We searched the Cochrane Library, MEDLINE, and Embase for content published in English between Jan 1, 2005, and June 30, 2021. We used variations of the search term “congenital adrenal hyperplasia” in combination with the terms “21-alpha hydroxylase” “diagnosis/diagnostics”, “genetics”, “CAH-x”, “prenatal”, “adrenal crisis”, “glucocorticoid”, “mineralocorticoid”, “screening”, “prenatal”, “bone mineral density”, “pregnancy”, “treatment/therapy/therapeutic”, “fertility/fecundity”, “surgery”,
SeminarCongenital adrenal hyperplasia
Introduction
Congenital adrenal hyperplasia is caused by pathogenic variants in specific genes of adrenal steroidogenic enzymes. Mutations of the gene CYP21A2 cause steroid 21-hydroxylase (21-OHase, henceforth 21OH) deficiency, which is the most common variant of the disease. This form accounts for more than 95% of cases with congenital adrenal hyperplasia1 and is the focus of this Seminar.
21OH is essential for the synthesis of two hormones in the adrenal glands: cortisol and aldosterone. Adrenal insufficiency occurs when the adrenal glands cannot produce enough cortisol, leading to a loss of the negative feedback to the hypothalamus–pituitary gland system and a counter-regulatory overproduction of adrenocorticotropic hormone, which in turn drives excessive adrenal androgen production and adrenal hyperplasia (figure 1).
If untreated, adrenal insufficiency in the most severe classic form might have lethal consequences within the first few weeks of life. Affected patients require life-long hormone replacement therapy. Since the introduction of glucocorticoid replacement therapy in the 1950s,2, 3 congenital adrenal hyperplasia has served as a model for treatable genetic diseases. Nowadays, national newborn screening programmes are in place in most high-income countries, and almost all patients survive, although mortality is still increased throughout lifetime, with a hazard ratio of 2–3.4
The primary aim of treatment is to replace the deficient hormones. The second aim is to diminish adrenal androgen excess. Limiting excessive production of adrenal androgens is achieved by the replacement of cortisol, as cortisol re-establishes the negative feedback on the hypothalamus and the pituitary gland. The adrenal androgen excess present already in utero causes prenatal virilisation in female individuals, a typical feature of the disease. Congenital adrenal hyperplasia is the most common reason for atypical external genitalia in affected individuals with 46,XX karyotype.
Two strategies have been used to correct the virilisation of the external genitalia: surgery during the first year of life or preventive prenatal treatment with dexamethasone, which is offered to the mother from the first weeks of subsequent pregnancies. Both of these strategies are highly controversial and the subject of ongoing debate.
The phenotypic spectrum of 21OH deficiency ranges from the life-threatening, salt-wasting, classic form with prenatal virilisation in female individuals, to the non-classic (milder) form, which is characterised by no glucocorticoid deficiency. Female individuals with the non-classic form might present with symptoms of hyperandrogenism later in life or infertility, whereas male individuals with non-classic congenital adrenal hyperplasia frequently go undiagnosed (figure 2).
The classic form is a rare disease and its frequency in most populations varies between one in 10 000 and one in 20 000. The non-classic form is more common, affecting between one in 200 and one in 2000.1, 5, 6 Although a study in 19857 reported substantial differences in prevalence of the non-classic form among various ethnic groups, later studies found that differences in carrier frequencies might be smaller than previously reported.8, 9
With advances in genetics, metabolomics, and treatment options, our understanding of congenital adrenal hyperplasia has substantially improved, but life-long management of this complex disease remains one of the major challenges in endocrinology. In this Seminar, we review the genetics and clinical presentation of congenital adrenal hyperplasia and the current approaches for diagnosis, treatment, and long-term management, highlighting current controversies and future developments. For the purposes of this Seminar, we will henceforth use congenital adrenal hyperplasia and 21OH deficiency as synonyms, unless otherwise specified.
