Gigantism
Erica A. Eugster and
Ora H. Pescovitz
Section of Pediatric Endocrinology/Diabetology, Department of
Pediatrics, James Whitcomb Riley Hospital for Children, Indiana
University School of Medicine, Indianapolis, Indiana 46202-5225
Address correspondence and requests for reprints to: Erica A. Eugster, M.D., Assistant Clinical Professor of Pediatrics, Pediatric Endocrinology/Diabetology, Riley Hospital #5984, 702 Barnhill Drive, Indianapolis, Indiana 46254. E-mail: eeugster{at}iupui.edu
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Introduction
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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, 5, 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.
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Etiologies of Gigantism
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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.
Primary pituitary GH excess
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.
Gs
mutations
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 Gs
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
Gs
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.
Allelic deletion of the 11q13 locus
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.
Secondary GH excess
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.
GHRH excess
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).
Abnormal Somatostatin tone
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).
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Consequences of Prolonged GH Excess
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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.
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Clinical Aspects of Gigantism
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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 Table
2.
Laboratory findings
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.
Psychological aspects of tall stature/gigantism
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).
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Treatment of Gigantism
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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 armamentarium for GH hypersecretion. Therapeutic
response to octreotide, found to be highly effective in the majority of
patients with gigantism or acromegaly, may be predicted by the
decrement in serum GH levels after one sc dose (48). The new
sustained-release somatostatin analog preparation lanreotide given in
the form of an im injection every 2 weeks, has also been shown to be
successful in returning GH levels to normal in acromegalic adults with
pituitary adenomas (49) as 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 represents a potentially major
advance in the treatment of gigantism and disorders of glucose
homeostasis in pediatric patients. Side effects of somatostatin
analogues consist mainly of mild transient gastrointestinal complaints
and an increased risk of gallstones. Additional pharmacological therapy
consists of the dopamine agonist 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 time (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 tumors as well as ectopic GHRH hypersecretion (52, 53).
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Conclusion
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In summary, our current understanding of GH excess represents the
end result of a unique blend of multidisciplinary investigation.
Further illumination regarding the unexplained aspects of this
interesting disease undoubtedly will occur as collaborative efforts
continue into the new century.
Received July 21, 1999.
Revised September 28, 1999.
Accepted September 28, 1999.
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