Archives of Disease in Childhood, 1988, 63, 1399-1404

Personal practice

Management of congenital adrenal hyperplasiaI A HUGHES

Department of Child Health, University of Wales College of Medicine, Cardiff

Congenital adrenal hyperplasia is the commonestadrenal disorder in infancy and childhood andresults from a deficiency in the activity of one of thefive enzymes required for cortisol biosynthesis.1More than 90% of cases are due to a deficiency of21-hydroxylase enzymes required for the conversionof 170H-progesterone to 11-deoxycortisol and ofprogesterone to 11-deoxycorticosterone. The inheri-tance is autosomal recessive and the monogenic traitis closely linked to the HLA locus on chromosome6.2 A further 5% of cases are associated with adeficiency of the 11i-hydroxylase enzyme involvedin the terminal steps of cortisol and aldosteronebiosynthesis. The clinical hallmark of both enzymedefects is virilisation consequent upon increasedadrenocorticotrophic hormone secretion causingexcess adrenal androgen production. The remainingenzyme defects causing congenital adrenal hyper-plasia are very rare and their management is notdiscussed. ,

Clinical presentation

Fetal adrenal steroidogenesis is established in earlygestation so that a female fetus with congenitaladrenal hyperplasia invariably has virilised externalgenitalia at birth. The degree of virilisation canrange from mild isolated clitoromegaly or partiallabial fusion to complete fusion of the labioscrotalfolds ('scrotalised' labia) and pronounced clitoro-megaly with a phallic urethra. The latter variant maymasquerade as a cryptorchid 'male' with or withouthypospadias. The consequences of inappropriategender assignment can be tragic when the true sex isrealised in later life.3 The clitoris and labia minoramay be sufficiently prominent in an otherwisenormal preterm female infant to raise a suspicion ofpartial virilisation of the genitalia. Sometimes anaffected girl does not show signs of virilisation atbirth. This late onset variant of congenital adrenalhyperplasia usually presents with the onset of earlypubic or labial hair growth and accelerated lineargrowth. A boy with congenital adrenal hyperplasia

rarely has signs of virilisation at birth despite plasmatestosterone concentrations which are often withinthe normal adult male range. Increased pigmentationof the scrotal skin may sometimes be a clue to thediagnosis. Typically the affected boy is recognised asthe result of a salt losing crisis, which presentsduring the second or third week of life. A mistakendiagnosis of pyloric stenosis has been made occasion-ally but the electrolyte pattern should distinguish thetwo disorders. Many families with patients who havecongenital adrenal hyperplasia report a history ofprevious unexplained male infant deaths.4 It is myimpression that with the increased awareness of thedisorder by paediatricians, and the availability ofrapid diagnostic tests, cases of salt losing congenitaladrenal hyperplasia are now rarely missed in thiscountry.About one third of patients with congenital

adrenal hyperplasia due to 21-hydroxylase deficiencyare non-salt losers. Males with this form of congeni-tal adrenal hyperplasia are not clinically detected atbirth and show signs of virilisation in late infancyand childhood. The signs include growth of the penisand pubic hair, increased muscle bulk, and rapidlinear growth. The testes remain prepubertal in size.This is an important clinical sign to indicate that theincreased androgen production arises from aperipheral (adrenal) source which is independent ofcentral gonadotrophin stimulation. It is now recog-nised that there is a wide range of clinical manifes-tations of 21-hydroxylase deficiency. The examplesare summarised in table 1. A simple classificationinto classical and non-classical forms of congenitaladrenal hyperplasia has been proposed based onphenotype (symptomatic or asymptomatic).5 In clas-sical congenital adrenal hyperplasia, there is prenatalvirilisation, which may also be accompanied by earlypostnatal salt wasting. Non-classical congenitaladrenal hyperplasia includes patients with postnatalor late onset virilisation or those who are asympto-matic but show abnormalities on biochemical testing.These are referred to as cryptic cases in table 1 andare usually identified when relatives of an index case

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Table 1 Clinical manifestations of 21-hydroxylasedeficiency

Newborn Later life

Ambiguous genitalia: Pseudoprecocious pubertyComplete Isolated pubarcheIsolated clitoromegaly Isolated clitoromegalyIsolated labial fusion Rapid growth

HirsutismCryptorchid, hypospadic 'male' Menstrual disorders

InfertilitySalt wasting Cryptic cases

with classical congenital adrenal hyperplasia areinvestigated.

