- Email: [email protected]
Treatment of acromegaly with a somatostatin analog in a patient with McCune-Albright syndrome
740
Clinical and laboratory observations
2. Benke PJ. The isotretinoin teratogen syndrome. JAMA 1984;251:3267 -9. 3. Braun JT, Franciosi RA, Mastri AR, Drake RM, O'Neil BL. Isotretinoin dysmorphic syndrome. Lancet 1984;1:506-7. 4. de la Cruz E, Sun S, Vangvanichyakorn K, Desposito F. Multiple congenital malformations associated with maternal isotretinoin therapy. Pediatrics 1984;74:428-30. 5. Fernhoff PM, Lammer EJ. Craniofacial features of isotretinoin embryopathy. J PEDIATR 1984;105:595-7. 6. Hill RM. Isotretinoin teratogenicity. Lancet 1984;1:1465. 7. Lott IT, Bocian M, Pribram HW, Leitner M. Fetal hydrocephalus and ear anomalies associated with maternal use of isotretinoin. J PEDIATR 1984;105:597-600. 8. Hansen LA, Pearl GS. Isotretinoin teratogenicity: case report with neuropathologic findings. Acta Neuropathol (Berl) 1985;65:335-7. 9. Lammer E J, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med 1985;313:837-41. 10. Rosa FW, Wilk AL, Kelsey FO. Vitamin A congeners. In: Sever JL, Brent RL, eds. Teratogen update: environmentally
The Journal of Pediatrics November 1987
1i. 12.
13.
14.
15.
16.
induced birth defect risks. New York: Alan R. Liss, 1986:6170. Hall JH. Vitamin A: a newly recognized human teratogen. Harbinger of things to come? J PEDIATR 1984;105:583-4. Cohlan SQ. Congenital anomalies in the rat produced by excessive intake of vitamin A during pregndncy. Pediatrics 1954;13:556-7. Hassel JR, Greenberg JH, Johnston MC. Inhibition of cranial neural crest cell development by vitamin A in the cultured chick embryo. J Embryol Exp Morphol 1977;39:267-71. Keith J. Effects of excess vitamin A on the cranial neural crest in the chick embryo. Ann R Coil Surg 1977;59:49783. Davis LA, Sadler TW. Effects of vitamin A on endocardial cushion development in the mouse heart. Teratology 1981;24:139-48. Schmid M, Schroder M, Langenbeck U. Familial microtia, meatal atresia, and conductive deafness in three siblings. Am J Med Genet 1985;22:327-32.
Treatment of acromegaly with a somatostatin analog in a patient with McCune-Albright syndrome Mitchell E. Geffner, MD, Ronaid A. Nagei, MD, Rosalind B. Dietrich, MD, ChB, and Solomon A. Kaplan, MD From the Departments of Pediatrics and Radiological Sciences, University of California, Los Angeles, School of Medicine
Polyostotic fibrous dysplasia, cafe au lait spots, and sexual precocity form the classic triad of M C A S . Various endocrinopathies, including thyrotoxicosis, hypercortisolism, hyperparathyroidism, and acromegaly have been described in this syndrome? The acromegaly has been treated by conventional means including surgery, 2,3 radiation). 4-5 and bromocriptine, T M with varying degrees of success. Because of known physiologic inhibitory action of native somatostatin on G H secretion in vitro 9 and in vivo, ~~ a long-acting analog was synthesized that has been used successfully in many ~ but not all ~z patients with acromegaly as a result of other causes. This analog, S M S 201-995 (Sandoz Pharmaceuticals, Inc., East Hanover, N.J.), may lead to prompt and sustained (up to 8 hours) suppression of G H secretion, improvement of certain clinical features of
Submitted for publication April 27, 1987; accepted June 16, 1987. Reprint requests: Mitchell E. Geffner, M.D., Department of Pediatrics, UCLA Medical Center, Los Angeles, CA 90024.
