Down Syndrome

Down syndrome is by far the most common and best known chromosomal disorder in humans and the most common cause of intellectual disability.[3, 4, 5, 6, 7] It is characterized by intellectual disability, 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. The term mongolism was once commonly used for Down syndrome but is now considered obsolete.[8, 9, 10]

Like most diseases associated with chromosomal abnormalities, trisomy 21 gives rise to multiple systemic complications as part of the clinical syndrome. This 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.[1]

The extra chromosome 21 affects almost every organ system and results in a wide spectrum of phenotypic consequences. These include life-threatening complications, clinically significant alteration of life course (eg, intellectual disability), and dysmorphic physical features. Down syndrome decreases prenatal viability and increases prenatal and postnatal morbidity. Affected children have delays in physical growth, maturation, bone development, and dental eruption.

Two different hypotheses have been proposed to explain the mechanism of gene action in Down syndrome: developmental instability (ie, loss of chromosomal balance) and the so-called gene-dosage effect.[11] According to the gene-dosage effect hypothesis, the genes located on chromosome 21 have been overexpressed in cells and tissues of Down syndrome patients, and this contributes to the phenotypic abnormalities.[12]

The extra copy of the proximal part of 21q22.3 appears to result in the typical physical phenotype, which includes the following:

• Intellectual disability - Most patients with Down syndrome have some degree of cognitive impairment, ranging from mild (intelligence quotient [IQ] 50-75) to severe impairment (IQ 20-35); patients show both motor and language delays during childhood

• Characteristic facial features

• Hand anomalies

• Congenital heart defects - Almost half of affected patients have congenital heart disease, including ventricular septal defect and atrioventricular canal defect

Molecular analysis reveals that the 21q22.1-q22.3 region, also known as the Down syndrome critical region (DSCR), appears to contain the gene or genes responsible for the congenital heart disease observed in Down syndrome. A new gene, DSCR1, identified in region 21q22.1-q22.2, is highly expressed in the brain and the heart and is a candidate for involvement in the pathogenesis of Down syndrome, particularly with regard to intellectual disability and cardiac defects.

Abnormal physiologic functioning affects thyroid metabolism and intestinal malabsorption. Patients with trisomy 21 have an increased risk of obesity. Frequent infections are presumably due to impaired immune responses, and the incidence of autoimmunity, including hypothyroidism and rare Hashimoto thyroiditis, is increased.

A study by Baksh et al indicated that the risk of contracting coronavirus disease 2019 (COVID-19) is increased in persons with Down syndrome, finding that 7.4% of study subjects with Down syndrome had a COVID-19 diagnosis, compared with 5.6% of controls (odds ratio [OR] = 1.35). Moreover, individuals with Down syndrome who had a chronic respiratory disease were found to have an even greater chance of being diagnosed with COVID-19, the odds ratio (with the exclusion of asthma) being 1.71.[13]

A study by Tarani et al of prepubertal children with Down syndrome indicated that neutrophins and immune-system pathways are disrupted in these patients. The investigators found that in these children, brain-derived neurotrophic factor (BDNF) levels were higher than in controls, while there was a significant reduction in serum levels of tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), monocyte chemoattractant protein-1 (MCP-1), interleukin 1α (IL-1α), IL-2, IL-6, IL-10, and IL-12.[14]

Patients with Down syndrome have decreased buffering of physiologic reactions, resulting in hypersensitivity to pilocarpine and abnormal responses on sensory-evoked electroencephalographic (EEG) tracings. Children with leukemic Down syndrome also have hyperreactivity to methotrexate.

Decreased buffering of metabolic processes results in a predisposition to hyperuricemia and increased insulin resistance. Diabetes mellitus develops in many affected patients. Premature senescence causes cataracts and Alzheimer disease. Leukemoid reactions of infancy and an increased risk of acute leukemia indicate bone-marrow dysfunction.

Children with Down syndrome are predisposed to developing leukemia, particularly transient myeloproliferative disorder and acute megakaryocytic leukemia. Nearly all children with Down syndrome who develop these types of leukemia have mutations in the hematopoietic transcription factor gene, GATA1. Leukemia in children with Down syndrome requires at least 3 cooperating events: trisomy 21, a GATA1 mutation, and a third, undefined genetic alteration.

Musculoskeletal manifestations in patients with Down syndrome include reduced height, atlanto-occipital and atlantoaxial hypermobility, and vertebral malformations of the cervical spine. These findings may lead to atlanto-occipital and cervical instability, as well as complications such as weakness and paralysis.

About 5% of patients with Down syndrome have GI manifestations, including duodenal atresia, Hirschsprung disease, and celiac disease. Many patients with trisomy 21 have otorhinolaryngologic manifestations, including hearing loss and recurrent ear infections. About 60% of patients have ophthalmic manifestations.

A study by Romano et al indicated that in persons with Down syndrome, brain cortical thickness is reduced with increasing age. The study involved 91 persons with Down syndrome, none of whom had dementia, with cortical thickness measured using magnetic resonance imaging (MRI). Frontal, temporal, parietal, and cingulate gyrus measurements showed bilateral cortical thinning in association with age, with thickness apparently declining more significantly and rapidly between the ages of 20 and 30 years.[15]

The American College of Obstetricians and Gynecologists (ACOG) has published pertinent guidelines on screening for fetal chromosomal abnormalities.[16]

Down syndrome is caused by the following 3 cytogenic variants:

• Three full copies of chromosome 21

• Chromosomal translocation that results in 3 copies of the critical region for Down syndrome

• Mosaicism

In 94% of patients with Down syndrome, full trisomy 21 is the cause; mosaicism (2.4%) and translocations (3.3%) account for the remaining cases. Approximately 75% of the unbalanced translocations are de novo, and approximately 25% result from familial translocation.

A free trisomy 21 results from nondisjunction during meiosis in one of the parents. This occurrence is correlated with advanced maternal and paternal age. About 95% of the time, the error is maternal nondisjunction, with meiosis I errors occurring three times as frequently as meiosis II errors. The remaining 5% cases are paternal in origin, and meiosis II errors predominate.

Advanced maternal age remains the only well-documented risk factor for maternal meiotic nondisjunction. However, understanding of the basic mechanism behind the maternal age effect is lacking.

Translocation occurs when genetic material from chromosome 21 becomes attached to another chromosome, resulting in 46 chromosomes, with 1 chromosome having extra material from chromosome 21 attached. It may occur de novo or be transmitted by one of the parents. Translocations are usually of the centric fusion type. They frequently involve chromosome 14 (14/21 translocation), chromosome 21 (21/21 translocation), or chromosome 22 (22/21 translocation).

Mosaicism is considered a postzygotic event (ie, one that occurs after fertilization). Most cases result from a trisomic zygote with mitotic loss of one chromosome. As a result, two cell lines are found: one with a free trisomy and the other with a normal karyotype. This finding leads to great phenotypic variability, ranging from near normal to the classic trisomy 21 phenotype.

Cytogenetic and molecular studies suggest that dup21(q22.1-22.2) is sufficient to cause Down syndrome. The DSCR contains genes that code for enzymes, such as superoxide dismutase 1 (SOD1), cystathionine beta-synthase (CBS), glycinamide ribonucleotide synthase-aminoimidazole ribonucleotide synthase-glycinamide formyl transferase (GARS-AIRS-GART).

