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Pediatric Endocrinology |
Pediatric Endocrinology Unit, Hôpital des Enfants Malades (R.R., E.M., R.B., H.C.), and the Pediatric Endocrinology Unit, Hôpital Robert Debré (J.L., P.C.), Paris; Hôpital Pédiatrique (J.M.L.), Angers; Hôpital Purpan (P.R.), Toulouse; and Hôpital Hautepierre (S.S.), Strasbourg, France; and Alpha 5 (C.L.), Riva San Vitale, Switzerland
Address all correspondence and requests for reprints to: R. Rappaport, M.D., Unité d’Endocrinologie Pédiatrique, Hôpital des Enfants Malades, 149 rue de Sèvres, 75015 Paris, France.
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Abstract |
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In group A, the mean height SD score increased from -1.1 ± 0.6 to 0.35 ± 1.0 SD (P < 0.001) in the first year and remained in the normal range throughout the following 4 yr. In group B after 4 yr of treatment, the mean height SD score for age had increased from -3.6 ± 1.0 SD (time zero) to -0.9 ± 1.2 SD. During the fourth year of therapy, the mean height gain of 0.2 ± 0.2 SD was significant (P < 0.001). After 5 yr of treatment, a plateau was reached with a corresponding height SD score (CA) of -0.8 ± 1.2 SD (95% confidence interval between -1.3 and -0.2 SD). This value remained significantly below normal for age (P < 0.001), indicating that catch-up growth was incomplete. Only four patients (16%) remained below -2SD for CA. The 5-yr height gain was negatively correlated with the height SD score at the start of treatment (r = -0.6; P < 0.005) and the first year height gain was the most predictive parameter. There was no significant influence of intrauterine growth retardation, body mass index and age at the start of treatment, or parental target height. Bone maturation was significantly retarded over CA by a mean value of 1.1 ± 0.9 yr (P < 0.0001), with a mean bone age/CA ratio of 0.8 ± 0.2 after a mean treatment duration of 5.1 ± 1.1 yr.
In conclusion, the rapid and almost complete return to normal height obtained in this study supports the need for GH treatment in early diagnosed GH-deficient children. The present dosage may be considered the minimum to obtain satisfactory catch-up growth ensuring a favorable outcome for these children. In addition, it allowed growth at a rate normal for age in patients diagnosed before growth retardation.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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This 5-yr study was a noncomparative multicenter prospective long term evaluation of the response to defined, adjusted dosage, GH therapy by children diagnosed and treated before the age of 3 yr. Informed consent was obtained from the parents. To be eligible, the children had to meet the French Pituitary Agency criteria: 1) height SD score for age below -2SD, and 2) peak GH responses to two pharmacological stimuli (glucagon, arginine, ornithine, or arginine-insulin tolerance test) of less than 10 µg/L. Because of the early diagnosis, the classic criterium of growth rate less than -1 SD for bone age (BA) could not be fulfilled. Some children referred because of hypoglycemia and/or micropenis showed no growth retardation. In this group when pharmacological stimulation could not be performed because of sustained hypoglycemia, GH treatment was started if the low basal serum GH concentration was combined with a pituitary stalk defect and/or an ectopic posterior pituitary bright spot at pituitary magnetic resonance imaging or with evidence of associated pituitary deficiencies. GH deficiency was then confirmed by a stimulation test performed at a later age.
A total of 49 GH-deficient infants (22 girls and 27 boys) were included in the protocol and assigned to 1 of 2 cohorts according to their initial height SD score. One cohort (group A) contained 8 patients who had an initial height within the normal range [<2 SD below the normal mean for chronological age (CA)]. The follow-up in this group was 24–60 months. The patients received treatment for 24 (n = 8), 36 (n = 7), 48 (n = 4), and 60 months (n = 3). The second cohort contained 41 patients with an initial height SD score greater than 2 SD below the normal mean for age, and they were followed for at least 36 months. Twenty-five of them were treated for 60 months or more (group B). There was no difference in the GH response to provocative stimuli between groups A and B. Follow-up of the patients with multiple pituitary hormone deficiencies included measurement of free T4. None of the children showed signs of pubertal development at the time of the last evaluation. The distribution between idiopathic GH deficiency and multiple pituitary hormone deficiency was 19/30 in the total initial cohort, 2/6 in group A, and 8/17 in group B.
