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Congenital adrenal hyperplasia
ADRENAL
Congenital adrenal hyperplasia Ieuan Hughes
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders of adrenal steroid biosynthesis. Clinical manifestations are pleiotropic, depending on the severity of steroid enzyme deficiency and the age of presentation. The condition is life-long, but classically presents at birth with ambiguity of the external genitalia in an affected female infant. CAH is the most common cause of newborn intersex.
Epidemiology The incidence of CAH is 1/10,000 to 1/15,000 live births, based on figures from newborn screening programmes in several Western countries. The milder late-onset form has an incidence as high as 1/1000.
Pathophysiology The adrenal cortex produces cortisol and aldosterone, which are essential for normal homeostasis. Cortisol production is adrenocorticotrophic hormone (ACTH) dependent via a classical endocrine negative feedback mechanism. Aldosterone production is under the control of the renin–angiotensin system. Cholesterol is the starting point for steroid synthesis, with several enzymatic steps required for cortisol and aldosterone production. Figure 1 shows the pathophysiological consequences of 21-hydroxylase deficiency, which is the most common enzyme deficiency causing CAH. The continued drive for ACTH production leads to excessive production of adrenal androgens, which are converted in the liver to testosterone. A fetus with CAH produces excess androgens from as early as 8 weeks’ gestation; if the fetus is female, enlargement of the clitoris and fusion of the labioscrotal folds leads to ambiguity of the external genitalia at birth. The same enzyme is needed to synthesize aldosterone, so salt loss also occurs in most newborns with CAH. This is the only clue to the diagnosis in affected male newborns. The 21-hydroxylase form of CAH accounts for more than 95% of cases and is caused by mutations in the CYP21 gene. The type of mutation dictates the phenotype (e.g. severe salt-losing, nonsalt-losing, milder late-onset).
Ieuan Hughes is Professor of Paediatrics at the University of Cambridge, UK. Conflicts of interest: none declared.
MEDICINE 33:11
25
© 2005 The Medicine Publishing Company Ltd
ADRENAL
Clinical features of congenital adrenal hyperplasia
Clinical features and diagnosis Figure 2 summarizes the different modes of presentation according to age. The key modes are: • ambiguous genitalia in a female newborn • a salt-losing crisis in a male newborn • a syndrome of hirsutism, acne and irregular periods in an adolescent female. The diagnosis is confirmed by elevated levels of 17OH-progesterone – a precursor steroid that accumulates as a result of ACTH hypersecretion. Serum testosterone increases to the adult male range (10–30 nmol/litre); hyponatraemia and hyperkalaemia indicate a salt-losing crisis. In the late-onset form, there is an exaggerated 17OH-progesterone response to short-acting ACTH stimulation. Genetic analysis is performed to identify the specific CYP21 mutation.
Infancy Early childhood Late childhood Adolescence/ young adult
Male
Childhood and adolescence: steroid replacement aims to prevent excess androgens and avoid growth suppression. Treatment is monitored by measuring growth, bone age and biochemical indices such as serum 17OH-progesterone, testosterone and renin. Normal onset and timing of puberty and, in girls, a normal menarche are the treatment aims in adolescence. Longer-acting glucocorticoids such as prednisolone and dexamethasone are often used in young adults to achieve ovulatory cycling and fertility, which is reduced in women with CAH.
Infancy: gender assignment must be resolved urgently in cases of newborn intersex. CAH is confirmed by fluorescence in situ hybridization analysis showing the sex chromosomes to be 46,XX, karyotyping, and elevated 17OH-progesterone; the gender assignment is then female, even when the external genitalia are male-like in appearance. Salt-losing crises are treated with intravenous saline and hydrocortisone. Thereafter, glucocorticoid and mineralocorticoid replacement are given orally as hydrocortisone, 15–20 mg/m2/day, and fludrocortisone, 0.1–0.15 mg/day.
Surgery: girls born with ambiguous genitalia need surgery to reduce the size of the clitoris and externalize the vaginal opening. This is generally undertaken at about 12–18 months of age. Clitoroplasty damages the highly innervated tissue of the clitoris, which may affect sexual function. Mild clitoromegaly is now seldom treated. Vaginoplasty may be deferred until puberty. Boys with CAH do not need surgery. Some adolescents develop testicular masses as a consequence of ectopic adrenal cells being stimulated by ACTH hypersecretion when compliance with treatment is poor. These masses do not need to be excised and often regress with improved medical treatment.