acromegaly (including soft tissue swelling, headaches, joint discomfort, hyperhidrosis, depression, voice change, and carpal tunnel syndrome), and, in some cases, partial tumor shrinkage? 1 This report describes the use of this analog in the treatment of acromegaly associated with MCAS. MCAS CT GH TRH GnRH SmC GRF
McCune-Albright syndrome Computed tomography Growth hormone Thyrotropin-releasing hormone Gonadotropin-releasing hormone Somatomedin-C Growth hormone-releasing factor
CASE REPORT
The patient is now a 20-year-old Japanese-American woman with MCAS originally diagnosed at 8 months of age, at which time she had breast development, vaginal bleeding, advanced bone age, irregularly bordered cafe au lait spots, and fibrous dysplasia involving long bones, pelvis, and skull. At age 3.7 years she
Volume 111 Number 5
developed hyperthyroidism that was initially treated elsewhere by partial thyroidectomy and subsequently has been controlled with several courses of methimazole. Her current height is 147.5 em (<5th percentile) and weight is 57 kg (50th percentile). At 17.8 years of age the patient developed recurrent migrainelike headaches. CT scan of the head revealed a suprasellar mass with lateral extension, suggestive of a pituitary adenoma. Evaluation of pituitary function revealed increased basal GH (82 and 88 ng/mL) and prolactin (66 ng/mL) concentrations and a paradoxical increase of the serum GH concentration after combined administration of TRH (400 #g intravenous bolus) and GnRH (100 #g intravenous bolus). The serum SmC concentration of 3. l U/mL was elevated for her age (normal adult range 0.61 to 2.04 U/mL). Hypothalamic-pituitary function was otherwise unremarkable except for mild hypothyroidism that resolved after discontinuation of methimazole. The patient had normal visual fields and no papilledema; however, borderline glaucoma was detected. She had no current signs or symptoms related to either acromegaly or hyperprolactinemia. Heel pad thickness was 19 mm (normal <25 ram). The serum GH concentration measured by radioreceptor assay was 64.5 ng/mL; the simultaneous GH concentration measured by radioimmunoassay was 58.0 ng/mL, suggesting normal GH bioactivity (measured by Dr. Stephen LaFranchi). The patient had had an elevated random serum GH concentration 4 years previously, measured at a time when she had a single episode of apparent galactorrhea. Additional evaluation at that time revealed a normal serum prolactin concentration and normal sellar polytomography. At the time of diagnosis of acromegaly, the patient was thought to be a high-risk candidate for surgery because of extensive fibrous dysplasia of the cranium4; radiation therapy was not considered because of possible sequelae. Therefore, treatment with bromocriptine mesylate was instituted. After the initial 2.5 mg dose of bromocriptine, the serum GH concentration fell from a mean pretreatment value of 85 ng/mL to 45 ng/mL, and the serum prolactin concentration fell from 66 ng/mL before treatment to 5.7 ng/mL. Subsequently, serum GH levels failed to decrease further despite increasing the dose of bromocriptine to 60 mg daily, so the drug was discontinued after a 12-month trial. Bromocriptine was well tolerated6 and there was no development of acromegaly during this time. A plasma GRF level, measured postprandially while the patient was receiving bromocriptine, was 1.29 ng/mL (normal <0.4 ng/mL in an unextracted assay) (measured by Dr. Michael Thorner). The size of the pituitary mass decreased approximately 20% during the bromocriptine trial as determined by sequential CT scans. Treatment with the somatostatin analog was then initiated after a 4-week washout period from the bromocriptine, with informed consent and after approval by the Departmental Treatment and Evaluation Committee, The plasma GRF level at the termination of the washout period, before starting somatostatin, was <0.4 ng/mL. Pituitary function tests at this time (using simultaneous doses of insulin, 0.1 U regular/kg intravenously, TRH, and GnRH) were generally similar to those found before the bromocriptine trial. Additionally, the serum GH concentration failed to
Clinical and laboratory observations
ISt Dose 50 qd
I Mo. 2 Mo. ~-,--v-~--~ , I00 I 0 0 qd 8h
7 Mo. ~,.. 200 q8h
74 1
9
100
E
50 T (.9
y .l
j,t
V
I
6
24,
I0'
I
8
I
I
t
I
8f 8 t st 8
HOURS
Figure. Serum GH dynamics with various doses of somatostatin analog (SS 201-995). The height of each stippled block corresponds to the number of micrograms of SS 201-995 per dose; this dose is indicated immediately over the corresponding block along with its frequency of administration. Above the daily dose the time point in the course of treatment with SS 201-995 when the GH sampling study was performed is indicated by brackets (after the initial dose and then after 1 month, 2 months, and 7 months of therapy; in the latter three circumstances the patient was receiving the dose tested for at least 2 weeks before GH sampling). Individual sampling intervals (see x axis) range between 8 and 24 hours with four to six GH determinations per 8-hour interval. The corresponding upper and lower arrows refer to times of administration of SS 201-995. In the fourth block (200 ~,g q8h after 7 months of treatment), four noncontinuous 8-hour intervals were monitored during the course of 48 hours.
decrease significantly in response to 100 gm oral glucose (basal GH 82 ng/mL; nadir GH 56 ng/mL at 120 minutes). The patient had normal glucose tolerance, increased basal and stimulated serum insulin values, and a glycosylated hemoglobin concentration of 3.8% (normal 4% to 7%). The serum SmC concentration was elevated to 5.7 U / m E Treatment with somatostatin was initiated at a dose of 50 #g once daily given by subcutaneous injection to maintain sustained near normalization of serum GH levels; the dose was gradually increased to 200 #g every 8 hours (Figure). After 7 months of somatostatin therapy, further tumor shrinkage was evident by magnetic resonance imaging (before
742
Clinical and laboratory observations
The Journal of Pediatrics November 1987
somatostatin the tumor was 2.1 by 0.9 by 1.4 cm and after 7 months of treatment it was 1.6 by 0.6 by 1.0 cm). After 14 months of somatostatin therapy there continues to be no development of acromegalic features and no biochemical escape. Other than transient local burning at injection sites there have been no side effects related to somatostatin therapy by either clinical examination or repetitive laboratory testing.
hypothalamic dysregulation is responsible for the increase in circulating GH concentrations. Because patients with MCAS appear to be at significantly increased risk to develop acromegaly, 17 early and ongoing screening of serum GH levels is indicated. Somatostatin offers a promising alternative in the treatment of such patients.
