Gigantism

FROM ANCIENT history throughout the modern age, individuals of extraordinar y physical proportions have figured prominently in myths and tales of magic. Th e concept of superhuman size, whether in the form of Goliath, Hercules, or Bigf oot, has consistently inspired a sense of awe and enthrallment. No less intriguin g are the well-documented cases of true gigantism, including that of Robert Wa dlow (The Alton Giant) who, at 8 feet 11 inches (272 cm) at his death, remains t he tallest person ever recorded (1), and that of SA (Fig. 1 ), the current tallest li ving woman at 7 feet 5.5 inches (227 cm). In recent years, scientific breakthrou ghs regarding the molecular genetic, histologic, and hormonal basis of GH exce ss have enhanced our understanding of this inherently fascinating disease and have provided important insights into its pathogenesis, prognosis, and the poten tial for therapeutic intervention.

Gigantism refers to GH excess that occurs during childhood when open epiphys eal growth plates allow for excessive linear growth, whereas acromegaly indicat es the same phenomenon occurring in adulthood. Although this review focuses primarily on gigantism, the two disorders may be thought of as existing along a spectrum of GH excess, with principal manifestations determined by the develo pmental stage during which such excess originates. Supporting this model has been the observation of clinical overlap between the two entities, with approxim ately 10% of acromegalics exhibiting tall stature (2) and the majority of giants ev entually demonstrating features of acromegaly (3). The mean age for the onset of acromegaly is within the 3rd decade of life, whereas gigantism may begin at any age prior to epiphyseal fusion. Even a congenital onset of GH excess has b een suggested by linear growth acceleration occurring within the first few month s of life in young children with documented gigantism (4, 5, 6). The incidence of acromegaly is calculated to be three to four cases per million per year (7), wher eas gigantism is extremely rare, with approximately 100 reported cases to date (2), although this is probably an underestimate of the true number. Etiologies of Gigantism Excessive GH secretion has several potential causes and may occur in the cont ext of a number of heterogeneous disorders. Among these, a variety of specific pathophysiologic mechanisms have been elucidated or proposed, all of which re sult in GH excess as the final common abnormality. Cases of GH hypersecretio n may be subdivided into two main categories: those originating from a primary pituitary source and those that seem to be caused by increased GHRH secretio n or dysregulation. A spectrum of pathologic pituitary morphology exists, rangin g from isolated pituitary adenomas typically seen in cases of primary pituitary G H hypersecretion to pituitary hyperplasia, which is usually found in the context o f prolonged GHRH excess. Although gigantism typically occurs as an isolated di sorder, it may also be a feature of an underlying medical condition such as multi ple endocrine neoplasia (MEN) type-1, McCune-Albright syndrome (MAS), neur ofibromatosis, or Carney complex. The various etiologies of GH excess along wi th their associated characteristics are summarized in Table 1 and discussed f urther.

Primary pituitary GH excess

Many cases of gigantism result from primary GH secretion by pituitary tumors co mprised of somatotrophs (GH-secreting cells) or mammosomatotrophs (GH and PRL-secreting cells), either in the form of a pituitary microadenoma or, rarely, ma

Gs mutations
The heterotrimeric G-proteins play an integral role in postligand signal transduct ion in many endocrine cells, in which they act by stimulating adenylyl cyclase, re sulting in cAMP accumulation and subsequent gene transcription. Activating poi nt mutations of the G-protein stimulatory subunit Gs are known to form the basi s for McCune-Albright syndrome (MAS), a rare disorder characterized by the cla ssic triad of precocious puberty, caf au lait spots, and fibrous dysplasia of bone (12). Constitutive activation refers to the autonomous and uncontrolled activa tion of G-protein-mediated cAMP formation that occurs in MAS, resulting in hyp erfunction of endocrine and nonendocrine tissues. In some patients with MAS, e ndocrine abnormalities include gigantism caused by the development of pituitar y mammosomatotroph adenomas or hyperplasia. The reported point mutations observed in multiple affected tissues of patients with MAS (13), including those with gigantism (14), involve a single amino acid substitution within codon 201 (e xon 8) or codon 227 (exon 9) of the Gs gene. Interestingly, these same mutatio ns have also been identified in somatotrophs of up to 40% of sporadic GH-secre ting pituitary adenomas (15). The resulting oncogene, gsp, is thought to induce t umorigenesis by virtue of persistent activation of adenylyl cyclase with subsequ ent GH hypersecretion (16). In contrast to tumors without such mutations, gsp-c ontaining pituitary adenomas tend to be smaller, with morphologic characteristic s suggestive of slow growth, despite an absence of detectable differences in dis ease progression between the two groups.

