Congenital Adrenal Hyperplasia (Adrenogenital Syndrome): Clinical Guidelines

List of Abbreviations

BP – blood pressure

AH – arterial hypertension

ACTH – adrenocorticotropic hormone

CAH – congenital adrenal hyperplasia

AGS – adrenogenital syndrome

21-DOC – 21-deoxycortisol

TMS – tandem mass spectrometry

US – ultrasound examination

HR – heart rate

MC – mineralocorticoids

IVF – in vitro fertilization

11-DOC – 11-deoxycortisol

17-OHP – 17-hydroxyprogesterone

DHEA – dehydroepiandrosterone

DHEAS – dehydroepiandrosterone sulfate

SD – standard deviation score

SS – sex steroids

CT – computed tomography

MRI – magnetic resonance imaging

Terms and Definitions

Congenital adrenal hyperplasia (adrenogenital syndrome, congenital adrenal hyperplasia) is a group of autosomal recessive disorders caused by a defect in one of the enzymes or transport proteins involved in cortisol biosynthesis in the adrenal cortex.

Premature adrenarche – isolated appearance of pubic hair in children under 8 years of age.

Gonadotropin-dependent precocious puberty – the appearance of secondary sexual characteristics in girls under 8 years and boys under 9 years, caused by premature activation of the hypothalamic-pituitary-gonadal axis.

Determination of a wide profile of steroids by liquid chromatography-tandem mass spectrometry (LC-MS/MS) – quantitative determination of major steroid hormones and their metabolites in blood serum using tandem mass spectrometry (LC-MS/MS).

Level of evidence – the degree of confidence that the observed effect of a medical intervention is true.

Level of убедительности рекомендаций (Grade of Recommendation) is the degree of certainty in the validity of the intervention effect and that following the recommendations will bring more benefit than harm in a particular situation.

Good clinical practice – (good practice point, GPP) is used for recommendation statements relating to patient history taking, physical examination, and medical care organization (medical process management) in the absence of evidence derived from systematic searches and selection of clinical studies.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Congenital adrenal hyperplasia (adrenogenital syndrome, congenital adrenal hyperplasia) – a group of disorders with an autosomal recessive inheritance pattern, based on a defect in one of the enzymes or transport proteins involved in cortisol biosynthesis in the adrenal cortex [1,3,78].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

All forms of CAH are based on pathogenic variant substitutions in genes responsible for the synthesis of steroidogenesis enzymes or coenzymes, as well as the STAR gene encoding the protein involved in cholesterol transport into the mitochondria [30,33,34,36,38,50,56,92]. An autosomal recessive inheritance pattern has been proven for all forms of CAH, i.e., mutations on both alleles are required for the disease to manifest. Furthermore, all forms of the disease exhibit genotype-phenotype correlation, where the severity of clinical manifestations directly depends on the degree of enzyme function impairment. Thus, classic forms of the disease with clinical onset in the early neonatal period and non-classic (late-onset) forms of the disease, where the clinical picture develops in later childhood, puberty, or even in young adults, have been described [34,83,89]. In the presence of compound heterozygous mutations, the clinical picture is determined by the less "severe" mutation.

In all forms of CAH, cortisol deficiency is observed, which, via a negative feedback mechanism, leads to increased ACTH levels and adrenal hyperplasia. As a result of adrenal stimulation, there is an excessive accumulation of steroids preceding the enzymatic block. The clinical picture of each form of CAH is due to the deficiency of hormones whose synthesis is impossible due to the specific enzymatic block, and the excess of precursors.

1.3 Epidemiology of the Disease or Condition

The most frequent form of CAH, accounting for over 90% of patients, is 21-hydroxylase deficiency. The global prevalence of 21-hydroxylase deficiency, calculated from neonatal screening data, is 1 case per 14,000 live newborns [65]. In Russia, according to neonatal screening data, the frequency of classic forms of 21-hydroxylase deficiency is 1 case per 9,638 live newborns [7]. There is a variation in the prevalence of the disease across regions of the Russian Federation, with the maximum frequency in the Ural Federal District (1:6,749) and the minimum in the Northwestern Federal District (1:14,876) [5,7,8,12,16]. The global prevalence of the non-classic form of 21-hydroxylase deficiency is 0.1–0.2%; among Ashkenazi Jews, this form is significantly more common at 1–2%. The minimum prevalence of the non-classic form of 21-hydroxylase deficiency, calculated based on the carrier frequency of the two most common mutations in the CYP21A2 gene using the Hardy-Weinberg formula for the Moscow Region, was 1 case per 2,206 newborns [4].

The second most common form of CAH is 11β-hydroxylase deficiency. Worldwide, this form of CAH is 10 times less common than the classic forms of 21-hydroxylase deficiency. The prevalence of 11β-hydroxylase deficiency in Russia has not been studied. The remaining forms of CAH are significantly rarer. Some rare forms of CAH are characterized by a high frequency in certain populations, which is explained both by the frequency of consanguineous marriages and the founder effect. Thus, a high prevalence of 3β-hydroxysteroid dehydrogenase deficiency has been described, amounting to 1 case per 22,679 live newborns in the Republic of North Ossetia-Alania [13].

Given the overwhelming predominance of 21-hydroxylase deficiency among all forms of CAH, the majority of clinical guidelines pertain specifically to the diagnosis and treatment of this form.

1.4 Features of Coding the Disease or Condition

E25 - Adrenogenital disorders

E25.0 - Congenital adrenogenital disorders associated with enzyme deficiencies

E25.8 - Other adrenogenital disorders

E25.9 - Adrenogenital disorder, unspecified

1.5 Classification of the disease or condition

To date, 7 forms of congenital adrenal hyperplasia (CAH) are known:

• Lipoid congenital adrenal hyperplasia (mutations in the gene encoding the StAR protein);

• 20,22-desmolase deficiency (11α-hydroxylase deficiency);

• 17α-hydroxylase/17,20-lyase deficiency;

• 3β-hydroxysteroid dehydrogenase deficiency;

• 21-hydroxylase deficiency;

• 11β-hydroxylase deficiency;

• Oxidoreductase deficiency.

Within each form, classic and non-classic variants are distinguished depending on the severity and timing of clinical manifestations. The division into classic and non-classic forms is due to varying degrees of reduced enzyme activity determined by the specific mutation.

In 21-hydroxylase deficiency, 3 clinical forms are distinguished: two classic forms – salt-wasting and simple virilizing, and the non-classic form of the disease. With zero enzyme activity, a total deficiency of glucocorticoids and mineralocorticoids occurs, leading to a salt-wasting state in the neonatal period and marked virilization of the external genitalia in girls. With residual enzyme activity of 1 to 10%, the simple virilizing form of the disease develops without impairing mineralocorticoid function, but leads to prenatal virilization of the fetus. With enzyme activity greater than 10%, virilization manifests only after birth in the form of premature adrenarche at 4–5 years, accelerated growth, and advanced bone age [7,18,78].

1.6 Clinical presentation of the disease or condition

Cortisol deficiency, characteristic of all forms of CAH, manifests as a tendency toward hypoglycemia syndrome, which is especially pronounced in infants and during stress situations. A specific symptom of cortisol deficiency is skin hyperpigmentation due to high levels of pro-opiomelanocortin and its derivatives.

Depending on the level of the enzymatic block, all forms of CAH can be divided into 2 groups: with an enzyme deficiency in the early stages of steroidogenesis (11α-hydroxylase deficiency, StAR protein defect, 17α-hydroxylase deficiency), there is a block in the androgen synthesis pathway in both the adrenal glands and the gonads, leading to inadequate masculinization of the external genitalia in fetuses with a 46,XY karyotype; with an enzyme deficiency in later stages of steroidogenesis occurring exclusively in the adrenal glands (21-hydroxylase deficiency, 11β-hydroxylase deficiency), adrenal androgens accumulate, leading to prenatal virilization in fetuses with a 46,XX karyotype. In 3β-hydroxysteroid dehydrogenase deficiency, atypical external genitalia are observed at birth in both 46,XX and 46,XY karyotypes, because there is a block in the testosterone synthesis pathway leading to inadequate masculinization in boys, while weak androgens (DHEA) accumulate in excess, causing mild virilization in girls. Additionally, atypical external genitalia in both boys and girls may be observed in oxidoreductase deficiency.

In the postnatal period, forms accompanied by excess adrenal androgens manifest with accelerated growth, advanced bone age, and premature adrenarche. Conversely, in CAH forms with impaired sex steroid synthesis, hypergonadotropic hypogonadism develops in both boys and girls during adolescence.

