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PITUITARY GIGANTISM

Page history last edited by PBworks 12 years, 10 months ago


 

Presentation and Differential Diagnosis

A. Presentation: The presentation of the disease (i.e. the symptoms caused by the disease).

-Quickened skeletal growth

-Increased ultimate height (but with little bony deformity)

-Swelling of soft tissues

-Enlarged peripheral nerves

-Delayed puberty

-Eunuchoid Habitus

(Merck 2005)

 

Above: Features of acromegaly/gigantism. A 22-year-old man with gigantism due to excess growth hormone is shown to the left of his identical twin. The increased height and enlarged foot of the affected twin are apparent. Their clinical features began to diverge at the age of approximately 13 years. (Harrison 2005)

 

B. Differential Diagnosis: The differential diagnosis, or DDx (i.e. the list of all diseases or conditions that might possibly be causing these symptoms in this patient).

Quickened Skeletal Growth:

-Marfan Syndrome

 

Increased ultimate height:

-Acromegaly

-Androgen Insensitivity Syndrome

-Connective Tissue disorders

-Klinefelter Syndrome

-Marfan Syndrome

-McCune-Albright Syndrome

-Pituitary cancer

-Soto's Syndrome

 

Soft Tissue Swelling:

-Carpal Tunnel Syndrome

-Compartment syndrome

-Acromegaly

-Rheumatoid arthritis

 

Enlarged Peripheral Nerves:

-Dejerene-Sottas syndrome

-Amyloidosis

-Acromegaly

-Refsum Disease

 

Delayed Puberty:

-Sickle Cell anemia

-Addison's disease

-Adrenal failure

-Adiposogenital dystrophy

 

Eunuchoid Habitus:

-Hypogonadotropic Hypogonadism

 

 

SYMPTOMDIFFERENTIAL DIAGNOSIS
Quickened skeletal growthMarfan Syndrome
Increased ultimate heightAcromegaly
Androgen Insensitivity Syndrome
Connective Tissue disorders
Klinefelter Syndrome
Marfan Syndrome
McCune-Albright Syndrome
Pituitary cancer
Soto's Syndrome
Soft Tissue SwellingCarpal Tunnel Syndrome
Compartment syndrome
Acromegaly
Rheumatoid arthritis
Enlarged Peripheral NervesDejerene-Sottas syndrome
Amyloidosis
Acromegaly
Refsum Disease
Delayed PubertySickle Cell anemia
Addison's disease
Adrenal failure
Adiposogenital dystrophy
Eunuchoid HabitusHypogonadotropic Hypogonadism

 

Tests

The tests you would run to narrow down the list, the results from these tests, and what these results mean.

 

Many times Pituitary Gigantism is well recognized by physicians because of the abnormal body growth (3). The difference between acromegaly and pituitary gigantism is that the latter is an excess of Growth Hormone (GH) that affects young children while the epiphyseal plate is still growing and thus results in the common characteristics for pituitary gigantism like linear or longitudinal growth whereas the former is excess GH after the epiphyseal plates have already fused. Aside from observational tests a physician can run an hormonal evaluation as well as growth hormone assays.

 

One can measure an excess of Growth Hormone by doing an oral glucose tolerance test. If there is in fact an excess of GH it cannot be suppressed by an oral administration of glucose (5). A blood sample is taken as a baseline then a dose of 75-100g of oral glucose is given and the patient must sit without movement and blood samples are then drawn in subsequent intervals of 1, 2, and 3 hours (6). This test would just determine excess GH but if gigantism is already suspected then the next test is more effective.

 

Measuring serum insulin-growth factor 1 (IGF-1) is an important test. IGF-1 is a polypeptide protein hormone that structurally resembles insulin. It is produced in the liver and its production is stimulated by Growth Hormone. The results from the tested individual must be compared to relative age and puberty stages of an average specimen (4). This can be difficult because of such a large range that is considered normal but close, accurate, and constant tests will help diagnose. One would see an elevated IGF-1 level because of an inability to control Growth Hormone levels therefore they stimulate IGF-1 to be made.

 

Measuring IGF-1 is a better tool than measuring actual Growth Hormone because GH is released in a pulsatile fashion and thus any single measurement could result in a false positive or negative depending on when the sample is taken.

 

An Magnetic Resonance Imaging (MRI) or Computerized Tomography (CT) scan is taken to visualize an adenoma on the pituitary.

 

Diagnostic Algorithm

Describe the logical path you took to arrive at your final diagnosis. Ideally, you should put this information in the form of a DIAGNOSTIC ALGORITHM that others can consult when confronted with the same symptoms (you can find many diagnostic algorithms in Harrison's, as examples). If you can find an algorithm for that disease, feel free to use it verbatim (i.e. it's OK to copy one and to work from it).