Pathophysiology of congenital adrenal hyperplasia Adrenocorticotrophic hormone
Prenatal: in affected families, the risk of CAH is 1/4. Virilization can be prevented by giving steroids to the mother antenatally, to inhibit fetal adrenal androgen production. Dexamethasone readily crosses the placenta unmetabolized. However, treatment must start early and ‘blind’, before CAH is confirmed or excluded by chorionic villus sampling at 10–11 weeks. Treatment is continued only when the fetus is female and DNA analysis confirms the presence of the familial CYP21 mutation. There is no evidence of harm to children exposed to antenatal steroids. Nevertheless, this treatment remains experimental and should be undertaken only within clinical trials with strategies for longer-term surveillance.
Cholesterol
17OH-progesterone (21-hydroxylase absent)
Salt loss
Cortisol deficiency
Adrenal failure
Androgen excess
Screening: the case for screening rests primarily on the need to detect the disorder before the onset of life-threatening salt loss, particularly in male newborns. Screening for CAH is currently not undertaken in the UK.
Virilization
The most common enzyme defect (21-hydroxylase) is shown. The dotted line indicates several enzymatic steps from cholesterol to steroid hormone production. Accumulation of 17OH-progesterone acts as a substrate for increased androgen production. Hypersecretion of adrenocorticotrophic hormone occurs from the negative feedback effect of cortisol deficiency.
FURTHER READING Creighton S. Surgery for intersex. J Roy Soc Med 2001; 94: 218–20. Lajic S, Nordenstrom A, Ritzen E M et al. Prenatal treatment of congenital adrenal hyperplasia. Eur J Endocrinol 2004; 151: U63–9. Speiser P W, White P C. Congenital adrenal hyperplasia. N Engl J Med 2003; 349: 76–88.
1
MEDICINE 33:11
Ambiguous genitalia Salt loss Virilization, rapid growth Early pubic hair, rapid growth Delayed menarche, irregular menses, hirsutism, acne, weight gain, infertility Testicular masses
2
Management
Aldosterone deficiency
Female Male Male Female Female
26
© 2005 The Medicine Publishing Company Ltd
Congenital adrenal hyperplasia Ieuan Hughes
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders of adrenal steroid biosynthesis. Clinical manifestations are pleiotropic, depending on the severity of steroid enzyme deficiency and the age of presentation. The condition is life-long, but classically presents at birth with ambiguity of the external genitalia in an affected female infant. CAH is the most common cause of newborn intersex.
Epidemiology The incidence of CAH is 1/10,000 to 1/15,000 live births, based on figures from newborn screening programmes in several Western countries. The milder late-onset form has an incidence as high as 1/1000.
Pathophysiology The adrenal cortex produces cortisol and aldosterone, which are essential for normal homeostasis. Cortisol production is adrenocorticotrophic hormone (ACTH) dependent via a classical endocrine negative feedback mechanism. Aldosterone production is under the control of the renin–angiotensin system. Cholesterol is the starting point for steroid synthesis, with several enzymatic steps required for cortisol and aldosterone production. Figure 1 shows the pathophysiological consequences of 21-hydroxylase deficiency, which is the most common enzyme deficiency causing CAH. The continued drive for ACTH production leads to excessive production of adrenal androgens, which are converted in the liver to testosterone. A fetus with CAH produces excess androgens from as early as 8 weeks’ gestation; if the fetus is female, enlargement of the clitoris and fusion of the labioscrotal folds leads to ambiguity of the external genitalia at birth. The same enzyme is needed to synthesize aldosterone, so salt loss also occurs in most newborns with CAH. This is the only clue to the diagnosis in affected male newborns. The 21-hydroxylase form of CAH accounts for more than 95% of cases and is caused by mutations in the CYP21 gene. The type of mutation dictates the phenotype (e.g. severe salt-losing, nonsalt-losing, milder late-onset).
Ieuan Hughes is Professor of Paediatrics at the University of Cambridge, UK. Conflicts of interest: none declared.
