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Down Syndrome Clinical Presentation

  • Author: Harold Chen, MD, MS, FAAP, FACMG; Chief Editor: Maria Descartes, MD  more...
 
Updated: May 05, 2016
 

History

When recording the history from the parents of a child with Down syndrome, the clinician should include the following[17] :

  • 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 gastrointestinal (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

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.
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Physical Examination

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

  • Flat occiput and a flattened facial appearance
  • Brachycephaly
  • 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
  • Diastasis recti
  • Single transverse palmar crease
  • Short fifth finger with clinodactyly
  • A wide space between the first and second toes

General physical features in patients with Down syndrome may include the following[18, 19, 20, 21, 22, 23] :

  • Shortened extremities
  • Short, broad hands, with short fifth middle phalanx and single transverse palmar creases (~60% of patients)
  • Joint hyperextensibility or hyperflexibility
  • Neuromuscular hypotonia
  • 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

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, acquired lens opacity (30-60%), retinal detachment, and keratoconus in adults are observed (see the images below).[24]

Infant with Down syndrome. Note up-slanting palpeb Infant with Down syndrome. Note up-slanting palpebral fissures, bilateral epicanthal folds, flat nasal bridge, open mouth with tendency for tongue protrusion, and small ear with overfolded helix.
Child with Down syndrome. Note up-slanting palpebr Child with Down syndrome. Note up-slanting palpebral fissures, bilateral epicanthal folds, small nose with flat nasal bridge, open mouth with tendency for tongue protrusion, and small ears with overfolded helix.

Nose

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

Characteristic flat facies with hypertelorism, dep Characteristic flat facies with hypertelorism, depressed nasal bridge, and protrusion of tongue, as well as single palmar simian crease in 2-year-old girl with Down syndrome. Image courtesy of L. Dourmishev, MD, PhD, DSc.

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.

Hypodontia in patient with Down syndrome. Image co Hypodontia in patient with Down syndrome. Image courtesy of L. Dourmishev, MD, PhD, DSc.

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).

Ear of infant with Down syndrome. Note characteris Ear of infant with Down syndrome. Note characteristic small ear with overfolded helix.
Small auricle and anomalies of folds in patient wi Small auricle and anomalies of folds in patient with Down syndrome. Image courtesy of L. Dourmishev, MD, PhD, DSc.

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.

Patient with Down syndrome with protuberant abdome Patient with Down syndrome with protuberant abdomen and umbilical hernia. Image courtesy of L. Dourmishev, MD, PhD, DSc.

Skin

Xerosis, localized hyperkeratotic lesions, elastosis serpiginosa, alopecia areata (< 10%), vitiligo, folliculitis, abscess formation, and recurrent skin infections are observed.[25, 26] 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.[27]

Congenital 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:

About 30% of patients have several cardiac defects. The most common lesions are patent ductus arteriosus (16%) and pulmonic stenosis (9%). About 70% of all endocardial cushion defects are associated with Down syndrome.

Gastrointestinal tract abnormalities

GI abnormalities occur in approximately 12% of patients. Duodenal atresia or stenosis, Hirschsprung disease (< 1%), tracheoesophageal fistula, Meckel diverticulum, imperforate anus, and omphalocele are observed.

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.

Genitourinary tract abnormalities

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

Growth and skeletal anomalies

Failure to thrive due to hypotonia occurs in infancy. Short stature and obesity occurs during adolescence.

Broad, short hands, feet, and digits; a short curved fifth finger (dysplasia and shortening of the mid phalanx) 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.

Wide gap between first and second toes and onychom Wide gap between first and second toes and onychomycosis in patient with Down syndrome. Image courtesy of L. Dourmishev, MD, PhD, DSc.

Endocrine abnormalities

Hashimoto thyroiditis that causes hypothyroidism is by far the most common acquired thyroid disorder in patients with Down syndrome.[28] The onset is usually from school age onwards, but onset in infancy is reported.[29] More rarely, Hashimoto thyroiditis can cause hyperthyroidism[30] ; the incidence of Graves disease is also increased.[31]

The prevalence of thyroid disorders (eg, congenital hypothyroidism, primary hypothyroidism, autoimmune thyroiditis, and compensated hypothyroidism or hyperthyrotropinemia) is reportedly 3-54% in individuals with Down syndrome and increases with increasing age. Diabetes and decreased fertility can also occur.

Hematologic abnormalities

Children with Down syndrome have an increased risk of developing leukemias, including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).[32] 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 this from true leukemia frequently poses a diagnostic challenge.[33]

Although the risk for leukemia is higher in individuals with Down syndrome, these patients have a lower risk of developing solid tumors, with the exception of germ cell tumors and, perhaps, retinoblastomas and lymphomas.[34, 35] Leukemia cutis is also observed in these patients.

Approximately 10% of newborns with Down syndrome develop a preleukemic clone, originating from myeloid progenitors in the fetal liver that is 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.[36, 37] This preleukemia is referred to as transient leukemia (TL), transient myeloproliferative disease (TMD), or transient abnormal myelopoiesis (TAM).[38]

TMD is a hematologic abnormality that primarily affects infants with Down syndrome in the neonatal period.[39, 40] It is characterized by an excessive proliferation of myeloblast cells in the infant’s blood and bone marrow.[41] Approximately 10% of infants with Down syndrome have TMD.[42] However, this estimate probably identifies only patients whose symptoms were severe enough to warrant a complete blood count (CBC) and in whom the presence of blasts was of concern to the primary care provider.[43]

An estimated 25% of infants with Down syndrome who present with TMD develop megakaryocytic leukemia 1-3 years later.[44] 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.[45, 46] Despite the high rate of spontaneous regression, TMD can be a preleukemic disorder in 20-30% of children with Down syndrome.

