USMLE Step 3 Review Course

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Medical Genetics
A. Akhter, MD

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Medical Genetics

A. Akhter, MD

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USMLE Step 3 Review Course

Online Course
Medical Genetics
A. Akhter, MD

Basics

Humans have 23 pairs of chromosomes that includes 22 pairs of autosomes and 1 pair of sex
chromosomes (XX in females and XY in males). Most somatic cells are diploid
(46 chromosomes), and germ cells (sperm and egg) are haploid (23 chromosomes)
The haploid genome contains about 3 billion base pairs of DNA and is estimated to contain
50,000 to 100,000 genes. Each gene has a locus, or position, on one of the chromosomes.

Normal Karyotype

Genes are composed of introns and exons. The exons represent the coding portion of the gene
and code for amino acids. The code comprises four bases, adenine (A), cytosine (C), guanine
(G), and thymidine (T). The genes are coded from the 5' end to the 3' end of the DNA.
DNA sequences of a gene are called alleles. If a person has the same allele of a gene on both
copies of the chromosome, that person is said to be homozygous. If the two alleles of a gene
differ, the person is said to be heterozygous.

Autosomal recessive disorders

When a mutation in both alleles of a gene on an autosome (not on the X or Y chromosome) is

required for the disease to occur.
Males and females are affected equally because the mutation is in a gene on an autosome.
The affected person is either homozygous for the mutation (both alleles have the same mutation)
or a compound heterozygote (each allele has a different mutation).
Carriers of Autosomal recessive disorders have one allele with a mutation and one normal allele,
and are unaffected.
Horizontal pattern of pedigree single generation affected

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USMLE Step 3 Review Course

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Medical Genetics
A. Akhter, MD

Autosomal Dominant Disorders

When a mutation in one allele of a gene causes disease.

Males and females are equally affected, with some exceptions.
The affected person has one normal and one abnormal allele, and thus is heterozygous.
The disease gene is on an autosome, not on the X or Y chromosome.
Autosomal dominant disorders are inherited through generations. Because of late expression of
phenotype and poor penetrance.
Although the mutated gene should be present in successive generations in which there are more
than one or two offspring, it may appear that a generation is skipped if there is reduced
penetrance.
Penetrance means frequency, with which a specific phenotype is expressed by those
individuals with a specific genotype.
Vertical pattern of pedigree more than one generation affected

X-linked inheritance

Males are more severely affected than female.

There is no male to male transmission of phenotype
All the daughters of affected male are heterozygous

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USMLE Step 3 Review Course

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Medical Genetics
A. Akhter, MD

Genetic Testing

1: Diagnostic testing: When patient having an existing condition, and test is done to confirm it.
Turner syndrome or Downs syndrome
2: Predictive: Can be done prenatal, to make reproductive choice decision- Downs syndrome
3: Presymptomatic: When there is a family history of a genetic disease and family members wish
to know their status. e.g: Huntington disease.

Lists of Autosomal Recessive Disorders

1: Phenylketonuria
2: Glycogen storage disease
3: Tay-Sachs disease
4: Cystic Fibrosis
5: Citrullinemia
6: Alkaptonuria
7: Gauchers disease
8: Homocystinuria
9: Congenital adrenal hyperplasia (21 Hydroxylase deficiency or CYP21A2 deficiency)
10: Sickle cell anemia
11: Wilsons disease
12: Xeroderma Pigmentosum
13: Albinism
14: Ataxia Telangeictasia
15: Cystinuria

List of Autosomal Dominant Disorders

1: Acute Intermittent Porphyria

2: Familial Hypercholesterolemia
3: Marfans syndrome
4: Huntingtons disease
5: Adult Polycystic kidney disease
6: Ehlers-Danlos Syndrome
7: Von Rcklinghausens disease
8: Tuberous Sclerosis

Chromosomal Aberrations

1: Downs syndrome: 47XX, XY+21

2: Turner syndrome: 45 XO
3: Klinefelter syndrome: 47, XXY
4: Cri-du Chat syndrome Deletion 5p
5: Fragile X-syndrome fragile site at long arm of X-chromosome

Downs syndrome

Clinical feature: Typical facial feature, Flattened Occiput, Epicanthal fold, Up-slanted palpebral
fissure, speckled iris (Brushfield spots), protruding tongue, small low set ear.
Single palmer crease.

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A. Akhter, MD

Atrioventricular Septal defect- 45%, this is also called Endocardial Cushion defect. Ventricular
septal defect- 35%
GI- duodenal atresia and Hirschsprung's disease
Hemtologic- AML in first three years, ALL afterwards.
Eye- refractive errors
Alzheimer like dementia is evident in the 4th and 5th decade.
Increased maternal age: can be screened with feto protein in early second trimester and nuchal
thickness in fetal ultrasound exam. Diagnosis is confirmed by amniontic fluid analysis and
karyotype.

Fragile X syndrome

A fragile site a X-chromosome (CGG repeats at this site)

Second most common cause of mental retardation.
Clinical feature: Affected male show enlarged testes after puberty, large ears and prominent jaw,
high pitched voice, sometimes joint hyper-mobility and mitral valve prolapse.
Confirmation is done by DNA diagnosis.

