We searched PubMed for articles published in English on congenital adrenal hyperplasia between 1998 and 2004, with MeSH terms “adrenal hyperplasia, congenital” and “steroid 21 hydroxylase” as well as natural-language equivalents “congenital adrenal hyperplasia”, “(adrenal OR hyperplas*) AND CAH”, “cyp21 OR cyp-21”, or “21-hydroxylase AND deficien*”. The results of these searches were pooled, and subsearches were run with additional MeSH and natural-language terms as well as floating
SeminarCongenital adrenal hyperplasia
Section snippets
Epidemiology
Data from several neonatal screening programmes show that CAH due to 21-hydroxylase deficiency is common. Data from roughly 6·5 million newborn infants screened in 13 countries (USA, France, Italy, New Zealand, Japan, UK, Brazil, Switzerland, Sweden, Germany, Portugal, Canada, and Spain) show an overall incidence of one in 15 000 livebirths for the classic form.2, 3 Thus, the carrier frequency of classic CAH is about one in 60 individuals. Salt-losing CAH accounts for 67% of the cases reported
Genetics
The 21-hydroxylase gene is located on chromosome 6p21·3 within the HLA histocompatibility complex.9 There are two highly homologous 21-hydroxylase genes resulting from ancestral duplication: an active gene, CYP21A2 (CYP21B), and an inactive pseudogene CYP21A1P (CYP21A, CYP21P).10 CAH is unusual among genetic disorders in that most of the mutant alleles (about 90%) are generated by recombinations between the pseudo and active genes.11, 12 When deleterious sequences normally present in the
Pathophysiology
The pathophysiology of 21-hydroxylase-deficiency-related CAH is closely linked to the degree of enzyme deficiency. A defect in cortisol biosynthesis leads to a compensatory increase in pituitary production of corticotropin and hypothalamic production of corticotropin-releasing hormone (CRH) owing to a lack of the usual negative feedback by cortisol. Physiological glucocorticoid and mineralocorticoid replacement fails to replicate the close temporal relation between release of CRH,
Clinical features
The severity of CAH depends on the degree of 21 hydroxylase deficiency caused by CYP21A2 mutations. The classic forms present in childhood and are characterised by striking overproduction of cortisol precursors and adrenal androgens. In the most severe form, concomitant aldosterone deficiency leads to loss of salt. In the mildest form, there is sufficient cortisol production, but at the expense of excess androgens.
Female infants with classic CAH typically have ambiguous genitalia at birth
Diagnosis
A very high concentration of 17-hydroxyprogesterone (more than 242 nmol/L; normal less than 3 nmol/L at 3 days in full-term infant) in a randomly timed blood sample is diagnostic of classic 21-hydroxylase deficiency.51 Typically, salt-losing patients have higher 17-hydroxyprogesterone concentrations than non-salt-losers. False-positive results from neonatal screening are common with premature infants, and many screening programmes have established reference ranges that are based on weight and
Medical treatment
In classic CAH, glucocorticoids are given in doses sufficient to suppress adrenal androgen secretion partly, without total suppression of the HPA axis; mineralocorticoids are given to return electrolyte concentrations and plasma renin activity to normal. Physiological cortisol secretion rates are about 6 mg/m2 daily,56, 57, 58 and most patients have satisfactory control of androgen production with hydrocortisone doses of 12–18 mg/m2 daily divided into two or three doses. The target
Stress dosing
Patients with classic CAH cannot mount a sufficient cortisol response to physical stress and need pharmacological doses of hydrocortisone in situations such as febrile illness, surgery, and trauma. Dose guidelines include doubling or tripling the glucocorticoid maintenance dose for the whole day. If a patient is unable to take medication orally, hydrocortisone should be given intramuscularly, and medical advice about the need for intravenous hydration should be promptly sought. The combination
Prenatal therapy
In pregnancies in which the fetus is at risk of classic CAH, maternal dexamethasone treatment has successfully suppressed the fetal HPA axis and reduced the genital ambiguity of affected female infants.66, 67 Masculinisation of the external genitalia begins by 8 weeks of gestation. Therefore, if treatment is desired, it should be started as soon as the pregnancy is confirmed. Chorionic-villus sampling or amniocentesis should be done as early as possible. If the fetus is male or a female not
Pharmacological approach
Promising experimental approaches to the treatment of CAH are being developed. Blockade of excess sex steroid production to allow the use of lower glucocorticoid doses is currently being studied as an alternative regimen. Children receiving a four-drug regimen of low-dose hydrocortisone, fludrocortisone, flutamide (an androgen-receptor antagonist), and testolactone (an aromatase inhibitor that blocks oestrogen production) showed normal linear growth and bone maturation after 2 years of
Conclusion
There have been striking improvements during the past 50 years in our understanding of the pathophysiology of CAH, and the management and treatment of patients with this disorder continues to improve. Genetic, pathological, and clinical heterogeneity makes the diagnosis and treatment particularly challenging. Several unresolved clinical issues in the management of this complex disorder demand further investigation. Ultimately, improvement of the quality of life of patients with CAH requires a
Search strategy and selection criteria
References (153)
- et al.
