Genetic 3 Genetic Diseases

1. Recognize the clinical features of the following chromosomal disorders

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   1. Trisomy 21

   • Also known as Down syndrome.

• Extra copy of chromosome 21.

—Caused by three copies of long chromosome 21:

1. Trisomy 21: 93-96%= 47, 21 (most common)

2. Robertsonian translocation: 2-5% 14:21, 21:21, 13:21, 15:21, 22:21 (unrelated to maternal age)

3. Mosaicism- 2-4% =-1.92 47, 21/46 (milder phenotype)

Overall risk: 1/800

• Risk increase with maternal age: The older the mother, the higher the risk.

Pregnant women can have tests to estimate the chance that the baby has Down syndrome.

Blood screening tests: AFP, Quad screen, and NIPT

Children with Down syndrome commonly have up-slanting eyes, epicanthal folds, a flat nasal bridge, an open mouth with a protruding tongue, and hypotonia. These characteristic facial features help clinicians recognize the condition.

—Single palmer crease (Clinodactyly)

— Small, dysplastic ears

— Bursfield spots

Associated problems:

• Intellectual impairment (near 100%)

• Cardiac malformations (40-50%) —children need detailed cardiac evaluation.

• Duodenal atresia- a congenital condition where a portion of the small intestine is narrowed or blocked, often requiring surgical intervention to ensure proper digestion.

• Hirshsprung disease- a congenital condition affecting the large intestine, leading to problems with passing stool due to a lack of nerve cells in the bowel.

• Hypothyroidism —a condition where the thyroid gland does not produce enough thyroid hormones, leading to various developmental issues and metabolic dysregulation.

• Leukemia-

• Alzheimer's disease.

Down syndrome survival:

— Many babies with Down syndrome do not survive the pregnancy.

As pregnancy progresses, the number of fetuses with Down syndrome decreases because some are lost before birth.

• Decreased in-utero survival- babies with Down syndrome have a lower chance of surviving in the womb compared with babies without Down syndrome.

• Increased rate of spontaneous abortion- Down syndrome → Higher miscarriage risk.

• Only 25% of conceptuses survive to birth- A conceptus is a fertilized egg/embryo/fetus.

• Neonatal mortality associated with cardiac malformations.

• Adults develop early Alzheimer disease-

UNBALANCED TRANSLOCATION:

You do NOT need an entire extra chromosome 21 to develop Down syndrome. Even an extra copy of the important part (21q22, the "critical region") can cause many of the classic Down syndrome features.

-Partial trisomy 21- Extra piece of chromosome 21 → Partial trisomy (unbalanced translocation).

-Critical region- The most important part of chromosome 21 that causes Down syndrome features.

-Trisomy of 21q22 causes heart defects, facial features, intellectual deficits.

-Observation of parts of Down syndrome phenotype allow mapping of region of 21 containing genes causing phenotype.

Down Syndrome risks:

-Diagnostic tests for down syndrome risk: amniocentesis or chorionic villus sampling (CVS).

-Prenatal diagnosis is offered if risk is greater than 1 in 200.

High risks individual:

-Maternal age (older women are at high risk)

-Translocation carriers

-Maternal Screening tests

Recurrence risks:

Higher risks for older women

Recurrence risk for translocation increased if parent is a translocation carrier

10 - 15% if mother is a carrier

2 – 5% if father is a carrier

Mosaic Down syndrome does not increase the risk of future pregnancies because it occurs as a random error after fertilization.

DOWN SYNDROME- TREATMENT

—Cardiac evaluation (echocardiogram) even if asymptomatic.

—Thyroid hormone screening

—Hearing screening

—Dietary counseling

—Educational intervention

—Family Support

MATERNAL SCREENING TESTS

Triple/Quad screen/AFP (maternal serum)

-AFP screen for neural tube defects (spina bifida)

-Low AFP associated with Down syndrome risk

-Triple/Quad screen more accurate

-Screening test, not diagnostic

High resolution ultrasound

-Increased nuchal lucency in DS fetuses

-Not diagnostic

NIPT – Non Invasive Prenatal Testing

-Test of fetal DNA in maternal blood

-Chromosomal analysis – trisomies

-Screening test

Must be confirmed with diagnostic testing

1. Trisomy 18- Trisomy 18 (Edwards syndrome) is caused by an extra chromosome 18 and is characterized by growth restriction, clenched hands with overlapping fingers, heart defects, a prominent occiput, and severe intellectual disability.

— Rocker-buttom feet; Overlapping fingers

Trisomy 13

-Trisomy 13 (Patau syndrome) is a condition where a baby has 3 copies of chromosome 13 instead of 2.