 

Rapid growth during childhood is a distinct characteristic of pituitary gigantism. In young children, the rapid growth may not seem abnormal, but eventually, the extreme growth becomes more evident. As mentioned above, other conditions can present with excessive tallness, include androgen insensitivity syndrome and Marfan syndrome. Androgen insensitivity syndrome is characterized by estrogen resistance in bone, which produces the same effects as excess growth hormone (GH) in pituitary gigantism. With Marfan syndrome, a genetic mutation causes a defect in the structure of connective tissue, resulting in increased height. As a result, the simplest and most definitive diagnostic screening test to differentiate pituitary gigantism from these other diseases is to measure serum insulin-growth factor 1 (IGF-1). In cases of pituitary gigantism, levels of IGF-1 are elevated compared to age- and sex-matched reference ranges. It is important to note that during puberty, healthy adolescents may have marked increases in IGF-1 as compared to adulthood (5). All other conditions, unassociated with the presentation of pituitary gigantism, will display normal levels of IGF-1.

 

Although pituitary gigantism is usually found to occur in isolation, in rare instances, it can accompany such conditions as multiple endocrine neoplasia type 1 (MEN-1) and McCune-Albright syndrome (MAS) (7). In both cases, excessive endocrine hormone secretion is stimulated by a benign tumor of the pituitary gland. Pituitary gigantism is a secondary effect of both MEN-1 and MAS. Just as GH secretion is elevated, other pituitary hormones, such as prolactin, adrenocorticotropin (ACTH), thyrotropin (TSH), follicle stimulating hormone (FSH), and leutenizing hormone (LH) may also have altered levels of secretion. Additionally, a positive screening test for mutation in the MEN-1 gene and occurrence of hyperparathyroidism can aid in the diagnosis of MEN-1 (8).

 

Since the pituitary gigantism occurs before fusion of epiphyseal plates at puberty, it can be differentiated from acromegaly, a condition in which increased GH secretion occurs after calcification of the epiphyseal plates usually around the ages of 30 to 50 (9). In acromegaly, bone growth is limited to the terminal regions of the body and does not affect their height. In contrast, excessive GH during childhood greatly affects their stature, resulting in increased height.

 

When GH is found to be in excess, an MRI should be conducted to confirm the presence of a pituitary adenoma. Below is a gross image and MRI scan of a pituitary adenoma. In some cases, a pituitary adenoma may not be visible due the presence of an occult pituitary microadenoma or ectopic tumor. The lungs and pancreas are good candidates for location of an ectopic tumor producing GHRH.

 

Gross anatomy of pituitary adenoma.

The Internet Pathology Laboratory for Medical Education. Florida State University http://www-medlib.med.utah.edu/WebPath/ENDOHTML/CNS142.html

 

Pituitary adenoma detected in MRI scan.

Otolayngology Houston, October 21, 2006. http://www.ghorayeb.com/PituitaryMRI.html

 

Normal Pituitary and Pathology

A. Normal Pituitary: The normal structure and function of the organ in question. For this section, you should use information from other courses (esp. Anatomy and Physiology) as well as Histology.

 

The Pituitary Gland

 

 

The pituitary gland is also sometimes called the "master" gland of the endocrine system, because it controls the functions of other endocrine glands. The pituitary gland is the size of a pea, and is located at the base of the brain. The gland is attached to the hypothalumus by nerve fibers.

 

The pituitary gland itself consists of three sections:

1. Anterior lobe

2. Intermediate lobe

3. Posterior lobe

 

Each lobe of the pituitary gland produces certain hormones which have distinct effects.

 

 

Anterior lobe

-- Growth hormone - Primary cause of putuatiary guigabtism.

-- Prolactin - Stimulates milk production in mother after child birth

-- ACTH (adrenocorticotropic hormone) - Stimulates adrenal glands

-- TSH (thyroid-stimulating hormone) - Stimulates the thyroid gland

-- FSH (follicle-stimulating hormone) - Stimulates the ovaries and testes

-- LH (luteinizing hormone) - Stimulate the ovaries or the testes

 

Intermediate lobe:

-- melanocyte-stimulating hormone - to control skin pigmentation

 

Posterior lobe:

-- ADH (antidiuretic hormone) - Increases absorption of water into the blood

by the kidneys

-- Oxytocin - Contraction of uterus during childbirth and Stimulation of milk production

 

 

B. Pathology: The pathological appearance of the organ in question, for this particular disease or condition.

 

Pituitary Gigantism is usually caused due to adenomas (or abnormalities) in the anterior pituitary. Pathologically (or Histological) the pituitary adenomas appear as uniform masses of tissue distinct from the normal pituitary tissue. Anatomically these appear as enlargement of the anterior pituitary itself.

 

 

Normal Pituitary

 

Pituitary Adenoma:

Notice the monotonous appearance of the cells

 

Pitutiary Adenoma:

(residual pituitary tissue on the left and the adenoma on the right)

 

High power view of the Adenoma.

 

Pathophysiology

 

(image from http://ocw.tufts.edu/Content/14/Lecturenotes/265915)

 

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.

 

(from http://www.clevelandclinicmeded.com/diseasemanagement/endocrinology/pituitary/pituitary.htm#table2)

 

 

Distribution, Frequency, Method(s) of Treatment, and Prognosis

A. Distribution and Frequency: The distribution (where does it occur? who gets it? age, sex, race, or socioeconomic differences?) and frequency of the disorder or disease.

