11/16- Genetic Disorders You Don't Want to Miss 1 Flashcards
Case 1)
- DR is a 28 yo Caucasian male who is planning to start a family and is worried about his family history of Polycystic kidney disease
- He is asymptomatic; denies abdominal or flank pain, denies hematuria or recurrent urinary tract infections; never been diagnosed with HTN
- He had a renal USG at 24 yo for a bladder infection that reportedly did not reveal any cysts
- Currently he and his wife are undergoing infertility workup and are considering in vitro fertilization
- What do you think?
- Adult Polycystic Kidney Disease
- Even though he didn’t have cysts on ultrasound, he was young; doesn’t mean he won’t develop it in the future. This disorder has an age-dependent penetrance
What does this pedigree show?
Autosomal dominant disorder
- Like polycystic kidney disease (PKD)
What do these pictures show?
Autosomal dominant Polycystic Kidney Disease
What is the inheritance pattern for PKD?
Autosomal dominant (ADPKD)- most common
PKD is the most common ___________
- Prevalence
PKD is the most common inherited renal cystic disease
- 1/800 across all ethnic groups
What are clinical features of ADPKD?
1. Age-dependent cysts: Kidney, liver, pancreas and spleen
2. Cardiovascular abnormalities: Hypertension, mitral valve prolapse, intracranial aneurysms and aortic aneurysm and dissection
3. Connective tissue abnormalities: hernias, colonic diverticulae
What are signs and symptoms of ADPKD?
- Abdominal/flank pain
- Hematuria
- Renal insufficiency
- Colonic diverticuli
- Hypertension
Diagnostic test: Renal USG
Describe the genetics of ADPKD
- Gene(s) involved
- De novo?
- Which is more severe
- Caused by 2 genes: PKD1 (85%) and PKD2 (15%)
- 5-10% cases are de novo
- PKD1: more severe kidney disease (also lead to renal insufficiency 20 years earlier)
What is the management for ADPKD?
1. End stage renal failure
- Renal transplantation
- Hemodialysis
- Peritoneal dialysis
2. Intracranial aneurysm
- Conservative mgmt for aneurysms < 10 mm in diameter
- Surgery for > 10 mm
3. UTI
- Prompt treatment of infection
What is surveyed in someone with APKD?
1. Hypertension: annual monitoring from teenage years
2. Plasma Creatinine: annually; if abnormal, refer to nephrologist
3. Intracranial aneurysm screening: MRA every 5 years if family history
4. Aortic aneurysm/dissection: Echocardiogram; repeat annually if abnormal
5. Pregnancy: Monitor hypertension; risk of pre-eclampsia
6. Drugs: Avoid NSAIDs
Describe cyst development in renal tubules: pathogenesis
- ADH and cAMP promote kidney-cyst cell proliferation and fluid secretion
- Tolvaptan is a vasopressin V2-receptor antagonist
- Slowed increase in total kidney volume and decline of GFR
Describe contiguous gene syndrome with PKD?
Deletion of 16p involving PKD1 and TSC2 will give rise to both ADPKD and tuberous sclerosis in the same individual
Describe the autosomal recessive form of PKD
- How common (vs. AD)
- Prevalence
- Clinical features
- Genetic cause
- Much rarer than ADPKD
- 1 in 20,000 births (carrier frequency 1:70)
Clinical Features:
- Enlarged kidneys perinatally, 30% die of pulmonary hypoplasia; severe early onset systemic HTN (in 80%)
- Kidneys are diffusely affected at birth
- >50 % develop ESRD within the first decade of life
- Congenital hepatic fibrosis is present
Caused by mutations in PKHD1 (polycystic kidney and hepatic disease I)
What is variable expressivity?
Intra and inter-familial variation in age at onset and severity
What is genetic heterogeneity?
Locus heterogeneity also causes variable expressivity; ADPKD2 has milder disease
What is the two-hit hypothesis?
Both alleles must lose function for cysts to form
Case 2)
- 44y/o Caucasian woman with history of recurrent nosebleeds almost every day, since she was young
- Several episodes of severe nasal bleeding requiring ER visits and nasal packing
- Bleeding from gums since the last 5-6 years
- Telangiectasia removed from inside of lip two years ago
- Fresh blood in stool for past 3-4 months
- What are you thinking?
Hereditary Hemorrhagic Telangiectasia (HHT)
What does this pedigree show?
Autosomal dominant inheritance pattern
- Ex) Hereditary Hemorrhagic Telangiectasia (HHT)
What is seen here?
Classic telangiectasias on the ear and in the oropharynx in a patient with HHT
What are the criteria for diagnosing HHT (Hereditary Hemorrhagic Telangectasia)?
1. Epistaxis: spontaneous, recurrent nosebleeds
2. Telangiectases: multiple, characteristic sites (lips, oral, fingers, nose)
3. Visceral lesions: e.g. GI telangiectasia, pulmonary AVM, hepatic AVM, cerebral AVM, spinal AVM
4. Family history: 1st degree relative with HHT
What are the clinical manifestations of HHT?
- Typical age of presentation?
1. Nosebleeds
2. Mucocutaneous telangiectasia
3. GI hemorrhage
4. Arteriovenous malformation: pulmonary, cerebral, hepatic
By 16 yrs, 71% will have developed some sign of HHT, rising to >90% by age 40yrs
What investigations should be done on someone with HHT?
1. CBC: anemia
2. Bubble echocardiogram or chest CT without contrast: pulmonary AVM
3. Colonoscopy: AVM in the GIT
4. Brain MRI and MRI: cerebral AVM
Describe the genetics of HHT
- Inheritance pattern
- Penetrance
- Gene(s) involved
- Autosomal dominant
- Fully penetrant by age 40yrs
- ENG and ACVRL1: main genes
- SMAD4: HHT with juvenile polyposis
What is the management for HHT?
