Acquired refractoriness to growth hormone in a patient with isolated growth hormone deficiency: Growth and plasma somatomedin-C response to high-dose growth hormone therapy

908

6.

7.

8. 9.

10.

Clinical and laboratory observations

Failure of treatment with cyproheptadine. Br Med J !:686, 1977. D'Ercole A J, Morris MA, Underwood LE, van Wyk J J: Treatment of Cushing disease in childhood with cyproheptadine. J PEt)IA'rR90:834, 1977. Grant DB, Atherden SM: Cushing's disease presenting with growth failure: Clinical remission during cyproheptadine therapy. Arch Dis Child 54:466, 1979. Krieger DT: Physiopathology of Cushing's d!sease. Endocrine Rev. 4:22, 1983. Gold EM: Cushing's syndrome: A tripartite entity. In Krieger DT, ttughes JC, editors: Neuroendocrinology. Sunderland, Mass., 1980, Sinauer Associates, p 313. Ishibashi M, Yamaji T: Direct effects of thyrotropin-releasing hormone, cyproheptadine and dopamine on adrenocortico-

The Journal of Pediatrics June 1984

tropin secretion from human corticotroph adenoma cells in vitro. J Clin Invest 68:1018, 1981. I I. Suda T, Tozawa F, Mouri T, Sasaki A, Shibasaki T, Demura H, Shizuma K: Effects of cyproheptadine, reserpine, and synthetic corticotropin-releasing factor on pituitary glands from patients with Cushing's disease. J Clin Endocrinol Metab 56:t094, 1983. 12. Lankford }IV, St. George Tucker H, Blackard WG: A cyproheptadine-reversible defect in ACTH control persisting after removal of the pituitary tumour in Cushing's disease. N Engl J Med 305:1244, 1981. 13. Blankstein J, Falman C, Reyes FI, Schroeder ML, Winter JSD: Adult-onset familial adrenal 21-hydroxylase deficiency. Am J Med 68:441, 1980.

Acquired refractoriness to growth hormone in a patient with isolated growth hormone deficiency: Growth and plasma somatomedin-C response to high-dose growth hormone therapy Jorg Winterer, M.D., Ph.D., George Chrousos, M.D., Fernando Cassorla, M.D., and D. Lynn Loriaux, M.D., Ph.D. Bethesda, Md.

PROGRESSIVE REFRACTORINESS to growth hormone therapy after an initial growth response is rarei; it is even more rare for such children to fail to respond to an increase in the dose of growth horm0ne3 Causes of such an intercurrent poor response to growth hormone replacement include inaccurate diagnosis of growth hormone deficiency, the type of growth hormone deficiency (organic versus idiopathic), the relative size of the patient in relation to dose, the particular regimen, lack of compliance, the presence of antibodies to growth h o r m o n e ) progressive hypothyroidism, 4 failure to secrete somatomedin-C, and psychosocial dwarfism? Clinical situations characterized by poor growth, in which poor or absent response to growth hormone therapy is expected, include chronic renal and cardiac disease, malnutrition, diabetes mellitus, corticosteroid excess, 6 and inflammatory bowel disease. 7 The latter two conditions may have subtle clinical presentations.

Front the Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health. Reprint requests: dorg IVinterer, 3LD., Ph.D.. Bldg. 10. Rm. lOB09, National Institutes of Health, 9000 Rockville Pike, Bethesda. MD 20205.

We present a patient with dwarfism who, after an initial growth spurt, failed to respond to treatment with conventional doses of hGH. All of the above causes were systematically excluded in this patient, except for failure to secrete SM-C. Acquired refractoriness to growth hormone was demonstrated by an altered dose response of plasma somatomedin levels to various doses of h G H and by an increase in height velocity only during high doses of hGH. See related

[

SM-C

article, p. 885

Somatomedin-C

[

CASE R E P O R T This boy was the 3.52 kg product of an uncomplicated full-term pregnancy in a 26-year-old gravida 4 para 3 woman. Birth length was 50.7 cm. The neonatal course was normal except for poor feeding. Development was slow, the child sitting unassisted at 9 months and not walking until 19 months. Growth failure was apparent by 2 years of age (Figure). The father's height was 176 cm, and the mother's 163 cm. At age 3%2 years the patient was referred to the National Institutes of Health, where L-dopa and

