Elsevier

The Lancet

Volume 401, Issue 10372, 21–27 January 2023, Pages 227-244
The Lancet

Seminar
Congenital adrenal hyperplasia

https://doi.org/10.1016/S0140-6736(22)01330-7Get rights and content

Summary

Congenital adrenal hyperplasia is a group of autosomal recessive disorders leading to multiple complex hormonal imbalances caused by various enzyme deficiencies in the adrenal steroidogenic pathway. The most common type of congenital adrenal hyperplasia is due to steroid 21-hydroxylase (21-OHase, henceforth 21OH) deficiency. The rare, classic (severe) form caused by 21OH deficiency is characterised by life-threatening adrenal crises and is the most common cause of atypical genitalia in neonates with 46,XX karyotype. After the introduction of life-saving hormone replacement therapy in the 1950s and neonatal screening programmes in many countries, nowadays neonatal survival rates in patients with congenital adrenal hyperplasia are high. However, disease-related mortality is increased and therapeutic management remains challenging, with multiple long-term complications related to treatment and disease affecting growth and development, metabolic and cardiovascular health, and fertility. Non-classic (mild) forms of congenital adrenal hyperplasia caused by 21OH deficiency are more common than the classic ones; they are detected clinically and primarily identified in female patients with hirsutism or impaired fertility. Novel treatment approaches are emerging with the aim of mimicking physiological circadian cortisol rhythm or to reduce adrenal hyperandrogenism independent of the suppressive effect of glucocorticoids.

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

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”,

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.

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