Regarding the impairment of the mineralocorticoid function of the adrenal glands, all forms of CAH can also be divided into 2 groups: those presenting with mineralocorticoid deficiency (11α-hydroxylase deficiency, StAR protein defect, 3β-hydroxysteroid dehydrogenase deficiency, 21-hydroxylase deficiency, oxidoreductase deficiency), and those presenting with mineralocorticoid excess (11β-hydroxylase deficiency, 17α-hydroxylase deficiency). The clinical manifestations of mineralocorticoid deficiency are signs of salt-wasting syndrome: nausea, uncontrollable vomiting, decreased blood pressure, weight loss, loose stools, and dehydration. Mineralocorticoid deficiency is characterized by electrolyte changes in the form of hyperkalemia and hyponatremia, with an elevated blood renin level serving as a hormonal marker. Mineralocorticoid excess leads to persistent arterial hypertension accompanied by pronounced hypokalemia with characteristic symptoms of muscle weakness, polyuria, and polydipsia, with a decreased plasma renin level serving as a hormonal marker. The clinical presentation of all forms of CAH is shown in Table 1.

Table 1. Clinical and hormonal characteristics of various forms of CAH

Thus, the physical examination of newborns primarily involves assessing the structure of the external genitalia using the Prader scale and identifying signs of salt-wasting syndrome: dehydration, weight loss, regurgitation, persistent vomiting.

Examination of children involves assessing general condition, measuring height and body weight with evaluation of standard deviations from population norms, and assessing secondary sexual characteristics. Blood pressure measurement is mandatory for children with suspected CAH.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Introduction: various forms of CAH are characterized by a diversity of clinical manifestations. Symptoms of the disease are determined by the deficiency of certain classes of steroids and the excess of others, caused by a specific enzymatic block. The main laboratory method for diagnosing all forms of CAH is the determination of various corticosteroids in blood serum. In classic variants of the disease, steroid compounds preceding the enzymatic block are elevated tens of times, which causes no difficulty in making a diagnosis. It should be borne in mind that all steroid compounds have a similar chemical structure, which leads to significant cross-reactivity between them when determining their concentration by enzyme immunoassay or radioimmunoassay. Currently, the multisteroid analysis method with prior separation of all steroids using chromatography or mass spectrometry has maximum informativeness. Using this method, one can not only determine the exact concentration of steroid compounds but also evaluate the ratio of precursors and products of various enzymes. Table 1 presents the clinical features and hormonal markers of each form of CAH.

2.1 Complaints and Anamnesis

Introduction: in classic forms of the disease, the clinical presentation typically debuts in the neonatal period as atypical external genitalia and salt-wasting syndrome. Exceptions are hypertensive forms of CAH, in which the increase in blood pressure usually begins in early childhood.

In non-classic (mild) forms of CAH, clinical manifestations may debut either in childhood or during puberty, and sometimes the diagnosis is established already in adulthood.

2.2 Physical Examination

Introduction: physical examination of newborns primarily involves assessing the structure of the external genitalia using the Prader scale and identifying signs of salt-wasting syndrome: dehydration, weight loss, regurgitation, persistent vomiting.

Examination of children involves assessing general condition, measuring height and body weight with evaluation of standard deviations from population norms, and assessing secondary sexual characteristics.

Comments: the Prader scale is presented in Appendix G1.

Comments: clinical manifestations of salt-wasting syndrome in the form of regurgitation, weight loss, loose stools, decreased blood pressure, and signs of exicosis typically occur on the 10th–20th day of life, whereas electrolyte changes in the form of hyperkalemia and hyponatremia can be detected earlier.

Comments: a distinctive feature of congenital adrenal hyperplasia from idiopathic premature adrenarche is growth acceleration of more than 2 SD and a bone age advancement of more than 2 years compared to passport age.

Comments: the Tanner scale for assessing the stage of sexual development is presented in Appendix (G2-G3). Dissociation between the stage of sexual development and prepubertal testicular size may indicate an adrenal origin of androgens and requires ruling out the virilizing/non-classic form of 21-hydroxylase deficiency or 11β-hydroxylase deficiency.

2.3 Laboratory Diagnostics

2.3.1. Diagnosis of 21-hydroxylase deficiency within neonatal screening

21-Hydroxylase deficiency is well-suited for newborn screening programs because it is a common, potentially lethal condition with a clear diagnostic marker and effective treatment. Since 1977, total newborn screening for congenital adrenal hyperplasia (CAH) has been introduced, initially in the state of Alaska, USA, and subsequently in other regions. Literature data confirm the effectiveness of screening [26,40,65,82,85]. Neonatal mortality from undiagnosed salt-wasting crises ranged from 4 to 10%, and misassignment of sex in female infants occurred in up to 10% of cases [9]. Following the implementation of screening, the numbers of boys and girls identified with CAH became equal, and the disease incidence increased [26,40,82,85].

Comments: in Russia, newborn screening has been in place since mid-2006, resulting in more than a twofold increase in the detection rate of this condition. Furthermore, the time to diagnosis and the severity of hyponatremia have decreased, which, according to the literature, subsequently improves children's learning abilities.

The screening procedure involved blood collection from full-term newborns on the 4th day of life, from preterm infants on the 7th–10th days, and the determination of 17-OHP levels in the samples using specialized screening kits. In 2023, modifications were made to the screening program: for neonatal screening for congenital and/or hereditary diseases and expanded neonatal screening for congenital and/or hereditary diseases, blood samples are collected from the newborn's heel 3 hours after feeding, at 24–48 hours of life in full-term infants and on the 7th day (144–168 hours) of life in preterm newborns.

Different cutoff values are used depending on birth weight, as determined by each laboratory [65]. If the screening result is positive, information is forwarded to the child's local outpatient clinic, followed by a repeat blood draw for retesting.

According to the literature, grading the diagnostic threshold of 17-OHP in preterm newborns is more informative when gestational age is taken into account rather than birth weight [44].

Comments: the positive predictive value of the first stage of newborn screening ranges from 1 to 5%, meaning that among all positive results, only 1 to 5 children out of 100 positive samples actually have CAH, while the remaining cases are false positives. Given the high economic and emotional costs associated with a large number of false-positive cases, it has been proposed to perform retesting using tandem mass spectrometry (TMS). According to German authors, the use of TMS and the calculation of the derived index (the sum of 17-OH-progesterone and 21-deoxycortisol levels divided by the cortisol level) increases the positive predictive value to 100% [42]. In addition to detecting 21-hydroxylase deficiency, TMS also enables the diagnosis of rare forms of CAH [43].

Comments: considering the possibility of false-positive newborn screening results, as well as the fact that newborn screening detects a small percentage of children with the non-classical form of 21-hydroxylase deficiency who do not require treatment, all children with a positive newborn screening result need an evaluation by a pediatric endocrinologist. Abnormal external genitalia combined with a positive screening result definitively establishes the diagnosis in girls and allows therapy to be initiated. At the same time, all boys and girls with normal external genitalia may require further workup.

Comments: the detection of hyponatremia combined with hyperkalemia allows for the diagnosis of the salt-wasting form of 21-hydroxylase deficiency. It should be noted that one of the goals of newborn screening is to diagnose the disease before the clinical picture of salt-wasting crisis develops, which typically manifests in the 2nd to 3rd weeks of life. By the time screening results are received (the 10th–14th day of the child's life), even in the absence of clinical signs of the salt-wasting syndrome, the patient already has electrolyte imbalances.

Comments: in cases of borderline 17-OHP values ("gray zone") during newborn screening and subsequent hormonal workup, foreign literature recommends performing an stimulation test with ACTH-group drugs (H01AA), which is the "gold standard" for diagnosing CAH. If test results are inconclusive or cannot be performed, molecular genetic testing of the CYP21A2 gene is recommended.

21-Hydroxylase deficiency is caused by numerous mutations in the CYP21A2 gene encoding this enzyme. The gene is located on the short arm of chromosome 6 near the major histocompatibility complex (HLA). In close proximity to the CYP21A2 gene lies the CYP21P pseudogene. These genes are highly homologous; however, only CYP21A2 participates in the transcription of 21-hydroxylase, possessing 10 transcribed exons and 9 introns in its structure, whereas CYP21P is a pseudogene because it contains a series of mutations that render the protein it encodes completely devoid of activity. The tandem organization of highly homologous genes creates conditions for frequent recombination between them, in the form of the replacement of a large fragment of the CYP21A2 gene with a homologous fragment from the pseudogene, or the transfer of small pseudogene fragments into the active gene (gene conversion). Such mutations can lead to complete or partial loss of 21-hydroxylase enzymatic activity. More than three hundred mutations in CYP21A2 leading to 21-hydroxylase deficiency have been described to date, but 85% of all cases are accounted for by 12 frequent mutations transferred from the pseudogene. Certain correlations have been found between the type of mutation and the clinical course of the disease [30].

