Seminar
`
`Lancet 2005; 365: 2125–36
`
`Pediatric and Reproductive
`Endocrinology Branch,
`National Institute of Child
`Health and Human
`Development and the Warren
`Grant Magnuson Clinical
`Center, National Institutes of
`Health, Bethesda, MD, USA
`(D P Merke MD); and
`Department of Internal
`Medicine III, University of
`Dresden, Dresden, Germany
`(S R Bornstein MD)
`
`Correspondence to:
`Dr Deborah P Merke, National
`Institutes of Health, Building 10,
`Room 1-2740, 10 Center Dr
`MSC 1932, Bethesda,
`MD 20892–1932, USA
`dmerke@nih.gov
`
`Congenital adrenal hyperplasia
`
`Deborah P Merke, Stefan R Bornstein
`
`Congenital adrenal hyperplasia (CAH) due to deficiency of 21-hydroxylase is a disorder of the adrenal cortex
`characterised by cortisol deficiency, with or without aldosterone deficiency, and androgen excess. Patients with the
`most severe form also have abnormalities of the adrenal medulla and epinephrine deficiency. The severe classic
`form occurs in one in 15 000 births worldwide, and the mild non-classic form is a common cause of
`hyperandrogenism. Neonatal screening for CAH and gene-specific prenatal diagnosis are now possible. Standard
`hormone replacement fails to achieve normal growth and development for many children with CAH, and adults can
`experience iatrogenic Cushing’s syndrome, hyperandrogenism, infertility, or the development of the metabolic
`syndrome. This Seminar reviews the epidemiology, genetics, pathophysiology, diagnosis, and management of CAH,
`and provides an overview of clinical challenges and future therapies.
`
`Congenital adrenal hyperplasia (CAH) describes a group
`of autosomal recessive disorders of cortisol biosynthesis.
`We discuss here 21-hydroxylase deficiency, which is the
`cause of about 95% of CAH cases. CAH caused by
`deficiency of 21-hydroxylase is characterised by cortisol
`deficiency, with or without aldosterone deficiency, and
`androgen excess.
`CAH shows a range of severity. The clinical phenotype
`is typically classified as classic, the severe form, or non-
`classic, the mild or late-onset form. Classic CAH is
`subclassified as salt-losing or non-salt-losing (simple-
`virilising),
`reflecting
`the degree of aldosterone
`deficiency.
`The lives of patients with CAH have improved greatly
`since the discovery that cortisone was an effective
`treatment for the disorder in the 1950s.1 Neonatal
`screening is being done in several countries. Gene-
`specific prenatal diagnosis is now feasible. Research on
`the pathophysiology of CAH has shown endocrinopathies
`beyond the characteristic abnormalities of the adrenal
`cortex,
`including adrenomedullary dysfunction and
`insulin resistance. Despite these advances, existing
`treatment has failed to achieve normal growth and
`development for many children with CAH, and the
`clinical management of adults
`is complicated by
`iatrogenic Cushing’s syndrome, hyperandrogenism, or
`infertility. We review here the epidemiology, genetics,
`pathophysiology, diagnosis, and management of CAH
`and provide an overview of the clinical challenges and
`future therapies that await further investigation.
`
`Epidemiology
`Data from several neonatal screening programmes show
`that CAH due to 21-hydroxylase deficiency is common.