The mean gestational age was 39.2 ± 2.5 weeks (n = 27), with a mean height at birth of -0.9 ± 1.25 SD (P < 0.0001) and a mean weight at birth of -0.3 ± 1.3 SD (P = NS), according to the method of Sempé et al. (7). The mean midparental height SD score (-0.3 ± 1.2 SD) was not different from normal.
Twenty-five patients had MRI of the pituitary. Pituitary stalk interruptions were found in 12, and isolated pituitary hypoplasia was found in five. Invasive lesions were ruled out in all subjects by MRI or CT scan.
Treatment
Each patient was examined every 3 months throughout this study to adjust dose to weight progression and to check compliance. Recombinant hGH (Saizen, Serono) was prescribed at a dose of 0.6 U/kg·week (0.2 mg/kg·week) given daily or 6 days/week by sc injections at bedtime. The records of doses given showed mean values of 0.68, 0.66, 0.60, 0.60, and 0.58 in group A, and 0.65, 0.60, 0.60, 0.61, and 0.60 IU/kg·week in group B, from 1–5 yr.
Patients with multiple pituitary deficiencies were given replacement therapy as needed (L-T4 up to 5 µg/kg·day and/or hydrocortisone up to 15 mg/m2·day). Patients with other underlying conditions were excluded.
Methods
Auxological parameters recorded every 3 months included height, height SD score, height velocity, weight, body mass index (BMI), and BMI SD score. The BA considered for the purpose of this study was the last measurement obtained after at least 36 months of therapy. The corresponding CA was then estimated for each patient to compare the changes in BA and CA over the longest possible time.
The French standards of the Children’s International Center and Sempé were used for height and weight (7). BMI was expressed according to national standards (8). BA radiographs were obtained after at least 3 yr of treatment. The determinations were made blindly according to the method of Greulich and Pyle (9). Target height was calculated on the basis of parental heights according to Tanner (10). Plasma GH was measured separately at each center. The assays compared as part of a permanent survey of the French Pituitary Agency showed a 24% interassay coefficient of variation at a concentration of 9.7 µg/L. Other pituitary functions were evaluated by basal or hypoglycemia-induced plasma cortisol and plasma free T4 measurements.
Statistics
The data are reported as the mean ± SD (range). The SD score for height was calculated as: height - mean height for normal subjects of the same age and sex/SD of height for normal subjects of the corresponding age. Groups were compared using the Wilcoxon signed rank test because of the small number of patients. The McNemar test was used to analyze catch-up growth frequency, comparing each yearly value to the closest previous value that already indicated a significant change. Stepwise multiple regression analysis was used to explore predictive factors of catch-up growth in response to GH therapy. The kinetics of catch-up growth were assessed by the nonparametric estimation from incomplete observations of Kaplan and Meier.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Eight patients had no definitive evidence of growth retardation at
diagnosis and start of treatment. All were treated for at least 2 yr,
and three of them were treated for 5 yr. Their mean height
SD score was -1.1 ± 0.6 SD (-1.8 to
0.1) at the start of treatment, for a mean CA of 0.7 ± 0.9 yr
(0.2–3). Their mean height SD score significantly improved
during the first treatment year, reaching a mean of 0.35 ± 1.0
SD (P < 0.001). There was no further
significant change during the following years (Fig. 1
).
The mean height SD score was 0.5 ± 0.8 (individual
values ranging from -0.2 to 1.4SD) after 5 yr of treatment
(n = 3). Because of the arbitrary cut-off at -2SD
below the mean used to define group A, these data indicate that some
group A patients had already suffered from their GH deficiency at the
time of diagnosis and, therefore, showed initial catch-up growth. Bone
maturation could be evaluated in only three patients after a mean
treatment duration of 5.3 yr, at a mean age of 5.5 ± 1.7 yr. The
mean BA was 4.5 ± 1.3 yr, with a mean BA/CA ratio of 0.8 ±
0.1, indicating a retarded BA, as in group B (see below). The small
number of patients in this group prevented statistical evaluation of
bone maturation.