At the first stage of molecular genetic diagnostics, screening for frequent mutations in the CYP21A2 gene can be performed. The detection of a homozygous mutation or two heterozygous mutations confirms the diagnosis. If a single heterozygous mutation is detected or if frequent mutations are absent, complete sequencing of the CYP21A2 gene is performed [30].

2.3.2. Diagnosis of 21-hydroxylase deficiency outside of neonatal screening

Comments: the primary criterion for the hormonal diagnosis of 21-hydroxylase deficiency is an elevated serum 17-OHP level. In classic forms of the disease, 17-OHP levels exceed age-specific normal reference values for the child by more than 10-fold.

• When congenital adrenal hyperplasia is suspected, it is advisable to perform a comprehensive determination of steroid hormone concentrations using tandem mass spectrometry [69].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Comments: it should be borne in mind that all steroid compounds share a similar chemical structure, which leads to significant cross-reactivity among them when determining their concentration. Currently, multi-steroid profiling with prior separation of all steroids using chromatography or mass spectrometry has the highest diagnostic value. This method not only allows for the precise determination of the concentration of steroid compounds but also makes it possible to assess the ratios of precursors and products of various enzymes. Detection of elevated 21-deoxycortisol levels in a blood sample is a specific marker of 21-hydroxylase deficiency.

Comments: the first stage involves screening for common mutations in the CYP21A2 gene. The identification of a homozygous mutation or two heterozygous mutations makes it possible to establish the diagnosis. If a single heterozygous mutation is detected or if common mutations are absent, full sequencing of the CYP21A2 gene is performed.

Comments: in congenital adrenal hyperplasia, high doses of dexamethasone** lead to a significant decrease in androgen levels, whereas in androgen-producing tumors, androgen levels remain unchanged during dexamethasone** administration. The test protocol is identical to the low-dose dexamethasone test used in the diagnosis of hypercortisolism: a blood test is taken before the test to determine androgens (assessing blood levels of 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, and total testosterone) and cortisol; then, dexamethasone** is administered at a dose of 0.5 mg 4 times daily (4 mg total per test) for 2 days, and on the morning of the third day, blood tests are performed to measure androgens (17-hydroxyprogesterone, dehydroepiandrosterone sulfate, and total testosterone) and blood cortisol levels.

Comments: a significant elevation in plasma renin (greater than 10 ng/mL/h for plasma renin activity or greater than 100 mcIU/mL for direct renin) points towards mineralocorticoid deficiency.

2.3.3 Diagnosis of rare forms of congenital adrenal hyperplasia

Introduction: the main clinical symptoms and laboratory markers of rare forms of congenital adrenal hyperplasia are presented in Table 1.

Comments: lipoid congenital adrenal hyperplasia, 11-alpha-hydroxylase deficiency, 17-alpha-hydroxylase deficiency, 3-beta-hydroxysteroid dehydrogenase deficiency, and oxidoreductase deficiency are characterized by atypical or female external genitalia in the presence of a 46,XY karyotype; conversely, 11-beta-hydroxylase deficiency is characterized by atypical external genitalia with a 46,XX karyotype, while 3-beta-hydroxysteroid dehydrogenase deficiency and oxidoreductase deficiency with a 46,XX karyotype may present with mild virilization of the external genitalia.

Comments: multi-steroid profiling in children with differences of sex development makes it possible to diagnose all classic variants of steroidogenesis disorders. Each form of congenital adrenal hyperplasia is characterized by the elevation of specific steroids, as indicated in Table 1.

Comments: the development of a salt-wasting crisis in newborns can lead to severe consequences, up to and including death; therefore, all newborns with atypical genital structure—which may be caused by rare forms of congenital adrenal hyperplasia—must undergo blood potassium and sodium testing. Hyperkalemia combined with hyponatremia are signs of mineralocorticoid deficiency and require the immediate initiation of therapy.

Comments: an elevated ACTH level in a newborn with atypical external genitalia allows for the diagnosis of one of the variants of congenital adrenal hyperplasia. Elevated blood renin combined with low aldosterone levels are observed in forms of congenital adrenal hyperplasia presenting with mineralocorticoid deficiency (lipoid adrenal hyperplasia, 11-alpha-hydroxylase deficiency [20,22-desmolase deficiency], 3-beta-hydroxysteroid dehydrogenase deficiency).

Comments: low-renin arterial hypertension combined with symptoms of hyperandrogenism is characteristic of 11-beta-hydroxylase deficiency, which is confirmed by high levels of 11-deoxycortisol and 11-deoxycorticosterone along with elevated adrenal androgens.

2.4 Instrumental Diagnostics

Comments: bone age advancement by 2 years or more relative to chronological age is characteristic of congenital adrenal hyperplasia, as opposed to idiopathic premature adrenarche.

Comments: girls with menstrual irregularities associated with amenorrhea may exhibit moderately elevated 17-hydroxyprogesterone levels. The detection of enlarged ovaries on ultrasound (greater than 12 mL) is one of the findings supporting an ovarian origin of hyperandrogenism.

Comments: the absence of a uterus in a newborn with a 46,XY karyotype and ambiguous or female external genitalia may occur in congenital adrenal hyperplasia (due to lipoid adrenal hyperplasia, 11β-hydroxylase deficiency, 17α-hydroxylase deficiency, or 3β-hydroxysteroid dehydrogenase deficiency).

2.5 Other Procedures

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

Introduction: the mainstay of therapy for all forms of CAH is the administration of glucocorticoids, which replace cortisol deficiency and thereby suppress excessive ACTH secretion. As a result, adrenal production of the steroids that are excessively synthesized due to the specific enzymatic block is reduced.

Comments:various medicinal products possessing glucocorticoid activity exist: hydrocortisone**, prednisolone**, cortisone, dexamethasone**. Long-acting synthetic glucocorticoids (prednisolone**, dexamethasone**) have a negative impact on growth processes. For children with open growth plates, especially of younger age, oral formulations of hydrocortisone** should be considered the most optimal drugs. The initial daily dose of hydrocortisone**, necessary to suppress excessive ACTH secretion in infants during the first year of life, can reach up to 20 mg/m². In children older than one year, the average daily dose of hydrocortisone** should be 10-15 mg/m². The drug is administered three times a day in equal doses every 8 hours.

Comments: in children with growth plates close to closure, it is possible to use long-acting glucocorticoids, which provide a more pronounced ACTH-suppressive effect. The daily dose of these drugs should correspond to the equivalent dose of hydrocortisone** of 10-15 mg/m² per day (prednisolone** - 5-7.5 mg/day in 2 doses, dexamethasone** - 0.25-0.5 mg/day in 1-2 doses). For maximum suppression of ACTH secretion, 1/3 of the daily dose is prescribed in the morning hours (at 7:00 AM) and 2/3 of the dose - before bedtime (at 11:00 PM).

Comments: the salt-wasting form of CAH requires therapy with the mineralocorticoid fludrocortisone**, which is prescribed at a dose of 0.05-0.15 mg/day in 1-2 doses (at 6:00-7:00 AM and 4:00-5:00 PM). In infants, the requirement for mineralocorticoids is higher and can reach 0.3 mg/day (the daily dose is recommended to be divided into 2-3 doses). Children without clinical manifestations of the salt-wasting syndrome may exhibit subclinical mineralocorticoid deficiency, the criterion for which is an elevated renin level. In such cases, the administration of fludrocortisone** is also indicated. Infants are indicated for an additional dietary intake of sodium chloride in the amount of 0.1-0.2 g per kg of body weight.

3.2 Surgical Treatment

Comments: currently, for girls with a low degree of virilization (up to stage 3 according to the Prader classification with a low subsphincteric form of urogenital sinus), a single-stage repair is recommended, including clitoral surgery with preservation of the neurovascular bundle and introitoplasty. For girls with a high form of urogenital sinus, the timing and scope of surgical intervention are still debated. Performing single-stage treatment in infancy has both advantages (single-stage treatment, the possibility of using preputial tissue for introitoplasty) and disadvantages (formation of vaginal scar stenosis, which requires dilation or repeat surgery). In two-stage treatment, the first stage, which includes clitoral surgery and, if necessary, dissection of the urogenital sinus, is performed during the first year of life, and the second stage — introitoplasty — after achieving good estrogenization of the genitalia. Further studies evaluating cosmetic outcomes and functional components in adulthood are required.

