Down syndrome


The most common chromosome change seen in newborns caused by an extra chromosome 21.

The 200-300 genes present on chromosome 21 as well as epigenetic factors contribute to the clinical features of the syndrome.
Trisomy 21 occurs either by nondisjunction, with the presence of 47 chromosomes, or by translocation of an additional chromosome 21 to another chromosome.

Down’s syndrome, which is caused by an extra copy of chromosome 21, is one of many abnormalities that result from such a failure of homologous recombination in meiosis:nondisjunction.

Prevalence strongly dependent on maternal age.

Seen in about 1 in 700-800 births.

Median age at death 57 years, with survival up to 82 years.

Average life expectancy has increased from 25 years in 1983 to 60 years in 2020.

Accounts for approximately 700 live births annually, and more than 200,000 persons or living with the disorder.
There are approximately 6 million individuals with down syndrome across the globe.
Down syndrome patients comprise the greatest population with genetically determined Alzheimer’s disease in the world.

Mortality after age 20 years is associated with cardiovascular, and respiratory disorders, with the severity of the level of intellectual disability, dementia, and mobility restrictions as important risk factors.

Prevalence decreasing over the past several decades as a result of increased screening and termination of Down syndrome related pregnancies.

Age and serum screen have a sensitivity of 90.5% and a false positive rate of 27%.

Age and serum screen and sonogram screening overall detection rate of 97.6%.

High risk of congenital disease, craniofacial abnormalities and gastrointestinal abnormalities.

Tendency for patients to be born early (Weijerman ME).

Sonographic markers include nuchal thickening, short femur or humerus, cardiac defects or an echogenic focus of the left ventricle, intracranial ventriculomeglay, choroid plexus cyst, pyeloectasis, echogenic bowel, clinodactyly, two-vessel umbilical cord and short ear.

Age of 35 years at delivery used as the cutoff for offering amniocentesis.

Majority of children with Down’s syndrome are born to women younger than 35 years.

Increased risk with a low alpha-fetoprotein level.

A screening test is considered positive if the second trimester risk is a least 1 in 270 pregnancies.

First trimester maternal serum pregnancy-associated plasma protein A (PAPP-A) levels are decreased in cases of trisomy 21.

First trimester ultrasonographic screening to assess nuchal translucency resulted in a 79% detection rate and a 5% false positive rate.

Alpha-fetoprotein, Beta-HCG and unconjugated estriol between 15 and 22 weeks of gestation can be used to adjust the risk based on maternal age alone.

Maternal serum inhibin A levels during the second trimester predicts the risk of fetal trisomy.

When inhibin A included in second trimester quadruple screen detection rate estimated to be 81% with 5% false positive rate.

Using cell-free DNA has altered the diagnostic prenatal screening approach.
Cell-free DNA (cfDNA) diagnosis has reduced the use of invasive testing such as amniocentesis  or chorionic villus sampling.
Genetic analysis of karyotype obtained by amniocentesis or chorionic villus sampling is 99% accurate.
cfDNA  has a high specificity for the detection of Down syndrome of 99.7%.and is a valuable test for a carrier of a translocation and for a woman at increased risk of having an affected fetus.

Children have a 10-15 fold increased risk of developing acute lymphoblastic and myelogenous leukemia.

Considerable phenotypic variation occurs among patients, and intellectual disability is most commonly moderate but ranges from mild to severe, whereas social function is relatively higher than the cognitive of impairment.

Relative risk of developing acute megakaryoblastic leukemia approximately 500 times greater than in children without Down syndrome.

Small number of neonates born with a variant of AMkL (acute megakaryocytic leukemia), the transient Myeloproliferative disorder which can resolve spontaneously, though approximately 20% can develop AML.

Leukemia develops in2-3% of all patients with DS, particularly acute myeloid leukemia, which responds  to therapies and acute lymphoblastic leukemia, which tends to have a poor prognosis than other children with ALL.