DISCUSSION
REFERENCES
Our patient is the first reported patient with acromegaly and MCAS to be treated with somatostatin. The ability to lower serum GH concentrations, as well as to reduce the size of the tumor, may make the somatostatin analog an important treatment option in patients with acromegaly secondary to MCAS. The greater potency of somatostatin compared with bromocriptine observed in our patient is consistent with the relative effects of these drugs in patients with acromegaly as a result of other causes& The etiology of the acromegaly of MCAS remains unknown. The other endocrinopathies associated with MCAS appear to result from autonomous hyperfunction of various glands, including the ovary, thyroid, parathyroid, and adrenal cortex. Acromegaly in MCAS could result from an autonomous pituitary adenoma, hypothalamic hypersecretion of GRF, or, perhaps, ectopic GRF secretion. In acromegaly unrelated to MCAS, an elevation of the peripheral plasma level in GRF appears helpful in distinguishing the third mechanism from the first two. TM Our patient's first plasma G R F level, although in the nanogram range, was less than that found in patients with proved extrahypothalamic GRF-producing tumors. TM Additionally, it was measured postprandially15 and while receiving bromocriptine. The second G R F level, measured when the patient was not receiving bromocriptine and in the fasting state, was below the lower limit of detection of the assay and makes it unlikely that the acromegaly was caused by ectopic GRF production. This finding suggests a central cause of the acromegaly but would not distinguish between hypothalamic and pituitary lesions. The prompt and sustained diminution of our patient's serum GH concentration and the shrinkage of the adenoma in response to somatostatin would suggest a hypothalamic cause. Previous investigators have suggested both pituitary 5 and hypothalamic3 causes for the acromegaly of MCAS. Cuttler et al. ~6recently reported two children with MCAS, gigantism, and hyperprolactinemia with normal CT scans of the head, normal plasma GRF concentrations, and normal GH responsiveness to administration of GRF. Their data indicate that the pituitary gland is not autonomous in patients with MCAS and that, more likely,
1. Mauras N, Blizzard RM. The McCune-Albright syndrome. Acta Endocrinol 1986;113(suppl):207-17. 2. Lightner ES, Penny R, Frasier SD. Pituitary adenoma in McCune-Albright syndrome:follow-upinformation [letter]. J PEDIATR 1976;89:159. 3. Joishy SK, Morrow LB. McCune-Albright syndrome associated with a functioning chromophobe adenoma. J Pediatr 1976;89:73-5. 4. Lipson A, Hsu T-H. The Albright syndrome associated with acromegaly: report of a case and review of the literature. Johns Hopkins Mcd J 1981;149:10-4. 5. PolychronakosC, Tsoukas G, Ducharme JR, Letarte J, Collu R. Gigantism and hyperprolactinemia in polyostotic fibrous dysplasia (McCune-Albright syndrome). J Endocrinol Invest 1982;5:323-6. 6. Chung KF, Alaghband-Zadeh J, Guz A. Acromegaly and hyperprolactinemiain McCune-Albright syndrome.Am J Dis Child 1983;137:134-6. 7. Lightner E, Winter JSD. Treatment of juvenile acromegaly with bromocriptine. J PEDIATR1981;98:494-6. 8. Nakagawa H, Nagasaka A, Sugiura T, et al. Gigantism associated with McCune-Albright's syndrome. Horm Metab Res 1985;17:522-7. 9. Shibasaki T, Hotta M, Masuda A, et al. Studies on the response of growth hormone (GH) secretion to GH-releasing hormone, tbyrotropin-releasing hormone, gonadotropinreleasing hormone, and somatostatin in acromegaly. J Clin Endocrinol Metab 1986;63:167-73. 10. Yen SSC, Siler TM, Devane GW. Effect of somatostatin in patients with acromegaly. N Engl J Med 1974; 290:935-8. 11. Lamberts SWJ, Uitterlinden P, Verschoor L, van Dongen KJ, del Pozo E. Long-term treatment of acromegaly with the somatostatin analog SMS 201-995. N Engl J Med 1985; 313:1576-80. 12. Comi RJ, Gorden P. The responses of serum growth hormone levels to the long-acting somatostatin analog SMS 201-995 in acromegaly. J Clin Endocrinol Metab 1987;64:37-42. 13. Chiodini PG, Cozzi R, Dallabonzana D, et al. Medical treatment of acromegaly with SMS 201-995, a somatostatin analog: a comparison with bromocriptine. J Clin Endocrinol Metab 1987;64:447-53. 14. Thorner MO, Frohman LA, Leong DA, et al. Extrahypothalamic growth-hormone-releasingfactor (GRF) secretion is a rare cause of acromegaly: plasma GRF levels in 177 acromegalic patients. J Clin Endocrinol Metab 1984; 59:846-9. 15. Kashio Y, Chihara K, Kita T, et al. Effect of oral glucose administration on plasma growth hormone-releasinghormone
Volume 111 Number 5
(GHRH)-like immunoreactivity levels in normal subjects and patients with idiopathic GH deficiency: evidence that GHRH is released not ordy from the hypothalamus but also from extrabypothalamic tissue. J Clin Endocrinol Metab 1987; 64:92-7. 16. Cuttler L, Levitsky LL, Zafar MS, Mellinger RC, Frohman
Clinical and laboratory observations
743
LA. Hypersecretion of growth hormone (GH) and pr01actin (PRL) in McCune-Albright syndrome [abstract.]. Pediatr Res 1986;20:213. 17. Lee PA, Van Dop CC, Migeon CJ. McCune-Albright syndrome: long-term follow-up. JAMA 1986;256:2980-4.
