March 1976 The Journal of P E D I A T R I C S

427

Laron dwarfism: Growth and immunoreactive insulin following treatment with human growth hormone A 13 1 ~2-year-old boy with features of growth hormone deficiency had elevated fasting plasma GH levels (5. 7 to 66 ng/ml). Serum somatomedin values remained low despite treatment with human growth hormone. Plasma GH values were suppressed following oral administration of glucose and increased following insulin-induced hypoglycemia, L-dopa, and arginine. Chlorpromazine suppressed GH, both fasting and during IIH. These results suggest that the neuroendocrine mechanisms mediating GH secretion seemed to be intact. Peak plasma insulin levels increased in response to glucose administration after HGH suggesting that GH has a direct effect on the pancreatic beta cell which is not mediated by Sin. Plasma testosterone values increased to adult male levels, but there was inadequate secondary sexual response. Growth was enhanced by H G H and may have been due to testosterone and~or insulin. Although Laron dwarfism may result from a receptor defect, an abnormality in GH structure is also possible.

Robert D. Clemons, M.D.,* Gertrude Costin, M.D., and Maurice D. Kogut, M.D.,** L o s A n g e l e s , Calif.

TH~ SYNDROME of dwarfism with elevated circulating immunoreactive growth hormone was first described in 1966 by Laron and associates ~ in three children. Twentyseven additional cases have been described ~-1~and the existence of five others has been cited. 4 It appears to be inherited in an autosomal recessive fashion, u Clinically, patients with Laron dwarfism closely resemble patients with isolated GH deficiency. In contrast to patients with hyposomatotropic dwarfism, however, low levels of circuFrom the Division of Endocrinology and Metabolism, Childrens Hospital of Los Angeles, and the Department' of Pediatrics, University of Southern California School of Medicine. Supported in part by grants from the General Clinical Research Centers Program (RR-86) o f the Division of Research Resources, National Institutes of Health and the Department o f Health, Education, and Welfare (No. 911). Presented in part before the APS-SPR meetings in Washington, D.C., April 28 to May 3, 1974. *Trainee, Metabolic Training .Gr~mt(No. 911). **Reprint address: Childrens Hospital of Los Angeles, 4650 Sunset Blvd., Los Angeles, Calif. 90027.

lating somatomedin persist following administration of exogenous human growth hormone in patients with Laron dwarfism. 12 Characteristically, these patients are resistant to most of the metabolic actions of GH? -1~ The basic abnormality in Laron dwarfism is not known. It has been suggested that impaired responsiveness to HGH may result from a peripheral receptor abnormality with lack of generation of somatomedin sharing in the defect?-" Abbreviations used Sm: somatomedin HGH: human growth hormone IIH: insulin-induced hypoglycemia RIA: radioimmunoassay IRI: immunoreactive insulin GHRF: growth hormone-releasing factor Alternatively, the patient may produce an abnormal GH molecule which competes with exogenous HGH for receptor sites? In the present report the results of studies designed to assess the hypothalamic-pituitary regulation of GH secretion and the long-term effects of chronic HGH treatment

Vol. 88, No. 3, pp. 427-433

428

Clemons, Costin, and Kogut

1 I:l

i

"

Fig. I, The patient at 13 1/2 years of a g e a t the ttme of study.

o n insulin responsiveness a n d linear growth in a 13 1/2year-old M e x i c a n b o y with L a r o n dwarfism are presented. CASE REPORT A 13 1/2-year old boy of Mexican descent was admitted to the Clinical Research Center of Childrens Hospital of Los Angeles in September, 1972, for evaluation of short stature. Birth weight and length were unknown. He had always grown slowly but had otherwise been healthy. There was no history of symptoms suggestive of hypoglycemia. His school performance was excellent. The father's height was 157.5 cm and the mother's height was 161 cm. The heights of seven siblings ranged from 122 cm (at age 8 years) to 168 cm. There was no family history of diabetes mellitus, excessive short stature, or consanguinity. On physical examination he had the typical appearance of hyp0somatotropic dwarfism with an immature-appearing facies and relative truncal obesity (Fig. 1). Height was 97.2 cm (height