`Data from roughly 6·5 million newborn
`infants
`screened in 13 countries (USA, France, Italy, New
`Zealand, Japan, UK, Brazil, Switzerland, Sweden,
`Germany, Portugal, Canada, and Spain) show an overall
`incidence of one in 15 000 livebirths for the classic
`form.2,3 Thus, the carrier frequency of classic CAH is
`about one in 60 individuals. Salt-losing CAH accounts
`for 67% of the cases reported and non-salt-losing CAH
`for 33%.2
`
`and
`ethnicity
`to
`according
`varies
`Incidence
`geographical area. The highest rates of classic CAH
`occur in two geographically isolated populations: the
`Yupic Eskimos of Alaska (one in 280)4 and the French
`island of La Réunion (one in 2100).5 High rates have
`also been reported in Brazil (one in 7500)2 and the
`Philippines (one in 7000).3 In the USA, the incidence of
`CAH is lower in African-Americans than in the white
`population (one in 42 000 vs 15 500).6
`Neonatal screening does not accurately detect non-
`classic CAH, so data on the incidence of the milder
`form of the disorder are lacking. However, non-classic
`CAH is estimated to be more common than classic
`
`Search strategy and selection criteria
`
`We searched PubMed for articles published in English on
`congenital adrenal hyperplasia between 1998 and 2004,
`with MeSH terms “adrenal hyperplasia, congenital” and
`“steroid 21-hydroxylase” as well as natural-language
`equivalents “congenital adrenal hyperplasia”, “(adrenal OR
`hyperplas*) AND CAH”, “cyp21 OR cyp-21”, or “21-
`hydroxylase AND deficien*”. The results of these searches
`were pooled, and subsearches were run with additional
`MeSH and natural-language terms as well as floating
`subheadings for the following: “epidemiology”, “diagnosis”,
`“genetics”, “therapy”, “management”, “pathophysiology”,
`“embryology”, “quality of life and psychological issues”,
`“classic or nonclassic CAH”. The citations not subdivided by
`any of these terms were examined individually. Web of
`Science was searched for articles published in English during
`the same years with search terms “congenital*and adren*
`and hyperpl*”, “OR CYP21 OR CYP 21 OR CAH OR”, “steroid
`and 21 and hydrox*”, or “21 and hydroxylase and deficien*”;
`citations and their cited references were examined
`individually and selected for relevance. We also reviewed
`books on congenital adrenal hyperplasia published in the
`same period. We reviewed selected references from articles
`retrieved by the initial search. Several earlier, commonly
`referenced key publications have been cited. Relevant
`references cited in the original source of references were also
`reviewed.
`
`www.thelancet.com Vol 365 June 18, 2005
`
`2125
`
`1
`
`NEUROCRINE 1016
`
`

`

`Seminar
`
`Hypothalamus
`
`CRH
`
`?
`
`?
`
`Corticotropin
`
`Pituitary
`
`Psychological
`effects
`
`Tumour
`formation
`
`Adrenal
`
`CYP21
`
`Cortisol
`
` Exogenous
`glucocorticoids
`
`Aldosterone
`
`Androgens
`
`Salt-wasting
`Hypovolaemia/shock
`
`Virilisation
`Precocious
`puberty
`
`Metabolic syndrome
`
`Epinephrine
`
`Hypoglycaemia
`Cardiovascular
`instability
`
`Figure 1: Endocrine imbalances characteristic of CAH
`Potential clinical manifestations are given in the text boxes.
`
`CAH, with a prevalence of one in 1000 in the white
`population.7,8 A study in New York City found that non-
`classic CAH is more frequent in certain ethnic
`populations, such as Jews of eastern European origin,
`Hispanics, and Yugoslavs (1·0–3·7%).7
`
`Genetics
`The 21-hydroxylase gene is located on chromosome
`6p21·3 within the HLA histocompatibility complex.9
`There are two highly homologous 21-hydroxylase genes
`resulting from ancestral duplication: an active gene,
`CYP21A2 (CYP21B), and an
`inactive pseudogene
`CYP21A1P (CYP21A, CYP21P).10 CAH is unusual
`among genetic disorders in that most of the mutant
`alleles (about 90%) are generated by recombinations
`between
`the pseudo and active genes.11,12 When
`deleterious sequences normally present in the pseudo-
`gene are transferred to the active gene, the latter
`becomes incapable of encoding a normal enzyme; this
`process is called gene conversion. In patients, 1–2% of
`affected alleles are spontaneous mutations.13 Spon-
`taneous
`recombinations between CYP21A2
`and
`CYP21A1P are detected in one in 103–105 sperm cells.14
`The high rate of intergenic recombination that occurs
`could be indirectly due to the position of the gene
`within the MHC.