Erythrocytosis associated with spontaneous erythroid colony formation and idiopathic hypererythropoietinemia Vipul N. Mankad, MD, R. Blaine Moore, PhD, Denis McRoyan, MD, and Kenneth Zuckerman, MD From the Departments of Pediatrics and Pathology, University of South Alabama College of Medicine, Mobile, and the DePartment of Medicine, University of Alabama, Birmingham
Erythrocytosis is defined as an elevated red cell count or hemoglobin level? In absolute erythrocytosis, the red cell mass is increased; in relative erythrocytosis, loss of plasma volume is responsible for increased red cell concentration. 1 Absolute erythrocytosis can be secondary to an appropriate or inappropriate increase in erythropoietin production. 2 In contrast, primary erythrocytosis is a disorder of unknown cause in which erythropoietin is not elevated. Polycythemia vera, rare in children, is characterized by an increase in several hematopoietic cell lines with subnormal erythropoietin levels; the bone marrow contains unusual erythroid progenitor cells, which grow in culture in the absence of added erythropoietin. When erythropoietin is added to the culture, colony formation in these patients exceeds that in controls? 7 Such spontaneous colony formation is considered typical of polycythemia vera and is not commonly found in patients with erythrocytosis secondary to increased erythropoietin. However, Dainiak et al. 8 have described an adult with erythropoietin-dependent erythrocytosis and endogenous colony formation. In this report, we describe a child wit h erythrocytosis with increased erythropoietin levels and spontaneous colony formation in vitro. Supported in part by Grants CA13148 and R23HL31226 from the National Institute of Health. Submitted for publication April 24, 1987; accepted June 16, 1987. Reprint requests: Vipu! N. Mankad, MD~ Division of Pediatric Hematology/Oncology, University of South Alabama College of Medicine, 2451 Fillingim St., Mobile, AL 36617.
CASE REPORT
A white boy was found to have a hemoglobin concentration of 18 g/dL during an evaluation for an upper respiratory tract infection at age 5 years. Investigations included chest radiograph, electrocardiogram, and arterial blood gas determinations; results were within normal limits. The patient had no symptoms at that time, but a t age 12 years had severe recurring headaches lasting approximately 2 hours a daY for 1 or 2 weeks, followed by 3 to 4 weeks without headaches. He also complained of lethargy. The family history was normal. Complete blood counts in the father, sister, and maternal aunt were within normal limits. The mother had a hemoglobin level of 17 g/dL and a history of chronic, excessive smoking. BFU-E 2,3-DPG
Burst-forming units, erYthroid 2,3-Diphosphoglycerate
[
Physical examination revealed an anxious child with ruddy complexion. Ophthalmologie examination showed a deficiency of accommodation. Results of cardiorespiratory examination were within normal limits. There was no splenomegaly. The remainder of the examination yielded normal findings. Complete blood count revealed hemoglobin 21.8 g/dL, hematocrit 58.7%, leukocyte count 5900/~L, platelet count 308,000/t~L, mean corpuscular volume 75 fL, mean corpuscular hemoglobin concentration 31.7%, and mean corpuscular hemoglobin 24%. 5~Cr-labe!ed red blood cell studies revealed red cell volume 53 mL/kg (normal <36 mL/kg), plasma volume 21 mL/kg, and whole blood volume 74 mL/kg. Arterial blood gas studies revealed pH 7.431 Pao2 119 torr, Paco2 21 torr, oxygen saturation 98.5%, H C O 3 20.0 mEq/L, methemoglobin 0.2%, and carboxyhemoglobin 1.81%. Oxygen equilibrium curves using the patient's whole blood were obtained at the laboratory of Dr. George Honig,
Clinical and laboratory observations
2. Benke PJ. The isotretinoin teratogen syndrome. JAMA 1984;251:3267 -9. 3. Braun JT, Franciosi RA, Mastri AR, Drake RM, O'Neil BL. Isotretinoin dysmorphic syndrome. Lancet 1984;1:506-7. 4. de la Cruz E, Sun S, Vangvanichyakorn K, Desposito F. Multiple congenital malformations associated with maternal isotretinoin therapy. Pediatrics 1984;74:428-30. 5. Fernhoff PM, Lammer EJ. Craniofacial features of isotretinoin embryopathy. J PEDIATR 1984;105:595-7. 6. Hill RM. Isotretinoin teratogenicity. Lancet 1984;1:1465. 7. Lott IT, Bocian M, Pribram HW, Leitner M. Fetal hydrocephalus and ear anomalies associated with maternal use of isotretinoin. J PEDIATR 1984;105:597-600. 8. Hansen LA, Pearl GS. Isotretinoin teratogenicity: case report with neuropathologic findings. Acta Neuropathol (Berl) 1985;65:335-7. 9. Lammer E J, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med 1985;313:837-41. 10. Rosa FW, Wilk AL, Kelsey FO. Vitamin A congeners. In: Sever JL, Brent RL, eds. Teratogen update: environmentally
The Journal of Pediatrics November 1987
1i. 12.
