Diagnosis and Management of Congenital Adrenal Hyperplasia in the Child and Adolescent


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Congenital adrenal hyperplasia is due to 21-hydroxylase deficiency in > 90% of cases. This is a very common
genetic disorder for which biochemical screening is now performed. The classical form occurs in 1:15,000–16,000
live births, while the nonclassical form occurs in 1:1000. Congenital adrenal hyperplasia is the most common cause
of primary adrenal insufficiency in childhood. Undertreatment of the condition leads to acute risk of adrenal crisis and to long-term risk of short adult stature and infertility, whereas overtreatment is associated with short stature, obesity and other effects of hypercortisolism, including, but not limited to, osteoporosis.

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Diagnosis and Management of Congenital Adrenal Hyperplasia in the Child and Adolescent

  1. 1. Diagnosis and Management of Congenital Adrenal Hyperplasia in the Child and Adolescent
  2. 2. Apollo Medicine 2011 December Review Article Volume 8, Number 4; pp. 261–265 © 2011, Indraprastha Medical Corporation Ltd Diagnosis and management of congenital adrenal hyperplasia in the child and adolescent IPS Kochar*, Radhika Jindal** *Senior Consultant, Paediatric and Adolescent Endocrinologist, Department of Paediatric and Adolescent Endocrinology, **DNB Trainee, Department of Endocrinologist, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi – 110076, India. ABSTRACT Congenital adrenal hyperplasia is due to 21-hydroxylase deficiency in >90% of cases. This is a very common genetic disorder for which biochemical screening is now performed. The classical form occurs in 1:15,000–16,000 live births, while the nonclassical form occurs in 1:1000. Congenital adrenal hyperplasia is the most common cause of primary adrenal insufficiency in childhood. Undertreatment of the condition leads to acute risk of adrenal crisis and to long-term risk of short adult stature and infertility, whereas overtreatment is associated with short stature, obesity and other effects of hypercortisolism, including, but not limited to, osteoporosis. Keywords: Congenital adrenal hyperplasia (CAH), cortisol, nonclassical adrenal hyperplasia (NCAH) Correspondence: Dr. IPS Kochar, E-mail: inderpal_kochar@yahoo.com doi: 10.1016/S0976-0016(11)60002-1 INTRODUCTION The clinical phenotype of congenital adrenal hyperplasia (CAH) depends on the nature and severity of the enzyme deficiency. The most common form is 21-hydroxylase deficiency (CYP21). About 50% of patients with classic CAH due to CYP21A mutations or deletions have salt wast- ing (SW) due to inadequate aldosterone synthesis; the sex of a neonate with CAH is often initially unclear because of genital ambiguity. Fetus Pathophysiology Cortisol deficiency triggers a compensatory rise in cortico- tropin (adrenocorticotropic hormone, ACTH) (first pro- duced at 7 week) through negative feedback from reduced cortisol (8–12 weeks). This results in the build-up of inter- mediates (including 17-hydroxyprogesterone [17-OHP]), leading to overproduction of androgens and virilization of the external genitalia in females. The affected males have normally formed external genitalia, as excess fetal androgen production pales compared with normal testicular androgen production. Steroidogenic Pathway for Cortisol, Aldosterone, and Sex Steroid Synthesis Glucocorticoid physiology during pregnancy: • Despite the lipophilic nature of glucocorticoids and, there- fore, their ability to cross-placenta quite readily, the cir- culating levels of cortisol are normally markedly higher in mother than in fetus. This is because the placental 11-hydroxyepiandrosterone-2 (11-HSD-2) forms a func- tional barrier restricting the free transfer of cortisol between the maternal and fetal compartments by converting cortisol into its much less active 11-keto form, cortisone. In con- trast, synthetic corticosteroids, such as dexamethasone, are poor substrates for 11B-HSD-2 and, therefore, readily cross placenta and can be used for fetal therapy in CAH. Prenatal diagnosis (after prior affected child) after confir- mation of pregnancy is required, and maternal treatment with dexamethasone (20μg/Kg in two or three divided doses) is effective if started by 9 weeks after mother’s last menstrual period. Confirmation or elimination of diag- nosis by chorionic villus sampling at 9–11 weeks or by amniocentesis at 15–18 weeks is required. • Only 1 of 8 fetuses (affected females) will need to con- tinue the treatment to the end of pregnancy.
