Egyptian Pediatric Association Gazette (2013) 61, 57–62

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FULL LENGTH ARTICLE

Growth in infants with congenital adrenal hyperplasia

due to 21-hydroxylase deficiency: An analysis

of the factors affecting height

Mona Mamdouh Hassan, Amany Ibrahim, Amina Abdel-Salam *, Hamsa Huthail

The Diabetes Endocrine and Metabolism Pediatric Unit, New Children’s Hospital, Cairo University, Cairo, Egypt

Received 20 August 2013; accepted 5 October 2013Available online 29 October 2013

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KEYWORDS

Factors affecting;

Growth;

Congenital adrenal hyper-

plasia;

Salt wasting;

Glucocoticoids;

Infancy

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eesh), Cairo University H

x 11562, Cairo, Egypt.

27816560.

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anyatt@yahoo.com (A. Ib

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Abstract Background: It has been suggested that overtreatment of infants with congenital adrenal

hyperplasia (CAH) due to 21-hydroxylase deficiency might affect their growth and final height.

Objective: To assess the axiological parameters of infants with CAH due to 21-hydroxylase defi-

ciency from their first presentation in neonatal period and during infancy, in an attempt to decide

the optimum doses of glucocorticoid, mineralocorticoid and salt therapy that can achieve androgen

suppression, prevent life-threatening salt-wasting crises, and allow normal growth velocity for age.

Materials and methods: Retrospective study conducted in the Diabetes Endocrine and Metabolism

Pediatric Unit at Children’s Hospital, Cairo University included baseline and follow-up data of 28

infants with 21-hydroxylase deficiency.

Results: Median age at presentation was 34 days. Lower doses of hydrocortisone (<20 mg/m2/

day) were associated with better growth, not reaching a statistical significance. Delta change in

length standard deviation score (SDS) was significantly higher in males (p= 0.01). Delta change

in length and weight SDS of cases with mean basal length SDS below �2 were significantly higher

than those with mean basal length SDS above �2 (p= 0.02 and 0.04 respectively). No correlations

w Children Hospital (Abu El

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58 M.M. Hassan et al.

were found between delta height-SDS and age at diagnosis, duration of follow-up, glucocrticoid or

mineralocorticoid dosing.

Conclusion: Poor growth in infants with salt wasting CAH was not related to age at diagnosis and

start of therapy, doses of glucocorticoid, fludrocortisones, or saline therapy. Male sex and mean

basal length SDS below �2 were associated with a more favorable growth catch up. Further

prospective studies with inclusion of intercurrent illnesses and nutritional status are needed.

ª 2013 Production and hosting by Elsevier B.V. on behalf of The Egyptian Pediatric Association.

Introduction

Congenital adrenal hyperplasia (CAH) is an autosomal reces-sive disorder due most commonly, to deficiency of 21-hydroxylase(21-OH) enzyme action that typically reduces cortisol and

aldosterone secretion while simultaneously increasing andro-gen production.1 Growth is considered a key concern in themanagement of congenital adrenal hyperplasia (CAH), as in-

fants often fail to reach their target height. Treatment ofCAH is based on the administration of glucocorticoid andmineralocorticoid, which decrease ACTH-stimulated excessof adrenal androgen. Higher doses of hydrocortisone may be

needed to achieve satisfactory androgen suppression, with sub-sequent hypercortisolism.2,3 The combination of hyperandrog-enism and hypercortisolism most likely explains the short adult

stature frequently observed in treated children with CAH.4

Whether this decreased height potential is caused by inade-quate suppression of adrenal androgens, excess steroid treat-

ment or the salt wasting state itself is a matter of debate.5

Current evidence suggests that infancy and peripubertalperiods are the time periods when height outcome is most sen-

sitive to glucocorticoid dose.6,7 Individualized treatment ap-proaches have been suggested to prevent growth failure.8

Monitoring of treatment during these critical periods is largelybased on the assessment of a certain biochemical investigation

with growth velocity and skeletal maturation. The growthvelocity and skeletal maturation are the most accurate predic-tors of long-term outcome of somatic growth.9

In this study we aimed to assess the axiological parametersof infants with congenital adrenal hyperplasia from their firstpresentation in the neonatal period and during infancy, in an

attempt to decide the optimum doses of glucocorticoid, miner-alocorticoid and salt therapy that can achieve androgen sup-pression, prevent life-threatening salt-wasting crises, andallow normal growth velocity for age.