13.
14.
15.
16.
induced birth defect risks. New York: Alan R. Liss, 1986:6170. Hall JH. Vitamin A: a newly recognized human teratogen. Harbinger of things to come? J PEDIATR 1984;105:583-4. Cohlan SQ. Congenital anomalies in the rat produced by excessive intake of vitamin A during pregndncy. Pediatrics 1954;13:556-7. Hassel JR, Greenberg JH, Johnston MC. Inhibition of cranial neural crest cell development by vitamin A in the cultured chick embryo. J Embryol Exp Morphol 1977;39:267-71. Keith J. Effects of excess vitamin A on the cranial neural crest in the chick embryo. Ann R Coil Surg 1977;59:49783. Davis LA, Sadler TW. Effects of vitamin A on endocardial cushion development in the mouse heart. Teratology 1981;24:139-48. Schmid M, Schroder M, Langenbeck U. Familial microtia, meatal atresia, and conductive deafness in three siblings. Am J Med Genet 1985;22:327-32.
Treatment of acromegaly with a somatostatin analog in a patient with McCune-Albright syndrome Mitchell E. Geffner, MD, Ronaid A. Nagei, MD, Rosalind B. Dietrich, MD, ChB, and Solomon A. Kaplan, MD From the Departments of Pediatrics and Radiological Sciences, University of California, Los Angeles, School of Medicine
Polyostotic fibrous dysplasia, cafe au lait spots, and sexual precocity form the classic triad of M C A S . Various endocrinopathies, including thyrotoxicosis, hypercortisolism, hyperparathyroidism, and acromegaly have been described in this syndrome? The acromegaly has been treated by conventional means including surgery, 2,3 radiation). 4-5 and bromocriptine, T M with varying degrees of success. Because of known physiologic inhibitory action of native somatostatin on G H secretion in vitro 9 and in vivo, ~~ a long-acting analog was synthesized that has been used successfully in many ~ but not all ~z patients with acromegaly as a result of other causes. This analog, S M S 201-995 (Sandoz Pharmaceuticals, Inc., East Hanover, N.J.), may lead to prompt and sustained (up to 8 hours) suppression of G H secretion, improvement of certain clinical features of
Submitted for publication April 27, 1987; accepted June 16, 1987. Reprint requests: Mitchell E. Geffner, M.D., Department of Pediatrics, UCLA Medical Center, Los Angeles, CA 90024.
