Chromosomal Defects

Question 1

What is the genetic abnormality in trisomy 21?

Answer 1

Trisomy 21 is caused by the presence of an extra copy of chromosome 21.

Question 2

What is considered to be the etiology of trisomy 21?

Answer 2

It is usually due to nondisjunction during meiosis.

Question 3

What is the only factor shown to increase the risk of trisomy 21?

Answer 3

The only known risk factor for Trisomy 21 is advanced maternal age (especially in mothers ≥35 years of age).

Question 4

Which screening tests indicate an increased risk of trisomy 21?

Answer 4

Low maternal serum α-fetoprotein, low unconjugated estriol, elevated hCG, and elevated inhibin levels.

Question 5

What are some (12) of the classic physical findings in children with trisomy 21?

Answer 5

Hypotonia, poor Moro reflex, bracydactyly (short, broad fingers and toes - especially broad space between 1st and 2nd toes), upslanted palpebral fissures, flat midface, full cheeks, protruding tongue, epicanthal folds, single transverse palmar crease, speckled irises (Brushfield spots), high-arched palate, hypoplasia of the middle phalanx of the 5th finger/clinodactyly.

Question 6

What are the common congenital heart defects found in a child with trisomy 21?

Answer 6

Heart defects occur in 50% of patients with Trisomy 21. Of these, 1/3 have AV canal defects, 1/3 have VSDs, and 1/3 have ASDs and Tetralogy of Fallot.

Question 7

What screening study should be performed in all patients with Trisomy 21?

Answer 7

Because 50% of all patients with Trisomy 21 have congenital heart defects, echocardiogram is mandatory for all children with suspected Trisomy 21.

Question 8

Which two GI defects are associated with trisomy 21?

Answer 8

Duodenal atresia and Hirschsprung disease

Question 9

Which ocular disorder occurs in ~5% of infants with Trisomy 21?

Answer 9

Congenital cataracts

Question 10

Which glandular disorder should you annually screen for in individuals with trisomy 21?

Answer 10

Hypothyroidism

Question 11

Describe transient myeloproliferative disorder as it relates to infants with Trisomy 21.

Answer 11

Transient myeloproliferative disorder is a type of leukemia that occurs in up to 10% of all infants with Trisomy 21 within the first 3 months of life. It is usually asymptomatic and resolves spontaneously within the first 3 months of life, but can require chemotherapy if complications arise.

Question 12

If a child with Trisomy 21 has a history of transient myeloproliferative disorder in infancy, what disorder are they at higher risk for later in life?

Answer 12

Patients with a history of transient myeloproliferative disorder have a 10 to 20 fold increased risk for development of acute myeloid leukemia as they grow older.

Question 13

A 30 year old mother has a child with trisomy 21 with three complete copies of chromosome 21. What is her risk of having another child with trisomy 21?

Answer 13

If the child has 3 complete copies of chromosome 21 and the mother is <35 years of age, her risk of having another child with Trisomy 21 is 1%.

Question 14

What is the sex distribution for Trisomy 18?

Answer 14

The ratio of girls to boys is 4:1.

Question 15

What is another name for Trisomy 18?

Answer 15

Edwards Syndrome

Question 16

What are the (10) classic features of a child with trisomy 18?

Answer 16

IUGR, intellectual disability, high forehead, microcephaly, small face and mouth, rocker-bottom feet, clenched fist with overlapping fingers (2 and 5 over 3 and 4), short sternum, hypoplastic nails, structural heart defects (90%, most commonly VSD with multiple dysplastic valves).

Question 17

What is the most common cause of death in patients with Trisomy 18?

Answer 17

Central apnea

Question 18

What is another name for Trisomy 13?

Answer 18

Patau Syndrome

Question 19

What are the (11) classic features of a child with trisomy 13?

Answer 19

Think midline defects: orofacial cleft, microphthalmia, postaxial polydactyly of the limbs, holoprosencephaly, heart malformations (80%), hypoplastic or absent ribs, genital anomalies, abdominal wall defects, aplasia cutis congenita, rocker-bottom feet, clenched hands.

