American Journal of Medical Genetics 42:667-670 (1992)

Growth Hormone Therapy in Achondroplasia _

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William A. Horton, Jacqueline T. Hecht, 0. Jean Hood, Robert N. Marshall, Wayne V. Moore, and Joseph G. Hollowell Division of Medical Genetics (W.A.H., J.T-H., OJ-H., RN.M.), Department of Pediatrics, University of Texas Medical School, Houston, Texas, and Department of Pediatrics (W.V.M.,J.G.H.), University of Kansas Medical School, Kansas City, Kansas A pilot study was carried out to examine the safety and efficacy of recombinant human growth hormone for growth-promoting therapy of achondroplasia. The data suggest that the agent in doses used to treat non-GH-deficient forms of short stature (0.3 mg/kg/wk) modestly increases overall height velocity in some children with achondroplasia. The effect was seen mainly in children with the lowest growth velocities prior to treatment. No untoward effects were noted. Several questions were raised that require further study.

KEY WORDS: chondrodysplasias, dwarfism, growth velocity INTRODUCTION Achondroplasia is the most common of the human chondrodysplasias[Scott, 1972;Scott, 1976;Horton and Hecht, 19911.Inherited as an autosomal dominant trait, it is characterized by a large head with a prominent forehead and midface hypoplasia, and disproportionate shortness of the limbs, especially the proximal segments. The disproportion is evident at birth and becomes more pronounced with time, as does the growth deficiency. Indeed, patients, whose length usually plots near the lower range of normal as newborn infants progressively drop below this range, ending up with an adult height typically from 112 to 136cm for women and 118 to 145 cm for men [Horton et al., 19781. In addition to being short, patients with achondroplasia have problems that result secondarily from the abnormal skeletal growth. Most notable is compression of the spinal cord and paraspinal nerves that traverse the spinal canal, which is much smaller than normal [Hecht et al., 1985; Hall and Rimoin, 1988; Hecht et al., 19891. Infants and young children may exhibit motor dysfunction and respiratory compromise from compression in Received for publication April 8,1991; revision received August 15, 1991. Address reprint requests to William A. Horton M.D., Division of Medical Genetics, Department of Pediatrics, University of Texas Medical School, P.O. Box 20708, Houston, TX 77225.

0 1992 Wiley-Liss, Inc.

the foramen magnum and upper cervical spine,whereas compression in the lumbar region typically presents during adulthood with neurologic symptoms in the legs. Currently there is no medical therapy to normalize bone growth in achondroplasia;there is no rational basis for such therapy yet. The causative mutation has not been identified; and even though it can be assumed to affect adversely endochondral bone growth, the mechanism by which this occurs is unknown. Microscopic studies of the skeletal growth plate have shown mild nonspecific irregularities, but the structure is generally considered to be normal [Ponsetti, 1970; Rimoin, 1975; Sillence et al., 19791. However, using morphometric methods we recently observed that the achondroplastic iliac-crest growth plate was slightly shorter than that of age-matched control individuals [Horton et al., 19881. The shortness was greater in homozygous than in heterozygous achondroplasia, suggesting a dose effect of the mutation. Furthermore, the shortness was greater in the proliferative zone compared to the hypertrophic zone, raising the possibility of defective chondrocyte proliferation. Such a defect would be consistent with the microscopic observations and would be potentially amenable to treatment with agents that promote chondrocyte mitosis. Growth hormone (GH)has long been recognized as an important regulator of linear skeletal growth [Isaksson, 19881. Despite debate over whether it acts directly on growth-plate chondrocytes, indirectly through local growth factors, or both, it is accepted that GH promotes chondrocyte proliferation [Nilsson et al., 19861. GH-dependent insulin-like growth factor I (IGF-I) has been shown to stimulate clonal expansion of human chondrocytes in vitro, and it has been postulated that GH increases responsiveness of the cells to IGF-I [Lindahl et al., 1987; Isaksson, 19881.Accordingly, could GH in the pharmacologic doses currently used to treat non-GHdeficient forms of short stature, such as Ullrich-Turner syndrome, increase growth-platechondrocyteproliferation in achondroplasia?While current dogma holds that GH is ineffective in stimulating growth in the disorder, we know of no investigations that have examined this question critically. The issue takes on relevance as the types of short stature treated with GH continue to enlarge, making it likely that children with achondroplasia will be treated

