Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is an autosomal recessive disorder caused by impaired corticosteroid synthesis. Between 90% and 95% of affected individuals have 21-hidroxylase deficiency (21OHD, OMIM #201910) with a variable blockade of the synthesis of glucocorticoids and mineralocorticoids and excessive androgen production, leading to a diversity of clinical syndromes that may manifest as early as the neonatal period (classic “salt-wasting” and “simple virilising” forms) or in childhood, adolescence or adulthood (some “simple virilising” and “nonclassic” forms).1,2

The management of classic forms of CAH is complex, individualised and multidisciplinary, and requires the development of a structured treatment and follow-up plan. Thus, these patients should be managed in referral comprehensive care centres (CCCs).

Several scientific societies (European, American, Australian and Japanese paediatric endocrinology societies) and patient associations have published guidelines for the management of this disease.

In this article, the Working Group on Congenital Adrenal Hyperplasia of the Sociedad Española de Endocrinología Pediátrica (Spanish Society of Paediatric Endocrinology) offers general recommendations that may be useful to paediatricians that care for patients with 21OHD based on published guidelines and the group members’ experience in the management of classic forms of disease.

The incidence of CAH varies based on the population under study and the method of data collection (whether data were or not collected from early intervention programmes): it is of 1/10000 to 1/20000 for classic forms in newborns,2 while in Spain it ranges between 1/10000 and 1/14000,3 which suggests that 1/50 to 1/60 individuals are carriers of serious mutations.

In the adrenal cortex, hydroxylation of the 21C residue is carried out by the steroid enzyme 21-hydroxylase (also known as cytochrome P450c21), which converts progesterone to deoxycorticosterone and 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol in a process that culminates in the synthesis of aldosterone and cortisol, respectively. Clinical manifestations depend on the severity of the functional impairment of the enzyme (Fig. 1).

Figure 1.

Synthesis of adrenal steroids.

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In 21OHD, there is a decrease in the synthesis of hormones downstream of the block (glucocorticoids and mineralocorticoids), an increased production of upstream products, such as 17OHP, and increased synthesis in the androgen pathway. Cortisol deficiency leads to a compensatory rise in corticotropin (ACTH) and adrenal hyperplasia.4

In severe forms there are defects in other metabolic pathways: decreased production of adrenalin in the adrenal medulla (tendency to circulatory collapse)5 and activation of dihydrotestosterone (DHT) synthesis by “backdoor” metabolic pathways that result in increased virilisation in female foetuses.6

The most severe forms manifest in the neonatal period due to cortisol and aldosterone deficiency with a potentially lethal loss of salt.1 Excess androgens cause virilisation and external genital ambiguity in newborn girls. The Prader scale is very useful to describe the degree of virilisation (Fig. 2). Without adequate treatment, the disease could lead to accelerated bone maturation, premature epiphyseal closure, precocious pseudopuberty and short stature in adulthood.

Figure 2.

(a) Prader stages. Prader 1: female external genitalia; Prader 5: male external genitalia. (b) Female newborn with 21OHD. It would be easy make a male sex assignment in an initial assessment (Prader 5).

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Less-severe forms of disease have onset in late childhood, adolescence or adulthood and are characterised by signs of virilisation: premature pubarche, accelerated growth and bone maturation, hirsutism, severe acne and oligomenorrhea, with no evidence of aldosterone deficiency. They may go undetected, and diagnosis is delayed in a large proportion of cases.

In many cases, 21OHD causes illness of intermediate severity.

This disease will be suspected in:

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  Child with symptoms of salt wasting in the early weeks of life.

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  Girls virilised at birth or with postnatal virilisation, premature pubarche or early puberty.

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  Boys with virilisation starting in childhood.

The diagnosis is based on testing of the steroid upstream of the block: 17OHP.

