Case60 Down Syndrome

Case Study 60: Down Syndrome 1

Eina Jane & Co. 2009.

I. Definition A. Trisomy 21: chromosome disorder

1. Low IQ, dysmorphic facial features, delays in physical developmental, broad array of multisystem anomalies caused by overexpression of specific genes from chromosome 21

2. Condition varies from mild to severe B. Named after 19th century physician John Langdon Down in 1866

1. Not 1st person to report it; recognized 20yrs earlier by French Dr. E. Seguin

2. Down described condition as “mongolism” – demeaning; wrongly believed evolution was reversed from superior Caucasian to an inferior Asian race

II. Prevalence A. Most common genetic cause of severe learning disabilities in children B. 1 in every 600‐800 live births in US C. Male to Female ratio 1.15:1.0

III. Significance A. Most common chromosomal abnormality that affects autosomes

(chromosomes that are NOT sex chromosomes = chromosomes 1‐22) 1. Represents the single most common cause of birth defects 2. Major cause of mental retardation

a. Accounts for 1/3 of moderate – severe mental handicaps in school children

b. Adults with DS can NOT lead totally independent lives due to low IQ (28 – 85, mean value ~50)

B. Significant embryonic, fetal, and neonatal mortality rates 1. ¾ embryo and fetuses with trisomy 21 die in utero 2. ¼ liveborn infants die during first years of life 3. Most frequent causes of death during neonatal period are respiratory

infections and congenital heart disease – birth defects of heart 4. Early mortality, respectively

a. Esophageal and duodenal atresias characterized by narrowing and obstruction of esophagus and duodenum

b. Leukemia C. Increased morbidity due to infections from deficient immune response

1. Irreversible spinal cord damage – serious complication of disease 2. Upper airway obstruction may eventually cause heart failure 3. Children delays in

a. Physical growth, maturation, bone development, dental eruption b. Visual and hearing impairments limit child’s ability to function and

learn language and interpersonal skills IV. Causes and Risk Factors

A. 3 established cytogenic variants that cause DS 1. Trisomy 21: most common cause – 94%



2. Mosaicism: some cells contain normal complement of 46 chromosomes and others contain 47 chromosomes with trisomy 21 – 3%

3. Translocation: simultaneous fragmentations in 2 chromosomes from different pairs with exchange of chromosomal material – 3%

B. Advanced maternal age = only well‐established risk factor for DS 1. Frequency of DS increases with advancing maternal age, especially >35yo 2. Majority of children with DS (80%) born to women younger than 35yo

because most pregnancies occur in age group 3. 95% of trisomy 21 cases, the extra chromosome 21 originates maternally;

some studies have reported correlation with advanced paternal age V. Pathophysiology: 3 Cytogenic abnormalities

A. Trisomy 21 1. Results from pathophysiologic process known as non‐disjunction: faulty

cell division occurs and chromosomes fail to separate during oogenesis or spermatogenesis

2. Non‐disjunction results in germ cells with even number of chromosomes (22 or 24) a. Products of conception result from fusion of abnormal germ cell with

a normal one and an uneven number of chromosomes, either 45 of 47 b. Extra chromosome 21 is replicated with every cell division as the

embryo and fetus grows c. When non‐disjunction occurs during oogenesis, it occurs 3x more

frequently during the 1st gate of meiosis (i.e. meiosis I) than meiosis II 3. Not clearly known why advanced maternal age = non‐disjunction

a. May be the result of the age of maternal egg cells, which are held in an arrested state of prophase I from the time that they are formed in the female embryo until they are extruded from the ovaries during ovulation

b. Long suspended state may allow for disturbances exposures to toxic chemicals or radiation that lead to disjunction

c. May also result from paternal non‐disjunction d. Meiosis II errors predominate when non‐disjunction occurs during

spermatogenesis B. Translocation

1. Approximately 75% of translocations that cause DS are de novo aberrations that occur just before or after conception a. 25% are familial where the child inherits chromosomal translocation

from one of the parents only form of DS that can be passed from parent to child

2. Have normal chromosome number of 46 3. Portion of chromosome 21 fragments during cell division and becomes

incorporated into another chromosome (usually chromosome 14) a. Molecular analysis reveals 21q22.1‐q22.3 (region 22.1‐22.3 of the

long arm of chromosome 21) appears to contain gene(s) responsible for the anomalies observed in DS



b. Gene delineated as DSCR1, newly identified from this region, is highly expressed in the brain and heart pathogenesis of DS, mental retardation and congenital cardiac defects

