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Department of Pediatrics, University of Bologna and S. Orsola-Malpighi Hospital, 40138 Bologna, Italy
Address all correspondence and requests for reprints to: Prof. E. Cacciari, Dipartimento di Scienze Pediatriche Mediche e Chirurgiche, Az. Ospedaliera S. Orsola-Malpighi, Via Massarenti 11, 40138 Bologna, Italy. E-mail: antonio.balsamo{at}unibo.it.
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Abstract |
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2–3%) or compound heterozygous with any of the group A or B mutations; and group C (13 women and 7 men), homozygous for P30L or V281L or P453S mutations (RA, >30%) or compound heterozygous with any of the group A, B, or C mutations. Three patients showed unclassifiable genotypes. FH was similar in the female groups, whereas male patients in group B were shorter than males in groups A and C. Fifty-five percent of patients in group A, 33% in group B, and 40% in group C reached an FH within 0.5 SD of target height. Four of the 7 patients diagnosed via neonatal screening achieved an FH equal to or above the target height. In the entire group, early diagnosis (<1 yr) improved height outcome. Early diagnosed CAH patients who received lower cortisol equivalent doses during the first year of life reached a better FH. Our results underline the importance of mineralocorticoid therapy, as CAH subjects in groups A and B who did not receive this treatment showed reduced FH. Early diagnosis, the use of more physiological cortisol equivalent dosages during the first year of life, and the extension of mineralocorticoid therapy to all classical patients are shown to improve the auxological outcome. Genotypic analysis helped to interpret the height results of our cases and prospectively may represent a useful tool for improving the therapeutic choice and the height outcome. |
Introduction |
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Subjects and Methods |
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Group A (11 women and 9 men)
Group A consisted of patients homozygous or compound heterozygous for null (deletion, large/small conversion, Del8bp, CluE6) or In2 splice (In2) mutations [residual enzymatic activity (RA), <1%; Table 1
, cases 1–20) (7, 8).
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Group B consisted of 1) patients characterized by mutations determining a residual enzymatic activity of about 2% (I172N, R341P, and R426H) in homozygosity or compound heterozygosity with any of the group A or B mutations (Table 1
, cases 21–34); and 2) one neonatally virilized female patient with a nonclassifiable genotype and no salt wasting (Table 1, case 35).
Group C (13 women and 7 men)
Group C consisted of 1) patients homozygous for milder mutations (V281L, P30L, and P453S; RA, >30%) or compound heterozygous with a mild mutation in one allele and a mutation of either group B or A in the other (Table 1, cases 36–53); and 2) two female patients without genital virilization and with unclassifiable genotype (Table 1, cases 54 and 55), who clinically and hormonally fit the group [basal 17-hydroxyprogesterone (17OHP), 2500 ng/dl (75.6 nmol/liter) for case 54; basal/stimulated 17OHP, 500/2560 ng/dl (15.1/77.4 nmol/liter) for case 55].
Seven patients (Table 1, cases 3, 5, 8, 17, 28, 45, and 48) were diagnosed by Emilia-Romagna neonatal screening (4, 5).
The phenotype assignment reported in Table 1, reflects the clinical classification attributed at diagnosis before obtaining the results of genotype analysis.
Typical follow-up consisted of examinations at 3-month intervals in the first year of life and at 6-month intervals thereafter, with clinical checking (height, weight, and pubertal scoring), biochemical assessment [morning/pretherapy blood sample for ACTH, 17OHP, 
4-androstenedione (4A), testosterone, serum electrolytes, and plasma renin activity (PRA)], and bone age evaluation.
Growth was analyzed by examining longitudinal changes in statural growth and skeletal maturation and by comparing FH with target height (FH-TH). Height was considered adult when there were no changes in height for at least 1 yr or when radiographs showed epiphyseal fusion. TH was determined using standard equations (8). Growth data were plotted on Tanner and Whitehouse standard charts (9), and height SD scores were determined according to the same reference standards. These standards were used in our auxological analysis for two main reasons: 1) the recent Italian percentile charts (10) covered only the 6–20 yr age range; and 2) the suitability of the UK standards was verified by means of comparisons with the mean height of Italian conscripts born between 1960 and 1980 (Annuario Statistico Italiano; Edizioni 1983–2002) for males and adult height in recent Italian standards for females. Predicted heights were calculated using the Bayley-Pinneau tables (11), whose suitability for the Italian population was assessed by Vignolo et al. (12) and Aicardi et al. (13). Pubertal maturation was assessed by the Marshall and Tanner method (14, 15), whereas body mass index (BMI; kilograms per square meter) SD scores were calculated according to the reference standards of Roland-Cachera et al. (16) and Cacciari et al. (10) for children aged 0–6 and 6–20 yr, respectively.