`Most patients are compound heterozygotes (ie, they
`have different mutations on the two alleles), and the
`clinical phenotype is generally related to the less
`severely mutated allele and, consequently, to the
`residual 21-hydroxylase activity.13,15–17 Several studies
`have suggested high concordance rates between
`genotype and phenotype in patients with the most
`severe and mildest forms of the disease, but less
`genotype–phenotype relation in moderately affected
`patients.13,15–17
`
`Pathophysiology
`The pathophysiology of 21-hydroxylase-deficiency-
`related CAH is closely linked to the degree of enzyme
`deficiency. A defect in cortisol biosynthesis leads to
`a compensatory increase in pituitary production of
`corticotropin
`and hypothalamic
`production
`of
`corticotropin-releasing hormone (CRH) owing to a lack
`of the usual negative feedback by cortisol. Physiological
`glucocorticoid and mineralocorticoid replacement fails
`to replicate the close temporal relation between release
`of CRH, corticotropin, and subsequent cortisol pulses.
`Thus, supraphysiological doses of glucocorticoid are
`necessary in many patients to suppress excess adrenal
`production of androgens and oestrogens adequately.18
`Moreover, intrauterine glucocorticoid deficiency can
`affect postnatal sensitivity to feedback inhibition, thus
`blunting the central effects of treatment.19 The resulting
`iatrogenic hypercortisolism, in combination with excess
`adrenal androgens and oestrogens, can stunt growth in
`children and cause damaging metabolic side-effects,
`resulting in insulin resistance, metabolic syndrome, and
`infertility (figure 1).
`Increased expression of CRH may contribute to
`clinical manifestations of CAH, including psychological
`effects
`and
`changes
`in
`energy homoeostasis.
`Oversecretion of CRH has been found in states of
`anxiety and depression, and the hyperactivity of the
`hypothalamic-pituitary-adrenal (HPA) axis characteristic
`of CAH might have negative psychological effects.
`Adrenocortical tumours have been found in high
`frequency compared with the general population, which
`suggests that chronic corticotropin stimulation has a
`role in formation of adrenocortical tumours.20 These
`issues are currently being researched.
`Carriers or heterozygotes for CYP21 mutations have
`subtle abnormalities in the functioning of the HPA axis.
`After corticotropin stimulation, 50–80% of carriers show
`increased secretion of cortisol precursors, such as
`17-hydroxyprogesterone,
`compared with
`healthy
`individuals.21 Carriers also have higher testosterone
`concentrations,22 lower 24 h urinary excretion of free
`cortisol,23 and higher corticotropin secretion after CRH
`stimulation.23 Carriers might be at risk of
`the
`development of clinically inapparent adrenal masses20,24
`and, according to one study, have increased vulnerability
`to psychological stress.23 Carriers are mostly free of
`symptoms and do not experience adrenal crises,
`hyperandrogenic symptoms, or disorders of growth and
`puberty.
`Glucocorticoids are essential in the development and
`the continuing regulation of the adrenal medulla, and
`the
`adrenomedullary
`system
`is
`impaired
`in
`21-hydroxylase-deficient mice19,25,26
`and
`in severely
`affected patients.27 Glucocorticoids
`stimulate
`the
`expression of phenylethanolamine-N-methyltransferase,
`the
`enzyme
`that
`converts norepinephrine
`to
`epinephrine.28–31 Normal glucocorticoid secretion by the
`
`2126
`
`www.thelancet.com Vol 365 June 18, 2005
`
`2
`
`

`

`Seminar
`
`B
`
`Cortex
`
`A
`
`Cortex
`
`Medulla
`
`Figure 2: Immunostaining of adrenal-gland tissue from a patient with classic 21-hydroxylase deficiency
`A: Hyperplasia, poorly defined zonation, and intermingling of the chromaffin and cortical cells (arrows) is shown in
`the adrenal gland of a patient with 21-hydroxylase deficiency; original magnification ⫻40. B: Chromaffin cells form
`long cellular extensions and neurite outgrowth (arrows); original magnification ⫻200. Chromaffin cells were
`stained with anti-synaptophysin. Reactions were visualised with 3-amino-ethylcarbazole and haematoxylin
`(reddish-brown).
`
`M
`
`Female infants with classic CAH typically have
`ambiguous genitalia at birth because of exposure to high
`concentrations of androgens in utero, and CAH due to
`21-hydroxylase deficiency is the most common cause of
`ambiguous genitalia in 46XX infants (figure 3, A).
