Down Syndrome a.k.a (Trisomy 21)

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Down Syndrome a.k.a (Trisomy 21) by Mind Map: Down Syndrome a.k.a (Trisomy 21)

1. Genetic Details and Pathophysiologic Etiology

1.1. Aneuploidy

1.1.1. Those that do not contain a mutiple of 23 chromosomes

1.2. Trisomy of the 21st chromosome

1.2.1. People with Down syndrome are born with three, rather than two, copies of chromosome 21.

1.3. Seen in 1 out of 800 live births

1.4. Trisomy 21 is the most common chromosome abnormality among live births and the most frequent form of intellectual disability caused by a microscopically demonstrable chromosomal aberration

1.5. The three main types of cytogenetic abnormalities that result in the Down syndrome phenotype and their relative proportions are: ●Trisomy 21 (47,+21) – Approximately 95 percent. ●Robertsonian translocation involving chromosome 21 (figure 1) – 3 to 4 percent. (See "Chromosomal translocations, deletions, and inversions", section on 'Robertsonian translocations'.) ●Trisomy 21 mosaicism (47,+21/46) – 1 to 2 percent. Two populations of cell types, one with the normal 46 chromosomes and the other with 47,+21, are present.

2. Causative Factors

2.1. Caused by nondisjunction during the formation of one of the parent's gametes or during embryonic development

2.1.1. 97% of Down Syndrome Cases are caused by NONDISJUNCTION

2.1.2. In approximately 90-95% of cases, the nondisjunction occurs in the formation of the mother's egg cell

2.1.3. Paternal nondisjunction

2.1.4. Meiotic nondisjunction error is the cause in 95 percent of cases, and the error occurs at mitosis in somatic cells in the remaining 5 percent of cases This explains, in part, why the risk of this type of Down syndrome increases with advancing maternal age. The recurrence rate is approximately 1 percent in younger women; the maternal age-related risk is used if it is greater than 1 percent. Studies of infants with trisomy 21 identified paternal trisomy in 7 percent of cases. A slightly higher rate (approximately 11 percent) of a paternally derived extra copy of chromosome 21 is seen in cases of trisomy 21 diagnosed prenatally

2.2. Caused by Translocation

2.2.1. Translocation Down syndrome refers to the type of Down syndrome that is caused by rearranged chromosome material. In this case, there are three # 21 chromosomes, just like there are in trisomy 21, but one of the 21 chromosomes is attached to another chromosome, instead of being separate

2.2.2. In Down syndrome patients with an unbalanced Robertsonian translocation, the entire long arm of one chromosome 21 is translocated to the long arm of an acrocentric chromosome (ie, chromosome 13, 14, 15, 21, or 22). The most common form of this translocation involves chromosomes 14 and 21. These individuals have 46 chromosomes, but one chromosome 14 contains the long arms of both chromosomes 14 and 21. Therefore, they actually have three copies of the long arm of chromosome 21 (two normal chromosome 21s and a third long arm translocated to chromosome 14), which results in Down syndrome. Trisomy 21 resulting from a Robertsonian translocation is not related to maternal age.

3. Risk Factors of having a child with Down Syndrome

3.1. Maternal Age

3.1.1. Risk begin to rise substantially after 35 years of age

3.1.2. Reaches 3% to 5% for women older than 45 yrs old

3.1.3. Women younger than 30 have a risk ranging 1 in 1,000 births-1 in 2,000 births

3.2. Family History

4. Diagnostic Tests

4.1. Prenatal Diagnosis

4.1.1. Amniocentesis

4.1.2. Chorionic Villus Sampling

4.1.3. Analysis of fetal DNA Down syndrome is usually diagnosed during pregnancy. If Down syndrome is not diagnosed during pregnancy, health care providers can usually diagnose Down syndrome based on the infant's appearance. In such cases, the diagnosis should be confirmed using a blood test that examines the child's chromosomes (karyotype).

