Management of the child with congenital adrenal hyperplasia

Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 193–208

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Management of the child with congenital adrenal hyperplasia Peter C. Hindmarsh, BSc, MD, FRCP, FRCPCH, Professor of Paediatric Endocrinology * Developmental Endocrinology Research Group, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK

Keywords: hydrocortisone fludrocortisone circadian rhythm emergency therapy chronic care transition

Classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency leads to glucocorticoid and mineralocorticoid deficiency. Management should be viewed as a process of care which requires input from an interdisciplinary team. Glucocorticoid therapy should take the form of hydrocortisone in a starting dose of 15 mg/m2/day (divided into three doses), and the dose should be titrated to blood or urine profiles of cortisol and 17hydroxyprogesterone. Mineralocorticoid replacement (9a-fludrocortisone) requires higher doses in infancy and childhood than in adolescence. The starting dose should be 150 mg/m2/day, and the dose thereafter titrated to plasma renin activity and blood pressure. Despite adequate glucocorticoid substitution and concordance with medical therapy, control can be difficult during puberty due to alterations in the clearance of hydrocortisone, and dosing schedules may need to be adjusted to account for this. Follow-up should address the many facets of CAH, which should be assessed at an annual review, and a suggested protocol is presented. Ó 2008 Elsevier Ltd. All rights reserved.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is an autosomal recessive condition in which deletions or mutations of the cytochrome P450 21-hydroxylase gene result in glucocorticoid and mineralocorticoid deficiency. This leads to increased secretion of adrenocorticotropic hormone (ACTH) by the anterior pituitary, adrenal hyperplasia, accumulation of steroid precursors prior to the enzymatic defect, and increased production of androgens. Glucocorticoid substitution therapy is given to suppress the excessive secretion of corticotropin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) by the hypothalamus and anterior pituitary, * Tel.: þ44 207 905 2840; Fax: þ44 207 905 2838. E-mail address: [email protected] 1521-690X/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.beem.2008.10.010

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respectively, and to reduce the circulating concentrations of androgens and androgen precursors. Treatment efficacy, therefore, reflects the adequacy of adrenocortical suppression and traditionally has been assessed by monitoring annualized growth velocity, the rate of skeletal maturation, and serum concentrations of androgen precursors.1,2 Despite adequate substitution therapy, however, control of classical 21-hydroxylase deficiency is often difficult. Limitations of current medical therapy include inability to control hyperandrogenism without inducing hypercortisolism, hyperresponsiveness of the adrenal glands to ACTH, and difficulty in suppressing the anterior pituitary with glucocorticoids, given that glucocorticoid feedback is only one of the mechanisms governing ACTH secretion.3 Whilst the initial focus is rightly placed on the medical aspects of CAH care, this tends to utilize the classic medical model for care delivery. Although CAH does not comprise all the complex components of the more classic disease, diabetes mellitus, it does contain sufficient components – in terms of chronic nature, adherence to relatively complex treatment regimens, and the development of longterm complications – that it probably should be approached, after initial diagnosis, using the chronic care model. Chronic care and CAH As medical science and technology have advanced at a rapid pace, the health-care delivery system for chronic care has struggled to provide consistent high-quality care. CAH is no exception, and perhaps has fared worse than diabetes because at least in diabetes there are some hard end-points and surrogate markers. This is less obvious in CAH other than biochemical markers of control. Currently there is a heavy focus on these markers without much development in other important components of how CAH impacts on the life and family of the young person with CAH. CAH, like diabetes mellitus, is a classic chronic disease that requires continuous monitoring/input, and involves different specialities and a high level of patient/parent involvement. Although the complexity is acknowledged, in practice there is little evidence that health-care systems really understand these complexities and tend to go on providing the same kind of care that was delivered 10–20 years ago without the benefit of complete and holistic information about the patient’s condition and the services provided in the numerous settings that the individual may find themselves in during their day-to-day activities. Service provision has improved in the United Kingdom, but is prone to widespread inconsistencies in care delivery and outcomes, remains firmly medico-centric despite clear evidence that this approach is less than helpful4, and has to operate in an increasingly dysfunctional and disconnected health purchasing environment. One of the reasons that CAH sets itself up as a model for chronic care is that the underlying physiology and treatment modalities force the clinician and the patient/carers to embark on a more equal interrelationship rather than the classical medical model. The pharmacology of glucocorticoid replacement requires that medication is administered three or four times per day with adjustments made according to overall control and events such as illness. This necessitates devolution of decisionmaking to the patient/carer. This is superimposed upon the ongoing needs of the condition, such as any planned surgery or the management of additional problems such as excessive weight gain. Over the last 10–15 years our understanding of the process of self decision-making and the concept of patient autonomy has advanced considerably. Health care in the latter part of the 20th century was characterized by an increasing recognition of the autonomy of the patient. Medical ethicists have extended this principle to a number of areas of patient care, carefully refining the argument that involvement of the individual in all decision-making regarding their health and welfare is an essential component in modern health-care practice.5 This switch necessitates, however, a rethink in education training programmes that are provided by health-care professionals for children and adolescents with CAH and their families, and indeed for the health-care professionals themselves. Education and training become an absolute necessity rather than a desirable part of health-care provision. The challenge is to provide the patient with easy access to the information they require for executing their daily tasks plus a background feedback system of how well they are performing with respect to the overall targets they have set themselves and agreed with their health-care practitioners.