`Characteristic findings include an enlarged clitoris,
`partly fused and rugose labia majora, and a common
`urogenital sinus in place of a separate urethra and
`vagina. The internal female organs, the uterus, fallopian
`tubes, and ovaries, are normal; wolffian duct structures
`are not present. Boys with classic CAH have no signs of
`CAH at birth, except subtle hyperpigmentation and
`possible penile enlargement (figure 3, B). Thus, the age
`at diagnosis in boys varies according to the severity of
`aldosterone deficiency. Boys with the salt-losing form
`typically present at 7–14 days of life with vomiting,
`weight loss, lethargy, dehydration, hyponatraemia, and
`hyperkalaemia, and can present in shock. Girls with the
`salt-losing form, if not treated soon after birth, would
`also experience a salt-losing adrenal crisis in the
`neonatal period. However, the ambiguous genitalia
`typically lead to early diagnosis and treatment. Boys with
`the non-salt-losing form present with early virilisation at
`age 2–4 years (figure 3, C).
`Patients with non-classic CAH do not have cortisol
`deficiency, but
`instead have manifestations of
`hyperandrogenism, generally later in childhood or in
`early adulthood.43,44 These patients can present with early
`pubarche, or as young women with hirsutism (60%),
`oligomenorrhoea or amenorrhoea (54%) with polycystic
`ovaries, and acne (33%).45 5–10% of children with
`precocious pubarche46,47 have been found to have non-
`classic CAH. Conversely, some women with non-classic
`CAH have no apparent clinical symptoms, and many
`men with non-classic CAH remain free of symptoms.48
`The proportion of patients with non-classic CAH who
`remain symptom-free is unknown, and women can go
`on to develop symptoms of hyperandrogenism later in
`
`zona fasciculata of the adrenal cortex is necessary for
`adrenomedullary organogenesis, and a developmental
`defect in the formation of the adrenal medulla has been
`shown in patients with salt-losing CAH.27 In human
`21-hydroxylase-deficient adrenal glands, we found that
`chromaffin cells formed extensive neurites expanding
`between adrenocortical cells (figure 2). These findings
`accord with those from in-vitro studies that adrenal
`androgens promote outgrowth, whereas glucocorticoids
`preserve neuroendocrine cells.32,33
`The clinical implications of epinephrine deficiency in
`patients with CAH have been investigated lately.
`Measurement of adrenomedullary function could be a
`useful biomarker for disease severity in CAH. In one
`study, molecular genotype and plasma concentrations
`of free metanephrine, the O-methylated metabolite of
`epinephrine, predicted clinical phenotype with similar
`accuracy.34 The usefulness of measuring plasma
`metanephrine concentrations in newborn infants has
`not been studied. Epinephrine has a role in glucose
`homoeostasis, especially
`in young children, and
`patients with CAH receiving standard glucocorticoid
`replacement therapy have decreased adrenomedullary
`reserves27 and reduced epinephrine and blood-glucose
`responses to high-intensity exercise.35 Administration
`of additional hydrocortisone (double dose) before
`exercise was not beneficial36 and had no effect on the
`impaired metabolic response to exercise. Epinephrine
`deficiency most likely plays a major part in the
`hypoglycaemia
`observed
`in
`association with
`intercurrent
`illness
`in patients with CAH.37–39
`Production and possibly action of leptin is inhibited by
`epinephrine, and insulin resistance and raised serum
`leptin concentrations have been described in patients
`with CAH.34 Hyperinsulinism has also been reported in
`patients with non-classic CAH, even before
`the
`institution of glucocorticoid therapy.40 Hyperandro-
`genism is an independent risk factor for hyper-
`insulinism in adolescent girls41 and in women42 and
`might have a role in the development of insulin
`resistance or polycystic ovaries in patients with CAH.
`Thus, many endocrinopathies, including glucocorticoid
`and sex-steroid
`imbalances and adrenomedullary
`hypofunction, contribute to the metabolic disturbances
`observed in patients with CAH and theoretically put
`these patients at risk of development of the metabolic
`syndrome (figure 1).