Volume 104 Number 6

arginine-insulin stimulation tests failed to evoke a serum growth hormone response >4 ng/ml. The patient's serum cortisol concentration rose from 9.0 /~g/dl to 17.0 /Jg/dl in the course of the arginine-insulin stimulation test. Thyroid function tests produced normal results: T~ 155 ng/dl; fT~ 1.0 ng/dl; T4 5.3 #g/dl. Skull radiographs revealed an abnormally small sella turcica using the Di Chiro criteria for ageS; the bone age was estimated as 18 months by the standards of Greulich and Pyle. The patient was also noted to have a single central incisor. At 590 years growth hormone replacement therapy was begun, with an initial dose of 2 U three times weekly. Before growth hormone therapy, the patient was growing at a rate of <4 cm/yr. Growth hormone treatment increased his height velocity to 8 cm/yr during the first year of therapy. Thereafter, his growth rate reverted to <4 cm/yr. An increase in the dose of growth hormone to 4 U intramuscularly three times a week, at age 9~~ )'ears, improved growth velocity transiently to 5 cm/yr. At 115/~2years of age his height was at the 50 percentile for a 4t~ boy, and his bone age was 7 years, tte was prepubertal. A C T scan performed at age 12 years revealed an empty sella. A careful survey was made to exclude known causes of failure to respond to exogenous growth hormone. Results of thyroid function studies and serum cortisol levels were normal on repeated occasions. Consideration was given to a diagnosis of psychosocial dwarfism, because there had been considerable turmoil and disharmony in the patient's household. To exclude this possibility, our patient was admitted to the Nlll pediatric ward for 6 weeks. Adequate caloric intake was documented. No bizarre food-related behavior such as hoarding or stealing was observed. Growth did not improve. No serum growth hormone antibodies were found (see below). We excluded gastrointestinal tract dysfunction as a cause of hyposomatomedinemia, particularly celiac disease and regional enteritis, by arranging for exhaustive gastroenterologic evaluation, including a small bowel biopsy; no abnormalities were found. At age 13~'~2years growth hormone therapy was discontinued. METIIODS Assays. Somatomedin-C determinations were performed by the Nichols Institute, San Juan Capistrano, Calif. lnterassay variation for this assay is 7.3%, based on 30 samples, and intra-assay variation is 6.7% for 10 duplicate samples. Growth hormone was measured by a direct double-antibody radi0immunoassay using a n t i human growth hormone antisera. 9 Growth hormone antibodies were measured as follows: An aliquot of the patients' serum was 'combined with "q-labelled growth hormone sufficient to register 15,000 cpm. Separation of bound and free tracer was effected by addition of a second antibody raised in rabbits against human g a m m a globulin. The pellet was counted in a g a m m a counter. A reading >10% above nonspecific binding was interpreted as positive for anti-growth hormone antibodies. hGH stimulation test. After a 4-month hiatus without

Clinical and laboratory observations

909

190 180 170

crn

160

gO 80

cm

70

50

kg

40 30 20 kg 4

6

8

10

12

14

16

18

AGE (Years)

6 Units/Wk

~40 Unffs/~Vk i |

12 Units/Wk

I Growth Hc~mone Dosage

I

Figure. Patient growth chart. Normative standards for height and weight for chronologic age according to Hamill et alJ ~ growth hormone replacement, the patient's basal plasma S M - C level was 0.1 U / m l . At this time he was 12' 88 years old. His height was 114.2 cm; he weighed 21.7 kg, and was still totally prepubertal. In an effort to stimulate S M - C production in a stepwise pattern, a higher dose of h G H was administered and the S M - C response monitoredJ ~ We initially chose a dose of 5 U h G H for 5 consecutive days. There was no S M - C response to this challenge (Table, A). We then increased the h G H dose from 5 to 30 U on successive days for an extended growth hormone challenge. The patient's plasma S M - C increased into the normal range, and reached a plateau on day 8 of the challenge at a dose of 15 U h G H (Table, B). Clinically, the patient developed an uncharacteristically ravenous appetite. No serum growth hormone antibodies were detected. To examine the possibility that the administered growth hormone might be inactivated at the site of injection and never reach the peripheral circulation, serum levels of h G H were monitored hourly for 24 hours after the 20 U injection. Adequate levels of h G H , generally >50 ng/ml, were maintained throughout the period and were similar to

