Theodore C. Friedman, M.D., Ph.D. (the Wiz) Professor of Medicine-UCLA Chairman, Department of Internal Medicine Charles R. Drew University Dr. Friedman

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Theodore C. Friedman, M.D., Ph.D. (the Wiz)
Professor of Medicine-UCLAChairman, Department
of Internal MedicineCharles R. Drew
UniversityDr. Friedmans Endocrinology
ClinicFamilial Cushings Could it Be
Genetic?MAGIC Adult Convention Chicago, ILJuly
22, 2016
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Cushings patients ask me

• Why did I get Cushings?
• Is it my genes (DNA)?
• Can it be passed on to my children?
• Should I be tested for genetic changes?

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I have

• 4 families that have more than one member with
  Cushings suggesting the importance of genetics.
• So far their genetic testing has been negative
  (Professor Márta Korbonits).
• Im 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.

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Genes vs Environment

• Nature vs Nurture
• Must be some reason one person gets Cushings and
  not the next person

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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.

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What are genes?

• Twenty-two pair of chromosomes are the autosomes
  and the 23rd pair that determines your gender
  (XY-male 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.

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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 5050
  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.

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Dominant Disorders
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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.

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Recessive Disorders
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What kind of mutations are there?

• Inheritable mutations (germline mutations) are
  present in an individuals 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 someones environment
  (epigenetics)

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Different types of Cushings Syndorme

• Pituitary-Cushings Disease- overgrowth of one
  ACTH-producing 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)

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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 dont 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
  Carney complex together account for about 5 of
  patients with pituitary adenomas.

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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
  non-functioning 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.

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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 Cushings disease were
  tested for AIP and did not have it.

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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
  5050 chance of inheriting the genetic changes in
  the family.

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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 Wermers 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.

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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 (dont
  measure gastrin when on PPI).
• Severe ulcers in the stomach and small intestine
• Diarrhea
• Insulinomas-hypoglycemia

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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
  non-functioning pituitary adenoma or growth
  hormone-secreting adenoma.
• Cushings disease is very rare in MEN1
• MEN2 (parathyroid, medullary carcinoma of thyroid
  and pheochromocytoma) does not involve the
  pituitary.

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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.

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Carney complex

• Other common features of Carney complex are
  Cushings syndrome and multiple thyroid nodules
  or growth hormone-secreting tumors.
• The Cushings 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.

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Testicular orphan receptor 4 (TR4)

• Testicular orphan receptor 4 (TR4) (Dr. Tony
  Heaney) was found in higher quantities than
  normal in human Cushings 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.

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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 Cushings Disease.

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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.

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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-of-function USP8 mutations are common and
  contribute to ACTH overproduction in Cushings
  disease.
• More studies are needed to see if new drug
  therapy targeting EGF receptor overfunction could
  be used in Cushings disease.

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Pituitary Genes

• AIP, MEN1, PTTG, TR4, Carney and USP8 all may
  contribute to familial Cushings
  (USP8-non-familial).
• Currently only testing for AIP and MEN1 is
  available and only under research settings.
• Cushings still needs to be diagnosed
  biochemically.

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Adrenal Tumors

• In most cases, adrenal Cushings 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 Cushings syndrome.
• This mutation was not found in normal adrenal
  tissue, nonfunctioning adrenal adenomas, tumors
  producing aldosterone, or those producing
  subclinical Cushings syndrome.

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Bilateral Adrenal Hyperplasia

• Some cases of bilateral adrenal hyperplasia have
  been reported to occur in families, indicating
  that inherited genetic defects are involved.

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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.

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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.

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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.

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Summary

• In summary, the genetic basis for pituitary
  tumors responsible for Cushings 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
  Cushings syndrome still needs to be done the
  traditional way.

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What should a patient with Cushingssyndrome be
on the look out for on other family members?

• Very unlikely that family members will get
  Cushings
• If they do get it, it will probably will be the
  same type of Cushings
• 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
  Cushings is confirmed.

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If a second family member is diagnosed with
Cushings.

• Measure calcium and PTH to look for MEN1.
• If pituitary, consider contacting Dr. Korbanits
  at St. Bartholomew's Hospital in London
  info_at_fipapatients.org
• If adrenal, consider contacting Dr. Stratakis at
  the NIH.

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How do you contact Dr. Friedmans office for an
appointment or to get more information?

• www.goodhormonehealth.com
• Talk will posted in a few days
• mail_at_goodhormonehealth.com
• www.fipapatients.org
• https//csrf.net/category/doctors-articles/molecul
  ar-mechanism-of-cushings/

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Thanks

• Magic Foundation for inviting me and doing great
  work!
• Great job Dianne