`
`Clinical features
`The severity of CAH depends on the degree of
`21-hydroxylase
`deficiency
`caused
`by CYP21A2
`mutations. The classic forms present in childhood and
`are characterised by striking overproduction of cortisol
`precursors and adrenal androgens. In the most severe
`form, concomitant aldosterone deficiency leads to loss of
`salt. In the mildest form, there is sufficient cortisol
`production, but at the expense of excess androgens.
`
`www.thelancet.com Vol 365 June 18, 2005
`
`2127
`
`3
`
`

`

`Seminar
`
`Figure 3: Clinical presentation of classic 21-hydroxylase deficiency
`A: Female infants present at birth with ambiguous genitalia as a result of
`in-utero exposure to androgens. B: Boys with salt-losing CAH present at
`7–10 days of age with a salt-losing adrenal crisis; some have hyperpigmentation
`on physical examination (note scrotal hyperpigmentation). C: Boys with the
`non-salt-losing form present with early virilisation and accelerated growth at age
`2–4 years. Panels A and B reproduced with permission from Adis International
`Limited.
`
`life.45 Overall, the frequency of non-classic CAH among
`women with infertility or presenting with symptoms of
`androgen excess is 1–2%.49,50 Although endocrinological
`testing reveals mild abnormalities in adrenal function,
`carriers typically do not have symptoms or signs of
`excess androgens and do not need treatment.22
`
`Diagnosis
`A very high concentration of 17-hydroxyprogesterone
`(more than 242 nmol/L; normal less than 3 nmol/L at
`3 days in full-term infant) in a randomly timed blood
`sample
`is diagnostic of
`classic 21-hydroxylase
`deficiency.51 Typically, salt-losing patients have higher
`17-hydroxyprogesterone concentrations than non-salt-
`losers. False-positive results from neonatal screening are
`common with premature infants, and many screening
`programmes have established reference ranges that are
`based on weight and gestational age.52,53 A corticotropin
`stimulation test (250 ␮g cosyntropin) can be used to
`assess borderline cases. Genetic analysis can be helpful
`to confirm the diagnosis.54
`17-hydroxyprogesterone
`Randomly
`measured
`concentrations can be normal in patients with non-
`classic CAH. Thus, the gold standard for diagnosis of the
`non-classic form is a corticotropin stimulation test, with
`measurement of 17-hydroxyprogesterone at 60 min. This
`test can be done at any time of day and at any time
`during the menstrual cycle. A stimulated concentration
`of 17-hydroxyprogesterone higher than 45 nmol/L
`is diagnostic of 21-hydroxylase deficiency. Many
`carriers
`have
`slightly
`raised
`concentrations of
`17-hydroxyprogesterone (less than 30 nmol/L) after a
`corticotropin stimulation test.51 An early-morning (before
`0800 h) measurement can be used for screening,55 but it
`is not as sensitive or specific as a corticotropin
`stimulation test. Early-morning 17-hydroxyprogesterone
`concentrations of less than 2·5 nmol/L in children and
`less than 6·0 nmol/L in women during the follicular
`phase rule out the diagnosis of non-classic CAH in most
`cases; higher values warrant a corticotropin stimulation
`test to establish the diagnosis.55
`
`Medical treatment
`In classic CAH, glucocorticoids are given in doses
`sufficient to suppress adrenal androgen secretion partly,
`without
`total
`suppression of
`the HPA
`axis;
`mineralocorticoids are given
`to return electrolyte
`concentrations and plasma renin activity to normal.
`Physiological cortisol secretion rates are about 6 mg/m2
`
`2128
`
`www.thelancet.com Vol 365 June 18, 2005
`
`4
`
`

`

`Seminar
`
`daily,56–58 and most patients have satisfactory control of
`androgen production with hydrocortisone doses of
`12–18 mg/m2 daily divided into two or three doses. The
`target 17-hydroxyprogesterone range is 12–36 nmol/L
`when measured in the early morning before medication.
`Adrenal androgen concentrations later in the day and
`after medication has been taken will be lower, but they
`should not be suppressed below the normal range
`because of risk of iatrogenic Cushing’s syndrome.