3.3 Other Treatment

Introduction: one of the complications of prolonged decompensation of those forms of CAH that proceed with excessive synthesis of adrenal androgens (21-hydroxylase deficiency and 11β-hydroxylase deficiency) is the advancement of bone age. Upon reaching pubertal bone age values, children may develop gonadotropin-dependent precocious puberty. To confirm premature activation of the hypothalamic-pituitary-gonadal axis, a gonadotropin-releasing hormone agonist stimulation test is performed. In case of an unsatisfactory growth prognosis (projected final height of less than 150 cm in women and less than 160 cm in men), the administration of gonadotropin-releasing hormone agonists (ATX code L02AE) according to standard protocols is possible [31]. As puberty is blocked, children's growth velocity generally decreases. In such cases, the additional use of growth hormone preparations is possible to improve the growth prognosis [7,59].

Many clinicians note the complexity of achieving disease compensation in congenital adrenal hyperplasia during puberty, which is related both to the psychological characteristics of adolescents leading to non-adherence with medication regimens, and to the physiological features of the pubertal period resulting in altered pharmacokinetics of glucocorticoids. To compensate for the clinical manifestations of hyperandrogenism when glucocorticoid dose escalation is not feasible, the prescription of anti-androgens (ATX code G03H) to adolescent girls may be considered [53].

Comments: gonadotropin-releasing hormone agonists (ATX code L02AE) (#triptorelin** at a dose of 3.75 mg i.m. once every 28 days or 11.25 mg i.m. once every 12 weeks, #leuprorelin** at a dose of 7.5 mg i.m. once every 28 days or 11.25 mg i.m. once every 12 weeks — treatment is carried out in accordance with the relevant clinical guidelines «Precocious Puberty» [94]. Growth hormone preparations (somatropin** at a dose of 0.035 mg per kg/day s.c. in the evening hours daily) may also be prescribed in case of an unsatisfactory growth prognosis (projected final height less than 150 cm in women and less than 160 cm in men).

Comments: if arterial hypertension persists despite glucocorticoid therapy in hypertensive forms of CAH, the administration of additional antihypertensive therapy is indicated when glucocorticoid dose escalation is not feasible [45,51].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: the birth of a child with abnormal external genitalia, i.e., with ambiguous genitalia, is often a stressful event for the family, requiring qualified psychological counseling. The need for lifelong hormone replacement therapy and the threat of acute conditions such as acute adrenal crisis cause concern for both the children and their parents. Psychological support for patients and their families not only improves the patients' quality of life but also increases adherence to treatment. During adolescence, many patients with CAH who have undergone plastic surgery on the external genitalia have questions about their gender identity and prospects for sexual life and fertility, which sometimes requires sessions with a psychologist to accept the diagnosis.

5. Prevention and Dispensary Observation

5.1 Prevention of acute conditions

Introduction: prevention in congenital adrenal hyperplasia is aimed at preventing crises of acute adrenal insufficiency.

Comments: children with classic forms of CAH have chronic adrenal insufficiency; therefore, the release of an adequate amount of glucocorticoids in response to stress is impossible. This necessitates increasing the glucocorticoid dose in situations such as surgical treatment, fever, dehydration, or severe trauma. During intercurrent illnesses, the glucocorticoid dose is increased by 2–3 times. When an adrenal crisis develops, parenteral administration of glucocorticoids is required.

Comments: administer parenteral bolus of hydrocortisone** 50–100 mg/m² or calculated as 2–4 mg/kg. Dose calculation is also possible based on the patient's age: IM or IV bolus up to 2 years (< 15 kg) – 25 mg, from 2 to 6 years (15–25 kg) – 50 mg, from 6 years and older (> 25 kg) – 100 mg of hydrocortisone**. Then continue hydrocortisone** administration at a dose of 50–75–100 mg/m² /day either as a continuous infusion or in four divided doses administered every 6 hours intravenously or intramuscularly, or administration of hydrocortisone** at a dose of 2 mg/kg every 6 hours.

Parenteral fluid resuscitation:

- for shock or moderate/severe dehydration, administer 0.9% sodium chloride** solution IV at 10–20 ml/kg;

- initiate subsequent maintenance infusion therapy: 0.9% sodium chloride** solution or 5% dextrose** solution;

- if blood glucose is less than 3.5 mmol/L, administer 10% dextrose** solution IV bolus at 2–5 ml/kg.

Every 2 hours, test blood levels of potassium, sodium, and glucose, and measure peripheral blood pressure and heart rate.

Upon normalization of potassium and sodium levels, switch to intramuscular administration of hydrocortisone** solution with a gradual dose reduction and transition to oral medications. Fludrocortisone** is prescribed when the hydrocortisone** dose is < 50 mg/day.

Comments: during surgical operations with general anesthesia, feminizing genitoplasty, severe trauma, labor, and conditions requiring intensive care: immediately before anesthesia, a bolus injection of hydrocortisone** at a dose of 2 mg/kg IV or IM (for premature infants and newborns under 28 days of life at a dose of 4 mg/kg) is required, followed by continuous IV infusion of hydrocortisone** at a rate calculated as follows:

- body weight less than 10 kg: 25 mg per 24 hours;

- body weight 10–20 kg: 50 mg per 24 hours;

- body weight more than 20 kg: in prepubertal children – 100 mg per 24 hours, in pubertal children – 150 mg per 24 hours.

In the postoperative period during the first 24 hours, continuous IV infusion at the above doses may be continued, or a switch can be made to bolus IV or IM administration of hydrocortisone** at 2 mg/kg every 4 hours. After stabilization, switch to oral administration of hydrocortisone** in stress doses (increase the standard daily dose by 2 times for 48 hours, followed by a gradual reduction to the usual therapeutic dose. When switching to oral hydrocortisone** in a patient with mineralocorticoid deficiency, it is recommended to prescribe fludrocortisone** at the standard dose the patient was receiving prior to surgery).

5.2 Follow-up (therapy monitoring) in 21-hydroxylase deficiency

Introduction: the goal of therapy in CAH is to select the minimum effective dose of glucocorticoids. Follow-up of patients with 21-hydroxylase deficiency requires maintaining a constant balance between glucocorticoid excess—leading to iatrogenic Cushing's syndrome with growth suppression, weight gain, and hypertension—and glucocorticoid deficiency—leading to hyperandrogenism with accelerated growth, advanced bone age, and signs of virilization.

Comments: infants during the first year of life should be monitored every 1–3 months. The primary criterion for the adequacy of replacement therapy in infants is the weight gain curve. Satisfactory weight gain and the absence of regurgitation indicate effective treatment. Blood electrolyte levels are determined monthly to adjust the fludrocortisone** dose. There are no clear criteria for plasma renin activity in infants under 3 months of life, making this parameter difficult to use for assessing adequate mineralocorticoid replacement therapy. The 17-OHP level is determined every 3 months to adjust the hydrocortisone** dose. It should be noted that insufficient suppression of hyperandrogenism in the first year of life does not lead to significant bone age progression, whereas glucocorticoid overdosage during this period negatively affects the final adult height of patients.

Comments: children older than one year should be examined by a pediatric endocrinologist every 3–6 months. For this age category, the growth curve and bone age progression dynamics come to the forefront among the criteria for therapeutic adequacy. A decrease in growth velocity indicates glucocorticoid overdosage. An increase in growth velocity compared to age-standard norms and a bone age advancement exceeding chronological age by more than one year over the course of a single year indicate an insufficient glucocorticoid dose. The target 17-OHP level is the upper limit of normal or slightly above it. In prepubertal children and adolescent girls, determining the testosterone level can be informative, as it reflects the duration of existing hyperandrogenism. A slight elevation in 17-OHP levels with normal testosterone levels does not require increasing the hydrocortisone** dose.

Comments: adolescents with CAH require special attention, as future fertility is determined and growth potential is realized during this age period. Glucocorticoid overdosage at this time leads to short final stature in patients. Due to the specifics of cortisol metabolism during puberty, it is very difficult to achieve adequate suppression of hyperandrogenism without causing symptoms of overdosage. Therefore, adolescents with CAH must be monitored every 3–6 months. In this age group, a transition to long-acting glucocorticoid preparations is possible, provided that growth plates are close to closure and final height has been achieved. The criteria for therapeutic adequacy are growth and weight dynamics, as well as the rate of sexual development progression. Both hyperandrogenism and iatrogenic hypercorticism lead to delayed sexual development.

In cases of prolonged disease decompensation, additional diagnostic methods are required. To rule out the development of secondary adenomas, an adrenal ultrasound is performed. In boys, an additional scrotal ultrasound is performed to detect hyperplasia of ectopic adrenal tissue in the testes. The presence of secondary adenomas in the adrenal glands or mass lesions in the testes requires stricter control of hyperandrogenism. In such cases, either the hydrocortisone** dose is increased, or the patient is switched from hydrocortisone** to long-acting glucocorticoid preparations.

