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Achieving normal adult height is one of the most important goals in the treatment of children with 21-OHD. In several retrospective studies, it has been shown that mean final height remains below that of healthy controls(1–5). Treatment with inadequate doses of hydrocortisone leads to androgen excess, which causes acceleration of bone maturation and loss of growth potential. On the other hand, glucocorticoid excess may suppress growth hormone secretion and reduce bone growth directly(6).

Bone age evaluation and biochemical assessment have been used to monitor hormonal substitution and to achieve optimal growth. Attempts at biochemical control on its own have been disappointing in terms of long-term results(3). Some authors have suggested that normal growth velocity is the best index of adequate long-term hormonal balance and will result in satisfactory adult stature(7, 8). In addition to height velocity, body mass index during childhood also seems to correlate with adult stature(2). Because children with 21-OHD only start to attend endocrine units after the diagnosis has been made, much less is known about growth patterns before the diagnosis. Accelerated growth is one of the main findings in late diagnosed 21-OHD. In a few retrospective studies it has been observed that, unlike later in childhood, growth velocity is not significantly accelerated during the 1st y of life(9, 10).

The aims of our study were to analyze growth before and after the diagnosis of 21-OHD and to determine factors that affect adult stature. The growth of all the identified Finnish 21-OHD patients was evaluated in this retrospective study.

METHODS

Patients with 21-OHD were sought in all the five university and 16 central hospitals in Finland. Diagnosis registers and personal contacts were used to locate the patients.

A total of 119 patients were found. Due to inadequate growth data, 27 patients (4 male and 23 female) were excluded from the study. They were mostly late diagnosed older patients, whose growth had not been monitored before the diagnosis. The adult height of these men was 166.4 cm and that of the women was 152.2 cm. The remaining 92 patients were divided into two groups according to the age at diagnosis. The group of early diagnosed children consisted of patients diagnosed before the age of 1 y and the group of late diagnosed children consisted of the patients diagnosed after the age of 1 y. All the children were receiving hydrocortisone substitution therapy and those with mineralocorticoid deficiency had also 9-α-fluorocortisol substitution.

Patient characteristics, early diagnosed children. This group consisted of 56 patients: 35 female and 21 male. All the girls in this group had ambiguous genitalia at birth and, except for one girl who was diagnosed at the age of 9 mo, they had all been diagnosed by the age of 8 wk. Two girls had a simple virilizing form and 33 girls had a salt-wasting form of 21-OHD. Definitions of the phenotypes are those cited by Miller(11). All the boys suffered from the salt-wasting form of 21-OHD and were diagnosed by the age of 8 wk. Eighteen patients, 8 female and 10 male, had attained adult height. The remaining 38 patients, 27 girls and 11 boys, were still growing.

Late diagnosed children. This group consisted of 36 patients, 14 female and 22 male. The mean age at diagnosis of the girls was 4.1 y (range 1.0-8.5 y) and of the boys 4.9 y (range 1.0-10.4 y). Evidence of mineralocorticoid deficiency (elevated plasma renin activity) had been found in 7 boys and 3 girls. Three girls had a nonclassical form of 21-OHD, and 11 girls suffered from the simple virilizing form of classical 21-OHD(11). Adult height had been achieved by 24 patients, 14 male and 10 female. The remaining 12 children were still growing.

Procedure. Data relating to duration of gestation, length or height and weight, PSEH, age at diagnosis, bone age at diagnosis, timing of puberty, and medication were obtained from the patient records. Birth length and weight had been measured at obstetric clinics. Growth had been monitored in well baby clinics before the diagnosis and at endocrine outpatient clinics after the diagnosis. Pubertal stage and bone age had been recorded by the pediatric endocrinologists in charge for the treatment of the patients. Length or height and weight data were collected at 1-y intervals until cessation of growth. Growth data were plotted on growth charts, which are based on longitudinal growth data of 2156 healthy Finnish children born in 1959-1961 and 1969-1971. These charts provide length or height as SDS and weight as percentages in relation to the mean weight for height(12, 13). To exclude the influence of a secular trend on the results concerning birth lengths, this analysis was repeated using the Finnish birth register from the year 1994. The mean birth lengths of 27 726 healthy boys and 27 232 girls whose gestational ages were 40 wk± 14 d were used as references. The PSEH was calculated as determined by Pere et al.(14). Doses of hydrocortisone(milligrams/body surface area/24 h) and 9-α-fluorocortisol(milligrams/24 h) were collected at half-year intervals during infancy and later at 2-y intervals.

One sample t test was used to compare birth lengths and weights of 21-OHD patients with mean birth lengths and weights of Finnish children. A paired t test was used to compare relative lengths at birth and at the age of 1 y. Pearson's correlation test was used to evaluate correlation of the 1st y of growth, mean relative weight, and mean hydrocortisone dose with the final height.

RESULTS

Early diagnosed children. The mean birth length of the girls was +0.6 SDS (51.3 cm) and of the boys +1.2 SDS (52.9 cm). These were significantly greater (p < 0.001) than the mean national birth lengths (50.2 cm for girls and 50.7 cm for boys). When compared with the mean birth lengths of the Finnish children born in 1994 (50.2 cm for the girls and 51.0 cm for the boys), the difference was still significant (p = 0.004 for the girls and p = 0.002 for the boys). The mean birth weight of the girls was 3.67 kg and that of the boys was 4.00 kg. Also these were significantly greater (p = 0.004 for the girls and p< 0.001 for the boys) than the mean national birth weights (3.44 kg for the girls and 3.54 kg for the boys). The mean lengths or heights at various ages and mean hydrocortisone doses are illustrated in Figure 1. During the 1st y, the mean relative length diminished from +0.8 SDS (both sexes combined) to -1.0 SDS (p < 0.001). Hydrocortisone doses were greatest during the 1st y, up to 37.3 mg/m2/24 h. After the 1st y, mean hydrocortisone doses varied from 14.7 to 16.3 mg/m2/24 h.

