- Erica A Eugster, MD
Erica A Eugster, MD
- Professor of Pediatrics
- Indiana University School of Medicine
Pituitary gigantism refers to growth hormone (GH) excess that occurs before fusion of the epiphyseal growth plates. Therefore, by definition the condition is only seen in growing children. In this setting, elevated levels of serum GH and IGF-I cause rapid, excessive linear growth and, if unchecked, extremely tall adult stature. In contrast, GH excess that begins in adulthood, after complete epiphyseal fusion, has no effect on stature and is called acromegaly. Although many historical claims of gigantism have been exaggerated, case reports of true pituitary giants with heights of up to 8 feet 11 inches (272 cm) are documented in the medical literature . (See "Causes and clinical manifestations of acromegaly".)
Pituitary gigantism is a rare disorder. Most pediatric endocrinologists may see at most one or two patients with the condition during their careers. In one large series of 2367 children and adolescents with pituitary adenomas, only 15 (0.6 percent) had pituitary gigantism . Much of our understanding of this disease is derived from isolated case reports and extrapolation from the adult literature . No sex predilection is known. Gigantism may occur at any age, and has been observed as early as the first six to nine months of age.
Pituitary gigantism typically is a sporadic and isolated condition. However, it may occur within the context of a coexisting disorder or arise according to a pattern of familial inheritance.
Syndromes in which gigantism is a well-recognized feature include McCune Albright Syndrome (MAS), multiple endocrine neoplasia type 1 (MEN1), and Carney complex. The frequency of gigantism seen in these conditions varies:
●Approximately 20 percent of patients with MAS are thought to have GH hypersecretion [4,5], although few large case series are available . In one review of 112 patients with MAS and acromegaly, the mean age at diagnosis of acromegaly was just over 24 years . Subclinical GH excess also has been reported in MAS, where it results in unexpected normal (rather than short) stature in the setting of untreated precocious puberty . (See "Definition, etiology, and evaluation of precocious puberty", section on 'McCune-Albright syndrome'.)
- Behrens, LH, Barr, DP. Hypopituitarism beginning in infancy: The Alton giant. Endocrinology 1932; 16:120.
- Abe T, Tara LA, Lüdecke DK. Growth hormone-secreting pituitary adenomas in childhood and adolescence: features and results of transnasal surgery. Neurosurgery 1999; 45:1.
- Eugster EA, Pescovitz OH. Gigantism. J Clin Endocrinol Metab 1999; 84:4379.
- Ringel MD, Schwindinger WF, Levine MA. Clinical implications of genetic defects in G proteins. The molecular basis of McCune-Albright syndrome and Albright hereditary osteodystrophy. Medicine (Baltimore) 1996; 75:171.
- Dumitrescu CE, Collins MT. McCune-Albright syndrome. Orphanet J Rare Dis 2008; 3:12.
- de Sanctis C, Lala R, Matarazzo P, et al. McCune-Albright syndrome: a longitudinal clinical study of 32 patients. J Pediatr Endocrinol Metab 1999; 12:817.
- Salenave S, Boyce AM, Collins MT, Chanson P. Acromegaly and McCune-Albright syndrome. J Clin Endocrinol Metab 2014; 99:1955.
- Akintoye SO, Chebli C, Booher S, et al. Characterization of gsp-mediated growth hormone excess in the context of McCune-Albright syndrome. J Clin Endocrinol Metab 2002; 87:5104.
- Yoshimoto K, Saito S. [Clinical characteristics in multiple endocrine neoplasia type 1 in Japan: a review of 106 patients]. Nihon Naibunpi Gakkai Zasshi 1991; 67:764.
- Marx S, Spiegel AM, Skarulis MC, et al. Multiple endocrine neoplasia type 1: clinical and genetic topics. Ann Intern Med 1998; 129:484.
- Stratakis CA, Schussheim DH, Freedman SM, et al. Pituitary macroadenoma in a 5-year-old: an early expression of multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 2000; 85:4776.
