Case 29: Down Syndrome

Question 1

Down Syndrome

• genetics/pathophysiology:
• RFs:
• epidemiology:
• common features:
• complications:

Answer 1

• genetics: Trisomy 21 (47XY,+21), unbalanced translocation Trisomy 21, mosaic Trisomy 21
• RFs: AMA (>35yo); majority of infants with Down syndrome are born to <35yo (b/c more pregnancies, and here more likely to be a translocation); hypothyroidism
• epidemiology: 1/700
• common features: HYPOTONIA (“sleeps more”), upslanting palpebral fissures; small ears; flattened midface; epicanthal folds, nuchal skin (redundant skin on back of neck); short stature

Complications:

• leukomoid rxns, transient myoloproliferative d/o
• Fe-deficiency anemia (d/t lower dietary iron intake than peers)
• hypothyroidism
• atlantoaxial instability (spinal cord impingement)
• vision problems
• hearing problems
• 50% risk of cardiac defect

Question 2

association between down syndrome and hypothyroidism

Answer 2

for infants with Down Syndrome,

increased risk of congenital hypothyroidism and later-onset hypothyroidism
==> important to assess thyroid status d/t concerns about short stature (common in Down syndrome)

Question 3

indications of chromosomal analysis in pediatric pts

Answer 3

• clinical features of a known chromosome d/o (e.g. Down syndrome)
• unrecognized malformation syndrome
• known genetic condition + additional/more severe findings
• mental retardation + short stature
• BORN STILLBORN with multiple malformation
• features of chromosome breakage syndrome
• TUMOR (e.g. leukemia) associated with chromosome abnormalities +/- tissue biopsy

IN PARENTS

• multiple pregnancy
• FHx chromosome rearrangement

Question 4

most consistent finding in infants with Down Syndrome

Answer 4

hypotonia

Question 5

types of chromosomal genetic tests

Answer 5

• karyotype
• array comparative genomic hybridiation== detecting submicroscopic chromosome deletions/duplications (using FISH probes)

Question 6

describe the concept of mosaicism in Trisomy 21

Answer 6

• when determining Trisomy 21 (or any karyotype / cytogenetic study) –> you are looking at a small sampling of cells. Theoretically you could have mosaicism (if don’t get the right cells)

Mosaic == defined by cytogenetic finding of mosaicism / atypical patient clinical findings

otheriwse == non-mosaic

Question 7

differentiate prenatal testing v. screening for Down Syndrome

Answer 7

prenatal testing (specific)

1) chromosome analysis of amniotic fluid cells (amniocentesis) and chorionic villous sampling of fetal cells
- complications: risk of miscarriage
2) “Harmony testing in first trimester)

screening (less specific for Down)

1) maternal serum screening ==> alpha-fetoprotein, hcG, estriol, PAPP-A, inhibin
2) fetal ultrasound for anatomic/physical deformities ==> nuchal skin thickness, nasal bone ossification, growth parameters, cardiac defects

Question 8

Fragile X syndrome

• epidemiology:
• genetics:
• sxs:

Answer 8

• epidemiology: 1/4000 males (all mothers of affected sons are carriers of at least 1 premutation of CGG)
• genetics: X-linked. inheritance of abn # of CGG repeats in FMR1 gene (usually inherited from Mom)
• sxs: long face + large mandible; large/prominent ears; CT abnormality (joint laxity, pectus excavatum, flat feet), large testicles post-puberty
• psychiatric/behavioral problems; mental retardation.

Question 9

most common genetic causes (#1, #2) of intellectual disability

Answer 9

#1) Down Syndrome
#2) Fragile X

#1 genetic == Down syndrome
#1 familial / inherited == Fragile X

Question 10

Disorders of sex chromosomes

• epidemiology:
• genetics/pathophysiology:
• sxs:
• associated conditions:

Answer 10

1) TURNER SYNDROME (45, XO)
- epidemiology: 1/2000 female live births (99% of conception with Tuner syndrome miscarry in T1)
- pathophysiology: lymphedema in utero
- sxs: low ear placement, webbed neck; “shield” chest + widely spaced nipples; edema of hands and feet, hyperconvex nails
- associated conditions: coarctation of aorta (20%), short stature (esp. in early adolescence); delayed sexual maturation (gonadal dysgenesis)
NORMAL IQ

2) KLINEFELTER SYNDROME (47,XXY OR 47, XXXY)
- sxs - ESP IN PUBERTY/ADULT ==> infertility (testicular atrophy); eunuchoid body habitus; gynecomastia; behavior problems.
- XXY (more x’s == more intellectual disability, developmental delay).

Question 11

differentiate the common trisomies

• incidence:
• clinical features:

Answer 11

PED

TRISOMY 13 = PATAU SYNDROME (“p”)

• incidence: 1/10,000 births
• clinical features: microphthalmia, microcephaly, severe ID, polydactyly, cleft lip and palate, cardiac and renal defects, umbilical hernias, cutis aplasia

TRISOMY 18 = EDWARDS SYNDROME (“e”)

• incidence: 1/6000
• clinical features: severe ID; prominent occiput, micrognathia, low-set ears, short neck, overlapping fingers, heart defects, renal malformations, limited hip abduction, rocket-bottom feet.