Section snippets
Other forms of congenital adrenal hyperplasia
In addition to pathogenic variants in the CYP21A2 gene causing 21OH deficiency, pathogenic variants in genes of other key enzymes involved in steroid biosynthesis are known to cause congenital adrenal hyperplasia.5 Steroid 11β-hydroxylase deficiency is caused by mutations in the CYP11B1 gene and accounts for the majority of the rarer forms (affecting one in 100 000 patients). Other conditions, such as classic forms caused by deficiency of 3β-hydroxysteroid dehydrogenase type 2 (due to mutations
Genetics and clinical presentation
The CYP21A2 gene, which encodes 21OH, is located on chromosome 6 within the human leukocyte antigen region and adjacent to the non-functional pseudogene (CYP21A1P), which has 98% sequence identity with the active gene.10 More than 300 pathogenic variants have been reported to date11 and 10 point mutations, derived from the pseudogene and the deletion of the active gene, are responsible for more than 90–95% of all cases of 21OH deficiency, thus allowing genotype–phenotype correlations to be
Clinical presentation
21OH deficiency is divided into classic and non-classic types according to the underlying genetic pathogenic variants and the correlated clinical symptoms (Figure 1, Figure 2). This type of congenital adrenal hyperplasia is characterised by a broad continuum of phenotypes, with good genotype–phenotype correlation—that is, disease severity can be generally predicted with the genotypes for the different types of classic and non-classic forms.10, 17, 18 Classic 21OH deficiency is subclassified
Steroidogenesis and diagnosis
The primary biomarker for the diagnosis of congenital adrenal hyperplasia due to 21OH deficiency is 17α-hydroxyprogesterone (17OHP), which is the substrate for 21OH and thus the direct upstream steroid precursor accumulating before the enzymatic block. Increased concentrations (>240 nmol/L) of 17OHP in a random blood sample taken at any time are diagnostic of classic 21OH deficiency. Early-morning 17OHP concentrations less than 2·5 nmol/L in children and less than 6·0 nmol/L in adults have been
Neonatal screening
Neonatal screening for 21OH deficiency is now done in more than 40 countries worldwide and is mandatory in all US states.1 The main goal of neonatal screening programmes is to prevent adrenal crises and deaths in the neonatal period, particularly among male infants, in whom 21OH deficiency is otherwise not clinically apparent since external genitalia are not atypical.1, 19, 21 Because screening results should be communicated before the occurrence of life-threatening adrenal crises, the timing
Investigations on clinical suspicion
For diagnostic purposes on clinical suspicion, 17OHP samples should be taken in the morning because 17OHP follows the diurnal rhythm of adrenocorticotropic hormone secretion. In women, samples should be taken during the follicular phase of the menstrual cycle because, during the periovulatory period and luteal phase, morning (baseline) 17OHP concentrations are slightly higher.50 After adrenocorticotropic hormone stimulation, 17OHP concentrations higher than 30 nmol/L (1000 ng/dL) substantiate
Treatment
Treatment of the classic forms of congenital adrenal hyperplasia due to 21OH deficiency is based on two pillars: the first is glucocorticoid and mineralocorticoid replacement and the second is androgen control.
Controversial therapies
The main controversies about congenital adrenal hyperplasia are related to the treatment of virilised female external genitalia. Both prenatal treatment for prevention of virilisation and postnatal surgical correction of virilised genitalia are highly controversial.
Fertility in female patients
Reduced fertility117 and adverse pregnancy outcomes have been reported,118, 119 such as an increase in the number of children being small for gestational age or with congenital anomalies born to mothers with classic congenital adrenal hyperplasia. Primary caesarean deliveries are common among women with congenital adrenal hyperplasia, because genital virilisation or previous genital surgery might complicate vaginal delivery.117 Genital surgery and the associated psychological burden might
Transition of care
The transition of care from a paediatric to an adult specialist unit forms the basis for the continuation of adequate and regular medical check-ups to avoid or reduce long-term sequelae and improve quality of life.152, 153 Adolescents should become independent and familiar with the disease, the treatment strategy, and how to avoid life-threating adrenal crises. Fertility, sexuality, and continuous access to psychological support should be part of the information discussed with the patient
Conclusions
Congenital adrenal hyperplasia is characterised by multiple, complex hormonal imbalances with potential life-threatening consequences, and disease-related and treatment-related high morbidity and increased mortality.
Research in the past decades has advanced our understanding of disease genetics and pathophysiology. Alternative steroid pathways have been identified and a multitude of novel treatment approaches are being developed. Optimising diagnostic and treatment strategies, a successful
Search strategy and selection criteria
Declaration of interests
NR is a Principal Investigator of clinical trials sponsored by Diurnal, Spruce Biosciences, and Neurocrine Biosciences at the Medizinische Klinik IV, Klinikum der Universität München, Munich, Germany, and reports scientific consultancy fees from Diurnal, Spruce Biosciences, and Neurocrine Biosciences. All other authors declare no competing interests.
References (155)
- et al.
Ethnic-specific distribution of mutations in 716 patients with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency
Mol Genet Metab
(2007) - et al.
Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians
Genet Med
(2017) - et al.
High-throughput screening for CYP21A1P-TNXA/TNXB chimeric genes responsible for Ehlers-Danlos syndrome in patients with congenital adrenal hyperplasia
J Mol Diagn
(2019) - et al.
Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus
J Biol Chem
(1990) - et al.
A missense mutation at Ile172→Asn or Arg356→Trp causes steroid 21-hydroxylase deficiency
J Biol Chem
(1990) - et al.
One hundred years of congenital adrenal hyperplasia in Sweden: a retrospective, population-based cohort study
Lancet Diabetes Endocrinol
(2013) - et al.
Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia
J Steroid Biochem Mol Biol
(2018) - et al.
Studies on ovarian and adrenal steroids at different phases of the menstrual cycle: II. A comparative assessment of the circadian variation in steroid and lutropin levels during the follicular, periovulatory and luteal phases
Contraception
(1981) - et al.
Diagnosis of 21-hydroxylase deficiency by urinary metabolite ratios using gas chromatography–mass spectrometry analysis: reference values for neonates and infants
J Steroid Biochem Mol Biol
(2016) - et al.