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Twenty-five patients followed during at least 60 months had
an initial mean height SD score for CA of -3.6 ± 1.0
SD (-6.2 to -2.0 SD) at a mean CA of 1.4
± 0.7 yr (0.1–2.7 yr). The height SD score for CA
significantly increased each year, until the fourth year of therapy,
reaching a mean of -0.9 ± 1.2 SD for CA, with a
significant height gain of 0.2 ± 0.2 (P < 0.001)
and a cumulative height gain of 2.7 ± 1.3 SD, ranging
from 0.9–5.9 SD (Table 1). The mean height
gain during the fifth year of treatment over the preceding year of
0.1 ± 0.3 SD was not significant. The corresponding
mean height SD score (CA) at 60 months was -0.8 ±
1.2 SD (-3.4 to 2.2 SD), with a 95%
confidence interval between -1.3 and -0.2 SD, indicating
that catch-up growth was not complete at that time (significantly
different from zero, P < 0.001). The mean cumulative
height gain reached 2.8 ± 1.3 SD (1.0–5.8
SD) during that treatment period. For the first 3-yr
follow-up, similar results were obtained in the initial cohort of 41
patients with growth retardation, which included these 25 cases; the
height SD score for CA significantly increased each year,
with mean values of -1.7 ± 1.0, -1.1 ± 1.0, and
-0.9 ± 1.0 SD (P < 0.001) after 1,
2, and 3 yr of treatment, respectively. After 3 yr of GH treatment, the
mean height gain was 2.5 ± 1.0 SD, ranging from
0.9–5.5 SD. The mean yearly height SD scores
for CA during treatment of groups A and B were compared; there was a
significant difference until the fourth year of treatment
(P < 0.001 at 1, 2, and 3 yr; P <
0.01 at 4 yr treatment), but the small number (n = 3) of patients
in group A after 5 yr of treatment precluded further statistical
comparison (Fig. 1
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). The mean midparental height in
this population was not significantly different from normal. The mean
difference between height SD score and target height
SD score was -3.4 ± 0.9 SD at time zero.
There was significant improvement until the fourth treatment year,
reaching a mean of -0.7 ± 1.5 SD and indicating a
sustained catch-up growth during that period. A mean value of
-0.6 ± 1.5 (to 2.1 SD), which indicated no further
change, was achieved after 5 yr of treatment. This value was not
significantly different from zero (P = 0.06). The
percentage of patients reaching levels of -2 SD and -1
SD below the normal mean for age was calculated to analyze
the height distribution of this population. After 5 yr of treatment,
the height SD score for CA remained below -2
SD in 16% of the patients. The same result was obtained
when considering height in relation to target height. These data
indicate that full catch-up growth was not achieved, as shown in Fig. 2, which also shows that 50% of the patients remained
below the -2 SD line for height after treatment for 12
months and below the -1 SD line after 36 months. Four
patients whose heights were below -2 SD after 5 yr of
treatment were arbitrarily defined as poor responders (Table 3); their heights for CA ranged from -2.0 to -3.4
SD. When heights for CA were compared to parental target
heights, only two of them (cases 1 and 2) remained more than 2
SD below their target height. Two of them (cases 1 and 4)
had suffered from intrauterine growth retardation. However, 7 of the 21
good responders also had intrauterine growth retardation. Three
patients had mental retardation and persistent feeding difficulties,
with low BMI SD scores (detail not shown). This condition
was not found among the good responders.
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, significantly increased from -0.6
± 1.3 SD to -0.5 ± 1.0, -0.3 ± 1.6, 0.0
± 1.6, and 0.4 ± 2.0 SD from yr 2 to yr 5
(P < 0.05). The BMI value at yr 1 was not
significantly different from that at time zero.
Bone maturation could be evaluated in only 21 of the 25 patients after
a mean treatment duration of 5.1 ± 1.1 yr at a mean CA of
6.5 ± 1.1 yr. BA was significantly retarded over CA by a mean of
1.1 ± 0.9 yr, with a mean BA/CA ratio of 0.8 ± 0.2
(P < 0.0001; Table 4).
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). The correlation was expressed for each variable
after the effect of the other variables had been removed: birth weight
for gestational age, BMI, age at the start of treatment, familial
target height, height deficit corrected for familial target height at
the start of treatment. None had a significant influence. Only one
variable influenced height gain: height SD score at the
start of therapy. The independent variable most significantly
predictive of the total height gain (SD) was height
SD score at the onset of GH treatment (r = -0.6;
P < 0.005), indicating that the most retarded infants
had better catch-up growth. The most powerful predictive equation
obtained by multiple regression analysis was: total height gain
SD (5 yr) = 0.16 - 0.31 height SD score
at start + 0.82 height gain SD score (first
year) · (r2 = 0.63; P < 0.0001).
