clinica, diagnostico y manejo del sindrome de down
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Clinical features, diagnosis and management of Down syndrome
Author
Nancy J Roizen, MDSection EditorsJan E Drutz, MD
Helen V Firth, DM, FRCP, DCHDeputy Editor
Mary M Torchia, MD
INTRODUCTIONDown syndrome (DS) is the most common chromosomeabnormality among liveborn infants. It is the most frequent form of intellectual disability
(mental retardation) caused by a microscopically demonstrable chromosomal aberration.
DS is characterized by a variety of dysmorphic features, congenital malformations, and
other health problems and medical conditions. Not all of them are present in each affectedindividual.
DYSMORPHIC FEATURESEach characteristic dysmorphic feature is present in 47
to 82 percent of cases [1,2]. These features predominantly affect the head and neck and the
extremities.
Head and neckCharacteristic dysmorphic features of DS affecting the head and neck
include:
Brachycephaly
Upslanting palpebral fissures Epicanthic folds (picture 1) Brushfield spots Flat nasal bridge Folded or dysplastic ears Small ears Open mouth Protruding tongue (picture 1) Furrowed tongue Narrow palate Abnormal teeth Short neck Excessive skin at nape of the neck
ExtremitiesCharacteristic dysmorphic features of DS affecting the extremities include:
Short broad hands Hypoplastic mid phalanx of fifth finger Incurved fifth finger
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Transverse palmar crease (picture 2) Space between the first and second toes (sandal gap deformity) Hyperflexibility of joints
Neonatal featuresAmong the characteristic dysmorphic features, ten are common in
newborns with DS and are usually recognized soon after birth. In a series of 48 affectednewborns, all had four or more features and 89 percent had six or more [1,3].
Flat facial profile Poor Moro reflex Excessive skin at nape of the neck Slanted palpebral fissures Hypotonia (picture 3) Hyperflexibility of joints Dysplasia of pelvis Anomalous ears Dysplasia of midphalanx of fifth finger Transverse palmar (Simian) crease (picture 2)
INTELLECTUAL DISABILITY (MENTAL RETARDATION)Almost all
individuals with DS have cognitive impairment, although the range is wide. Most aremildly to moderately intellectually disabled, with IQ in the 50 to 70 or 35 to 50 range,
respectively, although some are severely impaired with IQ 20 to 35 [4].
Developmental impairment becomes apparent in the first year of life. In general, the
average age of sitting (11 months), creeping (17 months), and walking (26 months) is twice
the typical age [5]. Although the sequence of language development is the same, the rate isslower, with the average age for the first word at 18 months [6]. The child with DS
continues to learn new skills. However, IQ declines through the first 10 years of age,
reaching a plateau in adolescence that continues into adulthood [2,7,8].
The profile of cognitive impairment in DS appears to differ from other forms of intellectual
disability. The most common profile, in which language comprehension is equal to mental
age and language production is more delayed, occurs in 64 percent of affected children [9].In 34 percent, language comprehension, mental age, and language production are equal.
Impairment in expressive language was noted in another study of children with DS, who
had fewer different and total words and decreased mean length of utterance compared to
controls matched for nonverbal mental age [10]. Vocabulary skills accelerated more rapidlythan syntax (average sentence length and structure) and surpassed mental age in
adolescence. Similar findings of increasing differences in comprehension with age were
noted in another report, in which children with DS developed relatively stronger skills invocabulary compared to syntax [11]. Other selective deficits have been described, such as
greater difficulty understanding sequences or grammatical rules [2,12].
HEART DISEASEApproximately one-half of individuals with DS have congenital
heart disease. In the largest population-based study, cardiac evaluations were available on
227 of 243 liveborn infants with trisomy 21 identified by the Atlanta Down Syndrome
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Project [13]. Of these, 44 percent had congenital heart defects. The following lesions were
identified:
Atrioventricular septal defect (also called endocardial cushion defect) with orwithout other lesions45 percent
Ventricular septal defect with or without other lesions35 percent
Isolated secundum atrial septal defect8 percent Isolated persistent patent ductus arteriosus7 percent Isolated tetralogy of Fallot4 percent Other1 percent
Some asymptomatic adolescents and adults without structural heart disease develop valve
abnormalities [14,15]. In a series of 35 patients with DS at an average age of 20 years,
mitral valve prolapse occurred in 16 (46 percent) and aortic regurgitation in two [14]. In
another report of 30 adults, mitral valve regurgitation occurred in 17 percent [15].
