University of South Florida College of Medicine and the All Childrens Hospital St. Petersburg, Florida 33701
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Introduction |
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Nevertheless, the data offer a subtle hint that rhGH therapy may have increased final height slightly: more treated than control subjects (70% vs. 48%) reached the third percentile for height and achieved a height comparable to the target height (42% vs. 15%). Buchlis et al. (1) included the criterion of a slow growth rate to be eligible for rhGH therapy, indicating that not only stature but growth velocity must be considered in selecting non-GH deficient short children for a trial of therapy with rhGH, the usual practice of most pediatric endocrinologists (2). In an uncontrolled study, Bernasconi et al. (3) recently reported that in 71 subjects (17 female) with non-GH deficient short stature who received rhGH (approximately 0.25 mg/kg/week) for an average of 4.2 yr, achieved final height SD, predicted adult height SD, and midparental target height SD did not differ.
Among the problems encountered in clarifying the effects of rhGH in
patients with non-GH deficient short stature has been the heterogeneity
of this group of children. Ranke (4) has proposed criteria to
categorize a child as one with "idiopathic short stature" (Table 1); if widely accepted this designation
would lead to some consistency between investigators, although the data
of Buchlis et al. (1) would then be biased because children
with normal growth rates were excluded from their study.
Reckers-Mombarg et al. (5) have constructed growth curves
for children with idiopathic short stature, including in their
definition a peak GH secretory response to one or more provocative
stimuli of
10 ng/mL. The subjects from which these curves were
generated were small (but >-2 SD in length) at birth
(boys: -0.8 SD, girls: -1.3 SD); height at 2
yr was -1.7 SD in both sexes and fell to -2.7
SD at 13 yr in girls and at 16 yr in boys; final heights
were -1.5 SD (164.8 cm) in boys and -1.6 SD
(152.7 cm) in girls. In males with familial short stature, adult height
(166.9 cm, n = 32) was 2.1 cm less than midparental target height;
in those with nonfamilial short stature, final height (163.1 cm, n
= 48) was 8.1 cm less than target height. In females with familial
short stature, adult height (152.3 cm, n = 18) was 1.6 cm less
than target height; in those with nonfamilial short stature, final
height (153.0 cm, n = 34) was 6.8 cm less than target height.
These data should be helpful in assessing the long-term effectiveness
of growth promoting treatment in such children.
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Patients with homozygous or compound heterozygous mutations in the gene
encoding the growth hormone receptor (GHR), particularly its GH-binding
extracellular domain, are resistant to the biologic action of GH.
Heterozygous mutations in but one allele of the GHR have been
associated with familial intrinsic short stature (7). In a mother and
daughter with height SD -3.6, Ayling et al. (8)
identified a heterozygous mutation (G C transition at N876-1) in
the last nucleotide of intron 8 resulting in deletion of exon 9 and
reduction of the cytoplasmic portion of the GHR to 7 amino acids, thus
leading to a GHR that is unable to activate intracellular signal
transduction, because it lacks a binding site for JAK tyrosine kinase.
Because the mutated GHR is unable to be internalized, it accumulates on
the cell surface and exerts a dominant-negative effect on the wild-type
GHR by avid heterodimer formation. Further evaluation of the GHR in
patients with familial intrinsic short stature will undoubtedly
disclose comparable mutations in other subjects, as well as elsewhere
throughout the GH axis (9, 10).
In the second report in JCEM, Coutant et al. (11) (see page 1075) studied the effects of rhGH therapy on adult height in 70 children with short stature (height <2 SD) associated with IUGR (birth length <2 SD) of unknown cause and peak GH secretory responses to two provocative stimuli less than 10 ng/mL or an integrated concentration of GH less than 3 ng/mL. The children began treatment at 10 yr of age (height -2.9 SD) and received rhGH (approximately 0.2 mg/kg/week in 67 doses/week) for 4.6 yr. Growth rate increased during administration of rhGH, but in most subjects pubertal development occurred thus obscuring the growth-promoting effect of rhGH. The mean final height (-2.0 SD) of the rhGH-treated subjects was similar to that of 40 untreated short subjects with IUGR and "normal" hGH secretion (-2.2 SD). In addition, in 42/52 rhGH-treated children, repeat testing of GH secretion in late adolescence-young adulthood revealed normal GH secretion. In subjects with persistently low GH secretion the growth response to rhGH was twice that of the subjects in whom GH secretion "normalized," but final heights were similar in the two groups. The investigators in this study concluded that 1) the criteria for GH deficiency were inadequate, and 2) treatment with rhGH in the manner described did not affect adult stature in children with IUGR.
While several studies have reported that rhGH increases growth velocity in short children born SGA (12), there are few final height data in such patients. Ranke and Lindberg (13) reported that 16 SGA patients treated with rhGH for 4.3 yr achieved an adult stature that was 1.0 SD greater than the pretreatment height SDS. However, this was an uncontrolled study. Coutant et al. (9) reported that in untreated short SGA children final height was +0.63 SD greater than height at initial evaluation. Overall, available date suggest that rhGH does not increase adult height of non-GH deficient, short SGA subjects.
The adverse effects of short stature on psychological well-being and educational attainment have been emphasized by several investigators. However, Downie et al. (14) assessed 106 short normal children at 1113 yr and found that compared with matched, normal-statured control subjects the two groups were similar in measures of self esteem, self perception, parents perception, and behavior. Short children had lower intelligence quotients, reading and number skills, but the investigators reported that "... social class was a better predictor than height of all measures ... . Attainment scores were predicted by class and IQ together rather than by height ... ." Besides possible gain in stature, are there long-term psychosocial benefits of rhGH therapy in non-GH deficient children? Downie et al. (15) evaluated the psychological response to 5 yr of rhGH therapy in short normal children. They found no differences between treated and nontreated control subjects in intellect, scholastic attainment, behavior, self esteem, locus of control, self perception, or parental perceptions of competence. These authors concluded that "... no psychological benefits of treatment have been demonstrated, ... nor have there been any discernible ill effects ...." In a Dutch study, healthy, short statured adults (height less than the third percentile as children) had social achievements (education, profession, income, partner, and living situation) comparable with those of normal statured subjects, whereas adults with childhood-onset GH deficiency had lower professional scores, income, fewer partners and children, and were more often living with parents, suggesting that it was growth hormone deficiency and not short stature per se that was the cause of suboptimal social status (16).
When considering the use of GH for nonconventional purposes, Kodesh and
Cuttler (17) have posed several questions that should be considered
before treatment is initiated (Table 2).
Each of these queries could generate pages of discussion. Nevertheless,
ultimately most of us are faced with trying to decide whether an
otherwise apparently normal, non-GH deficient, short child should be
treated with rhGH. Current data suggest that it is unlikely that rhGH
treatment will result in substantial increase in adult stature over
that anticipated, at least in the majority of male subjects. As the
results of further therapeutic trials of rhGH in non-GH deficient short
children become available, this issue should be resolved. Even more
important will be data that tell us whether rhGH treatment is
associated with substantial improvement in the educational, social, and
economic achievements of the short child that justify the large expense
and possible adverse effects that accompany therapy with rhGH (2, 18).
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References |
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