Education Resource from the Society for Endocrinology
Endocrine Nurses Training Course 2005, John MacIntyre Centre, The University
of Edinburgh, 18 Holyrood Park Road, Edinburgh EH16 5AY, UK
30 August - 1 September 2005
Congenital adrenal hyperplasia ( CAH) is the commonest cause of newborn intersex ( see presentation by Dr. Midgeley)
Primary aim of medical management is replacement with minimum amount of glucocorticoid to inhibit ACTH-induced hyperandrogenism without incurring steroid side effects. Salt-losers need adequate mineralocorticoid replacement to ensure normal salt and water homeostasis.
Treatment is monitored by a combination of (a) clinical indices ( growth, pubertal development, ovulatory rates and in males, testis morphology and spermatogenesis) (b) biochemical indices.
Outcome in adult life is aimed at achieving a final height commensurate with genetic potential ( rarely do CAH adult heights achieve or exceed the population mean) and a potential for fertility in females and males.
CAH is a family of inherited disorders of adrenal steroid biosynthesis. The
commonest enzyme defect is 21-hydroxylase deficiency. This enzyme converts
17OH-progesterone to 11-deoxycortisol, the penultimate step in cortisol biosynthesis.
Deficiency of cortisol signals the hypothalamic-pituitary axis via a classical
negative feedback loop to generate an increased ACTH drive for normalising
cortisol levels. The accumulated 17OH-progesterone substrate is shunted in
to androgens which cause the profound virilisation of an affected female fetus.
Affected males are not ‘super-vrilised’ at birth despite exposure
to massive concentrations of testosterone. Virilisation in males occurs in
the second year of life, manifest as rapid growth, increased size of the penis
and increased musculature.
The same 21-hydroxylase enzyme is required for aldosterone biosynthesis. Decreased
aldosterone and hence salt depletion, triggers the renin-angiotensin system
via a feedback loop. Virtually all 21-hydroxylase deficient patients are aldosterone
deficient to varying degrees. The most severe form can result in a salt-losing
crisis, an occurrence which may lead to death of an affected newborn male if
the diagnosis is not made in time. This has been the stimulus for including
CAH in the newborn screening program in many Western countries……but
not in the UK.
CAH is an autosomal recessive disorder. The gene encoding for 21-hydroxylase is on the short arm of chromosome 6, termed CYP21. A number of mutations have been identified and are distributed throughout the gene. About 10 mutations account for more than 90% of 21-hydroxylase cases and are screened for by Molecular Genetics Service Laboratories. The laboratory at Manchester provides an excellent service. The type of CYP21 mutation is predictive of the severity of CAH. For example, a large deletion of the gene or a common mutation affecting intron 2 invariably result in the severe, salt-losing form of CAH. In contrast, V281L ( a mutation at codon 281 which changes a valine to a leucine amino acid)is associated with the milder, non-salt-losing form of CAH. Consequently, there is good concordance between the genotype and phenotype in CAH, a finding which does not occur in many single gene disorders. It is important to genotype the family of a child with CAH if there are plans to have further children. This allows genetic counselling, including discussion of the options for prenatal treatment.
Growth is a useful biomarker of control together with serial measurements of bone age. Growth will be suppressed if glucocorticoid doses are excessive; this often occurs in infancy when hydrocortisone doses in excess of 30 mg/M2/ day may be used. Under-treatment allows testosterone levels to rise abnormally which is a powerful stimulus for rapid growth and advanced bone age. Once bone age is advanced, say by 3 years compared with chronological age, the ‘lost’ years of growth can never be retrieved. If this occurs in later childhood, early puberty may then ensue which compounds the problem of rapid growth, further bone maturation and an early closure of the growth epiphyses. If the growth period ( on average 15-16 years) is significantly truncated, then final height will inevitably be reduced. The problem can only be avoided by strict adherence to glucocorticoid replacement from the outset, adequate salt replenishment and regular clinical and biochemical monitoring. Attempts to enhance final height potential when rapid bone maturation and early puberty are in train include the use of GnRH analogues, aromatase inhibitors and GH supplements…all rather desperate measures which are not very successful in general.
Allied to the problems described for growth is the onset of obesity at puberty, particularly in girls. This is a very difficult management problem. Glucocorticoids are reduced in an attempt to avoid side effects of steroids but this leads to increased androgens with side effects such as hirsutism, acne, irregular menses and anovulation. The addition of an anti-androgen may reduce the androgenic side effects. Obesity may be compounded by insulin resistance. While not proven, it is possible that these problems manifest at puberty may be the outcome of excess glucocorticoid treatment in infancy. Occasionally, adrenalectomy is required for the obese adolescent girl who remains persistently hyperandrogenaemic despite several different glucocorticoid regimens.
The adolescent/adult male with CAH has fewer problems generally. However, treatment compliance, particularly in the non-salt-loser, is common once growth is complete. This may lead to testicular masses which arise from adrenal rest cells that are hyperstimulated by increased ACTH levels. It is important to distinguish from primary testicular tumours because orchidectomy is not needed. The masses may regress with adequate glucocorticoid treatment. Oligospermia may occur and sperm counts can normalise once adequate treatment is re-established. Males with CAH should start having regular testicular US from puberty onwards.
There is a 1 in 4 risk of recurrence in a family with CAH. Prenatal treatment to prevent virilisation of an affected female fetus is an option. Dexamethasone is given to the mother as soon as pregnancy is confirmed and continued to term if the fetus is an affected female. This has been very successful in preventing a major congenital malformation. There are, however, some caveats. Treatment has to be started early in pregnancy as the fetal adrenal gland is already producing excess precursor steroids by 6-8 weeks of gestation. This means that 7 out of 8 fetuses are exposed unnecessarily to prenatal steroids until around 14 weeks of gestation when the results of genetic analysis of a chorionic villus sample are available. All male fetuses, affected or otherwise, and unaffected female fetuses do not need treatment. CAH has an equal sex incidence, hence the 7 out of 8 calculation.
Dexamethasone is used as it is not metabolised by placental enzymes. It is an intriguing question as to how glucocorticoids given so early in pregnancy can inhibit an immature fetal hypothalamo-pituitary-adrenal axis. Nevertheless, the treatment works by virtue of suppressed maternal estriol levels ( synthesised from substrates produced by the fetal adrenal gland), a reduction in amniotic fluid 17OH-progesterone levels and a normal or near normal appearance to the female external genitalia of the newborn. The dose of dexamethasone is 20 microgramme / kg/ day in 3 divided doses. This can cause side effects for the mother such as excess weight gain and striae, hypertension, and glycosuria. Those with a history of cardiovascular disease and previous toxaemia should not be treated. The outcome for infants exposed to prenatal steroids for this purpose appears normal in terms of growth and neurodevelopment. This is based on more than 20 years of experience with treatment. Longer term outcomes from early fetal exposure to steroids are clearly unknown. It is for these reasons that this form of treatment should only be undertaken within the aegis of a clinical trials unit such as that operated by the BSPED.
Revised:
30-Oct-2006