Gigantism (from Greek gigas, gigantas “giant”) is an excessive secretion of growth hormone or IGF-I (insulin-like growth factor I) during childhood, before the closure of the bone growth plates. This excess growth hormone causes overgrowth of the long bones and very tall stature.
Acromegaly is the same disorder of IGF-I excess when it occurs after the growth-plate cartilage fuses in adulthood. Gigantism is a nonspecific term referring to any standing height more than 2 standard deviations above the mean for the person’s sex, age, and Tanner stage (ie, height Z score > +2.0). These disorders exist along a spectrum of IGF-I hypersecretion wherein the developmental stage when such excess originates determine the principal manifestations.

Pituitary gigantism

Pituitary gigantism due to growth hormone excess is the single condition that accounts for nearly all cases of pathologic extreme height. The excess growth hormone usually results from oversecretion by a group of somatotrope cells of the anterior pituitary gland (termed a “somatotrope adenoma”). These cells do not respond to normal controls of growth or function. They grow very slowly, so that for many years the only effects of such an adenoma are the secretion of excessive growth hormone. Over decades, such an adenoma may reach a large enough size (2 cm or more in diameter) to cause headaches, impair vision, or damage other pituitary functions. Many years of growth hormone excess can cause other problems as well.
The primary effect of growth hormone excess in childhood is excessive growth, but the extreme height is accompanied by a characteristic physique recognizable to an endocrinologist. The typical physique involves heavy, thick bones, with large hands and feet and a heavy jaw. Once puberty is complete and adult height is achieved, continued thickening of the skin and growth of the jaw results in a combination of features referred to as acromegaly.
If a physician suspects pituitary gigantism or acromegaly, the simplest diagnostic screening test is measurement of insulin-like growth factor 1 in the blood. This is usually quite elevated but levels must be interpreted in relation to age and pubertal status. Additional confirmatory testing may include magnetic resonance imaging (MRI) of the pituitary to look for a visible adenoma, and suppressibility of growth hormone levels by glucose. Treatment depends on the size of the adenoma and may involve removal by a neurosurgeon, drugs such as octreotide or bromocriptine, or radiation. Treatment is discussed in more detail in the acromegaly article.
Childhood pituitary gigantism is a rare condition, and those affected are often unusual enough to attain a degree of celebrity status (for example, André the Giant). Acromegaly is the term used for the condition of growth hormone excess when it occurs in adults. Acromegaly is a far more common disease in adults than pituitary gigantism is in children.

Frequency

In the US: Gigantism is extremely rare, with approximately 100 reported cases to date. Acromegaly is found more frequently than giantism, with an incidence of 3-4 cases per million people per year and a prevalence of 40-70 cases per million population.

What causes gigantism?

Causes of excess IGF-I action may be divided into 3 categories: (1) those originating from primary growth hormone (GH) excess released from the pituitary; (2) those caused by increased GH-releasing hormone (GHRH) secretion or hypothalamic dysregulation; and (3) hypothetically those related to the excessive production of IGF-binding protein, which prolongs the half-life of circulating IGF-I.
By far, most people with giantism have GH-secreting pituitary adenomas or hyperplasia. Although gigantism is typically an isolated disorder, rare cases occur as a feature of other conditions, such as multiple endocrine neoplasia (MEN) type I, McCune-Albright syndrome (MAS), neurofibromatosis, tuberous sclerosis, or Carney complex. Approximately 20% of patients with gigantism have MAS (the triad of precocious puberty, café au lait spots, fibrous dysplasia), and they may have either pituitary hyperplasia or adenomas.

Symptoms

  • Excessive growth during childhood.
  • Frontal bossing and a prominent jaw
  • Thickening of the facial features
  • Disproportionately large hands and feet with thick fingers and toes
  • Increased perspiration
  • Weakness
  • Secretion of breast milk
  • Irregular menstruation
  • Headache
  • Delayed onset of puberty
  • Double vision or difficulty with peripheral vision

Signs and tests

  • An increase in insulin growth factor-I (IGF-I) levels
  • A failure to suppress serum growth hormone (GH) levels after an oral glucose challenge (maximum 75g)
  • A CT or MRI scan of the head showing pituitary tumor
  • High prolactin levels

Other hormone levels may be low due to damage to the pituitary, including thyroid hormone, testosterone (boys), estradiol (girls), or cortisol.

