down syndrome update 2007 tamison jewett, md
TRANSCRIPT
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DOWN SYNDROME UPDATE2007
Tamison Jewett, MDWake Forest University Health Sciences
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Down syndrome
occurs in ~1:650 live births The underlying causes:
– 94% due to nondisjunction (unequal cell division) resulting in 47 chromosomes
– 3.3% due to an unbalanced translocation– ~2.4% are mosaic (46/47)– <1% have a duplication of the Down syndrome
“critical region”
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Down syndrome--History
First described by Dr. John Langdon Down in England in 1866
In 1956, scientists discovered that the typical human cell has 46 chromosomes
In 1958, Lejeune discovered that the cells from an individual with DS had an extra chromosome 21
In 1959, 9 people with DS were found to have an extra chromosome 21
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Abnormal cell division leading to abnormal chromosome distribution can occur in EITHER PARENT. As women age, our risk for this to occur increases, as follows:
Maternal Age Incidence of DS at delivery 15-29 1 in 1500 30-34 1 in 800 35-39 1 in 270 40-44 1 in 100 45 and over 1 in 50
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Ideogram of the human chromosomes
p-arm
q-arm<= centromere
autosomes
Sex chromosomes
NOR, ==>acrocentic
<= Xp21
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Syndrome
a recognizable pattern of features, usually owing to a specific cause., e.g., Down syndrome, wherein the cause is extra
chromosome 21 material
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Down syndrome--features
Brachycephaly Excess nuchal skin Hypoplastic midface Upslanting palpebral fissures Small ears w/ overfolded helices 5th finger clinodactyly Wide gap between 1st and 2nd toes Single transverse palmar crease(s)(40%) Heart defect in 40% Fine, soft hair
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It is important to remember that individuals with DS look mainly like their families; it is the
characteristic pattern of features that causes them to resemble one another.
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Robertsonian Translocations
Can result in Down syndrome
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Ideogram of the human chromosomes
p-arm
q-arm<= centromere
autosomes
Sex chromosomes
NOR, ==>acrocentic
<= Xp21
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Current dilemmas in clinical care for persons with DS
Celiac disease
Thyroid disorders
Atlantoaxial instability
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Celiac disease (CD)
Autoimmune disorder caused when the body reacts to gluten, the protein in barley, wheat, and rye
Damage occurs to the absorbing surface of the small intestine
Ongoing damage results in reduced absorption of nutrients and in diarrhea/constipation, bloating, and poor growth
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Celiac disease
Can show itself after only 6 months of exposure to gluten
May not appear until late childhood or adulthood
May not be associated with “classic” symptoms above
Can be screened for with blood tests
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Recommended blood tests to screen for celiac disease
Serum IgA
Serum IgA tissue transglutaminase (tTG)
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Celiac disease
Diagnosis is confirmed by intestinal biopsy
Treatment is the removal of gluten from the diet
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Celiac disease prevalence
1:133 individuals in the general population
Is higher in individuals with type 1 diabetes (childhood onset), some immune disorders, and Turner, Williams, and Down syndromes
Is reported to occur in 5-17% of individuals with DS
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Celiac disease
Can be difficult to diagnose in the general population due variability of symptoms
In individuals with DS, symptoms may be attributed to DS rather than to CD; these include
– Growth failure– Recurrent abdominal pain– Constipation– Irritability– Behavior changes
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Celiac disease
In one study of DS individuals with CD,– 69% had classical symptoms (diarrhea, failure to
thrive)– 11% had atypical symptoms (such as behavior
changes, irritability)– 20% had “silent” disease (minimal, if any,
nonspecific symptoms) There does not appear to be any negative effect from
this on people with DS
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Celiac disease
People with type 1 diabetes and with autoimmune thyroid disease are at increased risk for CD
People with DS are at increased risk for type 1 diabetes and for autoimmune thyroid disease = further evidence for increased risk for CD in Down syndrome
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Unresolved issues regarding celiac disease for individuals with DS
When to screen?– Some say 2 years old; some say 3; there is no consensus
Is there a need to re-screen?– It is documented that some individuals who are initially
screen-negative will later become positive and have CD– No re-screening protocol is agreed upon at this time– Any person who develops symptoms of CD after having
