Gigantism

FROM ANCIENT history throughout the modern age, individuals of extraordinary physical proportions have figured prominently in myths and tales of magic. The concept of superhuman size, whether in the form of Goliath, Hercules, or Bigfoot, has consistently inspired a sense of awe and enthrallment. No less intriguing are the well-documented cases of true gigantism, including that of Robert Wadlow (The Alton Giant) who, at 8 feet 11 inches (272 cm) at his death, remains the tallest person ever recorded (1), and that of SA (Fig. 1), the current tallest living woman at 7 feet 5.5 inches (227 cm). In recent years, scientific breakthroughs regarding the molecular genetic, histologic, and hormonal basis of GH excess have enhanced our understanding of this inherently fascinating disease and have provided important insights into its pathogenesis, prognosis, and the potential for therapeutic intervention. Gigantism refers to GH excess that occurs during childhood when open epiphyseal growth plates allow for excessive linear growth, whereas acromegaly indicates 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 developmental stage during which such excess originates. Supporting this model has been the observation of clinical overlap between the two entities, with approximately 10% of acromegalics exhibiting tall stature (2) and the majority of giants eventually 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 been suggested by linear growth acceleration occurring within the first few months of life in young children with documented gigantism (4–6). The incidence of acromegaly is calculated to be three to four cases per million per year (7), whereas gigantism is extremely rare, with approximately 100 reported cases to date (2), although this is probably an underestimate of the true number. SA, the tallest living woman, standing with one of the authors (EAE). Excessive GH secretion has several potential causes and may occur in the context of a number of heterogeneous disorders. Among these, a variety of specific pathophysiologic mechanisms have been elucidated or proposed, all of which result in GH excess as the final common abnormality. Cases of GH hypersecretion may be subdivided into two main categories: those originating from a primary pituitary source and those that seem to be caused by increased GHRH secretion or dysregulation. A spectrum of pathologic pituitary morphology exists, ranging from isolated pituitary adenomas typically seen in cases of primary pituitary GH hypersecretion to pituitary hyperplasia, which is usually found in the context of prolonged GHRH excess. Although gigantism typically occurs as an isolated disorder, it may also be a feature of an underlying medical condition such as multiple endocrine neoplasia (MEN) type-1, McCune-Albright syndrome (MAS), neurofibromatosis, or Carney complex. The various etiologies of GH excess along with their associated characteristics are summarized in Table 1 and discussed further. Causes of excessive GH secretion Causes of excessive GH secretion Many cases of gigantism result from primary GH secretion by pituitary tumors comprised of somatotrophs (GH-secreting cells) or mammosomatotrophs (GH and PRL-secreting cells), either in the form of a pituitary microadenoma or, rarely, macroadenoma (6). The relative contributions of inherent pituitary defects vs. hypothalamic factors in the pathogenesis of pituitary tumors are far from resolved, however. The monoclonal nature of most pituitary adenomas (8), confirmed by X-inactivation studies, has implied that they originate from a single altered cell. The concept of an intrinsic pituitary defect is further supported by the discovery that specific molecular genetic abnormalities seem to form the basis of GH hypersecretion in many cases. In contrast, evidence also exists to suggest an important role for GHRH in disease progression because the number of GHRH messenger RNA transcripts within pituitary adenomas correlates strongly with their clinical behavior (9). The exact functional consequence of locally produced GHRH remains to be clarified, although an autocrine or paracrine role has been suggested by the finding of an elevated plasma GHRH concentration in association with a pituitary somatotroph adenoma, which normalized following surgical removal of the adenoma (10). An approach that integrates the different theories of pituitary adenoma formation has recently been proposed, in which tumor growth ensues via a multistep process. In this model, the initial event consists of genetic transformation of cells, with abnormal growth being subsequently promoted by hypophysiotrophic hormones and other growth factors (11). Identified molecular genetic abnormalities implicated in the pathogenesis of primary pituitary GH