 

The distribution of pituitary gigantism has a ratio of 2:1 amongst men to women. And there is no prevalence based on race. In the United States alone there have only been 100 reported cases (14).

 

B. Method(s) of Treatment: Method(s) of treatment, including, where appropriate, a comparison of the treatments (efficacy, cost, etc.)(13).

 

Methods of treatment include pharmacotherapy (medications), radiation and surgical excision of the tumor. There are two classes of medication administered, but they are typically the third best method of treatment and are usually used to help reduce the size of the tumor before surgical removal. The first class is dopamine analogues. They are administered orally 2-3 times daily, and are used to suppress the secretion of GH. Disadvantages of dopamine analogues are nausea, vomiting, orthostatic hypotension, and nasal congestion. The second class is somatostatin analogues. It is administered by injection over eight hours. This treatment is more common for non-tumor related acromegaly. Disadvantage of somatostatin analogues is the effects that it has on GI function. Patients can have issues with digestive function and gallstone development is common in 25% of cases.

 

Treatment via radiation takes a long time to achieve results (an average of 5 years). This is a treatment that is recommended if surgical success was not achieved. A major disadvantage of radiotherapy is that the response time it too long.

 

Treatment via surgery is the number one preferred method. Depending on the size of the tumor surgical method can be transsphenoidal or craniotomy. Transsphenoidal has been proposed to be the best method, but can only be used if the tumor is below a certain size.

 

C. Prognosis

 

After treatment the key goals are to reduce plasma GH < 2.5ng/mL; plams GH after oral glucose tolerance test (OGTT) < 1ng/mL; and IGF-1 should return back to normal values. Depending on which method of treatment was used will determine the outcome and overall success for the patient. See the table below for success rates for each category(13).

 

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After any treatment the patient must have follow-ups done in order to monitor any recurrences. 15% of cases do have recurrence. Overall mortality and morbidity rates are unknown(14).

 

 

Group members

  • Iris Corbin
  • Soleil Leilabadi
  • Christine Mata
  • Amanpreet Sherwal
  • Sinh Tran
  • Kimberly Zamor

 

 

Sources

 

  1. Merck Manuals, Online Medical Library, 2005; http://www.merck.com/mmpe/sec12/ch151/ch151f.html
  2. Harrison's Principles of Internal Medicine - 16th Ed. (2005), http://online.statref.com/Document/Document.aspx?DocId=2100&FxId=55&Scroll=1&Index=2&SessionId=8850D3TWLIQGRJLW
  3. www.skullinstitute.com/acromegaly_gigantism.htm
  4. Healthcares.net. http://endocrine_disorders.health-cares.net/gigantism.php
  5. Ferry, Robert J, Jr, MD and Melanie Shim MD. Emedicine, July 27, 2006. http://www.emedicine.com/ped/topic2634.htm
  6. WebMD. http://www.webmd.com/hw/being_pregnant/hw44896.asp#hw44939
  7. Hurd, Robert, MD. MedlinePlus Medical Encyclopedia, August 11, 2006. http://www.nlm.nih.gov/medlineplus/ency/article/001174.htm
  8. Marx, Stephen J., MD. Endocrine and metabolic diseases, March 2006. http://www.endocrine.niddk.nih.gov/pubs/men1/men1.htm
  9. The Merck Manuals Online Medical Library, February 2003. http://www.merck.com/mmhe/sec13/ch162/ch162e.html
  10. Lechan, Ronald, MD, PhD. Tufts University. http://ocw.tufts.edu/Content/14/Lecturenotes/265915
  11. Hamrahian, Amir, MD. http://www.clevelandclinicmeded.com/diseasemanagement/endocrinology/pituitary/pituitary.htm#table2
  12. Virginia Commonwealth University, Department of Pathology <http://www.pathology.vcu.edu/index.html>
  13. Une, Karina N. "Endocrinology." MedStudents.com. 18 Jan. 2007 <http://www.medstudents.com.br/endoc/endoc8.htm>.
  14. "Acromegaly/Gigantism." Skull Base Institute. Skull Base Institute. 18 Jan. 2007 <http://www.skullbaseinstitute.com/acromegaly_gigantism.htm>.

 

Drafts

 

Draft 1

Draft 2

Comments (7)

Anonymous said

at 3:00 am on Jan 18, 2007

Okay, I'm done with my part. Let me know if there's anything else I could do, and feel free to make necessary changes. Thanks.
- Sinh

Anonymous said

at 10:34 pm on Jan 18, 2007

I'm done with my part as well. Please feel free to suggest and make necessarty changes.
Thanks. - Aman

Anonymous said

at 10:57 pm on Jan 18, 2007

I am done with my part as well.

Anonymous said

at 10:57 pm on Jan 18, 2007

Should we erase our names from each section???

Anonymous said

at 11:51 am on Jan 19, 2007

Who is going to turn the link in? If everyone is finished I can do it now...I'll check back in a bit... -Soleil

Anonymous said

at 3:16 pm on Jan 19, 2007

I turned in the link. Looks like everyone's part was done. It all looks great! I cc'ed everyone on the e-mail as well.

Anonymous said

at 3:17 pm on Jan 19, 2007

-soleil

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