Download Familial Cushing`s: Could it Be Genetic?

Theodore C. Friedman, M.D., Ph.D.
(the Wiz)
Professor of Medicine-UCLA
Chairman, Department of Internal Medicine
Charles R. Drew University
Dr. Friedman’s Endocrinology Clinic
Familial Cushings: Could it Be Genetic?
MAGIC Adult Convention
Chicago, IL
July 22, 2016
Cushing’s patients ask me
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Why did I get Cushing’s?
Is it my genes (DNA)?
Can it be passed on to my children?
Should I be tested for genetic changes?
I have
• 4 families that have more than one member with
Cushing’s suggesting the importance of genetics.
• So far their genetic testing has been negative
(Professor Márta Korbonits).
• I’m part of the International FIPA (Familial
Isolated Pituitary Adenomas Consortium
• I have several patients from the same location
(central New Jersey) that suggest environment plays
a role.
Genes vs Environment
• Nature vs Nurture
• Must be some reason one person gets Cushing’s
and not the next person
What are genes?
• Genes are the coded instructions that control the
growth and development of our cells.
• DNA (Deoxyribose Nucleic Acid) is the coding
molecule that allows human cells to replicate and
function.
• Human DNA is organized into compact structures
called chromosomes of which humans have 23
pairs.
• In each pair, one chromosome comes from the
mother, and one from the father.
What are genes?
• Twenty-two pair of chromosomes are the autosomes
and the 23rd pair that determines your gender (XYmale and XX-female).
• Genes come in pairs; one of each pair is inherited
from each parent.
• Some conditions tend to manifest when one copy of
a pair of genes is altered.
• These are called dominant disorders.
• Other conditions need both genes to be affected in
order to develop the condition.
• These are called recessive disorders.
Dominant Disorders
• Both men and women who have a one copy of an
abnormal gene and one copy of the normal gene (a
so called 'heterozygote' state) have a 50:50 chance
of passing the abnormal gene on to the next
generation.
• However, not all patients who carry the abnormal
gene will develop the disease, this is called
incomplete penetrance.
Dominant Disorders
Recessive Disorders
• Both genes are needed to get the condition.
• Patients with one gene are carriers and are
unaffected, but can pass the genes to their children.
• In some conditions, those with one gene are mildly
affected.
Recessive Disorders
What kind of mutations are there?
• Inheritable mutations (germline mutations) are
present in an individual’s DNA from conception.
These are inherited from the parents and can be
passed on to their children.
• Non-inheritable mutations (i.e., sporadic mutations)
occur after birth, most often in a single cell. These
mutations are not inherited from the parents and
cannot be passed on to their children.
• These may be changed by someone’s environment
(epigenetics)
Different types of Cushing’s Syndorme
• Pituitary-Cushing’s Disease- overgrowth of one ACTHproducing cell in the pituitary, which multiplies
abnormally to become a benign tumor that produces too
much ACTH
• Adrenal –Adrenal Adenoma- is caused by a single benign
adrenal tumor (adenoma) on one adrenal gland.
• Ectopic-Outside the pituitary-not yet found to be genetic
• Adrenal enlargement (hyperplasia) (most often genetic)
Pituitary adenomas
• Almost all pituitary tumours are benign, these are called
adenomas.
• This means that they are not cancerous, and do not spread.
• Most of the time pituitary adenomas grow slowly and it
takes years before they get diagnosed.
• The vast majority of pituitary adenomas occur
spontaneously which means that they are not inherited and
don’t run in families.
• However, a small group of patients with pituitary
adenomas (about 1 in 20) also have family members with
similar disease.
• If no other hormone abnormality and family members have
other pituitary tumors, the patients has Familial Isolated
Pituitary Adenoma or FIPA.
• Familial pituitary adenomas due to FIPA, MEN1 or
Pituitary adenomas
• Families with pituitary adenomas, FIPA families, can be
divided into two groups.
• In about 80% of families the gene causing the disease is
unknown. The pituitary tumor types occurring in these
families are most commonly growth hormone-secreting
adenomas (causing acromegaly or acromegalic gigantism),
prolactin-secreting adenomas (prolactinomas) or nonfunctioning pituitary adenomas (NFPA), very rarely
ACTH-secreting adenomas (causing Cushing's disease) or
TSH-secreting adenomas.
• The disease most often starts in adulthood, very rarely in
childhood.
• These families usually only have two or three patients
known with the disease.
AIP
• In about 20% of families a gene has been identified
causing the disease, called Aryl hydrocarbon receptor
Interacting Protein, or AIP.
• Patients with AIP mutations most often have acromegaly
or occasionally prolactinoma, very rarely other types of
adenomas.