Down syndrome is the most common autosomal abnormality. The frequency is about 1 case in 800 live births. Each year, approximately 6000 children are born with Down syndrome.[17] Down syndrome accounts for about one third of all moderate and severe mental handicaps in school-aged children. The prevalence of Down syndrome worldwide has increased because of increases in life span in the last few decades.

Age-related demographics

Down syndrome can be diagnosed prenatally with amniocentesis, percutaneous umbilical blood sampling (PUBS), chorionic villus sampling (CVS), and extraction of fetal cells from the maternal circulation. It is often diagnosed shortly after birth by recognizing dysmorphic features and the distinctive phenotype. The characteristic morphologic features will be obvious in children older than 1 year. Some dermatologic features increase with advancing age.

Occurrence is strongly dependent on maternal age. The incidence of this syndrome at various maternal ages is as follows:

• 15-29 years - 1 case in 1500 live births

• 30-34 years - 1 case in 800 live births

• 35-39 years - 1 case in 270 live births

• 40-44 years - 1 case in 100 live births

• Older than 45 years - 1 case in 50 live births

On rare occasions, the disease can be observed in a few members of a family. The risk for recurrence of Down syndrome in a patient’s siblings also depends on maternal age.

Sex-related demographics

Overall, the two sexes are affected roughly equally. The male-to-female ratio is slightly higher (approximately 1.15:1) in newborns with Down syndrome, but this effect is restricted to neonates with free trisomy 21.

Perhaps 50% of female patients with trisomy 21 are fertile, and these females have up to a 50% chance of having a live child who also has trisomy 21. (However, many affected fetuses abort spontaneously.) On the other hand, men with Down syndrome are usually infertile, except for those with mosaicism.

Race-related demographics

Down syndrome has been reported in people of all races; no racial predilection is known. African American patients with Down syndrome have substantially shorter life spans than white patients with trisomy 21.

The overall outlook for individuals with Down syndrome has dramatically improved. Many adult patients are healthier and better integrated into society, and life expectancy has improved from 25 years in 1983 to 60 years or higher today.

Approximately 75% of concepti with trisomy 21 die in embryonic or fetal life. Approximately 25-30% of patients with Down syndrome die during the first year of life. The most frequent causes of death are respiratory infections (bronchopneumonia) and congenital heart disease. The median age at death is in the mid-50s.

Congenital heart disease is the major cause of morbidity and early mortality in patients with Down syndrome. In addition, esophageal atresia with or without transesophageal (TE) fistula, Hirschsprung disease, duodenal atresia, and leukemia contribute to mortality. The 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.[18] Clinically, 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 institutionalization are associated with mortality.

Individuals with Down syndrome have a greatly increased morbidity, primarily because of infections involving impaired immune response. Large tonsils and adenoids, lingual tonsils, choanal stenosis, or glossoptosis can obstruct the upper airway. Airway obstruction can cause serous otitis media, alveolar hypoventilation, arterial hypoxemia, cerebral hypoxia, and pulmonary arterial hypertension with resulting cor pulmonale and heart failure.

Leukemia, thyroid diseases, autoimmune disorders, epilepsy, intestinal obstruction, and increased susceptibility to infections (including recurrent respiratory infections) are commonly associated with Down syndrome.

The aging process seems to be accelerated in patients with Down syndrome. Many patients develop progressive Alzheimer-like dementia by age 40 years, and 75% of patients have signs and symptoms of Alzheimer disease.[19]

A delay in recognizing atlantoaxial and atlanto-occipital instability may result in irreversible spinal-cord damage. Visual and hearing impairments in addition to intellectual disability may further limit the child’s overall function and may prevent him or her from participating in important learning processes and developing appropriate language and interpersonal skills. Unrecognized thyroid dysfunction may further compromise central nervous system (CNS) function.

A questionnaire study by Matthews et al of caregivers of persons with Down syndrome aged 20 years or older reported that, while adults with Down syndrome who had a greater amount of health issues tended not to be independent and social and although current health problems impacted communication skills in these individuals, the number of congenital abnormalities in adults with Down syndrome was not significantly associated with scores for independence/life skills.[20]

Career preparation should include acquisition of job skills, choice of job area, development of work-support behavior, and opportunities for job mobility. The goal of successful transition from school to the world of work is meaningful employment and optimal function in the least restrictive environment.

Opportunities to participate in community life should be made available. Individuals should be encouraged to pursue daily living tasks with minimal or no assistance. They should participate in cultural, leisure, and recreational activities during the growing years. Patients may qualify for supplemental security income (SSI) depending on their family’s income.

A parent’s guide to the genetics of Down syndrome is available.[9]  Parents might benefit from joining a local Down syndrome support group. Additional resources can be obtained from the following organizations:

• National Down Syndrome Society, 666 Broadway, 8th floor, New York, NY 10012; 800-221-4602; www.ndss.org/

• National Down Syndrome Congress, 30 Mansell Court, Suite 108, Roswell, GA 30076; 800-232-NDSC (6372), 770-604-9500; www.ndsccenter.org/

• National Association for Down Syndrome, 1460 Renaissance Drive, Suite 405, Park Ridge, IL 60068; 630-325-9112; www.nads.org/

• American Academy of Pediatrics (guidelines)[2] : Bull MJ, for the Committee on Genetics. Health supervision for children with Down syndrome. Pediatrics. 2011;128(2):393-406. PMID: 21788214. Full text: http://pediatrics.aappublications.org/content/128/2/393.long.

Books for parents[2] : 

• Skallerup SJ. Babies with Down Syndrome: A New Parents Guide.
• Pueschel SM, ed. A Parent's Guide to Down Syndrome: Toward a Brighter Future.
• Simmons J. The Down Syndrome Transition Handbook: Charting Your Child's Course to Adulthood. 

When recording the history from the parents of a child with Down syndrome, the clinician should include the following[21] :

• Parental concern about hearing, vision, developmental delay, respiratory infections, and other problems

• Feeding history to ensure adequate caloric intake

• Prenatal diagnosis of Down syndrome

• Vomiting secondary to GI tract blockage by duodenal web or atresia

• Absence of stools secondary to Hirschsprung disease

• Delay in cognitive abilities, motor development, language development (specifically expressive skills), and social competence

• Arrhythmia, fainting episodes, palpitations, or chest pain secondary to heart lesion

• Symptoms of sleep apnea, including snoring, restlessness during sleep, difficulty awaking, daytime somnolence, behavioral changes, and school problems

• A history of possible physical or sexual abuse

Symptoms of atlantoaxial instability include the following:

• About 13-14% of patients have radiographic evidence of atlantoaxial instability but no symptoms

• Only 1-2% of patients have symptoms that require treatment

• Symptoms 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, hyperreflexia, clonus, extensor-plantar reflex, loss of upper-body strength, abnormal neurologic reflexes, change in bowel and bladder function, increased muscle tone in the legs, and changes in sensation in the hands and feet

• These symptoms often remain relatively stable for months or years

• In rare cases, the symptoms progress to paraplegia, hemiplegia, quadriplegia, or death

On physical examination, patients with trisomy 21 have characteristic craniofacial findings, such as the following:

• Flat occiput and a flattened facial appearance

• Small brachycephalic head

• Epicanthal folds

• Flat nasal bridge

• Upward-slanting palpebral fissures

• Brushfield spots

• Small nose and small mouth

• Protruding tongue

• Small and dysplastic ears

• Generous nuchal skin

General physical features in patients with Down syndrome may include the following[22, 23, 24, 25, 26, 27] :

• Shortened extremities

• Short, broad hands, with short fifth finger with hypoplasia of the middle phalanx and clinodactyly, along with single transverse palmar creases (~60% of patients)

• Joint hyperextensibility or hyperflexibility

• A wide space between the first and second toes (sandal gap)

• Neuromuscular hypotonia

• Diastasis recti

• Dry skin

• Premature aging

• Wide range of intelligence quotients (IQs)

• Congenital heart defects

These findings and features are described more fully below.

