0021-972X/78-0047-0461S02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1978 by The Endocrine Society
Vol. 47, No. 2 Printed in U.S.A.
GROWTH FAILURE WITH NORMAL SERUM RIA-GH AND LOW SOMATOMEDIN ACTIVITY: SOMATOMEDIN RESTORATION AND GROWTH ACCELERATION AFTER EXOGENOUS GH A.A. Kowarski, J. Schneider, E. Ben-Galim, V.V. Weldon, and W.H. Daughaday The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 and Washington University School of Medicine, St. Louis, Missouri 63110 ABSTRACT; Two three-year-old boys with dwarfism (height ages 1-4/12 and 111/12 years) and delayed bone ages (1-4/12 and 1-9/12 years) had normal growth hormone (GH) responses after stimulation and low levels of somatomedin. Unlike patients with Laron Syndrome, the two patients generated normal levels of somatomedin after administration of exogenous hGH. Treatment with hGH (2 IU every other day) brought about a significant increase in the growth rate of both patients. The growth rate of the first patient increased from 2 cm/year before treatment to 12 cm/year on therapy. The growth rate of the second patient was 4.5 cm/year before treatment, and 8.3 cm/year while on treatment. The two cases represent a new syndrome of dwarfism which may be caused by secretion of a biologically inactive but immunoreactive GH. The syndrome of familial dwarfism with high plasma immunoreactive growth hormone (RIA-GH) was first described by Laron and his associates (1). In this syndrome the clinical features of growth hormone deficiency are associated with elevated plasma RIA-GH levels and low levels of plasma somatomedin. The failure of hGH treatment to correct these abnormalities (2) and the normal radioreceptor activity of endogenous GH (3) makes it likely that this condition is the result of abnormal tissue receptors for GH. The purpose of this report is to describe two cases of dwarfism who appeared to be refractory to endogenous GH but who did respond to exogenous hGH.
Submitted January 20, 1978. Supported by Grants HD 06284, AM 00180, AM 01526 RR 52, RR 36 and T 32 AM 07116 of the NIH. The hGH was donated by the National Pituitary Agency.
t
Presented in part at the VI Congress Amrigs in Porto Allegre, Brazil (Oct. 1977) and the Soc. Ped. Res., N.Y. (April 1978). Pediatric Research 12:415, 1978.
Age (years)
Fig. 1. Growth curves of patient 1 (o-o) and patient 2 (•-•). Periods of treatment with growth hormone delineated by the squares. Clinical Description Case 1 was born after a full term gestation with a birth length of 53.3 cm and a birth weight of 3.1 kg. The post natal growth of this boy was soon noted to be retarded (Fig. 1 ) . At the age of 3-9/12 years his height was 80.7 cm; bone age was 1-5/12 years. His body proportions were appropriate for his height. His face was relatively undeveloped and his voice was high pitched. He exhibited the pudginess frequently observed in pituitary dwarfs. Case 2 was born after a 34 week gestation with a birth length of 43
461
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RAPID COMMUNICATIONS
cm and a weight of 2.3 kg. The subsequent growth of this boy was less than the third percentile. When examined at3-9/12 years, his height was 89.4 cm and his bone age was 1-9/12 years. He had normal body proportions and subcutaneous fat was not considered abnormal. There was no history of short stature in the families of either patient. The parents were not consanguineous. The family environment for each child was considered to be good. Methods Radioimmunoassay of serum GH was carried out by two different methods (4, 5 ) . The purified hGH standard was a gift from Dr. A.E. Wilhelmi, provided through the National Pituitary Agency. There was good agreement between the results of the two methods. Dilution studies showed good parallelism with hGH standard. Radioreceptor assays for GH (RRA) were performed by a previously published method (6). The hypophysectomized rat bioassay for somatomedin activity (7) was carried out before and after exogenous hGH administration (Table 2). No evidence of a serum inhibitor was detected. Results The baseline serum GH concentrations were within normal limits (Table 1) and the responses to provocative testing were unequivocally normal. In patient 1 the cortisol response to hypoglycemia was normal. The hypoglycemia following insulin administration was also normal. Plasma T4 and TSH in each patient were normal. Serum samples of these two patients were examined by radioreceptor assay and the results compared to results obtained with radioimmunoassay (Table 2 ) . The ratio of serum RRA/RIA was lower in Case 1 than in Case 2 and appeared to be less than serum ratios in 18 patients with elevated GH which were run in the same series of assays.
