Clinical Vignettes

Question 1

What are the chromosomal abnormalities associated with Down Syndrome?

Answer 1

Trisomy 21

Question 2

How do you test for the chromosomal abnormalities associated with Down Syndrome?

Answer 2

Quad screen in early 2nd Trimester can identify risk for having a baby with trisomyWoman may be offered a procedure to determine karyotype (amniocentesis) performed at 16 weeks.High risk women may be offered chorionic villus sampling (VS) at 11-12 weeks.

Question 3

What is a major risk factor for having a baby with Down Syndrome?

Answer 3

Advanced Maternal Age (>35)

Question 4

What are the two chemical mechanisms for testing for trisomy?

Answer 4

Karyotyping (count 47 chromosomes)FISH testing: faster results

Question 5

What are the physical features (phenotypes) associated with Down Syndrome?

Answer 5

Normal growth parameters, brachecephaly, mid face hypoplasia, up-slanting palpebral fissures, epicanthal folds, Brushfield spots, dysplastic small pinnae, heart murmur may be present, genitalia may be abnormal, especially in males (undescended testicles, small phallus, hypospadias), incurving 5th finger, small digits, increased space b/w 1st and 2nd toes, increased joint range of motion, diffuse hypotonia.

Question 6

What are the most serious (requiring surgery) medical problems seen in Down syndrome?

Answer 6

Congenital heart disease (1/3-1/2 of babies). Endocardial cushion defect, which is also called atrioventricular canal (AVC).GI tract defects: 10-15% of babies with DS. Esophageal or duodenal atresias, which leads to polyhydramnios during pregnancy.Both require surgical repair.

Question 7

What are some other medical issues common in patients with Down Syndrome?

Answer 7

Small tear ducts, small eustachion tubes, small airway, eye problems (stabismus, nysatmus, cataracts, myopia), ear problems (infections, hearing loss), thyroid problems, celiac disease, diabetes, feeding issues, GERD, constipation, intellectual disabilities, autism, depression, Alzheimers.

Question 8

What is the developmental and behavioral phenotype of those with Down Syndrome?

Answer 8

Decreased IQ, Intellectual disabilities. Increased incidence of depression.

Question 9

What are the chromosome 15 abnormalities associated with Prader-Willi Syndrome?

Answer 9

A deletion of 15q11-q13 from the paternal allele. Or, there could be maternal disomy.

Question 10

How do you test for the chromosomal abnormalities associated with Prader-Willi Syndrome?

Answer 10

FISH testing can confirm the deletion.Methylation testing can also help identify PWS.

Question 11

What is the role of imprinting disorders involving chromosome 15?

Answer 11

It is critical for the information from the maternal and the paternal allele to be present in order for the baby to be normal. The region of chromosome 15 that is important is imprinted (methylated). If there is an imprinting error, the chromosomes will be marked incorrectly, resulting in either Prader-Willi or Angelman syndrome.

Question 12

What are the physical features (phenotypes) of those with Prader-Willi syndrome?

Answer 12

Infant: floppy child, undescended testicles, lighter pigmentation, almond shaped eyes, severe feeding problems.Toddlers: feeding becomes voracious, obesity, strabismus, nysagmus

Question 13

What are the medical problems seen in patients with PWS?

Answer 13

Eye problems (strabismus, nystagmus), scoliosis, obstructive sleep apnea (contraindication to the use of growth hormone), obesity.

Question 14

What is the developmental and behavioral phenotype of those with PWS?

Answer 14

Mild-moderate cognitive disabilities are usually found, behavioral issues are common.

Question 15

Recognize the clinical presentation of patients with Turner Syndrome

Answer 15

Eye: Inner canthal folds, blue sclerae, ptosisEar, nose: Prominent Auricles, low-set, high narrow mouth palate; small mandibleNeck: Low posterior hairline, webbingChest: Broad widely spaced Nipples; pectus excavatumSkeleton: Cubitus valgus, short fourth metacarpal and/or metatarsal, madelung deformity, scoliosis

Question 16

Enumerate challenges across the lifespan in patients with Turner Syndrome

Answer 16

Has trouble with math, is short, late development of sexual characteristics, infertility, concerns regarding health and aging.