Periods of prolonged glucocorticoid overdosage can cause complications, which include obesity, hyperinsulinemia, and insulin resistance. In childhood and adolescence, these complications do not require additional examination, and treatment involves diet therapy and physical exercise in addition to adjusting glucocorticoid therapy.

At all age periods except infancy, plasma renin activity or direct renin levels are used to monitor mineralocorticoid therapy, and these should be maintained at the upper limit of normal.

Prolonged mineralocorticoid overdosage leads to persistent arterial hypertension and suppressed renin levels. In such cases, reducing the fludrocortisone** dose must be carried out under the control of plasma renin activity or direct renin levels, since the normalization of blood pressure may occur slowly and may even require the temporary administration of antihypertensive therapy (calcium channel blockers are used).

An increase in plasma renin activity, even in the absence of electrolyte changes, dictates the need to increase the mineralocorticoid dose.

5.3. Follow-up (therapy monitoring) in children with rare forms of CAH

6. Organization of Medical Care

Indications for hospital admission to a medical organization:

1. Hospitalization in a hospital or day hospital for children with atypical external genitalia to clarify the cause of the disease and assign sex of rearing;

2. Emergency hospital admission for children with signs of salt-wasting syndrome to clarify the diagnosis and carry out emergency measures to manage an adrenal crisis;

3. Emergency hospital admission for children with a diagnosed congenital adrenal hyperplasia in the event of an acute adrenal insufficiency crisis;

4. Elective hospitalization in a hospital or day hospital for children with suspected congenital adrenal hyperplasia if primary outpatient evaluation cannot be performed in full;

5. Elective hospitalization in a specialized hospital or day hospital for children with suspected precocious puberty if it is impossible to clarify the diagnosis and determine management tactics within the current medical organization;

6. Elective hospitalization in a hospital or day hospital for children with established congenital adrenal hyperplasia if full outpatient evaluation is not feasible;

7. Elective hospitalization of children for surgical treatment (plastic surgery of external genitalia).

Indications for discharging a patient from a medical organization:

1. Upon hospitalization of a newborn with a difference of sex development, discharge is possible after determining the management strategy regarding sex assignment and treatment;

2. In case of emergency hospitalization of a child with an adrenal insufficiency crisis, discharge from the hospital is carried out after the crisis of adrenal insufficiency is relieved and the child is transferred to oral medications;

3. In the case of hospitalization of a child with suspected congenital adrenal hyperplasia, discharge of the patient from the hospital or day hospital is carried out after clarifying the diagnosis and determining treatment tactics;

4. In the case of hospitalization of a child with established congenital adrenal hyperplasia for follow-up examination and therapy adjustment, the patient may be discharged after completing the scope of examination provided by clinical guidelines and adjusting the ongoing therapy.

5. In the case of hospitalization of a patient with CAH for surgical treatment, the patient may be discharged home at the end of this stage of surgical treatment, provided their general condition is satisfactory and there are no signs of adrenal insufficiency.

7. Additional Information

Introduction: as with any monogenic disease, prenatal and preimplantation genetic diagnosis is available for all forms of congenital adrenal hyperplasia in families that already have children with this condition.

Comments: prenatal diagnosis requires knowing the genotype of both parents. The diagnostic procedure is performed at 9–10 weeks of gestation by obtaining DNA from chorionic villus sampling and determining the presence of mutations in the gene responsible for the development of this form of congenital adrenal hyperplasia (CAH). Preimplantation genetic testing is available for CAH. Preimplantation genetic testing can only be performed using assisted reproductive technologies, specifically in vitro fertilization (IVF) with intracytoplasmic sperm injection.

Comments: prenatal therapy is administered to prevent or reduce the degree of external genitalia virilization in female fetuses with 21-hydroxylase or 11β-hydroxylase deficiency. The treatment utilizes dexamethasone**, which is not inactivated by placental 11β-hydroxysteroid dehydrogenase and crosses to the fetus. Since therapy must be initiated as soon as pregnancy is established—when fetal cortisol levels are very low—glucocorticoid levels will significantly exceed physiological levels during certain periods. Prenatal therapy does not eliminate the need for lifelong treatment later on and does not prevent salt-wasting crises in the postnatal period. Therapy is indicated exclusively for female fetuses with 21-hydroxylase deficiency. 21-hydroxylase deficiency is an autosomal recessive disorder; in a family with an affected child, the probability of conceiving an affected female fetus is 12.5%. Since prenatal diagnosis is only feasible at 10 weeks of gestation, in 87.5% of cases the fetus will receive high doses of glucocorticoids unnecessarily from 4–6 weeks until 10 weeks of gestation. The adverse effects of dexamethasone** exposure on the mother during pregnancy are well documented: pathological weight gain, impaired carbohydrate metabolism, and an increased risk of arterial hypertension. The potential effects of high-dose dexamethasone** exposure on the fetus in early gestation are not yet fully understood. Consequently, prenatal therapy cannot be recommended for routine clinical practice. Further research is required.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

LEADERS:

Peterkova Valentina Aleksandrovna – D.Sc. in Medicine, Professor, Academician of the Russian Academy of Sciences, Scientific Director of the Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health; Head of the Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology of the Russian Ministry of Health; Chief freelance pediatric endocrinologist of the Russian Ministry of Health.

Bezlepkina Olga Borisovna – D.Sc. in Medicine, Professor, Director of the Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health; Professor at the Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

TEXT AUTHORS:

Kolodkina Anna Aleksandrovna – Ph.D. in Medicine, Head of the Department of Hereditary Diseases and Early-Onset Endocrinopathies, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health; Associate Professor at the Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Chugunov Igor Sergeevich – Ph.D. in Medicine, Head of the Pediatric Department of Endocrine Tumors, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health; Associate Professor at the Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Kopylova Irina Vladimirovna – Ph.D. in Medicine, Senior Researcher at the Pediatric Department of Endocrine Tumors, Institute of Pediatric

Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

Kalinchenko Natalya Yurievna – Ph.D. in Medicine, Leading Researcher at the Pediatric Department of Thyroidology, Reproductive and Somatic Development, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

EXPERTS:

Bashnina Elena Borisovna – D.Sc. in Medicine, Professor at the Department of Endocrinology named after Academician V.G. Baranov, North-Western State Medical University named after I.I. Mechnikov; Chief freelance pediatric endocrinologist of the North-Western Federal District.

Galkina Galina Aleksandrovna – D.Sc. in Medicine, Professor, Head of the Pediatric Endocrinology Department, Research Institute of Obstetrics and Pediatrics, Rostov State Medical University of the Russian Ministry of Health; Chief freelance pediatric endocrinologist of the Rostov Region and the Southern Federal District.

Kiyaev Aleksey Vasilyevich – D.Sc. in Medicine, Professor at the Department of Hospital Pediatrics, Ural State Medical University of the Russian Ministry of Health; Head of the Regional Center of Pediatric Endocrinology, Regional Children's Clinical Hospital; Chief freelance pediatric endocrinologist of the Sverdlovsk Region and the Ural Federal District.

Kostrova Irina Borisovna – Head of the Pediatric Endocrinology Department, Children's Republican Clinical Hospital named after N.M. Kuraev; Chief freelance pediatric endocrinologist of the Republic of Dagestan and the North-Caucasian Federal District.

Malievsky Oleg Arturovich – D.Sc. in Medicine, Professor at the Department of Hospital Pediatrics, Bashkir State Medical University of the Russian Ministry of Health; Chief freelance pediatric endocrinologist of the Privolzhsky Federal District.

Petryaikina Elena Efimovna – D.Sc. in Medicine, Director of the Russian Children's Clinical Hospital – branch of the Pirogov Russian National Research Medical University of the Russian Ministry of Health; Head of the Department of Endocrinology, Institute of Motherhood and Childhood, Pirogov Russian National Research Medical University of the Russian Ministry of Health; Chief freelance pediatric endocrinologist of the Moscow Healthcare Department and the Central Federal District.

Samsonova Lyubov Nikolaevna – D.Sc. in Medicine, Professor, Head of the Department of Pediatric Endocrinology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health.

Taranushenko Tatyana Evgenyevna – D.Sc. in Medicine, Head of the Department of Pediatrics, Institute of Postgraduate Education, Krasnoyarsk State Medical University named after Professor V.F. Voyno-Yasenetsky of the Russian Ministry of Health; Chief freelance pediatric endocrinologist of the Krasnoyarsk Territory and the Siberian Federal District.

