Down Syndrome

Down syndrome Definition Down syndrome, also called trisomy 21, is the most common autosomal chromosomal irregularity, occurring approximately 1: 700 lives births. The risk of a trisomy 21 pregnancy increases with maternal age. Most individuals with down syndrome have full trisomy 21, which occurs due to meitotic non disjunction and results in a genotype with three complete copies of chromosome 21 and a total of 47 chromosomes. Other less common forms of Down syndrome are translocation trisomy 21 and mosaic trisomy 21. Epidemiology • Most common viable autosomal chromosome aberration (~ 1:700 live births ) and most common genetic cause of cognitive impairment • The risk of about syndrome pregnancy increase with maternal age. ◦Incidence of 20 years: 1:2000 ◦Incidence of 30 years: 1:900 ◦Incidence of 40 years: 1:100 ◦Incidence of 45 years: 1:30 The general risk or trisomy 21 increases with maternal age. This does not, however, apply to translocation trisomies ! Etiology Full trisomy 21 (~ 95% of cases ) • Definition: three complete copies of chromosome 21 are present in cells, with a total of 47 chromosomes • Occurrence: full trisomy 21 is not A hereditary disease; the chromosomal irregularity occurS spontaneously • Pathogenesis: meiotic non disjunction ◦Maternal non disjunction occur during meiosis I in approximately 70% of cases and during meiosis II in approximately 20% of cases. ◦May occur due to paternal non disjunction during spermatogenesis, more commonly dunno meiosis II ( approximately 5% of cases. • Karyotype: female: 47 xx + 21 or male: 47 XY + 21 Translocation trisomy 21 ( 3%- 4% cases ) • Definition: three copies of chromosomes although Th 21 are present, one of which is attached to another chromosome, usually chromosome 14 ( less likely attaches to chromosomes 13, 15, or 22 • Occurrence: independent of maternal age; occurs as a spontaneous translocation • Pathogenesis and karyotype: carries of balanced robertsonian translocation have a normal phenotype. Children of a translocation carrier can inherit A normal karyotype, balanced translocation or unbalanced translocation ( trisomy 21 ) ◦In approx. 50% of cases, a balanced translocation is inherited from a parent, usually the mother who does not show phenotype expression of trisomy 21 ‣ Balanced robertsonian translocation: translocation of long arm of chromosome 21 to the long arm of chromosome 14 • Karyogram shows a total number of 45 chromosomes and may be expressed as either female: 45, XX,t( 14; 21 ) or male: 45 XY, t( 14; 21 ) • Affected individuals inherit a balanced translocation from their phenotypically normal parent.. ‣ Unbalanced robertsonian translocation: clinical features of trisomy 21 caused by inheritance of A translocation chromosome and a normal chromosomes. • Although there are only 46 chromosomes present, there are three copies of genetic material from chromosome 21 • Result in the karyotypes female: 46 XX +21 t( 14; 21 ) and male: 46 XY + 21 t( 14;21 ) ‣ Pregnancy can end in miscarriage ◦The Other cases of balanced robertsonian translocation are caused by new translocations during meiosis Although a symptoms may be less severe in mosaic trisomies, the clinical manifestation generally provides no indication of the Mosaic trisomy 21 ( 1% - 2% of cases ) underlying genetic mutation • Definition: two cell lines are present, the trisomy 21 cell line and the normal cell line • Pathogenesis: ◦Non disjunction during mitosis that occur after fertilization To remember that Down syndrome is ◦Depending on the timing of the mitotic error, there is a variable proportion of trisomic and normal cent caused by trisomy 21, think of the ◦Phenotypic expression varies according to the ratio of healthy trisomic cells drinking age of 21 • Karyotype: either female: 46, XX / 47, XX + 21 or male i 46, XY, + 21 Clinical features • Eyes: ◦Upward - slanting palpebral fissures ◦Epicanthal folds ◦Ocular hypertelorism: a distance between the eyes greater than the 95th percentile ◦Brushfield spots: an aggregation of connective tissue in the periphery of the iris, visible as white or grayish - brown spots. ◦Refractive errors ( e.g myopia, astigmatism ) ◦Strabismus ◦Cataracts ( congenital, infantile, or juvenile ) • Mouth: ◦A small oral cavity, together with a large and furrowed tongue results in the appearance of a protruding tongue ◦High -arched and narrow palate ◦Teeth: late development, small size with short roots, large gaps between teeth • Further features: ◦Brachycephaly ◦Hypoplastic nasal bones, broad and flat nasal bridge ◦Ear anomalies ( small, round, low set ears, adherent earlobes ) ◦Short neck, excess skin at the nape of the neck ( may be seen on prenatal ultrasound ) Extremities, soft tissue, and skeletal features • Extremities ◦Transverse palmar crease: single crease that runs across the palm, along the metacarpophalangeal joints perpendicular to the fingers. ◦Sandal gap: a medical displacement of the first toe leading to large space between the first and second toes. ◦Clinodactyly: abnormal curvature of a finger ( typically refers to inward curvature of the 5th finger ) ◦Camptoclactyly ‣ A congenital, fixed digital flexion deformity most often seen in the 5th digit ‣ Associated with several congenital syndromes, including Down syndrome ◦Brachydactyly • Soft tissue: ◦Connective tissue deficiency → ↑ risk of umbilical and inguinal hernias ◦Marked hyperextension of joints • Obesity: prevalence is approx. 