• The majority of the patients who carry a mutation in the
AIP gene and develop a pituitary adenoma, become
diagnosed before the age of 30 years.
• Interestingly, two third of the patients with AIP mutation
positive pituitary adenoma are males.
• 15-20% of childhood onset acromegaly patients, with no
apparent family history, carry an AIP mutation.
• Two of my families with Cushing’s disease were tested for
AIP and did not have it.
AIP
• If you carry one abnormal copy of the AIP gene, you do
not necessarily develop the disease.
• Only a third of those who inherit such a genetic change go
on to develop a pituitary tumor (penetrance is only around
30%).
• If you as a parent have been identified to have the gene,
then your future children would have a 50:50 chance of
inheriting the genetic changes in the family.
Multiple Endocrine Neoplasia type 1 (MEN1)
• MEN1 is an inherited disorder that causes tumors in
various endocrine glands.
• MEN1 is sometimes called multiple endocrine
adenomatosis or Wermer’s syndrome.
• MEN1 is rare, occurring in about one in 30,000 people.
• MEN1 is autosomal dominant.
• 3 Ps-parathyroid (95%), pancreas (80%), pituitary (40%).
• In MEN1 patients, all four parathyroid glands tend to be
overactive, causing hyperparathyroidism.
• This leads to hypercalcemia-reasonable to measure Ca if
suspect MEN1.
Multiple Endocrine Neoplasia type 1 (MEN1)
• Pancreatic tumors involve the islet cells, giving rise to
gastrinomas or insulinomas.
• Duodenal tumors can also produce gastrinomas
• Very acidic stomach-high gastrin levels (don’t measure
gastrin when on PPI).
• Severe ulcers in the stomach and small intestine
• Diarrhea
• Insulinomas-hypoglycemia
Multiple Endocrine Neoplasia type 1 (MEN1)
• Pituitary tumors (25%)
• Prolactinomas most common
• High prolactin levels can cause excessive production of
breast milk, irregular periods or interfere with fertility in
women or with libido and fertility in men.
• Other pituitary tumor types in MEN1 can be nonfunctioning pituitary adenoma or growth hormonesecreting adenoma.
• Cushing’s disease is very rare in MEN1
• MEN2 (parathyroid, medullary carcinoma of thyroid and
pheochromocytoma) does not involve the pituitary.
Carney complex
• Carney complex is a hereditary condition associated with
spotty skin pigmentation, myxomas (benign or
noncancerous connective tissue tumors), and benign or
cancerous tumors of the endocrine glands such as the
adrenal, thyroid and pituitary gland.
• Symptoms of Carney complex typically develop when a
person is in his or her early 20s.
• Skin pigmentation and heart myxomas or other heart
problems are usually the first signs of the condition.
• The spotty skin pigmentation is found on lips, inner and
outer corners of the eyes, the conjunctiva (membrane
lining) of the eye, and around the genital area.
Carney complex
• Other common features of Carney complex are Cushing’s
syndrome and multiple thyroid nodules or growth
hormone-secreting tumors.
• The Cushing’s syndrome from Carney complex is usually
adrenal and will be discussed there, but rarely can be
pituitary.
• Although people with Carney complex have an increased
risk of cancer, most tumors are benign.
Testicular orphan receptor 4 (TR4)
• Testicular orphan receptor 4 (TR4) (Dr. Tony Heaney)
was found in higher quantities than normal in human
Cushing’s disease tumors.
• TR4 was shown to stimulate ACTH secretion and tumor
growth in cells in test tubes.
• Additional studies are needed to determine if TR4 can
explain the development of pituitary tumors and if drugs
could be targeted to decrease its levels.
Pituitary transforming gene (PTTG)
• Pituitary transforming gene (PTTG) is a protein that
regulates important signals that stimulate cell
multiplication.
• A drug called R-roscovitin, which targets PTTG, was able
to decrease ACTH, cortisol production, and tumor growth
in animal models.
• Further studies are needed to determine the role of PTTG
in patients with Cushing’s Disease.
USP8 gene (deubiquitinase gene)
• In 2014, Reinke and many others reported that 4 out of 10
(40%) ACTH-secreting tumors studied showed somatic
(not inheritable) mutations in the USP8 gene.
• These mutations were shown to increase the activity of a
receptor for an important growth factor called epidermal
growth factor (EGF) which stimulates the secretion of
ACTH by the tumors.
• In 2015 Ma and others in China found similar mutations in
the USP8 gene in 67 of 108 (62%) ACTH secreting
pituitary tumors.
• The USP8 mutations were found mostly in smaller tumors
compared to larger tumors.