All working group members declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Pediatric endocrinologist;

2. Pediatrician;

3. Neonatologist;

4. Obstetrician-gynecologist;

5. Pediatric urologist-andrologist.

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Rating scale for levels of evidence (LE) for preventive, therapeutic, and rehabilitation methods (interventions)

Table 3. Scale for assessing levels of evidence (LE) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Steroidogenesis pathway indicating enzymes involved in cortisol synthesis, defects of which lead to congenital adrenal hyperplasia

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

What does "Adrenogenital syndrome" mean?

The term "Adrenogenital syndrome" or the name adopted in Russian medicine, "Congenital adrenal hyperplasia" (CAH), refers to a functional disorder of the adrenal glands that frequently leads to alterations in the external genitalia.

The adrenal glands are paired organs, no larger than a bean, located in close proximity to the kidneys. They consist of 2 main parts. The inner part, the so-called medulla, produces adrenaline. The second part—the outer part—is called the cortex, whose function is impaired in CAH.

What is the function of the adrenal cortex?

The cortex produces a number of hormones called steroids, which enter the bloodstream directly and play an important role in maintaining the body's basic vital functions.

These steroids are synthesized from cholesterol and divided into 3 main groups: cortisol, aldosterone, and androgens, or, as they are otherwise known, male sex hormones.

Cortisol regulates the function of many body systems, including blood circulation and the maintenance of blood glucose levels. Cortisol also helps the body cope with stressors such as infections and trauma.

Aldosterone is responsible for maintaining the required level of salt (sodium) in the body. The amount of salt we consume daily with food depends on the types of foods eaten, and the kidneys prevent its accumulation in the body, otherwise it could cause an increase in blood pressure. At the same time, the kidneys prevent excessive loss of salt from the body. A lack of salt can lead to symptoms of dehydration and vomiting. Aldosterone helps the body retain salt, and if a person consumes little salt with food, aldosterone comes into action. Conversely, if there is a lot of salt in the diet, the adrenal cortex reduces aldosterone synthesis and allows salt to be excreted in the urine.

Androgens (male sex hormones) are produced by the adrenal cortex in both sexes. In addition, in males, androgens are synthesized by the testes. In boys and girls, androgens are responsible for the appearance of pubic hair during puberty.

How does the adrenal cortex produce the required amount of cortisol?

The amount of cortisol produced by the adrenal glands is controlled by a coordinating gland—the pituitary gland—which is located in the cranial cavity and connected to another gland, the hypothalamus. If the cortisol content in the circulating blood is insufficient to maintain vital functions, the hypothalamus detects this and prompts the pituitary gland to produce corticotropin or adrenocorticotropic hormone (ACTH).

ACTH enters the bloodstream, is captured by the adrenal cortex, and cortisol production increases. When the normal cortisol concentration is reached, this is registered by the hypothalamus, and the stimulation of ACTH production by the pituitary gland ceases. If the patient receives exogenous cortisol preparations in the form of tablets or injections, the hypothalamus senses this acutely and suppresses ACTH production by the pituitary gland. The adrenal cortex is not stimulated. This point is extremely important for understanding the therapy of CAH.

What is the cause of adrenogenital syndrome?

The process of cortisol synthesis from cholesterol involves a whole chain of transformations, where each stage is carried out by special proteins called enzymes. If at least one of the 5 enzymes involved in cortisol synthesis at various stages fails to function normally, a disease occurs: congenital adrenal hyperplasia. When there is a deficiency of cortisol in the circulating blood, the pituitary gland detects this low concentration and attempts to increase its effect on the adrenal cortex through enhanced production of ACTH. This secondarily leads to excessive stimulation of the cortex and its thickening. Thus, so-called “cortical hyperplasia” occurs. The classical form of CAH is caused by 21-hydroxylase deficiency, which disrupts the synthesis of both cortisol and aldosterone while androgen production is preserved. This means that excess ACTH leads to constant stimulation of the adrenal cortex and its only surviving function: androgen production. Thus, depending on the severity of the enzymatic defect, 21-hydroxylase-deficient CAH manifests as cortisol and aldosterone deficiency and excess androgen production.

How does adrenogenital syndrome affect children's health?

The manifestations of classical CAH depend on the child's sex and the degree of 21-hydroxylase enzyme deficiency.

Boys with complete absence of the 21-hydroxylase enzyme: At birth, the child's appearance is normal, and the first manifestations are usually poor appetite, weight loss, and episodes of vomiting between 1 and 2 weeks of life. This is due to the loss of salt and water associated with aldosterone deficiency. This condition requires immediate medical intervention.

Girls with complete deficiency: In utero, the female fetus is exposed to excess adrenal androgens, which causes changes in the appearance of the external genitalia towards a male phenotype. As a result, the labia majora resemble a scrotum in structure, and the clitoris is significantly enlarged and may resemble a penis in appearance. Sometimes the clitoris is so enlarged that at first glance it is impossible to tell whether the child is female or male, which causes severe psychological stress for the parents.

The internal genital organs of the girl are formed normally: the uterus, vagina, and ovaries are present. Subsequently, the girl needs plastic surgery to correct the appearance of the genitalia. If the diagnosis of CAH is not established immediately, the symptoms of salt and fluid loss described above join the clinical picture.

Boys with partial 21-hydroxylase deficiency: the first manifestations appear later (between 2 and 4 years of life): accelerated growth and penile enlargement. Pubic hair may also appear as a result of excess androgens.

Girls with partial 21-hydroxylase deficiency: All the same signs of androgen excess will be characteristic, such as tall stature, pubic hair, and slight enlargement of the clitoris.

Boys and girls will have a comparatively tall height for their age, but without treatment, their final height will be short due to the effect of androgens on bone maturation. Growth plates close early, and bones lose their ability to grow.

Children with partial 21-hydroxylase deficiency do not have clinical symptoms of salt loss, but more careful biochemical and hormonal tests may reveal signs of hidden salt loss.

Finally, there is a term “non-classical form of CAH”, in which the enzyme deficiency is insignificant. In childhood, this diagnosis is practically never made, but it can be the cause of menstrual irregularities and excessive hair growth in young women.

How does adrenogenital syndrome develop?

The disease is inherited. To understand this mechanism, it is necessary to know some information about genes and chromosomes.

Pregnancy occurs when the father's sperm and the mother's egg fuse. Then the cells begin to divide and differentiate into cells of various organs and tissues: brain tissue, muscle tissue, liver, skin, etc. The information that allows a human to be recreated from a single cell is located in genes, and genes form thread-like structures called chromosomes. Each cell contains 23 pairs of chromosomes, with one chromosome from each pair being maternal and the other paternal.

In CAH, one of the genes located on the two pairs of the 6th chromosome is damaged, which prevents the enzyme from being synthesized normally. In the parents of a sick child, one chromosome contains the damaged gene and the other contains the healthy one.

Such parents are called “healthy carriers”. If the father's chromosome with the defective gene combines with the mother's chromosome with the defective gene, they will form a chromosome pair with two pathological genes, inheriting which the child will have clinical manifestations of CAH.

If the father's defective chromosome fuses with the mother's normal chromosome (or vice versa), the child will be a “healthy carrier”, just like their parents. When two normal chromosomes fuse, the child will be healthy and will not be a “healthy carrier”.

In a family where the parents are “healthy carriers”, the probability of having a sick child is 25%. This type of inheritance is called recessive. It must be emphasized that if the parents are carriers, the risk of having a sick child is 1:4 for each subsequent pregnancy. If the family already has one sick child, this does not mean that 3 children from subsequent pregnancies will be healthy.

Can grandchildren inherit the same pathology?

When a child with CAH grows up and has children of their own, the probability that the partner's chromosome will contain the pathological gene is small. Assuming the partner is healthy and not a “healthy carrier”, the pathological gene will be compensated by the presence of a normal one, and all children from such a marriage will be “healthy carriers”. The probability of two healthy carriers meeting is 1:50. The risk increases significantly in consanguineous marriages if the mother and father are first cousins.

For children from a marriage between a person suffering from CAH and a “healthy carrier”, the risk increases to 1:2.

Is puberty normal in children with CAH, and can children with CAH have children of their own?

In children receiving regular and adequate replacement therapy, normal timing of the onset and course of puberty can be expected. There is a tendency towards later menarche and ovarian dysfunction. Glucocorticoid treatment also affects the establishment of menstrual function, so it is extremely important to continue monitoring girls during adolescence and adulthood.

Girls with congenital adrenal hyperplasia have properly formed uteruses and ovaries, so there is no reason to believe that they cannot have children, and many women have reported a normal pregnancy course. Girls who have a pronounced salt-wasting component may experience certain difficulties during pregnancy, so it is necessary to closely monitor the adequacy of therapy, especially when a girl decides to become a mother.