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The steps to progression in terms of competency have been greatly assisted by improved understanding of motivational change management. The evidence appears to support the clinical view that developmentally appropriate negotiated responsibility has beneficial outcomes.6,7 Thus the switch in thinking moves from a hierarchical ‘you must do’ approach to one of negotiation in the light of what is important to the individual. This process is summarized in Fig. 1. The clinician still has a duty to point out practices that are dangerous, but setting such information in the context of the patient’s beliefs is more likely to be successful than the more traditional confrontational style. The clinician has a role in that they must discuss the consequences of any action undertaken. Thus the shift in perspective is not a laissez-faire approach to a serious condition but a more explicit description of the relationship(s) between carers and patients/families. The process is more mature in a way as it enacts the style of discussion between informed parties. Care becomes a series of steps, therefore, and is better viewed as a process of care rather than a single entity. The next section looks at this process at the point of diagnosis and considers how it might evolve with time. Process of care The management of CAH should be viewed as a process of care, and because of its many facets input from a number of specialities is needed. At presentation the predominant input is from paediatric endocrinologists whose task it is to confirm the diagnosis by biochemical and molecular means, commence therapy with gluco- and mineralocorticoids, and manage the salt-losing state, if applicable, as some cases will be simple virilizers. This should run in parallel with input from paediatric urology in cases of virilization of the external genitalia of the female as well as psychology input to assist the family in adjustment to the diagnosis and to provide ongoing support and advocacy for the child and family. Gender assignment is rarely an issue in this condition. Initial medical management The likely presentation in the first 3 months of life is as a virilized female, raising the question of a disorder of sexual determination (DSD) or as a salt-losing crisis (predominantly in males) or failure to thrive. The steps to identify the correct diagnosis in the virilized female have been well described in the Consensus Document.8 In brief, rapid fluorescence in-situ hybridization (FISH) for sex-determining region Y (SRY) with confirmation of the karyotype should be undertaken, along with measurement of serum concentrations of 17-hydroxyprogesterone (17OHP), 11-deoxycortisol, androstenedione and cortisol. Traditionally, this has been undertaken after day 3 of life using extraction assays to avoid crossreactivity with fetal adrenal steroids. The increased use of tandem mass spectroscopy should allow for earlier measurement of these precursors. Urine steroid profile analysis is extremely helpful in this situation and should be undertaken as an adjunct. Care must be exercised in the interpretation of solitary 17OHP measurements, particularly if they are not excessively raised. Prematurity and

To allow children and young people with CAH to discover and develop their own capacity to be responsible for their The choices made every

Chemical tests are

day in the self

merely an imperfect

management of CAH

reflection/measure

produce consequences

of those choices

Fig. 1. Definition of what congenital adrenal hyperplasia (CAH) is about from a patient-focused perspective.

