Practice Essentials

Down syndrome is by far the most common and best known chromosomal disorder in humans and the most common cause of intellectual disability. It is primarily caused by trisomy of chromosome 21, which gives rise to multiple systemic complications as part of the syndrome. However, not all defects occur in each patient; there is a wide range of phenotypic variation.

Essential update: First-trimester blood test for fetal cell-free DNA detects trisomy 21
In 2 prospective studies one involving 1!!" singleton pregnancies and the other involving #$% singleton pregnancies&, a first'trimester maternal blood test for fetal cell' free D() cfD()& reliably detected Down syndrome trisomy 21&.*1, 2, +, -he first study found that cfD() testing at 1! weeks detected trisomies 21, 1$, and 1+ and had a lower false'positive rate !.1. vs +.%.& and higher sensitivity than combined testing maternal age, fetal nuchal translucency thickness on ultrasonography, maternal serum free beta'human chorionic gonadotropin, and pregnancy'associated plasma protein )& at 12 weeks.*%, -he screen'positive rate was 1./. for cfD() testing and ".!. for combined testing at the recommended risk cut'off of 101!!. 1oth protocols identified all trisomies. -he second study offered cfD() testing to about +2. of cases detected by first'line screening with combined testing alone, 21. of those detected by combined testing with serum placental growth factor and alpha'fetoprotein )34&, and 11. of those detected by combined testing plus serum placental growth factor, )34, and ductus venosus pulsatility inde5 for veins.*", -esting for cfD() contingent on combined test results at 11'1+ weeks6 gestation detected #$. of Down syndrome cases; fewer than !.". of cases re7uired invasive testing for confirmation.

Signs and symptoms

8hen recording the history from the parents of a child with Down syndrome, the clinician should include the following0

4arental concern about hearing, vision, developmental delay, respiratory infections, and other problems 3eeding history to ensure ade7uate caloric intake 4renatal diagnosis of Down syndrome 9omiting secondary to gastrointestinal tract blockage by duodenal web or atresia )bsence of stools secondary to Hirschsprung disease Delay in cognitive abilities, motor development, language development specifically e5pressive skills&, and social competence

)rrhythmia, fainting episodes, palpitations, or chest pain secondary to a heart lesion :ymptoms of sleep apnea, including snoring, restlessness during sleep, difficulty awaking, daytime somnolence, behavioral changes, and school problems

;n physical e5amination, patients with trisomy 21 have characteristic craniofacial findings, such as the following0

)nteriorly and posteriorly flattened head flat occiput and a flattened facial appearance& Dysplastic low'set ears :mall nose with depressed nasal bridge 4rotruding tongue High'arched palate Dental abnormalities :hort, broad neck

<eneral physical features in patients with Down syndrome may include the following0

:hortened e5tremities :hort, broad hands, with short fifth middle phalan5 and simian palmar creases =2!. of patients& >oint hypere5tensibility or hyperfle5ibility (euromuscular hypotonia Dry skin 4remature aging 8ide range of intelligence 7uotients ?ongenital heart defects

?omplications of Down syndrome can involve almost every organ system of the body. :ee 4resentation for more detail.

Diagnosis
@aboratory studies that may be helpful include the following0

?omplete blood count with differential 1one marrow e5amination -hyroid'stimulating hormone -:H& and thyro5ine -%& 4apanicolaou smears every 1'+ years in se5ually active women ?ytogenetic studies karyotyping& Interphase fluorescence in situ hybridiAation 3I:H& for rapid diagnosis )ssessment of mosaicism for trisomy 21 lymphocyte preparations, buccal mucosa cellular preparations, 3I:H, scoring fre7uency of trisomic cells& Immunoglobulin <

Baternal serum biochemical markers

Imaging studies that may be considered include the following0

Cadiography of the skull and neck Bammography yearly in women older than "! years& Dchocardiography to identify congenital heart disease. Eltrasonography

Invasive diagnostic tests that may be warranted include the following0

)mniocentesis criterion standard& ?horionic villus sampling ?9:& 4ercutaneous umbilical blood sampling 4E1:& 8ith in vitro fertiliAation, preimplantation diagnosis of single'gene disorders, se5 selection for F'linked disorders, and identification of chromosomal aneuploidies

(oninvasive diagnostic and other tests that may be warranted include the following0

Bultiple5ed, massively parallel se7uencing of maternal plasma D() )uditory brainstem response )1C&, or brainstem auditory evoked response 1)DC& 4ediatric ophthalmic e5amination <rowth charts specifically for children with Down syndrome Cigorous dental hygiene and dental evaluation

:ee 8orkup for more detail.

Management
-here are no medical treatments for mental retardation associated with Down syndrome, but improved medical care has greatly enhanced 7uality of life and increased life e5pectancy. Dlements of medical care include the following0

<enetic counseling :tandard immuniAations and well child care Banagement of specific manifestations of Down syndrome and associated conditions eg, endocrine, infectious, cardiac, respiratory, neurologic, psychiatric, dermatologic, or dental disorders& Darly intervention programs

:pecial considerations in adolescents are as follows0

;ngoing monitoring measures, including annual audiologic evaluation and annual ophthalmologic evaluation

;ngoing management of manifestations of the syndrome and associated conditions Discussion of issues related to the transition to adulthood

)ppropriate surgical management of associated conditions should be provided, as follows0

-imely surgical treatment of cardiac anomalies may be necessary 4rompt surgical repair is necessary for <I anomalies :urgical intervention may be necessary to stabiliAe the upper segment of the cervical spine if neurologic deficits are clinically significant ?ongenital cataracts must be e5tracted soon after birth and subse7uent correction with glasses or contact lenses provided ?areful anesthetic airway management is needed because of the associated risk of cervical spine instability ?ervical radiography is needed if a neurologic deficit suggests spinal'cord compression )denotonsillectomy may be performed to manage obstructive sleep apnea

:ee -reatment and Bedication for more detail.

mage library

<'banded karyotype showing trisomy 21 of isochromosome arm 217 type *%2,FG,i 21& 71!&,.

!ac"ground
Down syndrome is by far the most common and best known chromosomal disorder in humans and the most common cause of intellectual disability. *2, %, ", /, $, It is characteriAed by mental retardation, dysmorphic facial features, and other distinctive phenotypic traits. Down syndrome is primarily caused by trisomy of chromosome 21; this is the most common trisomy among live births. -he term mongolism was once commonly used but is now considered obsolete.*#, 1!, 11,

@ike most diseases associated with chromosomal abnormalities, trisomy 21 gives rise to multiple systemic complications as part of the clinical syndrome. -his chromosomal anomaly leads to both structural and functional defects in patients with Down syndrome. However, not all defects occur in each patient; there is a wide range of phenotypic variation.

Pat#op#ysiology
-he e5tra chromosome 21 affects almost every organ system and results in a wide spectrum of phenotypic conse7uences. -hese include life'threatening complications, clinically significant alteration of life course eg, mental retardation&, and dysmorphic physical features. Down syndrome decreases prenatal viability and increases prenatal and postnatal morbidity. )ffected children have delays in physical growth, maturation, bone development, and dental eruption. -wo different hypotheses have been proposed to e5plain the mechanism of gene action in Down syndrome0 developmental instability ie, loss of chromosomal balance& and the so' called gene'dosage effect.*12, )ccording to the gene'dosage effect hypothesis, the genes located on chromosome 21 have been overe5pressed in cells and tissues of Down syndrome patients, and this contributes to the phenotypic abnormalities.*1+, -he e5tra copy of the pro5imal part of 21722.+ appears to result in the typical physical phenotype, which includes the following0

Bental retardation ' Bost patients with Down syndrome have some degree of cognitive impairment, ranging from mild intelligence 7uotient *IH, "!'/"& to severe impairment IH 2!'+"&; patients show both motor and language delays during childhood ?haracteristic facial features Hand anomalies ?ongenital heart defects ' )lmost half of affected patients have congenital heart disease, including ventricular septal defect and atrioventricular canal defect

Bolecular analysis reveals that the 21722.1'722.+ region, also known as the Down syndrome critical region D:?C&, appears to contain the gene or genes responsible for the congenital heart disease observed in Down syndrome. ) new gene, DSCR1, identified in region 21722.1'722.2, is highly e5pressed in the brain and the heart and is a candidate for involvement in the pathogenesis of Down syndrome, particularly with regard to mental retardation and cardiac defects. )bnormal physiologic functioning affects thyroid metabolism and intestinal malabsorption. 4atients with trisomy 21 have an increased risk of obesity. 3re7uent infections are presumably due to impaired immune responses, and the incidence of autoimmunity, including hypothyroidism and rare Hashimoto thyroiditis, is increased.