Diagnosis in newbornsEarly detection programme: neonatal screening

The early detection of 21OHD, which is recommended internationally,2 is only performed in a few autonomous communities in Spain. It consists in the measurement of 17OHP levels in capillary blood samples taken on the second day of life for the early-detection screening of various diseases. The purpose of this test is to anticipate salt-wasting crises, prevent incorrect sex assignment and diagnosing simple virilising forms early.7

Each reference laboratory must establish normal ranges for their specific population based on gestational age, birth weight and sex. Although at present 17OHP levels are measured by fluorescence assay (DELFIA), the use of mass spectrometry will alleviate overestimation of 17OHP levels due to cross-reactivity with other adrenal steroids. Genotyping of CYP21A2 is useful as a second-tier test.8

Prenatal administration of glucocorticoids can reduce the levels of 17OHP and give rise to false negatives. Administration of spironolactone can lead to false positives.

Table 1 presents the diagnostic algorithm for patients with a positive result.

Table 1.

Diagnostic algorithm: newborn with positive detection in neonatal screening (DELFIA) (born to term and with adequate weight for gestational age).

17-OHP, 17-hydroxyprogesterone; 21OHD, 21-hydroxylase deficiency; ABB, acid–base balance; BW, birth weight; CCC, comprehensive care centre; HyperK: Hyperkalaemia; HypoNa, Hyponatraemia; PRA, plasma renin activity; WG, weeks of gestation.

Clinical diagnosis in newborns

Table 2 presents the approach to the diagnosis of a newborn with suspected 21OHD due to elevation of 17OHP, excluding transient elevations (preterm birth, low weight, severe neonatal illness) that usually normalise within one year.8

Table 2.

Algorithm for the diagnosis of a newborn with suspected CAH.

17-OHP, 17-hydroxyprogesterone; ABB, acid–base balance; CAH, congenital adrenal hyperplasia.

Salt wasting (weight loss, anorexia/excessive thirst, vomiting, lethargy, coma) results in hyponatraemia, hyperkalaemia, increased risk of hypoglycaemia, elevated levels of 17OHP, androstenedione, testosterone, DHEA and ACTH, decreased levels of cortisol and aldosterone, and increased plasma renin activity (PRA).

In the neonatal period, direct immunoassays (the technique used most frequently in Spain) may suffer from cross-reactivity and falsely detect elevations of 17OHP in healthy children or aldosterone levels within “normal” ranges in newborns with salt wasting. Performance of an ACTH stimulation test is not necessary due to the high levels of 17OHP.

Genotyping of the CYP21A2 gene is very useful in confirming the diagnosis.9,10

The karyotype of a female patient with 21OHD and ambiguous genitalia is 46 XX. Ultrasound examination of the abdomen and genitalia can be useful in diagnosis, allowing the visualisation of ovaries, fallopian tubes and uterus.

Diagnosis of older children and adolescents

The diagnosis of male patients with simple virilising forms may be delayed due to the lack of manifestations in the neonatal period. Some girls may exhibit clitoromegaly and signs of masculinisation during childhood. Table 3 summarises the protocol for the diagnosis of a child or adolescent with suspected 21OHD.

Table 3.

Algorithm for the diagnosis of a child or adolescent with suspected 21OHD.

17-OHP, 17-hydroxyprogesterone; 21OHD, 21-hydroxylase deficiency; ACTH, corticotropin.

CYP21A2 genotyping is useful to differentiate these patients, as they have severe mutations in both alleles.

The goals of treatment are replacing the physiological secretion of glucocorticoids and mineralocorticoids to prevent salt wasting, controlling manifestations associated with hyperandrogenism and improving adult outcomes. Surgical reconstruction of the external genitalia is recommended in girls.14

Overproduction of adrenal androgens and high-dose glucocorticoid therapy are the factors that lead to short stature in adulthood. Patients may also experience peripheral precocious puberty, which requires treatment with gonadotropin-releasing hormone analogues.