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cross-reactivity are two major confounders, but conditions such as 3b-hydroxysteroid dehydrogenase or the more common cytochrome P450 oxidoreducatase deficiency9 can lead to elevation of serum 17OHP concentrations, although not necessarily to the same degree as classical CYP21 deficiency. Plasma ACTH concentration estimation can be helpful. Electrolyte and blood glucose measurements should be undertaken at point of diagnosis and monitored daily in the case of electrolytes and 4-hourly in the case of blood glucose. Further fluid management will depend upon the presentation. In the case of those diagnosed in the first week of life, monitoring should aim to detect early salt loss, of which a rising potassium concentration may be the first sign and usually develops after day 7 of life. For those that present with a salt-losing crisis or failure to thrive, acute management of dehydration, hypoglycaemia and hyperkalaemia will take precedence. Plasma renin activity and aldosterone concentration should be measured at point of diagnosis or at the sign of rising potassium concentration. Once a biochemical diagnosis has been established, it should be confirmed from a molecular standpoint. This will then aid the subsequent discussion on future antenatal diagnosis and treatment. Regular review to assess growth and development is required on a 6-weekly basis for the first 6 months of life. This is a particularly critical time frame not just because of the rapid growth but also the high prevalence of intercurrent infections at this age. This age group has a particularly high mortality rate, about 19 times that expected, mostly resulting from inadequate increases in hydrocortisone therapy during periods of intercurrent illness.10 After 6 months, reviews can be undertaken at 3-monthly intervals until 3 years of age, and thereafter at 6-monthly intervals until puberty when 3-monthly appointments will be needed to keep pace with changes in glucocorticoid needs. Dosing schedules for hydrocortisone and 9a-fludrocortisone are considered below. Management of salt loss In the salt-losing form of CAH the presenting features in males may range from failure to thrive through to acute circulatory collapse. In girls, the presence of virilization alerts the clinician to the possibility of salt loss which initially manifests with a rising plasma potassium concentration. The mainstay of acute therapy is intravenous resuscitation with saline and glucose along with the commencement of hydrocortisone and 9a-fludrocortisone. In the first 6 months of life, milk feeds deliver only maintenance sodium requirements (2 mmol/kg/day), so sodium supplementation to replenish total-body sodium depletion will be required until weaning. In addition, several of the steroid precursor molecules accumulating in 21-hydroxylase deficiency are anti-aldosterone in nature, resulting in a greater need for 9a-fludrocortisone replacement than later in life. That said, increasing the 9a-fludrocortisone dose will not lead to greater sodium retention, unless there is supplementation, but will lead to overexposure to glucocorticoid due to its dexamethasone-like potency. Figure 2 illustrates the impact of sodium supplementation – which may range up 10 mmol/kg/day11 – on plasma renin activity and sodium concentration. During the first and second years of life 9a-fludrocortisone dosing is 150 mg/m2/day, but thereafter 100 mg/m2/day is sufficient, and the total dose should not need to be more than 100 mg daily. During 140

50 40

Plasma Renin Activity

Plasma Sodium 130

30 20

120

10 110

0 At Diagnosis Therapy and No Salt

Therapy and Salt

At Diagnosis Therapy and No Salt

Therapy and Salt

Fig. 2. Changes in plasma renin activity and sodium during treatment of congenital adrenal hyperplasia in infancy.

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adolescence the dose generally decreases, so that by the time of transfer to adult services the dose may range between 50 and 100 mg per day. Monitoring is based on the plasma renin activity (target values 2–8 pmol/mL/h) and blood pressure measurement which should always be interpreted using appropriate height-adjusted standards.12 Surgical input It is not the purpose of this chapter to detail the issues and options that are available for surgical correction of the virilized female genitalia. Suffice to say that early involvement of a surgical team experienced in the management of individuals with CAH should be sought. The surgical team may be paediatric urologists or gynaecologists or a combination of the two. Close collaboration with adult surgical practitioners in this area is to be recommended to enhance feedback of long-term surgical outcomes.13 Pelvic ultrasound examination can be of value in delineating the internal anatomy, but a more definitive procedure of cystoscopy is almost certainly required. Contrast sinograms have been utilized in the past, although not without hazard in terms of infection risk, and more direct visualization with a cystoscope is to be preferred. Decision-making regarding any surgical intervention and its timing should be between the interdisciplinary team and the family. Role of psychology The role for psychological input encompasses at least three areas. First, facilitation of the family to cope with the diagnosis and to progress through the grieving process. Second, to utilize techniques from motivational and cognitive therapies to assist families and young people to engage in the management process, a key component of how chronic care is managed. This involves mentorship for the families and young people as well as a role in education and training of health-care professionals. Third, to act as an advocate for the families and young people at different life stages. In order to generate prepared, informed and motivated patients and families, information is required about the expected course of the disease, expected complications, and effective strategies to prevent complications and to manage any symptoms that arise. This needs to be introduced at an early stage, and the time of diagnosis is an important start point. It is very easy at this point to focus on the practicalities of the condition, including decisions on surgery, and to forget that the individual and family are going through a grieving process. The latter needs to be recognized, because there is a tendency, as in many other grieving situations, for individuals to become stuck at the various stages in the evolution of the grieving process. Glucocorticoid dosing The daily production rate of cortisol is approximately 8 mg/m2/day, to which needs to be added the entero-hepatic circulation of cortisol, yielding an average hydrocortisone replacement dose of 10– 12 mg/m2/day. For suppression of the adrenal axis, which is required to control androgen excess in CAH, a slightly higher dose of 15 mg/m2/day is required. This is usually given as a thrice-daily regimen, with the highest dose in the morning (Fig. 3). Giving the highest dose in the evening will not suppress the ACTH surge, as the pharmacology of hydrocortisone is such that suppression will be lost around 3 a.m., i.e., around the time when the early-morning ACTH rise starts to take off. One way around this might be to give the dose as late as possible in the evening or preferably about 1 a.m. Prednisolone and dexamethasone should be avoided in children because of the risk of growth suppression and weight gain. Table 1 depicts equivalence doses for these two glucocorticoids against hydrocortisone. Data such as these are based on anti-inflammatory potencies which are likely to be different from growthsuppressing effects. Of note is the impact of 9a-fludrocortisone, which has not only mineralocorticoid but also potent glucocorticoid activity (Table 1).14 As a result, when calculating total daily glucocorticoid dosing, the contribution of 9a-fludrocortisone needs to be included in the total. Glucocorticoid metabolism varies among individuals, so doses should be titrated against blood profiles of cortisol and 17OHP to ensure adequacy of suppression in terms of 17OHP (<10 nmol/L) or