Patients were treated with the doses of glucocorticoids and mineralocorticoids required to maintain normal growth rates, adrenal androgen levels, PRA secretion, and electrolyte levels. Before 1980, the most common glucocorticoid treatment during prepuberty and early puberty consisted of oral cortone acetate (C), administered two or three times a day, whereas after 1980 hydrocortisone was preferred. In late puberty and postpuberty, prednisone (P) or dexamethasone (D) was administered once or twice a day. Before 1971, SW patients were treated with daily NaCl supplement (1–3 g/d). Intramuscular injections of pancortivis (adrenal extracts containing hydrocortisone, deoxycorticosterone, aldosterone, and dehydroepiandrosterone) or deoxycorticosterone acetate were only used in cases of adrenal crisis. After 1971, fluorohydrocortisone (F), at oral doses ranging from 0.025–0.2 mg/once or twice a day was used. For cases 10, 12, 18, and 19, pancortivis and NaCl supplements were only used at diagnosis, with no further mineralocorticoid supplement thereafter. Mean dosages of glucocorticoids (milligrams per square meter per day) over the period of treatment were converted to milligrams equivalent of hydrocortisone according to potency ratios of 0.8 for C, 5 for P, and 80 for D (17), respectively. An adjunctive hydrocortisone equivalent dose, with a potency ratio of 10, was also calculated for F (18). Individual steroid therapy is reported in Table 1.
To slow the progression of puberty, two patients (Table 1, cases 7 and 54) were treated with medroxyprogesterone acetate from 6.0 and 4.4 to 7.0 and 7.2 yr of age, respectively; four patients (Table 1, no.17, 32, 34, and 40) were treated with GnRH analog at a constant dose of 3.75 mg/28 d from 6.7, 9.4, 9.5, and 7.8 to 9.3, 10.9, 10.5, and 12.3 yr of age, respectively. Patient 8, GH deficient according to both pharmacological (arginine peak, 5.3 ng/ml; L-dopa peak, 0.2 ng/ml) and physiological (mean nocturnal GH, 1.5 ng/ml) tests, was treated with synthetic human GH at a dosage of 5 mg/m2·wk from 8.2–13.7 yr of age.
After obtaining informed consent, we performed the genotype study in all patients and the parents by means of Southern analysis, specific PCR amplification, and direct sequencing of all the exonic and intronic CYP21 gene regions (5). Functional studies of enzymatic activity, recently performed in collaboration with the Karolinska Hospital of Stockholm and not yet published, indicated a 1–3% residual activity for the R341P and R426H mutations.
Patients were considered as diagnosed early or late if the age of diagnosis was before or after the first year of life. Data were analyzed with respect to sex (males vs. females), genotype/clinical form (SW, SV, or NC), time of diagnosis (early vs. late), height below or above -1 SD at 1 yr of age, and year of birth (before or after 1980, the first year of CAH neonatal screening). Hormonal control was assessed according to Cabrera et al. (19), who considered patients with 50% or more of the available baseline serum 17OHP concentrations of less than 1000 ng/dl and 4A concentration and PRA within normal age limits to be well controlled.
Results are presented as the mean ± SD. Differences between the groups, paired comparison of the parameters, and correlations between the parameters were assessed by t test or Kruskal-Wallis test, paired t test or Mann-Whitney test, and the r correlation coefficient or Spearman’s correlation test, according to the numerical distribution of the parameters, respectively. P 
0.05 was considered statistically significant.