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with the hormone [Bierich, 1989; Rosenfeld, 19891. Indeed, this raises a second question of whether it is safe to treat children with achondroplasia with pharmacologic doses of GH. In particular, if GH treatment fails to stimulate endochondral ossification but promotes membraneous ossification, which is thought to be normal in achondroplasia, the spinal stenosis could theoretically be worsened. This is because the inner border of the foramen magnum is equivalent to the periosteal surface of a long bone; it grows by membraneous ossification. If periosteal growth were stimulated in the face of reduced or absent sutural growth at this site, the foramen magnum diameter would diminish. Ordinarily this would probably be inconsequential and go unnoticed, but in achondroplasia even a slight reduction might bring on or aggravate preexisting spinal compression. The current investigation was therefore carried out as a pilot study to examine the efficacy and safety of GH treatment of achondroplasia.

METHODS Six children with typical features of (heterozygous) achondroplasia were studied. The protocol was approved by the Institutional Committee for the Protection of Human Subjects. Identifying information is given in Table I. None had a history of significant neurologic or respiratory dysfunction. After initial measurements were taken, they were followed for 6 months to determine pretreatment growth velocity. They were then evaluated with physical and neurologic examinations and height measurements. Most of the children had a computerized tomography (CT) of the skull and somatosensory evoked potentials (SEPs) to evaluate the transmission of neural impulses through the foramen magnum. Some of the children had skeletal roentgenograms and a battery of laboratory studies, which included CBC, UA, chemistry profile, thyroxine, and antibodies to human GH. Recombinant human GH (rmethGH, Genentech, S. San Francisco, CAI was started at a dose of 0.3 mglkgl wk. It was given subcutaneously or intramuscularly 3 times a week or every other day for 6 months. In the children who had laboratory studies performed, glucose and antibodies to human GH were measured at 1,2,and 4 months after starting the trial; and the battery of tests was repeated a t the end of the trial. The children who had SEPs and foramen magnum CT measurements before the trial had them repeated a t the end of the trial. Parents were asked for their assessment of the child‘s

response to GH. After the trial, the children were followed for 6 more months to determine post-treatment growth velocity. Growth velocity values during these periods were compared to “normal” values for achondroplasia [Horton et al., 19781. Statistical comparisons were not performed because of the small sample size.

RESULTS Six children were studied. Their sex, age, height relative to achondroplasia standards at the onset of the study, and growth velocities are listed in Table I. Compared to age- and sex-matched patients with achondroplasia, their pretreatment height ranged from - 2.2 to + 2.5 SD. Growth velocities are depicted in Fig. 1;and the results of SEPs, CT, and laboratory tests are given in Table 11. None of the patients exhibited signs of puberty during or after the study. Four children showed increases in growth velocity during GH treatment compared to before and after treatment; 2 exhibited substantial increases. The latter 2 children had the lowest growth velocitiesprior to treatment (Fig. 1). Two children showed no increase in growth velocity during treatment. No complications were detected, although patient 1 fell during a school accident during the last week of the GH trial, resulting in a subdural hematoma, which was evacuated without complication. Of the children who had SEFs done, all were normal before and after GH treatment. Foramen magnum measurements determined from the brain CTs before and after treatment were unchanged, and there was no noticeable change in foramen magnum shape. No abnormalities were detected by the laboratory testing, except for GH antibodies (titer = 1.4), which were found in patient 3 only a t the end of the GH trial. DISCUSSION These data suggest that recombinant human GH in doses used to treat non-GH-deficientforms of short stature (0.3 mg/kg/wk) increases short-term height velocity in some children with achondroplasia. When growth velocity on treatment was compared to velocity off (average of before and after) treatment, it increased, on the average, by a factor of 2.3. However, the response was variable, being greatest in children with the lowest growth velocities before treatment. Four children whose velocities were within the expected range for achondroplasia showed an average increase of 1.3. There was no obvious correlation of response to GH with sex or age,

