AUTHOR INFORMATION

Section 1 of 12

Authored by Harold Chen, MD, MS, FAAP, FACMG, Chief, Professor, Department of Pediatrics, Section of Perinatal Genetics, 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, American Medical Association, American Society of Human Genetics, and Teratology Society

Edited by James Bowman, MD, Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Harold Chen, MD, MS, FAAP, FACMG
Editor's Email:	James Bowman, MD

eMedicine Journal, January 23 2006, VOLUME 7, Number 1

INTRODUCTION

Section 2 of 12

Background: In 1866, Down described clinical characteristics of the syndrome that now bears his name. In 1959, Lejeune and Jacobs et al independently determined that trisomy 21 is the cause. Down syndrome is by far the most common and best known chromosomal disorder in humans. Mental retardation, dysmorphic facial features, and other distinctive phenotypic traits characterize the syndrome.

Pathophysiology: 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, mental retardation), and dysmorphic physical features. Down syndrome decreases prenatal viability and increases prenatal and postnatal morbidity. Affected children have delayed physical growth, maturation, bone development, and dental eruption.

The extra copy of the proximal part of 21q22.3 appears to result in the typical physical phenotype: mental retardation, characteristic facial features, hand anomalies, and congenital heart defects. Molecular analysis reveals that the 21q22.1-q22.3 region, or 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, in the mental retardation and/or cardiac defects.

Abnormal physiologic functioning affects thyroid metabolism and intestinal malabsorption. Frequent infections are presumably due to impaired immune responses, and the incidence of autoimmunity, including hypothyroidism and rare Hashimoto thyroiditis, is increased.

Patients with Down syndrome have decreased buffering of physiologic reactions, resulting in hypersensitivity to pilocarpine and abnormal responses on sensory-evoked electroencephalographic 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.

Frequency:

• In the US: The frequency is 1 case in 800 live births. Each year, approximately 6000 children are born with Down syndrome.

Mortality/Morbidity:

• Approximately 75% of concepti with trisomy 21 die in embryonic or fetal life. Approximately 85% of infants survive to 1 year, and 50% can be expected to live longer than 50 years. Congenital heart disease is the most important factor that determines survival. In addition, esophageal atresia with or without transesophageal (TE) fistula, Hirschsprung disease, duodenal atresia, and leukemia contribute to mortality. The high mortality rate later in life may be the result of premature aging.

• Individuals with Down syndrome have a greatly increased morbidity rate, 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.

• A delay in recognizing atlantoaxial and atlanto-occipital instability may result in irreversible spinal-cord damage. Visual and hearing impairments in addition to mental retardation 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 CNS function.

Race: No racial predilection is known.

Sex: The male-to-female ratio is increased (approximately 1.15:1) in newborns with Down syndrome. This effect is restricted to free trisomy 21.

Age:

• 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.

• Shortly after birth, Down syndrome is diagnosed by recognizing dysmorphic features and the distinctive phenotype.

CLINICAL

Section 3 of 12

History: When recording the history from the parents of a child with Down syndrome, the clinician should include the following (Cohen, 1996):

• 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



• Symptoms of atlantoaxial instability


• • 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.
  
  
  

Physical:

• Growth: Short stature and obesity occurs during adolescence.



• CNS: Moderate-to-severe mental retardation occurs, with an intelligence quotient (IQ) of 20-85 (mean, approximately 50). Hypotonia 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.



• Behavior: Natural spontaneity, genuine warmth, cheerful, gentleness, patience, and tolerance are characteristics. A few patients exhibit anxiety and stubbornness.



• Psychiatric disorders: The prevalence of psychiatric disorders is 17.6% in children and 27.1% in adults. Children and adolescents are at increased risk for autism, attention-deficit/hyperactivity disorder, and conduct disorder. Obsessive-compulsive disorder, Tourette syndrome, and depressive disorder may occur during the transition from adolescence to adulthood.



• Seizure disorder (5-10%): Infantile spasms are the most common seizures observed in infancy, whereas tonic-clonic seizures are most common in older patients.



• 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.



• 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 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%), and keratoconus in adults are observed.



• Nose: Hypoplastic nasal bone and flat nasal bridge are typical characteristics.



• Mouth and teeth: An open mouth with a tendency of 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, hypoplastic and hypocalcified teeth, malocclusion, taurodontism (0.54-5.6%), and increased periodontal destruction are noted.



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



• Neck: 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.



• Chest: The internipple distance is decreased.