Subjects and methods

This was a retrospective study that included 28 infants {21females (46, xx), and 7 males (46, xy)}. The infants were diag-nosed as congenital adrenal hyperplasia and were followed-upregularly at The Diabetes Endocrine and Metabolism Pediatric

Unit (DEMPU), Children’s Hospital of the Cairo University.The study protocol was approved by the University’s ResearchEthics Committee and was conducted in accordance with the

University’s bylaws for human research.The records of all infants and the baseline and data of fol-

low-up visits were reviewed with emphasis on the age at pre-

sentation, sex of rearing, presenting complaint, salt wastingsymptoms and signs, parental consanguinity, family historyof CAH or any abortion or prenatal death. The number of salt

wasting crises and number of admissions since start of therapy

for each patient were also recorded.All anthropometric data including length, weight at base-

line and at follow-up visits were reviewed. The supine lengthwas measured by using a Harpenden infanotometer and the

weight was measured by using an electronic digital scale. Mea-surements were taken and recorded every 3 months and theGrowth vision computer software provided by Novo Nordisk

was employed to assess length standard deviation score (SDS)and weight SDS to assess linear growth and weight gain foradjustment of the daily hydrocortisone dose.

According to the protocol adopted at our unit (DEMPU),all infants were treated with daily SC/IM hydrocortisone ther-apy calculated in mg/m2/day and given in two equally divided

doses till the age of 9 months, then on oral hydrocortisone (lo-cally manufactured Micort tablets, 10 mg/tab) with the totaldaily dose divided three times daily. They were also given dailyoral fludrocortisone at a dose of 0.05–0.15 mg and advised dai-

ly salt therapy. Hydrocortisone doses were adjusted so that17OH progesterone done every 3 months reaches target levelof biochemical control (5–10 ng/ml, 15.2–30.3 nmol/L), and

salt wasting crises are prevented. Hydrocortisone doses weredoubled with intercurrent illnesses or surgery to be returnedto original dose after recovery after recovery.

Statistical analysis

For statistical analysis the mean values of the daily hydrocorti-

sone and fludrocortisone doses were calculated for the wholeperiod of the follow up included in the study. Datamanagementand analysis were performed using SPSS for windows, version11.0.0. The numerical data were statistically presented in terms

of range, mean, standard deviation, median and interquartilerange (IQR). Categorical data were summarized as percentages.Comparisons between numerical variables within groups

at two different time points were done by Student’s pairedt-test for parametric data or Wilcoxon Signed Rank test fornon-parametric data. Comparisons between numerical vari-

ables of two groups were done by Student’s unpaired t-testfor parametric data or Mann–Whitney Rank Sum test fornon-parametric data. Correlations were tested by Pearsonco-efficiency for parametric variables and Spearman’s rank corre-

lation test for non-parametric variables.10 All p-values are twosidedand considered significantwhen p-values were less than 0.05.

Results

Table 1 illustrates the general characteristics and growthparameters during the studied period. The mean dose of

hydrocortisone therapy was 20.2 ± 6.1 mg/m2/day (range:8.6–36 mg/m2/day), and for fludrocortisone therapy the mean

Table 1 General characteristics, basal and final anthropometric data of the studied cases (n= 28).

General characteristics of the studied cases (n= 28)

Genetic sex:

Males (n;%) 7 (25%)

Females (n;%) 21 (75%)

Initial sex of rearing:

Males (n;%) 17 (60.7%)

Females (n;%) 11 (39.3%)

Age at presentation (days):

Median (range & IQRa) 34 (range: 7–180, IQRa: 14.25–80)

Presenting complaint:

Salt-wasting (n;%) 17 (60.7%)

Ambiguous genitalia (n;%) 11 (39.3%)

Duration of follow-up (mos):

Median (range) 13.14 (range: 10–23, IQR*: 1.05–1.37)

Parental consanguinity (n;%) 17 (60.7%)

+ve FHb of CAHc (n;%) 11 (39.3%)

Basal Final Delta change p-Value

Length SDSd: Mean ± SD �2.3 ± 1.7 �2.0 ± 1.5 0.3 ± 1.5 0.100

Weight SDSd:

Mean ± SD �1.7 ± 1.5 �1.6 ± 1.1 0.1 ± 1.1 0.442

Growth velocity cm/year:

Mean ± SD 13.6 ± 4.7

Growth velocity SDSd:

Mean ± SD �0.2 ± 1.6

a IQR: interquartile range.b FH: family history.c CAH: congenital adrenal hyperplasia.d SDS: standard deviation score.