Prednisolone in the treatment of adrenal insufficiency: a re-evaluation of relative potency
J Pediatr
(2003)
Effect of androgen excess and glucocorticoid exposure on metabolic risk profiles in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency
J Steroid Biochem Mol Biol
The sixth edition of the WHO laboratory manual for the examination and processing of human semen: ensuring quality and standardisation in basic examination of human ejaculates
Fertil Steril
Management considerations for the adult with congenital adrenal hyperplasia
Mol Cell Endocrinol
Gender dysphoria and gender change in disorders of sex development/intersex conditions: results from the dsd-LIFE study
J Sex Med
Surgical complications following early genitourinary reconstructive surgery for congenital adrenal hyperplasia-interim analysis at 6 years
Urology
Urinary continence outcomes following vaginoplasty in patients with congenital adrenal hyperplasia
J Pediatr Urol
Post-operative complications following feminizing genitoplasty in moderate to severe genital atypia: results from a multicenter, observational prospective cohort study
J Pediatr Urol
Self- and proxy-reported outcomes after surgery in people with disorders/differences of sex development (DSD) in Europe (dsd-LIFE)
J Pediatr Urol
Restoring normal anatomy in female patients with atypical genitalia
Semin Perinatol
Should we question early feminizing genitoplasty for patients with congenital adrenal hyperplasia and XX karyotype?
J Pediatr Surg
Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline
J Clin Endocrinol Metab
The suppression of androgen secretion by cortisone in a case of congenital adrenal hyperplasia
Bull Johns Hopkins Hosp
Effect of cortisone on excretion of 17-ketosteroids and other steroids in patients with congenital adrenal hyperplasia
Helv Paediatr Acta
Increased mortality in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency
J Clin Endocrinol Metab
Mechanisms in endocrinology: rare defects in adrenal steroidogenesis
Eur J Endocrinol
High frequency of nonclassical steroid 21-hydroxylase deficiency
Am J Hum Genet
Carrier frequency of congenital adrenal hyperplasia (21-hydroxylase deficiency) in a middle European population
J Clin Endocrinol Metab
Genotype–phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency
Proc Natl Acad Sci USA
Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency
J Clin Endocrinol Metab
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency: a comprehensive focus on 233 pathogenic variants of CYP21A2 gene
Mol Diagn Ther
Tenascin-X deficiency mimics Ehlers-Danlos syndrome in mice through alteration of collagen deposition
Nat Genet
Tenascin-X, congenital adrenal hyperplasia, and the CAH-X syndrome
Horm Res Paediatr
The prevalence of the chimeric TNXA/TNXB gene and clinical symptoms of Ehlers-Danlos syndrome with 21-hydroxylase deficiency
J Clin Endocrinol Metab
Genotype/phenotype correlations in 538 congenital adrenal hyperplasia patients from Germany and Austria: discordances in milder genotypes and in screened versus prescreening patients
Endocr Connect
Genotype–phenotype correlation in 153 adult patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: analysis of the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) cohort
J Clin Endocrinol Metab
Nationwide neonatal screening for congenital adrenal hyperplasia in Sweden: a 26-year longitudinal prospective population-based study
JAMA Pediatr
Sex-typed toy play behavior correlates with the degree of prenatal androgen exposure assessed by CYP21 genotype in girls with congenital adrenal hyperplasia
J Clin Endocrinol Metab
Female preponderance in congenital adrenal hyperplasia due to CYP21 deficiency in England: implications for neonatal screening
Horm Res
Gender role behavior, sexuality, and psychosocial adaptation in women with congenital adrenal hyperplasia due to CYP21A2 deficiency
J Clin Endocrinol Metab
Suboptimal psychosocial outcomes in patients with congenital adrenal hyperplasia: epidemiological studies in a nonbiased national cohort in Sweden
J Clin Endocrinol Metab
Children with classic congenital adrenal hyperplasia experience salt loss and hypoglycemia: evaluation of adrenal crises during the first 6 years of life
Eur J Endocrinol
Mutational spectrum of the steroid 21-hydroxylase gene in Sweden: implications for genetic diagnosis and association with disease manifestation
J Clin Endocrinol Metab
CYP21A2 mutation update: comprehensive analysis of databases and published genetic variants
Hum Mutat
Expression of human 21-hydroxylase (P450c21) in bacterial and mammalian cells: a system to characterize normal and mutant enzymes
Mol Endocrinol
Growth and development in children with classic congenital adrenal hyperplasia
Curr Opin Endocrinol Diabetes Obes
Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women
Hum Reprod Update
Management of endocrine disease: diagnosis and management of the patient with non-classic CAH due to 21-hydroxylase deficiency
Eur J Endocrinol
The spectrum of clinical, hormonal and molecular findings in 280 individuals with nonclassical congenital adrenal hyperplasia caused by mutations of the CYP21A2 gene
Clin Endocrinol (Oxf)
Adrenomedullary dysplasia and hypofunction in patients with classic 21-hydroxylase deficiency
N Engl J Med
Adrenomedullary function may predict phenotype and genotype in classic 21-hydroxylase deficiency
J Clin Endocrinol Metab
Cited by (22)
Steroid profiling in adrenal disease
2024, Clinica Chimica ActaFertility and pregnancy in adrenal insufficiency
2024, Endocrine Connections