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A 1200

Cortisol (nmol/L)

1000

800

600

400

200

0 8

12

16

20

24

4

8

Time (hours)

B

20.0 18.0 16.0

17OHP (nmol/L)

14.0 12.0 10.0 8.0 6.0 4.0 2.0 0.0 8

12

16

20

24

4

8

Time (hours) Fig. 3. Serum cortisol (A) and 17-hydroxyprogesterone (17OHP) (B) concentration profiles resulting from thrice-daily administration of hydrocortisone.

androstenedione concentrations, and that suppression is not achieved by overexposure to cortisol. Preand 2-hour-post-dose samples will capture peak and trough dosing, but fine tuning can be achieved with hourly blood profiles or short timed urine collections. Figure 3 matches serum cortisol and 17OHP concentrations following hydrocortisone administration and demonstrate the failure of the evening dose to totally suppress the early-morning ACTH rise and therefore 17OHP. Puberty During puberty glucocorticoid therapy may need revision, as the endocrinology of puberty may result in inadequate suppression despite apparently optimal therapy and concordance with treatment.

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Table 1 Equivalent doses of glucocorticoids.15 Steroid

Glucocorticoid anti-inflammatory effect

Dosing effect on anti-inflammation

Growth-retarding effect

Dosing effect on growth

Mineralocorticoid effect

Hydrocortisone Prednisolone Prednisone Dexamethasone Fludrocortisone

1.0 4.0 4.0 30.0 15.0

20 mg 5 mg 5 mg 0.6 mg 1.2 mg

1.0 5.0

20 mg 4 mg

80

0.4 mg

1.0 0.8 0.8 0 200

Cortisol clearance increases at puberty.16 This results from a number of pubertal changes. First, the increase in growth hormone secretion associated with the pubertal growth spurt results in decreased activation of cortisone to cortisol and, effectively, hypocortisolism.17 Second, the increase in circulating sex steroid concentrations, particularly oestradiol, impact upon cortisol binding globulin. Third, hyperinsulinism, secondary to the increase in growth hormone, results in increased adrenal and ovarian androgen production.18,19 Both hypocortisolism and hyperandrogenism result in increased ACTH secretion, which may further potentiate hypocortisolism by increasing the metabolic clearance rate of cortisol20, thus establishing a vicious cycle. Pubertal females would be expected to be more effected than males. The situation is likely to be compounded further by the presence of polycystic ovaries, especially if there has been longstanding hyperandrogenism and/or obesity. The association of hyperandrogenism and obesity may result in hyperinsulinism and insulin resistance, which will further stimulate adrenal and ovarian steroidogenesis and aggravate the situation.18 Furthermore, hyperandrogenism may be amplified in hyperinsulinaemic states because insulin suppresses the synthesis of sex hormone binding globulin by the liver.21 This is not to say that all control problems during adolescence are physiological. There are certainly the normal interactions of adolescents with chronic illness as they test boundaries and assert individuality. These need to be recognized. In diabetes practice a particular problem exists with concordance with insulin therapy, particularly in girls, where individuals become expert at maintaining very good poor control in order to maintain a constant body weight.22 A similar situation of fine-line hydrocortisone dosing probably also exists in a number of young people and possibly adults with CAH. Emergency situations and illness Addisonian crisis remains an ever-present concern, and parent and child familiarization with an emergency treatment regimen is essential. Details are provided below. The patient must have and wear a Medic Alert bracelet or equivalent. Education of the parents and/or young person is paramount, and they need to be empowered to alert professionals if the child’s need for steroids increases during intercurrent illnesses. They should carry with them, in addition to the Medic Alert bracelet, details of their steroid therapy, which can be entered onto one of the many steroid replacement cards that are available. Parents should be trained in the intramuscular administration of hydrocortisone and advised to seek medical advice if the child becomes unwell. Emergency management of an ill child with congenital adrenal hyperplasia (CAH) Level 1. Assessment suggests child is unwell but fluids are tolerated. Steroid dosing should be doubled or trebled. Level 2. If there is associated vomiting, intramuscular hydrocortisone should be administered (Table 2). Following administration of intramuscular hydrocortisone, the child should be taken to the nearest accident and emergency department.

