0021-972X/99/$03.00/0
The Journal of Clinical Endocrinology & Metabolism
Copyright © 1999 by The Endocrine Society
Vol. 84, No. 12
Printed in U.S.A.
COMMENTARY
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
F
ROM 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.
Received July 21, 1999. Revision received September 28, 1999. Accepted September 28, 1999.
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: [email protected].
Etiologies of Gigantism
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 ade-
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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 Gsa 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
FIG. 1. SA, the tallest living woman, standing with one of the authors
(EAE).
noma (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.
Gsa 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 Gsa 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
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.
COMMENTARY
4381
TABLE 1. Causes of excessive GH secretion
Source of GH excess
Primary pituitary GH excess
Clinical context
Associated findings
Gsa mutation
Pathogenetic mechanism
Sporadic pituitary adenomas
Pituitary adenomas or hyperplasia in
association with MAS
Loss of 11q13 heterozygosity
Sporadic pituitary adenomas
gsp oncogene
Café au lait macules,
polyostotic fibrous
dysplasia, precocious
puberty
Increased tumor
invasiveness
Autosomal dominant
inheritance, neoplasia
of pancreas, pituitary,
parathyroids
Autosomal dominant
inheritance, multiple
lentigines myxomas,
endocrine neoplasias
Absence of identifiable
source of GH or GHRH
hypersecretion
Close association of tumor
neurons with pituitary
GH-secreting cells
Extremely rare cause of
gigantism
One reported case of
acromegaly
Infiltration into
somatostatinergic
pathways
MEN type 1
Secondary GH excess
Abnormality at 2p16
Carney complex
Hypothalamic GHRH excess
Pituitary hyperplasia
Intracranial tumor secretion of
GHRH
Gangliocytoma, neurocytoma
Ectopic GHRH excess
Carcinoid, pancreatic, bronchial
neoplasias
Lymphoma
Ectopic GH excess
Abnormal somatostatin tone
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
Neurofibromatosis with optic
gliomas/astrocytomas
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).
Consequences of Prolonged GH Excess
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
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EUGSTER AND PESCOVITZ
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.
Clinical Aspects of Gigantism
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
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TABLE 2. Most common causes of tall stature/growth
acceleration
Normal variant
genetic tall stature
Endocrine abnormalities
Precocious puberty
Hyperthyroidism
Gigantism
Exogenous obesity
Syndromes
Sotos
Beckwith-Wiedemann
Marfan
Homocystinuria
Weaver
Fragile X
Sex chromosome aneuploidy
Klinefelter syndrome
47, XYY
47, XXX
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
COMMENTARY
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).
Treatment of Gigantism
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).
Conclusion
In summary, our current understanding of GH excess represents the end result of a unique blend of multidisciplinary
investigation. Further illumination regarding the unex-
4383
plained aspects of this interesting disease undoubtedly will
occur as collaborative efforts continue into the new century.
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Embryos, Embryonic Stem Cells, and Transplantation
April 27, 2000
The Hyatt Canberra, Canberra, Australia
For more information, contact Yolanda Masterson, Serono Symposia Australasia, P.O. Box 351, Frenchs
Forest NSW 1640. Int’l Phone: 02 9975 3100; Int’l fax: 02 9975 1516; E-mail: [email protected].