- Stratakis CA, Kirschner LS, Carney JA. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab 2001; 86:4041.
- Carney JA, Gordon H, Carpenter PC, et al. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore) 1985; 64:270.
- Fuqua JS, Berkovitz GD. Growth hormone excess in a child with neurofibromatosis type 1 and optic pathway tumor: a patient report. Clin Pediatr (Phila) 1998; 37:749.
- Drimmie FM, MacLennan AC, Nicoll JA, et al. Gigantism due to growth hormone excess in a boy with optic glioma. Clin Endocrinol (Oxf) 2000; 53:535.
- Stephen MD, Zage PE, Waguespack SG. Gonadotropin-dependent precocious puberty: Neoplastic causes and endocrine considerations. Int J Pediatr Endocrinol 2011.
- Gadelha, MR, Kineman, RD, Frohman, LA. Familial Somatotropinomas: Clinical and genetic aspects. Endocrinologist 1999; 9:277.
- Asa SL, Scheithauer BW, Bilbao JM, et al. A case for hypothalamic acromegaly: a clinicopathological study of six patients with hypothalamic gangliocytomas producing growth hormone-releasing factor. J Clin Endocrinol Metab 1984; 58:796.
- Daughaday WH. Pituitary gigantism. Endocrinol Metab Clin North Am 1992; 21:633.
- Manski TJ, Haworth CS, Duval-Arnould BJ, Rushing EJ. Optic pathway glioma infiltrating into somatostatinergic pathways in a young boy with gigantism. Case report. J Neurosurg 1994; 81:595.
- Zhou C, Jiao Y, Wang R, et al. STAT3 upregulation in pituitary somatotroph adenomas induces growth hormone hypersecretion. J Clin Invest 2015; 125:1692.
- Melmed S. Acromegaly. N Engl J Med 1990; 322:966.
- Gelber SJ, Heffez DS, Donohoue PA. Pituitary gigantism caused by growth hormone excess from infancy. J Pediatr 1992; 120:931.
- Blumberg DL, Sklar CA, David R, et al. Acromegaly in an infant. Pediatrics 1989; 83:998.
- Zimmerman D, Young WF Jr, Ebersold MJ, et al. Congenital gigantism due to growth hormone-releasing hormone excess and pituitary hyperplasia with adenomatous transformation. J Clin Endocrinol Metab 1993; 76:216.
- Moran A, Asa SL, Kovacs K, et al. Gigantism due to pituitary mammosomatotroph hyperplasia. N Engl J Med 1990; 323:322.
- Keil MF, Stratakis CA. Pituitary tumors in childhood: update of diagnosis, treatment and molecular genetics. Expert Rev Neurother 2008; 8:563.
- Shimon I, Melmed S. Genetic basis of endocrine disease: pituitary tumor pathogenesis. J Clin Endocrinol Metab 1997; 82:1675.
- Dötsch J, Kiess W, Hänze J, et al. Gs alpha mutation at codon 201 in pituitary adenoma causing gigantism in a 6-year-old boy with McCune-Albright syndrome. J Clin Endocrinol Metab 1996; 81:3839.
- Georgitsi M, Raitila A, Karhu A, et al. Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia. J Clin Endocrinol Metab 2007; 92:3321.
- Gadelha MR, Une KN, Rohde K, et al. Isolated familial somatotropinomas: establishment of linkage to chromosome 11q13.1-11q13.3 and evidence for a potential second locus at chromosome 2p16-12. J Clin Endocrinol Metab 2000; 85:707.
- Kirschner LS, Carney JA, Pack SD, et al. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet 2000; 26:89.
- Lytras A, Tolis G. Growth hormone-secreting tumors: genetic aspects and data from animal models. Neuroendocrinology 2006; 83:166.
- Trivellin G, Daly AF, Faucz FR, et al. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N Engl J Med 2014; 371:2363.
- Raverot G, Arnous W, Calender A, et al. Familial pituitary adenomas with a heterogeneous functional pattern: clinical and genetic features. J Endocrinol Invest 2007; 30:787.