The patient’s risk of carrying hepatitis B is increased if he or she was previously institutionalized.

Immunodeficiency

Patients have about a 12-fold increased risk of infectious diseases, especially pneumonia, because of impaired cellular immunity.

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.[47] The phenotype of persons having mosaicism for trisomy 21 and Down syndrome reflects the percentage of trisomic cells present in different tissues.[48]

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Complications

Complications of Down syndrome involve almost every organ system of the body.[49]

Cardiac and cardiovascular complications

Cardiovascular complications are important in Down syndrome.[20] Children who seem asymptomatic at birth and do not have a murmur may have a significant cardiac defect. If increased pulmonary vascular resistance is noted, the left-to-right shunt may be 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, 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).

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.

Gastrointestinal complications

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

Common eye disorders include fractive errors, such as myopia, hyperopia, and astigmatism, which can be corrected with glasses if the child is willing to wear them. Other common eye disorders include strabismus and nystagmus. Congenital cataracts 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

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 hypothyroidism, is relatively common in Down syndrome. Hyperthyroidism can also occur. Diabetes mellitus occurs with higher frequency.

Hematologic complications

Patients with Down syndrome exhibit a unique pattern of malignancies, yielding intriguing insights into cancer biology.[50] 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 3 distinct disease entities (ie, TMD, AML, and ALL) and have a lower risk for solid tumors.

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 leukemoid reaction, transient abnormal myelopoiesis, or transient leukemia); in some cases, it 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. Immunoglobulin (Ig) A deficiency as well as 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.

Orthopedic complications

Approximately 20% of all patients with Down syndrome experience orthopedic problems.[51] 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.[52] 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.[53]

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

Psychiatric and behavioral complications

Psychiatric disorders are reported in 13-17.6% of children with Down syndrome[54] ; 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.[55] In one Down syndrome study, the incidence of autism was 7%.[56] Current evidence indicates that autism affects 1 of every 150 children.[57]

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.[58]

Alzheimer disease or Alzheimer-type dementia can occur at a relative early age. The disease is characterized by memory loss, inability to learn new information, and a decline in intellectual skills. Behavioral changes in Down syndrome diagnosed with Alzheimer dementia include the following[18] :

  • 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
  • Excessively uncooperative
  • Anxiety and fearfulness
  • Sadness
  • Stealing and general regressive behavior
  • Personality changes
  • Increased dependence
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Contributor Information and Disclosures
Author

Harold Chen, MD, MS, FAAP, FACMG Professor, Department of Pediatrics, Louisiana State University Medical Center

Harold Chen, MD, MS, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

Lois J Starr, MD, FAAP Assistant Professor of Pediatrics, Clinical Geneticist, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center

Lois J Starr, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Acknowledgements

James Bowman, MD Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago

James Bowman, MD is a member of the following medical societies: Alpha Omega Alpha, American Society for Clinical Pathology, American Society of Human Genetics, Central Society for Clinical Research, and College of American Pathologists

Disclosure: Nothing to disclose.

David Flannery, MD, FAAP, FACMG Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia

David Flannery, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics and American College of Medical Genetics

Disclosure: Nothing to disclose.

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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Infant with Down syndrome. Note up-slanting palpebral fissures, bilateral epicanthal folds, flat nasal bridge, open mouth with tendency for tongue protrusion, and small ear with overfolded helix.
Child with Down syndrome. Note up-slanting palpebral fissures, bilateral epicanthal folds, small nose with flat nasal bridge, open mouth with tendency for tongue protrusion, and small ears with overfolded helix.
G-banded karyotype showing trisomy 21 (47,XY,+21).
G-banded karyotype showing trisomy 21 of isochromosome arm 21q type [46,XY,i(21)(q10)].
Hand of infant with Down syndrome. Note transverse palmar crease and clinodactyly of fifth finger.
Ear of infant with Down syndrome. Note characteristic small ear with overfolded helix.
Characteristic flat facies with hypertelorism, depressed nasal bridge, and protrusion of tongue, as well as single palmar simian crease in 2-year-old girl with Down syndrome. Image courtesy of L. Dourmishev, MD, PhD, DSc.
Small auricle and anomalies of folds in patient with Down syndrome. Image courtesy of L. Dourmishev, MD, PhD, DSc.
Palmar simian crease in patient with Down syndrome. Image courtesy of L. Dourmishev, MD, PhD, DSc.
Patient with Down syndrome with protuberant abdomen and umbilical hernia. Image courtesy of L. Dourmishev, MD, PhD, DSc.
Wide gap between first and second toes and onychomycosis in patient with Down syndrome. Image courtesy of L. Dourmishev, MD, PhD, DSc.
Hypodontia in patient with Down syndrome. Image courtesy of L. Dourmishev, MD, PhD, DSc.
 
 
 
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