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Table 2 Intramuscular hydrocortisone doses for emergency use. Age range (years)

Dose (mg)

0–1 1–5 >5

25 50 100

The child should not be discharged until the following have been measured: 1. urea and electrolyte concentrations; 2. blood glucose concentration; 3. blood pressure. Should any of these measurements be abnormal, or in any situation of doubt, the child should be admitted for glucose, electrolyte and blood-pressure monitoring. Level 3. Where there is loss of consciousness and/or circulatory collapse, or when there is failure to respond to intramuscular hydrocortisone, other explanations for collapse should be considered and intravenous hydrocortisone administration commenced: 1. if shut down peripherally and hypotensive, give stat intravenous infusion of 20 mL/kg of 0.9% sodium chloride; 2. loading intravenous bolus dose of hydrocortisone 2 mg/kg; 3. hydrocortisone infusion (Table 3); 4. monitor urea and electrolyte (2-hourly) and blood glucose (hourly) concentrations and blood pressure (hourly) until normalized and stable, and strictly monitor input and output, with replacement of all fluid loss and correction of any dehydration; 5. sodium should be corrected to 120–125 mmol/L at a rate of 0.5 mmol/L/h, thereafter correction to normal values should take place over several days. Surgery Where elective surgery is planned, prior liaison with the anaesthetist is essential. The patient should preferably be placed first on the surgical list in the morning. The normal evening dose of glucocorticoid should be given and blood glucose concentrations carefully monitored from 06:00 h. At the same time a dextrose–saline infusion should be commenced and maintained until oral fluids can be tolerated. Blood glucose should be monitored on an hourly basis up until premed. Regular postoperative blood glucose measures should be undertaken at 2-hourly intervals. If the patient is on the afternoon surgical list then the patient should receive their usual morning glucocorticoid dose.

Table 3 Infusion rate to achieve the average serum cortisol concentration achieved on the paediatric intensive care unit (PICU) during sepsis of 1000 nmol/L (0.36 mg/mL). Situation

Cortisol clearance (mL/24 h)

Infusion rate (mg/24 h)

Pre-pubertal: <10 kg 10–20 kg >20 kg Pubertal Post-pubertal

74 147 294

25 50 100

430 290

155 105

Infusion rate (mg/24 h) ¼ clearance (mL/24 h)  steady state cortisol concentration (mg/mL).

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Table 4 Hydrocortisone dosing and surgery. Minor surgery (e.g. cystoscopy): At induction: hydrocortisone i.v. 2 mg/kg, repeated if procedure exceeds 4 h Post-op: Can use repeat i.v. regimen of hydrocortisone (2 mg/kg) in lieu of routine medication until oral fluids tolerated, then return to oral therapy which must include that day’s fludrocortisone dose Major surgery (e.g. genitoplasty): At induction: hydrocortisone i.v. 2 mg/kg During op: repeat i.v. hydrocortisone on 4-hourly basis or hydrocortisone infusion Post-op: can use repeat i.v. regimen of hydrocortisone; alternatively, when postoperative recovery is likely to be slow, consider hydrocortisone infusion. Continue i.v. administration until fluids tolerated. Then return to oral therapy at twice normal dose for 24 hours (postoperative dosing schedule will be determined by the extent of the surgical procedure and should be conducted in liaison with the endocrine team), then return to normal requirements. As soon as the patient is on oral therapy reintroduce fludrocortisone dose Fluids: 100 mL/kg/day if weight <10 kg 80 mL/kg/day if weight 10–30 kg 60 mL/kg/day if weight >30 kg If salt-losing CAH use 5% glucose with 0.45% sodium chloride For other cases use 4% glucose with 0.18% sodium chloride Hydrocortisone infusion (Table 3)