• Congenital heart defects: Congenital heart defects are common (40-50%); they are frequently observed in patients with Down syndrome who are hospitalized (62%), and they are a common cause of death in this aneuploidy in the first 2 years of life. The most common congenital heart defects are endocardial cushion defect (43%), ventricular septal defect (32%), secundum atrial septal defect (10%), tetralogy of Fallot (6%), and isolated patent ductus arteriosus (4%). 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.



• Abdomen: Diastasis recti and umbilical hernia occur.



• GI system (12%): Duodenal atresia or stenosis, Hirschsprung disease ( <1%), TE fistula, Meckel diverticulum, imperforate anus, and omphalocele are observed.



• Genitourinary tract: Renal malformations, hypospadias, micropenis, and cryptorchidism occur.



• Skeleton: Short and broad hands, clinodactyly of the fifth fingers with a single flexion crease (20%), hyperextensible finger joints, increased space between the great toe and the second toe, and acquired hip dislocation (6%) are typical presentations.



• Endocrine system: Hypothyroidism (16-20% of young patients), diabetes, and decreased fertility occur.



• Hematologic system: The relative risk of acute leukemia in the first 5 years of life is 56 times that of non-DS individuals. Approximately 1 in 150 patients develops leukemia. Acute myeloid leukemia (AML) is as common as acute lymphoid leukemia (ALL). Neonatal leukemoid reactions (ie, pseudoleukemia) are common, and distinguishing this from true leukemia frequently poses a diagnostic challenge. 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.

• Skin: Xerosis, localized hyperkeratotic lesions, elastosis serpiginosa, alopecia areata ( <10%), vitiligo, folliculitis, abscess formation, and recurrent skin infections are observed.

• Dermatoglyphics: 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.

Causes:

• The cause of Down syndrome is full trisomy 21 in 94% of patients. Mosaicism (2.4%) and translocations (3.3%) account for the rest. Approximately 75% of the unbalanced translocations are de novo, and approximately 25% result from familial translocation.



• The most common error is maternal nondisjunction in the first meiotic division, with meiosis I errors occurring 3 times as frequently as meiosis II errors. The remaining cases are paternal in origin, and meiosis II errors predominate.



• Most mosaic cases result from a trisomic zygote with mitotic loss of 1 chromosome.



• 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.


• • With a maternal age of 35 years, the risk is 1 in 385.
  
  
  
  • With a maternal age of 40 years, the risk is 1 in 106.
  
  
  
  • With a maternal age of 45 years, the risk is 1 in 30.
  
  
  
• Cytogenetic and molecular studies suggest that dup21(q22.1-22.2) is sufficient to cause Down syndrome. The DSCR contains genes coding for enzymes, such as superoxide dismutase 1 (SOD1), cystathionine beta-synthase (CBS), glycinamide ribonucleotide synthase-aminoimidazole ribonucleotide synthase-glycinamide formyl transferase (GARS-AIRS-GART).

DIFFERENTIALS

Section 4 of 12

Trisomy 18

Other Problems to be Considered:

49,XXXXY chromosome
Other high-order multiple X chromosomes
Zellweger syndrome
Other peroxisomal disorders

WORKUP

Section 5 of 12

Lab Studies:

• Cytogenetic studies: The clinical diagnosis 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.
  
  
  
• Interphase fluorescence in situ hybridization (FISH): FISH may be used for rapid diagnosis. It can be successful in both prenatal diagnosis and diagnosis in the neonatal period.



• Thyroid function tests: Thyroid-stimulating hormone (TSH) and thyroxine (T4) levels should be obtained at birth and annually thereafter.



• Measurement of immunoglobulin G (IgG): This test is used to identify a deficiency 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.
  
  
  
• Papanicolaou test (Pap smear): Perform Pap smears every 1-3 years in sexually active women starting at the age of first intercourse.

Imaging Studies:

• Skeletal radiography


• • Craniofacial anomalies include brachycephalic microcephaly and hypoplastic facial bones and sinuses.
  
  
  
  • 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 anesthesia is given if signs suggest spinal cord compression.
  
  
  
  • 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: This test should be performed on all infants with Down syndrome to identify congenital heart disease, regardless of findings on physical examination.



• Mammography: Obtain yearly mammograms in women older than 50 years.

Other Tests:

• ABR testing: Also known as brainstem auditory evoked response (BAER), the ABR demonstrates 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



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



• Developmental chart: A developmental chart for noninstitutionalized children based on a modified Denver Developmental Screening Test is available for assessing developmental milestones.



• Growth charts: Growth charts are available for children with Down syndrome.