Central nervous system

Moderate to severe intellectual disability occurs as a constant feature, with IQs ranging from 20 to 85 (mean, approximately 50). Muscle hypotonia is seen in newborns with decreased response to normal stimuli; this improves with age. Articulatory problems are present. Sleep apnea occurs when inspiratory airflow from the upper airway to the lungs is impeded for 10 seconds or longer; it often results in hypoxemia or hypercarbia.

Seizure disorders are present in 5-10% or patients. Infantile spasms are the most common seizures observed in infancy, whereas tonic-clonic seizures are most common in older patients.

Behavior and psychiatric status

In general, natural spontaneity, genuine warmth, cheerfulness, gentleness, patience, and tolerance are characteristics of patients with Down syndrome. A few patients exhibit anxiety and stubbornness.

Most children with Down syndrome do not have a coexisting psychiatric or behavioral disorder. The available estimates of psychiatric comorbidity range from 18-38%. The disorders include attention-deficit/hyperactivity 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, seizures, neoplasms, degenerative vascular disease, loss of adaptive abilities, and increased risk of senile dementia of Alzheimer type are observed.

For more detailed information on this topic, please consult the following article: Zigman WB. Atypical aging in Down syndrome. Dev Disabil Res Rev. 2013;18(1):51-67. PMID: 23949829[28]

Skull

Brachycephaly, 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 maxillary sinuses occur.

Eyes

Up-slanting palpebral fissures, bilateral medial epicanthal folds, Brushfield spots (speckled iris), refractive errors (50%), strabismus (44%), nystagmus (20%), blepharitis (33%), conjunctivitis, tearing from stenotic nasolacrimal ducts, congenital cataracts (3%), pseudopapilledema, spasm nutans (a type of nystagmus associated with head bobbing), acquired lens opacity (30-60%), retinal detachment, and keratoconus in adults are observed (see the images below).[29]

Nose

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

Mouth and teeth

Characteristic 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 (50%), tooth agenesis, malformed teeth, delayed tooth eruption, microdontia (35-50%) in both the primary and secondary dentition (see the image below), hypoplastic and hypocalcified teeth, malocclusion, taurodontism (0.54-5.6%), and increased periodontal destruction. Cleft lip or palate may occur but is rare.

Ears

The ears are small with an overfolded helix (see the images below). Chronic otitis media and hearing loss are common. About 66-89% of children have hearing loss of greater than 15-20 dB in at least 1 ear, as assessed by means of the auditory brainstem response (ABR).

Neck

The neck is typically broad and short, with excess skin on the back. Atlantoaxial instability (14%) can result from laxity of transverse ligaments that ordinarily hold the odontoid process close to the anterior arch of the atlas. Laxity can cause backward displacement of the odontoid process, leading to spinal cord compression in about 2% of children with Down syndrome.

Chest and abdomen

The internipple distance is decreased. The abdomen is frequently protuberant. Diastasis recti and umbilical hernia (see the image below) may occur.

Skin

Skin disorders occur in up to 80% of children with Down syndrome. Xerosis, localized hyperkeratotic lesions, elastosis serpiginosa, alopecia areata (< 10%), vitiligo, folliculitis (especially common in adolescents), abscess formation, and recurrent skin infections are observed.[30, 31] Distal axial triradius in the palms, transverse palmar creases, a single flexion crease in the fifth finger, ulnar loops (often 10), a pattern in hypothenar, and interdigital III regions are observed.[32]

Heart defects

Congenital heart defects are common (40-50%); they are frequently observed in patients with Down syndrome who are hospitalized (62%) and are a common cause of death in this aneuploidy in the first 2 years of life.

The most common congenital heart defects are the following:

• Endocardial cushion defect (43%), which results in atrioventricular septal defect (AVSD)/AV canal defect

• Ventricular septal defect (32%)

• Secundum atrial septal defect (10%)

• Tetralogy of Fallot (6%)

• Isolated patent ductus arteriosus (4%).

About 30% of patients have more than one cardiac defect. The most common secondary lesions are patent ductus arteriosus (16%), atrial septal defect, and pulmonic stenosis (9%). About 70% of all endocardial cushion defects are associated with Down syndrome.

Valve abnormalities, such as mitral valve prolapse or aortic regurgitation may develop in up to 40-50% of adolescents and adults who were born without structural heart disease.[33]

Gastrointestinal tract abnormalities

Newborns with Down syndrome may often have initial difficulty in establishing successful breastfeeding.

GI abnormalities occur in approximately 12% of patients. Duodenal atresia or stenosis (occasionally associated with annular pancreas) may be seen in 2.5% of newborns with Down syndrome. Hirschsprung disease (< 1%), tracheoesophageal fistula, Meckel diverticulum, imperforate anus, and omphalocele are also observed. About 25% of infants with duodenal atresia, stenosis, or annular pancreas have Down syndrome.

An increased incidence of celiac disease has been reported in Down syndrome. Signs and symptoms include growth failure, abdominal pain, and loose stools. Prevalence in individuals with Down syndrome is reportedly 5-15% in different European and US studies. Celiac disease occurs in genetically susceptible individuals, specifically those who have the human leukocyte antigen (HLA) heterodimers DQ2 (observed in 86-100% of individuals with celiac disease) and DQ8. These are strong linkages with high sensitivity and poor specificity.

Gastroesophageal reflux and swallowing difficulties are also common in individuals with Down syndrome.

Genitourinary tract abnormalities

Renal malformations, hypogenitalism (micropenis or small scrotum and testes), hypospadias, cryptorchidism, and delayed and incomplete puberty may occur.

A study by Postolache et al indicated that children with Down syndrome tend to have smaller kidneys (by length and volume) than sex-and-age–matched controls. There is also evidence that kidney function is reduced in children with Down syndrome. Forty-three percent of the children with Down syndrome in the study had an estimated glomerular filtration rate (eGFR) of below 90 mL/min/1.73 m2.[34]

Growth and skeletal anomalies

Newborns with Down syndrome have lower birth weight, length, and head circumference compared with control newborns. Growth parameters continue to be low up to puberty. Growth charts for children with Down syndrome have been published.[35] Failure to thrive is common in infancy, especially in patients with cardiac and gastrointestinal problems. Short stature occurs during adolescence and may be especially severe in patients with congenital heart disease. The exact etiology of growth retardation in Down syndrome is unknown; however, a deficiency of insulinlike growth factor 1 (IGF-1) has been described in some studies.[36]  Obesity usually starts in early childhood, and up to 50% of adults may be obese. Obesity is thought to be related to a reduced metabolic rate.[37]

Broad, short hands, feet, and digits; a short curved fifth finger (dysplasia and shortening of the midphalanx) or clinodactyly of the fifth finger with a single flexion crease; dysplasia of the pelvis (a shallow acetabular angle with small iliac wings); joint laxity; a wide gap between the first and second toes (see the image below); and atlanto-occipital instability are typical presentations.

Endocrine abnormalities

Hypothyroidism is common in Down syndrome, occurring in about 1% of newborns, 10% of children, and up to 50% of adults. Causes include congenital hypothyroidism, as well as acquired hypothyroidism secondary to Hashimoto thyroiditis.