been negative should be considered for re-screening
What is the prevalence of CD in adults with DS?– We don’t know
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Thyroid disorders in DS
Occur in 15% of individuals with DS (there is a 3-54% prevalence among studies)
Symptoms of hypothyroidism (increase in weight with reduced height velocity, dry skin, constipation) overlap with features of DS
While decreased thyroid function is most common, increased function is also described in DS
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Thyroid disorders: detection
Newborn screening– Congenital hypothyroidism occurs more commonly in DS
Blood testing after the newborn period (one month onward)
– Thyroxine (T4) and thyroid stimulating hormone (TSH) levels should be performed at 6 months, 1 year, and every year thereafter
– Autoimmune thyroiditis is detected by measuring thyroid antibodies in addition to the above
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Thyroid disorders: treatment
When T4 is low and TSH is high and antithyroid antibodies are normal, this is primary hypothyroidism
When T4 is low and TSH is high, and antithyroid antibodies are present, this is secondary hypothyroidism
Hypothyroidism is treated with thyroid hormone replacement = thyroxine
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Thyroid disorders: treatment
When T4 is high, there is hyperthyroidism
Symptoms of hyperthyroidism include rapid heart rate, weight loss or poor weight gain, and irritability
Management usually involves treatment with anti-thyroid drugs later followed by thyroid ablation with radioactive iodine followed by thyroid hormone replacement
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Thyroid disorders: concerns
Studies show that many physicians do not screen their patients as recommended
Further studies should be done to determine whether individuals with DS are being treated adequately once thyroid dysfunction is discovered
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Thyroid disorders
For the present, current screening recommendations should continue
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Atlanto-axial instability (AAI)
Is defined as a measurement of greater than 5mm and up to 7mm between the posterior portion of the first cervical vertebra (C1) and the anterior portion of the second cervical vertebra (C2) as measured by xrays of the neck in flexion, neutral, and extension
Measurements of more than 7mm are markedly abnormal, and MRI is warranted
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Atlantoaxial instability (AAI)
15% of individuals with DS who are less than 21 yo have laxity of the atlantoaxial joint measurement of 5-7mm)
– Most are asymptomatic
– 10% (~2% of all with DS in this age group) develop spinal cord compression
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Atlantoaxial instability
Xray screening for AAI was initially recommended in 1983 for athletes wishing to participate in Special Olympics
Later, this recommendation was adopted for a number of health supervision protocols for persons with DS
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Atlantoaxial instability
There is debate about whether screening is necessary for all DS individuals because– Measurements are sometimes inaccurate– Persons with AAI are not necessarily at risk
for spinal cord injury– Abnormal measurements may actually return to
normal in future– People with normal measurements early on may
have abnormal measurements later– Most people with spinal cord injuries do not
sustain them during athletic activity
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Atlantoaxial instability
The Down Syndome Medical Interest Group (DSMIG) of the UK no longer recommends routine screening
– Doctors are reminded to be aware of signs/symptoms of spinal cord compression (neck pain, head tilt, change in gait, change in bowel/bladder function, etc.) and to act accordingly
The DSMIG of the US continues to recommend routine screening at 3-5 yrs. of age
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Atlantoaxial instability: recommendations for future
Physicians caring for individuals with DS must remain alert to signs/symptoms of spinal cord compression despite a history of normal screening neck xrays
Be aware that the risk for neck injury is greater during surgical neck manipulation (for anesthesia) than for athletic participation BUT IS STILL LOW
Current recommendation should be continued for now (until more data available), with the addition of neural canal width measurements on xrays taken
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Atlantoaxial instability: future directions
A multidisciplinary group of neurologists, neurosurgeons, radiologists, etc. should perform a large study to determine if there is a more sensitive method to screen for AAI in people with DS
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Prenatal Screening for Down Syndrome
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What’s all the talk about?
This month (January ’07), the American College of Obstetrics and Gynecology (ACOG) has issued new practice guidelines for the screening of pregnancies for DS and other aneuploidies (extra chromosome conditions).