• • An increased incidence of celiac disease has been reported in Down syndrome.
  
  
  
  • Evaluation should be prompted by recognition of signs and symptoms, such as growth failure, abdominal pain, and loose stools.
  
  
  
• Dental care: Rigorous dental hygiene and dental evaluation, beginning after tooth eruption

TREATMENT

Section 6 of 12

Medical Care: Despite continued work, no notable medical treatments for mental retardation associated with Down syndrome have been forthcoming. However, the dramatic improvements in medical care described below have greatly improved the quality of life for patient and increased their life expectancy.

• Genetic counseling


• • Trisomy 21: If the couple has a child with trisomy 21, the risk of recurrence is about 1%. The risk does not appear to be increased in siblings of affected individuals.

  • Translocation Down syndrome: If the child has a translocation, a balanced translocation must be excluded in the parents.

  • Robertsonian translocation: In cases of de novo Robertsonian translocation, the risk of Down syndrome in a subsequent pregnancy is an estimated 2-3%. If either parent has a translocation, start additional family studies and counseling. A parent with a balanced Robertsonian translocation is phenotypically normal but has an increased risk of having a chromosomally unbalanced offspring. 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%.

  • Mosaic Down syndrome: 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 germinal tissue of a parent is postulated to be the cause of more than 1 trisomic child in the family.

  • Reproduction: Affected individuals rarely reproduce. About 15-30% of females with trisomy 21 are fertile, and they have a 50% risk of having an affected child. No affected male is known to have fathered a child.
  
  
  
• Vaccination and medication


• • Usual immunizations and well childcare should be performed as the American Academy of Pediatrics recommends.

  • Thyroid hormone for hypothyroidism is needed to prevent intellectual deterioration and improve the individual’s overall function, academic achievement, and vocational abilities.

  • Subacute bacterial endocarditis prophylaxis is needed in susceptible children with cardiac disease when they undergo dental work or other invasive procedures.

  • Digitalis and diuretics are usually required for cardiac management.

  • Prompt treatment of respiratory tract infections and otitis media is necessary.

  • Children with chronic cardiac and respiratory disease are candidates for pneumococcal and influenza vaccination.

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

  • Provide pharmacologic agents, psychotherapy, and/or behavior therapies 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.

  • Early intervention programs are promising. Programs for infants aged 0-3 years are designed to comprehensively 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.

  • Megadoses of vitamins and minerals supplemented with zinc and/or selenium were not beneficial in a number of well-controlled scientific studies.
  
  
  
• Medical care and monitoring for the adolescent with Down syndrome


• • Perform annual audiologic evaluation.

  • Perform annual ophthalmologic evaluations for keratoconus or corneal opacities and/or cataracts.

  • 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.

  • Swallowing difficulties may persist through the adolescent years and must be addressed.

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

  • Treatment options should include bone marrow transplantation if leukemia occurs.

  • Treat airway obstruction medically and surgically.

  • Special attention to perioperative modalities because of atlantoaxial instability and problems with the respiratory system.

  • Screen for hypothyroidism and diabetes mellitus.

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

  • 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.

  • Facilitate referrals for respite care and treatment of parental problems.

  • Assist the patient's eventual medical transition and occupational issues.

  • During adolescence, an additional 2% of patients die from complications of congenital heart disease, infections, leukemia, and accidents.
  
  
  

Surgical Care:

• Down syndrome alone does not adversely affect surgical outcomes in the absence of pulmonary hypertension.

• Timely surgery of cardiac anomalies, which are common during the first 6 months of life, may be necessary to prevent serious complications.



• Prompt surgical repair is necessary for GI anomalies, such as TE fistula, pyloric stenosis, duodenal atresia, annular pancreas, aganglionic megacolon, and imperforate anus.



• Adenotonsillectomy may be performed to manage obstructive sleep apnea.



• 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.



• Anesthetic airway management may be needed.


• • 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.
  
  
  
• 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 ensure adequate vision.

Consultations:

• Clinical geneticist



• Developmental pediatrician



• Cardiologist



• Ophthalmologist



• Neurosurgeon



• Orthopedic specialist

• Psychiatrist

• Physical and occupational therapist

• Speech-language pathologist

• Audiologist

Diet:

• 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.

Activity:

• No restriction of activities is necessary. Advise the patient to exercise to maintain an appropriate weight.



• Patients with symptoms of arrhythmia, episodes of fainting, abnormal findings on ECG, and palpitations or chest pain should refrain from participating in sports and strenuous exercise.