MEDICINE 33:11
25
© 2005 The Medicine Publishing Company Ltd
ADRENAL
Clinical features of congenital adrenal hyperplasia
Clinical features and diagnosis Figure 2 summarizes the different modes of presentation according to age. The key modes are: • ambiguous genitalia in a female newborn • a salt-losing crisis in a male newborn • a syndrome of hirsutism, acne and irregular periods in an adolescent female. The diagnosis is confirmed by elevated levels of 17OH-progesterone – a precursor steroid that accumulates as a result of ACTH hypersecretion. Serum testosterone increases to the adult male range (10–30 nmol/litre); hyponatraemia and hyperkalaemia indicate a salt-losing crisis. In the late-onset form, there is an exaggerated 17OH-progesterone response to short-acting ACTH stimulation. Genetic analysis is performed to identify the specific CYP21 mutation.
Infancy Early childhood Late childhood Adolescence/ young adult
Male
Childhood and adolescence: steroid replacement aims to prevent excess androgens and avoid growth suppression. Treatment is monitored by measuring growth, bone age and biochemical indices such as serum 17OH-progesterone, testosterone and renin. Normal onset and timing of puberty and, in girls, a normal menarche are the treatment aims in adolescence. Longer-acting glucocorticoids such as prednisolone and dexamethasone are often used in young adults to achieve ovulatory cycling and fertility, which is reduced in women with CAH.
Infancy: gender assignment must be resolved urgently in cases of newborn intersex. CAH is confirmed by fluorescence in situ hybridization analysis showing the sex chromosomes to be 46,XX, karyotyping, and elevated 17OH-progesterone; the gender assignment is then female, even when the external genitalia are male-like in appearance. Salt-losing crises are treated with intravenous saline and hydrocortisone. Thereafter, glucocorticoid and mineralocorticoid replacement are given orally as hydrocortisone, 15–20 mg/m2/day, and fludrocortisone, 0.1–0.15 mg/day.
Surgery: girls born with ambiguous genitalia need surgery to reduce the size of the clitoris and externalize the vaginal opening. This is generally undertaken at about 12–18 months of age. Clitoroplasty damages the highly innervated tissue of the clitoris, which may affect sexual function. Mild clitoromegaly is now seldom treated. Vaginoplasty may be deferred until puberty. Boys with CAH do not need surgery. Some adolescents develop testicular masses as a consequence of ectopic adrenal cells being stimulated by ACTH hypersecretion when compliance with treatment is poor. These masses do not need to be excised and often regress with improved medical treatment.
Pathophysiology of congenital adrenal hyperplasia Adrenocorticotrophic hormone
Prenatal: in affected families, the risk of CAH is 1/4. Virilization can be prevented by giving steroids to the mother antenatally, to inhibit fetal adrenal androgen production. Dexamethasone readily crosses the placenta unmetabolized. However, treatment must start early and ‘blind’, before CAH is confirmed or excluded by chorionic villus sampling at 10–11 weeks. Treatment is continued only when the fetus is female and DNA analysis confirms the presence of the familial CYP21 mutation. There is no evidence of harm to children exposed to antenatal steroids. Nevertheless, this treatment remains experimental and should be undertaken only within clinical trials with strategies for longer-term surveillance.
Cholesterol
17OH-progesterone (21-hydroxylase absent)
Salt loss
Cortisol deficiency
Adrenal failure
Androgen excess
Screening: the case for screening rests primarily on the need to detect the disorder before the onset of life-threatening salt loss, particularly in male newborns. Screening for CAH is currently not undertaken in the UK.
Virilization
The most common enzyme defect (21-hydroxylase) is shown. The dotted line indicates several enzymatic steps from cholesterol to steroid hormone production. Accumulation of 17OH-progesterone acts as a substrate for increased androgen production. Hypersecretion of adrenocorticotrophic hormone occurs from the negative feedback effect of cortisol deficiency.
FURTHER READING Creighton S. Surgery for intersex. J Roy Soc Med 2001; 94: 218–20. Lajic S, Nordenstrom A, Ritzen E M et al. Prenatal treatment of congenital adrenal hyperplasia. Eur J Endocrinol 2004; 151: U63–9. Speiser P W, White P C. Congenital adrenal hyperplasia. N Engl J Med 2003; 349: 76–88.
1
MEDICINE 33:11
Ambiguous genitalia Salt loss Virilization, rapid growth Early pubic hair, rapid growth Delayed menarche, irregular menses, hirsutism, acne, weight gain, infertility Testicular masses
2
Management
Aldosterone deficiency
Female Male Male Female Female
26
© 2005 The Medicine Publishing Company Ltd