Case 29

Question 1

What are key findings from history in a 4 day old child with down syndrome?

Answer 1

Hypotonia, sleeps a lot, feeds well when awake, normal birth weight, no prenatal testing

Question 2

What are key findings from PE in a 4 day old child with down syndrome?

Answer 2

Reflexes present, flattened mid-face and epicanthal folds, incurving of fifth fingers, normal cardiac exam, mild diastasic recti. (separation of abdominal muscles)

Question 3

What is on the differential diagnosis for down syndrome?

Answer 3

Perinatal asphyxia, metabolic abnormalities, effects of maternal medications, chromosome abnormalities, benign neonatal hypotonia, Sepsis, CNS abnormalities.

Question 4

What are findings from lab testing for Down Syndrome?

Answer 4

Lymphocyte karyotype demonstrates Trisomy 21

Question 5

Syndromes with mental retardation:

Answer 5

• Down Syndrome
• Trisomy 13 (Patau syndrome)
• Trisomy 18 (Edwards syndrome)
• Fragile X syndrome

Question 6

What are syndromes involving sex chromosomes?

Answer 6

Turner syndrome (45XO), Klinefelter syndrome (47XXY)

Question 7

Down syndrome:

Answer 7

• Trisomy 21 is probably the most common cause of mental retardation that involves genetic material
• Several karyotypes involving extra material from chromosome 21 can cause Down syndrome phenotype:
• -Trisomy 21 is most common and most likely, regardless of mother’s age
• -Unbalanced chromosome translocations that result in extra chromosome 21 material
• -Mosaicism for a trisomy 21 cell line
• Syndrome is present in about 1 in 700 births in the US
• Clinical features may include mental retardation, epicanthic folds and flat facial profile, single palmar crease, redundant neck skin, heart defects, intestinal stenosis, umbilical hernia, predisposition to leukemia, hypothyroidism, hypotonia, short stature, and a gap between the first and second toes.

Question 8

What are risk factors for down syndrome?

Answer 8

• Maternal age greater than 35 years at delivery is a significant risk factor for having a child with down syndrome, although majority of down syndrome pregnancies occur to women under age 35
• No strong paternal age effect
• Consanguinity is not a risk factor

Question 9

Trisomy 13 (Patau syndrome):

Answer 9

• Incidence: 1/10,000 births
• Clinical features include microphthalmia, microcephaly, and severe mental retardation, polydactyly, cleft lip and palate, cardiac and renal defects, umbilical hernia, and cutis aplasia.

Question 10

Trisomy 18 (Edwards syndrome):

Answer 10

• Incidence: 1/6,000 births
• Clinical features may include severe mental retardation, prominent occiput, micrognathia, low-set ears, short neck, overlapping fingers, heart defects, real malforatmions, limited hip abduction, rocker-bottom feet.

Question 11

Fragile X syndrome:

Answer 11

• Fragile X syndrome is the most common familial cause of mental retardation
• Caused by the inheritance of an abnormal number of trinucleotide (CGG) repeats outside the coding region of the FMR1 gene on the X chromosome
• Clinical features may include large testicles (after puberty); large, everted ears; long face with large mandible

Question 12

Turner Syndrome:

Answer 12

(45XO)

• Incidence: 1/2000 female live births (but about 99 percent of conceptuses with Turner syndrome miscarry)
• Normal IQ
• More likely to be associated with physical differences at birth
• Associated findings: Lymphedema in utero (cause of many physical findings, including webbed neck, low placement of ears, edema of the hands and feet), hyper convex nails, “shield” chest, widely spaced nipples
• Coarctation of the aorta found in about 20 percent of affected girls
• Short stature
• Gonadal dysgenesis

Question 13

Klinefelter syndrome:

Answer 13

(47XXY)

• Boys with Klinefelter syndrome are usually normal at birth
• IQ varies, but is usually in the low-normal range
• Findings vary but usually include infertility due to testicular atrophy
• May be a eunuchoid body habits and gynecomastia in adolescence.