In boys with CAH, provided the disease is compensated, reproductive function is not impaired.

Can adrenogenital syndrome be detected before the child's birth, and is there any treatment at the prenatal stage of development?

Currently, in families that already have one sick child, prenatal diagnostics is performed. To do this, it is necessary to have the results of genetic testing of the blood of the parents and the child, and by examining the tissues or amniotic fluid of the fetus, the sex of the child and the presence of CAH can be determined. Using genetic blood tests of brothers and sisters, “carrier status” can also be established.

If the fetus is female, it is necessary to prevent masculinization of the external genitalia caused by excess androgens. This can be done by prescribing the glucocorticoid dexamethasone** in tablets to the mother. It enters the mother's bloodstream and crosses the placenta into the child's bloodstream, suppressing the fetal pituitary gland and preventing excessive synthesis of corticotropin by the pituitary gland. This treatment is effective if started immediately after pregnancy is confirmed.

Between 10 and 14 weeks of pregnancy, tissue is sampled from the mother through the cervix (chorionic villus sampling) to determine the sex of the child and the presence or absence of CAH in the fetus.

If the analysis shows that the fetus is healthy, dexamethasone** treatment can be stopped. A short treatment period will not have a negative impact on fetal development. If a male fetus is diagnosed with congenital adrenal hyperplasia, treatment can also be stopped, as the excess of androgens will not have a pathological intrauterine effect. If the fetus with congenital adrenal hyperplasia is a female, the mother must take dexamethasone** throughout the pregnancy. This significantly reduces masculinization of the external genitalia and decreases the scope of surgical intervention for external genital plastics that may be required later. As is known, dexamethasone** treatment has no pathological effect on the child's development. Possible complications for the mother are limited to weight gain and increased skin striae (stretch marks).

What is neonatal screening for adrenogenital syndrome?

Because congenital adrenal hyperplasia is a fairly common disease—affecting 1 in 10,000 newborns—many countries have included it in their neonatal screening programs. What does this mean? On the 4th day of life in the maternity hospital, a drop of blood is taken from each newborn's heel and applied to special filter paper. From this blood spot, the laboratory simultaneously tests for several common and severe diseases that require treatment immediately after birth. In our country, neonatal screening is performed for such diseases as phenylketonuria, congenital hypothyroidism, adrenogenital syndrome, cystic fibrosis, and galactosemia. Neonatal screening detects the disease on the 10th–14th day of the child's life. This allows treatment to be started in a timely manner, avoids severe situations such as salt-wasting crisis, and—in girls with pronounced genital virilization—prevents errors in assigned sex.

What treatment is required for adrenogenital syndrome?

Treatment is divided into 2 main groups: medical therapy (treatment with glucocorticoid and mineralocorticoid preparations) and surgical treatment, which is required by the majority of girls with congenital adrenal hyperplasia.

Medical treatment consists of administering cortisol or its analogues to prevent excessive production of adrenocorticotropic hormone by the pituitary gland. During stress, such as when the child is ill, the dose of cortisol medications must be increased, since a normally functioning adrenal cortex produces additional cortisol in this situation. Cortisol is prescribed to children in the form of tablets containing the active substance hydrocortisone**, which is identical to natural cortisol. Adolescents and adults may be prescribed other glucocorticoids: prednisolone** or dexamethasone**. These glucocorticoids differ in potency, are accessible, relatively inexpensive, and available in a convenient tablet form.

For children with symptoms of salt-wasting due to aldosterone deficiency, hydrocortisone** therapy alone is insufficient. Such children need replacement therapy with an aldosterone analogue, which is usually given in the form of fludrocortisone** tablets.

During the first year of life, children with a tendency toward salt-wasting require additional dietary table salt in their daily diet. After one year of age, the use of fludrocortisone** and a standard salt diet are usually sufficient to maintain a normal salt balance in the body.

The tactics for glucocorticoid administration and frequency of dosing are chosen by the physician individually for each specific child. Hydrocortisone** is usually prescribed 3 times a day, while prednisolone** and dexamethasone** are given in two doses. Fludrocortisone** is given 2 times a day, and table salt several times a day.

In certain situations, such as vomiting or if the child misses doses, hydrocortisone** must be administered via injection. Parents and older children must be thoroughly trained so that in an emergency, necessary assistance can be provided at home.

Surgical treatment: usually performed during the first or second year of life, when the child can be operated on safely, but is not yet old enough to be aware of the abnormal structure of the external genitalia.

The extent of surgery depends on the degree of virilization of the external genitalia. Typically, the surgeon needs to perform a very careful resection (excisions) of the clitoris while preserving blood vessels and nerve fibers to maintain sensitivity. The surgeon may also attempt to open the vaginal introitus. The length of hospital stay usually reaches up to 10 days.

Sometimes it is impossible to fully open the vaginal introitus during the first surgery, so for some girls the operation is performed in stages. Usually, the second stage is performed during puberty, before the onset of sexual activity. At the onset of puberty, the girl should be consulted either by the surgeon who previously operated on her or by a gynecologist to resolve the issue of a second surgical stage.

Does steroid therapy cause harm to health?

Treatment with glucocorticoids and mineralocorticoids is vital for the child's normal growth and development. With an adequate dose, there are no side effects from treatment because glucocorticoids replace the steroids that the adrenal cortex should normally produce. If the dose of glucocorticoids is inappropriately high, the growth rate decreases markedly. Conversely, an unjustifiably low dose leads to accelerated growth and signs of precocious puberty due to androgen excess.

Too high a dose of fludrocortisone** can lead to arterial hypertension, but this problem often occurs only in the first months of life. If the dose is exceeded, blood pressure temporarily rises and returns to normal after reducing the fludrocortisone** dose. Your attending physician may recommend regular blood pressure monitoring.

What doses are used for treatment? What laboratory tests are needed to monitor treatment adequacy? How often should clinic consultations take place?

Drug dosages are individual for each patient. Generally, children without the salt-wasting component require lower doses than those with the salt-wasting form. Naturally, as the child grows and ages, higher doses of the medication are required. During puberty, the dosage may change more rapidly.

The adequacy of the hydrocortisone** dose is assessed by growth rate and skeletal maturation parameters. Growth metrics should be carefully recorded during regular clinic check-ups (3–4 times a year).

The next diagnostic indicator used alongside growth rate assessment is hand X-ray data. This study is called bone age determination and is informative starting from 2 years of age. If bone age progresses too rapidly, it means that the hydrocortisone** dose is insufficient.

Children with congenital adrenal hyperplasia must visit the clinic 3–4 times a year for dose adjustment. On average, the drug dose is increased by the physician once a year. Blood pressure must be measured at each visit. Bone age determination is performed once a year (twice a year for special indications). Blood tests are taken at the physician's discretion. Typically, monitoring of 17-OHP (17-hydroxyprogesterone) levels is performed—an indicator that rises in congenital adrenal hyperplasia. Blood for testing should be drawn in the morning before 9 AM, two hours after taking medications. The 17-OHP level may be moderately elevated against the background of treatment. This does not mean that the hydrocortisone** dose is insufficient.

Conversely, with low 17-OHP levels, the physician will recommend reducing the hydrocortisone** dose, as there is a risk of drug overdose in this case. The fludrocortisone** dose is monitored by plasma renin and serum potassium and sodium levels. Insufficient fludrocortisone** dosing leads to elevated renin and potassium levels and decreased sodium. Conversely, fludrocortisone** overdose is accompanied by decreased renin and potassium levels in the blood. Any test results will be evaluated by the physician in conjunction with the child's general well-being, blood pressure readings, and weight and height dynamics. Only then may the physician change the dose of the medications taken.

Will my child grow normally and achieve a satisfactory final height?

With adequate treatment, children with congenital adrenal hyperplasia can achieve a final height within the normal range. However, even with good treatment, it is not always possible to improve growth rates, and the final height of some patients may be lower than expected. Sometimes the dose required to treat congenital adrenal hyperplasia creates issues with weight gain, which is particularly relevant for adolescent girls. In turn, excess weight makes it harder to compensate for the condition; elevated 17-OHP levels force the physician to increase the hydrocortisone** dose, which may further increase the patient's weight. This creates a vicious circle, which can be broken by strict adherence to a diet.

At what time of day should the child be given the medication?