Congenital adrenal hyperplasia due to 21 hydroxylase deficiency: newborn screening and its relationship to the diagnosis and treatment of the disorder
Screening
(1993) Newborn screening for congenital adrenal hyperplasia
Endocrinol Metab Clin North Am
(2001)- et al.
Improved test to identify heterozygotes for congenital adrenal hyperplasia without index case examination
Lancet
(1990) - et al.
Combinatorial code of growth factors and neuropeptides define neuroendocrine differentiation in PC12 cells
Exp Neurol
(2003) - et al.
Studies of the neuronal transdifferentiation process in cultured human pheochromocytoma cells: effects of steroids with differing functional groups on catecholamine content and cell morphology
Steroids
(1998) - et al.
Clinical and metabolic findings in adolescent females with hyperandrogenism
J Pediatr Adolesc Gynecol
(2004) - et al.
21-Hydroxylase-deficient nonclassic adrenal hyperplasia is a progressive disorder: a multicenter study
Am J Obstet Gynecol
(2000) - et al.
Improved precision of newborn screening for congenital adrenal hyperplasia using weight-adjusted criteria for 17 hydroxyprogesterone levels
J Pediatr
(1997) - et al.
Screening for 21-hydroxylase-deficient nonclassic adrenal hyperplasia among hyperandrogenic women: a prospective study
Fertil Steril
(1999) - et al.
Cortisol production rate in childhood and adolescence
J Pediatr
(1990)
Prednisolone in the treatment of adrenal insufficiency: a re-evaluation of relative potency
J Pediatr
Prenatal treatment of congenital adrenal hyperplasia
Trends Endocrinol Metab
Neonatal dexamethasone therapy: short- and long-term consequences
Trends Endocrinol Metab
Mortality in patients with congenital adrenal hyperplasia: a cohort study
J Pediatr
Congenital adrenal hyperplasia complicated by central precocious puberty: linear growth during infancy and treatment with gonadotropin-releasing hormone analog
Metabolism
Experience with long-term therapy in congenital adrenal hyperplasia
J Pediatr
Height outcome in congenital adrenal hyperplasia caused by 21-hydroxylase deficiency: a meta-analysis
J Pediatr
Glucocorticoid treatment of girls with congenital adrenal hyperplasia: effects on height, sexual maturation, and fertility
J Pediatr
Pregnancy outcomes in women with congenital virilizing adrenal hyperplasia
Endocrinol Metab Clin North Am
Further studies on the treatment of congenital adrenal hyperplasia with cortisone: IV, effect of cortisone and compound B in infants with disturbed electrolyte metabolism, by John F Crigler Jr, MD, Samuel H Silverman, MD, and Lawson Wilkins, MD
Pediatrics
Pediatrics
A pilot newborn screening for congenital adrenal hyperplasia in Alaska
J Clin Endocrinol Metab
Worldwide experience in newborn screening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Pediatrics
Results of screening 1·9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia
Pediatrics
High frequency of nonclassical steroid 21-hydroxylase deficiency
Am J Hum Genet
Genotyping of CYP21, linked chromosome 6p markers, and a sex-specific gene in neonatal screening for congenital adrenal hyperplasia
J Clin Endocrinol Metab
Genetic mapping of the 21-hydroxylase-deficiency gene within the HLA linkage group
N Engl J Med
Evolutionary origin of mutations in the primate cytochrome P450c21 gene
Am J Hum Genet
De novo mutation causes steroid 21-hydroxylase deficiency in one family of HLA-identical affected and unaffected siblings
J Clin Endocrinol Metab