  3. 3. 262 Apollo Medicine 2011 December; Vol. 8, No. 4 Kochar and Jindal © 2011, Indraprastha Medical Corporation Ltd No adverse effects to fetus reported (although there are some theoretical concerns). Mothers are at risk for edema, stretch marks, and weight gain, but no diabetes or hypertension. Treatment should only be undertaken after full discussion. NEWBORN Diagnosis • Ambiguous genitalia: What caused the ambiguity? • Immediate prognosis: What can go wrong? What do I tell the family? • Sex assignment: What is the appropriate sex of rearing and what name should be used? • Long-term prognosis: What does the future hold? Definitions • Hyperplasia: Increased growth and/or function of cells, tissues or entire glands. • Classical adrenal hyperplasia: CAH (synonymous with con- genital adrenal hyperplasia, CAH, and more severe form). • Simple virilizing (SV): 25%. • Salt wasting (SW): 75%. • Nonclassical adrenal hyperplasia: NCAH (synonymous with late-onset and acquired adrenal hyperplasia and less severe form), possibly the most common human autosomal- recessive genetic disorder. Newborn Screening Indications The condition should be an important health problem. Severe SW form affects 75% of patients. If females with CAH are all identified at birth by genital ambiguity, then the estimated prevalence of males with salt loss is 1:40,000 and could avoid incorrect gender assignment in females. The condition is not otherwise recognizable at birth (in males) and could cause early death: Urinary sodium loss and reciprocal rise in serum potassium level develop gradu- ally and clinical adrenal insufficiency usually becomes manifest between 10 and 20 days of age. Nonsalt-losing males present at several years of age with precocious Cholesterol StAR/20,22 demolase Pregnenolone 17-OHP Dehydroepiandrosterone Androstenediol 3-β hydroxysteroid dehydrogenase Progesterone Deoxycorticosterone CYP21A/21 hydroxylase CYP11B2/Aldosterone synthetase CYP17/17-a hydroxylase/ 17,20 desmolase CYP11B1/11-β hydroxylase Corticosterone Aldosterone 11-deoxycortisol Estrone Estradiol Cortisol 17-ketosteroid reductase 17-OHP Androstenedione Testosterone Aromatase Figure 1 Steroid biosynthetic pathway.
  4. 4. Diagnosis and management of CAH in the child and adolescent Review Article 263 © 2011, Indraprastha Medical Corporation Ltd puberty. A reliable screening test/protocol is available: 17-OHP. An effective therapy that prevents serious out- comes must be available: Glucocorticoid and mineralocor- ticoid replacement. The cost of case-finding (including the diagnosis and treatment of patients) should be economically balanced in relation to the possible expenditure on medical care as a whole: Although the comparison of screened to nonscreened populations failed to show higher rate of diag- nosis of SW in screened cohort, screening in male infants is associated with significantly earlier diagnosis, reduced morbidity and shorter lengths of hospitalization. Newborn Screening Methods Filter paper 17-OHP measured in Auto Delfia Assay. First-tier 17-OHP measurement fraught with frequent false-positives is an unnecessary worry by families 0.5% (1:200 unaffected newborns require follow-up for every true case of CAH. Few cases of NCAH are detected because of the relatively low baseline levels of 17-OHP and, conversely, it is not known what proportion of cases of NCAH diagnosed by new born screening (NBS) eventually become symptomatic and hence need treatment. Limitations of 17-OHP level in diagnosing CAH: False- positives, sick term newborn (17-OHP may reach 3300ng/dL), prematurity/birth weight (secondary to delayed expression of l l-hydroxylase), early sampling age, poor kidney func- tion, stress, cross-reactivity of antibodies against 17-OHP used in radioimmunoassays with other steroids, most nota- bly 17-OH pregnenolone, secondary to reduced activity of 3-HSD that is seen in newborns. Limitations also include false-negatives secondary to the maternal treatment