4.2. Carrier Screening

4.3. Diagnosis should be confirmed with a genetic test (eg, a karyotype performed on a blood sample). Alternative methods (eg, interphase fluorescent in situ hybridization [FISH] for trisomy 21 or quantitative fluorescence-polymerase chain reaction [QF-PCR]) may be used to expedite diagnosis, but these investigations should always be followed by a full karyotype in order to detect DS due to translocations (eg, Robertsonian translocations involving chromosome 21) or mosaic DS.


4.4.1. Quadruple marker test Combined test Integrated tests - Full integrated test - Serum integrated test - Step-wise sequential testing - Contingent testing Circulating cell-free DNA


4.5.1. Timing Type of hCG Quantifying and reporting analyte levels


5. Common Findings and Associated Medical Conditions


5.1.1. HEAD AND NECK Characteristic dysmorphic features of DS affecting the head and neck include: ●Upslanting palpebral fissures ●Epicanthic folds ●Flat facial profile/flat nasal bridge ●Folded or dysplastic ears ●Low-set small ears ●Brachycephaly ●Brushfield spots ●Open mouth ●Protruding tongue ●Furrowed tongue ●Short neck ●Excessive skin at nape of the neck ●Narrow palate ●Abnormal teeth

5.1.2. EXTREMITIES Characteristic dysmorphic features of DS affecting the extremities include: ●Short broad hands ●Incurved fifth finger with hypoplastic mid phalanx ●Transverse palmar crease ●Space between the first and second toes (sandal gap) ●Hyperflexibility of joints

5.1.3. NEONATAL FEATURES Ten of the characteristic dysmorphic features are common in newborns with DS and are usually recognized soon after birth. In a series of 48 affected newborns, all had four or more features, and 89 percent had six or more: ●Flat facial profile ●Slanted palpebral fissures ●Anomalous ears ●Hypotonia ●Poor Moro reflex ●Dysplasia of midphalanx of fifth finger ●Transverse palmar (Simian) crease ●Excessive skin at nape of the neck ●Hyperflexibility of joints ●Dysplasia of pelvis


5.2.1. Almost all individuals with DS have cognitive impairment, although the range is wide. Most are mildly to moderately intellectually disabled, with an intelligence quotient (IQ) in the 50 to 70 or 35 to 50 range, respectively, although some are severely impaired with an IQ of 20 to 35

5.2.2. IQs between 25-70

5.2.3. IQ declines through the first 10 years of age, reaching a plateau in adolescence that continues into adulthood

5.2.4. The cognitive deficits are primarily in morphosyntax, verbal short-term memory, and explicit long-term memory

5.2.5. Behavioral/Psychiatric Disorders Disruptive behavioral disorders, such as attention-deficit hyperactivity disorder, conduct/oppositional disorder, or aggressive behavior, were most common psychiatric disorders, most often consisting of major depressive illness or aggressive behavior, affected 25.6 percent of DS adults Autism is a common comorbidity of DS, affecting as many as 7 percent of children with DS . The diagnosis is often delayed compared with children without DS

5.2.6. Dementia/Alzheimer disease Adults with DS usually develop neuropathologic and functional changes typical of Alzheimer disease by the sixth decade of life

6. Treatments

6.1. Early Intervention and Educational Therapy

6.1.1. Public Law 10517(2004): The Individuals with Disabilities Education Act (IDEA) makes it possible for children with disabilities to get free educational services and devices

6.2. Treatment Therapies

6.2.1. Physical Therapy Congenital Heart Defects affect about 1/3 to 1/2 of live born children help build motor skills, increase muscle strength, and improve posture and balance

6.2.2. Speech-language Therapy improve communication skills and use of language skills, provide alternate means of communication, such as sign language and pics, until he or she learns to speak, improve comprehension

6.2.3. Occupational Therapy teaches self care such as eating, getting dressed, writing, and using a computer, apply for jobs in high school level

6.2.4. Emotional and Behavioral Therapy help them find useful responses to both desirable and undesirable behaviors help deal with emotions and build coping and interpersonal skills