Question 20

What is the genotype of a patient with Klinefelter Syndrome?

Answer 20

47, XXY

Question 21

Describe the features of a patient with Klinefelter syndrome.

Answer 21

Typically, these patients are tall with gynecomastia and secondary sexual development is delayed. They almost always have azoospermia and small testes and are infertile.

Question 22

Describe the phenotype of an individual with 47, XYY genotype.

Answer 22

XYY males are generally taller than average, but are otherwise no different from the general population.

Question 23

What is the genotype of a patient with Turner Syndrome?

Answer 23

45, XO

Question 24

Describe the features of a patient with Turner syndrome.

Answer 24

These patients are phenotypically female and have short stature with ovarian failure/gonadal dysgenesis and subsequent lack of secondary sexual development. ~50% have cardiovascular anomalies (most common: bicuspid aortic valve, coarctation of the aorta). At birth: broad, webbed neck; shieldlike chest; posteriorly rotated ears; lymphedema of hands and feet; short metacarpals; cubitus valgus.

Question 25

Which patients with Turner Syndrome require removal of streak gonads?

Answer 25

About 5-10% of patients with Turner Syndrome have Y chromosome material in all or some cells. This puts them at risk for gonadoblastoma, so internal streak gonads should be removed.

Question 26

How is a genetic deletion characterized if it occurs on the short arm of a chromosome?

Answer 26

“p deletion”

Question 27

How is a genetic deletion characterized if it occurs on the long arm of a chromosome?

Answer 27

“q deletion”

Question 28

What are the classic features of a child with 4p deletion?

Answer 28

Distinctive facial features (Greek Helmet): ocular hypertelorism, prominent glabella, frontal bossing, short philtrum, relative smallness of lower part of the face. Severe growth deficiency, microcephaly, kidney problems (HTN, renal failure), hypotonia, congenital cardiac anomalies (50%), seizures (90%), variable developmental delay.

Question 29

What is another name for 4p deletion syndrome?

Answer 29

Wolf-Hirschhorn Syndrome

Question 30

What is another name for 5p deletion syndrome?

Answer 30

Cri-Du-Chat Syndrome

Question 31

What are the classic features of a child with 5p deletion?

Answer 31

Characteristic “cat’s cry”, “Moon face” with telecanthus (widely spaced eyes) in infancy and early childhood, down-slanting palpebral fissures, hypotonia, short stature, microcephaly, high-arched palate, wide and flat nasal bridge, intellectual disability, cardiac abnormalities (33%).

Question 32

What causes the distinctive “cat’s cry” in Cri-Du-Chat Syndrome?

Answer 32

It is due to an anatomic change in the larynx.

Question 33

What is another name for 18q deletion syndrome?

Answer 33

de Grouchy Syndrome

Question 34

What are the classic findings in 18q deletion syndrome?

Answer 34

Think “Grouchy Frog”. Microcephaly, developmental delay; atretic or narrowed ear canals; “froglike” position with legs flexed, externally rotated, and hyperabducted; depressed midface, protruding mandible, deep-set eyes, everted lower lip (carplike mouth), and intellectual disability.

Question 35

Which deletion syndrome is associated with trigonocephaly?

Answer 35

9p deletion syndrome

Question 36

What testing modalities are utilized in the identification of microdeletion syndromes?

Answer 36

FISH and chromosomal microarray. The microdeletions are too small to be visualized on standard karyotype.

Question 37

Which parent is responsible for the genetic defect associated with Angelman Syndrome?

Answer 37

Angelman is due to Maternal silencing of 15q11-13.

Question 38

Which parent is responsible for the genetic defect associated with Prader-Willi Syndrome?

Answer 38

Prader-Willi is due to Paternal silencing of 15q11-13.

Question 39

Describe a child with Angelman syndrome, and explain the genetic mechanisms that caused it.

Answer 39

Jerky ataxic movements, inappropriate laughter, microcephaly, characteristic gait, hypotonia, fair hair, midface hypoplasia, prognathism, seizures, severe intellectual disability, absent or severely delayed speech. The syndrome is caused by genomic imprinting, with maternal silencing of 15q11-13.