An intravenous dose of hydrocortisone (2 mg/kg body weight) (Table 4) should be given at induction. For operations expected to exceed 4 hours, a further bolus of hydrocortisone during the procedure will be required. Alternatively, for prolonged procedures, and when postoperative recovery is likely to be slow, consideration should be given to a hydrocortisone infusion. It is important to remember that hydrocortisone has mineralocorticoid activity, and care must be exercised in situations where water retention would be a disadvantage, e.g. during neurosurgery when dexamethasone should be used. Monitoring CAH Many of the problems that are associated with CAH relate to the degree of control of the hypothalamic–pituitary–adrenal (HPA) axis achieved with glucocorticoid therapy. However, glucocorticoid treatment may be associated in its own right with potential problems. As a result, it is probably wise to approach long-term monitoring of the condition in a similar way to that adopted for diabetes mellitus with an annual review of various aspects of the condition. In Table 5 an annual review programme is suggested, including short-, medium- and long-term issues that might need to be addressed. This presents a very medical approach to the condition, and one challenge for future work is to determine measures relating to patient/family satisfaction and coping. Three specific aspects of problems associated with CAH are considered below: growth and puberty, reproductive function and the metabolic syndrome. Growth and puberty Following the initial success of glucocorticoids in preventing death from hypocortisolism it became apparent that growth suppression was a major complication of therapy. As time has progressed the dosing schedule has been refined, so that total daily doses of glucocorticoid (hydrocortisone plus the contribution from 9a-fludrocortisone) >15–18 mg/m2/day are rarely required. Regular estimation of height and calculation of height velocity are important, along with an annual assessment of skeletal maturation. Further fine tuning can be achieved with the dosing schedule using cortisol and 17OHP profiles as described above. The aim of therapy is to maintain a height velocity that averages on the 50th centile with a slight delay in bone age. Under-dosing will lead to growth acceleration and advance in skeletal maturation, whereas over-dosage will lead to a reduction in height velocity and bone age delay. Poor growth is likely when total glucocorticoid doses exceed 30 mg/m2/day23 and during the

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Table 5 Annual review programme for children and young people with congenital adrenal hyperplasia (CAH).

Short-term

Medium-term

End point

Rationale

Measure

1. Growth acceleration 2. Weight changes

1. Assess control 2. Assess dosing

3. Correct dose for size 4. Blood pressure 5. Puberty

3. Optimize therapy 4. Treatment effects 5. Timing can be altered in CAH

1. Acceleration >2 cm/y needs attention 2. Weight gain in excess of 2 kg/year needs attention 3. 1 and 2 above and blood tests 4. Blood pressure and plot on centile charts 5. Tanner Staging

1. Bone maturation 2. Pubertal status

1. Rate of skeletal maturation 2. Early puberty or rapid progression 3. Optimize therapy

3. Hydrocortisone dose 4. Fludrocortisone dose

6. Metabolic status

4. Avoid high blood pressure endocrinopathy 5. CAH might influence how they work 6. Insulin insensitivity and lipids

1. Growth 2. Bone mineralization 3. Fertility

1. Outcome 2. CAH/treatment effect on bone 3. Effect of CAH

4. Cardiovascular risk

4. CAH/treatment effect

5. Ovary and testes health

Long-term

1. Yearly bone age 2. Tanner staging 3. Cortisol and 17OHP profiles over 24-h period 4. Plasma renin activity 5. Pelvic ultrasound for girls; careful exam for boys 6. Fasting glucose, insulin and lipids 1. Final height within target height of parents 2. DEXA scan 3. Check for regular menstrual cycle (girls) and adrenal rests in testes in boys 4. Fasting glucose and insulin, blood pressure, fasting lipids

17OHP, 17-hydroxyprogesterone; DEXA, dual energy x-ray absorptiometry.

first year of life when doses of 40 mg/m2/day have been utilized.24 Prednisolone use appears to be uniformly associated with poor long-term growth prognosis.25 Figure 4 summarizes data for salt-wasting CAH over the last 30 years.26–30 The general trend upwards is reassuring, although the precision of the estimate of improvement is hard to judge given the diverse populations studied. For example, the 1997 report is from Scandinavia, which probably explains the slight difference between that and the 2001 data which are from Greece. As the expected secular trend in height over this 30-year period would be approximately 2 cm, the data suggest a general improvement. For comparison, the UK Growth Reference Dataset places the average height for males at 178.5 cm and for females at 165.5 cm. Overall, males would appear to fare better than females in all sets apart from the 1997 Scandinavian set, which might reflect problems in dosing during puberty. Not all individuals with CAH do well in terms of growth. Those particularly at risk are those with the simple virilizing form who often do not present until mid-childhood with accelerated height velocity,

180 175

Male Female

170 165 160 155 150 145 140 135 1977

1986

1991

1997

2001

Fig. 4. Trend in final height in patients with salt-wasting form of CYP21 congenital adrenal hyperplasia. Dates refer to references 26–30.