JCE&M Vol47
1978 No 2
Serum somatomedin under basal conditions was less than 0.2 units per ml on repeated occasions in each case (Table 3). After the administration of hGH serum somatomedin rose promptly to normal levels. After the completion of the above studies the patients were treated with human growth hormone 2 IU every other day. The growth velocity of Case 1 increased from 2 cm/year to 12 cm/year during the first year of treatment. The second patient, whose initial growth velocity was 4.5 cm/year, had a growth velocity of 8.3 cm/year during 8 months of treatment. No significant increase in weight occurred during this period of study. Discussion The two patients described above had decreased plasma somatomedin levels on repeated occasions despite normal levels of serum growth hormone. The growth hormone response to provocative stimuli was, if anything, supernormal. The possibility that the endogenous growth hormone of these patients was ineffective was suggested by the normal rise of serum somatomedin after growth hormone administration; it was further supported by the stimulation of skeletal growth which followed the therapeutic trial with GH in the usual low dose employed for the treatment of hypopituitary dwarfism. The somatomedin and growth responses clearly distinguish these cases from cases of Laron dwarfism who are refractory to exogenous hGH treatment (2). Low levels of somatomedin are associated with high levels of serum growth hormone in patients with severe protein calorie malnutrition (8); however, the nutritional state and emotional stability of our patients were apparently normal. The characterization of the circulating growth hormone in our patients is still incomplete. The serum growth hormone reacted normally in the radioimmunoassay. The growth hormone in serum from patient 1 did
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463
Table 1:
Serum levels of radioimmunoassayable GH following stimulation with Arginine-Insulin (patient 1) or Arginine-L-Dopa (patient 2 ) . (The tests were carried out twice on each patient.) Time RIA GH, ng/m] (min) Patient 1 Patient 2 0 10.4 20.4 1.5 3.6 15 8.2 5.7 2.1 0.94 30 7.2 6.9 45 9.5 13.07 14.0 34.3 60 12.1 48.8 31.8 28.0 80 5.0 21.5 90 18.7 8.46 32.0 11.5 105 10.7 8.3 120 13.6 4.39 6.9 3.3
Table 2:
RIA and RRA assay of serum GH. RRA RIA Case Serum ng/ml ng/ml
Vol. 47, No. 2 Printed in U.S.A.
GROWTH FAILURE WITH NORMAL SERUM RIA-GH AND LOW SOMATOMEDIN ACTIVITY: SOMATOMEDIN RESTORATION AND GROWTH ACCELERATION AFTER EXOGENOUS GH A.A. Kowarski, J. Schneider, E. Ben-Galim, V.V. Weldon, and W.H. Daughaday The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 and Washington University School of Medicine, St. Louis, Missouri 63110 ABSTRACT; Two three-year-old boys with dwarfism (height ages 1-4/12 and 111/12 years) and delayed bone ages (1-4/12 and 1-9/12 years) had normal growth hormone (GH) responses after stimulation and low levels of somatomedin. Unlike patients with Laron Syndrome, the two patients generated normal levels of somatomedin after administration of exogenous hGH. Treatment with hGH (2 IU every other day) brought about a significant increase in the growth rate of both patients. The growth rate of the first patient increased from 2 cm/year before treatment to 12 cm/year on therapy. The growth rate of the second patient was 4.5 cm/year before treatment, and 8.3 cm/year while on treatment. The two cases represent a new syndrome of dwarfism which may be caused by secretion of a biologically inactive but immunoreactive GH. The syndrome of familial dwarfism with high plasma immunoreactive growth hormone (RIA-GH) was first described by Laron and his associates (1). In this syndrome the clinical features of growth hormone deficiency are associated with elevated plasma RIA-GH levels and low levels of plasma somatomedin. The failure of hGH treatment to correct these abnormalities (2) and the normal radioreceptor activity of endogenous GH (3) makes it likely that this condition is the result of abnormal tissue receptors for GH. The purpose of this report is to describe two cases of dwarfism who appeared to be refractory to endogenous GH but who did respond to exogenous hGH.
Submitted January 20, 1978. Supported by Grants HD 06284, AM 00180, AM 01526 RR 52, RR 36 and T 32 AM 07116 of the NIH. The hGH was donated by the National Pituitary Agency.
t
Presented in part at the VI Congress Amrigs in Porto Allegre, Brazil (Oct. 1977) and the Soc. Ped. Res., N.Y. (April 1978). Pediatric Research 12:415, 1978.
