Does Growth Hormone Have a Role in the Management of Children with Nongrowth Hormone Deficient Short Stature and Intrauterine Growth Retardation?

Allen W. Root

University of South Florida College of Medicine and the All Children’s Hospital St. Petersburg, Florida 33701


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The effectiveness of recombinant human growth hormone (rhGH) in increasing adult stature in non-GH deficient subjects has been the subject of inconclusive discussion for many years, primarily because of the paucity of data on the final height of rhGH-treated short subjects. In this issue of JCEM, two papers address this subject. Buchlis et al. (1) (see JCEM p. 1075) report the adult (or near adult) stature of 36 (6 females) normal short subjects [normal size at birth, height <2 SD scores at initial contact, growth rate <5 cm/yr, delayed skeletal maturation, and "normal" secretion of GH in response to provocative stimuli (peak GH >=10 ng/mL by polyclonal radioimmunoassay)] treated with rhGH (0.3 mg/kg/week in 6–7 injections per week) for a mean of 41 months. They excluded patients with systemic disease, intrauterine growth retardation (IUGR), and chromosomal anomalies. The adult heights of the rhGH-treated subjects were compared with those of 58 (17 females) untreated subjects with similar characteristics evaluated before the widespread availability of rhGH. Final height was greater in the group of rhGH-treated subjects (-1.5 SD) than in the nontreated subjects (-2.1 SD, <0.001). However, the increase in achieved over predicted adult height of the 6 rhGH-treated females (+3.7 cm) was substantially more than that of the 30 males (+1.5 cm) and accounted for much of the net gain in stature attributed to the administration of rhGH. It was only in the rhGH-treated female subjects that the increase in mean final height seemed clinically significant (-1.3 vs. -2.5 SD in the untreated group). Because the achieved heights of the treated and untreated males were not significantly different than pretreatment predicted heights, it is difficult to discern a positive effect of rhGH on growth in male subjects.

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 1Go); 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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Table 1. Criteria for the diagnosis of "idiopathic short stature"

 
Several genes associated with familial short stature have been identified. Subjects with deletions of the pseudoautosomal regions (PAR1) of Xp and Yp are often intrinsically short. Rao et al. (6) have identified a homeobox-containing gene (one that influences regional development by activating multiple target genes) related to short stature within a 170 kb DNA segment of PAR1 in 6 patients with partial monosomy for PAR1. They termed this gene short stature homeobox-containing gene (SHOX). This gene has 6 exons from which are derived by alternative splicing of exon 5 two isoforms: SHOXa—292 amino acids; SHOXb—225 amino acids. SHOXa is expressed in the brain, hypothalamus, and pituitary, while SHOXb expression is restricted to fetal kidney, skeletal muscle, and bone marrow fibroblasts. PAR1 was deleted in all subjects studied with short stature and rearrangements of Xp22 or Xp11.3. In 1/91 normal subjects with heights below the third percentile, a mutation in SHOX (C -> T transition at N:674) was found, resulting in a termination codon at amino acid 195 and a truncated protein. The same mutation was present in all short family members, but not in those with normal stature. Although the mechanism(s) through which SHOX influences growth are unknown, its effect may be dosage-sensitive; that is, haploinsufficiency of the gene product of SHOX appears to be sufficient to inhibit normal linear growth. It will be of interest to determine if polymorphic variations of this gene influence the range of heights characteristic of a population.

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 6–7 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 11–13 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 2Go). 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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Table 2. Questions to be considered for the nonconventional use of recombinant human growth hormone

 


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 Introduction
 References
 

  1. Buchlis JG, Irizaryy L, Crotzer BC, et al. 1998 Comparison of final heights of growth hormone treated versus untreated children with idiopathic growth failure. J Clin Endocrinol Metab. 83:1075–1079.[Abstract/Free Full Text]
  2. Cuttler L, Silvers JB, Singh J, et al. 1996 Short stature and growth hormone therapy. A national study of physician recommendation patterns. JAMA. 276:531–537.[Abstract]
  3. Bernasconi S, Street ME, Volta C, et al. 1997 Final height in non-growth hormone deficient children treated with growth hormone. Clin Endocrinol. 47:261–266.[Medline]
  4. Ranke MB. 1996 Towards a consensus on the definition of idiopathic short stature. Horm Res. 45(suppl 2):64–66.
  5. Reckers-Mombarg LTM, Wit JM, Massa GG, et al. 1996 Spontaneous growth in idiopathic short stature. Arch Dis Child. 75:175–180.[Abstract]
  6. Rao E, Weiss B, Fukami M, et al. 1997 Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet. 16:54–62.[Medline]
  7. Goddard AD, Covello R, Luoh S-M, et al. 1995 Mutations of the growth hormone receptor in children with idiopathic short stature. N Engl J Med. 33:1093–1098.[CrossRef]
  8. Ayling RM, Ross R, Towner P, et al. 1997 A dominant-negative mutation of the growth hormone receptor causes familial short stature. Nat Genet. 16:13–14.[Medline]
  9. Roback EW, Barakat AJ, Dev VG, et al. 1991 An infant with deletion of the distal long arm of chromosome 15 (q26.1-qter) and loss of insulin-like growth factor 1 receptor gene. Am J Med Genet. 38:74–79.[Medline]
  10. Woods KA, Camacho-Hubner C, Savage MO, Clark AJL. 1996 Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med. 335:1363.[Free Full Text]
  11. Coutant R, Carel JC, Bouvattier C, et al. 1998 Response to GH treatment and final height in children with short stature secondary to intrauterine growth retardation. J Clin Endocrinol Metab. 83:1070–1074.[Abstract/Free Full Text]
  12. Wilton P, Albertsson-Wikland K, Butenandt O. 1997 Growth hormone treatment induces a dose-dependent catch-up growth in short children born small for gestational age: A summary of four clinical trials. Horm Res. 48(suppl 1):67–71.
  13. Ranke MB, Lindberg A. 1996 Growth hormone treatment of short children born small for gestational age or with Silver-Russell syndrome: results from KIGS (Kabi International Growth Study), including the first report on final height. Acta Paediatr. (Suppl)47 :18–26.
  14. Downie AB, Mulligan J, Stratford RJ, et al. 1997 Are short normal children at a disadvantage? The Wessex growth study. Br Med J. 314:97–100.[Abstract/Free Full Text]
  15. Downie AB, Mulligan J, McCaughey ES, et al. 1996 Psychological response to growth hormone treatment in short normal children. Arch Dis Child. 75:32–35.[Abstract]
  16. Rikken B, van Busschbach J, le Cassie S, et al. 1995 Impaired social status of growth hormone deficient adults as compared to controls with short or normal stature. Clin Endocrinol (Oxf). 43:205–211.[Medline]
  17. Kodish E, Cuttler L. 1996 Ethical issues in emerging new treatments such as growth hormone therapy for children with Down’s syndrome and Prader-Willi syndrome. Curr Opin Pediatr. 8:401–405.[Medline]
  18. Blethen SL, Allen DB, Graves D, et al. 1996 Safety of recombinant DNA-derived growth hormone (rhGH): The National Cooperative Growth Study experience. J Clin Endocrinol Metab. 81:1704–1710.[Abstract]