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virilization, and an advance in skeletal maturation. Introduction of glucocorticoid therapy controls the rapid growth but is often associated with an early onset of puberty, presumably due to a ‘priming’ effect of adrenal androgens on the HPA axis. Holding up puberty in this situation with a gonadotrophinreleasing hormone analogue can be helpful. In cases of CAH where control has been lost, the use of an aromatase inhibitor to block androgen-to-oestrogen conversion may be useful. Treatment with biosynthetic human growth hormone has been reported to be of some use, although extensive data on outcome are unavailable.31 The improvements in final height, although reassuring, need to be balanced against changes in body weight and fat mass. This appears to have an early origin32,33 and may reflect the use, certainly in the past, of high doses of glucocorticoids during the first year of life.24 Figure 5 shows the evolution of this problem over the first decade of life, and suggests that further work be undertaken to better define glucocorticoid replacement therapy during this critical window. This may prove to be extremely important given the other issues described in the next two sections. Reproductive health The majority of children with CAH enter puberty around the normal time, and progress through puberty appears to take place with the normal tempo. Exceptions to this have been mentioned already with respect to poor overall control and the situation in simple virilizers brought under metabolic control. Menarche may be delayed and the menstrual cycle irregular in a manner akin to that observed in patients with polycystic ovarian syndrome. The excess androgen exposure that can result in utero and/or during episodes of poor control have been suggested to predispose the individual to the development of polycystic ovaries. The definition by ultrasound of polycystic ovaries, a finding apart from actual polycystic ovarian syndrome, can vary between studies. Hague et al34 found the association of CAH with ultrasonically detected polycystic ovaries in 83% of adult patients, 40% of post-pubertal girls and 3% of pre- and peri-pubertal girls. However, the finding of two homozygous non-classical CAH-affected adult sisters with polycystic ovaries and, conversely, of ten heterozygous adult relatives and of 12 postmenarcheal CAH patients with normal ovaries, suggested that the ovarian morphological change may be independent of the adrenal lesion.34 A more recent study has largely confirmed that the

n = 13

+3

n = 16

n = 16

+2 +1 0 -1 -2 -3 -4

BMI SD score for chronological age

Height SD score for chronological age

+3

*

+2

*

+1 0 -1 -2 -3 -4 1

5

10

Age (years) Fig. 5. Changes in height and body mass index expressed as standard deviation scores over the first decade of life in children with salt-wasting form of CYP21 congenital adrenal hyperplasia. BMI, body mass index.

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prevalence of a polycystic ovarian appearance on ultrasound is little different from that in the general population, although the sample size was small.35 This latter study also evaluated the presence of ovarian adrenal rest tumours as sporadic reports have appeared in the literature. None were found, leading the authors to conclude that routine ovarian scanning for these lesions was not justified.35 However, in view of the absence of an adequate sample size and repeat confirmatory studies, an open mind should be kept at this stage. In an ultrasound-based study of 17 males, 94% had a detectable testicular lesion which was bilateral in ten patients. Maximal size ranged from 2 to 40 mm, with 17 of the 20 lesions <2 cm in diameter. The lesions may develop from some small, hypoechoic, and multifocal nodules and coalesce to large hypoechoic lesions with hyperechoic reflections on ultrasound.36 In an extension to this study the authors reported a much lower prevalence of 24%. In none of the patients were the tumours palpable. Two children were aged between 5 and 10 years old. No effect was observed on endocrine function.37 Based on these observations, regular ultrasonographic monitoring is probably indicated, with attention paid to careful control. Careful control is particularly important anyway in males in order to allow for spermatogenesis. Because of the need for intratesticular testosterone generation for sperm maturation, any excess adrenal androgen production resulting from poor CAH control may impact upon the hypothalamic– pituitary–gonadal axis leading to reduced gonadal testosterone production. Long-term health: the metabolic syndrome and osteoporosis The combination of poor insulin responsiveness, obesity, hypertension and dyslipidaemia is often referred to as the metabolic syndrome38, although whether the syndrome is actually a distinct entity is in doubt.39,40 Nonetheless, the concept provides a useful framework to consider cardiovascular risk. Whether patients with CAH are at increased risk of cardiovascular disease is unclear, as there are very few patients who have reached the age group 50–60 years. There are reports, however, that suggest that CAH patients may have components of the metabolic syndrome if not all of them. Insulin resistance41 and hypertension42 have been reported. The mechanism(s) may differ from that unifying the metabolic syndrome which focuses on loss of insulin responsiveness. Instead, altered adrenomedullary function due to loss of endogenous cortisol production has been proposed.43 For hypertension, a number of explanations are possible. Early treatment with relatively high doses of corticosteroids may predispose to obesity and hypertension as noted above. In preterm babies, antenatal glucocorticoid therapy is associated with higher diastolic blood pressure in adolescence.44 Early ‘programming’ need not be invoked given the clear effects of acute alterations in glucocorticoid concentrations on blood pressure.45,46 A role for 9a-fludrocortisone needs to be considered. Hypertension and obesity are common, and the question arises whether the blood pressure observations are simply a surveillance effect and/or whether families with CYP21 also have family incidence of obesity and hypertension. Females with CAH appear to be particularly prone to this combination of factors. This might suggest that the advantageous shift in the cardiovascular mortality curve that females benefit from throughout life47 may be lost in this population. This shift in the curve has been suggested to be due to early androgen exposure, and this may be an important element in understanding the aetiology of these observations. In addition to risk factors for cardiovascular disease, a further public health problem that may be faced by CAH patients is osteoporosis. There is a clear relationship between bone mineral content and risk for osteoporotic fractures in adults with values >2 standard deviations below the mean, raising the risk for fracture. Infancy, childhood, and adolescence are critical periods for skeletal mineralization; thus, chronic diseases may impair bone mass peaking, particularly if children and adolescents are overexposed to glucocorticoids, as may occur in patients with CAH. Data on this question are mixed and again derived from small cohort studies. Gussinye et al48 found no difference in bone mineral density between controls and children and young people with CAH, although 50% of the CAH group were prepubertal. In contrast, Paganini et al49 suggested a slight reduction in bone mineral density, although this was perhaps less important than the authors claimed if adjusted for the height of the study population.