Replacing height gain during the first treatment year with age at onset
gave a new equation (not shown) with a lower r2 value of
0.35 (P < 0.002). According to this model, the gain in
height SD score was more pronounced for children with
severe height deficit at the start of treatment.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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This prospective study was designed to assess the growth response to rhGH therapy of infants given single daily injections of hormone, a regimen now considered to be optimal (14). Because lack of compliance is a major problem, a special effort was made to follow the patients, and the GH dose was adjusted to weight increments by visits every 3 months. The pattern of catch-up growth in the group of infants with a growth deficit at diagnosis indicates a sustained and significant effect during the first 4 yr, with a further slight increase during the fifth year. Although the distribution of heights remained slightly below normal after 5 yr of treatment when expressed as the SD score, 84% of the treated patients have reached a height above 2 SD below the mean after 5 yr of treatment, and only two children had height remaining below that limit compared to their target heights. Catch-up was positively correlated with growth retardation. We did not find a significant effect of age at onset of treatment, and our results suggest an equal ability to respond to GH treatment up to 3 yr of age. Hence, the most powerful predictive equation of the 5-yr treatment result was obtained when growth velocity during the first year of treatment was considered, as found in a larger study of prepubertal children (2). When patients with height SD score less than 2 SD below the mean for age were diagnosed and treated before severe growth retardation was documented, their heights were within the normal range after the first year of treatment and remained normal for age. These data may indicate that the present dosage is close to the theoretical physiological requirement as calculated in prepubertal boys (6).
However, our results also suggest that the GH dose given in this protocol is probably the minimal dose required, as it resulted in catch-up growth until the fourth year of therapy with a plateau in the fifth year, without full recovery of normal height. One may speculate that a slightly greater GH dose would allow more rapid and complete catch-up growth in early childhood. Previous studies have shown that catch-up growth was incomplete after 4 yr of treatment in patients with severe growth retardation at the start of treatment (5) and led to the conclusion that more time may be required to achieve normal height. As a plateau was reached during the fifth treatment year in the present study, a minimal impairment of growth potential cannot be ruled out.
This study was also designed to identify factors that would negatively influence GH-stimulated growth. Intrauterine growth retardation was previously suggested to be a negative factor in the short term response to therapy. In the present study, only two patients were poor responders of nine who were small for gestational age and initially growth retarded. These data do not confirm that intrauterine growth retardation is a negative factor in the response to therapy (15). These infants also suffered from feeding difficulties associated with mental retardation. Poor nutrition, although not further documented in the present study, may have limited the growth response in these patients.
Bone maturation remained significantly retarded after more that 3 yr of replacement therapy, as previously noticed (11). Although the young age of our patients precluded any reliable estimation of predicted final height, it is likely that such a condition is a favorable factor for further growth. Achievement of heights close to normal in most patients should also allow the height at the start of puberty to be optimized, which may be very important for a satisfactory long term outcome (16).
In conclusion, early growth retardation due to GH deficiency should be treated with GH as soon as diagnosed. The dose used in the present study may be considered as the minimum to obtain effective catch-up growth within 5 yr and before puberty. In addition, they ensured growth at a rate normal for age in patients diagnosed before growth retardation. Hence, early GH treatment appears to be a favorable factor in the outcome of these patients.
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Acknowledgments |
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Footnotes |
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2 The French Serono Study Group included: R. Brauner, G. Pinto, C.
Pauwels (Paris), S. Sauvion (Bondy), C. Allisy (Argenteuil), D. Simon
(Paris), C. Radet (Angers), M. Lecornu and M. de Kerdanet (Rennes), M.
Tauber (Toulouse), C. Ponte, C. Stuckens, G. A. Loeuille and J. Weill
(Lille), J.G. Juif and F. Schmitt-Lepage (Strasbourg), Y. Lebouc, S.
Cabrol and M. Gourmelen (Paris), A.M. Bertrand (Besançon), S.
Nivot et J.F. Duhamel (Caen), M. Bost (Grenoble), A. David (Nantes), F.
Freycon (St Etienne), P. Garandeau (Palavas), M. Colle (Bordeaux), A.
Burtscher (Munster), V. Sulmont (Reims), F. Despert (Tours).
Received August 26, 1996.
Revised October 28, 1996.
Accepted November 11, 1996.
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