- Epstein LH, Wing RR, Valoski A. Childhood obesity. Pediatr Clin North Am 1985; 32:363.
- Ritzén EM, Wettrell G, Davies G, Grant DB. Management of pituitary gigantism. The role of bromocriptine and radiotherapy. Acta Paediatr Scand 1985; 74:807.
- Espiner EA, Carter TA, Abbott GD, Wrightson P. Pituitary gigantism in a 31 month old girl: endocrine studies and successful response to hypophysectomy. J Endocrinol Invest 1981; 4:445.
- Colao A, Pivonello R, Di Somma C, et al. Growth hormone excess with onset in adolescence: clinical appearance and long-term treatment outcome. Clin Endocrinol (Oxf) 2007; 66:714.
- Bondanelli M, Bonadonna S, Ambrosio MR, et al. Cardiac and metabolic effects of chronic growth hormone and insulin-like growth factor I excess in young adults with pituitary gigantism. Metabolism 2005; 54:1174.
- Alvi NS, Kirk JM. Pituitary gigantism causing diabetic ketoacidosis. J Pediatr Endocrinol Metab 1999; 12:907.
- Kuzuya T, Matsuda A, Sakamoto Y, et al. A case of pituitary gigantism who had two episodes of diabetic ketoacidosis followed by complete recovery of diabetes. Endocrinol Jpn 1983; 30:329.
- Ali O, Banerjee S, Kelly DF, Lee PD. Management of type 2 diabetes mellitus associated with pituitary gigantism. Pituitary 2007; 10:359.
- Barkan AL, Beitins IZ, Kelch RP. Plasma insulin-like growth factor-I/somatomedin-C in acromegaly: correlation with the degree of growth hormone hypersecretion. J Clin Endocrinol Metab 1988; 67:69.
- Juul A, Bang P, Hertel NT, et al. Serum insulin-like growth factor-I in 1030 healthy children, adolescents, and adults: relation to age, sex, stage of puberty, testicular size, and body mass index. J Clin Endocrinol Metab 1994; 78:744.
- Grinspoon S, Clemmons D, Swearingen B, Klibanski A. Serum insulin-like growth factor-binding protein-3 levels in the diagnosis of acromegaly. J Clin Endocrinol Metab 1995; 80:927.
- Melmed S, Jackson I, Kleinberg D, Klibanski A. Current treatment guidelines for acromegaly. J Clin Endocrinol Metab 1998; 83:2646.
- Bidlingmaier M, Freda PU. Measurement of human growth hormone by immunoassays: current status, unsolved problems and clinical consequences. Growth Horm IGF Res 2010; 20:19.
- Holl RW, Bucher P, Sorgo W, et al. Suppression of growth hormone by oral glucose in the evaluation of tall stature. Horm Res 1999; 51:20.
- Misra M, Cord J, Prabhakaran R, et al. Growth hormone suppression after an oral glucose load in children. J Clin Endocrinol Metab 2007; 92:4623.
- Pieters GF, Hermus AR, Smals AG, Kloppenborg PW. Paradoxical responsiveness of growth hormone to corticotropin-releasing factor in acromegaly. J Clin Endocrinol Metab 1984; 58:560.
- Duchowny MS, Katz R, Bejar RL. Hypothalamic mass and gigantism in neurofibromatosis: treatment with bromocriptine. Ann Neurol 1984; 15:302.
- Lu PW, Silink M, Johnston I, et al. Pituitary gigantism. Arch Dis Child 1992; 67:1039.
- Felix IA, Horvath E, Kovacs K, et al. Mammosomatotroph adenoma of the pituitary associated with gigantism and hyperprolactinemia. A morphological study including immunoelectron microscopy. Acta Neuropathol 1986; 71:76.
- Nomikos P, Buchfelder M, Fahlbusch R. The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical 'cure'. Eur J Endocrinol 2005; 152:379.
