Down Syndrome Clinical Presentation

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.