4atients with Down syndrome have decreased buffering of physiologic reactions, resulting in hypersensitivity to pilocarpine and abnormal responses on sensory'evoked electroencephalographic DD<& tracings. ?hildren with leukemic Down syndrome also have hyperreactivity to methotre5ate. Decreased buffering of metabolic processes results in a predisposition to hyperuricemia and increased insulin resistance. Diabetes mellitus develops in many affected patients. 4remature senescence causes cataracts and )lAheimer disease. @eukemoid reactions of infancy and an increased risk of acute leukemia indicate bone'marrow dysfunction. ?hildren with Down syndrome are predisposed to developing leukemia, particularly transient myeloproliferative disorder and acute megakaryocytic leukemia. (early all children with Down syndrome who develop these types of leukemia have mutations in the hematopoietic transcription factor gene, GATA1. @eukemia in children with Down syndrome re7uires at least + cooperating events0 trisomy 21, a GATA1 mutation, and a third undefined genetic alteration. Busculoskeletal manifestations in patients with Down syndrome include reduced height, atlanto'occipital and atlantoa5ial hypermobility, and vertebral malformations of the cervical spine. -hese findings may lead to atlanto'occipital and cervical instability, as well as complications such as weakness and paralysis. )bout ". of patients with Down syndrome have gastrointestinal <I& manifestations, including duodenal atresia, Hirschsprung disease, and celiac disease. Bany patients with trisomy 21 have otorhinolaryngologic manifestations, including hearing loss and recurrent ear infections. )bout 2!. of patients have ophthalmic manifestations. -he )merican ?ollege of ;bstetricians and <ynecologists )?;<& has published pertinent guidelines on screening for fetal chromosomal abnormalities.*1%,

Etiology
Down syndrome is caused by the following + cytogenic variants0

-risomy 21 ?hromosomal translocation Bosaicism

In #%. of patients with Down syndrome, full trisomy 21 is the cause; mosaicism 2.%.& and translocations +.+.& account for the remaining cases. )ppro5imately /". of the unbalanced translocations are de novo, and appro5imately 2". result from familial translocation. ) free trisomy 21 results from nondisIunction during meiosis in one of the parents. -his occurrence is correlated with advanced maternal and paternal age. -he most common error is maternal nondisIunction in the first meiotic division, with meiosis I errors

occurring + times as fre7uently as meiosis II errors. -he remaining cases are paternal in origin, and meiosis II errors predominate. )dvanced maternal age remains the only well'documented risk factor for maternal meiotic nondisIunction. However, understanding of the basic mechanism behind the maternal age effect is lacking. Baternal age risk factors are as follows0

8ith a maternal age of +" years, the risk is 1 in +$" 8ith a maternal age of %! years, the risk is 1 in 1!2 8ith a maternal age of %" years, the risk is 1 in +!

-ranslocation occurs when genetic material from chromosome 21 becomes attached to another chromosome, resulting in %2 chromosomes with 1 chromosome having e5tra material from chromosome 21 attached. It may occur de novo or be transmitted by one of the parents. -ranslocations are usually of the centric fusion type. -hey fre7uently involve chromosome 1% 1%J21 translocation&, chromosome 21 21J21 translocation&, or chromosome 22 22J21 translocation&. Bosaicism is considered a postAygotic event ie, one that occurs after fertiliAation&. Bost cases result from a trisomic Aygote with mitotic loss of one chromosome. )s a result, 2 cell lines are found0 one with a free trisomy, and the other with a normal karyotype. -his finding leads to great phenotypic variability, ranging from near normal to the classic trisomy 21 phenotype. ?ytogenetic and molecular studies suggest that dup21 722.1'22.2& is sufficient to cause Down syndrome. -he D:?C contains genes that code for enAymes, such as supero5ide dismutase 1 :;D1&, cystathionine beta'synthase ?1:&, glycinamide ribonucleotide synthase'aminoimidaAole ribonucleotide synthase'glycinamide formyl transferase <)C:')IC:'<)C-&.

Epidemiology
Down syndrome is the most common autosomal abnormality. -he fre7uency is about 1 case in $!! live births. Dach year, appro5imately 2!!! children are born with Down syndrome.*1", Down syndrome accounts for about one third of all moderate and severe mental handicaps in school'aged children.

Age-related demograp#ics
Down syndrome can be diagnosed prenatally with amniocentesis, percutaneous umbilical blood sampling 4E1:&, chorionic villus sampling ?9:&, and e5traction of fetal cells from the maternal circulation. It is often diagnosed shortly after birth by recogniAing dysmorphic features and the distinctive phenotype. -he characteristic morphologic features will be obvious in children older than 1 year. :ome dermatologic features increase with advancing age.

;ccurrence is strongly dependent on maternal age. -he incidence of this syndrome at various maternal ages is as follows0

1"'2# years ' 1 case in 1"!! live births +!'+% years ' 1 case in $!! live births +"'+# years ' 1 case in 2/! live births %!'%% years ' 1 case in 1!! live births ;lder than %" years ' 1 case in "! live births

;n rare occasions, the disease can be observed in a few members of a family. -he risk for recurrence of Down syndrome in a patient6s siblings also depends on maternal age.

Se$-related demograp#ics
;verall, the 2 se5es are affected roughly e7ually. -he male'to'female ratio is slightly higher appro5imately 1.1"01& in newborns with Down syndrome, but this effect is restricted to neonates with free trisomy 21. 3emale patients with trisomy 21 have a "!. chance of having a child who also has the syndrome. However, many affected fetuses abort spontaneously. ;n the other hand, men with Down syndrome may be infertile, e5cept for those with mosaicism.

%ace-related demograp#ics
Down syndrome has been reported in people of all races; no racial predilection is known. )frican )merican patients with Down syndrome have substantially shorter life spans than white patients with trisomy 21.

Prognosis
-he overall outlook for individuals with Down syndrome has dramatically improved. Bany adult patients are healthier, are better integrated into society, and have increased longevity than before. However, their life e5pectancy is still reduced. )ppro5imately /". of concepti with trisomy 21 die in embryonic or fetal life. )ppro5imately 2"'+!. of patients with Down syndrome die during the first year of life. -he most fre7uent causes of death are respiratory infections bronchopneumonia& and congenital heart disease. -he median age at death is %# years. However, some patients many reach their si5th decade. ?ongenital heart disease is the maIor cause of morbidity and early mortality in patients with Down syndrome. In addition, esophageal atresia with or without transesophageal -D& fistula, Hirschsprung disease, duodenal atresia, and leukemia contribute to mortality. -he high mortality later in life may be the result of premature aging.