6.3. Drugs and Supplements

6.3.1. Amino Acid Supplements

6.3.2. Psychoactive Drugs

6.4. Assistive Devices

6.4.1. Amplification devices for hearing problems

6.4.2. Bands that help with movement

6.4.3. Special pencils to make writing easier

6.4.4. Touchscreen computers

6.4.5. Computers with large-letter keyboards

6.5. Down Syndrome Registry

6.5.1. Parents and families of children can connect with other families and people with Down Syndrome from around the world

6.6. Counselling

6.6.1. ●The Association for Children with Down Syndrome ●National Down Syndrome Society

7. Fast Facts

7.1. By 40 yrs of age, individuals with Down Syndrome virtually always develop symptoms of Alzheimer's disease

7.2. About 3/4 of fetuses with Down Syndrome are spontaneously aborted or stillborn

7.3. About 20% of infants born with Down Syndrome die during their first 10 yrs of life

7.4. For those surviving beyond 10 yrs of life, average life expectancy is now about 60 years

7.5. Down syndrome is the most common form of intellectual disability in the world. It occurs in approximately 1 out of every 1000 babies born alive, and it is caused by a genetic abnormality that affects something called a chromosome.



8.1.1. Approximately one-half of individuals with DS have congenital heart disease The secondary lesion was most commonly an atrial septal defect (ASD) or patent ductus arteriosus (PDA). The following primary lesions were identified: ●Complete atrioventricular septal defect (CAVSD) – 37 percent ●Ventricular septal defect (VSD) – 31 percent ●ASD – 15 percent ●Partial atrioventricular septal defect (PAVSD) – 6 percent ●Tetralogy of Fallot (TOF) – 5 percent ●PDA – 4 percent ●Miscellaneous – 2 percent


8.2.1. Children with trisomy 21 are at increased risk for gastrointestinal tract anomalies Duodenal atresia or stenosis, sometimes associated with annular pancreas, is the most characteristic lesion, occurring in 2.5 percent Hirschsprung disease is more common in DS than in the general population, although the risk is less than 1 percent A strong association appears to exist between DS and celiac disease


8.3.1. Birth weight, length, and head circumference are less in DS compared with typical infants

8.3.2. Short stature

8.3.3. Obesity This is thought to result from the reduced resting metabolic rate in children and adults with DS


8.4.1. Ophthalmologic disorders that require monitoring and intervention affect the majority of children with DS. Disorders that are the most common include: ●Refractive errors (myopia, hyperopia, astigmatism) – 35 to 76 percent ●Strabismus – 25 to 57 percent ●Nystagmus – 18 to 22 percent

8.4.2. Cataracts occur in 5 percent of newborns

8.4.3. Starting in the second decade of life, many individuals develop corneal opacities

8.4.4. Children occasionally develop glaucoma.

8.4.5. keratoconus, an abnormal shape or thinning of the cornea that impairs visual acuity.


8.5.1. Congenital hearing loss is also more common in DS


8.6.1. include thyroid dysfunction and diabetes


8.7.1. Hematologic abnormalities affecting red blood cells, white blood cells, and platelets are common in DS, particularly during childhood. The lifetime risk of leukemia in DS is 1 to 1.5 percent polycythemia Children with DS often have macrocytosis

8.7.2. Transient myeloproliferative disorder

8.7.3. Acute megakaryoblastic leukemia

8.7.4. Acute lymphoblastic leukemia


8.8.1. Acute lymphoblastic leukemia

8.8.2. Respiratory tract infections are also more frequent and often more severe than in children without DS.

8.8.3. disorders of the pulmonary vasculature, parenchymal lung disease, upper and lower airway abnormalities, and chronic aspiration

8.8.4. Sleep apnea


8.9.1. Palmoplantar hyperkeratosis – 41 percent ●Seborrheic dermatitis – 31 percent ●Fissured tongue – 20 percent ●Cutis marmorata – 13 percent ●Geographic tongue – 11 percent ●Xerosis – 10 percent ●Alopecia areata – 8 percent