- Orvidas LJ, Kasperbauer JL, Meyer FB, Zimmerman D. Pediatric transseptal transsphenoidal pituitary surgery. Am J Rhinol 2000; 14:265.
- Mindermann T, Wilson CB. Pediatric pituitary adenomas. Neurosurgery 1995; 36:259.
- Ciric I, Ragin A, Baumgartner C, Pierce D. Complications of transsphenoidal surgery: results of a national survey, review of the literature, and personal experience. Neurosurgery 1997; 40:225.
- Lüdecke DK, Herrmann HD, Schulte FJ. Special problems with neurosurgical treatments of hormone-secreting pituitary adenomas in children. Prog Exp Tumor Res 1987; 30:362.
- Näntö-Salonen K, Koskinen P, Sonninen P, Toppari J. Suppression of GH secretion in pituitary gigantism by continuous subcutaneous octreotide infusion in a pubertal boy. Acta Paediatr 1999; 88:29.
- Moran, A, Pescovitz, OH. Long-term treatment of gigantism with combination octreotide and bromocriptine in a child with McCune-Albright syndrome. Endocr J 1994; 2:111.
- Tajima T, Tsubaki J, Ishizu K, et al. Case study of a 15-year-old boy with McCune-Albright syndrome combined with pituitary gigantism: effect of octreotide-long acting release (LAR) and cabergoline therapy. Endocr J 2008; 55:595.
- Morange I, De Boisvilliers F, Chanson P, et al. Slow release lanreotide treatment in acromegalic patients previously normalized by octreotide. J Clin Endocrinol Metab 1994; 79:145.
- Zacharin M. Paediatric management of endocrine complications in McCune-Albright syndrome. J Pediatr Endocrinol Metab 2005; 18:33.
- Feuillan PP, Jones J, Ross JL. Growth hormone hypersecretion in a girl with McCune-Albright syndrome: comparison with controls and response to a dose of long-acting somatostatin analog. J Clin Endocrinol Metab 1995; 80:1357.
- Petersenn S, Farrall AJ, De Block C, et al. Long-term efficacy and safety of subcutaneous pasireotide in acromegaly: results from an open-ended, multicenter, Phase II extension study. Pituitary 2014; 17:132.
- Higham CE, Trainer PJ. Growth hormone excess and the development of growth hormone receptor antagonists. Exp Physiol 2008; 93:1157.
- Trainer PJ, Drake WM, Katznelson L, et al. Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N Engl J Med 2000; 342:1171.
- van der Lely AJ, Hutson RK, Trainer PJ, et al. Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet 2001; 358:1754.
- Müssig K, Gallwitz B, Honegger J, et al. Pegvisomant treatment in gigantism caused by a growth hormone-secreting giant pituitary adenoma. Exp Clin Endocrinol Diabetes 2007; 115:198.
- Rix M, Laurberg P, Hoejberg AS, Brock-Jacobsen B. Pegvisomant therapy in pituitary gigantism: successful treatment in a 12-year-old girl. Eur J Endocrinol 2005; 153:195.
- Bergamaschi S, Ronchi CL, Giavoli C, et al. Eight-year follow-up of a child with a GH/prolactin-secreting adenoma: efficacy of pegvisomant therapy. Horm Res Paediatr 2010; 73:74.
- Goldenberg N, Racine MS, Thomas P, et al. Treatment of pituitary gigantism with the growth hormone receptor antagonist pegvisomant. J Clin Endocrinol Metab 2008; 93:2953.
- Hofland LJ, van der Hoek J, van Koetsveld PM, et al. The novel somatostatin analog SOM230 is a potent inhibitor of hormone release by growth hormone- and prolactin-secreting pituitary adenomas in vitro. J Clin Endocrinol Metab 2004; 89:1577.
- Mear Y, Blanchard MP, Defilles C, et al. Ghrelin receptor (GHS-R1a) and its constitutive activity in somatotroph adenomas: a new co-targeting therapy using GHS-R1a inverse agonists and somatostatin analogs. J Clin Endocrinol Metab 2014; 99:E2463.