In elderly persons with Down syndrome, relative preservation of cognitive and functional ability is associated with better survival.*12, ?linically, the most important disorders related to mortality in this population are dementia, mobility restrictions, visual impairment, and epilepsy but not cardiovascular disease&. In addition, the level of intellectual disability and institutionaliAation are associated with mortality. Individuals with Down syndrome have a greatly increased morbidity, primarily because of infections involving impaired immune response. @arge tonsils and adenoids, lingual tonsils, choanal stenosis, or glossoptosis can obstruct the upper airway. )irway obstruction can cause serous otitis media, alveolar hypoventilation, arterial hypo5emia, cerebral hypo5ia, and pulmonary arterial hypertension with resulting cor pulmonale and heart failure. @eukemia, thyroid diseases, autoimmune disorders, epilepsy, intestinal obstruction, and increased susceptibility to infections including recurrent respiratory infections& are commonly associated with Down syndrome. -he aging process seems to be accelerated in patients with Down syndrome. Bany patients develop progressive )lAheimer'like dementia by age %! years, and /". of patients have signs and symptoms of )lAheimer disease. ) delay in recogniAing atlantoa5ial and atlanto'occipital instability may result in irreversible spinal'cord damage. 9isual and hearing impairments in addition to mental retardation may further limit the child6s overall function and may prevent him or her from participating in important learning processes and developing appropriate language and interpersonal skills. EnrecogniAed thyroid dysfunction may further compromise central nervous system ?(:& function.

Patient Education
?areer preparation should include ac7uisition of Iob skills, choice of Iob area, development of work'support behavior, and opportunities for Iob mobility. -he goal of successful transition from school to the world of work is meaningful employment and optimal function in the least restrictive environment. ;pportunities to participate in community life should be made available. Individuals should be encouraged to pursue daily living tasks with minimal or no assistance. -hey should participate in cultural, leisure, and recreational activities during the growing years. 4atients may 7ualify for supplemental security income ::I& depending on their family6s income. ) parent6s guide to the genetics of Down syndrome is available.*1!, )dditional resources can be obtained from the following organiAations0

(ational Down :yndrome :ociety, 222 1roadway, $th floor, (ew Gork, (G 1!!12'2+1/; 212'%2!'#++!; fa5, 212'#/#'2$/+; infoKndss.org

(ational Down :yndrome ?ongress, 1+/! ?enter Drive, :uite 1!2, )tlanta, <) +!++$; //!'2!%'#"!!; infoKndscenter.org (ational )ssociation for Down :yndrome, 4; 1o5 2!2, 8ilmette, I@ 2!!#1; 2+!'+2"'#112 International Cesource ?enter for Down :yndrome, ?leveland, ;H -he )rc, 1!1! 8ayne )venue, :uite 2"!, :ilver :pring, BD 2!#1!; +!1'"2"' +$%2 -he Down :yndrome 8eb site

3or patient education resources, see the 1rain and (ervous :ystem ?enter, as well as Down :yndrome.

&istory
8hen recording the history from the parents of a child with Down syndrome, the clinician should include the following*1/, 0

4arental concern about hearing, vision, developmental delay, respiratory infections, and other problems 3eeding history to ensure ade7uate caloric intake 4renatal diagnosis of Down syndrome 9omiting secondary to gastrointestinal <I& tract blockage by duodenal web or atresia )bsence of stools secondary to Hirschsprung disease Delay in cognitive abilities, motor development, language development specifically e5pressive skills&, and social competence )rrhythmia, fainting episodes, palpitations, or chest pain secondary to heart lesion :ymptoms of sleep apnea, including snoring, restlessness during sleep, difficulty awaking, daytime somnolence, behavioral changes, and school problems

:ymptoms of atlantoa5ial instability include the following0

)bout 1+'1%. of patients have radiographic evidence of atlantoa5ial instability but no symptoms. ;nly 1'2. of patients have symptoms that re7uire treatment. :ymptoms include easy fatigability, neck pain, limited neck mobility or head tilt, torticollis, difficulty walking, change in gait pattern, loss of motor skills, incoordination, clumsiness, sensory deficits, spasticity, hyperrefle5ia, clonus, e5tensor'plantar refle5, loss of upper'body strength, abnormal neurologic refle5es, change in bowel and bladder function, increased muscle tone in the legs, and changes in sensation in the hands and feet. -hese symptoms often remain relatively stable for months or years.

In rare cases, the symptoms progress to paraplegia, hemiplegia, 7uadriplegia, or death.

P#ysical E$amination
4atients with trisomy 21 have characteristic craniofacial findings, such as an anteriorly and posteriorly flattened head flat occiput and a flattened facial appearance&, dysplastic low'set ears, small nose, depressed nasal bridge, protruding tongue, high'arched palate, dental abnormalities, and a short and broad neck. <eneral physical features in patients with Down syndrome include shortened e5tremities, short limbs, short and broad hands, short fifth middle phalan5, simian palmar creases present in appro5imately 2!. of patients&, Ioint hypere5tensibility or hyperfle5ibility, neuromuscular hypotonia, dry skin, premature aging, a wide range of intelligence 7uotients IHs&, and congenital heart defects.*1$, 1#, 2!, 21, 22, 2+, -hese findings and features are described more fully below.

'entral ner(ous system

Boderate'to'severe mental retardation occurs as a constant feature, with IHs ranging from 2! to $" mean, appro5imately "!&. Buscle hypotonia is seen in newborns with decreased response to normal stimuli; this improves with age. )rticulatory problems are present. :leep apnea occurs when inspiratory airflow from the upper airway to the lungs is impeded for 1! seconds or longer; it often results in hypo5emia or hypercarbia. :eiAure disorders are present in "'1!. or patients. Infantile spasms are the most common seiAures observed in infancy, whereas tonic'clonic seiAures are most common in older patients.

!e#a(ior and psyc#iatric status

In general, natural spontaneity, genuine warmth, cheerfulness, gentleness, patience, and tolerance are characteristics of patients with Down syndrome. ) few patients e5hibit an5iety and stubbornness. Bost children with Down syndrome do not have a coe5isting psychiatric or behavioral disorder. -he available estimates of psychiatric comorbidity range from 1$'+$.. -he disorders include attention'deficitJhyperactivity disorder, oppositional defiant disorder, nonspecific disruptive disorder, autism spectrum disorders, and stereotypical movement disorder in prepubertal children with Down syndrome and depressive illness, obsessive' compulsive disorder, and psychosislike disorder in adolescents and adults with Down syndrome.

Premature aging

Decreased skin tone, early graying or loss of hair, hypogonadism, cataracts, hearing loss, age'related increase in hypothyroidism, seiAures, neoplasms, degenerative vascular disease, loss of adaptive abilities, and increased risk of senile dementia of )lAheimer type are observed.

S"ull
1rachycephaly, microcephaly, a sloping forehead, a flat occiput, large fontanels with late closure, a patent metopic suture, absent frontal and sphenoid sinuses, and hypoplasia of the ma5illary sinuses occur.

Eyes
Ep'slanting palpebral fissures, bilateral medial epicanthal folds, 1rushfield spots speckled iris&, refractive errors "!.&, strabismus %%.&, nystagmus 2!.&, blepharitis ++.&, conIunctivitis, tearing from stenotic nasolacrimal ducts, congenital cataracts +.&, pseudopapilledema, spasm nutans, ac7uired lens opacity +!'2!.&, retinal detachment, and keratoconus in adults are observed see the images below&.*2%,

Infant with Down syndrome. (ote up'slanting palpebral fissures, bilateral epicanthal folds, flat nasal bridge, open mouth with tendency for tongue

protrusion, and small ear with overfolded heli5. ?hild with Down syndrome. (ote up'slanting palpebral fissures, bilateral epicanthal folds, small nose with flat nasal bridge, open mouth with tendency for tongue protrusion, and small ears with overfolded heli5.

Nose
) flat facies with increased interocular distance hypertelorism&, hypoplastic nasal bone, and a flat nasal bridge is characteristic see the image below&.

?haracteristic flat facies with hypertelorism, depressed nasal bridge, and protrusion of tongue, as well as single palmar simian crease in 2'year' old girl with Down syndrome. Image courtesy of @. Dourmishev, BD, 4hD, D:c.

Mout# and teet#

?haracteristic features include a relatively& small mouth with a tendency for tongue protrusion, a fissured and furrowed tongue, mouth breathing with drooling, a chapped lower lip, angular cheilitis, partial anodontia "!.&, tooth agenesis, malformed teeth, delayed tooth eruption, microdontia +"'"!.& in both the primary and secondary dentition see the image below&, hypoplastic and hypocalcified teeth, malocclusion, taurodontism !."%'".2.&, and increased periodontal destruction. ?left lip or palate may occur but is rare.