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Historically…
Maternal age of >35 at the time of delivery has been used to identify women at greatest risk for having a child with DS and other aneuploidies– This is the age at which a woman’s risk to have a
child with DS equals her risk to have complication(s) from amniocentesis
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Historically…
In the ’80’s and ’90’s, biochemical markers (AFP, hCG, and uE3) were identified that could be measured in a pregnant woman’s blood, which increased our ability to detect fetuses at increased risk for DS– Still, 30% of affected babies were missed
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Historically…
In the mid-90’s, researchers found an association between the size of a fluid collection at the back of the fetal neck in the first trimester detected on ultrasound called “nuchal translucency” (NT) and the risk for DS as well as a number of other conditions
Guidelines for the measurement of NT have since been established
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Then…
We learned that the NT measurement combined with measures of maternal serum free-beta hCG and pregnancy-associated protein A (PAPP-A) in the first trimester can increase the detection rate of DS, and when used in conjunction with second trimester screening, can increase detection to ~95%*.
* this assumes a 5% false positive rate
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So, what’s the new recommendation?
Screening and subsequent diagnostic testing (such as amniocentesis), if indicated, should be available to all women who present for prenatal care before 20 weeks’ gestation regardless of maternal age.
Women should be counseled regarding their options as well as the differences between screening and diagnostic testing.
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Brothers and Sisters of Persons with Down Syndrome
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Brothers and sisters…
Current research supports that brothers and sisters of children with DS are more likely to be positively impacted by their DS sibling than adversely so.
Sibs of DS children tend to show more kindness and compassion.
Parents of DS siblings report more warmth and less conflict among their children than parents in control families.
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Brothers and sisters of children with DS…
Are not more prone to behavioral problems than other children, as was previously thought
Assume more caregiving activities than other children– Brothers assume as much responsibility as sisters
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Brothers-and-Sisters Workshops
The National Down Syndrome Society’s national conference and the National Down Syndrome Congress meetings as well as other settings have provided researchers with information about how DS siblings are faring.
More than 3, 380 DS brothers and sisters have participated.
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Common questions from DS brothers and sisters
Medical– How long will he/she live?– Why are some people with DS short?– Why does my brother/sister have DS/– How do they get the extra chromosome?– Why does his/her face look different?– Why can’t he/she walk very well?– Are all kids with DS strong?
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Common questions (cont.)
Social– Can people with DS have normal jobs?– How are people with DS different from people
who don’t have it?– Will he/she be different?– Will he/she be ugly?– My brother/sister knows that he/she has DS and
is different; does yours?
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Common questions (cont.)
Education– Does my sibling have to go to a special school?– Can people with DS graduate from college?– Does it take them longer to learn things?– Why did he/she do preschool twice?– How do they think?
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Common questions (cont.)
History– Why is it called DS?– Who was the first person in history to have DS?– Why did people in the old days call kids with DS
“M----”?
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What has been learned?
When a sibling questions their parent(s) about DS, he/she has been thinking about the issue well beforehand.
A running dialogue about DS is helpful. Parents should consider periodically asking siblings
if they have questions about DS. Researching questions together can be an enabling
discovery process. Allow siblings to express their negative feelings; they
are typically temporary.
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What has been learned?
Recognize the siblings’ difficult moments, e.g., someone picking on their DS sibling or asking them why their brother/sister looks different.
Limit caregiving responsibilities – although most siblings enjoy these to some
extent, they should not be “counted on” to be the caregiver and need their own space
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Parents should strive to…
Recognize the individuality and uniqueness of each child in the family
Be fair Take advantage of support opportunities for
siblings– Many comment on the benefits of meeting other
siblings of DS children
Seek support opportunities for themselves
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Conclusions
Persons with DS add an appreciated dimension to their families and deepen their siblings’ (and parents’) understanding of humanity.
Siblings of children with DS often have a deeper respect for diversity.
Siblings typically recognize that happiness is not defined by material possessions, accolades, or fame.
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My conclusion…
Everyone could benefit from having a child with Down syndrome in their family!
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