excess are discussed below. The heterotrimeric G-proteins play an integral role in postligand signal transduction in many endocrine cells, in which they act by stimulating adenylyl cyclase, resulting in cAMP accumulation and subsequent gene transcription. Activating point mutations of the G-protein stimulatory subunit Gsα are known to form the basis for McCune-Albright syndrome (MAS), a rare disorder characterized by the classic triad of precocious puberty, café au lait spots, and fibrous dysplasia of bone (12). “Constitutive activation” refers to the autonomous and uncontrolled activation of G-protein-mediated cAMP formation that occurs in MAS, resulting in hyperfunction of endocrine and nonendocrine tissues. In some patients with MAS, endocrine abnormalities include gigantism caused by the development of pituitary 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 (exon 8) or codon 227 (exon 9) of the Gsα gene. Interestingly, these same mutations have also been identified in somatotrophs of up to 40% of sporadic GH-secreting pituitary adenomas (15). The resulting oncogene, gsp, is thought to induce tumorigenesis by virtue of persistent activation of adenylyl cyclase with subsequent GH hypersecretion (16). In contrast to tumors without such mutations, gsp-containing pituitary adenomas tend to be smaller, with morphologic characteristics suggestive of slow growth, despite an absence of detectable differences in disease progression between the two groups. Loss of heterozygosity (LOH) at the site of a putative tumor suppressor gene located on chromosome 11q13 represents another molecular genetic abnormality, whose association with pituitary GH excess has been firmly established. First identified within tumors from patients with MEN-1 (17), the genetic mutation was originally believed to be related to the MEN-1 gene and was thought to be the cause of the GH excess in this disease. The recent cloning of the MEN-1 gene, however, has led to the revelation that the affected locus codes for a product that is distinct from the MEN-1 gene. This has been demonstrated by the finding of an intact MEN-1 sequence in individuals from two unrelated kindreds with familial acromegaly/gigantism and 11q13 LOH (18). In addition to familial non-MEN acromegaly/gigantism (19), LOH at 11q13 has also been observed in all types of sporadically 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 fact that LOH at 11q13 and other loci within pituitary adenomas has been correlated with an increased propensity for tumor invasiveness and biological activity (21). Additional theoretical intrinsic pituitary defects leading to abnormal cell proliferation and excessive GH secretion might result from abnormal activation of the GHRH receptor, somatostatin receptor, pituitary transcription factors, or other growth-related signal peptides. As information regarding the complex developmental cascade of pituitary ontogenesis continues to accumulate, new light will undoubtedly be shed on the underlying mechanisms of both normal and abnormal pituitary cell growth. Causes of secondary GH excess include those in which there is increased secretion of hypothalamic GHRH, either from an intracranial or ectopic source, and those in which abnormal regulation of the hypothalamic-pituitary GH axis has occurred. Secondary GH excess represents an important, if poorly understood, cause of gigantism. Advances in biochemical detection assays and molecular genetic characterization should allow improved localization of the underlying hormonal abnormality in these cases. Hypothalamic GHRH excess or dysregulation has been postulated to be the most common cause of GH hypersecretion in the pediatric population. Although not definitively proven, clinical cases that support this hypothesis include congenital gigantism with massive diffuse pituitary hyperplasia, in which biochemical studies suggested central GHRH hypersecretion (5), as well as a case of mammosomatotroph hyperplasia in which systemic GHRH concentrations were found to be normal (4). The involvement of mammosomatotrophs, frequently a feature of GH excess originating in childhood (22), is further suggestive of early onset increased GHRH exposure because this cell type predominates in fetal life but is rare in the adult. Despite this evidence, the underlying mechanism of the putative abnormality in GHRH action in these cases remains unknown. Theoretical possibilities include an activating mutation in hypothalamic GHRH neurons or a decrease in somatostatin tone (see below). Another form of intracranial GHRH excess occurs in the setting of a neural tumor, such as a gangliocytoma (23, 24) or neurocytoma (25), arising within or in close proximity to the sella. Prolonged tumor secretion of GHRH leads to pituitary hyperplasia