Hashimoto thyroiditis that causes hypothyroidism is by far the most common acquired thyroid disorder in patients with Down syndrome.[38] The onset is usually from school age onwards, but onset in infancy is reported.[39] More rarely, Hashimoto thyroiditis can cause hyperthyroidism;[40] the incidence of Graves disease is also increased.[41]

Individuals with Down syndrome are at higher risk of developing type I diabetes mellitus. In addition, infertility is nearly universal in males and can occur in up to 50% of females.

Hematologic abnormalities

The most important hematologic abnormality in Down syndrome involves the white blood cells. Children with Down syndrome have an increased risk of developing leukemias, including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).[42] AML is as common as ALL in these individuals. Acute megakaryocytic leukemia is the most common form of AML in affected children and is uncommon in children who do not have Down syndrome.

The relative risk of acute leukemia in the first 5 years of life is 56 times that of individuals without Down syndrome. Approximately one in 150 patients develops leukemia. (Neonatal leukemoid reactions [ie, pseudoleukemia] are common, and distinguishing these from true leukemia frequently poses a diagnostic challenge.)[43]

Approximately 10% of newborns with Down syndrome develop a preleukemic clone, originating from myeloid progenitors in the fetal liver that are characterized by a somatic mutation in GATA1, which is localized on the X-chromosome. Mutations in this transcription factor lead to a truncated mutant protein, GATA1short or GATA1s.[44, 45]  This preleukemia is referred to as transient leukemia (TL), transient myeloproliferative disease (TMD), or transient abnormal myelopoiesis (TAM).[46, 47, 48]

TMD is a hematologic abnormality that primarily affects infants with Down syndrome in the neonatal period.[49, 50] It is characterized by an excessive proliferation of myeloblast cells in the infant’s blood and bone marrow.[51]

An estimated 25% of infants with Down syndrome who present with TMD develop megakaryocytic leukemia 1-3 years later.[52] TMD is associated with pancytopenia, hepatosplenomegaly, and circulating immature white blood cells (WBCs). TMD spontaneously regresses within the first 3 months of life. In some children, however, it can be life-threatening.[53, 54]

Although the risk for leukemia is higher in children with Down syndrome, this risk normalizes by the age of 20 years. By age 30 years, the risk of developing leukemia is 2.7%. On the other hand, the risk of developing most solid tumors, such as cervical, lung, and prostate cancer, is lower; however, there is an increased risk for ovarian and testicular germ cell tumors and, perhaps, retinoblastomas and lymphomas.[55, 56, 57]

Another hematologic abnormality, polycythemia, is common in the newborn period.

Immunodeficiency

Patients have about a 12-fold increased risk of infectious diseases, especially pneumonia, because of impaired cellular immunity. Chemotactic defects, as well as decreased immunoglobulin levels, have also been reported in studies of Down syndrome.

Tumor profile

The tumor profile of patients with Down syndrome is different from that of other people. Syringomas occur more often in patients with Down syndrome than in other patients. These benign appendiceal tumors are observed in 18.5-39% of patients with this disease. Females are affected more than twice as often as males. Lesions are usually limited to regions around the eyes, but disseminated syringomas are also observed. The presence of tumors is not related to IQ or any other manifestation of the disorder.

Trisomy 21 mosaicism

Trisomy 21 mosaicism can present with absent or minimal manifestations of Down syndrome and may be underdiagnosed as a cause of early onset Alzheimer disease.[58] The phenotype of persons having mosaicism for trisomy 21 and Down syndrome reflects the percentage of trisomic cells present in different tissues.[59]

Complications of Down syndrome involve almost every organ system of the body.[60]

Cardiac and cardiovascular complications

Cardiovascular complications are important in Down syndrome.[24, 61] Children who seem asymptomatic at birth and do not have a murmur may have a significant cardiac defect. Children who have left-to-right shunts, such as atrioventricular septal defects, may develop signs of heart failure at age 1-2 months, manifested by tachypnea, poor feeding, and failure to thrive. If increased pulmonary vascular resistance is noted, the left-to-right shunt may be minimized, thus preventing early heart failure. However, if left undetected, this condition may lead to persistent pulmonary hypertension with irreversible pulmonary vascular changes.

Generally, 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 6-9 months. Most children do very well and thrive after the procedure.

In patients with an atrioventricular septal defect (AVSD), 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, Eisenmenger syndrome). To reduce the risk of this complication, children with a large AVSD without pulmonary obstruction should have their defect repaired before the age of 4 months.[2]

Patients with Down syndrome are considered to be at higher risk for pulmonary arterial hypertension than patients without Down syndrome. This is because of the diminished number of alveoli, the thinner media of pulmonary arterioles, and the impaired endothelial function in these patients.

Early corrective cardiac surgery is warranted to prevent irreversible pulmonary vascular lung damage. Moreover, new medical treatment strategies (eg, prostacyclin, endothelin receptor antagonist and phosphodiesterase-5-inhibitor) have been demonstrated to substantially improve clinical status and life expectancy of patients with pulmonary arterial hypertension.

Coronary artery disease–related mortality is surprisingly low. Pathologic studies have revealed decreased levels of atherosclerosis in Down syndrome. Individuals with Down syndrome also have a decreased risk of hypertension.

Acquired heart valve disease is common in Down syndrome and includes mitral valve prolapse and aortic regurgitation.[33]

Respiratory complications

Respiratory problems are among the most common reasons for hospital admissions and mortality in children and adults with Down syndrome.[61] Hypotonia, developmental delay, obstructive sleep apnea, craniofacial anomalies, immune deficiency, and cardiac problems, as well as gastroesophageal reflux, all contribute to the increased risk of developing respiratory complications, such as lung infection, aspirations, and cor pulmonale.[57, 62]

A French study, by Alimi et al, indicated that Down syndrome is a risk factor for pulmonary hemosiderosis and that the condition appears to be more severe in the presence of Down syndrome. Of 34 patients under age 20 years with pulmonary hemosiderosis, nine (26.5%) presented with Down syndrome. Pulmonary hemosiderosis in patients with Down syndrome was more likely to have earlier onset and to be associated with greater dyspnea at diagnosis, a higher incidence of secondary pulmonary hypertension, and a greater risk of fatal evolution.[63]

Gastrointestinal complications

Gastroesophageal reflux is commonly seen in children with Down syndrome and can be severe enough to result in aspiration of stomach contents, causing respiratory symptoms such as persistent coughing, wheezing, and pneumonia. Infants with oral-motor difficulties may present with choking and gagging on feedings, as well as the respiratory symptoms mentioned. Dysphagia may affect children as well as adults.  Celiac disease is more common in patients with Down syndrome than in those without it. Chronic constipation is frequently seen.

Obesity is common. Patients need to have specific dietary guidelines on caloric needs and portion sizes. An active lifestyle with routine exercises is recommended for the whole family. Children should be encouraged to participate in recreational activities, such as swimming, dancing, walking, and playing outdoors.

Ophthalmologic complications

Eye disorders affect a majority of patients with Down syndrome.[64]  Refractive errors, such as myopia, hyperopia, and astigmatism, occur in 35-75% of individuals and can be corrected with glasses.[65] Other common eye disorders include strabismus and nystagmus. Congenital cataracts may affect 5% of newborns and can lead to blindness if left untreated. Additional serious eye disorders include glaucoma and keratoconus. Blockage of tear ducts (nasolacrimal duct stenosis) is common and can lead to increased tear stasis and conjunctivitis.