`Hydrocortisone is the glucocorticoid of choice during
`childhood.59,60 Cortisone must be converted to cortisol for
`biological activity. Differences in the rate of conversion
`influence drug efficacy; thus, cortisone acetate is not
`recommended. Longer-acting glucocorticoids, such as
`prednisone (5·0–7·5 mg per day in two doses) and
`dexamethasone (0·25–0·50 mg at bedtime or in two
`doses), can be used in adults, but they are generally
`avoided in children because of concerns about growth
`suppression. However, the growth-suppressive effects of
`longer-acting glucocorticoid preparations could be dose
`related. A retrospective study of 17 children with CAH
`showed that once-daily administration of dexametha-
`sone at a 70 to one relative potency to hydrocortisone
`could achieve normal growth,61 and nine children with
`adrenal insufficiency had normal short-term (6-month)
`growth velocity when receiving prednisolone at a dose of
`15 to one relative potency to hydrocortisone.62 These
`relative potency ratios are substantially greater than
`previously suggested dose equivalencies. The use of
`longer-acting glucocorticoid preparations in children
`needs further study.
`is achieved with
`Mineralocorticoid replacement
`fludrocortisone. The dose should be adjusted
`to
`maintain plasma renin activity in the mid-normal range.
`A typical daily dose of fludrocortisone ranges from
`100 μg to 200 μg. The dose is independent of body size
`from childhood to adulthood, although higher doses are
`commonly needed
`in early
`infancy. The use of
`fludrocortisone therapy in patients with non-salt-losing
`classic CAH is recommended and allows management
`with lower doses of glucocorticoid.18,59,60
`Infants with salt-losing CAH commonly need
`supplementation of sodium chloride (1–2 g daily).
`Routine salt supplementation is typically not needed
`after the first 6–12 months of life. However, patients
`should be encouraged to use salt freely to satisfy salt
`cravings. Additional salt intake may be needed with
`exposure to hot weather or with intense exercise.
`Many patients with non-classic CAH do not need
`treatment. Treatment is recommended only for those
`with symptoms and aims to reduce hyperandro-
`genism.59,60,63 Glucocorticoid treatment is indicated in
`children with androgen excess, whereas adult women
`might
`need
`adjuvant
`antiandrogen
`therapy.
`Dexamethasone and antiandrogen drugs should be used
`with caution and in conjunction with oral contraceptives
`in young women; both cross the placenta. When fertility
`
`is desired, ovulation induction might be necessary63 and
`a glucocorticoid that does not cross the placenta (eg,
`prednisolone or prednisone) should be used.
`Drugs that induce hepatic microsomal enzymes
`(CYP450), such as antiepileptic drugs, affect the
`metabolism of glucocorticoids and can greatly alter the
`appropriate glucocorticoid dose.64
`Flutamide, an
`antiandrogen, has also been reported
`to affect
`hydrocortisone metabolism.65 A prudent approach
`includes close clinical monitoring and
`laboratory
`assessment 4–6 weeks after the patient starts taking a
`new medication long term.
`
`Stress dosing
`Patients with classic CAH cannot mount a sufficient
`cortisol
`response
`to physical
`stress and need
`pharmacological doses of hydrocortisone in situations
`such as febrile illness, surgery, and trauma. Dose
`guidelines
`include
`doubling
`or
`tripling
`the
`glucocorticoid maintenance dose for the whole day. If a
`patient
`is unable
`to
`take medication orally,
`hydrocortisone should be given intramuscularly, and
`medical advice about the need for intravenous hydration
`should be promptly sought. The combination of cortisol
`deficiency and epinephrine deficiency puts patients at
`risk of hypoglycaemia with illness or fasting. During
`illnesses,
`intake of carbohydrates and glucose-
`containing fluids should be encouraged and glucose
`monitoring should be considered, especially in children.
`Patients and parents should receive instructions for
`these types of emergencies. All patients should wear or
`carry medical alert identification specifying adrenal
`insufficiency.