— Holoprosencephaly, Polydactyl, Cleft/Lip palate

Trisomy 13, 18= lethal trisomies

1. Turner syndrome- Turner syndrome is a female with only one X chromosome (45,X), causing short stature, infertility from ovarian failure, and congenital abnormalities such as coarctation of the aorta, bicuspid aortic valve and horseshoe kidney.

—Early ovarian failure.

—Short stature (SHOX gene)

—Cystic hygroma on back of the neck (broad webbed neck)

—1/2,500 girls (more frequent prenatally)

—Broad Chest

—Normal inteligence

—May demonstrate X-linked genetic traits (like males).

—Lack secondary sex characteristics

—Wide arm

Klinefelter syndrome- Klinefelter syndrome is a male with an extra X chromosome (47,XXY), causing tall stature, small testes, low testosterone, gynecomastia, and infertility.

—Normal intelligence (more in borderline)

— 1/500-1/1,000 males

Treatment: Treatment for Klinefelter syndrome includes testosterone replacement, infertility evaluation, monitoring for breast cancer, and family/genetic support.

Fragile X- X-linked disorder (Male disorder) caused by a CGG repeat expansion in the FMR1 gene, leading to intellectual disability, speech delay, ADHD, a long face, large ears, loose joints, and large testes after puberty.

• Normal at birth

• Most common genetic cause of intellectual disability in boys: 1/5,000

Recognize the clinical features of cancer predisposition syndromes

1. BRCA1

BRCA1 is a tumor suppressor gene that repairs DNA damage, and mutations increase the risk of breast, ovarian, prostate, pancreatic, and male breast cancers.

1. BRCA2-

BRCA2 is a tumor suppressor gene that repairs DNA, and mutations increase the risk of breast, ovarian, prostate, pancreatic, and especially male breast cancers. '

• BRCA1 → More ovarian cancer

• BRCA2 → More male breast & prostate cancer

HNPCC- Lynch syndrome (HNPCC) is an autosomal dominant disorder caused by mutations in DNA mismatch repair genes, leading to a high risk of colon cancer and endometrial cancer, along with increased risks of ovarian, stomach, pancreatic, urinary tract, and prostate cancers.

Treatment: Colonoscopy every 1-2 years after age 20.

Full colectomy after cancer occurs

Prophylactic hysterectomy and salpingo-oophorectomy after childbearing

FAP- FAP is an autosomal dominant disorder caused by an APC tumor suppressor gene mutation, resulting in hundreds to thousands of colon polyps and an almost 100% risk of colon cancer if left untreated.

Increased liver cancer (hepatomablasts) risk.

Identify different ways to manage and/or treat genetic disease.

• S = Supportive care

• P = Product replacement

• R = Replacement of enzymes

• D = Dietary restriction

• T = Toxic substance removal

• O = Organ transplant

• G = Gene therapy

—Genetic disorders can be managed by treating symptoms, replacing missing products or enzymes, avoiding harmful substances, removing toxic buildup, replacing damaged organs, or correcting the defective gene with gene therapy.

• Down syndrome → Flat face, hypotonia, AV septal defect

• Edwards syndrome → Overlapping fingers

• Patau syndrome → Polydactyly + cleft lip

• Turner syndrome → 45,X + short stature

• Klinefelter syndrome → 47,XXY + gynecomastia

• Fragile X → Large ears + large testes

• BRCA1 → Breast + ovarian cancer

• BRCA2 → Male breast + prostate cancer

• HNPCC (Lynch Syndrome) → Few/no polyps + early colon/endometrial cancer

• FAP → Hundreds of polyps + APC mutation + ~100% colon cancer risk

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  Disease	Most Tested Clue
  Down syndrome	Flat face, hypotonia, single palmar crease
  Edwards syndrome	Overlapping fingers
  Patau syndrome	Polydactyly + cleft lip
  Turner syndrome	45,X + short female + infertility
  Klinefelter syndrome	47,XXY + tall male + gynecomastia
  Fragile X	Large ears + long face + large testes
  BRCA1	Breast + ovarian cancer
  BRCA2	Breast + male breast + prostate cancer
  HNPCC	Colon cancer before age 50, few/no polyps
  FAP	Hundreds to thousands of colon polyps

Chromosomal Disorders

• 21 = Down syndrome → Flat face, hypotonia

• 18 = Edwards → Folded (overlapping) fingers

• 13 = Patau → Extra fingers (polydactyly)

• 45,X = Turner → Short female

• 47,XXY = Klinefelter → Tall male

• Fragile X = BIG

  • Big ears

  • Intellectual disability

  • Gonads (large testes)

Cancer Syndromes

• BRCA1 = Breast + Ovarian

• BRCA2 = Male Breast + Prostate

• Lynch = Colon + Uterus (Endometrium)

• FAP = Full of Polyps