Otolaryngologic complications

Hearing loss can occur in 40-75% of individuals with Down syndrome. Newborns with Down syndrome have a high incidence of congenital hearing loss. Many children experience recurrent ear infections or persistent middle ear effusions, probably caused by midfacial hypoplasia. Early and aggressive treatment of chronic ear disease can greatly reduce hearing loss in children with Down syndrome. Sinusitis and nasopharyngitis may occur secondary to narrow nasal passages and sinuses. Obstructive sleep apnea may develop secondary to enlarged tonsils or to other causes of upper airway obstruction.

Endocrine complications

Thyroid dysfunction, particularly acquired hypothyroidism, is relatively common in Down syndrome. Because of the increased risk, thyroid function tests should be performed in the newborn, repeated at ages 6 and 12 months, and then performed annually. Hyperthyroidism can also develop. In addition, type I diabetes mellitus occurs with higher frequency in Down syndrome.

Hematologic complications

Patients with Down syndrome exhibit a unique pattern of malignancies, yielding intriguing insights into cancer biology.[66] These patients also pose distinctive challenges to the oncologist because of their particular profile of treatment-related toxicities. Individuals with Down syndrome have a higher risk for leukemia, experiencing three distinct disease entities (ie, TMD, AML, and ALL), and have a lower risk for solid tumors.[67]

Childhood leukemia is relatively common; AML is more common in infants, whereas ALL is more common in children older than 1 year. Newborn infants with Down syndrome are prone to TMD (also known as transient abnormal myelopoiesis or transient leukemia). In some cases, TMD can progress to more severe disease, such as AML, within the first 4 years of life.

Immunologic complications

Children are more prone to recurrent respiratory and systemic infections secondary to deficiencies in some immunoglobulin levels. B cells are reduced in number and function. Reduction in immune function has been shown to be secondary to overexpression of immunity-related genes on chromosome 21.[68] Immunoglobulin (Ig) A deficiency, as well as deficiencies of IgG 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.[61]

Orthopedic complications

Approximately 20% of all patients with Down syndrome experience orthopedic problems.[69] Upper cervical spine instability has the most potential for morbidity and consequently requires close monitoring. Other 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.

Atlantoaxial instability, defined as increased mobility of the cervical spine at the level of the first and second vertebrae, can lead to subluxation of the cervical spine. Approximately 10-30% of individuals with Down syndrome have this condition.[70] Most are asymptomatic; however, 10% of individuals with atlantoaxial instability have symptoms, including neck pain, torticollis, changes in gait, changes in bowel or bladder control, or other signs of paralysis or weakness.[71]

Joint dislocations due to ligamentous laxity and hypotonia are observed. Other orthopedic conditions include genu valgus, overpronation of the ankle, and flat feet.

There is an increased risk of juvenile idiopathic arthritis in Down syndrome.[72]  Down syndrome is also associated with a greater risk of osteoporosis, and the incidence of fractures is high, especially in patients over age 50 years.[57]

Psychiatric and behavioral complications

Psychiatric disorders are reported in 13-17.6% of children with Down syndrome[73] ; these conditions include common psychiatric disorders such as depression, anxiety, obsessive-compulsive disorder, schizophrenia, and anorexia nervosa.

Other disruptive behavior disorders, such as attention-deficit/hyperactivity disorder, oppositional defiant disorder, and conduct disorder, can also be present. Children with Down syndrome have autism more often than expected.[74] In one Down syndrome study, the incidence of autism was 7%.[75] Current evidence indicates that autism affects 1 of every 150 children.[76]

A study by Foley et al indicated that while behavioral and psychiatric difficulties in persons with Down syndrome tend to improve with age, depressive symptoms, as well as problems in social relating behavior, can persist into adulthood. The investigators, who conducted the questionnaire study over 8 years, suggested that persistence of depressive symptoms in persons with Down syndrome may increase their chances of developing depressive illness in adulthood.[77]

Alzheimer disease

Alzheimer disease develops in about 50% of individuals with Down syndrome, often arising at a relative early age. Autopsy studies have shown that the characteristic plaques and tangles associated with Alzheimer disease are present in almost all individuals with Down syndrome by age 40 years.[78, 19] The increased risk of Alzheimer disease in Down syndrome is thought to be related to the presence of an extra copy of the APP gene, which codes for the amyloid precursor protein. Too much of this protein leads to accumulation of amyloid plaques in the brain, which impairs brain cell function. Alzheimer disease is characterized by memory loss, inability to learn new information, and a decline in intellectual skills.[79, 80] Behavioral changes in patients with Down syndrome diagnosed with Alzheimer dementia include the following[22] :

• Apathy

• Episodic noisy excitement

• Irritability

• Wandering and confusion

• Destructive, aggressive, or difficult behavior

• Lethargy, withdrawal, loss of interest

• Silliness

• Limited response to people

• Social inadequacy, isolation

• Extreme changes in appetite (typically leading to weight loss)

• Restlessness

• Sleep disturbance

• Incontinence

• Excessive uncooperativeness

• Anxiety and fearfulness

• Sadness

• Stealing and general regressive behavior

• Personality changes

• Increased dependence

Abuse

Individuals with Down syndrome are at high risk for physical and sexual abuse. Physicians taking care of Down syndrome patients should be alert to this risk and parents and patients should be appropriately educated about it. 

The diagnosis of Down syndrome is most commonly made by prenatal screening followed by definitive diagnostic testing. When prenatal diagnosis has not been made, Down syndrome is usually apparent from the clinical examination of the newborn. Diagnosis should be confirmed through chromosomal analysis. Since Down syndrome is associated with multisystem involvement, additional diagnostic studies are performed as appropriate.

A complete blood count (CBC) with differential and bone marrow examination to rule out leukemia is indicated. Thyroid-stimulating hormone (TSH) and thyroxine (T4) levels should be obtained at birth, at 6 and 12 months, and annually thereafter, to rule out hypothyroidism. Perform Papanicolaou smears every 1-3 years in sexually active women starting at the age of first intercourse.

Commonly performed studies in individuals with Down syndrome include the following.

Cytogenetic studies

The clinical diagnosis of trisomy 21 should be confirmed with cytogenetic studies. Karyotyping is essential to determine the risk of recurrence. In translocation Down syndrome, karyotyping of the parents and other relatives is required for proper genetic counseling (see the images below).

Interphase fluorescence in situ hybridization

Fluorescence in situ hybridization (FISH) may be used for rapid diagnosis of trisomy 21. It can be successful in both prenatal diagnosis and diagnosis in the neonatal period. A FISH study will detect the presence of trisomy 21; however, it does not provide information about whether trisomy 21 is secondary to a translocation. Therefore, a FISH test must be confirmed by a complete karyotype analysis.

Occult mosaicism for trisomy 21 may partially explain the association between family history of Down syndrome and risk of Alzheimer disease. Screening for mosaicism with FISH is indicated in selected patients with mild developmental delay and those with early onset Alzheimer disease.[58]

Evaluation of the proportion of cells with trisomy 21 in mosaic trisomy 21 includes the following[59] :

• Lymphocyte preparations

• Buccal mucosa cellular preparations

• FISH

• Scoring frequency of trisomic cells

Measurement of immunoglobulin G

Measurement of immunoglobulin (Ig) G levels focuses on identifying deficiencies of subclasses 2 and 4. Decreased levels of IgG subclass 4 is significantly correlated with bacterial infections. These deficits in cellular immunity have also been documented in individuals with gingivitis and periodontal disease.