acromegaly (including soft tissue swelling, headaches, joint discomfort, hyperhidrosis, depression, voice change, and carpal tunnel syndrome), and, in some cases, partial tumor shrinkage? 1 This report describes the use of this analog in the treatment of acromegaly associated with MCAS. MCAS CT GH TRH GnRH SmC GRF
McCune-Albright syndrome Computed tomography Growth hormone Thyrotropin-releasing hormone Gonadotropin-releasing hormone Somatomedin-C Growth hormone-releasing factor
CASE REPORT
The patient is now a 20-year-old Japanese-American woman with MCAS originally diagnosed at 8 months of age, at which time she had breast development, vaginal bleeding, advanced bone age, irregularly bordered cafe au lait spots, and fibrous dysplasia involving long bones, pelvis, and skull. At age 3.7 years she
Volume 111 Number 5
developed hyperthyroidism that was initially treated elsewhere by partial thyroidectomy and subsequently has been controlled with several courses of methimazole. Her current height is 147.5 em (<5th percentile) and weight is 57 kg (50th percentile). At 17.8 years of age the patient developed recurrent migrainelike headaches. CT scan of the head revealed a suprasellar mass with lateral extension, suggestive of a pituitary adenoma. Evaluation of pituitary function revealed increased basal GH (82 and 88 ng/mL) and prolactin (66 ng/mL) concentrations and a paradoxical increase of the serum GH concentration after combined administration of TRH (400 #g intravenous bolus) and GnRH (100 #g intravenous bolus). The serum SmC concentration of 3. l U/mL was elevated for her age (normal adult range 0.61 to 2.04 U/mL). Hypothalamic-pituitary function was otherwise unremarkable except for mild hypothyroidism that resolved after discontinuation of methimazole. The patient had normal visual fields and no papilledema; however, borderline glaucoma was detected. She had no current signs or symptoms related to either acromegaly or hyperprolactinemia. Heel pad thickness was 19 mm (normal <25 ram). The serum GH concentration measured by radioreceptor assay was 64.5 ng/mL; the simultaneous GH concentration measured by radioimmunoassay was 58.0 ng/mL, suggesting normal GH bioactivity (measured by Dr. Stephen LaFranchi). The patient had had an elevated random serum GH concentration 4 years previously, measured at a time when she had a single episode of apparent galactorrhea. Additional evaluation at that time revealed a normal serum prolactin concentration and normal sellar polytomography. At the time of diagnosis of acromegaly, the patient was thought to be a high-risk candidate for surgery because of extensive fibrous dysplasia of the cranium4; radiation therapy was not considered because of possible sequelae. Therefore, treatment with bromocriptine mesylate was instituted. After the initial 2.5 mg dose of bromocriptine, the serum GH concentration fell from a mean pretreatment value of 85 ng/mL to 45 ng/mL, and the serum prolactin concentration fell from 66 ng/mL before treatment to 5.7 ng/mL. Subsequently, serum GH levels failed to decrease further despite increasing the dose of bromocriptine to 60 mg daily, so the drug was discontinued after a 12-month trial. Bromocriptine was well tolerated6 and there was no development of acromegaly during this time. A plasma GRF level, measured postprandially while the patient was receiving bromocriptine, was 1.29 ng/mL (normal <0.4 ng/mL in an unextracted assay) (measured by Dr. Michael Thorner). The size of the pituitary mass decreased approximately 20% during the bromocriptine trial as determined by sequential CT scans. Treatment with the somatostatin analog was then initiated after a 4-week washout period from the bromocriptine, with informed consent and after approval by the Departmental Treatment and Evaluation Committee, The plasma GRF level at the termination of the washout period, before starting somatostatin, was <0.4 ng/mL. Pituitary function tests at this time (using simultaneous doses of insulin, 0.1 U regular/kg intravenously, TRH, and GnRH) were generally similar to those found before the bromocriptine trial. Additionally, the serum GH concentration failed to
Clinical and laboratory observations
ISt Dose 50 qd
I Mo. 2 Mo. ~-,--v-~--~ , I00 I 0 0 qd 8h
7 Mo. ~,.. 200 q8h
74 1
9
100
E
50 T (.9
y .l
j,t
V
I
6
24,
I0'
I
8
I
I
t
I
8f 8 t st 8
HOURS
Figure. Serum GH dynamics with various doses of somatostatin analog (SS 201-995). The height of each stippled block corresponds to the number of micrograms of SS 201-995 per dose; this dose is indicated immediately over the corresponding block along with its frequency of administration. Above the daily dose the time point in the course of treatment with SS 201-995 when the GH sampling study was performed is indicated by brackets (after the initial dose and then after 1 month, 2 months, and 7 months of therapy; in the latter three circumstances the patient was receiving the dose tested for at least 2 weeks before GH sampling). Individual sampling intervals (see x axis) range between 8 and 24 hours with four to six GH determinations per 8-hour interval. The corresponding upper and lower arrows refer to times of administration of SS 201-995. In the fourth block (200 ~,g q8h after 7 months of treatment), four noncontinuous 8-hour intervals were monitored during the course of 48 hours.
decrease significantly in response to 100 gm oral glucose (basal GH 82 ng/mL; nadir GH 56 ng/mL at 120 minutes). The patient had normal glucose tolerance, increased basal and stimulated serum insulin values, and a glycosylated hemoglobin concentration of 3.8% (normal 4% to 7%). The serum SmC concentration was elevated to 5.7 U / m E Treatment with somatostatin was initiated at a dose of 50 #g once daily given by subcutaneous injection to maintain sustained near normalization of serum GH levels; the dose was gradually increased to 200 #g every 8 hours (Figure). After 7 months of somatostatin therapy, further tumor shrinkage was evident by magnetic resonance imaging (before
742
Clinical and laboratory observations
The Journal of Pediatrics November 1987
somatostatin the tumor was 2.1 by 0.9 by 1.4 cm and after 7 months of treatment it was 1.6 by 0.6 by 1.0 cm). After 14 months of somatostatin therapy there continues to be no development of acromegalic features and no biochemical escape. Other than transient local burning at injection sites there have been no side effects related to somatostatin therapy by either clinical examination or repetitive laboratory testing.
hypothalamic dysregulation is responsible for the increase in circulating GH concentrations. Because patients with MCAS appear to be at significantly increased risk to develop acromegaly, 17 early and ongoing screening of serum GH levels is indicated. Somatostatin offers a promising alternative in the treatment of such patients.