TABLE I. Relationship to Achondroplasia Standards Patient 1 2 3 4

5 6

Age 10 10

Sex

7 7 6 10

F F M

Pretreatment height in SDs” - 0.6 -2.2 2.5 1.8 - 0.8

M

-0

M M

Growth velocity ( c d y r ) Before During After 1.o 6.2 1.2 1.4 6.6 2.8 3.6 5.0 3.4 4.8 6.8 4.2 4.8 4.4 2.6 5.2 4.8 4.0

Change on treatmentb 5.6 3.1 1.4 1.5 1.2 1.0

“Relative height in SDs compared to achondroplasia standards [Horton et al., 19781. Velocity during GH triallaverage velocity before and after trial.

GH in Achondroplasia

nt

P Before

During

After

Fig. 1. Graphic representation of the growth rates before, during, and after GH treatment of the 6 subjects.

although the 2 children showing the greatest response were 10-year-old prepuberal boys. There were probably many reasons for the variable response to GH. As noted above, pretreatment growth rate may be important. Patients 1and 2, whose average off-treatment velocity was substantially below that predicted for achondroplasia [Horton et al., 19781,exhibited increases of greater than 5- and 3-fold, respectively. Most striking about these children was their low beforeand after-treatment growth rates. It is conceivable that they had GH insufficiency that responded to GH treatment. This seems unlikely since they otherwise had typical achondroplasia and were not exceptionally short for the disorder. However, GH provocative testing was not done. The possibility must also be raised that the subdural hematoma suffered by patient 1 a t the end of the treatment trial disrupted hypothalamic/pituitary function and secondarily interfered with growth in the post-treatment period. This also seems unlikely since the lesion was treated in an effectiveand timely fashion, the post-trial growth velocity was the same as the pretreatment velocity, and subsequent follow-up showed no evidence of such dysfunction. A coincidental seasonal slow down in growth rate may have contributed to the off-treatment low growth rates in the 2 children. It would not have been detected because of the short duration of the study. No untoward effects were observed during the study. In particular, there was no evidence of spinal-cord com-

pression or narrowing of the foramen magnum. While the likelihood of such an event was anticipated to be low, examining this possibility was consideredimportant because of its insidious onset and potentially devastating effects. The youngest child studied was 6 years old. By this age, the foramen magnum has essentially reached its adult size in achondroplasia [Hecht et al., 19891. Thus, although the current data do not apply to the growing structure, i.e., especially during the first year, the results suggest that neurologic complicationswould not result from GH treatment of older children with achondroplasia. The effect of GH on the growing foramen magnum is not known; however, it is possible that it could even enhance growth of the structure. Two criticisms of the study are its short duration and the small number of patients. Ideally, evaluations of growth-promoting agents should be carried out over at least a year to compensate for seasonal variation in growth rate exhibited by many children. Likewise, they should be done in a large number of children to permit statistical analysis [Tanner et al., 19661. Such would have been desirable in this investigation. However, the rarity of the disorder, and especially safety concerns, i.e., unknown response of an abnormally growing skeleton to GH, led to the design of a short duration, “pilot,” study. Changes in bone age were not determined, as is usually done in evaluating growth-promoting agents. This was because of the possibility that achondroplasia may have altered the radiographic parameters used to assign bone age, making such determinations difficult to interpret, particularly in such a small number of patients at different ages. Clearly, a larger scale study is needed to resolve the issues raised, such as the effects of GH on skeletal maturation. Finally, a note of caution needs to be introduced regarding the use of GH as a growth-promoting agent in the chondrodysplasias. In many of the disorders, including achondroplasia,the gene mutation seems to &ect adversely only skeletal growth [Rimoin and Lachman, 1990; Horton and Hecht, 19911. Moreover, the growth plate, which is responsible for linear bone growth, appears to be a t least qualitatively intact by the morphologic and biochemical criteria currently used [Sillence et al., 1979; Horton and Hecht, 19911. Pathogenetically, such disorders may result from local disturbances in growthplate regulation. Accordingly, the use of GH may be a reasonable approach to therapy. It may be effective in some of these disorders and would not be expected to cause serious side effects. However, the growth plate is