The Journal of Pediatrics March 1976

age 3 2/12 years) and weight was 16.7 kg (weight age 4 2/12 years). Blood pressure was 110/65. There were no signs of puberty. The penis was 3.5 cm long and the testes measured 1.5 • 1.0 cm. Both testes were in the inguinal canal. Complete blood count, urinalysis, BUN, and serum concentra. tions of electrolytes were normal. Fasting blood glucose was 83 mg/dl. Total serum lipids were 571 mg/dl; plasma free fatty acids, 535 mg/dl; and serum concentration of cholesterol, 173 mg/dl. Serum T, by radioimmunoassay was 10.2/zg/dl (normal 5.0 to 13.0 ~g/dl); free T , 2.7 ng/dl (normal 1.5 to 4.0 ng/dl); and TSH, 7.7 ~U/nft (normal 2.0 to 10/~U/ml). Serum LH was 3.0 mlU/ml, FSH 2.6 mlU/ml, and testosterone (T) 85 ng/dl. Urinary excretion of 17-ketogenic steroids in a 24-hour urine sample was 1.0 mg and increased to 8.3 mg following oral metyrapone. Roentgenograms of the skull were normal and the bone age was 7 1/2 years according to the standards of Gruelich and Pyle. Following completion of studies to be described, the patient was started on HGH treatment, 4 IU three times weekly in January, 1973. The patient's growth rate before and during HGH treatment is shown in Fig. 2. Prior to treatment the growth rate was 0.33 era/ month, approximately one-half the expected rate for his chronologic age. During HGH treatment he grew 0.54 cm/month in the first three months, 0.69 cm/rnonth in the following three months, 0.64 cm/month in the next seven months, and 0.72 era/month during the next ten months. His rate of growth averaged 8.1 cm/ yr and exceeded that expected for his chronologic age. A rapid increase in bone age from 8 to 10 years was noted after six months of treatment. At that time, although there were no clinical signs of puberty, plasma T increased from 85 ng/dl to 425 ng/dl. After 13 months of treatment the bone age was 11 years and plasma T was 722 ng/dl. After 23 months of treatment the testes were at the stage of early adolescent devefopment and the penis was 6 era long; pubic and axiltary hair were not present. Serum T was 748 ng/dl; LH values obtained during sleep ranged from 12.5 to 15.5 mlU/ml, and bone age was 12 1/2 years. Serum T, (RIA) was 7.6/~g/dl. There were no significant changes in concentrations of blood glucose, BUN, fasting plasma FFA, and serum calcium and phosphorus during HGH treatment. Twenty-four-hour urinary excretion levels of calcium, phosphorus, creatinine, and hydroxyproline were not altered by HGH. A short-term effect of HGH on nitrogen retention was not noted. MATERIALS

AND METHODS

This study was a p p r o v e d b y the HospitaI C o m m i t t e e on Investigation, and i n f o r m e d c o n s e n t was o b t a i n e d from the patient and his father. All tolerance tests were p e r f o r m e d three days a p a r t a n d were preceded by a n o v e r n i g h t fast. T h e p a t i e n t received a 50% c a r b o h y d r a t e diet for three days b e f o r e a n d continuously during all studies. E x o g e n o u s H G H was withheld for a m i n i m u m o f 48 h o u r s p r i o r to all tests conducted after initiation o f l o n g - t e r m H G H t r e a t m e n t .

Volume 88 Number 3

Laron dwarfism

Growth Rote (cm/month)

0.6

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Testosterone

85

425

722

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748

(ng/lOOml) Bone Age (yr)

7.5

8.0 8.0

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(Yr.)