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Results |
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Individual characteristics of the 55 patients are presented in Table 1. Mean neonatal weight was similar for both sexes in the 3 groups of patients (Table 2), although 3 newborns were small for gestational age (SGA) in the group A males (Table 1, no. 1, 2, and 16) as was 1 in the group C females (Table 1, no. 44). Age at diagnosis was similar in the 2 sexes in groups A and C, but was significantly higher in group B males than in females (Table 2; P < 0.05). BMI SD varied at diagnosis in males, with group A showing significantly lower values than groups B (Table 2; P < 0.05) and C (Table 2; P < 0.005). This difference was lost at the end of growth (Table 2).
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). Sixty-five percent of patients in group A (54.5% of the women and 77.7% of the men), 73.3% in group B (81.8% of the women and 50.0% of the men), and 90.0% in group C (84.6% of the women and 100% of the men) reached a FH above or equal to the third percentile according to Tanner (-1.8 SD) (9). A highly significant positive correlation was found between FH SD and TH SD in the patients as a whole (r = 0.731; P < 0.0001), although when divided according to sex and genotype group, this significant positive correlation was found only among female patients (r = 0.471; P < 0.002). Group A females (r = 0.738; P < 0.005) made the major contribution to this correlation. Fifty-five percent of group A patients (54.5% of the women and 55.5% of the men), 33.3% in group B (36.3% of the women and 25.0% of the men), and 40% in group C (38.4% of the women and 42.8% of the men) reached a FH within 0.5 SD of TH. FH was achieved at a similar age in the three male groups, whereas group A females reached FH later than those in group C (P < 0.05; Table 2). Sexual dimorphism in body height between boys and girls was reduced only in group B (normal subjects, 13.4 cm; group B, 5.3 cm).
Puberty and fertility
Analysis of pubertal parameters was carried out only for patients not treated with drugs to delay puberty. At the onset of puberty (breast stage 2), group A females were older than both groups B (P < 0.005) and C (P < 0.0001; Table 3). Groups A and B had menarche at a later chronological age (CA) than group C (the difference was significant only for group A; P < 0.01; Table 3).
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). However, the height age/bone age ratio was significantly higher in group A males than in group B males (0.96 ± 0.14 vs. 0.77 ± 0.13; P < 0.025).
The mean duration of puberty was similar in both sexes in the three groups. Group A females and group B males showed a significantly lower height gain during puberty than females in groups B/C and males in group C (Table 3).
Four females (Table 1, no. 9, 13, 39, and 47) became pregnant and gave birth to five children [four simple heterozygous subjects and one (Table 1, no. 50) compound heterozygous with an In2 mutation inherited from the mother (no. 13) and a V281L mutation inherited from the father]. None of the male patients have, as yet, fathered a child, and only one has declared fertility problems.
Height prediction
Predicted height calculated in prepuberty (mean CA: females, 7.4 ± 2.2; males, 7.3 ± 1.0 yr; Table 4) and at the onset of puberty (mean CA: females, 10.1 ± 2.0; males, 10.1 ± 2.0 yr) correlated with FH in females (prepuberty: r = 0.625; P < 0.0001; onset of puberty: r = 0.663; P < 0.0001). In males this correlation was significant only at the onset of puberty (r = 0.635; P < 0.01). Evaluation of the same correlation by sex and genotype showed that FH correlated significantly with predicted height in both prepuberty and early puberty in groups A (r = 0.759; P < 0.01 and r = 0.656; P < 0.05, respectively) and B (r = 0.670; P < 0.025 and r = 0.676; P < 0.025, respectively). Group C females showed this correlation only in early puberty (r = 0.645; P < 0.025). In males, this correlation was found only in group C in early puberty (r = 0.812; P < 0.05). Individual predicted height showed that 18 of 35 (51.4%) prepubertal females and 7 of 19 (36.8%) prepubertal males had a predicted height value within 5.1 cm (confidence limit given by Bayley and Pinneau) of their FH. Different percentages were obtained when using the predicted height of early pubertal patients (72.4% for females and 55.5% for males).
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The time of diagnosis was early in 28 and late in 27 patients regardless of genotype classification (Table 5). No differences were found between females and males within the same groups. However, in the group as a whole, the FH SD and FH-TH SD of the early diagnosed patients were both significantly higher than those of the late diagnosed patients (P < 0.05 and P < 0.025, respectively), especially in males (P < 0.005 and P < 0.05, respectively; Table 5).