GI ABNORMALITIES
Children with trisomy 21 are at increased risk forgastrointestinal tract anomalies, which occur in approximately 5 percent of cases [16].Duodenal atresia or stenosis, sometimes associated with annular pancreas, is the most
characteristic lesion, occurring in 2.5 percent [2]. Imperforate anus and esophageal atresia
with tracheoesophageal fistula are seen less often. Conversely, DS affects 28 percent ofpatients with duodenal atresia or stenosis and 20 percent with annular pancreas.
Hirschsprung disease is more common in DS than in the general population, although therisk is less than 1 percent [4]. Among children with Hirschsprung disease, approximately 2
percent have trisomy 21, (with a range of 2 to 15 percent) [17-21].
A strong association appears to exist between DS and celiac disease. The prevalence of
biopsy-proven celiac disease has been reported to be between 5 and 16 percent,
representing a 5- to 16-fold increase compared to the general population [22-26].
GROWTHBirth weight, length, and head circumference are less in DS compared to
typical infants. Newborns with DS weigh approximately 0.18 to 0.37 kg less than theirsiblings [27]. Mean length at birth is approximately 0.5 standard deviation less than control
newborns [28].
In a study of 105 children with Down syndrome, length, weight, and head circumference
were below those of normal healthy children at birth; remained lower until puberty, with
the growth spurt being earlier (age 11 in boys and 9.5 in girls); and were blunted comparedwith controls [29].
Short statureGrowth rate is reduced in DS compared to typical children, especially ininfancy and adolescence. Growth is most reduced in children with severe congenital heart
disease [28,30]. In adults with DS, the average height in males and females is 61.7 and 57
inches (157 and 144 cm), respectively, and the average weight is 157 and 140 lb (71 and 64
kg) in males and females [31]. Growth charts for children with DS have been published inpopulations in the United States [30,32], Italy [33], the Netherlands [34], and Sweden [35].
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The cause of DS-associated growth retardation remains unknown; low circulating levels of
IGF-1 and diminished provoked and spontaneous secretion of GH have been reported in
some patients [36,37]. Serum GH levels are not low in children with DS [38,39], butsuboptimal endogenous GH production as a result of hypothalamic dysfunction has been
demonstrated [40]. Selective deficiency of IGF-1, but not IGF-II, has been seen in Down
syndrome patients who are older than two years [41,42]. IGF-1 receptors are present inbrain cells from fetuses with trisomy 21 [42].
ObesityThe prevalence of obesity (defined as a body mass index >27.8 kg/m2 in adult
males and >27.3 kg/m2 in adult females) is greater in DS than in the general population (45
versus 33 percent, 56 versus 36 percent, for males and females, respectively) [31]. This is
thought to result from the reduced resting metabolic rate in children and adults with DS[43,44]. In general, weight is less than expected for length in infants with DS, and then
increases disproportionally so that the majority of children are obese by age three to four
years [8].
EYE PROBLEMSOphthalmologic disorders that require monitoring and intervention
affect the majority of children with DS.
Disorders that are the most common include [8,45-49]:
Refractive errors (myopia, hyperopia, astigmatism)35 to 76 percent Strabismus25 to 57 percent Nystagmus18 to 22 percent
Cataracts occur in 5 percent of newborns. Starting in the second decade of life, many
individuals develop corneal opacities. Children occasionally develop glaucoma
The frequency of ocular disorders increases with age. In one report, eye abnormalities
occurred in 38 percent of infants two to 12 months of age and 80 percent of children agefive to 12 years [45]. These abnormalities may be more prevalent in adults. In one report, of
30 institutionalized adults with Down syndrome, only one had nearly normal ocular status
[50]. Nine had keratoconus, an abnormal shape or thinning of the cornea that impairs visualacuity.
HEARING LOSSHearing impairment affects 38 to 78 percent of individuals with DS
[8,51,52]. The characteristics of hearing loss were illustrated by a study of 47 children with
DS, two months to 3.5 years of age, evaluated by auditory brainstem response testing [52].