Prognosis of associated ALL is poorer than in children with ALL without Down’s syndrome.

DS associated with an increased risk of testicular cancer.
Autoimmune disease is including Hashimoto’s disease, type one diabetes, alopecia, celiac disease, juvenile idiopathic arthritis, and vitiligo occur in higher numbers in persons with DS compared with matched controls.
Patients with DS should be tested for thyroid disorders at birth, in early infancy, and annually throughout life whenever dry skin, constipation, changing growth trajectory, and unexplained weight gain occur.

Most common predisposing factor for the development of leukemia in children.

Patterns of hematologic disease include transient myeloproliferative disorder AML and ALL.

45-66% of children with DS have an elevated mean corpuscular volume.

In a review of 2,814 patients with this syndrome leukemias comprised 60% of malignancies overall with 97% of all malignancies under the age of 15 years (Hasle).

Older adult with this process have accelerated aging, with increased risk of cataracts, epilepsy, hearing loss, hypothyroidism, oteoporosis, sleep apnea, and elevated risk of Alzheimer’s disease.

Alzheimer’s disease is now the leading cause of mortality in adults with Down syndrome older than 35 years, being the proximate cause of death in 70% of cases,

Virtually all patients with Down syndrome, develop amyloid plaques, by the age of 40 years, and more than 95% develop Alzheimer’s disease dementia by the seventh decade, with an average age of dementia onset being 54 years.

People with Down syndrome, who have extra chromosome 21 material, almost never acquire diabetic retinopathy.

This protection appears to be due to the elevated levels of endostatin, an anti-angiogenic protein, derived from collagen XVIII.

The collagen XVIII gene is located on chromosome 21.

Solid tumors are much less frequent, across all age groups, than leukemia, with the possible exception of retinoblastoma and germ cell tumors.

AML associated with Down syndrome associated with rare induction failure and relapses with 5 year event free survival exceeding 80%.

Associated with an increased risk of germ cell tumors.

Associated with an increase of obstructive sleep apnea.

Cause of death most frequently nonmalignant, although leukemia remains a significant cause of death in children under the age of 10 years.

May be associated with nasolacrimal duct obstruction, epicanthus, blepharoconjunctivitis, ectropion,nystagmus, strabismus, high myopia, lens opacities, and keratoconus.

Pulmonary hypertension with or without congenital heart disease occurs in 1.2-5.2% of persons with DS.
Nearly half of individuals with Down syndrome have congenital heart disease and are at risk for complications of the heart defect.
Pulmonary arterial hypertension may become symptomatic in childhood or later.
Pulmonary arterial hypertension in DS is associated with obstructive airway disease, gastroesophageal reflux, and obesity.
Associated with atrial septal defects.

Ostium primum defects are less common than ostium secundum defects, but is usually associated with Down syndrome.

Patients with DS have small airways, micrognathia, relative macroglossia,tracheal stenosis caused by complete tracheal rings, hypotonia, and obstructive airway disease leading to difficult airway management.

Respiratory disorders are common causes of illness and death in children and adults with DS.
Social integration is important in building the intellectual abilities of a child with DS and outcomes depend on optimizing speech, communication and minimizing hearing impairment.
Obesity occurs in 25% of children and at least 50% of adults with history of DS.
Concomitant obesity complicates obstructive with sleep apnea, diabetes and cardio pulmonary conditions.
Hematologic abnormalities are common  in patients  with DS : transient abnormal myelopoiesis, iron deficiency in childhood, and that increased incidence of leukemia.
In about 10% of neonates with DS a transient abnormal myelopoiesis occurs and this is a form of myeloid preleukemia, due. To a mutation in the GATA1.
This preleukemia is seen predominantly in newborns and almost always before the age of five, and it usually resolves spontaneously.
This group of patients have a risk of leukemia is 20-30%.
Patients+with Down syndrome have decreased risk for cervical cancer and breast cancer, but higher risk for leukemia and testicular cancers.

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