8.10.1. Women with DS are fertile and may become pregnant. In one series, 30 pregnancies in 26 women resulted in 10 offspring with DS, 18 (including one set of twins) without DS, and 3 spontaneous abortions . Appropriate counseling should be provided for management of menstruation and contraception

8.10.2. Nearly all males with DS are infertile. The mechanism is impairment of spermatogenesis. However, cases have been reported of offspring from fathers with DS


8.11.1. These include hypospadias (1 in 250 males), cryptorchidism (14 to 27 percent of males), testicular cancer, and renal malformations (3.5 percent)


8.12.1. Atlantoaxial instability (AAI), defined as excessive mobility of the articulation of the atlas (C1) and the axis (C2), may lead to subluxation of the cervical spine



8.14.1. DS is associated with a variety of immunologic impairments that are thought to be related to the increased susceptibility to infection, autoimmune disorders, and malignancies



9.1.1. Patients with Down syndrome (DS) should be monitored for disturbances of growth associated with other disorders, such as hypothyroidism or celiac disease, and for excessive weight gain.


9.2.1. Interventions beginning at 24 months of age should include attention to diet and promotion of physical activity. Caloric intake should be less than recommended for age in typical individuals and supplemental vitamins and minerals should be provided. Calcium and vitamin D intake should be monitored closely to minimize bone loss, since adults with DS have lower bone mineral density than controls


9.3.1. All newborns with Down syndrome (DS) should be evaluated for congenital heart disease in consultation with a pediatric cardiologist. An echocardiogram is recommended to detect abnormalities that may not be symptomatic or apparent on physical examination. Continued clinical cardiac evaluation is needed because of the high risk of mitral valve prolapse and aortic regurgitation in adolescents and young adults


9.4.1. Newborns should have a newborn hearing screen with brainstem auditory evoked response (BAER) or otoacoustic emission (OAE) [1]. Infants with Down syndrome (DS) should have repeat hearing screening at six months of age. Hearing should be evaluated regularly throughout childhood, typically every six months until four to five years of age and then yearly. Any child who fails screening should be referred to an otolaryngologist for further evaluation and management.


9.5.1. An ophthalmologic assessment should be performed in the newborn period or at least before six months of age to detect strabismus, nystagmus, and cataracts.


9.6.1. Thyroid function testing (both total thyroxine [tT4] and thyroid-stimulating hormone [TSH]) should be obtained in the newborn period . The American Academy of Pediatrics (AAP) recommends that screening should be repeated at 6 and 12 months, and then annually


9.7.1. Screening for symptoms of celiac disease should begin at one year of age. Laboratory screening is recommended if signs or symptoms develop


9.8.1. A complete blood count and differential should be obtained at birth to evaluate for myeloproliferative disorders and polycythemia. Infants with transient myeloproliferative disorders should be followed with a complete blood count and differential every three months until three years of age and then every six months until six years of age.

9.8.2. A hemoglobin level should be obtained annually from 1 to 13 years of age to screen for anemia The anemia is usually due to iron deficiency secondary to the restricted diet that many children with DS develop as a result of delayed oral motor skills and dysphagia. However, anemia may also be a sign of leukemia.


9.9.1. Routine brushing should be encouraged. Dental visits are recommended every six months. Orthodontic problems, which occur in the majority of DS patients, should be evaluated and treated if possible


9.10.1. The American Academy of Pediatrics Committee on Genetics and the American Academy of Pediatrics (AAP) Committee on Sports Medicine and Fitness recommend careful neurologic evaluation for signs and symptoms consistent with spinal cord injury (eg, loss of motor skills, loss of bowel or bladder control, neck pain, neck stiffness) as the most important clinical predictor of symptomatic atlantoaxial instability (AAI) and dislocation


10.1. The prognosis for a child with Down syndrome used to be pretty grim. In 1983, the average lifespan of a person with the condition was just 25 years. Thanks to advances in the treatment and screening of people with Down syndrome, the landscape has changed. Just 14 years later, in 1997, the average lifespan had nearly doubled to 49 years.