TRISOMY 21 = DOWN SYNDROME (“d”)

• incidence: 1/700
• clinical features: ID, epicanthic folds, flat faicla profile, single palmar crease, redundant neck skin, heart defects, intestinal stenosis, umbilical hernia, predisposition to leukemia, hypotonia, gap b/w 1st/2nd toes

Question 12

the team in taking care of a kid with Down syndrome

Answer 12

• physician
• parents
• geneticist
• interventions with prinicipal/school
• speech/physical therapist

Question 13

diffdx for hypotonia in a newborn

Answer 13

• Down syndrome
• benign neonatal hypotonia == WITHOUT unusual facial/hand features
• Zellweger syndrome (peroxisomal disorder) == hypotonic, poorly responsive
• Family resemblance (nml)

Question 14

diagnostic testing for child with Trisomy 21

Answer 14

==> lymphocytic karyotype (peripheral blood lymphocytes)

Question 15

why are these studies not used in diagnosis of down syndrome?

• uncultured cells - Buccal smear for fluorescence in-situ hybridization using a chromosome 21 probe
• cytogenetic studies on skin fibroblasts
• Echocardiogram

Answer 15

• FISH of uncultured cells ==> not gold standard
• cytogenetic studies on skin fibroblasts ==> harder than peripheral lymphocyte study
• Echo == 50% of kids with Down syndrome will have normal cardiac anatomy, and even if have cardiac malformation - may not be Down syndrome

Question 16

follow-up evaluation for children with down syndrome

Answer 16

==> within first 10 years of life

1) CBC in first month == d/t leukomoid rxns, transient myoloproliferative d/o
2) H&H yearly (starting at 1yo) == for Fe-deficiency anemia (d/t lower dietary iron intake than peers)
3) annual thyroid screening == d/t risk of hypothyroidism
4) yearly MSK screening == for atlantoaxial instability (for concerns of spinal cord impingement)
5) for any anaesthetic, surgical, radiographic procedure == importance of cervical-spine-positioning precautions for protection of cervical spine

• vision screening
• hearing screening
• referral to pediatric cardiologist == 50% risk of cardiac defect

Question 17

In most pediatric clinical situations, how many generations should a family history cover? (Select the ONE best answer.)

Multiple Choice Answer:
A 2 generations: child, siblings, parents
B 3 generations: child, siblings, parents, aunts, uncles, cousins of child, grandparents
C 4 generations: answer B plus great-grandparents

Answer 17

B

One of the benefits of a three-generation pedigree is that it helps exclude consanguinity at the first-cousin level.

Question 18

Which of the following statements is true? (Select the ONE best answer.)

Multiple Choice Answer:
A Consanguinity among parents is a greater risk factor for Down syndrome than maternal age.
B Most babies with Down syndrome are born to mothers who are younger than 35 years of age.
C The maternal age effect is lower in multiparous women.
D Paternal age is as important as maternal age as a risk factor for Down syndrome.

Answer 18

B

many more pregnancies in younger women

consanguinity, nulliparity, and advanced is NOT a RF for down syndrome

Question 19

Which of the following evaluations will infants and children with Down syndrome need during the first 10 years of life? Select all that apply.
 Multiple Choice Answer:
A		Repeat thyroid testing	
B		Vision screening	
C		Hearing screening	
D		Head MRI	
E		Pediatric gastroenterology referral	
F		Pediatric immunology referral	
G		Complete blood count in first month	
H		Pediatric cardiology referral	
I		Examine for myelopathic signs and syptoms	
J		Annual hemoglobin and hematocrit	
K		Early intervention

Answer 19

A
B
C

G
H

J
K

no need for immunology or myelpathic signs/sxs - they are at right for leukomoid rxns and transient myelopathic disease, but nothing clinically significant.

Question 20

What types of prenatal diagnostic testing are available for Down syndrome? Select all that apply.
Multiple Choice Answer:
A Amniocentesis and chromosome analysis of amniotic fluid cells
B Chorionic villus sampling (CVS) and chromosome analysis of CVS tissue
C Maternal serum screening
D Ultrasound exam of the fetus

Answer 20

A, B

the rest are not diagnostic, only suggestive.

Question 21

Which of the following sex chromosome abnormalities is most likely associated with physical differences at birth? (Select the ONE best answer.)

 Multiple Choice Answer:
A		Klinefelter syndrome (47, XXY)	
B		Triple X (47, XXX)	
C		Turner syndrome (45, X)	
D		47, XYY

Answer 21

C

no GENETIC syndromes named XXX (more developmental delay) or XYY (taller)

Question 22

A 4-year-old male with a history of Down syndrome and no other medical problems is brought to his pediatrician’s office by his mother for increasing fatigue, intermittent fever, and decreased appetite for one week. On exam you note conjunctival pallor and hepatosplenomegaly. What is the best next step in the management of this patient?