Growth in infants with congenital adrenal hyperplasia due to 21-hydroxylase deficiency 59

dose was 24.6 ± 8.8 lg/m2/day (range: from 11.5 to 41.0 lg/m2/day). Mean length SDS at the end point was higher, with

a delta change 0.3 ± 1.5 (mean ± SD), but not reaching a sta-tistical significance (p = 0.1). The mean weight SDS showedan insignificant improvement from �1.7 ± 1.5 SDS at the

start to �1.6 ± 1.1 SDS by the end of the studied period(p= 0.4) with no detectable increase in weight in 7 infants(25%) during the studied period.

Salt losing symptoms and signs were the most common pre-

sentation followed by ambiguous genitalia. The median age atpresentation was 34 days (range 7–180 days). Genital ambigu-ity was overlooked in 10/21 (47.6%) females with incorrect

male gender assignment and delay in diagnosis. Delay in diag-nosis was also found in 5/7 (71.4%) males who were misdiag-nosed as sepsis, gastroenteritis and other conditions, with a

delay in diagnosis to up to 180 days (6 months). Parental con-sanguinity was found in 60.7%, and positive family history ofsimilar condition was found in 39.3% of subjects.

Fourteen infants (50%) were controlled on a mean hydro-

cortisone dose <20 mg/m2/day, while the other 14 infants(50%) needed a mean dose P20 mg/m2/day. The length andweight SDS of both groups showed statistically insignificant

changes from baseline to the end of the follow up period. How-ever, those on low dose showed improvement in both linearand ponderal growths although not reaching a statistical sig-

nificance. Salt-receiving (n = 18) and non salt-receiving infants(n= 10) showed insignificant changes in their length SDS(p= 0.6, 0.08 respectively), but non salt-receiving infants

(n= 10) showed a significant increase in their weight SDS(p= 0.048), (Table 2).

Males had a significant increase in their length and weightSDS on steroid therapy (p = 0.001, 0.04, respectively) while fe-

males showed insignificant changes. The length and weightSDS of infants with a basal mean Ht SDS P �2 (n = 11)

showed insignificant changes from baseline measurements tothe end of the follow up period (p= 0.4 and 0.2 respectively).While, the length SDS of cases with basal mean Ht SDS below

�2 (n= 17) showed a significant increase at the end of the fol-low up period (p= 0.03), but the weight SDS showed an insig-nificant decrease (p= 0.1), (Table 2).

The delta length SDS and delta weight SDS, growth veloc-

ity and growth velocity SDS showed insignificant differences inrelation to hydrocortisone dosing or salt supplementation (Ta-ble 3). While the delta change in length SDS was significantly

higher in males when compared to females (p = 0.01). The del-ta change in weight SDS, growth velocity and growth velocitySDS were comparable between both sexes (p = 0.2, 0.1, and

0.09 respectively). The delta change in length and weightSDS were significantly higher in infants with basal mean HtSDS below �2 compared to those with basal mean Ht SDSabove �2 (p= 0.02 and 0.04 respectively) (Table 3).

A significant proportionate correlation was found between Dlength-SDS and D weight-SDS (r= 0.5, p= 0.006), as well asgrowth velocity (r= 0.7, p less than 0.001).A significant propor-

tionate correlation was also found between D weight-SDS andduration of follow-up (r= 0.5, p= 0.04). No significant corre-lation was found between either D length-SDS or D weight-SDS

and hydrocortisone or fluodrocortisone doses. Other tested cor-relations were not statistically significant (Table 4).