with betamethasone or dexamethasone. CHILDHOOD Variable Presentations of Adrenal Hyperplasia • Females birth: Male-looking genitals (the fusion of labio- scrotal folds and the enlargement of clitoris) without (SV) or with salt loss (CAH). – Childhood: Early development of pubic hair with or without signs of virilization, including rapid linear growth (no salt loss, NCAH). – Adolescence and adulthood: Increased hair growth (60%), absence or loss of menstrual periods (54%), acne (33%) (no salt loss, NCAH). – Any age: No symptoms (NCAH). • Males birth: Not easily diagnosed (CAH or NCAH), already have high levels of testicular testosterone (?large phallus). – Infancy: Signs of salt loss (75%) at 10–20 days of life (CAH). – Childhood: Early development of pubic hair without or with signs of virilization, including rapid linear growth and advanced bone age (no salt loss, CAH or NCAH). – Adolescence: Not a common time of presentation (NCAH). – Any age: No symptoms (NCAH). Behavioral Issues Gonadal hormones, particularly androgens, direct certain aspects of brain development and exert permanent influ- ences on sex, a typical behavior in nonhuman mammals. Androgens also influence human behavioral development with most convincing evidence coming from the studies of sex-typical play. Girls with CAH exposed to unusually high levels of prenatal androgens that show increased preferences for toys and activities usually preferred by boys and for male playmates, and decreased preferences for toys and activities usually preferred by girls. These findings suggest that andro- gens during the early development influence the childhood- play behavior in humans at least in part by altering brain development. DiagnosticTests for Congenital Adrenal Hyperplasia Blood: 17-OHP (stat in infancy) before (sufficient if sig- nificantly elevated) and after 250ILg of synthetic ACTH 1–24 (cortrosyn=cosyntropin). Testosterone, electrolytes, renin and occasionally other cortisol precursors (e.g., spe- cific compound S=l L-desoxycortisol)+karyotype/FISH for sex chromosome determination+gene testing. Radiology: Pelvic ultrasound, genitogram and, possibly, pelvic MRI (females). Early-morning 17-OHP in symptomatic individ- uals beyond newborn period. Adrenocorticotropic Hormone-stimulated 17-hydroxyprogesterone (ng/dL) Levels Salt wasting classical adrenal hyperplasia up to 100,000; SVCAH 10,000–30,000; NCAH 1500–10,000. Genetics of 21-hydroxylase Deficiency 21-hydroxylase gene is located at 6p21.3 within human leukocyte antigens (HLA) histocompatibility complex. Two highly homologous 21-hydroxylase genes exist, of which CYP2IA2 codes for active 21-hydroxylase and CYP21AIP is inactive pseudogene. More than 90% of mutations of active CYP21A2 gene are generated by recombinations between active and inactive genes (most are compound
  5. 5. 264 Apollo Medicine 2011 December; Vol. 8, No. 4 Kochar and Jindal © 2011, Indraprastha Medical Corporation Ltd heterozygotes involving two or more single point mutations, intronic changes and complete deletions or conversions). • ‘Routine’ genetic testing only when biochemical testing is equivocal depending on the residual activity of the mutation. There is good correlation between the geno- type and the phenotype regarding salt loss CYP21A2 gene in adrenal hyperplasia. elevated renin suggesting subclinical salt loss). Sodium chloride (?ALL): 4mEq/Kg/day or 1–2g/day in divided doses (1st year). Adrenal Crisis in Congenital Adrenal Hyperplasia: Treatment Dehydration/hyponatremia: Intravenous (i.v.) fluids (saline). Hyperkalemia: Usually responds to hydrocortisone replace- ment, but may require specific emergency measures. Hypo- glycemia: Intravenous glucose. Cortisol and aldosterone replacement: High-dose (∼5–10×) i.v. hydrocortisone in four divided doses or as a continuous infusion (these high doses also provide significant aldosterone effect. In adrenally insuf- ficient individuals experiencing a physiological stressor, deficient