`that higher doses of
`There
`is no evidence
`glucocorticoid are needed in times of mental or
`emotional stress, and higher doses of glucocorticoid
`should be given only for physical stressors. Exercise,
`although a physical stressor, does not require increased
`dosing.36 However, the normal exercise-induced rise in
`blood glucose concentrations is blunted in patients with
`CAH, and extra intake of carbohydrates might be useful
`with exercise.36
`Patients with non-classic CAH do not need stress
`doses of hydrocortisone unless they have iatrogenic
`suppression of their adrenal glands by glucocorticoid
`treatment. Thus, a prudent approach is to treat patients
`with non-classic CAH who are receiving glucocorticoid
`therapy as if they have adrenal insufficiency.
`
`Clinical challenges
`Prenatal therapy
`In pregnancies in which the fetus is at risk of classic
`CAH, maternal
`dexamethasone
`treatment has
`successfully suppressed the fetal HPA axis and reduced
`the genital ambiguity of affected female infants.66,67
`Masculinisation of the external genitalia begins by
`8 weeks of gestation. Therefore, if treatment is desired, it
`
`www.thelancet.com Vol 365 June 18, 2005
`
`2129
`
`5
`
`

`

`Seminar
`
`should be started as soon as the pregnancy is confirmed.
`Chorionic-villus sampling or amniocentesis should be
`done as early as possible. If the fetus is male or a female
`not affected, treatment is discontinued. For an affected
`female
`fetus,
`treatment
`is continued
`throughout
`pregnancy. About 85% of prenatally treated female
`infants are born with normal or slightly virilised
`genitalia.59,60 Treatment failures could be due to early
`cessation of therapy, late start of treatment, non-
`adherence, suboptimum dosing, or differences
`in
`dexamethasone metabolism.
`Prenatal treatment is controversial, since the risk of
`having an affected female fetus is only one in eight when
`both parents are known carriers.68 Therefore, seven of
`eight fetuses will receive dexamethasone treatment
`unnecessarily. The efficacy and safety of prenatal
`dexamethasone treatment remains to be fully defined.
`Studies
`in animals have
`shown
`that prenatal
`dexamethasone exposure can impair somatic growth,
`brain development, and blood-pressure regulation.68,69
`Long-term human follow-up data are lacking. Potential
`maternal side-effects include the signs and symptoms of
`Cushing’s syndrome.67,70
`Prenatal dexamethasone therapy should be offered only
`to parents who have a clear understanding of the possible
`risks and benefits and who are able to adhere to the
`essential close monitoring throughout pregnancy. This
`treatment should be carried out in specialist centres,
`preferably with the use of an approved research protocol.
`
`Neonatal period
`Management of patients with classic CAH during the
`neonatal period is challenging. Two-thirds of these
`patients are salt-losers. Neonates are particularly
`vulnerable to hypovolaemia and electrolyte disturbances,
`as well as hypoglycaemia.37,38 Increased mortality has
`been reported in patients with CAH.71,72 Despite hormone
`replacement and parental education, about 8% of
`patients have been reported to experience hypoglycaemia
`during the first few years of life.39,73 These risks have led
`some practitioners to treat neonates with higher doses of
`hydrocortisone; however, there is no evidence that higher
`doses of glucocorticoid protect against hypoglycaemia or
`life-threatening
`complications,
`and
`epinephrine
`deficiency probably has a role. Moreover, many studies
`have found that excessive glucocorticoid use during the
`first 2 years of life is a risk factor for short stature in
`adulthood.74–77 The hydrocortisone dose in neonates
`should not exceed 25 mg/m2 daily, and monitoring of
`weight and length supplemented by serial measurement
`of adrenal steroid concentrations, plasma renin activity,
`and
`electrolyte
`concentrations
`should
`guide
`management. As in older children, the therapeutic goal
`in the neonatal period should be to find the lowest
`glucocorticoid
`dose
`that
`achieves
`acceptable
`concentrations of adrenal cortical hormones and an
`acceptable rate of linear growth.