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, no. 3, 5, 8, and 17). The only female in group B diagnosed via neonatal screening (Table 1, no. 28) showed FH SD and FH-TH SD above the mean control values. Among group C patients (Table 1, no. 45 and 48), case 48 showed -1.2 FH-TH SD, and case 45 achieved +1.0 FH-TH SD. A significant positive correlation (r = 0.626; P < 0.01) was found between height for CA SD (HCASD) at 1 yr of age and FH in classical patients (groups A and B). When we divided the classical patients into two groups according to height SD less than -1 (group 1) and more than -1 (group 2) at 1 yr of age, FH SD in group 1 patients (-0.57 ± 0.67) was higher than that in group 2 (-1.54 ± 0.53; P < 0.005). This difference can only partially be attributed to the better family height of the subjects in group 1 (TH SD: group A, -0.17; group B, -0.88), because the same group presented a lower FH-TH SD than group 2, although not significantly so (-0.39 vs. -0.70 SD).
Each group had different cortisol equivalent therapy (milligrams per square meter), calculated as mean integrated values during the first year of life (group 1, 34.5 ± 13.2; group 2, 44.2 ± 17.5 mg/m2·eq). Finally, there was an improvement in FH SD and FH-TH SD in the CAH patients born after 1980 (26 cases; -0.84 ± 0.96 and -0.46 ± 0.94, respectively) compared with those born before 1980 (29 cases; -1.25 ± 0.80 and -0.90 ± 0.83, respectively; P = NS). At least some of these differences can be attributed to the secular trend still active in the Italian population.
Mineralocorticoid therapy
Group A and B patients (classical forms) showed a negative correlation between the age of starting therapy with mineralocorticoids and FH SD (35 cases: r = -0.450; P < 0.01). Considering each sex separately, the same correlation still holds for both males (13 cases; r = -0.687; P = 0.005) and females (22 cases; r = -0.367; P < 0.05). When further subdivided into groups A and B, this correlation persisted only for group A males (r = -0.731; P < 0.025) and group B females (r = -0.537; P = 0.05).
A significantly higher FH was found in a group of 10 females treated early (<3 yr of age) with combined glucocorticoids and mineralocorticoids than in a group of 12 subjects who were either never (8 cases) or later (>5 yr of age; 4 cases) treated with mineralocorticoids (Table 6). This result can also be partially attributed to the later diagnosis of the latter group (Table 6). The only male patient in group B treated early with mineralocorticoids (Table 1, case 32) achieved the best FH of group B males.
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reports the mean cortisol equivalent dosage (milligrams per square meter per day) according to genotype clustering and year of follow-up. A tendency toward overdosage until 4–5 yr of life was evident. This is principally due to the higher doses used in the older patients (before 1980). The degree of hormonal control did not correlate with FH.
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Discussion |
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, nos. 23, 37, 43, and 51), to get a clearer picture of the clinical and auxological aspects of the disease. In our cases, in fact, a simple clinical classification (Table 1, phenotype column) would have blunted the differences between group B and C males and would not have enabled us to confirm the suitability of mineralocorticoid treatment also for patients who had no clear biochemical signs of salt wasting, but were carriers of severe mutations (RA, <3%). To achieve full height potential, in accordance with conventional therapy, growing CAH patients should be treated with glucocorticoid doses sufficient to suppress adrenal androgen oversecretion while avoiding delayed skeletal maturation and statural growth. Almost all patients affected by classical forms also need mineralocorticoid substitutive therapy (20). An optimal balance between the two extremes is difficult to achieve, and short stature is a common feature in CAH. Several growth studies on classical and nonclassical CAH have been carried out to date, but have been unable to provide clear evidence as to whether FH correlates with the clinical variant of the disease (21, 22) or not (23, 24, 25, 26), with age at diagnosis/treatment (1, 26, 27, 28) or not (23, 29), and with degree of hormonal control (1) or not (22, 23, 24, 30).
The results of the present observation are in line with the recent meta-analysis by Eugster et al. (1), which reported that FH in classical CAH is often within 1 SD of TH, with a mean weighted FH SD of -1.37 for all studies of classical patients. Our patients did, in fact, present FH-TH SD and FH SD of -0.57 ± 0.82 and -0.95 ± 0.76, respectively, for group A (SW), -0.93 ± 0.87 and -1.36 ± 0.95 for group B (SV), and -0.56 ± 0.94 and -0.85 ± 0.86 for group C (NC).