4. Two hypotheses for pathophysiologic process to cause abnormalities of DS: loss of chromosomal balance and gene dosage effect a. Translocations reposition the DSCR1 gene that results in abnormal

expression and gene products b. Trisomy 21 results in triple dose of DSCR1 that results in

overexpression of gene and contribute to phenotypic abnormalities C. Mosaicism

1. Results when non‐disjunction of chromosome 21 takes place during cell division sometime after the initial cell division of the zygote has occurred a. Results in 2 populations of cells within embryo – some containing 46

and some containing 47 chromosomes, including 3 copies of chromosome 21

b. Clinical manifestations depend on proportion of normal and abnormal cells

2. Mosaics posses normal cell line of 46 chromosomes a. Physical abnormalities are not frequently severe b. IQ and childhood development are not as affected

D. Abnormal expression of a specific gene segment of chromosome 21 resulting in abnormal gene products can affect nearly every organ system and may result in a wide spectrum of phenotypic manifestations

VI. Diagnosis: Clinical Manifestations and Laboratory Tests A. Identified at birth or shortly thereafter B. Diagnosis based on physical characteristics with DS; mild to severe

1. Hypotonia (poor muscle tone) with decreased response to normal stimuli 2. Simian crease: single crease across the palm of the hand 3. Slightly flattened facial profile 4. Upward slanting of the eyes 5. Sloping forehead 6. Broad and flat nasal bridge 7. Epicanthal fold: eyes have rounded fold of skin rather than coming to a

point 8. Hypertelorism: interocular distance may be increased 9. Brushfield spots: unusual ring of tiny white spots around iris of eye 10. Microcephaly: head smaller than normal and abnormally shaped 11. Occiput (back of head) often flat rather than rounded 12. Mouth usually small and open; tongue is large (macroglossia) and

furrowed with a tendency to protrude 13. Ears typically small, low‐set on the head, malformed 14. Hands are broad, relatively short fingers (brachydactyly) and finger joints

are hyperextensible 15. Clinodactyly: 5th finger often curved inward 16. Space between first and second toes often increased bilaterally



17. Distance between nipples on chest is decreased relative to non DS newborns

18. Excess skin on back of neck at birth

19. C. DS infants may be of average size but typically grow slowly and remain

smaller than other children of similar age 1. Most never reach average adult height 2. Baby hair often fine and hypopigmented

D. Heart murmur from stethoscope often suggests congenital cardiac abnormality requires cxray, echocardiogram, electrocardiogram for further evidence of heart defect regardless of physical exam, echocardiography should be performed on all infants due to high incidence of heart disease associated with trisomy 21 (40%)

E. Massive vomiting may suggest duodenal obstruction gastrointestinal x‐ray often reveals precise location and severity of obstruction

F. Predisposed to hypothyroid disease serum thyroid‐stimulating hormone and thyroxine concentrations should be obtained at birth

G. Susceptible to serious bacterial infections quantify immunoglobulin G to identify a deficiency in antibody‐mediated immunity

H. Hearing tests are required; 2/3 have abnormal hearing I. Definitive diagnosis is only established by karyotyping (chromosome study)

1. Visual display of patient’s chromosomes organized by size, number, and distinct banding patterns

2. Majority will have simple trisomy 21 3. Newborns with translocation involving chromosome 21 may have

inherited cytogenetic pattern from a parent, in which case there is substantial recurrence risk for DS in subsequent offspring



J. Detecting DS for pregnant women: screening and diagnostic tests 1. Screening tests help to determine the probability that baby has DS

a. Most commonly used screening test: “triple screen” i. Combination of tests ii. Measure quantities of 3 substances in maternal blood: DS is

present if o α‐Fetoprotein and unconjugated estriol are low o Human chorionic gonadotropin is elevated

iii. Conducted between 15 – 20 wks of gestation iv. Highly accurate (98%) in detecting prenatally

o Can show physical traits o Helpful in calculating risk

b. Prenatal ultrasonography can detect approximately 7 in 10 cases of DS

2. Diagnostic tests determine whether or not the baby definitely has DS a. Chorionic villus sampling (CVS)

i. Cells taken from mother’s placenta used to analyze fetal chromosmes

ii. Between 10 – 13 wks gestation iii. Carries risk of miscarriage up to 1 in 100 iv. Accuracy greater than 95%