Girls with congenital adrenal hyperplasia due toll,-hydroxylase deficiency are also virilised at birthand the degree may be more severe than in the21-hydroxylase defect. Salt wasting is not a featureof untreated 11 3-hydroxylase deficiency and affectedboys are only recognised in later infancy andchildhood because of early signs of pseudoprecociouspuberty. Prepubertal gynaecomastia is anotherfeature peculiar to this enzyme defect. The clinicalhallmark of 11-hydroxylase deficiency is hyperten-sion secondary to increased mineralocorticoid pro-duction. Hypertensive encephalopathy and cerebro-vascular accidents are known complications but theseverity of hypertension is unrelated to the degree ofvirilisation.6 Hypertension is not a constant featureof ll,-hydroxylase deficiency, however, and israrely present at birth.

Diagnosis

The newborn infant with ambiguous genitalia is amedical emergency and appropriate investigationsmust be started quickly. The problem is a distressingone for the parents and they must be given a carefulexplanation of what will be done to determine thesex of the infant and how long this will take. Theremust be no guessing at the sex. It is important tonote that the commonest cause of ambiguousgenitalia of the newborn is congenital adrenalhyperplasia and the commonest cause of congenitaladrenal hyperplasia is 21-hydroxylase deficiency. Toconfirm this diagnosis two investigations are essen-tial: measurement of plasma 170H-progesteroneconcentration and determination of a peripheralkaryotype. A complete list of relevant investigationsis shown in table 2.The enzyme 21-hydroxylase is required for the

conversion of 170H-progesterone to 1 1-deoxycortisolin the pathway of cortisol biosynthesis. In itsabsence there is accumulation of 170H-progesterone,

which is readily measured in plasma. The test israpid and reliable for the diagnosis of 21-hydroxylasedeficiency.7 The assay is available routinely throughthe supraregional steroid assay service and can beperformed on filter paper blood spots as well as inplasma, saliva, and amniotic fluid. It is advisable todelay sample collection for 24 hours after birth toallow for the disappearance in 170H-progesteroneproduced by the placenta. The steroid is a stressrelated hormone and concentrations can be veryhigh in ill infants (particularly if preterm) withoutadrenal disease.9 A repeat measurement of170H-progesterone when the infant is better or anassessment of the 170H-progesterone response toadrenocorticotrophic hormone stimulation may benecessary to resolve the question of possible21-hydroxylase deficiency in a male preterm infantwith low plasma sodium concentrations.The peripheral karyotype must always be deter-

mined in an infant with ambiguous genitalia or in a'male' with bilateral cryptorchidism and hypospadias.A provisional result can be provided by mostcytogenetic laboratories within 48 hours of lympho-cyte culture. A definitive diagnosis of congenitaladrenal hyperplasia due to 21-hydroxylase deficiencyin a newborn infant with ambiguous genitalia can bemade two to three days after birth based on a 46 XXkaryotype and an increased plasma concentration of170H-progesterone (usually >200 nmol/l; normal<10 nmol/l in a full term infant). Other steroidconcentrations known to be raised in 21-hydroxylasedeficiency include 21-deoxycortisol, androstenedione,and testosterone. When the plasma 170H-pro-gesterone concentration is normal or only slightlyincreased, the concentration of plasma 11-deoxy-cortisol as an index of 11-hydroxylase deficiencyshould be determined. Additional confirmatoryevidence of this rarer enzyme defect can be obtainedby measurement of specific steroid metabolites inurine using detailed gas chromatographic analysis.