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Clearly glucocorticoid therapy is implicated in the generation of osteoporosis, but whether this pertains to CAH is unclear. Larger studies will be required to explore this question and to control for the paradoxical effect of poor control which, with the resulting increase in androgen concentrations, may ameliorate some of the adverse effects of high steroid dosing.

Transition Transition from paediatric to adult care represents a major milestone for young people with chronic illnesses. Despite this the literature highlights that it is often poorly organized and fails to meet the needs of the young person. Often young people are regarded as adults following transfer from paediatric services.50 However, this often occurs at a sensitive time when other life transitions are taking place, making young people a vulnerable group at risk of adverse events: e.g. getting ‘lost’ or ‘dropping out’ of services. Transitional care is a purposeful, planned movement of a young person from a child-centred to an adult-orientated health-care system, in contrast to transfer which is a sudden arbitrary event where the patient is transferred from paediatric to adult services with referral information only. Just as we considered CAH care to be a process, transition should not be considered an event but part of that process. This needs to begin in early adolescence to foster independence and communication skills and to incorporate health education. Components of transition that need to be considered are:      

self-advocacy; independent health-care behaviours; sexual health; psycho-social support; education and vocational planning; health and lifestyle.

When considering transition, it is important to consider that young people are developing their sense of self and personal identity; they are separating and individuating from their family of origin; they are beginning to manage long-term causes and consequences, negotiate peer and romantic relationships, take on community roles and social responsibilities, and make decisions around education and vocation. This needs to be recognized by staff working with young people. In fact transition is ongoing throughout childhood and adolescence (child: birth to 12 years; teenager: 13–16/18 years; young person: 16/18–25 years) as different stages of development are met and negotiated. These bands are not fixed, as they depend on developmental, social and emotional maturity.51 However, most transition appears to be based on age; although there is some flexibility, it appears to take place between 14 and 18 years, and in some instances is an administrative event. It is worth highlighting that most paediatric wards will not accept admissions over 16 years old. Most areas do not have adolescent facilities, so any in-patient work needs to consider this. It is acknowledged that ineffective transition can lead to young people being ‘lost’ or ‘dropping out’ of adult services, and therefore effective transition must focus on the partnership with the young person to ensure that a service is provided which takes into account their views and wishes. However, there appears to be little information about how young people view transition and how successful they feel it is. It is also difficult to find information to help health professionals assess when the young person is ready move on to adult services. This is an area that needs specific work to be undertaken in the context of CAH. It also needs to be considered that there are significant differences between paediatric and adult endocrine services which can impact on how successful transition is for the individual. Paediatric care is interdisciplinary, family and socially focused, and requires parental support and consent. It aims to provide holistic care. Conversely adult care is often patient-focused and requires autonomous independent skills on the part of the user. It rarely takes into account social and psychological elements of care and how this impacts on the young person and their family. Early work from diabetes care suggests that this is an important area, and again work in this area in the context of CAH is required.52

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Conclusions CAH is a chronic illness and needs to be managed in this context. Careful anthropometric and biochemical monitoring is required to ensure control of the condition without over-exposure to glucocorticoid. As glucocorticoids influence many metabolic pathways, assessment of control of CAH should reflect this, and an annual review approach is suggested. Special attention needs to be paid to the management of pubertal patients with classical CAH, and therapy should aim at providing adequate and frequent glucocorticoid substitution as well as preventing and/or treating hyperandrogenism and insulin resistance.

Practice points  tailor doses to body size and titrate against biochemical parameters  sodium supplementation in first 6 months of life is important to replace sodium deficit and low sodium content of breast and formula milk  all patients and their families must have education and training in emergency therapy

Research agenda  the optimal minimal dosing schedule in childhood needs to be established  alternative dosing schedules that more closely mimic physiology are needed  consideration needs to be given to factors that might increase cardiovascular risk in the long term  further work on transition needs is required

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