Question 40

Describe a child with Prader-Willi syndrome, and explain the genetic mechanisms that caused it.

Answer 40

In infancy, these patients have severe hypotonia and feeding difficulties. In childhood, they have hyperphagia and severe obesity, short stature, small hands and feet, hypogonadism, mild intellectual disability, and behavior disorders. The syndrome is caused by genomic imprinting, with paternal silencing of 15q11-13.

Question 41

What genetic abnormality is responsible for Williams Syndrome?

Answer 41

Williams syndrome is due to a microdeletion on the long arm of chromosome 7 (7q11.23 deletion).

Question 42

Describe a child with Williams syndrome.

Answer 42

Broad forehead, medial eyebrow flare, shortened upturned nose with a flat nasal bridge, elongated philtrum with prominent down-turned lower lip (Elfin facies), friendly “cocktail party” personality, stellate pattern of the iris, strabismus, supravalvular aortic stenosis, intellectual disability, hypercalcemia, connective tissue anomalies (joint laxity, soft skin), growth delay and short stature.

Question 43

The absence of which gene is responsible for the connective tissue abnormalities in Williams Syndrome?

Answer 43

≥95% of individuals with Williams Syndrome are missing the elastin gene from 1 of their 2 copies of chromosome 7, leading to the development of connective tissue abnormalities.

Question 44

What characterizes WAGR syndrome.

Answer 44

Wilms tumor, Aniridia, Genitourinary malformations, and Reduced intellectual capacity (intellectual disability).

Question 45

Which two genes are absent in patients with WAGR syndrome?

Answer 45

PAX6 and WT1 (Wilms tumor 1)

Question 46

What facial features are classically seen in patients with WAGR syndrome?

Answer 46

Long face, upward-slanting palpebral fissures, ptosis, aniridia, beaked nose, and poorly formed ears.

Question 47

What genetic abnormality is responsible for WAGR Syndrome?

Answer 47

11p13 deletion

Question 48

What inheritance pattern is associated with Alagille Syndrome?

Answer 48

Alagille syndrome has an autosomal dominant inheritance pattern.

Question 49

What genetic abnormality is responsible for Alagille Syndrome?

Answer 49

20p12 deletion

Question 50

Which gene is either absent or mutated in patients with Alagille Syndrome?

Answer 50

Jagged-1 (JAG1) gene

Question 51

Describe the classic findings in Alagille syndrome.

Answer 51

Triangular facies with pointed chin, long nose with broad midnose, bile duct paucity with cholestasis, pulmonary valve stenosis and peripheral pulmonic stenoses, ocular defects (posterior embryotoxon - a developmental abnormality marked by a prominent white ring of Schwalbe and iris strands that partially obscure the chamber angle), skeletal defects (butterfly vertebrae).

Question 52

What are the most common cardiac abnormalities in patients with Alagille Syndrome?

Answer 52

Peripheral and branch pulmonic stenoses (67%), and Tetralogy of Fallot (7-16%).

Question 53

How does hepatic dysfunction usually present in patients with Alagille Syndrome?

Answer 53

It usually presents in the first 3 months of life as cholestasis, jaundice, and pruritus. Some patients develop liver failure. Biopsy reveals a paucity of bile ducts.

Question 54

List the classic findings in 22q11.2 deletion syndrome.

Answer 54

CATCH-22: Cleft palate, Absent Thymus, Congenital heart disease, Hypoparathyroidism on the 22nd chromosome.

Question 55

List the (4) most common cardiac defects in patients with 22q11.2 deletion syndrome in decreasing order of frequency.

Answer 55

Tetralogy of Fallot > interrupted aortic arch > VSD > truncus arteriosus.

Question 56

Which pharyngeal pouches are affected in patients with 22q11.2 deletion syndrome?

Answer 56

This syndrome is caused by a developmental defect of derivatives of the 3rd and 4th pharyngeal pouches.