b. Amniocentesis i. Criterion standard of invasive diagnostic test for DS ii. Sample of amniotic fluid surrounding fetus is withdrawn with

needle inserted into mother’s uterus iii. Between 14 – 16 wks gestation iv. Risk of miscarriage 1 in 200 v. Accuracy 99.5%

c. Percutaneous umbilical blood sampling (PUBS) i. Blood taken from vein in umbilical cord and examined for

chromosomal defects after 20 wks of gestation ii. Approximately 95% successful in obtaining blood sample of

cytogenetic analysis iii. Pregnancy loss rate is 2.5%

VII. Appropriate Therapy A. No medical cure

1. Dramatic improvements in medical care and early intervention beginning with infancy greatly improved quality of life and increased life expectancy

2. Multidisciplinary care team approach required for best results B. Risk for multiple infections childhood immunizations are emphasized

1. Chronic cardiac disease, respiratory infections require pneumococcal and influenza vaccines

2. Prompt treatment of respiratory and middle ear infections are necessary to prevent complications



C. Timely surgeries 1. Cardiac malformations which frequently present during firs 6 months of

life 2. Repairs of GI anomalies: duodenal atresia 3. Removal of enlarged adenoids when patient demonstrates obstructive

sleep apnea 4. Surgery to stabilize spine for spinal cord compression 5. Congenital cataracts must be removed soon after birth to permit light to

reach retina 6. Appropriate correction glasses or contact lenses assure adequate vision

D. Early interventions for infants aged 0 – 3 years are designed to comprehensively monitor and enrich development 1. Focus on feeding, gross and fine motor development, development of

language, personal, and social skills 2. Social quotient may improve through early intervention 3. Positive developmental changes are possible: independence, ability to

function in community, quality of life E. Physical therapist may help infants to roll over, sit up, walk due to poor

muscle tone F. Speech pathologist or occupational therapist may help with feeding,

coordination, language skills G. Dental evaluation, hygiene, fluoride treatments, good dietary habits are

imperative to prevent dental caries and periodontal disease H. Drug therapy currently NOT a component of standard care for DS

1. Digitalis and diuretics may be used for heart failure secondary to congenital heart defect

2. Anticonvulsants are used for tonic‐clonic seizures 3. Antibiotic ointments or systemic antibiotic therapy for skin infections 4. Hypothyroidism: thyroid hormone therapy is required to prevent

intellectual deterioration and improve overall function, academic achievement and vocational abilities

5. Pharmacotherapy may also be necessary when patients present with a psychiatric disorder

I. Special diets are not typically required and restriction of activities is often unnecessary 1. Balanced diet and regular exercise to maintain appropriate weight 2. Those with arrhythmia, fainting spells, abnormal electrocardiograms,

palpitations or chest pain should refrain from sporting activities and strenuous exercise

J. Parents of DS child are at increased risk for having another child with the condition, genetic counseling is recommended 1. With trisomy 21, recurrence risk is 1% 2. De novo translocation, 2‐3% 3. Approximately 12% of progeny of translocation carrier of mothers and

3% translocation carrier fathers are born with DS



4. In rare case that a carrier parent has a 21q21q translocation, recurrence risk is 100%

VIII. Serious Complications and Prognosis A. Vision, hearing difficulties, increased susceptibility to infection, GI

obstruction, blocked airways during sleep, instability of bones at top of the neck that can ultimately result in compression of spinal cord

B. Have 3‐fold increase for developing acute lymphoblastic leukemia C. Develop progressive Alzheimer‐like dementia by age 40yrs, and 75%

ultimately manifest with Alzheimer disease D. Congenital heart disease is major cause of death and most important factor

that determines survival E. Overall outlook continues to improve

1. Adult patients are healthier, integrated into society better, increased longevity compared a decade ago

2. With proper medical care, pts with DS can lead healthy lives 3. 75yrs ago, most DS babies did not live to age 10yrs; today, average life

expectancy is 55yrs with many up to 60‐70s F. Affected individuals rarely reproduce

1. Up to 1/3 of females of DS are fertile 2. No evidence exists of an affected male fathering a child

G. Myths about DS 1. Children with DS should be placed in special education schools and adults

in institutions reality, most live with families, attend public schools, read/write, perform various jobs as adults, some attend college

2. Can live fulfilling independent or semi‐independent, even accomplished lives



Patient Case:

1. G3P2‐0‐2: 3 pregnancies, 2 term births, 0 abortions/miscarriages, 2 living children

2. Apgar score: 8 at 1 minute and 9 at 5 minutes after birth. Normal? Yes 3. Which of the following explanations below is accurate and appropriate?