DISCUSSION
REFERENCES
Our patient is the first reported patient with acromegaly and MCAS to be treated with somatostatin. The ability to lower serum GH concentrations, as well as to reduce the size of the tumor, may make the somatostatin analog an important treatment option in patients with acromegaly secondary to MCAS. The greater potency of somatostatin compared with bromocriptine observed in our patient is consistent with the relative effects of these drugs in patients with acromegaly as a result of other causes& The etiology of the acromegaly of MCAS remains unknown. The other endocrinopathies associated with MCAS appear to result from autonomous hyperfunction of various glands, including the ovary, thyroid, parathyroid, and adrenal cortex. Acromegaly in MCAS could result from an autonomous pituitary adenoma, hypothalamic hypersecretion of GRF, or, perhaps, ectopic GRF secretion. In acromegaly unrelated to MCAS, an elevation of the peripheral plasma level in GRF appears helpful in distinguishing the third mechanism from the first two. TM Our patient's first plasma G R F level, although in the nanogram range, was less than that found in patients with proved extrahypothalamic GRF-producing tumors. TM Additionally, it was measured postprandially15 and while receiving bromocriptine. The second G R F level, measured when the patient was not receiving bromocriptine and in the fasting state, was below the lower limit of detection of the assay and makes it unlikely that the acromegaly was caused by ectopic GRF production. This finding suggests a central cause of the acromegaly but would not distinguish between hypothalamic and pituitary lesions. The prompt and sustained diminution of our patient's serum GH concentration and the shrinkage of the adenoma in response to somatostatin would suggest a hypothalamic cause. Previous investigators have suggested both pituitary 5 and hypothalamic3 causes for the acromegaly of MCAS. Cuttler et al. ~6recently reported two children with MCAS, gigantism, and hyperprolactinemia with normal CT scans of the head, normal plasma GRF concentrations, and normal GH responsiveness to administration of GRF. Their data indicate that the pituitary gland is not autonomous in patients with MCAS and that, more likely,
1. Mauras N, Blizzard RM. The McCune-Albright syndrome. Acta Endocrinol 1986;113(suppl):207-17. 2. Lightner ES, Penny R, Frasier SD. Pituitary adenoma in McCune-Albright syndrome:follow-upinformation [letter]. J PEDIATR 1976;89:159. 3. Joishy SK, Morrow LB. McCune-Albright syndrome associated with a functioning chromophobe adenoma. J Pediatr 1976;89:73-5. 4. Lipson A, Hsu T-H. The Albright syndrome associated with acromegaly: report of a case and review of the literature. Johns Hopkins Mcd J 1981;149:10-4. 5. PolychronakosC, Tsoukas G, Ducharme JR, Letarte J, Collu R. Gigantism and hyperprolactinemia in polyostotic fibrous dysplasia (McCune-Albright syndrome). J Endocrinol Invest 1982;5:323-6. 6. Chung KF, Alaghband-Zadeh J, Guz A. Acromegaly and hyperprolactinemiain McCune-Albright syndrome.Am J Dis Child 1983;137:134-6. 7. Lightner E, Winter JSD. Treatment of juvenile acromegaly with bromocriptine. J PEDIATR1981;98:494-6. 8. Nakagawa H, Nagasaka A, Sugiura T, et al. Gigantism associated with McCune-Albright's syndrome. Horm Metab Res 1985;17:522-7. 9. Shibasaki T, Hotta M, Masuda A, et al. Studies on the response of growth hormone (GH) secretion to GH-releasing hormone, tbyrotropin-releasing hormone, gonadotropinreleasing hormone, and somatostatin in acromegaly. J Clin Endocrinol Metab 1986;63:167-73. 10. Yen SSC, Siler TM, Devane GW. Effect of somatostatin in patients with acromegaly. N Engl J Med 1974; 290:935-8. 11. Lamberts SWJ, Uitterlinden P, Verschoor L, van Dongen KJ, del Pozo E. Long-term treatment of acromegaly with the somatostatin analog SMS 201-995. N Engl J Med 1985; 313:1576-80. 12. Comi RJ, Gorden P. The responses of serum growth hormone levels to the long-acting somatostatin analog SMS 201-995 in acromegaly. J Clin Endocrinol Metab 1987;64:37-42. 13. Chiodini PG, Cozzi R, Dallabonzana D, et al. Medical treatment of acromegaly with SMS 201-995, a somatostatin analog: a comparison with bromocriptine. J Clin Endocrinol Metab 1987;64:447-53. 14. Thorner MO, Frohman LA, Leong DA, et al. Extrahypothalamic growth-hormone-releasingfactor (GRF) secretion is a rare cause of acromegaly: plasma GRF levels in 177 acromegalic patients. J Clin Endocrinol Metab 1984; 59:846-9. 15. Kashio Y, Chihara K, Kita T, et al. Effect of oral glucose administration on plasma growth hormone-releasinghormone
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(GHRH)-like immunoreactivity levels in normal subjects and patients with idiopathic GH deficiency: evidence that GHRH is released not ordy from the hypothalamus but also from extrabypothalamic tissue. J Clin Endocrinol Metab 1987; 64:92-7. 16. Cuttler L, Levitsky LL, Zafar MS, Mellinger RC, Frohman
Clinical and laboratory observations
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LA. Hypersecretion of growth hormone (GH) and pr01actin (PRL) in McCune-Albright syndrome [abstract.]. Pediatr Res 1986;20:213. 17. Lee PA, Van Dop CC, Migeon CJ. McCune-Albright syndrome: long-term follow-up. JAMA 1986;256:2980-4.