Table 2 Diagnostic tests for congenital adrenalhyperplasia

Blood: 170H-progesteroneTestosteroneAndrostenedioneAdrenocorticotrophic hormonePlasma renin11-Deoxycortisol (11fI-hydroxylase defect)Karyotype

Urine: 17-OxosteroidsPregnanetriolGas chromatographic steroid profile

Radiology: Pelvic ultrasound examinationVaginographyIntravenous urography

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Management of congenital adrenal hyperplasia 1401

Plasma concentrations of adrenocorticotrophic hor-mone are raised with both enzyme defects but theassay is available only in a few specialised centres.Ambiguous genitalia in an infant with a 46 XYkaryotype is a complex problem requiring investi-gation by a paediatric endocrinologist.At least two thirds of patients with 21-hydroxylase

deficiency are salt losers. Typically they develophyponatraemia, hyperkalaemia, azotaemia, earlymetabolic acidosis, increased urinary sodium excre-tion, and occasionally hypoglycaemia. Plasma reninactivity is a more sensitive index of mineralocorticoidinsufficiency and is increased soon after birth.10However, the results are seldom available im-mediately.

Early management

MEDICALThe salt losing crisis in an infant with congenitaladrenal hyperplasia requires treatment with in-travenous normal saline, the amount being calcu-lated based on the sodium deficit and the degree ofdehydration. Glucose should also be infused be-cause of the risk of hypoglycaemia. Hyperkalaemiamay rarely be severe enough to require moreimmediate treatment with insulin. Unless there isperipheral circulatory collapse, glucocorticoidsshould be withheld until blood samples for steroidanalyses have been collected. Glucocorticoid treat-ment can be started using a replacement dose fromthe onset; this will adequately suppress raised170H-progesterone concentrations within weeks.The alternative regimen of using a high initial doseof glucocorticoid is unnecessary and almost certainlyadversely affects the normal rapid growth ratecharacteristic of early infancy. I favour the use ofhydrocortisone (cortisol) as the preferred choice ofglucocorticoid. It is the physiological hormoneactive in man, the cortisol secretion rate is stan-dardised for surface area (about 12 mg/m2/day),"and there is 50% consistent absorption of an oraldose. A dose of 20 mg/m2/day is about 5 mg per dayfor an infant; this can be divided into dosages of 2-5,1*25, and 1-25 mg given at intervals of eight hours.The pharmacist will need to prepare hydrocortisonein solution to prescribe such small amounts. An oralpreparation of cortisol (Corlan, Glaxo) in the formof 2*5 mg hydrocortisone pellets designed for treat-ing mouth ulcers can be prescribed after the firstyear.

Salt replenishment during the early salt losingcrisis is usually adequately provided by intravenoussaline. It is seldom necessary to use a parenteralmineralocorticoid preparation. Oral9a-fludrocortisone(Florinef) is a potent mineralocorticoid which can be

started in a dose of 0-1-0-2 mg daily once the infantis rehydrated and taking oral feeds. Occasionallyhigher doses are required but the blood pressuremust be monitored regularly. Supplementing theoral feeds with 2-3 g of salt daily in divided dosesuntil semisolid feeding is established is occasionallyrequired.

Deoxycortisone pivalate is a long acting mineralo-corticoid which, in a dose of 12-5-25 mg monthly byintramuscular injection, is useful for the rare patientin whom there is a problem with treatment com-pliance.

SURGICALThe variable degree of virilisation of the externalgenitalia in girls with congenital adrenal hyperplasiahas already been emphasised. It is essential for theinfant to be seen early by a surgeon experienced inthe teChniques required for reconstruction of thegenitalia. There are basically two structural abnor-malities which require surgical treatment: reductionin the size of the enlarged clitoris and division of thefused labial folds to exteriorise the vaginal opening.The various surgical techniques used to perform thecitoroplasty and vagnioplasty are beyond the scopeof this review. Some or all of the radiologicalinvestigations listed in table 2 should be performedbefore surgery. Only clitoroplasty is normally per-formed in infancy; unless there is evidence that thelabial fusion and urogenital sinus is contributing toinfection, it is preferable to delay vaginoplasty untilthe time of puberty. The parents should understandthat the female internal genitalia are normallydeveloped. Pictures from a pelvic ultrasound ex-amination or vaginography to show the uterus andovaries can be most reassuring. The sex of rearingfor a girl with congenital adrenal hyperplasia shouldalways be female, whatever the degree of virilisation.

