ACEJO, Chelsea Angelica V.

University of the Philippines Manila

N204 Advance Pathophysiology

Acromegaly and Gigantism

Gigantism is a rare condition that causes abnormal growth in children. This change is most notable in
terms of height, but girth is affected as well. It occurs when your childs pituitary gland makes too much
growth hormone, which is also known as somatotropin.
Causes
The most common cause of too much growth hormone release is a noncancerous (benign) tumor of the
pituitary gland. Other causes include:

Genetic disease that affects the skin color (pigmentation) and causes benign tumors of the skin, heart,
and endocrine (hormone) system (Carney complex)
Genetic disease that affects the bones and skin pigmentation (McCune-Albright syndrome)
Genetic disease in which one or more of the endocrine glands are overactive or form a tumor (Multiple
endocrine neoplasia type 1)
Disease in which tumors form on the nerves of the brain and spine (neurofibromatosis)

Symptoms
The child will grow in height, as well as in the muscles and organs. This excessive growth makes the child
extremely large for his or her age.
Other symptoms include:
Delayed puberty
Double vision or difficulty with side (peripheral) vision
Very prominent forehead (frontal bossing) and a prominent jaw
Gaps between the teeth
Headache
Increased sweating
Irregular periods (menstruation)
Large hands and feet with thick fingers and toes
Release of breast milk
Sleep problems
 Thickening of the facial features
Weakness
Voice changes

Pathophysiology

Pituitary Gigantism is mostly caused by an excess of growth hormone, GH, before the fusion of the
epiphyseal plates. GH is under the control of GnRH (which promotes GH) and somatostatin (which inhibits
GH). GH in turn increases levels of IGF-1 (insulin-like growth factor-1). IGF-1 is produced by hepatocytes
in the Liver and is the main mediator of growth processes in the body; IGF-1 promotes protein synthesis,
skeletal growth, and cell proliferation. Hence, it is IGF-1 that is actually implicated in this disease. A high
IGF-1 level is the common factor seen in all cases of gigantism.

In theory, IGF-1 excess can be caused by any disorder along the GnRH-GH-IGF1 axis. According to
emedicine (http://www.emedicine.com/ped/topic2634.htm), the causes of excess IGF-1 can be
categorized as 1) GH excess from the pituitary; 2) GnRH excess from dysregulated hypothalamus; and 3)
excess IGF-binding proteins which maintain higher levels of IGF-1. Despite the various possible
pathophysiological explanations, pituitary gigantism is almost always a result of excess GH release from
the pituitary, more specifically, it is a result of an adenoma of the anterior pituitary cells known as the
somatotropes.

Adenomas of the pituitary can arise from a genetic mutation in the expression of excessive cells or a
disruption of the process that suppresses excess cells. One pathway in this disease involves the expression
of a GnRH receptor. From Dr. Lechan of Tufts university: Missense mutations replacing residue 201 (Arg
to Cys or His) or 227 (Gln to Arg or Leu) result in ligand-independent constitutive activation of the GHRH
receptor and thereby cAMP, which may contribute to the growth and hypersecretory state of these
adenomas. (http://ocw.tufts.edu/Content/14/Lecturenotes/265915 ). The GnRH receptor that normally
needs GnRH to start the pathway towards GH no longer needs to be binded by GnRH and also does not
respond to negative feedback. It is always on, and the excess cAMP causes continuously high GH levels
and hence, IGF-1. Multiple oncogene abnormalities can also be involved, such as G-protein dysfunction,
ras gene mutations, and p53 gene deletion and mutation. Although these adnormalities might not all lead
to pituitary gigantism, they are involved in adenomas of the pituitary, which can effect GH hormone
expression. Also, adenomas may be the result of excess secretion of basic fibroblast growth factor (FGF-
2) and a novel pituitary tumor transforming gene product, PTTG. These proteins may play a role in early
pituitary cell development.
Acromegaly
In acromegaly, GH hypersecretion usually starts between the 20s and 40s. When GH hypersecretion
begins after epiphyseal closure, the earliest clinical manifestations are coarsening of the facial features
and soft-tissue swelling of the hands and feet. Appearance changes, and larger rings, gloves, and shoes
are needed. Photographs of the patient are important in delineating the course of the disease.

Acromegaly (Facial Changes)

In adults with acromegaly, coarse body hair increases and the skin thickens and frequently darkens. The
size and function of sebaceous and sweat glands increase, such that patients frequently complain of
excessive perspiration and offensive body odor. Overgrowth of the mandible leads to protrusion of the
jaw (prognathism) and malocclusion of teeth. Cartilaginous proliferation of the larynx leads to a deep,
husky voice. The tongue is frequently enlarged and furrowed. In long-standing acromegaly, costal cartilage
growth leads to a barrel chest. Articular cartilaginous proliferation occurs early in response to GH excess,
with the articular cartilage possibly undergoing necrosis and erosion. Joint symptoms are common, and
crippling degenerative arthritis may occur.

Peripheral neuropathies occur commonly because of compression of nerves by adjacent fibrous tissue
and endoneural fibrous proliferation. Headaches are common because of the pituitary tumor. Bitemporal
hemianopia may develop if suprasellar extension compresses the optic chiasm. The heart, liver, kidneys,
spleen, thyroid gland, parathyroid glands, and pancreas are larger than normal. Cardiac disease (eg,
coronary artery disease, cardiomegaly, sometimes cardiomyopathy) occurs in perhaps one third of
patients, with a doubling in the risk of death from cardiac disease. Hypertension occurs in up to one third
of patients. The risk of cancer, particularly of the GI tract, increases 2-fold to 3-fold. GH increases tubular
reabsorption of phosphate and leads to mild hyperphosphatemia. Impaired glucose tolerance occurs in
nearly half the patients with acromegaly and in gigantism, but clinically significant diabetes mellitus occurs
in only about 10% of patients.

Pathophysiology

Acromegaly is characterized by hypersecretion of growth hormone (GH), which is caused by the existence
of a secreting pituitary tumor in more than 95% of acromegaly cases. Pituitary tumors are benign
adenomas and can be classified according to size (microadenomas being less than 10 mm in diameter and
macroadenomas being greater than 10 mm in diameter). In rare instances, elevated GH levels are caused
by extra pituitary disorders. In either situation, hypersecretion of GH in turn causes subsequent hepatic
stimulation of insulin-like growth factor-1 (IGF-1).
The clinical features of acromegaly result from either:
Pressure from the pituitary adenoma3
Elevated levels of GH and IGF-1, which work independently and in tandem to produce various signs
and symptoms associated with acromegaly3

Specifically, cardiovascular, respiratory, and metabolic co-morbidities and resultant potential for
mortality are associated with permanently elevated levels of GH and IGF-1.5