910

Clinical and laboratory observations

The Journal of Pediatrics June 1984

Table. Plasma somatomedin response to hGH therapy

A. Successive injections of 5 U hGtl IM hGH units 5 5 5 SM-C U/ml 0.22 0.11 0.15 B. Escalating consecutive doses of hGH IM hGH units 5 5 10 SM-C U/ml 0.I0 0.21 0.15 C. Successive injections of 10 U hGH IM hGH units I0 10 10 SM-C U/ml 0.10 0.60

5 0.32

5 0.31

10 0.38

15 0.55

15 0.81

15 1.6

15 2. I

20 2.9

20 2.2

10

10 2.2

10

10 2.5

10

10 2.6

10

those described by Parker et al.," who used a dose of 15 U (10 mg). Having demonstrated that a plasma SM-C response to hGH could be elicited, we next attempted to define a therapeutic regimen that could be supported by the available supplies of hGH. We chose a dose of 10 U/day, which we administered on 11 successive days, and then observed the decay of plasma somatomedin levels on the two successive days not preceded by hGH injections (Table, C). The patient's plasma SM-C came into the normal range on the fifth day of successive 10 U hGH injections. On the 2 days on which no hGH injections were given, the plasma SM-C levels were 3.4 and 2.5 U/ml. respectively. Thus the likelihood that 10 U administered every other day would constitute adequate therapy in this patient seemed good. In the course of this latter hGH challenge, results of oral glucose tolerance tests before and during the challenge were normal. Serum triglyceride concentrations increased from 24 to 135 mg/dl. Urinary hydroxyproline concentration increased from 16 to 37 mg/24 hours. BUN decreased from 17 to 5 mg/dl. RESULTS Treatment with 10 U hGH daily was continued for 1 month after the last challenge, and the patient's growth response was evaluated using a sensitive device capable of detecting short-term increments in ulnar bone length. ~ The patient's ulnar growth velocity prior to therapy was 0.138 mm per 3 weeks. During the 6 weeks that included the last challenge and the month of treatment with I0 U hGH every day, his ulnar growth velocity rose to 1.567 mm per 3 weeks, but declined to 0.434 mm per 3 weeks in the 6 weeks after therapy was terminated. These responses were corroborated by the less sensitive measurement of statural height. Prior to treatment the patient's statural height was 114.7 cm. This increased to 116.7 cm after the 6 weeks of hGH challenge and therapy. During the subsequent 6 weeks his height increased only 0.2 cm, to 116.9 cm (Figure).

20 2.6

30 2.9

0

0

3.3

3.4

2.5

DISCUSSION Patients with a single central incisor have been reported to have growth hormone deficiency. ~3Acquired refractoriness to growth hormone replacement can now be added to this association. All known causes of growth hormone resistance were systematically excluded in our patient. He appears to have acquired this refractoriness in the course of treatment. That this refractoriness can be overcome by higher doses'of growth hormone implies that it is partial. This is not the case in Laron dwarfism, in which higher than normal levels of endogenous growth hormone have been measured and in which attempts to induce SM-C synthesis with additional growth hormone have been unsuccessful. The mechanism of our patient's resistance remains obscure, but it is not mediated by antibodies directed against growth hormone.

REFERENCES 1. Daughaday WH: The adenohypophysis. In Williams RH, editor: Textbook of endocrinology. Philadelphia, 1981, WB Saunders, p 100. 2. Kaplan SL, Savage DCL, Suter S, Wolter R, Grumbach MM: Antibodies to human growth hormone arising in patients treated with human growth hormone: Incidence, characteristics, and effects on growth. In Raiti S, editor: Advances in human growth hormoxac research. Washington, DC, 19-/4, DHEW publication 74-612, p 731. 3. Groll A, Preece MA, Candy DCA, Tanner JM: Short stature as the primary manifestation of celiac disease. Lancet 2:1097, 1980. 4. Lippc BM, Van Herle AJ, LaFranehi SH, Uller RP, Lavin N, Kaplan SA: Reversible hypothyroidism in growth hormone deficientchildren treated with human growth hormone. J Clin Endocrinol Metab 40:612, 1975. 5. Powell GF, Brasel JA, Blizzard RM: Emotional deprivation and growth retardation simulating idiopathic hypopituitarism. N Engl J Mcd 276:1271, 1967. 6. Daughaday WH: The adenohypophysis. In Williams RH, editor: Textbook of endocrinology. Philadelphia, 1981, WB Saunders, p 98.