Later management

Treatment in congenital adrenal hyperplasia shouldaim to ensure normal growth in infancy and child-hood, the development of puberty at the appropriateage and later, the acquisition of adult reproductivepotential. This goal needs to be achieved using theminimum amount of glucocorticoid required tosuppress excess androgen production. There is adelicate balance to strike between the prevention ofandrogen induced rapid growth with advancedskeletal maturation on the one hand and theinhibition of normal growth from excessive gluco-corticoid replacement on the other.

Several glucocorticoid preparations have beentried as regular replacement treatment in congenitaladrenal hyperplasia. Their relative potencies in

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Table 3 Potency of steroid preparations used incongenital adrenal hyperplasia

Steroid Potency

Cortisol 1-0Cortisone 0 8Prednisolone 5-0Prednisone 4 0Dexamethasone 80-09a-Fludrocortisone 10-0

Cortisol is arbitrarily assigned a value of 1 for glucocorticoidpotency.

relation to cortisol (hydrocortisone) are shown intable 3. I favour the continued use of hydrocortisonethroughout childhood and puberty until staturalgrowth is almost complete. A dose as low as 12-15mg/m2/day is often sufficient but the treatment foreach individual needs to be tailored according to ageappropriate growth rates and various steroid indicesof control (see later). The daily amount of hydro-cortisone needs to be given in two or three divideddosages; it is customary to administer 50% of thedaily dose at bedtime but there is no evidence thatthis achieves any better control. Cortisone acetate isusually equally effective but hepatic conversion toactive cortisol may be unpredictable in some patients.Prednisolone is used for some to attenuate thepronounced rise in precursor steroid concentrationswhich occur during the night time hours.When statural growth is complete, dexamethasone

is an effective form of treatment to use in the longterm. The longer biological half life (about threeand a half hours? allows medication to be adminis-tered only once, 2 or at the most, twice daily. Singledaily medication should probably be given in themorning in a maximum dosage of 0-01 mg/kg/day orabout 0*25-0*5 mg/day. The individual dosagerequirement to achieve adequate control in con-genital adrenal hyperplasia can be quite variable.Certainly the potency of dexamethasone relative tocortisol is about 80:1 rather than the figure of 30:1quoted in standard texts. Treatment with dexa-methasone is particularly effective in regulatingmenses and ensuring ovulation in postmenarchalwomen with congenital adrenal hyperplasia. 13 Otherless conventional forms of medical treatment forcongenital adrenal hyperplasia include the use ofcyproterone acetate to block the tissue action ofandrogens and long acting analogues of luteinisinghormone releasing hormone, to slow down pubertyin patients who have an advanced bone age.'4Most patients with 21-hydroxylase deficiency are

probably salt losers if a sensitive index such asplasma renin activity is used to assess mineralocorti-

coid secretion.15 A previous annotation in thisjournal recommended that mineralocorticoid re-placement could be discontinued for salt losinginfants in later childhood.16 The practice is poten-tially dangerous as any reduction in an acquired highsalt intake can precipitate an adrenal crisis.Mineralocorticoid replacement should continue as9a-fludrocortisone in a daily dosage of 0*1-0-15 mg.When adequate mineralocorticoid treatment isgiven, improved linear growth often occurs.17 Theprinciples of glucocorticoid replacement in con-genital adrenal hyperplasia due to 1-hydroxylasedeficiency are the same. Suppression of the increasedconcentration of deoxycorticosterone, a potentmineralocorticoid, sometimes precipitates a saltlosing crisis.

How should control be monitored?

Clinical parameters of control in congenital adrenalhyperplasia include measurement of growth velocityand skeletal maturation (bone age), signs of hyper-cortisolism (striae, weight gain, hypertension), andnoting the pattern of menses in postpubertalwomen. These are essential to monitor regularly butthe parameters are insensitive indicators of controlin the short term and are of necessity retrospective.Assessment of skeletal maturity is unreliable duringinfancy at a time when satisfactory control isessential if normal growth is to be sustainedthroughout childhood and adolescence. The out-come for adult height in the first generation ofpatients treated regularly with glucocorticoid re-placement has generally been unsatisfactory.18 19Irregular menses and infertility in both sexes havebeen additional problems.