Hypodontia in patient with Down syndrome. Image courtesy of @. Dourmishev, BD, 4hD, D:c.

Ears
-he ears are small with an overfolded heli5 see the images below&. ?hronic otitis media and hearing loss are common. )bout 22'$#. of children have hearing loss of greater than 1"'2! d1 in at least 1 ear, as assessed by means of the auditory brainstem response )1C&.

Dar of infant with Down syndrome. (ote characteristic small ear

with overfolded heli5. :mall auricle and anomalies of folds in patient with Down syndrome. Image courtesy of @. Dourmishev, BD, 4hD, D:c.

Nec"
-he neck is typically broad and short, with e5cess skin on the back. )tlantoa5ial instability 1%.& can result from la5ity of transverse ligaments that ordinarily hold the odontoid process close to the anterior arch of the atlas. @a5ity can cause backward displacement of the odontoid process, leading to spinal cord compression in about 2. of children with Down syndrome.

'#est and abdomen

-he internipple distance is decreased. -he abdomen is fre7uently protuberant. Diastasis recti and umbilical hernia see the image below& may occur.

4atient with Down syndrome with protuberant abdomen and umbilical hernia. Image courtesy of @. Dourmishev, BD, 4hD, D:c.

S"in
Ferosis, localiAed hyperkeratotic lesions, elastosis serpiginosa, alopecia areata L 1!.&, vitiligo, folliculitis, abscess formation, and recurrent skin infections are observed.*2", 22, Distal a5ial triradius in the palms, transverse palmar creases, a single fle5ion crease in the

fifth finger, ulnar loops often 1!&, a pattern in hypothenar, and interdigital III regions are observed.*2/,

'ongenital #eart defects

?ongenital heart defects are common %!'"!.&; they are fre7uently observed in patients with Down syndrome who are hospitaliAed 22.& and are a common cause of death in this aneuploidy in the first 2 years of life. -he most common congenital heart defects are endocardial cushion defect %+.&, ventricular septal defect +2.&, secundum atrial septal defect 1!.&, tetralogy of 3allot 2.&, and isolated patent ductus arteriosus %.&. )bout +!. of patients have several cardiac defects. -he most common lesions are patent ductus arteriosus 12.& and pulmonic stenosis #.&. )bout /!. of all endocardial cushion defects are associated with Down syndrome.

)astrointestinal tract abnormalities

<I abnormalities occur in appro5imately 12. of patients. Duodenal atresia or stenosis, Hirschsprung disease L 1.&, tracheoesophageal fistula, Beckel diverticulum, imperforate anus, and omphalocele are observed. )n increased incidence of celiac disease has been reported in Down syndrome. :igns and symptoms include growth failure, abdominal pain, and loose stools. 4revalence in individuals with Down syndrome is reportedly "'1". in different Duropean and E: studies. ?eliac disease occurs in genetically susceptible individuals, specifically those who have the human leukocyte antigen H@)& heterodimers DH2 observed in $2'1!!. of individuals with celiac disease& and DH$. -hese are strong linkages with high sensitivity and poor specificity.

)enitourinary tract abnormalities

Cenal malformations, hypogenitalism micropenis or small scrotum and testes&, hypospadias, cryptorchidism, and delayed and incomplete puberty may occur.

)ro*t# and s"eletal anomalies

:hort stature and obesity occurs during adolescence. 1road, short hands, feet, and digits; a short curved fifth finger dysplasia of the mid phalan5& or clinodactyly of the fifth finger with a single fle5ion crease; dysplasia of the pelvis a shallow acetabular angle with small iliac wings&; Ioint la5ity; a wide gap between the first and second toes see the image below&; and atlanto'occipital instability are typical presentations.

8ide gap between first and second toes and onychomycosis in patient with Down syndrome. Image courtesy of @. Dourmishev, BD, 4hD, D:c.

Endocrine abnormalities
Hashimoto thyroiditis that causes hypothyroidism is by far the most common ac7uired thyroid disorder in patients with Down syndrome.*2$, -he onset is usually from school age onwards, but onset in infancy is reported.*2#, Bore rarely, Hashimoto thyroiditis can cause hyperthyroidism*+!, ; the incidence of <raves disease is also increased.*+1, -he prevalence of thyroid disorders eg, congenital hypothyroidism, primary hypothyroidism, autoimmune thyroiditis, and compensated hypothyroidism or hyperthyrotropinemia& is reportedly +'"%. in individuals with Down syndrome and increases with increasing age. Diabetes and decreased fertility can also occur.

&ematologic abnormalities
?hildren with Down syndrome have an increased risk of developing leukemias, including acute lymphoblastic leukemia )@@& and acute myeloid leukemia )B@&.*+2, )B@ is as common as )@@ in these individuals. )cute megakaryocytic leukemia is the most common form of )B@ in affected children and is uncommon in children who do not have Down syndrome. -he relative risk of acute leukemia in the first " years of life is "2 times that of individuals without Down syndrome. )ppro5imately one in 1"! patients develops leukemia. (eonatal leukemoid reactions ie, pseudoleukemia& are common, and distinguishing this from true leukemia fre7uently poses a diagnostic challenge.*++, )lthough the risk for leukemia is higher in individuals with Down syndrome, these patients have a lower risk of developing solid tumors, with the e5ception of germ cell tumors and, perhaps, retinoblastomas and lymphomas.*+%, +", @eukemia cutis is also observed in these patients. )ppro5imately 1!. of newborns with Down syndrome develop a preleukemic clone, originating from myeloid progenitors in the fetal liver that is characteriAed by a somatic mutation in GATA1, which is localiAed on the F'chromosome. Butations in this

transcription factor lead to a truncated mutant protein <)-)1short or <)-)1s.*+2, +/, -his preleukemia is referred to as transient leukemia -@&, transient myeloproliferative disease -BD&, or transient abnormal myelopoiesis -)B&.*+$, -BD is a hematologic abnormality that primarily affects infants with Down syndrome in the neonatal period.*+#, %!, It is characteriAed by an e5cessive proliferation of myeloblast cells in the infant6s blood and bone marrow.*%1, )ppro5imately 1!. of infants with Down syndrome have -BD.*%2, However, this estimate probably identifies only patients whose symptoms were severe enough to warrant a complete blood count ?1?& and in whom the presence of blasts was of concern to the primary care provider.*%+, )n estimated 2". of infants with Down syndrome who present with -BD develop megakaryocytic leukemia 1'+ years later.*%%, -BD is associated with pancytopenia, hepatosplenomegaly, and circulating immature white blood cells 81?s&. -BD spontaneously regresses within the first + months of life. In some children, however, it can be life'threatening.*%", %2, Despite the high rate of spontaneous regression, -BD can be a preleukemic disorder in 2!'+!. of children with Down syndrome. -he patient6s risk of carrying hepatitis 1 is increased if he or she was previously institutionaliAed.

mmunodeficiency
4atients have about a 12'fold increased risk of infectious diseases, especially pneumonia, because of impaired cellular immunity.

+umor profile
-he tumor profile of patients with Down syndrome is different from that of other people. :yringomas occur more often in patients with Down syndrome than in other patients. -hese benign appendiceal tumors are observed in 1$."'+#. of patients with this disease. 3emales are affected more than twice as often as males. @esions are usually limited to regions around the eyes, but disseminated syringomas are also observed. -he presence of tumors is not related to IH or any other manifestation of the disorder.