The following findings were noted:
The loss was unilateral or bilateral in 28 and 38 percent, respectively; 34 percent ofpatients had normal hearing
The loss was conductive in 19 ears, sensorineural in 16, and mixed in 14 The extent of loss was mild, moderate, and severe to profound in 33, 13, and 3 ears,
respectively
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Otitis media is a frequent problem, affecting 50 to 70 percent of DS children [4].
Monitoring for this condition is important to preserve hearing.
HEMATOLOGIC DISORDERSHematologic abnormalities affecting red cells, white
cells, and platelets are common in DS. The risk of leukemia in DS is 1 to 1.5 percent
[53,54].
Approximately 65 percent of newborns with trisomy 21 have polycythemia [55]. In onereport, plasmaerythropoietinconcentration measured in umbilical cord blood was higher in
infants with DS compared to controls, suggesting that chronic fetal hypoxemia may explain
the high incidence of polycythemia [56]. (See"Neonatal polycythemia".)
Children with DS often have macrocytosis [55,57]. In one study, mean corpuscular volume
(MCV) was greater in DS children age two to six years compared to controls (86.9 versus
80.6 fL), and MCV >95th percentile for age was more likely to occur (66 versus 11percent) [57]. Hematocrits were higher in the DS patients (39.1 versus 36.9 percent),
although all were normal for age.
White blood cell counts are decreased in DS [55,57]. In the study cited above, white blood
cell counts
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Most affected patients are asymptomatic. Vesiculopustular skin eruptions are common and
resolve as the hematologic disorder regresses [67,68]. The lesions contain cells similar to
the circulating blasts.
However, life threatening complications can occur [69,70]. In a prospective study
conducted by the Pediatric Oncology Group of 48 children with transient leukemia, sevendeveloped hepatic fibrosis and two had cardiopulmonary failure [69]. In retrospective
studies, clinical features associated with early death include preterm delivery, white blood
cell count 100,000 cells/microL, direct bilirubin 4.84 mg/dL (83 micromol/L), ascites,and bleeding diathesis [62,70].
Hepatic fibrosis presents as obstructive jaundice that is progressive and results in death in
approximately one-half of the cases [69,71]. The mechanism of fibrosis may be related to
increased expression of platelet-derived growth factor and transforming growth factor beta
1 in the blast cells [72].
Cardiopulmonary disease typically presents as generalized edema, with pulmonary edema,pericardial effusions, and ascites [69,73]. The mechanism is unknown, although myocardialinfiltration by blasts may play a role [63].
Acute megakaryoblastic leukemia (AMKL)In prospective and retrospective studies, up
to 26 percent of infants with transient leukemia later developed the FAB M7 subtype of
acute myeloid leukemia (AML-M7), also known as acute megakaryoblastic leukemia
(AMKL) [61,63,74].
AML-M7 occurs in approximately one in 50 to 200 children with Down syndrome. The
incidence is approximately 500 times greater in children with than without DS. Studiesunder way by the Children's Oncology Group and others will provide more information on
the natural history of transient leukemia, the proportion of patients who develop AML-M7
or acute lymphoblastic leukemia, their characteristics, and responses to treatment[65,75,76].
AML-M7 develops during the first four years of life. It is most commonly seen by twoyears of age and is invariably associated with mutations in GATA1 [54]. In contrast,
myeloid leukemias in people with DS aged four years or older are usually negative for
GATA-1 mutations, and their prognosis does not differ from AML in patients without DS.
Many affected patients (20 to 69 percent) present with myelodysplastic syndrome,consisting of progressive thrombocytopenia followed by anemia [53]. Some develop
hepatomegaly and liver failure due to fibrosis [73] Neutropenia and infection rarely are
seen [73]. Treatment issues are complex, as children with Down syndrome and either ALLor AML are subject to high initial rates of treatment-related mortality [77].
AML-M7 may result from a mutation in the gene on the X chromosome encoding thetranscription factor GATA-1 that is required for normal differentiation of megakaryocytes
[63,78-80]. In one report, mutations in GATA-1 were identified in blasts of all seven
infants with DS and transient leukemia [81]. In another study, GATA-1 mutations werefound in blasts of nine of 12 patients with DS and transient leukemia and all three with
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AML-M7 [82]. In one patient studied serially, the same mutation was identified in blasts
during transient leukemia diagnosed before one week of age and in subsequent AML-M7 at
one year, but not after remission at three years.