Allelic deletion of the 11q13 locus

Loss of heterozygosity (LOH) at the site of a putative tumor suppressor gene loc

ated on chromosome 11q13 represents another molecular genetic abnormality, whose association with pituitary GH excess has been firmly established. First id entified within tumors from patients with MEN-1 (17), the genetic mutation was o riginally believed to be related to the MEN-1 gene and was thought to be the ca use of the GH excess in this disease. The recent cloning of the MEN-1 gene, ho wever, has led to the revelation that the affected locus codes for a product that i s distinct from the MEN-1 gene. This has been demonstrated by the finding of a n intact MEN-1 sequence in individuals from two unrelated kindreds with familial acromegaly/gigantism and 11q13 LOH (18). In addition to familial non-MEN acr omegaly/gigantism (19), LOH at 11q13 has also been observed in all types of s poradically occurring pituitary adenomas (20). The exact nature of the encoded product and its role in tumor formation have yet to be clarified. Of note is the fac t that LOH at 11q13 and other loci within pituitary adenomas has been correlate d with an increased propensity for tumor invasiveness and biological activity (21 ). Additional theoretical intrinsic pituitary defects leading to abnormal cell proliferat ion and excessive GH secretion might result from abnormal activation of the GH RH receptor, somatostatin receptor, pituitary transcription factors, or other growt h-related signal peptides. As information regarding the complex developmental cascade of pituitary ontogenesis continues to accumulate, new light will undoubt edly be shed on the underlying mechanisms of both normal and abnormal pituit ary cell growth.

Secondary GH excess
Causes of secondary GH excess include those in which there is increased secr etion of hypothalamic GHRH, either from an intracranial or ectopic source, and t hose in which abnormal regulation of the hypothalamic-pituitary GH axis has oc curred. Secondary GH excess represents an important, if poorly understood, ca use of gigantism. Advances in biochemical detection assays and molecular gen etic characterization should allow improved localization of the underlying hormo nal abnormality in these cases.

GHRH excess
Hypothalamic GHRH excess or dysregulation has been postulated to be the mo st common cause of GH hypersecretion in the pediatric population. Although not definitively proven, clinical cases that support this hypothesis include congenita l gigantism with massive diffuse pituitary hyperplasia, in which biochemical studi es suggested central GHRH hypersecretion (5), as well as a case of mammoso matotroph hyperplasia in which systemic GHRH concentrations were found to b e normal (4). The involvement of mammosomatotrophs, frequently a feature of GH excess originating in childhood (22), is further suggestive of early onset incr eased GHRH exposure because this cell type predominates in fetal life but is ra re in the adult. Despite this evidence, the underlying mechanism of the putative abnormality in GHRH action in these cases remains unknown. Theoretical possi bilities include an activating mutation in hypothalamic GHRH neurons or a decre ase in somatostatin tone (see below). Another form of intracranial GHRH exces s occurs in the setting of a neural tumor, such as a gangliocytoma (23, 24) or ne urocytoma (25), arising within or in close proximity to the sella. Prolonged tumor secretion of GHRH leads to pituitary hyperplasia with or without adenomatous t ransformation, resulting in increased levels of GH and other adenohypophyseal

peptides. Electron microscopy in such cases has revealed intimate contact betw een neurons of the tumor and pituitary GH-secreting cells (23). GHRH excess m ay also originate from an extracranial and ectopic neoplastic source, which repr esents a well-recognized cause of acromegaly (26), but has only rarely been im plicated in cases of GH excess in children (3). Ectopic GHRH-secreting tumors have included carcinoid, pancreatic islet cell, and bronchial neoplasms. Recentl y, the first reported case of ectopic GH as the cause of acromegaly was identifie d, in which tumor cells from a malignant lymphoma were found to secrete high l evels of pituitary GH (27).