+risomy 21 mosaicism
-risomy 21 mosaicism can present with absent or minimal manifestations of Down syndrome and may be underdiagnosed as a cause of early'onset )lAheimer disease.*%/, -he phenotype of persons having mosaicism for trisomy 21 and Down syndrome reflects the percentage of trisomic cells present in different tissues.*%$,

'omplications
?omplications of Down syndrome involve almost every organ system of the body. *%#,

'ardiac and cardio(ascular complications

?ardiovascular complications are important in Down syndrome.*2!, ?hildren who seem asymptomatic at birth and do not have a murmur may have a significant cardiac defect. If increased pulmonary vascular resistance is noted, the left'to'right shunt may be minimiAed, thus preventing early heart failure. However, if left undetected, this condition may lead to persistent pulmonary hypertension with irreversible pulmonary vascular changes. <enerally, surgery to correct the heart defect is delayed until the infant is larger and is strong enough to tolerate the operation, which is usually performed at age 2'# months. Bost children do very well and thrive after the procedure. In patients with an atrioventricular septal defect, symptoms usually occur in infancy as a result of systemic'to'pulmonary shunting, high pulmonary blood flow, and an increased risk of pulmonary arterial hypertension. Increased pulmonary resistance may lead to a reversal of the systemic'to'pulmonary shunt accompanied by cyanosis ie, Disenmenger syndrome&. 4atients with Down syndrome are considered to be at higher risk for pulmonary arterial hypertension than patients without Down syndrome. -his is because of the diminished number of alveoli, the thinner media of pulmonary arterioles, and the impaired endothelial function in these patients. Darly corrective cardiac surgery is warranted to prevent irreversible pulmonary vascular lung damage. Boreover, new medical treatment strategies eg, prostacyclin, endothelin receptor antagonist and phosphodiesterase'"'inhibitor& have been demonstrated to substantially improve clinical status and life e5pectancy of patients with pulmonary arterial hypertension. ?oronary artery diseaseMrelated mortality is surprisingly low. 4athologic studies have revealed decreased levels of atherosclerosis in Down syndrome.

)astrointestinal complications
<astroesophageal reflu5 is commonly seen in children with Down syndrome and can be severe enough to result in aspiration of stomach contents, resulting in respiratory symptoms such as persistent coughing, wheeAing, and pneumonia. Infants with oral' motor difficulties may present with choking and gagging on feedings as well as the respiratory symptoms mentioned. ?eliac disease is more common in patients with Down syndrome than in those without. ?hronic constipation is fre7uently seen. ;besity is common. 4atients need to have specific dietary guidelines on caloric needs and portion siAes. )n active lifestyle with routine e5ercises is recommended for the whole family. ?hildren should be encouraged to participate in recreational activities, such as swimming, dancing, walking, and playing outdoors.

,p#t#almologic complications
?ommon eye disorders include fractive errors, such as myopia, hyperopia, and astigmatism, which can be corrected with glasses if the child is willing to wear them. ;ther common eye disorders include strabismus and nystagmus. ?ongenital cataracts can lead to blindness if left untreated. )dditional serious eye disorders include glaucoma and keratoconus. 1lockage of tear ducts nasolacrimal duct stenosis& is common and can lead to increased tear stasis and conIunctivitis.

,tolaryngologic complications
Bany children e5perience recurrent ear infections or persistent middle ear effusions, probably caused by midfacial hypoplasia. Darly and aggressive treatment of chronic ear disease can greatly reduce hearing loss in children with Down syndrome. :inusitis and nasopharyngitis may occur secondary to narrow nasal passages and sinuses. ;bstructive sleep apnea may develop secondary to enlarged tonsils or to other causes of upper airway obstruction.

Endocrine complications
-hyroid dysfunction, particularly hypothyroidism, is relatively common in Down syndrome. Hyperthyroidism can also occur. Diabetes mellitus occurs with higher fre7uency.

&ematologic complications
4atients with Down syndrome e5hibit a uni7ue pattern of malignancies, yielding intriguing insights into cancer biology.*"!, -hese patients also pose distinctive challenges to the oncologist because of their particular profile of treatment'related to5icities. Individuals with Down syndrome have a higher risk for leukemia, e5periencing + distinct disease entities ie, -BD, )B@, and )@@& and have a lower risk for solid tumors. ?hildhood leukemia is relatively common0 )B@ is more common in infants, whereas )@@ is more common in children older than 1 year. (ewborn infants with Down syndrome are prone to -BD also known as leukemoid reaction, transient abnormal myelopoiesis, or transient leukemia&; in some cases, it can progress to more severe disease, such as )B@, within the first % years of life.

mmunologic complications
?hildren are more prone to recurrent respiratory and systemic infections secondary to deficiencies in some immunoglobulin levels. Immunoglobulin Ig& ) deficiency as well as Ig< subclasses can be seen in individuals with Down syndrome. Individuals with Down syndrome are also more susceptible to autoimmune diseases, such as thyroid disease hypothyroidism more often than hyperthyroidism&, diabetes, and celiac disease.

,rt#opedic complications
)ppro5imately 2!. of all patients with Down syndrome e5perience orthopedic problems.*"1, Epper cervical spine instability has the most potential for morbidity and conse7uently re7uires close monitoring. ;ther conditions eg, scoliosis, hip instability, patellar instability, and foot problems& can cause disability if left untreated. In some of these conditions, early diagnosis can prevent severe disability. )tlantoa5ial instability, defined as increased mobility of the cervical spine at the level of the first and second vertebrae, can lead to sublu5ation of the cervical spine. )ppro5imately 1!'+!. of individuals with Down syndrome have this condition.*"2, Bost are asymptomatic; however, 1!. of individuals with atlantoa5ial instability have symptoms, including neck pain, torticollis, changes in gait, changes in bowel or bladder control, or other signs of paralysis or weakness.*"+, >oint dislocations due to ligamentous la5ity and hypotonia are observed. ;ther orthopedic conditions include genu valgus, overpronation of the ankle, and flat feet.

Psyc#iatric and be#a(ioral complications

4sychiatric disorders are reported in 1+'1/.2. of children with Down syndrome *"%, ; these conditions include common psychiatric disorders such as depression, an5iety, obsessive' compulsive disorder, schiAophrenia, and anore5ia nervosa. ;ther disruptive behavior disorders, such as attention'deficitJhyperactivity disorder, oppositional defiant disorder, and conduct disorder, can also be present. )utism spectrum disorders deserve mention because they occur at higher rates in children with Down syndrome than in the general population. ?urrent evidence indicates that autism affects 1 of every 1"! children.*"", )lAheimer disease or )lAheimer'type dementia can occur at a relative early age. -he disease is characteriAed by memory loss, inability to learn new information, and a decline in intellectual skills. 1ehavioral changes in Down syndrome diagnosed with )lAheimer dementia include the following*1$, 0

)pathy Dpisodic noisy e5citement Irritability 8andering and confusion Destructive, aggressive or difficult behavior @ethargy, withdrawal, loss of interest :illiness @imited response to people :ocial inade7uacy, isolation D5treme changes in appetite typically leading to weight loss& Cestlessness

:leep disturbance Incontinence D5cessively uncooperative )n5iety and fearfulness :adness :tealing and general regressive behavior 4ersonality changes Increased dependence

Diagnostic 'onsiderations
-he presence of $ or more of the characteristic clinical findings see 4resentation& leads to a definite diagnosis of Down syndrome. ?hromosomal analysis is recommended and of utmost importance in doubtful cases.*"2, "/, "$, In addition to the differential diagnosis, other problems to be considered include the following0

%#,FFFFG chromosome ?retinism ?hromosome 21, mosaic 21 syndrome ?hromosome 21, translocation 21 syndrome ;ther high'order multiple F chromosomes ;ther pero5isomal disorders Nellweger syndrome

Differential Diagnoses

-risomy 1$

-aboratory Studies
) complete blood count ?1?& count with differential and bone marrow e5amination is indicated. -hyroid'stimulating hormone -:H& and thyro5ine -%& levels should be obtained at birth and annually thereafter. 4erform 4apanicolaou smears every 1'+ years in se5ually active women starting at the age of first intercourse. In addition, the following studies should be considered.

'ytogenetic studies
-he clinical diagnosis should be confirmed with cytogenetic studies. Oaryotyping is essential to determine the risk of recurrence. In translocation Down syndrome,

karyotyping of the parents and other relatives is re7uired for proper genetic counseling see the images below&.