USP8 gene
• Other types of pituitary tumors were also studied and
USP8 mutations were not found in 150 non-ACTH
secreting pituitary tumors.
• Further work in cell culture with USP8 mutated cells
showed increased levels of the EFG receptor.
• A specific blocker of the EFG receptor called gefitinib
decreased ACTH secretion.
• The authors concluded, Taken together, somatic gain-offunction USP8 mutations are common and contribute to
ACTH overproduction in Cushing’s disease.
• More studies are needed to see if new drug therapy
targeting EGF receptor overfunction could be used in
Cushing’s disease.
Pituitary Genes
• AIP, MEN1, PTTG, TR4, Carney and USP8 all may
contribute to familial Cushing’s (USP8-non-familial).
• Currently only testing for AIP and MEN1 is available and
only under research settings.
• Cushing’s still needs to be diagnosed biochemically.
Adrenal Tumors
• In most cases, adrenal Cushing’s is caused by a single
benign adrenal tumor (adenoma) on one adrenal gland.
• Several different mutations have been identified in adrenal
adenomas; however, they seemed to be important in only a
very few cases.
• Researchers found mutations of the PRKACA gene that
increased the activity of protein kinase A, which is known
to be important in the secretion of cortisol.
• This mutation was found in 37% of adrenal adenomas
from patients with Cushing’s syndrome.
• This mutation was not found in normal adrenal tissue,
nonfunctioning adrenal adenomas, tumors producing
aldosterone, or those producing subclinical Cushing’s
syndrome.
Bilateral Adrenal Hyperplasia
• Some cases of bilateral adrenal hyperplasia have been
reported to occur in families, indicating that inherited
genetic defects are involved.
Primary Pigmented Nodular
Adrenocortical Disease (PPNAD)
• PPNAD is an adrenal disorder where very small nodules
are found in both adrenals.
• It can run in families and be associated with the Carney
Complex.
• Patients with Carney complex can also develop tumors in
the heart and other endocrine tissues and have increased
skin pigmentation.
• Mutations of important genes PRKAR1A, PDE11A or
PDE8B, which regulate signals to produce cortisol, have
been identified in a large number of affected patients with
PPNAD.
Bilateral Macronodular Adrenal
Hyperplasia
• Bilateral macronodular adrenal hyperplasia tissue can
contain a mutation in a gene called ARMC5.
• Inactivation of ARMC5 led to greater cell growth, perhaps
leading to hyperplasia and also to changes in cortisol
production.
Bilateral Macronodular Adrenal
Hyperplasia
• Bilateral macronodular adrenal hyperplasia tissue is
enlarged adrenals with multiple large nodules.
• Some mutations have been reported in bilateral
macronodular adrenal hyperplasia tissue however, there is
not one individual mutation that was shared among a large
number of patients.
• Some patients with bilateral macronodular adrenal
hyperplasia show increased cortisol production in response
to hormones other than ACTH , such as gastric inhibitory
polypeptide (GIP), vasopressin, adrenalin, serotonin, and
human chorionic gonadoptropin (hCG), but the genetic
basis of the hyperplasia is unknown.
Summary
• In summary, the genetic basis for pituitary tumors
responsible for Cushing’s disease is still unknown, but new
target proteins that can regulate their growth are under
study.
• It is likely that there will be advances in genetic screening
tools to detect affected family members at a much earlier
stage than before.
• While the work discussed is promising and the ultimate
goal is to have highly effective pharmaceuticals, diagnosis
and treatment of Cushing’s syndrome still needs to be done
the traditional way.
What should a patient with Cushing’s
syndrome be on the look out for on other
family members?
• Very unlikely that family members will get Cushing’s
• If they do get it, it will probably will be the same type of
Cushing’s
• Same signs and symptoms as the patient.
• 24 hr UFC, night time salivary cortisols, night time serum
cortisol
• Secondary 24 hr 17OHS, 10 hr 10 pm -8 am UFC/Cr.
• Imaging
• Would not do genetic testing until 2nd case of Cushing’s is
confirmed.
If a second family member is diagnosed
with Cushing’s.
• Measure calcium and PTH to look for MEN1.
• If pituitary, consider contacting Dr. Korbanits at St.
Bartholomew's Hospital in London [email protected]
• If adrenal, consider contacting Dr. Stratakis at the NIH.
How do you contact Dr. Friedman’s
office for an appointment or to get more
information?
• www.goodhormonehealth.com
• Talk will posted in a few days
• [email protected]
• www.fipapatients.org
• https://csrf.net/category/doctors-articles/molecularmechanism-of-cushings/
Thanks
• Magic Foundation for inviting me and doing
great work!
• Great job Dianne