Treatment

In pituitary tumors with well-defined borders, surgery is the treatment of choice and is curative is about 80% of cases.
For situations in which surgery cannot completely remove the tumor, medication is the treatment of choice. The most effective medications are somatostatin analogs (such as octreotide or long-acting lanreotide), which reduce growth hormone secretion.
Dopamine agonists (bromocriptine mesylate, cabergoline) have also been used to reduce growth hormone secretion, but these are generally less effective. A medication that blocks the effect of growth hormone, pegvisomant, has recently become available.
Radiation therapy has also been used to normalize growth hormone levels. However, it can take 5-10 years for the full effects to be seen and is almost always associated with deficiencies in other pituitary hormones. In addition, radiation has been associated with learning disabilities, obesity, and emotional changes in children. Most experts will use radiation only if surgery and medication fail.

Mortality/Morbidity

Because of the small number of people with gigantism, mortality and morbidity rates for this disease during childhood are unknown.
For individuals with acromegaly, the mortality rate is 2-3 times that of the general population. Successful treatment, with normalization of IGF-I levels, may be associated with a return to normal life expectancy.
For persons with acromegaly, the most frequent causes of death are cardiovascular and respiratory complications. Researchers disagree on whether malignancy is a significant cause of increased mortality. Although benign tumors (including uterine myomas, prostatic hypertrophy, and skin tags) are frequently encountered in acromegaly, documentation for overall prevalence of malignancies in patients with acromegaly remains controversial. Most studies suggest that as many as 30% of patients may have a premalignant colon polyp at diagnosis, and as many as 5% may have a colonic malignancy. However, the long-term effect of colonic lesions on morbidity and mortality has not been established. No clear evidence supports an increased risk for lung, breast, or prostate cancer. As a significant cause of morbidity, sleep apnea may be both obstructive and central.

Other conditions of overgrowth or excessive tallness in childhood

Children who are excessively tall are often referred to as Giantigionists. The majority of children who seem excessively tall or large to their parents usually have a combination of simple familial tallness and childhood obesity.
Early onset of obesity results in above-average growth in mid-childhood, such that over half of overweight children have heights in the 70 – 99 percentile range at around 10 years of age. The adult heights achieved by these children are what would be expected from their families because the excess mid-childhood growth is offset by attenuation of the pubertal growth spurt.
Precocious puberty and a variety of conditions associated with excessive amounts of testosterone or estrogen in childhood will result in tallness by mid-childhood. However, the acceleration of bone maturation by the early rise of estradiol results in early completion of growth, and adult heights for these children may actually be below average for genetic potential.
Extra sex chromosomes (beyond the normal two) with therefore extra copies of the SHOX gene (beyond the normal two) usually results in enhancement of height growth. The most common of these karyotypes are 47,XXY (Klinefelter syndrome), 47,XYY, and 47,XXX. The added height increment is usually modest.
Hypogonadism is the condition of deficiency of sex hormones due to reduced function of the testes or ovaries at adolescence. When secretion of testosterone or estradiol remains below average throughout the teenage years, a taller adult height will be gradually achieved by extra growth of the arms and legs. This long-limbed tallness is termed “eunuchoid” tallness, but rarely adds more than 2.5 – 7.5 cm (1-3 inches) to adult height. The extra growth is prevented if the child is given appropriate replacement of testosterone or estrogen from early adolescence.
A very rare but more extreme version of “eunuochoid” tallness occurs when a mutation of the estrogen receptor reduces the response of the bones to estradiol. Estradiol is a byproduct of testosterone in both males and females, and is the most potent accelerator of bone maturation and closure known. If a person fails to respond to estrogen, growth can continue until late-20s or longer, and the affected person can reach 8 feet or more in height. Estrogen resistance is the only other endocrine condition that can rival growth hormone excess in producing gigantism. In contrast, the tallness associated with the more common androgen insensitivity syndrome averages only a few inches, as estradiol is not produced directly but rather through conversion from androgens by aromatase.
Marfan syndrome is an uncommon genetic disease due to an inherited defect of connective tissue. In addition to moderate tallness, persons with this condition usually have a slender body build with unusually long fingers (arachnodactyly). Many can also develop a dislocation of the lens of the eye or, more seriously, a progressive deterioration of the walls of the aorta which can result in sudden death in adulthood. It is usually inherited as an autosomal dominant trait.
Sotos syndrome resembles acromegaly in its mild distortion of facial growth. In addition to tallness, the chief characteristics are large head size, slow development, and autosomal-dominant inheritance.
There are about 50 even rarer genetic syndromes in which childhood growth is above average. These conditions are often associated with developmental delay or other more serious problems, and adult height may or may not be mildly increased.

Sources: wikipedia, medlineplus, eMedicine

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