<'banded karyotype showing trisomy 21 %/,FG,P21&.

<'banded karyotype showing trisomy 21 of isochromosome arm 217 type *%2,FG,i 21& 71!&,.

nterp#ase fluorescence in situ #ybridi.ation

3luorescence in situ hybridiAation 3I:H& may be used for rapid diagnosis. It can be successful in both prenatal diagnosis and diagnosis in the neonatal period. ;ccult mosaicism for trisomy 21 may partially e5plain the previously described association between family history of Down syndrome and risk of )lAheimer disease. :creening for mosaicism with 3I:H is indicated in selected patients with mild developmental delay and those with early'onset )lAheimer disease.*%/, Dvaluation of the proportion of cells with trisomy 21 in mosaic trisomy 21 includes the following*%$, 0

@ymphocyte preparations 1uccal mucosa cellular preparations 3I:H :coring fre7uency of trisomic cells

Measurement of immunoglobulin )

Beasurement of immunoglobulin Ig& < levels focuses on identifying deficiencies of subclasses 2 and %. Decreased levels of Ig< subclass % is significantly correlated with bacterial infections. -hese deficits in cellular immunity have also been documented in individuals with gingivitis and periodontal disease.

%adiograp#y and /ltrasonograp#y

:kull series show evidence of flattened facial features including small or absent nasal bones&, hypoplastic sinuses, a flat occiput, microcephaly, and brachycephaly. ?ervical radiography with lateral fle5ion and e5tension views& is re7uired to measure the atlantodens distance and to rule out atlantoa5ial instability at the age of + years. Cadiography is also used before anesthesia is given if signs suggest spinal cord compression. Gearly mammograms should be obtained in women older than "! years. Ceduced iliac and acetabular angles may be present in young infants. :hort hands with shortened digits and clinodactyly due to hypoplastic middle phalan5 of the fifth finger may be present. Dchocardiography should be performed on all infants with Down syndrome to identify congenital heart disease, regardless of findings on physical e5amination.

Prenatal Screening and Diagnosis

-he first prenatal diagnosis of Down syndrome was made in 1#2$, and screening women on the basis of advanced maternal age with amniocentesis was gradually introduced into medical practice. @ow maternal serum alpha'fetoprotein B:)34& levels were associated with Down syndrome in 1#$+. @ater, elevated human chorionic gonadotropin h?<& and low unconIugated estriol uD+& levels were found to be markers for Down syndrome. 1y 1#$$, use of the + biochemical markers, together with maternal age, had been accepted as a method of prenatal screening for Down syndrome in the general population. ?urrently, in the general population, maternal age, ultrasound findings, and maternal serum markers in the first or second trimester& are used alone or in combination for risk calculation.*"#,

/ltrasonograp#y
8ith prenatal ultrasonography, trisomy 21 may be diagnosed in the second and third trimester of pregnancy. :uggestive prenatal ultrasound findings may be followed with amniocentesis and fetal chromosome analysis. 4renatal ultrasonography may reveal the following0

Eltrasonography soft markers observed in the second trimester for Down syndrome include absent or hypoplastic nasal bone, thickened nuchal fold, echogenic bowel, shortened long bones, and pyelectasis )bsent or hypoplastic nasal bone is observed in %+'22. of trisomy 21 fetuses, compared with !."'1.2. of normal fetuses ) thickened nuchal fold has been associated with a greatly increased risk of trisomy 21 and may be an early feature of fetal hydrops or cystic hygroma Dchogenic bowel has been observed in appro5imately 1". of fetuses with trisomy 21, compared with !.2. of normal fetuses; about +". of fetuses with true echogenic bowel have some underlying pathology, such as first trimester bleeding, fetal infections, and cystic fibrosis due to meconium ileus :hortened long bones humerus and femur& have been associated with an increased risk of chromosomal abnormalities; the humerus is a more reliable discriminator for Down syndrome than the femur and appears to be the ne5t most important marker after nasal bone and nuchal fold; other possible causes include skeletal dysplasia, especially if the long bones are severely shortened or abnormal in appearance eg, bowing fractures or reduced mineraliAation& 4yelectasis has been observed in appro5imately 1/. of fetuses with trisomy 21, and appro5imately 1 in every +!! fetuses with isolated pyelectasis has aneuploidy; pyelectasis has been associated with an increased risk of hydronephrosis and postnatal urinary reflu5 ;ther ultrasonographic abnormalities include cystic hygroma, duodenal atresia or stenosis double'bubble sign&, cardiac defects endocardial cushion defect with atrial and ventricular septal defects and abnormal mitral and tricuspid valves&, intracardiac echogenic focus, and prune belly anomaly

Eltrasonography should not be relied on as the primary method of diagnosing Down syndrome; the diagnosis can be missed in affected families.

Maternal serum bioc#emical mar"ers

8hen ultrasonography is used to estimate gestational age, the detection rate is about 2!. when only the B:)34 test is used, "#. when the double test B:)34 and h?<& is used, and 2#. when the triple test B:)34, h?<, uD+& is used. -he false'positive rate is ".. ;ther factors for adIustment are maternal age and weight, insulin'dependent diabetes mellitus, multiple pregnancies, racial background, previous pregnancy with Down syndrome, and first or repeat test in a pregnancy. ) positive screening result only suggests an increased risk for Down syndrome, and definitive testing with amniocentesis and chromosomal analysis is indicated. In a retrospective study of first'trimester screening for free beta'h?< and pregnancy' associated plasma protein ) 4)44')&, detection rates were as high as those associated with B:)34, h?<, or uD+ testing in the second trimester.*2!, 4rospective studies are needed to further assess first'trimester screening. :econd'trimester maternal serum

marker screening allows the detection of 2!'/!. of Down syndrome cases, with a false positive rate of "..*2!, Dffective screening for trisomy 21 is provided by assessment of a combination of maternal age, fetal nuchal translucency thickness, and maternal serum free Q'h?< and pregnancy'associated plasma protein') 4)44')& at 1!'1% weeks6 gestation.*21, 4rospective studies have demonstrated that combined screening can identify about #!. of affected fetuses, with a false'positive rate of "..*22, In nonstandard Down syndrome ie, mosaicism and translocation& cases, second'trimester maternal serum marker screening gives the same detection rate as for standard trisomy 21, e5cept in cases with low'level mosaicism L 1!.&.*"#, )fter fetal nucleated red blood cells C1?s& are sorted by using different cell transferrin and glycophorin') receptors on the cell surface, interphase 3I:H can be used to determine the chromosomal constitution. ?hromosome'specific probes available for F, G, 1+, 1$, and 21 permit diagnosis. -he 3I:H finding should be confirmed by using standard cytogenetic techni7ues.

n(asi(e diagnostic tests

)mniocentesis, routinely performed at 1%'12 weeks6 gestation, remains the criterion standard of invasive diagnostic tests. -esting for chromosomal disorders is ##.". accurate. Care cases of mosaicism are missed, and results can be inaccurate if maternal' cell contamination occurs. -he procedure is associated with a small risk of pregnancy loss 102!!'+!!&. ?horionic villus sampling ?9:& is performed at 1!'1+ weeks6 gestation; earlier testing is thought to be associated with a 1 in +!!'1!!! risk of fetal transverse limb deficiency, a small risk of maternal cell contamination, and a !."'1. risk of a fetal loss after the procedure. -he accuracy of ?9: #2'#$.& is less than that of midtrimester amniocentesis, because of confined placental mosaicism and maternal'cell contamination. 4ercutaneous umbilical blood sampling 4E1:& is appro5imately #". successful in obtaining a blood sample for cytogenetic testing. -he pregnancy'loss rate is +.2". for 4E1: done for chromosomal indications, compared with 1.2". and 2./". for 4E1: done for nonchromosomal indications. -he indication for the procedure greatly increases the risk of procedure'related pregnancy loss. -he availability of in vitro fertiliAation has allowed preimplantation diagnosis of single' gene disorders, se5 selection for F'linked disorders, and identification of chromosomal aneuploidies. )fter a biopsy sample is obtained from the first polar body, the blastocyst, or the 2'cell to $'cell embryo, 3I:H can then be used to diagnose fetal aneuploidy. However, standard cytogenetic confirmation is not possible for the preimplantation diagnosis.