Mutations in steroid 21-hydroxylase (CYP21)
Hum Mutat
Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21 hydroxylase deficiency
J Clin Invest
Gene conversions and unequal crossovers between CYP21 (steroid 21-hydroxylase gene) and CYP21P involve different mechanisms
Proc Natl Acad Sci USA
Steroid 21 hydroxylase deficiency: genotype may not predict phenotype
J Clin Endocrinol Metab
Population-wide evaluation of disease manifestation in relation to molecular genotype in steroid 21-hydroxylase (CYP21) deficiency: good correlation in a well defined population
J Clin Endocrinol Metab
Predicting phenotype in steroid 21-hydroxylase deficiency? Comprehensive genotyping in 155 unrelated, well defined patients from southern Germany
J Clin Endocrinol Metab
Congenital adrenal hyperplasia due to 21 hydroxylase deficiency
N Engl J Med
Prenatal dexamethasone treatment does not prevent alterations of the hypothalamic pituitary adrenal axis in steroid 21-hydroxylase deficient mice
Endocrinology
Adrenal incidentaloma and patients with homozygous or heterozygous congenital adrenal hyperplasia
J Clin Endocrinol Metab
Carriers of 21-hydroxylase deficiency are not at increased risk for hyperandrogenism
J Clin Endocrinol Metab
Endocrinologic and psychologic evaluation of 21-hydroxylase deficiency carriers and matched normal subjects: evidence for physical and/or psychologic vulnerability to stress
J Clin Endocrinol Metab
Increased prevalence of heterozygous 21-OH germline mutations in patients with adrenal incidentalomas
Clin Endocrinol (Oxf)
Steroid 21 hydroxylase deficiency in mice
Endocrinology
Adrenomedullary function is severely impaired in 21-hydroxylase-deficient mice
Faseb J
Adrenomedullary dysplasia and hypofunction in patients with classic 21-hydroxylase deficiency
N Engl J Med
Environmental influences in the development of neural crest derivatives: glucocorticoids, growth factors, and chromaffin cell plasticity
J Neurosci
Stress hormones: their interaction and regulation
Science
Adrenocortical control of the biosynthesis of epinephrine and proteins in the adrenal medulla
Pharmacol Rev
Glucocorticoids stimulate transcription of the rat phenylethanolamine N methyltransferase (PNMT) gene in vivo and in vitro
Cell Mol Neurobiol
Adrenomedullary function may predict phenotype and genotype in classic 21-hydroxylase deficiency
J Clin Endocrinol Metab
Patients with classic congenital adrenal hyperplasia have decreased epinephrine reserve and defective glucose elevation in response to high-intensity exercise
J Clin Endocrinol Metab
Stress dose of hydrocortisone is not beneficial in patients with classic congenital adrenal hyperplasia undergoing short-term, high-intensity exercise
J Clin Endocrinol Metab
Cited by (592)
Prenatal androgen exposure and sex-typical play behaviour: A meta-analysis of classic congenital adrenal hyperplasia studies
2024, Neuroscience and Biobehavioral ReviewsMaternal opioid addiction: A potential cause of elevated 17-OH progesterone in neonatal screening
2023, Archives de PediatrieMineralocorticoid Excess States
2023, Hypertension: A Companion to Braunwald's Heart DiseaseThe impact of genetic steroid disorders on human fertility
2023, Genetic Steroid Disorders: Second EditionOutcomes of one-stage feminizing genitoplasty in children with congenital adrenal hyperplasia and severe virilization
2024, Pediatric Surgery InternationalEffects of hormonal changes on the human voice: a review
2024, Egyptian Journal of Otolaryngology