriate fluid resuscitation, mineralocorticoids and glucocorticoids can be replaced orally, and ambiguous genitalia can be corrected with plastic surgery, but management is complicated and difficult.

    “After appropriate fluid resuscitation, the mineralocorticoids and glucocorticoids can be replaced orally, and the ambiguous genitalia can be corrected with a series of plastic surgical procedures, but the management is complicated and difficult (408, 410).”

    From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [410]

    The maintenance-therapy tables list glucocorticoid and fludrocortisone tablets, and the feminizing-surgery recommendation describes genital reconstruction for severely virilized patients (sections 7.0 and Supplemental Information; pages not provided). The guideline also says surgical decisions are difficult (section 7.3 Remarks). It does not establish the claimed sequence after fluid resuscitation or that surgery reliably corrects ambiguous genitalia; its discussion of surgical outcomes notes complications and variable results. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Additional challenges in the management of 21OHD derive from the uncertainties surrounding the optimal use of biomarkers to assess disease control.

    “Additional challenges in the management of 21OHD derive from the uncertainties surrounding the optimal use of biomarkers to assess disease control (10, 11).”

    From 24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency (2021) · cites this paper as [10]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

  • Adrenalectomy patient subgroups total 19, not 18

    Minor

    The four listed subgroups contain 14 + 2 + 1 + 2 = 19 patients, one more than the stated total of 18.

    Reported 18 · recomputed 19

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Authors
Speiser, P. W., Azziz, R., Baskin, L. S., Ghizzoni, L., Hensle, T. W., Merke, D. P., Meyer-Bahlburg, H. F. L., Miller, W. L., Montori, V. M., Oberfield, S. E., Ritzen, M., & White, P. C.
Affiliations
  • Hofstra University (US)
  • Cedars-Sinai Medical Center (US)
  • National Institutes of Health (US)
  • Columbia University (US)
  • Mayo Clinic (US)
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2010-09
Volume
95
Issue
9
Pages
4133-4160
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2009-2631
PMC
PMC2936060
OpenAlex
W1972087695
Cited by
1,484
References
342
Citations by year
2026: 18 · 2025: 41 · 2024: 96 · 2023: 103 · 2022: 130 · 2021: 130 · 2020: 98 · 2019: 123 · 2018: 118 · 2017: 97 · 2016: 105 · 2015: 85 · 2014: 87 · 2013: 83 · 2012: 71
FWCI
26.96
Type
journal article
Language
en
Open access
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
congenital adrenal hyperplasia, 21-hydroxylase deficiency, newborn screening, fetal therapy, glucocorticoid therapy, iatrogenic Cushing's syndrome, mineralocorticoids, sodium supplementation
MeSH terms
Adrenal Hyperplasia, Congenital, Algorithms, Female, Humans

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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