Discussion

To our knowledge, there are few previous reports of growthparameters in infants with 21-OHD 11–13. It is not clear which

Table 2 Comparison of length SDS & weight SDS before the start of treatment and at the end of the study period among subgroups

(n= 28).

Before the start of steroids At the study period p-Value

Mean ± SD Mean ± SD

Groups Length SDSa

Low HCb dose (<20 mg/m2/day) (n= 14) �2.6 ± 1.7 �2.0 ± 1.7 0.077

High HCb dose(P20 mg/m2/day) (n= 14) �2.1 ± 1.6 �2.0 ± 1.3 0.821

Salt-receiving (n= 18) �2.3 ± 1.8 �2.1 ± 1.6 0.560

Non-salt-receiving (n= 10) �2.5 ± 1.5 �1.8 ± 1.3 0.084

Males (n = 7) �3.4 ± 1.7 �2.0 ± 1.8 0.001 c

Females (n= 21) �2.0 ± 1.5 �2.0 ± 1.4 0.622

Basal height SDSa P�2 (n = 11) �0.66 ± 0.89 �1.04 ± 1.39 0.460

Basal height SDSa <�2 (n = 17) �3.44 ± 0.96 �2.58 ± 1.25 0.033 c

Weight SDSa

Low HCb dose (<20 mg/m2/day) (n= 14) �1.7 ± 1.7 �1.4 ± 1.2 0.420

High HCb dose (<20 mg/m2/day) (n = 14) �1.7 ± 1.2 �1.8 ± 1.0 0.868

Salt-receiving (n= 18) �1.5 ± 1.4 �1.7 ± 1.1 0.644

Non-salt-receiving (n= 10) �2.0 ± 1.7 �1.4 ± 1.1 0.048 c

Males (n = 7) �2.0 ± 1.8 �1.5 ± 1.4 0.039 c

Females (n= 21) �1.6 ± 1.4 �1.6 ± 1.0 0.897

Basal height SDSa P�2 (n = 11) �0.400 ± 1.339 �0.773 ± 1.184 0.233

Basal height SDSa <�2 (n = 17) �2.512 ± 0.863 �2.088 ± 0.625 0.111

a SDS: standard deviation score.b HC=Hydrocortisone.c p-Value is significant if <0.05.

Table 3 Comparison of anthropometric parameters of subgroups (n= 28).

Mean ± SD

D Length- SDSb D Weight-SDSb Growth velocity Growth velocity-SDSb

Low HCa dose (n = 14) 0.6 ± 1.2 0.3 ± 1.2 13.9 ± 5.0 0.3 ± 1.1

High HCa dose (n= 14) 0.03 ± 1.8 �0.04 ± 1.0 13.4 ± 4.5 �0.6 ± 1.9

p-Value 0.260 0.344 0.772 0.188

Salt-receiving (n= 18) 0.2 ± 1.4 �0.2 ± 1.0 13.1 ± 4.3 �0.03 ± 1.5

Non-salt receiving (n = 10) 0.6 ± 1.9 0.7 ± 0.9 14.6 ± 5.4 0.07 ± 1.91

p-Value 0.179 0.092 0.422 0.592

Males (n = 7) 1.4 ± 0.7 0.5 ± 0.5 16.1 ± 3.3 0.7 ± 1.0

Females (n= 21) �0.02 ± 1.60 �0.03 ± 1.2 12.8 ± 4.9 �0.5 ± 1.7

p-Value 0.012* 0.221 0.111 0.088

Basal Ht SDSb P�2 (n= 11) �0.47 ± 1.85 �0.37 ± 0.97 13.34 ± 5.39 �0.81 ± 1.82

Basal Ht SDSb <�2 (n= 17) 0.85 ± 1.08 �0.42 ± 1.03 13.84 ± 4.35 0.27 ± 1.34

p-Value 0.023 c 0.038 c 0.787 0.082

a HC= hydrocortisone.b SDS: standard deviation score.c p-Value is significant if <0.05.

