Management of Idiopathic Short Stature in a 14-Year-Old Girl

February 03, 2006

Question

A 14-year-old girl presented with idiopathic short stature. Her height is 52.5" (133.3 cm) and her bone age is 13.5-14.0 years. Is there any reason not to treat her with a combination of growth hormone (GH) and leuprolide? Would you use high-dose GH?

Response From the Expert

Alan M. Schindler, MD 
Department of Pediatrics, Albert Einstein Medical Center, Philadelphia, Pennsylvania

In trying to answer these questions, we need to consider 3 separate issues. First, why is this girl so short? Second, is GH an approved and/or appropriate treatment for her short stature? If so, what is an appropriate dose? And third, given that her bone age is nearing that of adult women, is there likely to be any advantage in using leuprolide (Lupron) to prevent her bone age from progressing?

There are many reasons that a girl might be very short, including:

  • familial short stature (we have no pertinent information in this case);

  • constitutional delay of growth -- the "slow grower" (but this girl has skeletal maturation consistent with her chronological age);

  • an intrauterine problem that affected her potential for growth (we have no information to corroborate this);

  • Turner syndrome, a common cause of short stature and sexual infantilism in girls (we have no information about her pubertal status; the bone age could be consistent with Turner syndrome and this possibility should be investigated) or some other syndrome associated with short stature (we have no relevant information);

  • an ongoing chronic illness that cannot be adequately managed and affects growth (we have no information to support this, but such conditions are usually symptomatic and delay the bone age); and

  • GH deficiency.

If a short child has none of these conditions and the height is more than 2.25 standard deviations below the mean (less than the 1.2 percentile) for age, then the child has "idiopathic short stature" (ISS).

GH therapy is US Food and Drug Administration (FDA) approved for children with proven GH deficiency, Turner syndrome, chronic renal failure awaiting transplantation, Prader-Willi syndrome, children born small for gestational age, and, most recently, children with ISS. Except in the case of children with GH deficiency, the effectiveness of GH treatment, while real, is limited in achieving adult heights consistent with parental heights.

In general, the earlier one starts treatment, the better the result. The best growth response to GH usually occurs in the first 1-2 years of treatment and appears to be dose dependent; thus, the reasonable question of whether to use high-dose GH (ie, 6.0 IU/m2/day vs the more usual 1.5-3.0 IU/m2/day) in this case. However, one study has suggested that the use of high-dose GH in prepubertal children may be detrimental, as advancing bone age and earlier onset of puberty have been reported in these children.[1]

Once a child's skeletal maturation age has reached the adult stage, there is no potential for further growth and administration of GH has no benefit, except for patients with GH deficiency). This girl's bone age of 13.5-14.0 years suggests that she is getting close to adult skeletal maturation. It also suggests that she should be well into puberty and beyond the peak of the pubertal growth spurt.

Estrogen is the major hormonal factor that promotes skeletal maturation. Blocking estrogen production (or effect) would thus seem to be a logical way to prolong the time for potential growth. That is one reason for the well-established use of Lupron in otherwise normal children with idiopathic precocious puberty. Lupron is a long-acting gonadotropin agonist that paradoxically but effectively decreases gonadotropin levels, reduces sex steroid levels, stops and even reverses pubertal development, and slows or stops the progression of skeletal maturation, thus helping the affected child to achieve his or her genetic potential for height.

For children with other causes of short stature, the usefulness of Lupron to slow skeletal maturation and to improve adult height is less certain. In children with GH deficiency, the combination of GH and Lupron appears to yield a greater adult height than the use of GH alone.[2] For children with ISS, the results are mixed and it is not clear whether the combination of GH and Lupron yields a better outcome than GH alone.

The best results seem to occur with longer periods of GH administration and if Lupron is added as puberty begins. However, although delaying puberty by decreasing sex steroid levels may provide a longer interval for potential growth, those lower levels may make the GH less effective.[3] Also, low estrogen levels during a time of normal bone growth may cause a loss of bone mass compared with expected bone mass as the child reaches adulthood,[2,4] something that could have long-term consequences for the child. With regard to potential psychosocial issues related to delaying puberty, these children do not seem to experience significant problems.[2]

My opinion, not a recommendation: Assuming that this girl does indeed have ISS, GH may still be helpful for her, but given her relatively advanced bone age, time is limited. High-dose GH and Lupron might give the best possible result. However, in deciding how, or even whether, to treat this child, one must remember, and inform the child and family, that:

  • treatment with growth hormone is very expensive ($50,000 or more per year);

  • there is no certainty of significantly improved adult height, with or without the use of Lupron;

  • lowering sex steroid levels during the teen years may have unintended undesirable consequences long into the future; and

  • the use of Lupron in this situation is "off-label" and does not represent an accepted standard of care at this time.

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