• Children with C1-C2 subluxation should be allowed to compete in the Special Olympics unless they have symptoms of cervical-cord compression.

MEDICATION

Section 7 of 12

Drug therapy is currently not a component of the standard of care for this syndrome.

FOLLOW-UP

Section 8 of 12

Further Inpatient Care:

• Manage cardiac defects medically or surgically.



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



• Cytogenetic studies are necessary to confirm the clinical diagnosis.

Further Outpatient Care:

• Audiologic evaluation for hearing loss



• Apnea monitoring

In/Out Patient Meds:

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

Complications:

• After adenotonsillectomy, patients have long periods of decreased oxygenation and slowed recovery times.



• Otitis media and upper respiratory tract infections are common.



• Feeding problems and poor weight gain may occur because of congenital heart disease.



• Congenital heart disease is the major cause of death.

Prognosis:

• The overall outlook for individuals with Down syndrome has improved dramatically. Many adult patients are healthier, they are better integrated into society, and they have increased longevity than before. However, their life expectancy is still reduced.



• Congenital heart disease is the major cause for early mortality.



• Leukemia, thyroid diseases, autoimmune disorders, and susceptibility to infections related to an abnormal serum IgG subclass pattern are common.



• Many patients develop progressive Alzheimer-like dementia by the age of 40 years, and 75% of patients have signs and symptoms of Alzheimer disease.

Patient Education:

• 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.

• Patients 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.



• Additional resources can be obtained from the following organizations:


• • The National Down Syndrome Society
    666 Broadway, 8th Floor
    New York, NY 10012-2317
    Phone: 212-460-9330 or 800-221-4602
    Fax: 212-979-2873
    E-mail: info@ndss.org
  
  
  
  • National Down Syndrome Congress
    1370 Center Drive, Suite 102
    Atlanta, GA 30338
    Phone: 770-604-9500 or 800-232-NDSC
    E-mail: info@ndscenter.org
  
  
  
  • National Association for Down Syndrome
    PO Box 206
    Wilmette, IL 60091
    Phone: 630-325-9112
  
  
  
  • International Resource Center for Down Syndrome, Cleveland, OH
  
  
  
  • The Arc
    The Arc of the United States
    1010 Wayne Avenue, Suite 650
    Silver Spring, MD 20910
    Phone: (301) 565-3842
  
  
  
  • The Down Syndrome WWW page
  
  
  
• For excellent patient education resources, visit eMedicine’s Brain and Nervous System Center. Also, see eMedicine’s patient education article Down Syndrome.

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• Failure to identify characteristic symptoms and signs of Down syndrome and to refer patient to a geneticist for evaluation and genetic counseling



• Failure to order chromosomal analysis when Down syndrome is clinically diagnosed



• Failure to offer prenatal screening to pregnant women



• Failure to offer prenatal diagnosis after a woman has an affected child



• Reliance on maternal serum triple-marker screening for prenatal diagnosis in a pregnancy at risk for Down syndrome (Amniocentesis and CVS are the criterion standard diagnostic tests for prenatal diagnosis in a pregnancy at increased risk.)

Special Concerns:

• Awareness: Physicians and parents should be aware of the range of psychomotor potential so that early intervention, schooling, and community placement are provided.

• Prenatal screening


• • Advanced maternal age: The first prenatal diagnosis of Down syndrome was made in 1968, and screening women on the basis of advanced maternal age with amniocentesis was gradually introduced into medical practice.
  
  
  
  • Maternal serum biochemical markers: 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. By 1988, use of the 3 biochemical markers, together with maternal age, had been accepted as a method of prenatal screening for Down syndrome in the general population.
    • When ultrasonography is used to estimate gestational age, the detection rate is about 20% when only the MSAFP test is used, 59% when the double test (MSAFP and hCG) is used, and 69% when the triple test (MSAFP, hCG, uE3) is used. The false-positive rate is 5%. Other factors for adjustment are maternal age and weight, insulin-dependent diabetes mellitus, multiple pregnancies, racial background, previous pregnancy with Down syndrome, and first or repeat test in a pregnancy. A positive screening result only suggests an increased risk for Down syndrome, and definitive testing with amniocentesis with chromosomal analysis is indicated.

    • In a retrospective study of first-trimester screening for free beta-hCG and pregnancy-associated plasma protein A (PAPP-A), detection rates were as high as those associated with MSAFP, hCG, or uE3 testing in the second trimester. Prospective studies are needed to further assess first-trimester screening.
  