Current evidence does not support performing routine screening radiographs for assessment of potential atlantoaxial instability in asymptomatic children. When obtained, skull series show evidence of flattened facial features (including small or absent nasal bones), hypoplastic sinuses, a flat occiput, microcephaly, and brachycephaly.

Cervical radiography (with lateral flexion and extension views) is required to measure the atlantodens distance and to rule out atlantoaxial instability at the age of 3 years. Radiography is also used before administering anesthesia if signs suggest spinal cord compression. Magnetic resonance imaging (MRI) is also recommended regularly for evaluation.

Reduced iliac and acetabular angles may be present in young infants. Short hands with shortened digits and clinodactyly due to hypoplastic middle phalanx of the fifth finger may be present.

Echocardiography should be performed on all infants suspected of having trisomy 21 to identify congenital heart disease, regardless of findings on physical examination.

Prenatal screening using a combination of maternal serum biomarkers and ultrasonography can detect up to 95% of pregnancies affected by Down syndrome.[84, 85, 86, 87, 88] The false positive rate is 5%. Recently updated guidelines from the American College of Obstetricians and Gynecologists[16] state the following: (1) all women should be offered screening for aneuploidy before 20 weeks' gestation and (2) all pregnant women, regardless of their age, should have the option of diagnostic testing.

The first prenatal diagnosis of Down syndrome was made in 1968, and screening women with amniocentesis on the basis of advanced maternal age was gradually introduced into medical practice. Low maternal serum alpha fetoprotein (MSAFP) levels were associated with Down syndrome in 1983. Later, elevated human chorionic gonadotropin (hCG) and low unconjugated estriol (uE3) levels were found to be markers for Down syndrome. More recently, elevated inhibin A levels (in the second trimester) and reduced pregnancy-associated plasma protein A (PAPP-A) levels (in the first trimester) have been used to screen for Down syndrome in pregnancy. Maternal serum biomarkers can also be used to detect nonstandard trisomy 21 (translocations and mosaicism); however, detection rates for low-level mosaicism may be low.[89]

A substantial proportion of pregnancies are terminated after a prenatal diagnosis of Down syndrome.[90]

Nuchal translucency scan

The nuchal translucency (NT) scan assesses the amount of fluid in the dorsum of the fetal neck and is best assessed at 11-14 weeks.[91]  An increased NT measurement is associated with an increased risk of genetic syndromes and can detect up to 70% of Down syndrome pregnancies. However, some centers may not have personnel with expertise in the scanning procedure, and fetal or maternal variables may lead to difficulties in obtaining an accurate measurement.

First-trimester screening

For pregnant women, for whom an early diagnosis is important, a first-trimester "combined test" performed at 11-14 weeks involving sonographic testing for NT together with testing for PAPP-A and hCG provides a detection rate of 82-87% for Down syndrome.

Second-trimester screening

Tests used for second-trimester screening include the triple and quadruple screens. The triple screen measures serum hCG, AFP and unconjugated estriol to calculate the risk of Down syndrome and can detect up to 69% of Down syndrome pregnancies. Currently, the quadruple test, usually performed at 15-18 weeks' gestation, is the most common screening test performed in the second trimester. This screen measures inhibin A in addition to the biochemical markers measured in the triple screen and provides an 81% detection rate for Down syndrome. In addition, the quadruple test serves as a screening test for open neural tube defects (since it involves measurement of AFP) and can also detect trisomy 18.

Integrated screening

With integrated screening, the pregnant woman undergoes a first-trimester screening (involving NT testing, PAPP-A, hCG) followed by the quadruple screen in the second trimester. This combined screening approach increases the detection rate of Down syndrome to 95%, with a false positive rate of only 5%.

Cell-free fetal DNA screening

Cell-free fetal DNA is composed of fragments of fetal DNA derived from the placenta that can be found in maternal plasma. The fragments can be seen in maternal circulation as early as 7 weeks' gestation and last throughout pregnancy, becoming undetectable in the maternal circulation a few hours after birth. The cell-free fetal DNA screening test can be done at any gestational age after 10 weeks and can detect about 99% of Down syndrome pregnancies. Adoption of cell-free DNA for screening women has been slow because of cost, but it is currently used at many centers for screening women at high risk for offspring with Down syndrome. Studies have shown that this test has a high sensitivity and specificity.[92, 93, 94, 95, 96, 97, 98]

A positive screening result with the above methods only suggests an increased risk for Down syndrome, and definitive testing with chorionic villus sampling or amniocentesis and chromosomal analysis is indicated.

Ultrasonography

 Prenatal ultrasonography may reveal the following in a fetus with Down syndrome:

• Ultrasonography soft markers for Down syndrome observed in the second trimester include absent or hypoplastic nasal bone, thickened nuchal fold, echogenic bowel, shortened long bones, and pyelectasis

• Absent or hypoplastic nasal bone is observed in 43-62% of trisomy 21 fetuses, compared with 0.5-1.2% of normal fetuses

• A 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; measurement of NT in the first trimester, as discussed above, can detect up to 70% of fetuses with Down syndrome

• Echogenic bowel has been observed in approximately 15% of fetuses with trisomy 21, compared with 0.6% of normal fetuses; about 35% of fetuses with true echogenic bowel have some underlying pathology, such as first trimester bleeding, fetal infections, and cystic fibrosis due to meconium ileus

• Shortened 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 next most important marker after nasal bone and nuchal fold

• Pyelectasis has been observed in approximately 17% of fetuses with trisomy 21, and approximately 1 in every 300 fetuses with isolated pyelectasis has aneuploidy; pyelectasis has been associated with an increased risk of hydronephrosis and postnatal urinary reflux

• Other 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

Ultrasonography should not be relied on as the primary method of diagnosing Down syndrome; the diagnosis can be missed in affected families. Suggestive prenatal ultrasonographic findings may be followed with amniocentesis and fetal chromosome analysis.

Invasive diagnostic tests

Amniocentesis, routinely performed at 14-16 weeks’ gestation, remains the criterion standard of invasive diagnostic tests. Testing for chromosomal disorders is 99.5% accurate. Rare cases of mosaicism are missed, and results can be inaccurate if maternal-cell contamination occurs. The procedure is associated with a small risk of pregnancy loss (1:200-300).

Chorionic villus sampling (CVS) is performed at 10-13 weeks’ gestation; earlier testing is thought to be associated with a 1 in 300-1000 risk of fetal transverse limb deficiency, a small risk of maternal cell contamination, and a 0.5-1% risk of a fetal loss after the procedure. The accuracy of CVS (96-98%) is less than that of midtrimester amniocentesis, because of confined placental mosaicism and maternal-cell contamination.

Percutaneous umbilical blood sampling (PUBS) is approximately 95% successful in obtaining a blood sample for cytogenetic testing. The pregnancy-loss rate is 3.25% for PUBS done for chromosomal indications, compared with 1.25% and 2.75% for PUBS done for nonchromosomal indications. The indication for the procedure greatly increases the risk of procedure-related pregnancy loss.

The availability of in vitro fertilization has allowed preimplantation diagnosis of single-gene disorders, sex selection for X-linked disorders, and identification of chromosomal aneuploidies. After a biopsy sample is obtained from the first polar body, the blastocyst, or the 6-cell to 8-cell embryo, FISH can then be used to diagnose fetal aneuploidy. However, standard cytogenetic confirmation is not possible for the preimplantation diagnosis.