Fig. 2. Growth rate (cm/month) in the patient before and during HGH treatment is indicated on the bar graph. The observed growth rate in the patient is indicated by the broken lines, and theexpected growth rate for the fiftieth percentile for chronologic age is indicated by the solid lines. The actual linear heights, plasma testosterone levels, and bone ages of the patient at various ages are plotted on the lower portion of the graph.

Blood glucos e, immunoreactive insulin, and GH levels were measured during fasting and at 30, 60, 90, 120, 180, 240, 300, and 360 minutes, respectively, following the administration of oral glucose (1.75 g m / k g body weight), and during fasting and at 15, 30, 60, 90, and 120 minutes, respectively, following initiation of intravenous administration of 10% solution of/-arginine HC1 (0.5 g m / k g body weight) infused over a 30-minute period. Following the intravenous administration of crystalline insulin (0.05 to 0.1 U/kg body weight), blood glucose and GH levels were measured fasting and at 15, 30, 60, 90, and 120 minutes, respectively. Blood GH levels were measured fasting and at 30, 60, 90, 120, and 150 minutes, respectively, following the oral administration of 250 mg of L-dopa. Chlorpromazine, 2.0 m g / k g / d a y in four divided doses, was administered by mouth for two weeks and at another time, dexamethasone, 2.0 mg/m2/day in four divided doses, was given by mouth for two days. Insulin tolerance tests as described above were performed following the chlorpromazine and dexamethasone treatment periods and one month before HGH was begun. Human growth hormone was administered, 4.0 IU three times weekly for 23 months, and oral glucose tolerance tests, as described above, were performed 3, 13, and 23 months, respectively, after treatment with HGH was begun. Blood glucose was measured by the glucose oxidase method 13 and plasma IRP" and GH TM ~5 by radioimmunoassay. Serum LH, FSH, and T were measured by standard RIA methods at Nichol's Institute for Endocrinology, Torrance, California. Serum Sm determinations

were performed in the laboratories of Dr. William H. Daughaday at the Washington University, St. Louis, using a modification of the pig cartilage disc method. 17 RESULTS Growth hormone levels. Fasting plasma GH levels ranged from 5.7 to 66 ng/ml, with a mean of 22.9 ng/ml. Plasma GH levels following glucose and provocative stimuli are shown in Table I. Plasma GH levels increased following insulin-induced hypoglycemia, L-dopa, and arginine to levels higher than those usually observed in normal prepubertal children. Somatomedin levels. The mean pretreatment serum Sm level was 0.35 U/ml (normal 0.4 to 1.5 U/ml). The mean Sm level was 0.21 U / m l following intramuscular HGH, 5.0 IU daily for five days. Several Sm values were below 0.4 U / m l during 12 months of HGH treatment (12 IU per week). Hypothalamic-pituitary regulation of GH secretion. T o further elucidate hypothalamic-pituitary regulation of GH secretion, responses to IIH were determined before and after administration of chlorpromazine and dexamethasone(Table II). After the administration of chlorpromazine for two weeks the mean value of several fasting GH levels was suppressed to less than 0.8 ng/ml; the peak GH level was 29 ng/ml following IIH and was less than the peak GH value of 46 ng/ml noted before any drug was administered. Administration of dexamethasone for two days failed to suppress either the elevated fasting GH level or the levels following IIH.

430

Clemons, Costin, and Kogut

The Journal of Pediatrics March 1976

Table I. Blood glucose (mg/dl), growth hormone (ng/ml), and immunoreactive insulin (/~U/ml) levels following oral glucose and L-dopa and intravenous arginine and insulin Minutes Provocative stimuli

Date of study

Glucose (1.75 gm/kg)

9/13/72

Arginine (0.5 gm/kg)

9/20/72

Insulin (0.05 U/kg) L-dopa (250 mg)

9/28/72 10/19/72

Blood Glucose GH IRI Glucose GH IRI Glucose GH Glucose GH IRI

--30 90.0