By David N. LeffScience Editor

For children whose short stature is due to growth-hormone insufficiency, recombinant human growthhormone (rhGH) therapy can work small wonders.

Ten years ago this month, the FDA approved GenentechInc.'s Protropin rhGH for growth retardation. Today,estimates molecular geneticist Audrey Goddard, aGenentech scientist, "there are probably two millionchildren in the U.S. who are under the third percentile[two standard deviations] for height. By that we meanthey are short enough to come to the attention ofdoctors."

Goddard told BioWorld Today, "About 20,000 of thesetoo-short infants and youngsters get treated withrecombinant human growth hormone." Of this number,"some 12,000 are actually growth-hormone deficient. Theremaining 8,000 are children who have other growth-retarding conditions, such as Turner's syndrome."

Earlier this month, South San Francisco-based Genentechfiled a new drug application with the FDA to permitmarketing of its Nutropin growth hormone for Turner's,which accounts for about 4,000 of the 8,000. (SeeBioWorld Today, Oct. 5, 1995, p. 1.)

Most of the remaining thousands are children withchronic renal insufficiency, awaiting kidney transplants.Genentech already has authority to provide rhGH fortreating their short stature.

This leaves a puzzling minority of otherwise healthyyoungsters whose pituitary glands secrete abundantgrowth hormone, but who nevertheless fail to growbeyond the critical third percentile. "We call theirsyndrome," Goddard said, "idiopathic short stature[ISS]."

They are the subject of the lead article in today's NewEngland Journal of Medicine (NEJM), of which Goddardis first author. Its title: "Mutations of the growth hormonereceptor in children with idiopathic short stature."

Idiopathic, as Goddard recalled, means literally `diseaseof unknown cause.' She and her fellow Genentechresearchers set out to discover that cause, or causes.

"We went into the Genentech National CooperativeGrowth Study data base," she said, "of patients who, forone reason or another, had failed to grow. It contains inthe neighborhood of 20,000 names."

They singled out the clinical records of children who metthree clinical criteria: shortness, normal growth-hormonesecretion, and above all, very low serum levels of growth-hormone binding protein (GHBP).

Goddard observed that GHBP can be thought of as acirculating form of growth hormone receptor, whichresides on the surface of liver cells. "One of GHBP'sjobs," she said, "is to serve as a taxi for growth hormone,to which it binds, and helps circulate through the bloodproperly."

That molecular taxi, Goddard explained, "helps growthhormone get from its site of production in the brain'spituitary gland to its site of action in the liver.

"There, one molecule of the hormone binds to two of itstransmembrane receptors, which then send signals intothe liver cells. These produce secondary messengers,which go back via the circulation to the long bones andrib cartilage, which induce skeletal growth."

This key messenger molecule is insulin-like growthfactor-I (IGF-I).

By screening their large data base, the team narrowedtheir search to 40 or 50 patients who met their threecriteria. They contacted their physicians, and managed tocollect blood samples from 14 of them.

Of this ISS cohort, the team found four _ 25 percent _who carried varied heterozygotic mutations [inheritedfrom one parent only] in their growth hormone receptorgenes, but none in 24 control subjects with normalstature.

"These mutations," Goddard surmised, "presumablyresult in reducing, but not abolishing, levels of activebinding protein in the blood, and of receptors on the cellsurface." These receptors are either too few or defective,so they don't interact correctly with the growth hormonethat these ISS patients produce."

First Peek Inside Black Box Of ISS

This paradoxical growth-retarding effect is termed"growth hormone insensitivity syndrome."

"That's very exciting," Goddard went on, "because forthe first time we've come up with a biochemical basis forsome ISS. It's starting to open up the black box of what'shappening in these patients."

They treated three of the four ISS children with normaldoses of rhGH. "All three responded with growth-rateincreases," Goddard said, "but not as much as a GH-deficient child's growth rate would, pre- and post-therapy. If we were to give them as much GH as wecould," she observed, "it might help to saturate thosereceptors that are able to work, and thus compensate fortheir partial insensitivity."

But that therapeutic outlook is getting ahead of the story,she suggested. "This is where we run into the timeproblem. Of the three children, two are very young, andhave only just started treatment with growth hormone. Soit's very difficult to say where they are going to end up.So I think," she concluded, "that there is a need forappropriate clinical trials."

"Alternatively," suggested pediatric endocrinologist RonRosenfeld, "such [ISS] children may benefit fromtreatment with insulin-like growth factor I, which hassucceeded, at least in the short term, in patients who arehomozygous [gene from both parents] for defects of theGH-receptor gene."

Rosenfeld, of Oregon Health Sciences University,Portland, contributed an editorial to the NEJM,commenting on Goddard's paper, titled "Broadening thegrowth hormone insensitivity syndrome." n

(c) 1997 American Health Consultants. All rights reserved.