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7. Sobel EH, Silverman FN, Lee C: Chronic regional enteritis. Am J Dis Child 103:569, 1962. 8. Fisher RL, Di Chiro G: The small sella turcica. Am J Radiol 91:996, 1964. 9. Odell WD, Rayford PL, Ross GT: Simple partially automated method for radioimmunoassay of human thyroid stimulating, growth, luteinizing and follicle stimulating hormone. J Lab Clin Med 70:973, 1967. 10. Copeland KC, Underwood LE, Van Wyk J J: Induction of immunoreactive somatomedin C in human serum by growth hormone: Dose-response relationships and effect on chromatographic profiles. J Clin Endocrinol Metab 50:690, 1980.

Clinical and laboratory observations

91 1

11. Parker NiL, Utiger RD, Daughaday WH: Studies on human growth hormone: The physiologic disposition and metabolic fate of human growth hormone in man. J Clin Invest 41:262, 1962. 12. Valk IM: Accurate measurement of the length of the ulna and its application in growth measurement. Growth 35:297, 1971. 13. Rappaport EB, Ulstrom RA, Gorlin RJ, Lucky AW, Colle E, Miser J: Solitary maxillary incisor and short stature. Pediatrics 91:924, 1977. 14. Hamill PVV, Drizd TA, Johnson CL, Reed RB, Roche AF, Moore WM: Physical growth: National Center for Health Statistics percentiles. Am J Clin Nutr 32:607, 1979.

Stature and weight in chronic granulomatous disease E. Stephen Buescher, M.D., and John I. Gailin, M.D. Bethesda, Md.

C H R O N I C G R A N U L O M A T O U S DISEASE of childhood is an inherited disease in which oxidative metabolism of phagocytic cells is deranged. Recently, Payne et al. ~ reviewed the growth of 16 patients (14 male) with CGD and reported the consistent finding of small stature and low weight for age throughout the period examined (ages 2 through 18 years). They were able to demonstrate that these findings were not explained by repeated episodes of infection, as had often been assumed. They hypothesized that the short stature in their child and adolescent patients with CGD may be directly related to the defect in phagocyte metabolic activity that characterizes the disease, and noted that their adolescent patients worried considerably over their short stature. We found this report fascinating, but were skeptical of the universality of short stature and low weight for age in patients with CGD, based on our own experience with patients who have been observed at the National Institutes of Health over the past 13 years. We therefore reviewed the height and weight data from our own patients (15 male, 6 female) from 16 kindreds with ages ranging from 2 years to 35 years.

METHODS Medical records were reviewed as appropriate, and telephone contact was made with patient families to Front the Bacterial Diseases Section, Laboratory of Clinical Investigation, National Institute of ,411ergy and Infectious Diseases. National Institutes of Health. Reprint requests: E. Stephen Buescher, IILD., Bacterial Diseases Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of tlealth. Bldg. I0, Rm II1VI14, Bethesda, MD 20205.

establish present heights and weights of patients and the parental height when these could not be acquired from a recent visit recorded in the medical chart. All patients have CGD as defined by abnormal bactericidal assay, abnormal nitroblue tetrazolium reduction test results, abnormal stimulated superoxide production, abnormal elicited membrane potential depolarization responses, and a clinical history of recurrent infections with catalase-positive organisms and granulomatous inflammatory responses to such infections.2.3 Bone ages were determined by interpretation of hand and wrist radiographs by the methods of Greulich and Pyle.4 One 17-year-old patient was not included in the weight, height, and bone age versus chronologic age analysis because the degree of his chronic illness was much greater than that in all the other patients and his growth failure was significantly affected by the chronic illness. I

CGD

Chronic granulomatous disease

!

RESULTS The patients were divided into two groups defined by age: "children," --<18 years, and "adults," >18 years. For the 13 patients grouped as children, one of whom is now deceased, the mean height percentile for age was 26.54 ___ 8.24 (mean _ SE), and the mean weight percentile for age was 21.69 ___ 5.74. For the eight adult patients, seven of whom are still living, seven had heights that fell between or were taller than those of their parents. The mean adult patient height of 174.5 cm was not significantly different from the mean average parental height of 175.71 cm. Adult male patients all had heights between or taller than those of their parents; the two adult female patients were