Nonin(asi(e diagnostic tests

) maIor goal in the field of prenatal screening has been to reduce the need for invasive procedures. )mong high'risk pregnancies clinically indicated for invasive prenatal diagnosis, noninvasive detection of fetal trisomy 21 can be achieved by using multiple5ed, massively parallel se7uencing of maternal plasma D(), which has 1!!. sensitivity and #/.#. specificity; this provides a #2.2. positive predictive value and 1!!. negative predictive value.*2+, ) prospective multicenter study, using chromosome'selective se7uencing of cell'free D() cfD()& from maternal plasma, attained an overall 1!!. sensitivity and ##.#/. specificity for trisomy 21 and #/.%. sensitivity and ##.#+. specificity for trisomy 1$ in a large cohort of primarily high'risk women. However, further e5perience in larger populations of average'risk women is needed to clarify the role and utility of cfD() in clinical practice.*2%, -he se7uencing test could be used to rule out trisomy 21 in high'risk pregnancies before proceeding to invasive diagnostic testing to reduce the number of cases that re7uire amniocentesis or chorionic villus sampling. However, its diagnostic performance and practical feasibility in the clinical setting have not been tested on a large scale. ;ffering noninvasive massively parallel shotgun se7uencing B4::& to women already at high risk for Down syndrome can reduce procedure'related losses by up to #2., while maintaining high detection.*2", ?urrently, B4:: testing cannot yet be considered diagnostic. ?onfirmation by invasive testing is still needed.

,t#er +ests
-he auditory brainstem response )1C&, also known as the brainstem auditory evoked response 1)DC& may be tested to demonstrate hearing loss. Dvaluation of the )1C in %/ nonselected children with Down syndrome aged 2 months to +." years indicated some hearing loss in 22. 2$. unilateral, +$. bilateral&. :peech evaluation may also be indicated. 4ediatric ophthalmic e5amination should be performed for vision screening and for detecting ophthalmologic disorders. <rowth charts are available for children with Down syndrome. ) developmental chart for noninstitutionaliAed children based on a modified Denver Developmental :creening -est is available for assessing developmental milestones. Cigorous dental hygiene and dental evaluation are indicated beginning after tooth eruption.

&istologic findings
In patients with Down syndrome who have clinical signs of dementia associated with )lAheimer disease, postmortem histopathologic findings of the brains show the typical microscopic findings of )lAheimer disease.

Surgical 'are
-imely surgical treatment of cardiac anomalies, which are common during the first 2 months of life, may be necessary to prevent serious complications. 4rompt surgical repair is necessary for gastrointestinal <I& anomalies, such as tracheoesophageal fistula, pyloric stenosis, duodenal atresia, annular pancreas, aganglionic megacolon, and imperforate anus. :urgical intervention may be necessary to reduce atlantoa5ial sublu5ation and to stabiliAe the upper segment of the cervical spine if neurologic deficits are clinically significant. ?ongenital cataracts occur in about +. of children and must be e5tracted soon after birth to allow light to reach the retina. )fterward, appropriate correction with glasses or contact lenses helps ensure ade7uate vision. :urgical intervention in children with Down syndrome has a high risk of complications, particularly infection and wound healing problems.*"1, ?areful anesthetic airway management is needed because of the associated risk of cervical spine instability. 4reoperative evaluation for anesthesia must include ade7uate evaluation of the airway and the patient6s neurologic status. ?ervical radiography with fle5ion and e5tension views& should be performed when any neurologic deficit suggests spinal'cord compression. During laryngoscopy and intubation, the patient6s head should be maintained in a neutral position, and hypere5tension should be avoided. )nticholinergics can be prescribed to control hypersecretion in the airways. ;ther airway complications include subglottic stenosis and obstructive apnea, which may result from a relatively large tongue, enlarged adenoids, and midfacial hypoplasia. )denotonsillectomy may be performed to manage obstructive sleep apnea.

Diet and Acti(ity

(o special diet is re7uired, unless celiac disease is present. ) balanced diet and regular e5ercise are needed to maintain appropriate weight. 3eeding problems and failure to thrive usually improve after cardiac surgery. (o restriction of activities is necessary. )dvise the patient to e5ercise to maintain an appropriate weight. 4atients with symptoms of arrhythmia, episodes of fainting, abnormal findings on electrocardiography D?<&, and palpitations or chest pain should refrain from participating in sports and strenuous e5ercise. ?hildren with ?1'?2 sublu5ation should be allowed to compete in the :pecial ;lympics unless they have symptoms of cervical'cord compression.

'onsultations
?onsultations with the following may be indicated0

?linical geneticist ' Ceferral to a genetics counseling program is highly desirable Developmental pediatrician ?ardiologist ' Darly cardiologic evaluation is crucial for diagnosing and treating congenital heart defects, which occur in as many as 2!. of these patients 4ediatric pneumonologist ' Cecurrent respiratory tract infections are common in patients with Down syndrome ;phthalmologist*2#, (eurologistJneurosurgeon M )s many as 1!. of patients with Down syndrome have epilepsy; therefore, neurologic evaluation may be needed ;rthopedic specialist ?hild psychiatrist ' ) child psychiatrist should lead liaison interventions, family therapies, and psychometric evaluations 4hysical and occupational therapist :peech'language pathologist )udiologist

Approac# 'onsiderations
4hysicians and parents should be aware of the range of psychomotor potential so that early intervention, schooling, and community placement are provided. Despite continued work, no notable medical treatments for mental retardation associated with Down syndrome have been forthcoming. However, the dramatic improvements in medical care described below have greatly improved the 7uality of life for patient and increased their life e5pectancy. Esual immuniAations and well childcare should be performed as the )merican )cademy of 4ediatrics recommends. )ssociated conditions should be monitored periodically as the child grows older.

:urgical management of associated conditions should be provided as appropriate. Down syndrome alone does not adversely affect surgical outcomes in the absence of pulmonary hypertension. 1ecause of potential atlanto'occipital instability, care should be taken when sedation and airway management are considered for procedures or for consideration of sports participation. 3urther outpatient care may include the following0

)udiologic evaluation for hearing loss )pnea monitoring

Cegular screening is necessary for institutionaliAed older adults to diagnose early'onset dementia, epilepsy, hypothyroidism, and early loss of visual acuity and hearing.

)enetic 'ounseling
+risomy 21
) previous history of trisomy can increase a woman6s risk for a recurrence.*22, If the couple has a child with trisomy 21, the risk of recurrence is about 1..*2/, -he risk does not appear to be increased in siblings of affected individuals.

+ranslocation
-he recurrence risk depends on the type of translocation. In most cases, the recurrence risk for de novo translocations is similar to that of the general population but may be slightly higher in some situations; it is estimated to be 2'+..*2$, If the child has a translocation, a balanced translocation must be e5cluded in the parents. ) parent with a balanced Cobertsonian translocation is phenotypically normal but has an increased risk of having a chromosomally unbalanced offspring. If either parent has a translocation, start additional family studies and counseling. -he theoretic recurrence risk for a Cobertsonian carrier parent to have a liveborn offspring with Down syndrome is 1 in +. However, only 1!'1". of the progeny of carrier mothers and only 2'+. of the progeny of carrier fathers have Down syndrome. -he reason for this difference is not clear. In a carrier parent with a 217217 translocation or isochromosome, the recurrence risk is 1!!..

Mosaicism
Bost patients with mosaic Down syndrome were once trisomy 21 Aygotes. -he phenotype varies and possibly reflects the variable proportion of trisomy 21 cells in the embryo during early development. In rare instances, low'level mosaicism in the germinal

tissue of a parent is postulated to be the cause of having more than one trisomic child in a family.