60 M.M. Hassan et al.

factors contribute to growth impairment in CAH. Previousstudies investigated associations with clinical phenotype, age

at start of treatment, hormonal control, and glucocorticoidsdosage.14–18 It was suggested that the high hydrocortisonedoses used during infancy and early childhood, critical periods

of rapid growth, lead to growth suppression and may lead toan irreversible loss of adult length.19,20

In this retrospective study we have carried out a cross sec-

tional periodic evaluation of a longitudinal follow up, focusingon the effect of the dose of hydrocortisone on the growth rate of28 childrenwith the salt losing formof congenital adrenal hyper-plasia due to 21 hydroxylase deficiency. We analyzed these

parameters in relation to the dose of hydrocortisone, fludrocor-

tisone, salt supplementation, age at presentation and gender. Tonormalize data, length, weight, delta change and growth veloc-

ity were analyzed in terms of standard deviation scores (SDSs).Regarding sex preponderance, this study revealed a female

to male ratio of 3:1. This is similar to previous reports in which

the majority of cases were females.21,22 However, because thegene for this disorder is autosomally recessive, it occurs equallyin males and females. This female preponderance can be

explained by the fact that males are significantly under-diagnosed and that some of the affected males die without acorrect diagnosis as they present only with salt losing crisisand with no genital ambiguity that arouses suspicion of par-

ents or physicians.23

Table 4 Correlations of D Length-SDS and D Weight-SDS

and other clinical variables.

D Length- SDS a D Weight-SDS a

r-Coeff. p-Value r-Coeff. p-Value

D Weight-SDSa 0.510 0.006b – –

Age at presentation 0.144 0.511 0.297 0.168

Duration of follow-up 0.272 0.275 0.485 0.041b

Hydrocortisone dose �0.146 0.459 0.051 0.808

Fludrocortisone dose 0.064 0.765 0.310 0.141

Growth-velocity 0.286 0.140 �0.054 0.784

Growth-velocity SDS a 0.655 0.0002b 0.314 0.103

a SDS: standard deviation score.b p-Value is significant if <0.05.

Growth in infants with congenital adrenal hyperplasia due to 21-hydroxylase deficiency 61

The median age at presentation was 34 days (range 7–180 days). Genital ambiguity was overlooked in 10/21(47.6%) females with incorrect male gender assignment and

delay in diagnosis. Delay in diagnosis was also found in 5/7(71.4%) males who were misdiagnosed as sepsis, gastroenteri-tis and other conditions, with a delay in diagnosis to up to

180 days (6 months). Survival of those infants to that age in-spite of the missed diagnosis can be explained by their receiv-ing repeated fluid therapy and steroids empirically for otherillnesses. Parental consanguinity was found in 60.7%. Analo-

gous data have been reported by Bhanji and colleagues whofound parental consanguinity in 52% of cases,24 while this per-cent decreased to 33% in the study of Al-Maghribi.25 The high

rate of consanguinity in the Egyptian population might beresponsible for the high incidence of CAH and necessitates ge-netic counseling for affected families. Positive family history of

similar condition was found in 39.3% of subjects. This almostagreed with Bhanji and collegues who reported siblings with asimilar condition in 30% of their cases.24 However, we noted

that the presence of a similar condition did not help in earlydiagnosis, as 6 out of 11 (54.5%) with a positive family historyremained unrecognized within the 1st month of life.

Salt losing symptoms and signs were the most common pre-

sentation followed by ambiguous genitalia, with unrecognizedambiguity and incorrect gender assignment in 10/21 (47.6%)females. This is different from the observations of Torok

et al.22 and Al-Maghribi,25 who reported genital ambiguityas the most common presentation followed by salt losingmanifestations.

All of the infants received hydrocortisone therapy in amean dose of 20.2 ± 6.1 mg/m2/day (range: 8.6–36.0 mg/m2/day), with fludrocortisone therapy in a mean dose of24.6 ± 8.8 lg/m2/day (range: 11.5–41.0 lg/m2/day), and in

18 infants (64.3%) parents supplied regular supplemental salttherapy.

On revising the growth parameters among our case series,

we found that the mean length and weight–SDS were negativebefore and remained so after therapy with an insignificant in-crease. A catch up effect was observed during the studied per-

iod as the delta length SDS and delta weight SDS reachedpositive values. The mean growth velocity of infants undertreatment was 13.643 ± 4.696 but growth velocity-SDS was

still negative (�0.154 ± 1.605). Six infants (21.4%) lengthdid not increase during the studied period, all of them weregirls with 5 on salt supplementation and 4 on hydrocortisonemore than 20 mg/m2/24 h.