50% ( higher than in the general population • Skeletal features: ◦Atlantoaxial instability ◦Short stature ‣ Reduced growth with shortening of long bones ‣ Average height: 150 cm (4 ft 11 in ) Organ malformations and associated conditions • Heart: congenital heart detect in trisomy 21 (~ 50% of cases ) ◦Atrioventricular septal defect ( endocardiaL cushion defect ) is the most common heart defect in individuals with down syndrome ◦Ventricular septal defect ◦Atrial septal defects ◦Tetralogy of fallot ◦Patent ductus arteriosus • Gastrointestinal tract ◦Duodenal atresia / stenosis. ◦Annular pancreas ◦Anal atresia ◦Megacolon ◦Rectal prolapse ◦Hirschsprung disease • Urogenital system ◦Hypogonadism ◦Cryptorchidism ◦Decreased fertility in men • Further features ◦Hypothyroidism ◦Type 1 diabetes ◦Celiac disease ◦Obstructive spleen apnea ◦Hearing loss due to recurrent otitis media ◦Increased risk or leukemia ( acute lymphoblastic leukemia, acute myeloid leukemia ) ◦Early onset alzheimer disease ( the amyloid precursor protein, which generates amyloid beta, is located on chromosome 21 ) ◦Increased risk of developing epilepsy Development • Motor skills ◦Delayed motor development ◦Muscle hypotonia • Intelligence ◦Varying levels of intellectual disability ( average IQ: 50 ) ◦Apparent within the first 12 months: developmental milestones ( eg sitting, walking, talking ) are achieved at approximately twice the age of children without Down syndrome • Behavioral and psychiatric disorders ◦Behavioral disorders ‣ ADHD ‣ Conduct disorder ◦Autism spectrum disorder Down syndrome is the most common genetic cause of intellectual disability To remember the most important features associated with Down syndrome, think of the 5 A 's: advanced maternal age, duodenal atresia, atrioventricular septal defect, AML/ ALL, early onset of alzheimer disease. Diagnosis Diagnostic approach • Diagnosis of Down syndrome is primarily prenatal and the diagnostic approach is dependent on the week of gestation • Initial screening test ◦Standard tests ‣ First trimester combined test ( 11 - 13 weeks ) ‣ Second trimester quadruple test ( 15 - 18 weeks ) ◦Additional tests, usually performed optional in high - risk pregnancies ( e.g maternal age > 35 years, history of prior pregnancy with trisomy, ultrasound features suggesting aneuploidy) ‣ Integrated tests over the first and second trimester ‣ Cell - free DNA ( 10- 20 weeks ) • If any of the above screening test yield an abnormal result, one of the following confirmatory diagnostic test is performed ◦Amniocentesis ( 15- 22 weeks ) ◦Chorionic villus sampling ( 9-14 weeks ) ◦Percutaneous umbilical cord sampling ( 18 - 22 weeks ) Prenatal screening Counseling • Precedes screening procedures • Provides information that screening is voluntary • Explains the option of terminating the pregnancy if trisomy 21 Screening procedures • Indications: recommended for all women prior to the 20th week of gestation • Combined test ( first trimester )( 11 - 13 weeks ) ◦Has a 90% detection rate ◦Maternal serum ‣ ↑ beta human chorionic gonadotropin ( B- HCG ) ‣ ↓ pregnancy-Associated plasma protein A ( pApp -A ) ◦Ultrasound ‣ Nuchal translucency measurement: nuchal translucency increases due to the large amount of fluid connecting behind the neck ‣ Short neck, thickened nuchal fold ‣ Absent or hypoplastic nasal bone ‣ Shortened middle phalanges of the fifth digits with clinodactyly ‣ Shortened long bones ( humerus, femur ) • Quadruple test ( second trimester )( 15- 18 weeks): ◦↓ free estriol ◦↓ alpha-fetoprotein ( AFP ) ◦↑ inhibin A ◦↑ B- HCG • Additional screening test: the following tests are optional and performed in addition to the above - mentioned test and they are evaluated along with the result from the second trimester quadruple test. ◦Sequential integrated test: combines the results from the first trimester combined test and second- trimester quadruples test ◦Cell free fetal DNA ( 10 - 20 weeks ): fetal DNA is isolated from a maternal blood specimen and evaluated for chromosomal abnormalities ‣ Noninvasive ( for the fetus ) but expensive test ‣ More predictive in women with a high risk ‣ The test is currently available but not guideline -recommended In the quadruple test HCG and inhibin - A are both high up (↑) and estriol and a fetoprotein are both deficiency (↓) Fetal kargotyping ( confirmatory test ) • Indications ◦Positive screening test ◦Previous trisomy 21 pregnancy ◦Parent with known chromosomal translocation or aberration • Procedures ◦Chorionic villus sampling ( 9- 14 weeks) ◦Amniocentesis ( 15 - 22 weeks) ◦Percutaneous umbilical cord sampling ( 18- 22 weeks ) • Complications ◦Bleeding. ◦Infections ◦Fetal injury ◦Amniocentesis has a lower risk or fetal loss compared to chorionic villus sampling Postnatal diagnostics • Chromosomal analysis • Screening for associated conditions, e.g echocardiography to detect heart defects Typical features and malformations are important indicators but diagnostic confirmations is still required Differential diagnosis • • • • • • • Treatment Isolated hypotonia Zellweger syndrome Congenital hypothyroidism Trisomy 13 Trisomy 18 Williams syndrome Turner syndrome • Evaluation, monitoring and treatment of the symptoms complex and malformation as necessary ( c.g cardiac screening with echocardiogram and heart surgery for cardiac malformations ) • Early, targeted intervention, educational program and support ◦Physical therapy ◦Behavioral therapy ◦Speech therapy ◦Occupational therapy Prognosis • Decreased life expectancy with an average lifespan of approx. 60 years • Common causes of death in individuals with Down syndrome ( in decreasing order or incidence ) ◦Infections, particularly pneumonia ◦Congenital malformation, particularly congenital heart disease ◦Circulatory disease ( eg, coronary artery disease ) ◦Dementia