  
  
  • Prenatal ultrasonography
    • In several prospective studies of midtrimester screening by expert ultrasonographers in high-risk women undergoing amniocentesis for chromosomal study, nuchal-fold thickening helped in identifying 75% of fetuses with Down syndrome, and a shortened humerus or femur helped identify 31%. An index based on thickened nuchal fold, major structural defects, and other abnormalities helped in identifying 69%.

    • Other sonographic abnormalities are 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), echogenic bowel, intracardiac echogenic focus, nasal bone hypoplasia, and renal pyelectasis.

    • Ultrasonography should not be relied on as the primary method of diagnosing Down syndrome, and the diagnosis can be missed in affected families.
  
  
  
  • Extraction of fetal cells from the maternal circulation: After fetal nucleated RBCs are sorted by using different cell transferrin and glycophorin-A receptors on the cell surface, interphase FISH can be used to determine the chromosomal constitution. Chromosome-specific probes available for X, Y, 13, 18, and 21 permit diagnosis. The FISH finding should be confirmed by using standard cytogenetic techniques.
  
  
  
• Prenatal diagnosis


• • 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 in 200-300).
  
  
  
  • CVS is performed at 10-13 weeks' gestation. Testing earlier than this 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 (96-98%) is less than that of midtrimester amniocentesis because of confined placental mosaicism and maternal-cell contamination.
  
  
  
  • 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 versus 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 for preimplantation diagnosis of single-gene disorders, for sex selection for X-linked disorders, and for identifying chromosomal aneuploidies. After a biopsy sample is obtained from the first polar body, the blastocyst, or the 6- to 8-cell embryo, FISH can then be used to diagnose fetal aneuploidy. However, standard cytogenetic confirmation is not possible for the preimplantation diagnosis.
  
  
  

TEST QUESTIONS

Section 10 of 12

CME Question 1: Which of the following is not a characteristic feature of Down syndrome?

A: Macrocephaly
B: Mental retardation
C: Up-slanting palpebral fissures
D: Small ears with over-folded helix
E: Single transverse palmar crease

The correct answer is A: Patients with Down syndrome usually have a small head size (microcephaly).

CME Question 2: Which of the following is not associated with Down syndrome?

A: Advanced maternal age
B: Elevated maternal serum alpha-fetoprotein (MSAFP) level
C: Elevated maternal human chorionic gonadotropin (hCG) level
D: Low maternal unconjugated estriol (uE3) level
E: Excess nuchal skinfold thickening on ultrasonography

The correct answer is B: Low MSAFP levels are associated with Down syndrome.

Pearl Question 1 (T/F): The most common heart defect in children with Down syndrome is an endocardial cushion defect.

The correct answer is True: Approximately 50% of children with Down syndrome have a congenital heart defect. Endocardial cushion defect is the most common.

Pearl Question 2 (T/F): The most common chromosomal abnormality in Down syndrome is full trisomy.

The correct answer is True: Full trisomy 21 occurs in 95% of patients. Translocation Down syndrome represents 4% of cases, and mosaic Down syndrome represents 1%.

Pearl Question 3 (T/F): For a carrier parent with 21q21q translocation or an isochromosome, the risk of recurrent Down syndrome is 100%.

The correct answer is True: All children of carrier parents with 21q21q translocation or isochromosome are affected. By contrast, 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.

Pearl Question 4 (T/F): For a man with trisomy 21, the risk of having a child with Down syndrome is 50%.

The correct answer is False: No affected male is known to have fathered a child.

PICTURES

Section 11 of 12

Caption: Picture 1. Infant with Down syndrome. Note up-slanting palpebral fissures, bilateral epicanthal folds, flat nasal bridge, open mouth with tendency of tongue protrusion, and small ear with overfolded helix.
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Caption: Picture 2. Child with Down syndrome. Note up-slanting palpebral fissures, bilateral epicanthal folds, a small nose with flat nasal bridge, open mouth with tendency for tongue protrusion, and small ears with overfolded helix.
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Caption: Picture 3. G-banded karyotype showing trisomy 21 (47,XY,+21).
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Caption: Picture 4. G-banded karyotype showing trisomy 21 of isochromosome arm 21q type [46,XY,i(21)(q10)].
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Caption: Picture 5. Hand of an infant with Down syndrome. Note the transverse palmar crease and clinodactyly of the 5th finger.
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Caption: Picture 6. Ear of an infant with Down syndrome. Note the characteristic small ear with overfolded helix.
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BIBLIOGRAPHY

Section 12 of 12

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