Abnormal Somatostatin tone

Secondary GH excess may also occur from disruption of somatostatin tone. Tu mor infiltration into somatostatinergic pathways has been hypothesized to form t he basis for GH excess in rare cases of gigantism associated with neurofibroma tosis and optic gliomas or astrocytomas (28, 29). Immunocytochemical studies i n this setting have demonstrated interruption of somatostatinergic neurons, whe reas neuroimaging has revealed diminished magnetic resonance signal intensit y in somatostatin-rich areas of the brain (30). Consequences of Prolonged GH Excess Transgenic mice models with targeted overexpression of GH, GHRH, and insuli n-like growth factor (IGF)-I have provided invaluable tools for the exploration of t he pathogenetic mechanisms underlying the physiological effects of chronic GH exposure. The first such model, constructed by fusion of the mouse metallothio nein-1 gene promoter to the rat GH gene (31), resulted in dramatically accelerat ed growth in transgenics as compared with control littermates, along with greatl y increased circulating GH and tissue GH messenger RNA levels. Subsequently , the role of elevated GHRH in GH hypersecretion was demonstrated by the find ing of pituitary hyperplasia and adenomas, increased somatic growth, and eleva ted plasma GH levels in transgenic mice overexpressing human GHRH (32). Th e differential effects of chronic GH exposure vs. IGF-I excess have been further investigated by comparing changes exhibited by animals with isolated overexpr ession of IGF-I with those observed in animals overexpressing GH or GHRH. A natomical and biochemical changes found to be unique to animals with chronica lly elevated GH levels have included renal and hepatic enlargement, glomerulos clerosis, skin abnormalities, and elevations of insulin and cholesterol (33). In lin e with the diverse clinical symptomatology observed in patients with acromegaly , these studies also emphasize the fact that excessive GH exposure has an imp act on all tissues in the body.

Clinical Aspects of Gigantism Unlike GH excess beginning in adulthood, in which an insidious onset and delay ed diagnosis are the norm, the presentation of gigantism is usually quite dramati c and the diagnosis is fairly straightforward. The cardinal clinical feature of giga ntism is growth acceleration. All growth parameters are affected, although not n ecessarily symmetrically because mild to moderate obesity is common and mac rocephaly has been noted to precede linear and weight acceleration in at least o ne case (34). Due to the small number of affected patients, there are no precise

figures regarding the prevalence of other signs and symptoms of GH excess in children with gigantism. However, a review of clinical case reports reveals sever al common features among such patients. All have been noted to have coarse f acial features and disproportionately large hands and feet with thick fingers and toes. Frontal bossing and a prominent jaw have frequently been present. Organ omegaly and deteriorating glucose tolerance were also documented in one pati ent observed over several years before treatment (29). In contrast, the myriad signs and symptoms of prolonged GH excess in adults w ith acromegaly have been well described (35). Enlargement of facial features, e xcess acral growth and soft tissue swelling are essentially ubiquitous among the se patients. Additional common manifestations include headaches, excessive s weating, peripheral neuropathy and arthritis. Frequently associated endocrinopa thies include hypogonadism, diabetes, thyromegaly, and galactorrhea. The mos t common cause of death in acromegaly is from cardiovascular disease (36). Re cent observations regarding other consequences of GH toxicity include a potenti al role for GH in normal and abnormal erythropoiesis (37) and in the pathogene sis of retinopathy (38). Physical examination of the child presenting with growth acceleration must inclu de a search for evidence of other etiologies of increased growth velocity, such a s excessive sex steroid levels, as well as careful attention to the presence of ad ditional physical findings that might suggest an underlying disorder, such as mul tiple caf au lait spots. The differential diagnosis of growth acceleration is contai ned in Table 2.

Laboratory findings
An elevated IGF-I on initial screening is suggestive of GH excess, as an excelle nt linear dose-response correlation between plasma IGF-1 levels and 24-h mea n GH secretion have been demonstrated (39). Potential confusion may arise wh en evaluating normal adolescents because significantly higher IGF-I levels occu r during puberty than in adulthood (40), a fact that emphasizes the importance o f using age-referenced norms. Although higher concentrations of IGF-I have be en reported in children and adolescents with constitutional tall stature (41), no si gnificant differences in neurosecretory dynamics of the GH-IGF-I axis have bee n found in healthy young adults with heights of more than three SD above the m ean as compared with controls (42). The gold standard for making the diagnosis of GH excess is a failure to suppress serum GH levels to less than 5 ng/dL afte r a 1.75 gm/kg oral glucose challenge (maximum, 75 g). Hyperprolactinemia is a n almost invariable finding in GH excess presenting in childhood, undoubtedly r elated to the fact that mammosomatotrophs are by far the most common type of GH-secreting cells involved in childhood gigantism. The coexistence of both G H and PRL has been clearly demonstrated within the secretory granules contain ed in the cytoplasm of these cells (22). Although not necessary to make the dia gnosis, GH response to additional stimuli such as TRH testing is typically parad oxical. Measurement of serum GHRH levels are useful in differentiating ectopic GHRH excess from other causes of GH hypersecretion. Imaging by magnetic re sonance imaging or computed tomography is an essential step in the evaluation following biochemical detection of GH excess.