`
`The surgical management of children born with
`ambiguous genitalia is complex and controversial. The
`Joint European Society for Paediatric Endocrinology and
`the Lawson Wilkins Pediatric Endocrine Society59,60
`recommend that surgery should be done in virilised girls
`with classic CAH at age 2–6 months because it is
`technically easier than at later ages; surgery should be
`done only in medical centres with substantial experience;
`and management ideally should be by a multidisciplinary
`team including specialists in paediatric endocrinology,
`paediatric surgery and urology, psychosocial services,
`and genetics. Intersex patients’ advocacy groups and
`others have proposed that medical teams and parents
`consider the option of not doing surgery so that the
`patient can decide at an older age and participate fully in
`an informed-consent process.78,79 One argument against
`surgery is that some rare causes of genital ambiguity
`have poor outcome in relation to psychosexual identity.80
`Such poor outcomes have not been reported for female
`patients with CAH. Overall, most girls and women with
`CAH identify as female,81 and feminising surgery in the
`neonatal period remains the standard practice for
`virilised girls with classic CAH.
`
`Growth and development during childhood
`The growth and development of many children with
`CAH is less than optimum. High concentrations of sex
`steroids induce premature epiphyseal closure, and excess
`glucocorticoids suppress growth. Retrospective studies
`have shown that the final height of treated patients is
`independent of the degree of control of adrenal androgen
`concentrations,75,82–84 which suggests that both hyper-
`androgenism and hypercortisolism contribute to the
`observed short stature. A meta-analysis of data from 18
`centres showed that the mean adult height of patients
`with classic CAH was 1·4 SD (10 cm) below the
`population mean.85
`Several studies have suggested that treatment during
`the first 2 years of life and that during puberty are the
`most important factors influencing height outcome.74–77,86
`Some investigators have shown improved adult height in
`patients diagnosed and treated early (salt-losers),85,87–90 and
`others have reported poor height outcome when higher
`glucocorticoid doses are used during the first 2 years of
`life.74,75 Another complication
`is central precocious
`puberty, which is most likely to develop when the
`diagnosis of CAH is delayed or with poor control of
`adrenal androgen secretion.77,91 The premature rise in
`gonadal steroid concentrations compounds the hazard of
`excess adrenal hormones.
`Patients with non-classic CAH have a more favourable
`height prognosis than those with the classic form. Those
`who have never been treated have slight growth
`impairment,75 and growth suppression secondary to
`iatrogenic hypercortisolism is also possible.92
`Obesity is common in patients with CAH, and the
`body-mass index of normally growing children with CAH
`
`2130
`
`www.thelancet.com Vol 365 June 18, 2005
`
`6
`
`

`

`Seminar
`
`increases throughout childhood more than the expected
`age-related increase.93 The cause of the obesity is
`unknown, and several factors are probably involved.
`However, patients with non-classic CAH seem to be at
`less risk of obesity than patients with the more severe
`form. In a multicentre study of patients with non-classic
`CAH, 21% of patients were obese (body-mass index
`30 kg/m2 or higher) at presentation, a proportion similar
`to that of the general populations of the countries
`studied.45
`
`Fertility
`Reduced fertility has been reported in patients with
`classic and non-classic CAH, especially in women.94–98
`Fertility rates of 60–80% and 7–60% have been reported
`in women with classic non-salt-losing and classic salt-
`losing CAH, respectively.94,97 In addition to hormonal
`causes, structural factors related to genital reconstructive
`surgery might
`reduce heterosexual activity and
`contribute to the infertility observed in patients with
`classic CAH.94,99,100
`Pregnancy rates of 50% have been reported in
`untreated patients with non-classic CAH compared with
`93–100% after treatment.101,102 However, the pregnancy
`rates reported for patients with non-classic CAH are
`from studies of those in whom the diagnosis of CAH
`was made after they presented with symptoms or signs
`of hyperandrogenism. Thus, the fertility data represent
`only patients with symptoms and might not be
`representative of the larger population of individuals
`affected with non-classic CAH. Overall, infertility is the
`presenting symptom in 13% of women with non-classic
`CAH.45
`An increased incidence of polycystic ovaries is a
`common finding in mild, but also in classic CAH, and
`this disorder could contribute
`to
`infertility.7,45,63,103
`About 40% of patients with non-classic CAH have
`polycystic ovaries.45,63