Turners syndrome

45XO
Primary hypogonadism
Short stature
Webb neck
High arch palate
Wide spaced nipples
Hypertension
GH is normal and patient have high LH and FSH
Confirmatory test: Chromosomal analysis- karyotype

Treatment
1: Daily injection of Growth hormone (0.1unit/kg/day) and androgen (Oxandrolone) for at least
four years before epiphyseal fusion.
2: After age 12, low dose estrogen (0.3mg) days 1-21 per month.
3: When growth stops treatment starts with estrogen and progestin.
Location: Office

CC: Short Stature and primary amenorrhea.

A mother brings her 12 year old daughter for evaluation since she is worried about her height.
Mother reports that, her daughter is significantly smaller than her classmates. Mother is also
concern about her menstrual periods. She reports that her father is 6 feet tall and she herself is 5
feet 7 inches tall. Her older sister had her first menstrual period around this age. On direct
questioning, she reports that she achieved all her developmental milestones in time or earlier.
She has received all her childhood vaccines. She denies any major medical illness except
frequent throat infection and few middle ear infections, which she was treated without
complication. There are no known allergies to medicine or food. Mother denies any tobacco,
alcohol or street drug use while she was pregnant with the patient.

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USMLE Step 3 Review Course

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Medical Genetics
A. Akhter, MD

This patient has short stature, which is most likely not secondary to familial reason or infection
or any chronic disease. So you have to evaluate thoroughly. The differential diagnosis of short
stature for this patient is Turners syndrome, Growth hormone deficiency, hypo or
hyperthyroidism.

Order Full Physical Examination:

Positive finding in physical examination:
Short stature
Webb neck
High arch palate
Wide spaced nipples
Note: After these findings, your suspicion of Turners syndrome is very high.
Order routine labs: CBC2,LFT, BMP, Albumin, Globulin, total protein, Growth hormone serum,
LH, FSH, TSHAt that point you may send the patient home and reschedule patient in two weeks
since your result of growth hormone will not be available until after few days.

Results: CBC, Chem. 8, TSH, Total Protein, Albumin and Globulin and Growth hormone is
normal, FSH and LH-> High

Note: Now the most important scenario is GH is normal and patient have high LH and FSH.
Your suspicion is very high for hypogonadism and most likely diagnosis is Turners syndrome.
At this point you order Chromosomal analysis- karyotype and send the patient home and
reschedule in 2 week.

Karyotype Result confirms Tunrners syndrome (45XO)

Note: Most likely, at this point, the computer will exit your case and a 5 minutes window will
appear. If this happens, still order the following. If at this point the computer does not exit your
case, order the following:
Order routine labs:
Skeletal survey
Echocardiography
Fasting Blood sugar
Pelvic and Abdominal Ultrasound- Streaked gonands.
Growth hormone androgen (Oxandrolone)
Vitamin D therapy- continuous
Hearing test or Audiometry
Consult Psychology for IQ evaluation and continued support and education or order intelligence
testing which means, you want a psychological evaluation.
Obstetrics and gynecology: (To access the gynecological status for any future pregnancy,
although most of them are infertile)
Change location and send the patient home, at this point, computer will exit your case, if it
already has not done. Set an appointment in 2 months.
Echocardiography every 2 years
TSH- q 1 year

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USMLE Step 3 Review Course

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Medical Genetics
A. Akhter, MD

Final Diagnosis:Turners Syndrome

Discussion: Treatment of Turners syndrome

1: Start treating the patient with GH as soon as the height falls below 5th percentile, which
usually occurs at around 5-7 years of age.
2: Once the girl reaches the age of 9-12years treat with GH and androgen (Oxandrolone)
3: If the patient is more than 13-14 then treat with estrogen and progestin to maintain the normal
cyclic uterine bleeding. Stop Oxandrolone when you start estrogen.
4: The dose of estrogen should be higher than used in postmenopausal women as Hormone
replacement therapy.
5: Most women with Turners syndrome are infertile.
6: Most common cardiac defect in Turners syndrome is Coarctation of aorta or bicuspid aortic
valve.
7: Those who have Coarctation of aorta needs surgical repair.
8: Most common cardiac defect in adults with Turners syndrome is Aortic root dilation. That is
the reason Echocardiography is recommended in adults every 5 years.
9: Almost 50% of patient of Turners syndrome have hearing defect. Most common hearing
defect is Sensorineural hearing loss, which deteriorates with age.

Klinefelter syndrome: 47, XXY

Normal in appearance before puberty

Disproportionately long arms, small testis, azospermia, learning problems despite normal IQ
High risk of male breast cancer and diabetes
Treatment: Testosterone after puberty

Tall and long arm

Genetics
Stature
Lens
Cardiac
status
IQ
Diagnosis

Homocystinuria
Autosomal recessive

Marfans syndrome
Autosomal dominant

Tall
Ectopia lentis
( displacement of
lens, downward )
Venous and arterial
thrombosis
Low

Tall
Ectopia lentis
( displacement of lens
upward)
Mitral valve prolapse, AR,
Aortic root dilatation
Normal IQ

Increased urine and

plasma homocystine
levels

Family history and genetic

testing
( mutation on
chromosome 15)

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Klinefelter syndrome
Chromosomal anomaly
( 47 XXY)
Tall
none
No valve abnormality
Normal IQ but learning
difficulty
Chromosomal analysis