Psychological aspects of tall stature/gigantism

One need only review the striking positive correlation between stature and finan cial/professional success in our society to be convinced that heightism is a tru e phenomenon. However, when present to an extreme degree, tallness ceases to be an advantage and may be perceived as a burden, resulting in both physic al, as well as psychological, handicaps. This has prompted the pharmacological treatment of constitutionally tall adolescents with sex steroids to accelerate epi physeal fusion, a practice that has been in existence since the 1950s (43). Whe reas tall girls, in particular, often report teasing and social difficulties as a result of their size, these problems generally disappear in adulthood, when the majorit y of normal tall men and women indicate satisfaction with their stature (44). Bec ause no convincing data indicating lifelong psychopathology as a result of tall st ature exists (45), it may be reasonable to pursue counseling as the initial treatm ent of choice for otherwise healthy tall adolescents with psychosocial difficulties related to their height. In contrast, pathologic tall stature as a result of GH exces s obviously results in heights that are far beyond those observed in constitution ally tall individuals. Although no in-depth information regarding the psychologica l profile of patients with gigantism is available, case series indicate a high incide nce of severe depression, social withdrawal, and low self-esteem (3). Treatment of Gigantism Several therapeutic modalities have been used in the treatment of GH hypersec retion. The optimal therapy in any given case is dictated by the characteristics o f the GH-secreting lesion and other coexisting factors. For well-circumscribed pit uitary adenomas, transsphenoidal surgery is the treatment of choice and may b e curative (46). Radiation therapy, used as adjunctive or primary treatment, has also been moderately successful in inducing normalization of growth hormone l evels (47). Major disadvantages to the use of irradiation exist, however, in the fo rm of delayed efficacy in reducing GH levels and a high incidence of hypopituita rism following treatment. The greatest progress in recent years in the treatment of GH excess has been within the realm of medical therapy. The development of somatostatin analogs, such as octreotide, represented a major addition to the pharmacological armam entarium for GH hypersecretion. Therapeutic response to octreotide, found to b e highly effective in the majority of patients with gigantism or acromegaly, may b e predicted by the decrement in serum GH levels after one sc dose (48). The ne w sustained-release somatostatin analog preparation lanreotide given in the for m of an im injection every 2 weeks, has also been shown to be successful in ret urning GH levels to normal in acromegalic adults with pituitary adenomas (49) a s well as in those with ectopic GHRH secretion (50). Although this drug is as yet untested in children, the improved dosing schedule of lanreotide clearly represe nts a potentially major advance in the treatment of gigantism and disorders of gl ucose homeostasis in pediatric patients. Side effects of somatostatin analogues consist mainly of mild transient gastrointestinal complaints and an increased ris k of gallstones. Additional pharmacological therapy consists of the dopamine ag onist bromocriptine, which can provide adjuvant medical treatment of gigantism and has been found to be safe when used in a child for an extended period of ti me (51). An exciting new therapeutic agent has recently emerged in the form of a competitive GHRH antagonist, which has been shown to effectively suppress GH and IGF-I levels in patients with acromegaly from pituitary somatotrophic tu mors as well as ectopic GHRH hypersecretion (52, 53).

Conclusion In summary, our current understanding of GH excess represents the end result of a u nique blend of multidisciplinary investigation. Further illumination regarding the unexpl ained aspects of this interesting disease undoubtedly will occur as collaborative effort s continue into the new century.

1.

Received July 21, 1999. Revision received September 28, 1999. Accepted September 28, 1999.

doi: 10.1210/jc.84.12.4379 The Journal of Clinical Endocrinology & Metabolism Dec ember 1, 1999 vol. 84 no. 12 4379-4384