with or without adenomatous transformation, resulting in increased levels of GH and other adenohypophyseal peptides. Electron microscopy in such cases has revealed intimate contact between neurons of the tumor and pituitary GH-secreting cells (23). GHRH excess may also originate from an extracranial and ectopic neoplastic source, which represents a well-recognized cause of acromegaly (26), but has only rarely been implicated in cases of GH excess in children (3). Ectopic GHRH-secreting tumors have included carcinoid, pancreatic islet cell, and bronchial neoplasms. Recently, the first reported case of ectopic GH as the cause of acromegaly was identified, in which tumor cells from a malignant lymphoma were found to secrete high levels of pituitary GH (27). Secondary GH excess may also occur from disruption of somatostatin tone. Tumor infiltration into somatostatinergic pathways has been hypothesized to form the basis for GH excess in rare cases of gigantism associated with neurofibromatosis and optic gliomas or astrocytomas (28, 29). Immunocytochemical studies in this setting have demonstrated interruption of somatostatinergic neurons, whereas neuroimaging has revealed diminished magnetic resonance signal intensity in somatostatin-rich areas of the brain (30). Transgenic mice models with targeted overexpression of GH, GHRH, and insulin-like growth factor (IGF)-I have provided invaluable tools for the exploration of the pathogenetic mechanisms underlying the physiological effects of chronic GH exposure. The first such model, constructed by fusion of the mouse metallothionein-1 gene promoter to the rat GH gene (31), resulted in dramatically accelerated growth in transgenics as compared with control littermates, along with greatly increased circulating GH and tissue GH messenger RNA levels. Subsequently, the role of elevated GHRH in GH hypersecretion was demonstrated by the finding of pituitary hyperplasia and adenomas, increased somatic growth, and elevated plasma GH levels in transgenic mice overexpressing human GHRH (32). The differential effects of chronic GH exposure vs. IGF-I excess have been further investigated by comparing changes exhibited by animals with isolated overexpression of IGF-I with those observed in animals overexpressing GH or GHRH. Anatomical and biochemical changes found to be unique to animals with chronically elevated GH levels have included renal and hepatic enlargement, glomerulosclerosis, skin abnormalities, and elevations of insulin and cholesterol (33). In line with the diverse clinical symptomatology observed in patients with acromegaly, these studies also emphasize the fact that excessive GH exposure has an impact on all tissues in the body. Unlike GH excess beginning in adulthood, in which an insidious onset and delayed diagnosis are the norm, the presentation of gigantism is usually quite dramatic and the diagnosis is fairly straightforward. The cardinal clinical feature of gigantism is growth acceleration. All growth parameters are affected, although not necessarily symmetrically because mild to moderate obesity is common and macrocephaly has been noted to precede linear and weight acceleration in at least one 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 several common features among such patients. All have been noted to have coarse facial features and disproportionately large hands and feet with thick fingers and toes. Frontal bossing and a prominent jaw have frequently been present. Organomegaly and deteriorating glucose tolerance were also documented in one patient observed over several years before treatment (29). In contrast, the myriad signs and symptoms of prolonged GH excess in adults with acromegaly have been well described (35). Enlargement of facial features, excess acral growth and soft tissue swelling are essentially ubiquitous among these patients. Additional common manifestations include headaches, excessive sweating, peripheral neuropathy and arthritis. Frequently associated endocrinopathies include hypogonadism, diabetes, thyromegaly, and galactorrhea. The most common cause of death in acromegaly is from cardiovascular disease (36). Recent observations regarding other consequences of GH toxicity include a potential role for GH in normal and abnormal erythropoiesis (37) and in the pathogenesis of retinopathy (38). Physical examination of the child presenting with growth acceleration must include a search for evidence of other etiologies of increased growth velocity, such as excessive sex steroid levels, as well as careful attention to the presence of additional physical findings that might suggest an underlying disorder, such as multiple café au lait spots. The differential diagnosis of growth acceleration is contained in Table1 2. An elevated IGF-I on initial