Figure 1
figure 1

Mean height SDS (±1 SD) in the group of early diagnosed children and their mean parent-specific expected height(×-×). Mean hydrocortisone doses (milligrams/m2/d) are also illustrated (*).

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Mean final adult height was -0.8 SDS (159.9 cm) for women, which was less than the mean national adult height (165.3 cm; p = 0.026). For men, the mean adult height was -0.8 SDS (173.6 cm), which was not significantly less than the national mean adult height (178.9 cm).

The mean hydrocortisone dose of the 1st y correlated negatively with the growth velocity (centimeters/y) of the 1st y (r = -0.598;p < 0.001). The growth velocity during the 1st y showed a weak positive correlation with adult height (SDS) (r = 0.535; p= 0.022), whereas the mean hydrocortisone dose of the 1st y did not correlate significantly with the adult height (SDS) (r = -0.229; NS). Mean relative weight during the growth period did have a significant negative correlation with the adult height (r = -0.620; p = 0.006). The childhood mean hydrocortisone dose correlated negatively with adult height, although this was not statistically significant (r = -0.416; NS).

Late diagnosed children. The mean birth length of the girls was+0.1 SDS (50.3 cm) and that of the boys was +0.4 SDS (51.4 cm); these did not differ significantly from mean national birth lengths for either group. The mean birth weight of the girls (3.39 kg) and that of the boys (3.70 kg) did not differ significantly from the national mean weights. Growth before the diagnosis is illustrated in Figure 2. The mean relative length had increased from +0.2 SDS at birth to +0.7 SDS by the age of 1 y(p = 0.023). However, there were 15 patients (42%) whose length did not increase during the 1st y. Clinical findings at and after the diagnosis are illustrated in Table 1.

Figure 2
figure 2

Growth before the diagnosis in the group of late diagnosed children. Lines represent mean height SDS (±1 SD). Mean parent-specific expected height is also illustrated (×-×).

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Table 1 Clinical data of the late diagnosed patients
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The mean adult height of women was within normal range (-0.5 SDS; 162.1 cm). The mean adult height of men was -2.1 SDS (165.3 cm), which is significantly less than the national mean adult height (178.9 cm) (p< 0.001). There were eight men whose adult heights remained more than -3 SDS less than the mean. Of these men, five men (cases 1-5, see Table 1) had Tanner genital stage 2 at diagnosis. Case 12 had been hospitalized three times before the diagnosis at the ages of 2 wk, 8 wk, and 2 y. He had had vomiting and hyponatremia, but no hypoglycemia had been observed. Later epilepsy and mental retardation were found without any recognized etiology. In case 14, adequate suppression of adrenal androgens was never achieved. He was obese and had an accelerated bone age, and he stopped growing at the age of 12 y.

DISCUSSION

The mean birth length of the early diagnosed patients with 21-OHD in this study was significantly greater than the mean birth length of Finnish children. This is a clear indication that adrenal hyperandrogenism can affect fetal growth. To our knowledge, there are no previous reports of birth length in patients with 21-OHD. Because 21-OHD is screened neonatally in several countries, this could be now easily studied prospectively.

The high hydrocortisone doses used during the 1st y led to diminished growth velocity, which also seemed to affect the adult height achieved. It is now well known that much lower doses (20-25 mg/m2/24 h) can suppress adrenal androgen secretion also during infancy(15, 16). Currently these lower doses have been used also in our country, and we have observed better growth velocities during infancy without inappropriate bone age advancement. We still do not have the final heights of all these patients to determine whether better adult heights are achieved. On the other hand, adult heights of men and women diagnosed during the 1st y can be regarded as psychosocially acceptable.

It has been suggested that, during infancy, unlike later in childhood, hyperandrogenism does not necessarily cause increased growth velocity or early maturation of bone age(9, 10). Our study shows that, in most patients, growth is already accelerated at infancy (mean height increased 0.5 SD units, Fig. 2), but there are also many children whose growth starts to accelerate only during the 2nd y of life. It still remains to be resolved why some children experience accelerated growth, whereas other children grow in a linear manner.

High relative weight correlated negatively with adult height, whereas there was no statistically significant correlation between hydrocortisone doses used and the final adult height. It is possible that high relative weight is a result of overtreatment, which is not necessarily detectable by biochemical indicators. On the other hand, it has been observed by Yu and Grant(2) that high body mass index is associated with early menarche in 21-OHD girls. It is clear that, in the treatment of 21-OHD, our aim should be to achieve a normal body mass index.

In the group of late diagnosed patients, there were two boys and four girls who achieved normal or even above average final heights despite advanced bone ages at diagnosis. This fact may partly be due to tall parents, but it also indicates that even in this group careful treatment may lead to a satisfactory result. The difference in final heights between late diagnosed boys and girls was surprising. It is well known that adrenal hyperandrogenism may prime central puberty in boys. Of those boys who had reached their adult height, none had received treatment for precocious central puberty. Careful monitoring of pubertal development and early treatment of too early pubertal development by gonadotropin-releasing hormone analogs could be one way to increase the adult height of these patients.