Aromatase inhibitors (anastrazole) and growth hormone therapy should only be used in patients with a very short predicted final stature or in clinical trials.15

Rises in ACTH can cause hyperplasia of sensitive tissues such as the adrenal glands and regions with ectopic adrenal rest tissue (testes and ovaries). The gold standard for evaluation is periodic ultrasound examination. Adrenal tumours require intensification of glucocorticoid therapy and, in some cases, surgery.20

Female patients with CAH may have reduced fertility. Androgen excess causes anovulatory cycles and alterations in the hypothalamic–pituitary–ovarian axis. They may experience painful intercourse due to stenosis of the vaginal introitus or anatomical abnormalities resulting from virilisation or surgery.

During pregnancy, glucocorticoid and mineralocorticoid therapy should continue at the previous doses, and mothers should be given parenteral hydrocortisone during labour, as it constitutes a highly stressful situation for the foetus.

Genetic counselling should be offered before conception.

Male patients with classic forms may also experience reduced fertility due to the associated hypogonadism and the presence of ectopic adrenal rest tissue in the testes. Inadequate treatment allows an increased production of androgens of adrenal origin that suppress FSH, leading to decreased sperm production.2

Chronic steroid therapy is a risk factor for osteoporosis that calls for prophylaxis with physical activity and adequate calcium and vitamin D intake.2

Obesity, hypertension, insulin resistance and carbohydrate intolerance are side effects that need to be prevented and treated.

Prenatal diagnosis should be considered in foetuses with a 1 in 4 probability of having severe disease (two parents carriers of severe mutations, one parent with disease, or history of CAH diagnosis in the family). Families with a known case of disease should undergo a full evaluation before planning a pregnancy.

The goal of prenatal treatment is to prevent the virilisation of genitalia in affected female foetuses, for whom there is a 1/8 probability in each pregnancy. It consists in the administration of dexamethasone to the mother in the early weeks of gestation (before week 7–8). Dexamethasone can cross the placenta and thus curb excess androgen production by the foetal adrenal gland, preventing the virilisation of female foetuses. When diagnostic test results become available, treatment is discontinued if the foetus is male or an unaffected female. The method that can be performed earliest to obtain an exclusively foetal sample for testing, usually around 12–14 weeks’ gestation, is chorionic villus sampling.

This treatment has been used since the 1990s and is effective in preventing virilisation of girls with 21OHD, the need for surgical interventions and the impact that the birth of a girl with virilised genitals has on the family.21,22

However, this approach entails the unnecessary exposure to dexamethasone of 7 out of 8 foetuses (all male foetuses and 3 unaffected female foetuses out of every 4). There is evidence that dexamethasone has teratogenic effects in mice, and its long-term effects are not well understood. It may also cause side effects in pregnant mothers.23

Currently, we recommend dexamethasone treatment as long as it is performed in facilities with an experienced staff and after obtaining informed consent.24

Analysis of foetal DNA in maternal blood can determine the sex of the foetus from 6 weeks of gestation, although its sensitivity does not reach 100% until week 10. It cannot identify pregnancies that require treatment so it cannot prevent treatment in female foetuses that are unaffected or carriers. Massive DNA sequencing of free foetal DNA will probably allow very early diagnosis (week 6) in foetuses with 21OHD, although this technique has yet to be introduced in the clinical setting. Due to the mixed presence of maternal and foetal DNA, testing requires the analysis of polymorphic markers, as the complexity of the CYP21A2 locus precludes a direct analysis.25

Preimplantation genetic diagnosis is not yet widely available. It must be done in experienced facilities, as it is performed on a single cell and requires in vitro amplification due to the particular characteristics of the locus of interest.

Patients with severe forms should be managed in CCCs with proven experience in CAH to avoid the fragmentation, delays and inadequacies in care that may otherwise occur despite the efforts of paediatric endocrinologists. Care must be based in tertiary-level hospitals with sufficient human and technical resources.26

Adolescents are likely to skip checkups and fail to adhere to treatment. Adult gonadal function depends on adequate adherence to treatment; ovarian dysfunction in women and testicular masses in men worsen when adherence is poor. In female patients, it is important to address issues related to genital anatomy and past surgical history. The plan for transitioning to adult care must be developed collaboratively and with the agreement of the patient, the paediatric endocrinologist and the endocrinologist.27

The authors have no conflicts of interest to declare.