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Case 29
Author: William G. Wilson, M.D., University of Virginia Children's Medical Center

Learning Objectives
1. Recognize the common physical findings in Down syndrome.
2. Understand the epidemiology of Down syndrome.
3. Identify the common complications of Down syndrome.
4. Identify the laboratory tests used to confirm the diagnosis of Down
5. Recognize appropriate "anticipatory guidance" in the management of
children with Down syndrome.

Summary of clinical scenario: A mother brings her 4-day-old son to clinic for a
weight check. The nurse notes concern regarding Daniels poor tone. Physical
exam findings include: Flattened mid-face and epicanthal folds, incurving of fifth
fingers, and mild diastasis rectiall hallmark features of Down syndrome.
Lymphocyte karyotyping demonstrates trisomy 21. Screening of hearing and
vision, echocardiogram, thyroid studies, and atlantoaxial instability assessment
are set up to assess for possible complications of Down syndrome.

Sleeps a lot
Key Findings from History Feeds well when awake
Normal birth weight
No prenatal testing

Reflexes present
Flattened mid-face and epicanthal
Key Findings from Physical
Incurving of fifth fingers
Normal cardiac exam

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Mild diastasis recti

Perinatal asphyxia
Metabolic abnormalities
Effects of maternal medications
Differential Diagnosis Chromosome abnormalities
Benign neonatal hypotonia
CNS abnormalities

Lymphocyte karyotype
Key Findings from Testing
demonstrates trisomy 21

Final Diagnosis Down syndrome

Case highlights: Students think through the differential for hypotonia in a

newborn. History and physical soon reveal that Daniel has characteristics
associated with Down syndrome. The case discusses the implications of a
diagnosis of chromosomal abnormality, congenital malformation, or other genetic
disorder, and identifies prenatal diagnostic techniques for predicting them. The
case also teaches about taking a family history, developing a pedigree, and the
concept of mosaicism. Multimedia features include: Image of a family pedigree for
a boy with hemophilia, photo of an infant with Down syndrome, photo of a girl
with Turners syndrome.

Key Teaching Points

Syndromes with mental retardation

Down syndrome

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
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 U.S.
Clinical features may include mental retardation, epicanthic folds and flat

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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.

Risk factors

Maternal age > 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

Trisomy 13 (Patau syndrome)

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.

Trisomy 18 (Edwards syndrome)

Incidence: 1/6,000 births

Clinical features may include severe mental retardation, prominent occiput,
micrognathia, low-set ears, short neck, overlapping fingers, heart defects,
renal malformations, limited hip abduction, rocker-bottom feet

Fragile X syndrome

Fragile X syndrome is the most common familial cause of mental

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

Syndromes involving sex chromosomes:

Turner syndrome (45XO):

Incidence: 1/2000 female live births (but about 99% 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), hyperconvex nails, "shield" chest, widely spaced nipples
Coarctation of the aorta found in about 20% of affected girls
Short stature
Gonadal dysgenesis

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Klinefelter syndrome (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 habitus and gynecomastia in adolescence.


Family pedigree

Detail needed in a family history varies with clinical situation.

Generally, a three-generation family history is obtained and recorded as
part of a complete evaluation; may be expanded if situation warrants.
Three-generation pedigree helps exclude consanguinity at the first-cousin
Ask questions about consanguinity with sensitivity, because it is
relatively common in some cultures.

Physical exam: The following features may be seen in an infant with trisomy 21,
but 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 variation:

Upslanting palpebral fissures

Epicanthal folds
Small ears (usually less than 34 mm at maximum dimension in a term
Flattened midface
Redundant nuchal skin
Single palmar crease
Incurving of fifth finger
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.

Differential diagnosis
More likely diagnoses

1. Benign neonatal hypotonia (congenital hypotonia): Diagnosis of

exclusion after extensive evaluation for other causes of hypotonia. By

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definition, the prognosis is good, and muscle tone and strength gradually

2. Down syndrome:
Hypotonia is most consistent finding
Diagnosis: Genetic testing
3. Zellweger syndrome:
Peroxisomal disorder
Causes significant hypotonia

Less likely diagnoses:

Perinatal asphyxia
Metabolic abnormality
Effect of maternal medications
Other chromosomal abnormality
Central nervous system abnormality

Lymphocyte karyotype:

The karyotype is standard for the laboratory diagnosis of Down syndrome.

In this study, the chromosomes of a small number of cellsusually all from
the same cell typeare analyzed.
Even in patients with multiple malformations that do not fit a recognizable
chromosomal syndrome there may be justification for doing chromosome
Some abnormalities may not be obvious on a routine cytogenetic study
(e.g., 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.

Indications for chromosome studies in an infant

1. Clinical features of a known chromosome disorder (such as Down syndrome)

2. Unrecognized malformation syndrome
3. Known genetic condition but with additional or more severe findings
4. Mental retardation and other unusual findings (including short stature)
5. Stillborn with multiple malformations
6. Features of a chromosome breakage syndrome (this type of study may
require special techniques)
7. Tumor (including leukemia) that may be associated with chromosome
abnormalities (can study a specific tissue)

Note: In addition to these, there are other indications for cytogenetic study that

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apply to adults (e.g., multiple pregnancy losses, family history of a chromosome

rearrangement, etc.).

Prenatal screening

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
Measurement of any of the following analytes in maternal serum offers an
indirect screening method; however, these tests are not specific for Down
Human chorionic gonadotropin
Pregnancy-associated plasma protein A (PAPP-A)
Ultrasound: Can look at nuchal skin thickness, nasal bone ossification, and
other growth parameters to help identify infants at risk.
Ultrasound in combination with maternal age and analyte measurement may
better refine risk of fetus being affected with Down syndrome or another
common chromosome abnormality.

Down syndrome:

Recommended screenings and evaluation:

Hearing and vision screenings

Pediatric cardiology referral and echocardiogram (40% incidence of
structural heart disease in patients with Down syndrome)
Repeat thyroid studies (at six months, and annually thereafter)
Incidence of both congenital hypothyroidism and hypothyroidism that
develops later in childhood is increased in infants with Down
Evaluation for atlantoaxial instability (X-rays), especially at school age
Consider the predisposition for leukemia

Delivering difficult news:

Inform the family of pertinent information, but avoid information overload.

Give families time to process the diagnosis and its implications.

Other considerations:

Additional information that should be addressed in discussing a diagnosis of

Down syndrome with the family:
Cause of Down syndrome

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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.
As child grows, encourage parental involvement in school setting and to act
as advocates for their child.

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