Several steroid parameters have been used tomonitor adequacy of treatment in congenital adrenalhyperplasia. Urinary 17-oxosteroid andpregnanetriolexcretion is an insensitive index of control and isseldom used now. Single random determinations ofplasma 170H-progesterone concentrations are diffi-cult to interprete because of the combined influencesof stress, an intrinsic circadian rhythm, and thetiming of previous glucocorticoid medication onadrenal steroid hormone concentrations. A veryhigh early morning concentration of 170H-progesterone can fall to normal values by lateafternoon even in a poorly controlled patient. Theinterpretation of a single estimation of 170H-progesterone would clearly be quite different forsamples collected in morning and afternoon clinics.The problem can be circumvented by the use ofdaily profiles of 170H-progesterone. The availabilityto measure this steroid in filter paper blood spotsand saliva makes it possible for frequent, serial

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Management of congenital adrenal hyperplasia 1403

samples to be collected at home by patients withcongenital adrenal hyperplasia of all ages.

Pictorial nomograms of 170H-progesterone rhythmshave recently been constructed to interpret the dailyprofiles of blood spot and saliva 170H-progesteronemeasurements in individual patients with congenitaladrenal hyperplasia.20 The magnitude of thecircadian rhythm is an important index of control.The disappearance of the rhythm is an early sign ofovertreatment. Table 4 contains examples of profilestypical of various categories of control in congenitaladrenal hyperplasia. Plasma testosterone measure-ment is also a useful marker of control and can beused singly as the concentrations do not fluctuate aswidely as 170H-progesterone. If daily 170H-progesterone profiles are not used, then a singleplasma measurement of this steroid and testosteroneat 0800 hours is often informative. Adequate controlis indicated by 170H-progesterone concentration inthe range of 30-70 nmol/l in blood, 260-1000 pmol/lin saliva, and plasma testosterone concentrations<0-5 nmol/l (prepubertal children) and between1-0-2-5 nmol/l (pubertal females). Measurement ofplasma testosterone is of no value in the pubertalmale due to the increasing contribution of testosteronefrom the testis which occurs at this age. Androstene-dione is also an index of adrenal androgen secretionand is an alternative marker to monitor control incongenital adrenal hyperplasia.21 22Measurement of plasma electrolytes is an insensi-

tive index of mineralocorticoid replacement incongenital adrenal hyperplasia. Sufficient mineralo-corticoid should be prescribed to maintain levels ofplasma renin activity within a range appropriate forage. This applies particularly during infancy whenconcentrations up to 20 pmol/ml/hour are observedfor normal infants. Measurement of plasma 11-deoxycortisol and testosterone are indices of controlin congenital adrenal hyperplasia due to ll,-hydroxylase deficiency.

Prenatal diagnosis and treatment

Considerable information has been gathered on thegenetics of congenital adrenal hyperplasia in recentyears and the interested reader is referred to twoexcellent reviews of the subject.23 24 Measurementof the concentration of 170H-progesterone inamniotic fluid collected during the second trimesterof pregnancy is a reliable test for the prenataldiagnosis of 21-hydroxylase deficiency.25 However,this is too late to prevent virilisation of an affectedfemale by giving oral dexamethasone to the mother.HLA typing of amniotic cells can also be used forprenatal diagnosis but the method is technicallymore complex and the result may be misleading.

Table 4 Typical daily profiles of 170H-progesterone incongenital adrenal hyperplasia related to degree of control

Time Undertreated Adequately treated Overtreated(hours)

Blood Saliva Blood Saliva Blood Saliva

0800 70-240 6000 30-70 1000 <10 5001200 15-140 4000 <15 500 <5 <1501800 10-100 2500 <10 200 <5 <1502200 10-20 2000 <10 150 <1 <150

The values given are only guidelines. Concentrations of170H-progesterone in blood are in nmol/l and in saliva in pmol/l,respectively.