Question 14

Features seen in an infant with trisomy 21:

Answer 14

Remember that almost all of these findings may be seen individually in people who do not have Down syndrome; it is the combination of findings that separates a syndrome from a normal variationL
-Upslanting palpebral fissures
-Epicanthal folds
-Small ears (usually less than 34 mm at maximum dimension in a term infant)
-Flattened midface
-Redundant nuchal skin
-Single palmar crease
-Incurving of fifth finger
-Hypotonia
-Diastasis recti (a ridgelike separation between the left and right side of the rectus abdominis muscle)
-Cleft lip or palate may be seen at a rate higher than that of the general population, but still is not common
As child grows, since short stature is very common finding, important to use growth chart specific for children with Down Syndrome.

Question 15

What are more likely differential diagnosis for Down Syndrome?

Answer 15

Benign neonatal hypotonia (congenital hypotonia), Down Syndrome, Zellweger syndrome

Question 16

What are less likely differential diagnosis for down syndrome?

Answer 16

Perinatal asphyxia, Metabolic abnormality, effect of maternal medications, other chromosomal abnormality, sepsis, CNS abnormality

Question 17

Benign neonatal hypotonia (congenital hypotonia):

Answer 17

Diagnosis of exclusion after extensive evaluation for other causes of hypotonia. By definition, the prognosis is good, and muscle tone and strength gradually improve.

Question 18

Down Syndrome:

Answer 18

• Hypotonia is most consistent finding

- Diagnosis: Genetic testing

Question 19

Zellweger syndrome:

Answer 19

• Peroxisomal disorder

- Causes significant hypotonia

Question 20

Lymphocyte karyotype:

Answer 20

• The karyotype is standard for the laboratory diagnosis of Down syndrome. In this study, the chromosomes of a small number of cells - usually all from the same cell type - are analyzed.
• Even in patients with multiple malformations that do not fit a recognizable chromosomal syndrome there may be justification for doing chromosome studies
• Some abnormalities may not be obvious on a routine cytogenetic study (eg, submicroscopic deletions) and may require specific fluorescence in-situ hybridization (FISH) probes for detection.
• Another, newer test for detecting submicroscopic chromosome deletions or duplications is array comparative genomic hybridization.

Question 21

Prenatal screening for down syndrome:

Answer 21

• Chromosome analysis of chorionic villus sampling (CVS) or amniotic fluid cells are most direct methods
• -Both methods have risk of complications, particularly of causing a miscarriage.
• Measurement of any of the following analyses in maternal serum offers an indirect screening method; however, these tests are not specific for Down Syndrome:
• -Alphafetoprotein
• -Human chorionic gonadotropin
• -Estriol
• -Pregnancy-associated plasma protein A (PAPP-A)
• -Inhibin
• US: Can look at nuchal skin thickness, nasal bone ossification, and other growth parameters to help identify infants at risk.
• US in combination with maternal age and analyze measurement may better refine risk of fetus being affected with Down Syndrome or another common chromosome abnormality

Question 22

Recommended screenings and evaluation for Down Syndrome:

Answer 22

• Hearing and vision screenings
• Pediatric cardiology referral and echocardiogram (40 percent incidence of structural heart disease in patients with Down Syndrome)
• Repeat thyroid studies (at 6 mo, and annually thereafter)
• -Incidence of both congenital and standard hypothyroidism that develops later in childhood is increased in infants with Down Syndrome
• Evaluation for atlantoaxial instability (X-rays), especially at school age
• Consider the predisposition for leukemia

Question 23

Additional information that should be addressed in discussing a diagnosis of Down syndrome with the family:

Answer 23

• Cause of Down Syndrome
• Relationship between chromosome abnormality and clinical findings
• Common complications
• Screening tests
• Anticipatory guidance and typical clinical course
• Information such as risk of recurrence and genetic implications for other relatives may be more appropriate for a geneticist to discuss with the family.