TABLE 11. Results of SEPs, CT, and Lab Tests Patient 1 2 3 4

5 6

SEPs N N N N ND ND

CT NC NC NC NC ND NC

Glucose N N ND ND N

N

669

GHAb

N N ND ND ND fa

Thyroid N N ND ND N N

Urine N N ND ND ND N

SMAC N N ND ND ND N

SEPs = somatosensory evoked potentials; CT = computerized tomography of head; GHAb = antibodies to human GH; Urine = urinalysis; SMAC = chemistry profile; N = normal before, during, and after GH trial; NC = no change; ND = not done. “Positive titer detected at 6th month of treatment.

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qualitatively abnormal in many other chondrodysplasias. Pharmacologic stimulation of such structures may produce effects that are unexpected and unwanted. For example, there is growing evidence that mutations of the gene encoding type I1 collagen are responsible for the spondylopeiphyseal dysplasia clinical phenotype [Byers, 1989; Horton et al., 1989; Lee et al., 1989; Vissing et al., 1989; Tiller et al., 19903. The resulting disturbances of cartilage matrix interfere with growth-plate function and predispose permanent cartilages, e.g., articular cartilage, to degeneration. The consequences of increased production of abnormal cartilage matrix resulting from GH therapy are not known. Cartilage-hair hypoplasia (McKusick-type metaphyseal chondrodysplasia), in which immune deficiency and malignancy may occur [Francomano et al., 19831, provides another example. Although GH therapy is thought to not predispose short but otherwise healthy individuals to malignancy [Stahnke and Zeisel, 19891,it may be wise to not use growth-promoting agents in patients already predisposed to malignancy. Thus, GH may be effective in stimulating growth in some, perhaps many, chondrodysplasias. But the potential benefits and side effects should be considered thoroughly before therapy is started; ideally, trials should be carried out in a setting where the potential complications unique to each disorder can be carefully monitored. In summary, recombinant GH was shown to safely increase short-term growth velocity in some children with achondroplasia. Studies evaluating more factors, i.e., body proportions, bone age, etc., utilizing a larger number of patients and longer treatment trials, will be needed to determine the long-term efficacy and safety of GH in achondroplasia,

ACKNOWLEDGMENTS This study was supported by a research grant (15,953) from the Shriners Hospitals for Crippled Children (WAH). We wish to think Genentech for supplying the GH (F’rotropin) and GH antibody measurements. REFERENCES Bierich J R (1989):Growth hormone therapy in short children without classical growth hormone deficiency. J Endocrinol Invest 12 (Suppl 3):25-33. Byers PH (1989):Molecular heterogeneity in chondrodysplasias. Am J Hum Genet 45:l-4. F’rancomano CA, Rojak J E , McKusick VA (1983):Cartilage hair hypoplasia in the Amish: Increased susceptibility to malignancy. Am J Hum Genet 35239. Hall JG, Rimoin DL (1988): Medical complications of dwarfing syndromes. Growth Genet Hormones 4:6-9.