Analysis of a chorionic villus biopsy using DNArestriction fragment length polymorphisms wouldallow earlier prenatal diagnosis. The current cDNAprobes for the 21-hydroxylase gene, however, showhomozygous deletions in only a minority of patientswith congenital adrenal hyperplasia. The analysisdoes allow for earlier fetal karyotype determinationwhich will affect the need for prenatal treatment.One option in the 'at risk' pregnancy is to startmaternal dexamethasone treatment (0-5-1F0 mgdaily) empirically as early as 5 weeks' gestation anddiscontinue treatment for 10 days before an amnio-centesis is performed at 16 weeks for steroidestimation. Treatment can be restarted if the concen-tration of 170H-progesterone is raised and the fetusis female. There are only isolated reports of thesuccess of this treatment. Generally, there is areduction, but not a complete absence, in virilisationof the female external genitalia.

Newborn screening

The incidence of congenital adrenal hyperplasiabased on several pilot newborn screening pro-grammes is about 1 in 10 000 white births, but ashigh as 1 in 230 among the Yupik Eskimos.Measurement of 170H-progesterone in a filter paperblood spot sample is simple to perform. However,false positive results are sometimes observed in sickpreterm infants. Table 5 lists the problems which are

Table 5 Problems potentially avoidable with newbornscreening for congenital adrenal hyperplasia

Salt wasting crisisInappropriate diagnosis and treatment of 'pyloric stenosis'Inappropriate gender assignmentPrecocious pubertyStunted growthSudden death

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potentially avoidable if screening for congenitaladrenal hyperplasia was practised routinely. Evenso, the incidence of cases that would not be detectedclinically must be very low. A retrospective surveyof a large number of patients with congenitaladrenal hyperplasia in Birmingham showed animprovement in early diagnosis in children bornafter 1970.26 The authors concluded that in countrieslike the United Kingdom, where a rapid 170H-progesterone measurement is readily available,neonatal screening for congenital adrenal hyperplasiawas not necessary.

Conclusion

Congenital adrenal hyperplasia is an uncommonchronic disorder which will present in the newbornnursery only about once every two years even in thebusiest maternity unit. A high clinical index ofsuspicion should be maintained for all infants withabnormal genitalia and boys who fail to thrive. Thediagnostic tests are readily available and reliable.Treated patients should expect a normal life spanand reproductive potential. This can be achieved bycareful attention to regular measurements of clinicalparameters of control and supplemented with theuse of more modern and sensitive biochemicalindices of control.

References

Finkelstein M, Schacfer JM. Inborn errors of steroid hiosyn-thesis. Phvsiol Rev 1979;59:353-406.

2 Dupont B, Oberfield SE. Smithwick EM. Lec TD, Levine LS.Close genetic linkage betwcn HLA aind congenital adrenalhyperplasia (21-hydroxylase deficiency). Lancet 1977jii:130)9-11.

3 Jonies I1W .Jr. A lonig look at the adrcrnogenital syndromic. JohnisHopkins Medical Jourtnal 1979; 145:143-9.

4 Murtaza L. Sibert J. Hughcs IA. Balfotr IC. Congenital adrenalhypcrplasia-a clinical and genetic survey. Are we detectingmale salt-losers'? Arc/h Dis Child 198();55:622-5.Kohn B. Lcvine LS. Pollack MS. et il. Latc-onset steroid 21-hydroxylasc deficiency: a variant of' classical congenital aidrenalhyperplasia. J Cliii ELndocrintol Metab 1982;55:817-27.Zachmann M, Tassinari D. 1'rader A. Clinical and biochemicalvariability of congcnital adrenal hyperplasia due to 1113-hydroxylase dcficiency. A sttudy of 25 paticnts. J Clii EtIdo-criniol Metaib 1983 ;56:222-8.