medullary catecholamine production and respon- siveness without which patients with CAH have additional risk factor for collapse during stress and responsiveness. Proper in utero glucocorticoid secretion by adrenal cortex is necessary for adrenomedullary organogenesis and epinephrine synthe- sis. Cortisol is a co-factor for phenylethanolamine N-methyl transferase (PNMT) enzyme activity necessary for the med- ullary conversion of norepinephrine to epinephrine (rate- limiting step in catecholamine synthesis). Nonclassical adrenal hyperplasia: Whom to treat with glucocorticoids? Children: Bone age significantly advanced, growth rate accelerated for age, rapidly progressing signs of puberty. Girls/women: Hirsutism or severe acne, oligomenorrhea, polycystic ovarian syndrome (may require specific therapy). Infertility (men or women), stress coverage (??), when to stop treatment (??), onset of puberty, growth complete, no symptoms, no fertility problems. Female surgical issues: Decision should be made by parents and requires an experienced surgeon who heads a designated surgical team that performs at least 3 or 4 cases per year. Goals of surgery: Genital appearance compatible with gender, unobstructed urinary emptying without incontinence or infections, good adult sexual and reproductive function. If high proximal junction between vagina and urethra: Best time is 3–6 months of age (techni- cally easier than at later times) and because female patients are able to undergo more natural psychological and sexual development when they have normal appearing vagina. More severely virilized females have high vagina entering into the masculine-appearing urethra at area of a false veru- montanum proximal to the external urethral sphincter for which techniques such as total urogenital sinus mobilization is employed. If junction is low between the vagina and ure- thra, i.e., near perineum, surgery may not be necessary. Anatomical studies required to make best decision. Clitoroplasty may not be necessary. If clitoroplasty is per- formed, must preserve neurovascular bundle, glans and preputial skin related to the glans. If surgery is done early, should be a one-stage repair using the newest techniques of Type Genotype Enzyme activity SWCAH deletions or None None nonsense mutations SVCAH missense Ilel72Asn (Iq72N) 1–2% mutations NCAH missense Val281Leu (V281L), 20–60% mutations Pro30Leu (P30L) SWCAH: salt wasting classical adrenal hyperplasia; SVCAH: simple virilizing classical adrenal hyperplasia; NCAH: nonclassical adrenal hyperplasia. Monitoring in Congenital Adrenal Hyperplasia Patients (q6 mo) Height and weight changes; clinical, e.g., regular menstrua- tion, lack of virilization. Blood tests: AM through 17-OHP, testosterone and rostenedione, renin+ACTH. Bone age. Urine tests generally not used. Effects of control: Day-to-day treatment of CAH (Table 1). Oral Hydrocortisone (ALL) At 10–20mg/m2 /day in divided doses (usually 1/4 in AM, 1/4 in afternoon and 1/2 at bedtime) with more at night to suppress normal overnight rise in ACTH. Higher doses required at diagnosis. In homogeneous suspensions to be avoided (tablets only). Higher doses required at puberty secondary to increased physiological clearance. Stress- dosing: Oral doses must be increased 2- to 3-fold during intercurrent illness and/or a parenteral form administered in CAH (although not necessarily in NCAH). Longer-acting synthetic forms, e.g., dexamethasone, can be used in the late adolescence and adulthood. Medical identification indicating adrenal insufficiency (?ALL), oral mineralocor- ticoid (?ALL): Fludrocortisone usually at 0.1mg/day (even for those without obvious salt loss, but perhaps with mildly Table 1 Effects of control on monitoring parameters. Parameter Undercontrolled Overcontrolled Height velocity Too fast Too slow Weight velocity Normal Too fast 17-OHP, testosterone, High Low renin Bone age Too fast Too slow Adult height Short Variable OHP: hydroxyprogesterone.