screening is suggestive of GH excess, as an excellent linear dose-response correlation between plasma IGF-1 levels and 24-h mean GH secretion have been demonstrated (39). Potential confusion may arise when evaluating normal adolescents because significantly higher IGF-I levels occur during puberty than in adulthood (40), a fact that emphasizes the importance of using age-referenced norms. Although higher concentrations of IGF-I have been reported in children and adolescents with constitutional tall stature (41), no significant differences in neurosecretory dynamics of the GH-IGF-I axis have been found in healthy young adults with heights of more than three sd above the mean 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 after a 1.75 gm/kg oral glucose challenge (maximum, 75 g). Hyperprolactinemia is an almost invariable finding in GH excess presenting in childhood, undoubtedly related to the fact that mammosomatotrophs are by far the most common type of GH-secreting cells involved in childhood gigantism. The coexistence of both GH and PRL has been clearly demonstrated within the secretory granules contained in the cytoplasm of these cells (22). Although not necessary to make the diagnosis, GH response to additional stimuli such as TRH testing is typically paradoxical. Measurement of serum GHRH levels are useful in differentiating ectopic GHRH excess from other causes of GH hypersecretion. Imaging by magnetic resonance imaging or computed tomography is an essential step in the evaluation following biochemical detection of GH excess. One need only review the striking positive correlation between stature and financial/professional success in our society to be convinced that “heightism” is a true phenomenon. However, when present to an extreme degree, tallness ceases to be an advantage and may be perceived as a burden, resulting in both physical, as well as psychological, handicaps. This has prompted the pharmacological treatment of constitutionally tall adolescents with sex steroids to accelerate epiphyseal fusion, a practice that has been in existence since the 1950s (43). Whereas tall girls, in particular, often report teasing and social difficulties as a result of their size, these problems generally disappear in adulthood, when the majority of normal tall men and women indicate satisfaction with their stature (44). Because no convincing data indicating lifelong psychopathology as a result of tall stature exists (45), it may be reasonable to pursue counseling as the initial treatment of choice for otherwise healthy tall adolescents with psychosocial difficulties related to their height. In contrast, pathologic tall stature as a result of GH excess obviously results in heights that are far beyond those observed in constitutionally tall individuals. Although no in-depth information regarding the psychological profile of patients with gigantism is available, case series indicate a high incidence of severe depression, social withdrawal, and low self-esteem (3). Several therapeutic modalities have been used in the treatment of GH hypersecretion. The optimal therapy in any given case is dictated by the characteristics of the GH-secreting lesion and other coexisting factors. For well-circumscribed pituitary adenomas, transsphenoidal surgery is the treatment of choice and may be curative (46). Radiation therapy, used as adjunctive or primary treatment, has also been moderately successful in inducing normalization of growth hormone levels (47). Major disadvantages to the use of irradiation exist, however, in the form of delayed efficacy in reducing GH levels and a high incidence of hypopituitarism 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 for GH hypersecretion. response to octreotide, found to be in the majority of patients with gigantism or acromegaly, may be by the in serum GH levels after one The new somatostatin given in the form of an has also been to be successful in GH levels to normal in adults with pituitary adenomas as well as in those with ectopic GHRH secretion Although this is as yet in the improved of clearly represents a major in the treatment of gigantism and disorders of glucose in pediatric patients. effects of somatostatin of mild and an increased of Additional pharmacological therapy consists of the which medical treatment of gigantism and has been found to be when used in a child for an of An new therapeutic has recently in the form of a GHRH which has been to suppress GH and IGF-I levels in patients with acromegaly from pituitary tumors as well as ectopic GHRH hypersecretion In our current understanding of GH excess represents the result of a unique of regarding the of this disease undoubtedly will occur as into the new common causes of tall acceleration common causes of tall acceleration