Erythrocytosis associated with spontaneous erythroid colony formation and idiopathic hypererythropoietinemia Vipul N. Mankad, MD, R. Blaine Moore, PhD, Denis McRoyan, MD, and Kenneth Zuckerman, MD From the Departments of Pediatrics and Pathology, University of South Alabama College of Medicine, Mobile, and the DePartment of Medicine, University of Alabama, Birmingham
Erythrocytosis is defined as an elevated red cell count or hemoglobin level? In absolute erythrocytosis, the red cell mass is increased; in relative erythrocytosis, loss of plasma volume is responsible for increased red cell concentration. 1 Absolute erythrocytosis can be secondary to an appropriate or inappropriate increase in erythropoietin production. 2 In contrast, primary erythrocytosis is a disorder of unknown cause in which erythropoietin is not elevated. Polycythemia vera, rare in children, is characterized by an increase in several hematopoietic cell lines with subnormal erythropoietin levels; the bone marrow contains unusual erythroid progenitor cells, which grow in culture in the absence of added erythropoietin. When erythropoietin is added to the culture, colony formation in these patients exceeds that in controls? 7 Such spontaneous colony formation is considered typical of polycythemia vera and is not commonly found in patients with erythrocytosis secondary to increased erythropoietin. However, Dainiak et al. 8 have described an adult with erythropoietin-dependent erythrocytosis and endogenous colony formation. In this report, we describe a child wit h erythrocytosis with increased erythropoietin levels and spontaneous colony formation in vitro. Supported in part by Grants CA13148 and R23HL31226 from the National Institute of Health. Submitted for publication April 24, 1987; accepted June 16, 1987. Reprint requests: Vipu! N. Mankad, MD~ Division of Pediatric Hematology/Oncology, University of South Alabama College of Medicine, 2451 Fillingim St., Mobile, AL 36617.
CASE REPORT
A white boy was found to have a hemoglobin concentration of 18 g/dL during an evaluation for an upper respiratory tract infection at age 5 years. Investigations included chest radiograph, electrocardiogram, and arterial blood gas determinations; results were within normal limits. The patient had no symptoms at that time, but a t age 12 years had severe recurring headaches lasting approximately 2 hours a daY for 1 or 2 weeks, followed by 3 to 4 weeks without headaches. He also complained of lethargy. The family history was normal. Complete blood counts in the father, sister, and maternal aunt were within normal limits. The mother had a hemoglobin level of 17 g/dL and a history of chronic, excessive smoking. BFU-E 2,3-DPG
Burst-forming units, erYthroid 2,3-Diphosphoglycerate
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Physical examination revealed an anxious child with ruddy complexion. Ophthalmologie examination showed a deficiency of accommodation. Results of cardiorespiratory examination were within normal limits. There was no splenomegaly. The remainder of the examination yielded normal findings. Complete blood count revealed hemoglobin 21.8 g/dL, hematocrit 58.7%, leukocyte count 5900/~L, platelet count 308,000/t~L, mean corpuscular volume 75 fL, mean corpuscular hemoglobin concentration 31.7%, and mean corpuscular hemoglobin 24%. 5~Cr-labe!ed red blood cell studies revealed red cell volume 53 mL/kg (normal <36 mL/kg), plasma volume 21 mL/kg, and whole blood volume 74 mL/kg. Arterial blood gas studies revealed pH 7.431 Pao2 119 torr, Paco2 21 torr, oxygen saturation 98.5%, H C O 3 20.0 mEq/L, methemoglobin 0.2%, and carboxyhemoglobin 1.81%. Oxygen equilibrium curves using the patient's whole blood were obtained at the laboratory of Dr. George Honig,