7 H ughes IA. Riad-Fahmv D, Grif't'iths K. Plasmna 17fH-progcstcronc concentrations in newborn infants. Arcli l)iN Child(1979;54:347-9.Dyias J. Rcad GF, Maulik TJ. Hughes IA. Riad-Fahmv D. Araipid assasy for 170)H-progcsteronc in plasma. saliva and

amniotic fluid using a magnctisable solid-phase antiserum. AlinC/iin Biochein 1984;21:417-24.Murphy JF, Joyce B, Dyas J, Hughes IA. Plasma 17-hydroxyprogesterone concentrations in ill newborn infants.Arch Dis Child 1983;58:532-4.Hughes IA, Winter JSD. Early diagnosis of salt-losing con-genital adrenal hyperplasia in a newborn boy. Can Med Assoc J1977;117:363-5.Kenny FM, Preeyasombat C, Migeon CJ. Cortisol productionrate. 11. Normal infants, children and adult. Pediatrics 1966;37:34-42.

12 Young MC, Cook N, Walker RF, Riad-Fahmy D, Hughes IA.Pharmacokinetics of dexamethasone in congenital adrenalhyperplasia. J Endocrinol 1988;117(suppl): 50.

13 Hughes IA, Read GF. Menarche and subsequent ovarianfunction in girls with congenital adrenal hyperplasia. Horm Res1982; 16: 100-6.

4 Pecovitz 011, Comite F, Cassorla F, et al. True precociouspuherty complicating congenital adrenal hyperplasia: treatmentwith a luteinizing hormone-releasing hormone analog. J ClinEnidocrinol Metab 1984;58:857-61.

5fHughes IA, Wilton A, Lole CA, Gray OP. Continuing need formineralocorticoid therapy in salt-losing congenital adrenalhyperplasia. Arch Dis Child 1979;54:350-5.

16 Newns GH. Congenital adrenal hyperplasia. Arch Dis Child1974;49:1-3.

7 Jansen M, Wit JM, Van Den Brande JL. Reinstitution ofmineralocorticoid therapy in congenital adrenal hyperplasia.Effects on control and growth. Acta Plaediatr Scand 1981;70:229-33.

1x Klingensmith GJ, Garcia SC, Jones HW Jr, Migeon CJ, BlizzardRM. Glucocorticoid treatment of girls with congenital adrenalhyperplasia; effects on height, sexual maturation, and fertility.J Pediatr 1977;90:99641004.

19 DiMartino-Nardi J, Stoner E, O'Connell A, New MI. The effectof treatment on final height in classical congenital adrenalhyperplasia. Acta Enidocriniol [Suppl/ (Copenih) 1986;279:30-5-14.

21) Young MC, Robinson JA, Read GF, Riad-Fahmy D, HughesIA. 170H-progesterone rhythms in congenital adrenal hyper-plasia. Arch Dis Child 1988;63:617-23.

21 Korth-Shutz S, Virdis R, Saenger P, Chow DM, Levine LS,New MI. Serum androgens as a continuing index of adequacy oftreatment of congenital adrenal hyperplasia. J Clini EnidocriniolMetab 1978,46:452-8.

22 Young MC, Walkcr RF, Riad-Fahmy D, Hughcs IA. Andros-tencdione rhythms in saliva in congenital adrenal hyperplasia.Arc-h Dis Child 1988;63:624-8.

23 Miller WL, Lcvine LS. Molccular and clinical advances incongenital adrenal hyperplasia. J Pediatr 1987;111:1-17.

24 White PC. New MI, Dupont B. Congenital adrenal hyperplasia.N Etngl J Med 1987;316:1519-24, 15811-6.

25 Hughes IA, Dyas J, Riad-Fahmy D, Laurence KM. Prenataldiagnosis of congenital adrenal hyperplasia: reliability of amnio-tic fluid steroid analysis. J Med Genet 1987;24:344-7.

26 Virdi NK, Rayner PHW, Rudd BT, Green A. Should we screenfor congenital adrenal hyperplasia? A review of 117 cases. ArchDis Child 1987;62:659-62.

Correspondence to Dr IA Hughes, Department of Child lhealth,University of Wales College of Medicinc, Heath Park. Cardiff CF44XN.

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