Hecht JT, Nelson FW, Butler IJ, Horton WA, Scott CI Jr, Wassman ER, Mehringer CM, Rimoin DL, Pauli RM (1985):Computerized tomography of the foramen magnum: Achondroplasticvalues compared to normal standards. Am J Med Genet 20:355-360. Hecht JT, Horton WA, Reid CS, Pyeritz RE, Chakraborty R (1989): Growth of the foramen magnum in achondroplasia. Am J Med Genet 32:528-535. Horton WA, Rotter JI, Rimoin DL, Scott CI, Hall J G (1978):Standard growth curves for achondroplasia. J Pediatr 93:435-438. Horton WA, Hood OJ, Machado MA, Campbell D (1988):Growth plate cartilage studies in achondroplasia. In Nicoletti B, Kopits SE, Ascani E, McKusick VA (eds): “Human Achondroplasia, A Multidisciplinary Approach.” New York Plenum Press, pp 81-89. Horton WA, Campbell D, Machado MA, Chou J (1989):?srpe I1 collagen screening in the human chondrodysplasias. Am J Med Genet 34:579-583. Horton WA, Hecht JT: Chondrodysplasias (1991).In RoyceP, Steinman B (eds): “Extracellular Matrix and Heritable Disorders of Connective Tissue.” (in press). Isaksson OGP, Lindahl A, Nilsson A, Isgaard J (1988):Action ofgrowth hormone: Current views. Acta Paediatr Scand [Suppl] 343:12-18. Lee B, Vissing H, Ramirez F, Rogers D, Rimoin DL (1989):Identification of the molecular defect in a family with spondylopeiphyseal dysplasia. Science 244:978-980. Lindahl A, Nilsson A, Isaksson OGP (1987):Effects of growth hormone and insulin-like growth factor-I on colony formation of rabbit epiphyseal chondrocytes at different stages of maturation. J Endocrinol 115:263-271. Nilsson A, Isgaard J, Lindahl A, Dahlstrom A, Skottner A, Isaksson OGP (1986):Regulation by growth hormone of number of chondrocytes containing IGF-I in rat growth plate. Science 233:571-574. Rimoin DL (1975):The chondrodystrophies. Adv Hum Genet 5:l-118. Rimoin DL, Horton WA (1978): Short stature: Parts I & 11. J Pediatr 92:523-528, 697-704. Rimoin DL, Lachman RS (1990): The chondrodysplasias. In Emery AEH, Rimoin DL (eds): “Principles and Practice of Medical Genetics.” London: Churchill Livingstone, pp 895-932. Rosenfeld RG (1989):Update on growth hormone therapy for ’hrner’s syndrome. Acta Paediatr Scand Suppl 356:103-110. Scott CI (1972):The genetics of short stature. Prog Med Genet 8:243299. Scott CI Jr (1976):Achondroplastic and hypochondroplastic dwarfism. Clin Orthop 114:18-30. Sillence DO, Horton WA, Rimoin DL (1979):Morphologicstudies in the skeletal dysplasias. Am J Pathol 96:813-870. Stahnke N, Zeisel HJ (1989):Growth hormone therapy and leukaemia. Eur J Pediatr 148:591-596. Tanner JM, Whitehouse RH, Takaishi M (1966):Standards from birth to maturity for height velocity, and weight velocity: British children, 1965. Arch Dis Childh 41:613-635. Tiller GE, Rimoin DL, Murray LW, Cohn DH (1990):lhndem duplication within a type I1 collagen gene (COL2A1)exon in an individual with spondyloepiphysialdysplasia. Proc Natl Acad Sci USA 87:3843. Vissing H, DAlessio M, Lee B, Ramirez F, Godfrey M, Hollister DW (1989): Glycine serine substitution in the triple helical domain of pro-alpha l(I1) collagen results in a lethal perinatal form of shortlimbed dwarfism. J. Biol Chem 264:18265.

Growth hormone therapy in achondroplasia.

A pilot study was carried out to examine the safety and efficacy of recombinant human growth hormone for growth-promoting therapy of achondroplasia. T...
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