- Surveillance for undiagnosed AVM
- Treatment for identified complications such as nosebleeds, GI bleeds, anemia, pulmonary AVMs, cerebral AVMs and hepatic AVMs
Describe the treatment mechanisms for HHT
- Bevacizumab: monoclonal antibody against vascular endothelial growth factor (VEGF)
- Directly inhibits the VEGF proteins elevated as a result of the HHT mutations
Case 3)
- 58y/o Caucasian male p/w weight loss, generalized fatigue x several months and increased skin pigmentation. No history of anemia or iron supplementation
- PMH: diabetes mellitus, joint pain, impotence
- Social Hx: drinks 3 glasses of alcohol/week
- What are you thinking?
Hereditary Hemochromatosis
What does this pedigree show?
- Ex) Hereditary Hemochromatosis
What are diagnostic features of Hereditary hemochromatosis?
(Early features are non-specific)
- Weakness and lethargy or fatigue
- Arthralgia
- Abdominal pain
- Impotence or amenorrhea
- Dyspnea (due to cardiomyopathy)
- Late features
- Bronzed skin pigmentation
- Cirrhosis
- Diabetes mellitus
What do iron studies show in cases of Hereditary Hemochromatosis?
- Serum Fe
- TIBC
- Transferrin saturation
- Ferritin
- Serum Iron (Fe): 191 ng/ml (NL 20-150 ng/ml)
- TIBC (total iron binding capacity): 220ng/ml (NL 250-450 ng/ml)
- Transferrin saturation: 87% (NL 20-50%)
- Ferritin- 750ng/ml (NL 20-300ng/ml for males, 20-120 ng/ml for females)
Who populations of people get acquired hemochromatosis?
Those who get many blood transfusions
How is the diagnosis made for Hereditary Hemochromatosis? When do you suspect it?
- Treatment?
- Suspect HHC when fasting transferrin saturation is >45% in males or >35% in premenopausal females on 2 separate occasions.
- Transferrin saturation = Fe/TIBC.
- Typically high Fe and low or low normal TIBC in HHC.
- Treatment:
- Phlebotomy
- Iron chelation
- HFE gene:
Describe the genetics of Hereditary Hemochromatosis
- Inheritance pattern
- Gender prevalence
- Carrier rate
- Gene(s) involved
- Autosomal recessive
- Disorder of excessive iron absorption
- Fe overload in tissues
- Males > females (5:1)
- Carrier rate: 1/8-10
- C282Y and H63D mutations common
- >90% are homozygous for C282Y and 5% are compound heterozygous
What is seen here?
Iron stain in liver of Hereditary hemochromatosis
Describe the pathogenesis behind Hereditary Hemochromatosis
Disorder of excessive iron absorption
- Hepcidin synthesized in liver is a circulating iron response hormone; blocks further absorption of iron when iron supplies are adequate
- Mutant HFE interferes with hepcidin signaling
Example case for future handling of cases with genetics
- Amy, age 21yrs, visits with her physician and elects to have complete genome sequencing
- F/up: learns of her genetic risk factors for heart disease, diabetes, breast cancer and colon cancer
- Risk scores and suggestions for lifestyle modifications given
- She is at particularly high risk for Type 2 DM, recommended a rigorous program of diet and exercise
- 1 yr later: she develops mild asthma, her physician selects an optimal therapy based on her genetic profile
- 5 yrs later: they consider family planning - information regarding having a child affected by a serious genetic disease
- Both she and her husband are carriers of SMA, seek further counseling
- At age 40, she begins colorectal cancer screening based on her higher than average risk factors
- At age 45, a precancerous polyp is detected in her colon and successfully removed
Look at this flowchart for the vision of Genetic Revolution in medicine
What are challenges of personalized medicine?
- Legislative logistics
- Intellectual property
- Regulatory oversight: FDA
- Reimbursement
- Privacy, confidentiality and patients’ rights
- IT infrastructure
What is GINA?
Genetic Information Nondiscrimination Act
- Makes it illegal for health insurers or employers to discriminate against individuals based on their genetic information.
- Prevents insurers from denying coverage, adjusting premiums on the basis of genetic information or requesting that an individual undergo a genetic test.
- Prohibits employers from using genetic information to make hiring, firing, or promotion decisions.
- Limits an employer’s right to request, require or purchase an employee’s genetic information.
What does GINA legislation NOT address?
Will help the advancement of genomic medicine overall, but does not address:
- Life insurance
- Disability insurance
- Long term care insurance
What is DTC?
- Direct-to-consumer (DTC) genetic testing refers to genetic tests that are marketed directly to consumers via television, print advertisements, or the Internet
- Also known as at-home genetic testing
- Provides access to a person’s genetic information without necessarily involving a doctor or insurance company in the process
Why do people choose DTC testing? Problems?
1. Identity-seeking: identifying ancestry, paternity and ethnicity
2. Disease risk-testing for health care
3. For curiosity – searching for a better lifesty
“My biggest concern is that members of the public are getting tests that they don’t understand, and their physicians may not understand, and they may be making big decisions that are ill-informed.”
What insurance is not protected by GINA?
- Life insurance
- Disability insurance
A company found that one of his employees who was up for promotion had a BRCA mutation and denied the raise stating that they anticipate health problems and hence do not want her in the higher post. Is this ok?
Not okay
Name two problems with DTC
- Validity of data
- Utility of risk SNPs in predicting disease