Age (years)
Fig. 1. Growth curves of patient 1 (o-o) and patient 2 (•-•). Periods of treatment with growth hormone delineated by the squares. Clinical Description Case 1 was born after a full term gestation with a birth length of 53.3 cm and a birth weight of 3.1 kg. The post natal growth of this boy was soon noted to be retarded (Fig. 1 ) . At the age of 3-9/12 years his height was 80.7 cm; bone age was 1-5/12 years. His body proportions were appropriate for his height. His face was relatively undeveloped and his voice was high pitched. He exhibited the pudginess frequently observed in pituitary dwarfs. Case 2 was born after a 34 week gestation with a birth length of 43
461
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462
RAPID COMMUNICATIONS
cm and a weight of 2.3 kg. The subsequent growth of this boy was less than the third percentile. When examined at3-9/12 years, his height was 89.4 cm and his bone age was 1-9/12 years. He had normal body proportions and subcutaneous fat was not considered abnormal. There was no history of short stature in the families of either patient. The parents were not consanguineous. The family environment for each child was considered to be good. Methods Radioimmunoassay of serum GH was carried out by two different methods (4, 5 ) . The purified hGH standard was a gift from Dr. A.E. Wilhelmi, provided through the National Pituitary Agency. There was good agreement between the results of the two methods. Dilution studies showed good parallelism with hGH standard. Radioreceptor assays for GH (RRA) were performed by a previously published method (6). The hypophysectomized rat bioassay for somatomedin activity (7) was carried out before and after exogenous hGH administration (Table 2). No evidence of a serum inhibitor was detected. Results The baseline serum GH concentrations were within normal limits (Table 1) and the responses to provocative testing were unequivocally normal. In patient 1 the cortisol response to hypoglycemia was normal. The hypoglycemia following insulin administration was also normal. Plasma T4 and TSH in each patient were normal. Serum samples of these two patients were examined by radioreceptor assay and the results compared to results obtained with radioimmunoassay (Table 2 ) . The ratio of serum RRA/RIA was lower in Case 1 than in Case 2 and appeared to be less than serum ratios in 18 patients with elevated GH which were run in the same series of assays.
JCE&M Vol47
1978 No 2
Serum somatomedin under basal conditions was less than 0.2 units per ml on repeated occasions in each case (Table 3). After the administration of hGH serum somatomedin rose promptly to normal levels. After the completion of the above studies the patients were treated with human growth hormone 2 IU every other day. The growth velocity of Case 1 increased from 2 cm/year to 12 cm/year during the first year of treatment. The second patient, whose initial growth velocity was 4.5 cm/year, had a growth velocity of 8.3 cm/year during 8 months of treatment. No significant increase in weight occurred during this period of study. Discussion The two patients described above had decreased plasma somatomedin levels on repeated occasions despite normal levels of serum growth hormone. The growth hormone response to provocative stimuli was, if anything, supernormal. The possibility that the endogenous growth hormone of these patients was ineffective was suggested by the normal rise of serum somatomedin after growth hormone administration; it was further supported by the stimulation of skeletal growth which followed the therapeutic trial with GH in the usual low dose employed for the treatment of hypopituitary dwarfism. The somatomedin and growth responses clearly distinguish these cases from cases of Laron dwarfism who are refractory to exogenous hGH treatment (2). Low levels of somatomedin are associated with high levels of serum growth hormone in patients with severe protein calorie malnutrition (8); however, the nutritional state and emotional stability of our patients were apparently normal. The characterization of the circulating growth hormone in our patients is still incomplete. The serum growth hormone reacted normally in the radioimmunoassay. The growth hormone in serum from patient 1 did
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RAPID COMMUNICATIONS
463
Table 1:
Serum levels of radioimmunoassayable GH following stimulation with Arginine-Insulin (patient 1) or Arginine-L-Dopa (patient 2 ) . (The tests were carried out twice on each patient.) Time RIA GH, ng/m] (min) Patient 1 Patient 2 0 10.4 20.4 1.5 3.6 15 8.2 5.7 2.1 0.94 30 7.2 6.9 45 9.5 13.07 14.0 34.3 60 12.1 48.8 31.8 28.0 80 5.0 21.5 90 18.7 8.46 32.0 11.5 105 10.7 8.3 120 13.6 4.39 6.9 3.3
Table 2:
RIA and RRA assay of serum GH. RRA RIA Case Serum ng/ml ng/ml