The administration schedule is primarily related to the individual characteristics of each child. The optimal treatment regimen is selected by the attending physician. Hydrocortisone** is usually recommended to be taken in equal doses three times a day: at 7:00 AM, 2:00 PM, and 10:00 PM. Prednisolone** is prescribed twice daily, at 7:00 AM and 10:00 PM. One-third of the dose is taken in the morning, and two-thirds at night. However, the physician may recommend a higher dose of prednisolone** in the morning and a lower one in the evening, depending on the child's individual needs. Dexamethasone** may sometimes be prescribed once daily at bedtime. Fludrocortisone** is recommended to be taken twice a day, at 9:00 AM and 5:00 PM. The larger dose is prescribed in the morning, or the drug is recommended to be taken in equal doses morning and evening. Infants under one year of age have a higher requirement for fludrocortisone** than older children; for such children, the physician may recommend taking the medication three times a day, concurrently with hydrocortisone**. In older children during puberty, disease compensation can be difficult, especially in overweight girls. In these cases, the physician may recommend a combination therapy using hydrocortisone** in the morning and afternoon, and prednisolone** at night, since prednisolone** has a longer duration of action and exerts its effect throughout the night and early morning hours.

What measures should be taken in an emergency situation in adrenogenital syndrome?

As already mentioned, hydrocortisone** plays a very vital role for the body in stressful situations. Normally, in a healthy body, cortisol production increases during illness, trauma, surgical interventions, etc. It is important to remember that the adrenal glands of people with congenital adrenal hyperplasia cannot mount an adequate response to stress; therefore, during stress, it is necessary to increase the hydrocortisone** dose, mimicking the natural response of the adrenal glands. To manage a child with congenital adrenal hyperplasia during an infectious disease or other condition affecting medication requirements, the following recommendations apply:

1) If the child's condition is not concerning, for example, with a mild cold, an increase in the hydrocortisone** dose is not required.

2) If the child is unwell (with a respiratory infection or digestive issues) and cannot maintain a normal routine (attending school, etc.), it is recommended to double the usual daily dose of hydrocortisone**, dividing it into three equal intakes. After 2–3 days of recovery, one can return to the previous dose. If there are even the slightest doubts about how to act in this situation, consult your doctor.

3) In severe illnesses, especially those accompanied by diarrhea and vomiting, hydrocortisone** must additionally be administered intramuscularly, since the child cannot absorb tablets. In case of repeated vomiting, weakness, or sweating in the child, hydrocortisone** must be administered by the parents immediately, without waiting for recommendations from your attending physician. Delay in this situation is extremely dangerous!!! If there are any doubts, it is always better to err on the side of caution by giving the injection and then asking the doctor questions! An injection of hydrocortisone** in this case will not cause any harm, and on the contrary, can play a decisive role in saving the child's life! Be sure to discuss this with your doctor in advance and learn the intramuscular injection technique. Vials of hydrocortisone** solution can be stored at room temperature. Be sure to monitor the expiration date of hydrocortisone** and replace expired vials!

An adequate dose of hydrocortisone** for intramuscular injection is considered to be: 25 mg for infants, 50 mg for preschool and early school-age children, and 100 mg for older children. Hydrocortisone** should be drawn into a syringe and given as an intramuscular injection into the mid-lateral part of the buttock. An intramuscular needle is used and inserted to its full length. Usually, the child's condition improves noticeably after this; however, despite this, it is necessary to notify the physician of the incident as soon as possible. If no improvement is noted and symptoms persist, especially in the case of vomiting, an ambulance or emergency medical service should be called, and the child taken to a hospital for correction of water-electrolyte balance via intravenous fluid administration.

4) Surgical procedures requiring general anesthesia must necessarily be performed after a preliminary injection of hydrocortisone** prior to the administration of anesthesia. Uncomplicated tooth extractions under local anesthesia usually do not require the aforementioned precautions. In any case, be sure to inform the dentist about your child's condition.

5) To facilitate communication between parents and the attending physician, it makes sense to constantly keep a symptom diary, noting the time and dose of medications taken in parallel.

Are prophylactic vaccinations contraindicated for the child?

No. The dose of glucocorticoids your child receives is equivalent to the amount of steroid hormones produced by the adrenal cortex of a healthy person, and with the adjusted dosage, there is no reason to cancel necessary prophylactic vaccinations.

If you and your child are away from home and/or abroad, you must carry a medical document prepared by your attending physician detailing not only the daily therapy but also appropriate recommendations in case of an emergency. Before taking a trip, consult a specialist regarding the medications you need to take with you.

Psychological problems in the family

As mentioned at the beginning, diagnosing congenital adrenal hyperplasia is usually a significant stress for the family members of a sick child. Especially in cases where the disease affects the appearance of a girl's genitalia, the family experiences major problems and discomfort when discussing this issue with other relatives and family members. A girl's genitalia are not a subject for family discussion. Only the closest relatives should know about this: parents and grandmothers if they are involved in caring for the child. It is not recommended to send the child to preschool institutions until surgical correction of the external genitalia has been performed. The girls themselves can be deeply depressed by the necessity of genital examinations and subsequent surgical intervention, especially if the girl is an adolescent. It should be noted that in cases where the surgery to correct the external genitalia was performed at an early age, there is no need to show the girl to a gynecologist until puberty. However, we can assure you that the feelings of depression and confusion experienced by parents are an adequate psychological response to the situation. Consultations with a specialized psychologist are available in medical institutions.

What support is provided to families of patients with adrenogenital syndrome?

For many parents, it is important to meet other families who have a child suffering from congenital adrenal hyperplasia. Ask your attending physician about this.

Regarding financial assistance to families, many parents apply for disability status for their children, which provides certain financial benefits. This is especially important for preschool-aged children who require more frequent and thorough medical supervision.

Congenital adrenal hyperplasia is a treatable condition. Children with congenital adrenal hyperplasia lead a normal lifestyle, and their life expectancy is comparable to that of healthy people with proper treatment. Hundreds of patients with this diagnosis have grown into adults, have normal families and healthy children, received education, became specialists in their field, and active members of society.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Prader scale for assessing the degree of virilization of external genitalia in congenital adrenal hyperplasia

Source Prader A Der genitalbefund beim pseudohermaphroditismus femininus der kongenitalen adrenogenitalen syndroms. // Helv Paediatr Acta, 1954, N9, p.231-248.

Purpose: assessment of the degree of virilization of external genitalia in girls (high posterior commissure).

Grade 2 virilization - clitoral hypertrophy and partial fusion of the labia majora.

Grade 3 virilization - hypertrophied clitoris with a formed glans, fusion of the labia forming a urogenital sinus - a single urogenital opening at the base of the clitoris.

Grades 4-5 virilization - hypertrophied clitoris resembling a normal penis, but with chordee (fixed to the perineum), urogenital sinus opening on the shaft or glans of the penis (penile urethra).

Appendix G2 - Tanner scale for assessing stages of sexual development in girls

Source: Marshall W. A., Tanner J. M. Variations in pattern of pubertal changes in girls.

Archives of Disease in Childhood. 1969;235(44):291-303.

Breasts:

Stage 1 - prepubertal breasts, glandular tissue absent, areolar diameter less than 2 cm, pale areolae.

Stage 2 - breast and areola form a conical elevation without distinct contours, areolar pigmentation appears.

Stage 3 - areola deeply pigmented, projecting as a second mound above the breast tissue.

Stage 4 - areola and nipple project above the breast level, areola deeply pigmented, projecting as a second mound above the breast tissue.

Stage 5 - adult contour of the breast with projection of the nipple only, the contour between the breast tissue and areola is smoothed out.

Pubic hair:

Stage 1 - no pubic hair.

Stage 2 - sparse pigmented hair growth on the labia majora.

Stage 3 - hair becomes darker and coarser, spreading over the pubic symphysis.

Stage 4 - coarse, adult-type hair not extending to the medial thighs.

Stage 5 - adult-type hair distributed in a classic triangle pattern.

Appendix G3 - Tanner scale for assessing stages of sexual development in boys

Source: Marshall W. A., Tanner J. M. Variations in the Pattern of Pubertal Changes in Boys. Archives of Disease in Childhood. 1970;239(45):13-23.

Stage 1 - no pubic hair; testes, scrotum, and penis are prepubertal, testicular volume 2-3 mL.

Stage 2 - growth of sparse pigmented hair around the base of the penis; scrotum enlarges and becomes slightly pigmented, testicular volume 4 mL.

Stage 3 - hair becomes darker and coarser, spreading over the pubic symphysis; initial linear growth of the penis; scrotum begins to rugate, testicular volume 10 mL.

Stage 4 - adult distribution of pubic hair, but sparing the thighs and lower abdomen; continued linear growth of the penis; enlargement of the glans diameter; external genitalia become pigmented, testicular volume $\ge$ 12 mL.

Stage 5 - adult diamond-shaped hair distribution; external genitalia reach adult size, testicular volume $\ge$ 15 mL.