Gigantism is a rare condition which leads to very tall stature in children due to abnormal growth. The most noticeable effect is on the height but girth may increase as well.
It is defined as a standing height more than 2 standard deviations above the mean for the person’s sex, age, and Tanner stage (stage of development of puberty).
The opposite of this, short stature is called dwarfism.
A pituitary tumor is the most common cause of gigantism. A pituitary adenoma causes hypersecretion of growth hormone which is responsible for gigantism.
But actually, the effects are caused by still excess of insulin growth factor -I or IGF-I. Growth hormone causes increases IGF-I but there are other causes too which could lead to increased IGF-I [see below] and gigantism.
IGF-I excess causes gigantism in childhood [while epiphyseal growth plates are still open] but if occurs after the closure of epiphysis, it results in acromegaly
Thus, acromegaly is the same disorder of IGF-I excess but occurs after the growth plate cartilage fuses in adulthood.
Gigantism is extremely rare. Only 100 cases have been reported so far.
Early diagnosis followed by timely treatment can stop or slow the changes.
- Familial isolated pituitary adenoma
- Due to aryl hydrocarbon receptor interacting protein (AIP) gene mutations
- Multiple endocrine neoplasia type 1 (MEN1)
- Genetic disorder
- Tumors in the pituitary gland, pancreas, or parathyroid glands.
- McCune-Albright syndrome
- Precocious puberty
- Café au lait spots
- Fibrous dysplasia
- Carney complex
- Autosomal dominant transmission
- Myxomas [myxoid tumors]
- Endocrine tumors
- Spotty pigmentation
- Tuberous sclerosis
What causes gigantism – Causes and Pathophysiology?
The final common abnormality in gigantism and acromegaly is IGF-I excess. IGF-I is primarily produced in hepatocytes.
Increase in growth hormone [GH] and an increase in growth hormone releasing hormone [GHRH secretion] both can cause IGF-I excess.
GH levels in a healthy person are
- Men: < 5 ng/mL or < 226 pmol/L
- Women: < 10 ng/mL or < 452 pmol/L.
- Children: 0-20 ng/mL or 0-904 pmol/L
Increased GH 95% of people with gigantism is due to GH secreting pituitary adenomas or hyperplasia. GH secretion can occur by nonendocrine tumors too.
Increased GHRH is seen in hypothalamic tumors and ectopic endocrine tumors like carcinoid, pancreatic islet-cell, and bronchial neoplasms.
Dysregulation of the hypothalamic-pituitary-GH may also cause increased secretion of growth hormone.
Clinical Presentation – Signs and Symptoms of Gigantism
The presentation of gigantism is more dramatic than acromegaly which has an insidious onset.
The patient presents with tall stature for age [fast linear growth caused by IGF-I].
Patients may complain of headaches. Visual changes may occur [ optic nerve compression]
On physical examination, the following features are noted
- Tall stature
- Large head
- Mild to moderate obesity or soft tissue hypertrophy
- Large hands and feet
- Thick toes and fingers
- Coarse facial features
- Frontal bossing
- Prominent jaw [Prognathism]
- Increased sweating
- Osteoarthritis [due to IGF-I]
- Carpal tunnel syndrome
Prolonged raised levels of IGF-1 may lead to cardiovascular problems like cardiac hypertrophy, raised blood pressure and left ventricular hypertrophy.
Endocrine problems like delayed puberty, diabetes, and raised prolactin levels may be raised.
All conditions which may be associated with tall stature.
Familial tall stature
Usually, in constitutional tall stature, the parents are also tall.
In this, the patient is very tall but with normal body proportions. However, the features are coarse with increased heel pad thickness. There may be evidence of raised intracranial tension.
Children with cerebral gigantism (Soto’s syndrome) have a large elongated head, prominent forehead, large ears and jaws, elongated chin, antimongoloid slant to the eyes and coarse facial features. They have subnormal intelligence and impaired coordination. The cause of this disorder is not known.
Sexual Precocity and Virilizing Disorders
In these children, the acceleration of linear growth occurs simultaneously with signs of premature sexual development or inappropriate virilization. This disorder may be due to congenital adrenal hyperplasia, adrenal tumor, gonadal tumor or premature secretion of gonadotropic hormones. The bone age is usually advanced so that the adult stature may be diminished.
These patients are tall with long limbs, narrow hands, long slender fingers (arachnodactyly), hyperextensible joints, dislocation of the lens, high arched plate, kyphoscoliosis, arm span greater than the height and the lower segment more than the upper segment.
This condition resembles Marfan’s syndrome.
- Lower segment more than the upper segment.
- Small, firm testes, azoospermia.
- Chromatin (Barr) body usually present. (Some may be chromatin negative).
- Mental retardation
- Associated with Mongolism and Leukemia.
- Chronic pulmonary disease, varicose veins and diabetes are more common.
- Beckwith-Wiedemann Syndrome
- Congenital Adrenal Hyperplasia
- Fragile X Syndrome
- McCune-Albright Syndrome
- Precocious Puberty
- Blood tests to measure insulin-like growth factor 1 (IGF-1) levels
- Blood growth hormone levels
- Oral glucose tolerance test,
- 75 g of glucose is given to drink after taking a fasting blood sample
- Additional measurements are carried out at 30, 60, 90 and 120 minutes
- In a normal person, growth hormone levels decrease after glucose
- Failure to decrease indicates hypersecretion
- GHRH levels if indicated
- Prolactin levels may be elevated
If the tests indicate gigantism, imaging using MRI is done.
Imaging should be done after confirmation of blood tests because many pituitary adenomas are non-functional and the finding could cause unnecessary distress.
MRI is able to tell about surrounding structures like optic chiasm, cavernous sinuses, etc.
CT scans of the abdomen/pelvis are done to evaluate for pancreatic, adrenal, and ovarian tumors secreting GH/GHRH when brain imaging is not conclusive.
CT chest is done to evaluate for bronchogenic carcinoma [may secrete GH/GHRH].
Treatment of Gigantism
Surgery is the Primary Choice
For pituitary adenomas, transsphenoidal surgery is usually considered the first line of treatment, followed by medical therapy for residual disease.
Radiation is given in recalcitrant cases.
Drugs are used when primary surgery fails to induce complete remission. The aim is to remove/ shrink the pituitary mass and restore GH secretory patterns to normal.
In addition, there should be a decrease in IGF-I levels and other pituitary hormones should be secreted and disease should not recur.
Following drugs are used-
Somatostatin analogues [octreotide]
It binds to the somatostatin receptor [II and V] inhibiting GH secretion.
Dopamine-receptor agonists (eg, bromocriptine, cabergoline)
- Bind to pituitary dopamine type 2 (D2) receptors and suppress GH secretion
- The exact mechanism is of action unclear.
- Add to the effectiveness of octreotide.
GH-receptor antagonists Pegvisomant
- Novel hepatic growth receptor antagonist
- Suppresses GH and IGF-I levels effectively in almost 90%on.
- Undertreatments require regular pituitary imaging to monitor for a possible increase in tumor size.
Radiation therapy is indicated when growth hormone hypersecretion is not normalized with surgery.
It also prevents further growth of the tumor in more than 97% of patients after surgery.
However, radiation treatment takes years to reduce/normalize GH/IGF-I levels.
Hypopituitarism may occur.