Postnatal diagnostic tests

The auditory brainstem response (ABR), also known as the brainstem auditory evoked response (BAER), may be tested to demonstrate hearing loss. Evaluation of the ABR in 47 nonselected children with Down syndrome aged 2 months to 3.5 years indicated some hearing loss in 66% (28% unilateral, 38% bilateral). Speech evaluation may also be indicated. A study by Rupela et al found evidence that childhood dysarthria (CD), childhood apraxia of speech (CAS), and motor speech disorder-not otherwise specified (MSD-NOS) are responsible for the motor speech characteristics of children with Down syndrome, with variability and overlapping symptoms occurring in these youngsters. This differs from the previous view that either CD or CAS causes such characteristics in these children.[99]

Infants with Down syndrome should undergo a car safety seat evaluation before discharge because they are at increased risk of apnea, bradycardia, and desaturation in a car seat secondary to hypotonia.

Pediatric ophthalmic examination should be performed for vision screening and for detecting ophthalmologic disorders.

Growth charts are available for children with Down syndrome.[35] A developmental chart for noninstitutionalized children based on a modified Denver Developmental Screening Test is available for assessing developmental milestones.

Rigorous dental hygiene and dental evaluation are indicated beginning after tooth eruption.

Histologic findings

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

Physicians 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 intellectual disability associated with Down syndrome have been forthcoming. However, the dramatic improvements in medical care described below have greatly improved the quality of life for patients and increased their life expectancy.[100]

Usual immunizations and well-child care should be performed as the American Academy of Pediatrics recommends. Associated conditions should be monitored periodically as the child grows older.

Surgical management of associated conditions should be provided as appropriate. Down syndrome alone does not adversely affect surgical outcomes in the absence of pulmonary hypertension. Because of potential atlanto-occipital instability, care should be taken when sedation and airway management are considered for procedures or for consideration of sports participation.

Further outpatient care may include the following:

• Audiologic evaluation for hearing loss

• Apnea monitoring

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

Timely surgical treatment of cardiac anomalies, detected during the newborn period or early infancy, may be necessary to prevent serious complications and is crucial for optimal survival.

Prompt surgical repair is necessary for GI anomalies, most commonly duodenal atresia and Hirschsprung disease. Other GI anomalies include tracheoesophageal fistula, pyloric stenosis, annular pancreas, aganglionic megacolon, and imperforate anus.

Surgical intervention may be necessary to reduce atlantoaxial subluxation and to stabilize the upper segment of the cervical spine if neurologic deficits are clinically significant.

Congenital cataracts occur in about 3% of children and must be extracted soon after birth to allow light to reach the retina. Afterward, appropriate correction with glasses or contact lenses helps to ensure adequate vision.

Surgical intervention in children with Down syndrome has a high risk of complications, particularly infection and wound healing problems.[69] Careful anesthetic airway management is needed because of the associated risk of cervical spine instability. Preoperative evaluation for anesthesia must include adequate evaluation of the airway and the patient’s neurologic status. Cervical radiography (with flexion and extension views) should be performed when any neurologic deficit suggests spinal-cord compression.

During laryngoscopy and intubation, the patient’s head should be maintained in a neutral position, and hyperextension should be avoided. Anticholinergics can be prescribed to control hypersecretion in the airways. Other airway complications include subglottic stenosis and obstructive apnea, which may result from a relatively large tongue, enlarged adenoids, and midfacial hypoplasia. Adenotonsillectomy may be performed to manage obstructive sleep apnea.

No special diet is required, unless celiac disease is present. A balanced diet and regular exercise are needed to maintain appropriate weight. Feeding problems and failure to thrive usually improve after cardiac surgery.

No restriction of activities is necessary. Parents should be counseled about sports with increased risk of spinal injury, such as football, soccer, and gymnastics. Advise the patient to exercise to maintain an appropriate weight. Patients with symptoms of arrhythmia, episodes of fainting, abnormal findings on electrocardiography (ECG), and palpitations or chest pain should refrain from participating in sports and strenuous exercise. Children with C1-C2 instability or subluxation may require specific preclearance to compete in the Special Olympics.[101]

A study by Diaz reported that US children with Down syndrome tend to engage less in regular physical activity than do other children, including children without disabilities and those with other developmental disabilities/special health-care needs. This indicated that interventions/programs promoting physical activity in children with Down syndrome are needed.[102]

Consultations with the following may be indicated:

• Clinical geneticist - Referral to a genetics counseling program is highly desirable

• Developmental pediatrician

• Cardiologist - Early cardiologic evaluation is crucial for diagnosing and treating congenital heart defects, which occur in up to 50% of these patients

• Pediatric pulmonologist - Recurrent respiratory tract infections are common in patients with Down syndrome

• Ophthalmologist[64]

• Dentist

• Neurologist/neurosurgeon – As many as 10% of patients with Down syndrome have epilepsy; therefore, neurologic evaluation may be needed; patients with atlantoaxial instability may need to be evaluated by a neurosurgeon

• Orthopedic specialist

• Child psychiatrist - A child psychiatrist should lead liaison interventions, family therapies, and psychometric evaluations

• Physical and occupational therapist

• Speech-language pathologist

• Audiologist

Trisomy 21

A previous history of trisomy can increase a woman’s risk for a recurrence.[103] If the couple has a child with trisomy 21, the risk of recurrence is about 1%.[104] The risk does not appear to be increased in siblings of affected individuals if it is confirmed to not be a translocation but rather full trisomy 21.

Translocation

The 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 2-3%.[105]

In any trisomy 21 patient with a translocation, karyotype testing must be recommended to both parents to look for a translocation. If a translocation is found in one of the parents, the recurrence risk is significantly higher, and further genetic counseling is crucial.

The theoretic recurrence risk for a Robertsonian carrier parent to have a liveborn offspring with Down syndrome is 1 in 3. However, only 10-15% of the progeny of carrier mothers and only 2-3% of the progeny of carrier fathers have Down syndrome. The reason for this difference is not clear. In a carrier parent with a 21q21q translocation or isochromosome, the recurrence risk is 100%.

Mosaicism

Most patients with mosaic Down syndrome were once trisomy 21 zygotes. The 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. Many geneticists believe that all full trisomy 21 patients are mosaic at some level.

Reproduction

Affected individuals rarely reproduce. About 15-30% of females with trisomy 21 are fertile and have up to a 50% risk of having child also affected with trisomy 21. Infertility in males has been attributed to defective spermatogenesis, but ignorance of the sexual act may be one of the contributing factors.

The standard immunizations and well-child care should be provided. In addition, specific manifestations of the syndrome and associated conditions must be addressed, as follows:

• Give thyroid hormone for hypothyroidism to prevent intellectual deterioration and to improve the individual’s overall function, academic achievement, and vocational abilities

• Give digitalis and diuretics as necessary for cardiac management

• Provide prompt treatment of respiratory tract infections and otitis media

• Consider pneumococcal and influenza vaccination for children with chronic cardiac and respiratory disease; consider prophylactic palivizumab, since infants with Down syndrome are at high risk for hospitalization with respiratory syncytial virus[106]  

• Administer anticonvulsants for tonic-clonic seizures or for infantile spasms (treat with steroids)

• Provide pharmacologic agents, psychotherapy, or behavioral therapy for psychiatric disorders

• Treat skin disorders with weight reduction, proper hygiene, frequent baths, application of antibiotic ointment, or systemic antibiotic therapy

• Prevent dental caries and periodontal disease through appropriate dental hygiene, fluoride treatments, good dietary habits, and restorative care

There are specific guidelines on when prophylaxis for subacute bacterial endocarditis is necessary and, unless there is a valve replacement or other clear reason, children with trisomy 21 are not routinely recommended to receive it.