C. These physical characteristics are highly suggestive so some type of chromosome abnormality

D. These phenotypic aberrations are pathognomonic (diagnostic) for Down syndrome)

4. Although many chromosome abnormalities occur due to abnormal cell division in the sperm or egg, they can also occasionally be inherited. The genetic basis for this baby’s anomalies can usually be determined by

A. Analyzing the chromosomes in the baby’s cells 5. The cause of this infant’s physical characteristics is most likely the result of

A. Non‐disjunction during meiosis I in the mother 6. The parents struggle to understand what happened to their baby. “w don’t

smoke, drink, or take drugs, so why did this happen?” the mother asks. Which of the following represents the most accurate explanation?

D. The risk for Down syndrome increases when the mother is older than age 35 and chromosomes in her eggs fail to separate properly during cell division

7. During the first 36 hours after birth, nurses in the neonatal unit carefully watch the baby for irritability and abdominal distention. They note that she has passed no stool since birth. Which of the following has to be considered?

B. Down syndrome babies occasionally have a serious gastrointestinal blockage that requires surgery

8. Having just learned that their daughter has trisomy 21 and is not a mosaic, the parents are concerned about the possibility of severe mental retardation. Which of the following statements is most accurate?

C. Every child with Down syndrome has some degree of mental retardation, but with early intervention affected individuals can live a long and relatively normal life

9. Upon examination of new infant, the pediatrician detects a heart murmur. Which of the following is the most accurate and appropriate statement?

C. A heart murmur in a child with Down syndrome may be a sign of a heart defect. However, further testing is necessary before a heart defect can be diagnosed.

10. Conduct a literature search to determine the most common type of heart defect observed in children with Down syndrome.

Cinccinnatichildrens.org Atrioventricular septal defects, ventricular septal defectatrial septal defect, patent ductus arteriosus, congestive heart failure, Tetralogy of Fallot, hypoplastic left heart syndrome

NDSS.org Heart and Down Syndrome AV septal defects, persistent ductus arteriosus, Teralogy of Fallot



i. An Atrioventricular Septal Defect is caused by a failure of tissue to come together in the heart during embryonic life. This results in a large opening in the center of the heart, with usually a hole between the two pumping chambers (a Ventricular Septal Defect) and between the two collecting chambers (an Atrial Septal Defect) as well as abnormalities of the two atrioventricular valves, the mitral and tricuspid valves. Of those children with Down syndrome who are born with congenital heart disease, an antrioventricular septal defect is the most common. In less severe cases, Ventricular Septal Defects and Atrial Septal Defects can also occur separately

ii. The ductus arteriosus is a channel between the pulmonary artery and the aorta. During fetal life it diverts blood away from the lungs because prenatal blood is already oxygenated from the mother. After birth this channel usually closes on the first day of life. If it does not close, it is termed "persistent" and results in an increased flow of blood into the lungs

iii. This is a term given to a heart condition composed of four abnormalities

1. Ventricular septal defect 2. Narrowing of the passage from the right ventrical to the

lungs 3. Overenlarged right ventrical because of the backup of

blood and 4. Overenlarged aorta, which carries blood from the left

ventrical to the body 11. Does the child have any abnormal laboratory blood test results and, if so,

what condition might explain these findings? Low WBC 6,500mm3 (9.0‐35.0x103/mm3) prone to infections Low T4 total 7ug/dL (10.1‐20.9mcg/dL) hypothyroidism

12. Identify fifteen distinct clinical signs from the patient’s physical examination that are consistent with a diagnosis of Down syndrome.

Microcephaly, epicanthal folds bilaterally, hypertelorism, broad flat nasal bridge, macroglossia with fissured tongue, protruding tongue

Systolic murmur Hypotonia, brachydactyly, clinodactyly, fifth finger bilaterally, simian

crease bilaterally, hyperextensible joints

Case60 Down Syndrome

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