  6. 6. Diagnosis and management of CAH in the child and adolescent Review Article 265 © 2011, Indraprastha Medical Corporation Ltd (flap) vaginoplasty (vaginal exteriorization), clitoral and labial surgery. Revision vaginoplasty often required at ado- lescence, surgery between 12 months of age and adoles- cence not recommended in the absence of complications causing medical problems, vaginal dilation before adoles- cence contraindicated, minimize genital examinations and photographs to only those absolutely necessary. Pros and cons of adrenalectomy as treatment for CAH (for patients who fail medical therapy). Pros: To help recalcitrant infer- tility, to control unsuppressible hyperandrogenism and worsening glucocorticoid-induced obesity, relatively safe procedure via laparoscopic surgery. Cons: Increases the risk of life-threatening Addisonian crises with complete loss of both adrenal cortex and medulla, problematic hyper- pigmentation, stimulation of testicular (and ovarian) rest tissue and may induce pituitary hyperplasia! Tumor. Adolescent and Adult: Puberty Onset in both sexes usually occurs at an expected age if treated satisfactorily from early life. However, the true pre- cocious puberty may occur in well-treated children. True precocious puberty may occur after the initiation of gluco- corticoid therapy secondary to a sudden decrease in sex steroids, which causes hypothalamic activation. In most untreated or poorly treated adolescent girls and in some adolescent boys, spontaneous true pubertal development does not occur until proper treatment is initiated. This is thought to result from excess adrenal male hormones (which are converted to female hormones) suppressing hypothalamic/pituitary hormones (gonadotropins) that reg- ulate puberty. Many patients with treated AH have regular menses after menarche. Menarche may not occur if treat- ment is withheld or can be delayed with overtreatment. However, menstrual irregularity and secondary amenorrhea are not uncommon in teenage girls with CAH and are thought to result from poorly controlled disease and can be corrected by suppressing excess adrenal male hormones with long-acting and potent glucocorticoids. Long-term Issues Height and weight: Some degree of adult short stature is common (height average −1 to −2 SD below normal popu- lation=2nd to 16th percentiles). Growth delay may occur with CAH or NCAH. Effects on the height are related to medication noncompliance, chronic high doses of gluco- corticoids, and late diagnosis and advanced bone age at time. With increasing age, there is a tendency toward obes- ity, which may be due to the dosing of glucocorticoids that does not mimic the normal daily pattern of cortisol secretion, because of the suppression of growth hormone that results in increased body fat, or both, and may be worse when long- acting glucocorticoids, e.g., dexamethasone, are used. Metabolic: Adult obesity, reduced insulin sensitivity, increased intimal medial thickness and reduced bone min- eral density. Reproductive function in females: Symptoms of poly- cystic ovarian syndrome (PCOS), including the lack of ovulation and absent or irregular periods, may develop dur- ing adolescence, 80% of women with SV and 60% of those with severe salt-losing are fertile. The rate of successful pregnancies has increased with improvements in surgical, medical and psychological therapies. Deliveries are usually by cesarean section. Potential causes of infertility, overpro- duction of progesterone (decreased rate of ovulation through suppression of pituitary LH/FSH, ‘mini-pill’), hyperandro- genism affecting uterine lining, hypoandrogenism affecting libido, increased insulin 2 to obesity (PCOS), psychological factors affecting the rate of sexual activity or the ability to reach orgasm, anatomical differences, e.g., narrow vagina preventing normal insemination. Reproductive Function in Males Compared with affected women, men with CAH have fewer problems with reproductive function. Most men have normal sperm counts and are able to father children.A common prob- lem is the development of benign testicular tumors (‘rests’ of adrenal tissue). These ‘rests’ of adrenal tissue can nearly replace all the normal tissues, and decreased sperm produc- tion has been reported in boys as young as 3 years of age. Boys with CAH require careful testicular examinations and sonographical screening beginning in adolescence; occur most often in under-treated SWs, are ACTH-sensitive and will usually shrink in response to pituitary suppression with dexamethasone (usually precluding the need for biopsy and/or surgery). REFERENCES 1. Speiser PW, Azziz R, Baskin LS, et al. Endocrine society. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95:4133–60. 2. Auchus, Feldman Witchel S, Leight KR, et al. Guidelines for the development of comprehensive care centers for congenital adre- nal hyperplasia: guidance from the CARES Foundation Initi- ative. Int J Pediatr Endocrinol 2010; doi: 10.1155/2010/275213. 3. Kwon C, Farrell PM. The magnitude and challenge of false- positive newborn screening test results. Arch Pediatr Adolesc Med 2000;154:714–8. 4. Pasterski V, Hindmarsh P, Geffner M, et al. Increased aggres- sion and activity level in 3- to 11-year-old girls with congenital adrenal hyperplasia (CAH). Horm Behav 2007;52:368–74.
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