Evaluating our own data according to sex and genotype, the most significant loss of FH occurred in group B males, who were significantly shorter than the other males and, in terms of FH SD, were also shorter than the group B females. The better height outcome of the group A males and group B females compared with the group B males may depend on the significantly earlier diagnosis/start of therapy. Regarding the group C males, who were diagnosed at CAs similar to the group B males and were clearly differentiated by genotype analysis, the differences in bone age at diagnosis (11.7 ± 2.0 vs. 13.0 ± 3.7 yr) and the longer duration of the growing period (10.2 ± 2.1 vs. 9.0 ± 2.5 yr) may partially explain their better FH achievement. A further explanation for these differences may be found in the error of not prescribing mineralocorticoids to patients diagnosed as SV (i.e. not SW). In fact, none of the male patients in group B, except one (Table 1, case 32), was given early treatment with mineralocorticoids. In the past, classical CAH patients were classified as SW or SV according to the presence or absence of clear signs of sodium depletion, and gluco-plus mineralocorticoid replacement therapy was usually only prescribed for the former patients. Moreover, difficulties relating to the availability of oral mineralocorticoids has meant that mineralo-active drugs were less frequently used than today. In 1977, some researchers (20) demonstrated that patients considered SV may also suffer from some subtle impairment of aldosterone biosynthesis and recommended mineralocorticoid treatment for these patients also. This recommendation was confirmed by our analysis of the response to treatment of group A and B females treated before or after 3 yr of age with combined glucocorticoid plus mineralocorticoid therapy. Those treated with mineralocorticoids after 3 yr of age or who were never given this treatment can be retrospectively considered to have received inappropriate treatment. Comparison of this group with those that were appropriately treated shows that the latter had significantly better height outcome.
Similar results were found by Manoli et al. (21) in SV males and by Di Martino-Nardi et al. (23) in female vs. male SV patients, whereas Hargitai et al. (31) found no significant differences. The latter study found no significant correlations between FH and age of starting therapy in the SV clinical form. Cabrera et al. (19), like Hargitai et al. (31), reported no differences between SW and SV males, whereas in our study the latter turned out to be significantly shorter, a result also reported by Styne et al. (30).
When female patients were compared by genotype, no differences were found in the initial or final auxological parameters, apart from differences in age at diagnosis.
The number of SGA newborns was higher in group A males, possibly reflecting the inability of fetuses to thrive in cases of severe adrenal insufficiency. The significantly lower BMI SD found in these patients may be the result of a low neonatal weight, which had not yet been regained by the SGA children at the time of diagnosis. Unfortunately, we do not have enough data on the neonatal length of our patients to be able to confirm the report by Jaaskailaineen et al. (27) that these newborns are longer than the general population.
The BMI SD at the onset of puberty and that at FH were similar for all of our patients, which means that the previously reported weight gap had already been regained during prepubertal growth.
In our retrospective review, patients diagnosed before 1 yr of age had a better FH outcome than those diagnosed later, a finding in line with work by Bergstrand et al. (22), Brook et al. (32), and Eugster et al. (1), but in contrast with that of Di Martino-Nardi et al. (23), Urban et al. (33), Kirkland et al. (24), New et al. (34), and Styne et al. (30).
The main evidence of lower FH outcome can be seen in the group of males treated late. Females in the same group also had lower FH SD scores, albeit not significantly so. This result is not dependent on differences in genetic growth potential, as demonstrated by the similar TH. It is worth noting that in our retrospective review, as in others, the mean dose of hydrocortisone was high during the first year of life, but that did not affect the final auxological outcome in these patients, who still show a better result than those who started treatment later. However, it is important to bear in mind that group B males showed a very bad height outcome, and this could negatively influence the poor result of the whole group with a late diagnosis.
A possible contribution of the NC forms to the good FH outcome of the group with early treatment can be excluded, as the group with late diagnosis (27 cases) included 17 subjects with the NC form compared with only 3 (no. 45, 48, and 50) in the group with early diagnosis (28 cases). Good height prognosis involves mainly the less symptomatic NC forms, who do not need to be treated, at least before puberty. Our patients, however, were all symptomatic and required treatment. We are still following up untreated NC patients who have not yet reached FH, and so were not able to compare treated vs. untreated NC patients.