Single Choice Answer:
Please select one answer.
A Advise the mother to use acetaminophen as needed for fever and discharge home with strict return precautions.
B Send CBC and peripheral smear
C Send patient for chest x-ray
D Send TSH
E Start the patient on a 7-day course of amoxicillin and send home with strict return precautions.

Answer 22

B

problems with anemia, low Hgb

fatigue, decreased appetite, anemia, and HSM are all clinical signs and symptoms that may be associated with acute leukemia, for which patients with Down syndrome are at increased risk. A CBC would be helpful both for assessing the white blood cell count as well as the degree of anemia. A peripheral smear would be indicated to further evaluate for leukemia.

Question 23

You are called to the delivery of an infant boy experiencing fetal distress. After a vaginal delivery with vacuum assist, the infant cries spontaneously but remains acrocyanotic, despite supplemental oxygen delivered by mask. The neonate is hypotonic and moves his extremities only in response to noxious stimuli. Physical exam reveals an open mouth with a protruding tongue, upslanting palpebral fissures, low-set ears, and a transverse crease across both palms. You immediately recognize this syndrome, and your attending asks you what is the most common cardiac defect in these patients?

 Single Choice Answer:
Please select one answer.  
A		Aortic insufficiency	
B		Coarctation of the aorta	
C		Endocardial cushion defects	
D		Patent ductus arteriosus	
E		Conduction pathway defects

Answer 23

C

acrocyanotic
hypotonic
protruding tongue, upslanting palpebral fissues, low-set ears, transverse crease

This patient has physical signs of Down syndrome. Approximately 50% of children with Down syndrome are born with endocardial cushion defects, such as ventricular septal defect, atrial septal defect, or complete atrioventricular canal defect.

Question 24

You are on the nursery service when your team is called to evaluate a 1-day-old infant. The infant was born via NSVD at 40 weeks’ gestation to a 38-year-old G1P1A0 mother who did not have access to prenatal care and did not receive prenatal testing. The infant weighed 7 lbs 12 oz at birth and had Apgar scores of 7 and 8. On exam the infant is sleeping comfortably. She is afebrile with normal vital signs but appears to have low tone on exam. You also notice her ears seem to be lower than her eyes and appreciate mild edema of the hands and feet. Additionally, you note a fluid-filled sac at the base of the neck that does not appear to interfere with breathing. A karyotype performed after birth reveals a chromosomal abnormality. Which of the following is the most likely cause of this patient’s condition?

 Single Choice Answer:
Please select one answer.  
A		Down syndrome	
B		Turner syndrome	
C		Fetal alcohol syndrome	
D		Benign neonatal hypotonia	
E		Cystic hygroma

Answer 24

B

hypotonia, low-set ears, mild edema of hands and feet
lymphedema in the neck

Turner syndrome is defined by the karyotype 45 XO. Characteristics of females with Turner syndrome include renal abnormalities, lymphedema (causing edema of hands and feet), low-set ears, congenital heart defects, dental abnormalities—such as narrow or high-arched palates—and cystic hygromas. Other possible physical findings include a webbed neck, widely-spaced nipples, and shield-like chest. As this mother did not have prenatal testing or a karyotype performed previous to her daughter’s birth, one should be performed to confirm the diagnosis.

Question 25

A 39-year-old G2P1 woman with a pre-pubertal 10-year-old boy with intellectual disability comes to the clinic for information on prenatal screening. The 10-year-old boy was born with large ears and long face but no other congenital malformations. The mother is worried that she will have a second child with similar problems. If she were to have a second male child with developmental impairment, what would be the most likely reason if maternal serum testing and fetal ultrasound were both normal?

 Single Choice Answer:
Please select one answer.  
A		Down syndrome	
B		Trisomy 13	
C		Fragile X syndrome	
D		Turner syndrome	
E		Klinefelter syndrome

Answer 25

C

large ears, long face

Fragile X

Fragile X syndrome is the most common familiar cause of developmental impairment and is due to an abnormal number of trinucleotide repeats. These children present with large ears, long face and mandible and, after puberty, large testicles.

Question 26

`A 4-day-old male infant was born by vaginal delivery to a 35-year-old G1P1 who declined prenatal screening. The infant has mild hypotonia, epicanthal folds, upslanting palpebral fissures and a flat face. On physical exam, he is in no acute distress, has normal oxygen saturation and has a continuous murmur. Lymphocyte karyotyping showed a particular change in chromosome number. What genetic abnormality is most likely?

 Single Choice Answer:
Please select one answer.  
A		Trisomy 18	
B		45 X0 karyotype	
C		Trisomy 13	
D		Trisomy 21	
E		47 XXY karyotype

Answer 26

D

down syndrome

trisomy 21

A = edwards
B= Turner's
C = Patau's
E = Klinefelter