Question 17

Recognize the clinical challenges related to patients with Turner Syndrome

Answer 17

Secret keepingDifficulty communicating an infertility diagnosisPerceived negative experiences with physicians

Question 18

What is thalassemia?

Answer 18

Thalassemia is a disorder with imbalanced globin synthesis leading to defective hemoglobin production leading to destruction of red blood cell precursors in the bone marrow.

Question 19

What is the diagnosis of thalassemia based on?What is the differential diagnosis?

Answer 19

Diagnosis is based on:Presence or absence of hepatosplenomegalyCBC and reticulocyte countNBS (Newborn screen)Hemoglobin electrophoresisDifferential diagnosis:Iron deficiency anemiaLead poisoningAnemia of chronic disease

Question 20

What is the incidence of thalassemia?

Answer 20

269 million carriers in the world, higher in Africans, SE Asians, and Mediterraineans350,000 babies born throughout the world each year with major hemoglobin disorders. Most die under-diagnosed, untreated, or under-treated.

Question 21

What is the genetic basis of thalassemia?

Answer 21

Several mutations and deficiencies in hemoglobin units.

Question 22

What is the treatment of thalassemias?

Answer 22

β Thalassemia major: Chronic transfusion, treatment of complications (eg: iron overload), Bone Marrow transplantβ Thalassemia trait / αThalassemia 1 or 2 gene deletion: No treatmentα Thalassemia 3 gene deletion (Hgb H disease): Occasional transfusion of PRBCs, Splenectomy

Question 23

Explain causes and risk factors of thrombocytopenia.

Answer 23

Diverse reasons for this.Decresed production or increased destruction of platelets. Hepatosplenomegaly can contribute to this. Spleen is clearing house for used up blood cells. When you have hepatosplenomegaly, spleen gets giant. By occupying more space, it acts like a big sponge. Physical expansion of spleen reduces platelet concentration in blood.

Question 24

Explain causes and risk factors of hepatosplenomegaly.

Answer 24

Infectious diseases, cirrhosis, cancer, vascular and organ failure, blood disorders. Spleen cycles all blood cells, liver is involved in metabolic diseases, which Gaucher’s is. Macrophages end up being stored in liver and spleen once this disease is initiated.

Question 25

Describe cellular pathology and clinical manifestation of Gaucher’s Disease.

Answer 25

Clinical manifestation: Hepatatosplenomegaly, bone syndromes, neurologic symptoms, anemia and thrombocytopenia, fatigue.Macrophages get engorged and turn into Gaucher cells

Question 26

Describe major subtypes of GD.

Answer 26

Type 1: Asymptomatic to early onset. Most common presentation: splenomegaly, hepatomegaly, bone, lung problemsType 2: Fatal w/in 1st 2-3 years of life. Neurological and visceral symptomsType 3: Same symptoms of type 2, but late onset. Can live to 30 or 40 years instead.

Question 27

How do you diagnose Gaucher disease?

Answer 27

Usually diagnosed during a clinical exam. Anemia, thrombocytopenia, fatigue, organ megaly, can confirm with enzyme assay, lymphocyte assay, or genotype analysis by DNA sequencing.

Question 28

What is the mode of inheritance for Gaucher disease?

Answer 28

Autosomal recessive

Question 29

Explain the etiology of Gaucher Disease.

Answer 29

Accumulation of glucocerebroside in macrophages because of lysosomal enzyme defects.

Question 30

Understand how to manage Gaucher disease and current therapies.

Answer 30

Enzyme replacement therapy: attach enzyme to mannose molecule. Cell membrane receptors accept the mannose-enzyme complex so the enzyme can act within the cell. Helps the most with hepatosplenomegaly.Bone symptoms: resolve on own, give pain medication and bisphosphonates as wellSplenectomyBone marrow transplantSubstrate reduction therapy

Question 31

Describe limitations of current therapies for GD, including cost; discuss ethical issues of ERT and identify the current needs for GD.

Answer 31

Limitations: Allergic reactions, medication doesn’t cross blood brain barrier,Costs $75-450k/year.Hard to produce this drug, not much of it.Very few people have this disease.Ethical issues: especially in a public health care system: is it right to spend so much on one person when there are other things to be treated, equity issues.