%eproduction
)ffected individuals rarely reproduce. )bout 1"'+!. of females with trisomy 21 are fertile and have a "!. risk of having an affected child. -he literature contains reports of % pregnancies fathered by + male patients with Down syndrome. Infertility in males has been attributed to defective spermatogenesis, but ignorance of the se5ual act may be one of the contributing factors.

P#armacologic +#erapy and Supporti(e 'are

-he standard immuniAations and well'child care should be provided. In addition, specific manifestations of the syndrome and associated conditions must be addressed, as follows0

<ive thyroid hormone for hypothyroidism to prevent intellectual deterioration and improve the individual6s overall function, academic achievement, and vocational abilities :ubacute bacterial endocarditis prophyla5is is needed in susceptible children with cardiac disease when they undergo dental work or other invasive procedures <ive digitalis and diuretics as necessary for cardiac management 4rovide prompt treatment of respiratory tract infections and otitis media ?onsider pneumococcal and influenAa vaccination for children with chronic cardiac and respiratory disease )dminister anticonvulsants for tonic'clonic seiAures or for infantile spasms treat with steroids& 4rovide pharmacologic agents, psychotherapy, or behavioral therapy for psychiatric disorders -reat skin disorders with weight reduction, proper hygiene, fre7uent baths, application of antibiotic ointment, or systemic antibiotic therapy 4revent dental caries and periodontal disease through appropriate dental hygiene, fluoride treatments, good dietary habits, and restorative care

Darly intervention programs are promising. 4rograms for infants aged !'+ years are designed to monitor and enrich their development by focusing on feeding, as well as gross and fine motor, language, personal, and social development. Darly intervention techni7ues may improve the patient6s social 7uotient. ;verall, positive developmental changes are observed in children with Down syndrome, particularly in terms of their independence, community functioning, and 7uality of life. Begadoses of vitamins and minerals supplemented with Ainc or selenium have not been found beneficial in a number of well'controlled scientific studies.

?hildren with Down syndrome and leukemia are more sensitive to some chemotherapeutic agents eg, methotre5ate& than other children. -hus, they re7uire careful monitoring for to5icity.

Special 'onsiderations in Adolescents

)s the patient with Down syndrome passes from infancy through childhood to adolescence, the following monitoring measures are indicated0

4erform annual audiologic evaluation 4erform annual ophthalmologic evaluations for keratoconus or corneal opacities or cataracts

Banifestations of the syndrome and associated conditions must be evaluated and addressed on an ongoing basis, as follows0

-reat dermatologic issues, such as folliculitis, 5erosis, atopic dermatitis, seborrheic dermatitis, fungal infections of skin and nails, vitiligo, and alopecia 4revent obesity by decreasing the patient6s caloric intake and increasing activity social and leisure& :creen for celiac disease symptoms such as constipation, diarrhea, bloating, poor growth, or weight loss&, and treat the patient with a gluten'free diet )ddress any swallowing difficulties that persist through the adolescent years 4rovide antibiotic prophyla5is during dental and surgical procedures in the presence of mitral valve prolapse ?onsider bone marrow transplantation if leukemia occurs -reat airway obstruction medically and surgically. 4ay special attention to perioperative modalities because of atlantoa5ial instability and problems with the respiratory system :creen for hypothyroidism and diabetes mellitus Banage neurologic problems, including mental retardation, hypotonia, seiAures, and strokes ?ontinue speech and language therapy, with a focus on e5pressive language and intelligibility Dvaluate and treat behavioral problems, such as disruptive behavior disorders, stereotypic behaviors, phobias, elimination difficulties, autism, eating problems, self'inIurious behavior, and -ourette syndrome; evaluate and treat psychiatric disorders, such as depression and self'talk ?ontinue subacute bacterial endocarditis prophyla5is in adolescents with cardiac defects; during adolescence, an additional 2. of patients die of complications of congenital heart disease, infections, leukemia, and accidents Cepeat cervical spine radiography as needed for :pecial ;lympics participation.

In particular, it is important to discuss issues related to the transition to adulthood0

DmphasiAe the importance of a well'balanced diet and routine e5ercise Ceview plans for school placement and plans after high'school graduation and future vocational plans Discuss plans for alternative long'term living arrangements eg, community living&; parents should update estate planning and custody arrangements Dncourage social and recreational programs with friends )ddress concerns regarding menstrual hygiene, se5ual abuse, pregnancy, and premenstrual syndrome Discuss se5uality and socialiAation, as well as the need for supervision and degree of supervision re7uired; review options for contraception if the teen is se5ually active; make recommendations for routine gynecologic care Bonitor the family6s need for supportive care or counseling, respite care, and behavior management techni7ues; facilitate referrals for respite care and treatment of parental problems 3acilitate the patient6s transfer to adult health care

Medication Summary
Drug therapy is not currently a component of the standard of care for Down syndrome. Bedications are indicated only for symptomatic treatment of pain. ;bviously, prolonged use of analgesics without diagnostic evaluation and an understanding of the underlying cause should not be encouraged. (o particular analgesic is superior. Diuretics and digo5in should be used to manage congestive heart failure secondary to congenital heart defect.

Analgesics0 ,t#er
'lass Summary
4ain control is essential to 7uality patient care. It ensures patient comfort and promotes pulmonary toilet, and analgesics have sedating properties that are beneficial for patients who have sustained trauma or inIuries. 9iew full drug information

Acetaminop#en and codeine 1+ylenol 230 'apital and 'odeine4

?odeine is a centrally acting analgesic; acetaminophen is a peripherally acting analgesic. -he combination is indicated for treatment of mild to moderately severe pain. -ablets contain acetaminophen +!! mg and codeine phosphate +! mg; eli5ir contains acetaminophen 12! mg and codeine 12 mg per " m@.

9iew full drug information

Morp#ine sulfate 1Duramorp#0 Astramorp#0 MS 'ontin0 ,ramorp# S%4

Borphine is a narcotic drug that interferes with opioid receptors; it mainly acts on the central nervous system ?(:& and the gastrointestinal <I& tract. 9iew full drug information

buprofen 1Motrin0 Ad(il0 'aldolor4

Ibuprofen is a member of the propionic acid group of nonsteroidal anti'inflammatory drugs (:)IDs&. It has anti'inflammatory, analgesic, and antipyretic activity. Its mode of action is not clear but might be related to prostaglandin synthetase inhibition. 9iew full drug information

Napro$en 1Ale(e0 Anapro$0 Naprosyn0 Naprelan4

(apro5en is an (:)ID of the arylacetic acid group. It inhibits prostaglandin synthesis.

Antidysr#yt#mics0 a
'lass Summary
)ntidysrhythmics may improve morbidity in patients with congestive heart failure secondary to congenital heart defect. 9iew full drug information

Digo$in 1-ano$in4

Digo5in is a cardiac glycoside with direct inotropic effects in addition to indirect effects on the cardiovascular system. It acts directly on cardiac muscle, increasing myocardial systolic contractions. Indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure.

Diuretics0 ,t#er
'lass Summary
Diuretics should be used to manage congestive heart failure secondary to congenital heart defects. 9iew full drug information

Furosemide 1-asi$4

3urosemide increases e5cretion of water by interfering with the chloride'binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule. -he bioavailability of oral furosemide is "!.. If a switch is made from intravenous to oral administration, an e7uivalent oral dose should be used. Doses vary depending on the patientRs clinical condition. 9iew full drug information

&ydroc#lorot#ia.ide 1Micro.ide4

HydrochlorothiaAide inhibits reabsorption of sodium in distal tubules, causing increased e5cretion of sodium and water as well as potassium and hydrogen ions. 9iew full drug information

Metola.one 15aro$olyn4

BetolaAone is a 7uinaAoline diuretic with properties similar to those of thiaAide diuretics. It inhibits sodium resorption at the cortical diluting site and the pro5imal convoluted tubule.