The mean length SDS in our study was much lower thanthat reported by de Almeida and associates;26 and Volklet al.27 but slightly lower than that reported by Aycan and col-

leagues.28 This lower length SDS of our study populationmay be related to bad compliance and poor control withconsequent increased steroid dosage. Other factors such as

nutritional status, inter-current illnesses, and the differentgenetic growth potentials could contribute.

No correlations were found between D Ht-SDS, D Wt-SDS

or growth velocity and glucocrticoid dosing. This was in linewith Manoli et al.21 who found no correlation between hydro-cortisone dosage and weight SDS. But contradicts Jaaskelai-nen & Voutilainen,29 who reported a significant negative

correlation between the mean daily glucocorticoid dose andheight velocity in the first year of life. However, our cases withhydrocortisone dose less than20 mg/m2/24 h showed some

improvement in their length SDS and weight SDS over thestudied period although not reaching a statistical significance;which means that this group of infants showed an improve-

ment in their length SDS on treatment.On the other hand, caseswith hydrocortisone dosemore than

20 mg/m2/24 h showed minimal changes in length and weight

SDS at the end of the follow up period. In addition, the deltachange in weight, length SDS, growth velocity, and growthvelocity SDS of cases with low dose were higher when comparedto cases with higher doses but not reaching a statistical signifi-

cance. Two out of 14 (14.3%) cases on low cortisone dose hadpoor growth rate versus 4/14 (28.6%) of the high cortisone dosegroup (p= 0.6). These findings agree with Stikkelbroeck et al.

who reported that glucocorticoid dose has growth-suppressingeffects during the age interval of 6 months to 1 year.30

Speiser & White31 stated that salt intake may add some

adrenal suppression but our results did not confirm this find-ing. We found that the Ht-SDS showed statistically insignifi-cant changes from baseline to the end of the follow up

period in cases with or without salt supplementation. How-ever, cases without salt supplementation showed a significantincrease in their weight SDS over time. The delta length SDSand delta weight SDS, growth velocity and growth velocity

SDS showed insignificant differences in relation to saltsupplementation.

Males had a significant increase in their length and weight-

SDS after therapy and the delta change in length-SDS was sig-nificantly higher in males when compared to females. Our re-sults revealed that those who were initially shorter acquired

significantly more length by the end of the period of followup compared to infants who were not pathologically short.Also, the D length-SDS and D weight-SDS were significantlyhigher in the initially shorter group. We suggest that regardless

of the glucocorticoid dose, those who were initially pathologi-cally shorter gained a significantly higher (better) length SDScompared to those who were not pathologically short. Growth

velocity and growth velocity SDS were comparable betweenboth groups although GV and GVSDS were higher in the firstgroup but the difference did not reach a statistical significance.

The present study had some limitations being an observa-tional retrospective study. Also, it is to be mentioned that glu-cocorticoid and fludrocortisone doses were collected in detail,

based on patient records (prescribed doses), but no systematicinformation was available about compliance or about thefrequency of temporary overdosing with intercurrent illnesses,and assessment of nutritional status was not available.

62 M.M. Hassan et al.

Conclusions

In conclusion, infants with salt wasting CAH had poor lin-ear growth and gain of weight during infancy, which was

related neither to the age at diagnosis and start of therapy,nor to the doses of glucocorticoids, fludrocortisones, or sal-ine replacement therapy. More favorable growth catch up

was found in male infants, and in those pathologicallyshort at presentation and start of therapy. Lower dosesof hydrocortisone (<20 mg/m2/day), compared to higherdoses, were also associated with better growth, but not

reaching a statistical significance. Further prospective stud-ies with a larger number of cases and with inclusion ofintercurrent illnesses and nutritional status in infants with

CAH are warranted.

Conflict of interest

None.

Acknowledgements

We thank all infants and parents who participated in ourstudy. We would like to express our appreciation to our col-leagues and nurses at The Diabetes Endocrine and Metabolism

Pediatric Unit (DEMPU) who facilitated this work. This workwas not funded.

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