When we subdivided the early diagnosed patients into two groups, according to height SD score less than -1 (group 1) and more than -1 (group 2) at 1 yr of age, we found that group 2 patients (who were shorter than group 1 patients at 1 yr of age and had been treated with higher cortisol equivalent doses) achieved the worst FH SD.
Our analysis of the patients diagnosed via neonatal screening is particularly interesting because it also included one SV and three NC forms, which often elude early diagnosis and therapy. Unfortunately, the number of these cases followed up to FH is too small to draw any reliable conclusions. However, three of these patients reached a higher FH than the TH. The case presenting the worst auxological outcome (Table 1, no. 48) was probably overtreated with dexamethasone over a significant growing period in an effort to lower 17OHP levels, as this was difficult to achieve with hydrocortisone.
Pubertal patterns of group A females differed from those of the other two groups. In fact, the main pubertal steps (age at B2, age at menarche, and age at FH) occurred about 1–2 yr later than in groups B and C. In these groups, the onset of puberty was early compared with the normal mean age of 11.2 yr (14), and this early activation of the hypothalamo-pituitary-gonadal axis was probably induced by the high androgenic levels that lasted a long time before therapy. Although these females showed a normal pubertal height gain, this was reduced in group A females. This may be due to the delaying effect on the onset of puberty induced by the higher doses of corticosteroids administered in prepuberty to group A compared with the other groups.
Our analysis of the puberty of male patients showed different characteristics in group B vs. the other two groups. The former apparently start puberty at an older CA and with a significantly more advanced bone age. The onset of puberty was evaluated by measuring the testicular volume increment, which may be slowed by high pretherapy androgenic levels. This phenomenon may be particularly evident in the most severe virilizing forms and makes a correct evaluation of the onset of puberty more difficult to achieve. Group C males as well as females showed a tendency to start puberty earlier than the normal population (15). For group C males, height gain during puberty was normal (15), whereas it was reduced for subjects in groups A and B.
The calculation of predicted height, carried out in the prepubertal phase and at the onset of puberty, showed the usefulness of this parameter in monitoring the efficacy of replacement therapy on growth in both sexes. In females, in fact, FH correlated with predicted height at both phases in over 50% of the cases (51.4% in prepuberty and 72.4% in early puberty). In males, however, a similar percentage (55.5%) was found only at the onset of puberty. This was mainly due to the different age of diagnosis for the two sexes. Females were normally diagnosed earlier than males and therefore received treatment over a longer period of time before the first height prediction. Therefore, predictions tended to be closer to FH than for males. It should also be pointed out that although calculations tended to underestimate FH in females, they tended to overestimate it in males.
In conclusion, we found that early diagnosis improved height outcome. Although the duration of puberty was similar in all groups, height gain was influenced by bone age at the onset of puberty. Despite a few therapeutic errors (lack of mineralocorticoid administration to some patients with latent SW forms), the height outcome was in the upper part of the weighted mean FH SD score of the meta-analysis by Eugster et al. (1). In our opinion, early diagnosis, the use of more physiological cortisol equivalent dosages during the first years of life, and the extension of mineralocorticoid therapy to all genetically classical patients can improve the auxological outcome of CAH patients. The genotypic analysis has helped to retrospectively interpret the height results of our cases and represents another possibility to improve the therapeutic choice and height outcome of CAH patients.
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Acknowledgments |
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Footnotes |
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Abbreviations: 4A, 4-Androstenedione; BMI, body mass index; C, cortone acetate; CA, chronological age; CAH, congenital adrenal hyperplasia; D, dexamethasone; F, fluorohydrocortisone; FH, final height; HCASD, height for chronological age SD; NC, nonclassical; 21OHD, 21-hydroxylase deficiency; 17OHP, 17-hydroxyprogesterone; P, prednisone; PRA, plasma renin activity; RA, residual enzymatic activity; SGA, small for gestational age; SV, simple virilizing; SW, salt-wasting; TH, target height.
Received January 27, 2003.
Accepted September 10, 2003.
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J, Tichet J, Rossignol C, Charraud A 1991 Body mass Index variations: centiles from birth to 87 years. Eur J Clin Nutr 45:13–21[Medline]
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