Early intervention programs are promising. Programs for infants aged 0-3 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. Early intervention techniques may improve the patient’s social quotient. Overall, positive developmental changes are observed in children with Down syndrome, particularly in terms of their independence, community functioning, and quality of life.

A literature review by Sugimoto et al indicated that neuromuscular training can improve strength in children and young adults with Down syndrome. The study found that such training can have a moderate to large impact on general strength, as well as a small to moderate effect on maximal strength. Only a small impact on functional mobility tasks was reported.[107]

Megadoses of vitamins and minerals supplemented with zinc or selenium have not been found beneficial in a number of well-controlled scientific studies.

Children with Down syndrome and leukemia are more sensitive to some chemotherapeutic agents (eg, methotrexate) than other children. Thus, they require careful monitoring for toxicity.

In adolescents and young adults with Down syndrome, the following monitoring measures are indicated[2] :

• Perform annual audiologic evaluation

• Perform ophthalmologic evaluations every 3 years for keratoconus or corneal opacities or cataracts

Manifestations of the syndrome and associated conditions must be evaluated and addressed on an ongoing basis, as follows:

• Treat dermatologic issues, such as folliculitis, xerosis, atopic dermatitis, seborrheic dermatitis, fungal infections of skin and nails, vitiligo, and alopecia

• Prevent obesity by decreasing the patient’s caloric intake and increasing activity (social and leisure)

• Screen for celiac disease (symptoms such as constipation, diarrhea, bloating, poor growth, or weight loss), and treat the patient with a gluten-free diet

• Address any swallowing difficulties that persist through the adolescent years

• Provide antibiotic prophylaxis during dental and surgical procedures in the presence of mitral valve prolapse

• Consider bone marrow transplantation if leukemia occurs

• Discuss sleep apnea, treat airway obstruction medically and surgically.

• Pay special attention to perioperative modalities because of atlantoaxial instability and problems with the respiratory system

• Screen for hypothyroidism and diabetes mellitus

• Manage neurologic problems, including mental retardation, hypotonia, seizures, and strokes

• Continue speech and language therapy, with a focus on expressive language and intelligibility

• Evaluate and treat behavioral problems, such as disruptive behavior disorders, stereotypic behaviors, phobias, elimination difficulties, autism, eating problems, self-injurious behavior, and Tourette syndrome; evaluate and treat psychiatric disorders, such as depression and self-talk

• Examine annually to check for development of acquired heart valve disease; perform an echocardiogram if a new murmur or gallop or symptoms of heart failure develop.

• Continue subacute bacterial endocarditis prophylaxis in adolescents with cardiac defects; during adolescence, an additional 2% of patients die of complications of congenital heart disease, infections, leukemia, and accidents

• Counsel regarding the importance of protecting the cervical spine during anesthetic or surgical interventions; monitor for signs and symptoms of cervical myopathy; repeat cervical spine radiography as needed for sports/Special Olympics participation.

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

• Emphasize the importance of a well-balanced diet and routine exercise

• Review 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

• Encourage social and recreational programs with friends

• Address concerns regarding menstrual hygiene, sexual abuse, pregnancy, and premenstrual syndrome

• Discuss sexuality and socialization, as well as the need for supervision and degree of supervision required; review options for contraception if the teen is sexually active, as well as for prevention of sexually transmitted diseases; make recommendations for routine gynecologic care

• Monitor the family’s need for supportive care or counseling, respite care, and behavior management techniques; facilitate referrals for respite care and treatment of parental problems

• Facilitate the patient’s transfer to adult health care

In 2016, the American College of Obstetricians and Gynecologists updated their guidelines for prenatal screening for Down syndrome.[16]

Guidelines for health supervision of Down syndrome individuals from birth to early adulthood have been published by the American Academy of Pediatrics.[2]  Recommendations include the following:

• Frequent ear exams and auditory evaluations (annually after early infancy) may need to be performed because of the increased risk for otitis media and secondary hearing loss
• Monitor for obstructive sleep apnea; all children should be referred for a sleep study by age 4 years
• Thyroid function testing should be performed in the newborn period, at 6 months, at 12 months, and annually thereafter, because of the high risk for acquired hypothyroidism
• Monitor for gastroesophageal reflux and swallowing difficulties and for the development of celiac disease
• Monitor for the development of leukemias in the first few years of life
• Infants with Down syndrome who have congenital heart disease should be monitored for the development of heart failure and pulmonary hypertension in early infancy; adolescents and adults should be monitored for the development of acquired heart valve disease
• Annual eye exams are required because of the increased risk for refractive errors
• Individuals with Down syndrome must be monitored for the development of atlantoaxial instability; evaluation for new-onset signs and symptoms of myelopathy should be performed at every visit
• Monitor cognitive function and evaluate for behavioral problems, autism, and the development of seizures
• Parents should be counseled that individuals with Down syndrome are at increased risk for sexual abuse and that the likely perpetrators are people well-known to the child

Drug therapy is not currently a component of the standard of care for Down syndrome. Medications are indicated only for symptomatic treatment of pain. Obviously, prolonged use of analgesics without diagnostic evaluation and an understanding of the underlying cause should not be encouraged. No particular analgesic is superior.

Diuretics and digoxin should be used to manage congestive heart failure secondary to congenital heart defect.

Class Summary

Pain control is essential to quality 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 injuries.

Acetaminophen and codeine (Tylenol #3, Capital and Codeine)

Codeine is a centrally acting analgesic; acetaminophen is a peripherally acting analgesic. The combination is indicated for treatment of mild to moderately severe pain. Tablets contain acetaminophen 300 mg and codeine phosphate 30 mg; elixir contains acetaminophen 120 mg and codeine 12 mg per 5 mL.

Morphine sulfate (Duramorph, Astramorph, MS Contin, Oramorph SR)

Morphine is a narcotic drug that interferes with opioid receptors; it mainly acts on the central nervous system (CNS) and the gastrointestinal (GI) tract.

Ibuprofen (Motrin, Advil, Caldolor)

Ibuprofen is a member of the propionic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). It has anti-inflammatory, analgesic, and antipyretic activity. Its mode of action is not clear but might be related to prostaglandin synthetase inhibition.

Naproxen (Aleve, Anaprox, Naprosyn, Naprelan)

Naproxen is an NSAID of the arylacetic acid group. It inhibits prostaglandin synthesis.

Class Summary

Antidysrhythmics may improve morbidity in patients with congestive heart failure secondary to congenital heart defect.

Digoxin (Lanoxin)

Digoxin 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.

Class Summary

Diuretics should be used to manage congestive heart failure secondary to congenital heart defects.

Furosemide (Lasix)

Furosemide increases excretion 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. The bioavailability of oral furosemide is 50%. If a switch is made from intravenous to oral administration, an equivalent oral dose should be used. Doses vary depending on the patient's clinical condition.

Hydrochlorothiazide (Microzide)

Hydrochlorothiazide inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water as well as potassium and hydrogen ions.

Metolazone (Zaroxolyn)

Metolazone is a quinazoline diuretic with properties similar to those of thiazide diuretics. It inhibits sodium resorption at the cortical diluting site and the proximal convoluted tubule.