There is evidence that these GATA-1 mutations are acquired in utero and that finding such
mutations at birth might serve as a biomarker for an increased risk of transient leukemiaand subsequent AMKL [83,84]. In one study, three of four children with DS and AMKL
had the same GATA-1 mutation in a neonatal blood spot (Guthrie card) that was found atthe time of clinical diagnosis of AMKL 12 to 26 months later [85].
Gene expression profiling may help in distinguishing transient leukemia from AMKL [86],as well as distinguishing the AMKL seen in children with DS from AMKL seen in those
without DS [87].
Acute lymphoblastic leukemia (ALL)The risk of developing acute lymphoblasticleukemia (ALL) is approximately 10 to 20 times higher in DS compared to non-DS
children [26,88-90] and accounts for 1 to 3 percent of all patients with ALL. The clinicalpresentation is similar to that in children without DS.
In a report comparing ALL in DS and non-DS children, the following findings were notedat presentation [53,88]:
Leukocyte count and leukemic cell mass were similar Age distribution and immunophenotype were similar Clinically they were indistinguishable [54] Mediastinal mass (1.6 versus 8.9 percent) and CNS leukemia (0 versus 2.7 percent)
were less common in DS, favorable prognostic signs
Less T-cell leukemia or translocation of (9;22) or t(4;11) were seen in DS, bothunfavorable prognostic signs
Cytogenetic differences occurred, including less hyperdiploidy in DS, anunfavorable prognostic sign
Children with DS who develop ALL often respond to chemotherapy as well as do childrenwithout DS. The treatment and outcome for children with DS and ALL are discussed
separately.
IMMUNE DEFICIENCYDS is associated with a variety of immunologic impairments
that are thought to be related to the increased susceptibility to infection, autoimmune
disorders, and malignancies [91-93]. Chemotactic defects [94], decreased IgG4 levels [95],and quantitative and qualitative abnormalities of the T-cell and B-cell systems have been
inconsistently demonstrated [91-93,96]. Whether these represent a primary immune
deficiency or early senescence of the immune system is uncertain.
Support for an intrinsic immune deficiency is provided by a cross-sectional study, in which
immunophenotyping was used to evaluate lymphocyte subpopulations in 96 children with
DS who ranged in age from one to 20 years [97]. Compared to previously published data onhealthy children without DS [98], children with DS had a diminished expansion of T and B
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cell lymphocytes in the first years of life. Although T lymphocytes eventually
approximated normal levels, B lymphocytes remained diminished (with 88 percent of
values below the 10th percentile).
ENDOCRINE DISORDERSEndocrine abnormalities in DS include thyroid
dysfunction and diabetes.
Thyroid diseaseThyroid disorders are common in DS. The prevalence varies, dependingin part upon the population studied and the age of testing. In reports of adults with DS, the
prevalence of hypothyroidism ranged from three to 54 percent [99]. Hyperthyroidism is
also relatively common, occurring in 2.5 percent of institutionalized adults [100].
Thyroid disease is also common in children with DS, as indicated in the following reports.
In a longitudinal study of 85 DS patients up to 25 years of age, 30 (35 percent) hadhypothyroidism. One-half developed the disorder before age eight years [99]. Two
patients (2.3 percent) had hyperthyroidism. In 320 children with DS aged five days to 10 years, 90 (28 percent) had abnormal
thyroid function tests [101]. Of these, diagnoses included primary congenital
hypothyroidism in six, acquired hypothyroidism in one, transienthyperthyrotropinemia in two, compensated hypothyroidism (T4 concentration
normal or close to the lower limit of normal and increased thyroid-stimulating
hormone level) in 16, and mild compensated hypothyroidism (mildly elevated TSH
concentration) in 65. None had hyperthyroidism.
In a large cohort from a neonatal screening program, T4 concentrations in newbornswith DS had a normal distribution, but were shifted to lower concentrations than the
general population [102]. Mean TSH concentration was significantly increased(9.76 versus 3.96 mIU/L) and T4-binding globulin was normal compared to control.
DiabetesThe risk of type I diabetes appears to be increased in DS [26,103-105]. Datafrom a Dutch study in children up to 14 years of age suggest the risk of type I diabetes isthree times greater in DS than in the general population (50 versus 12.4 per 100,000 per
year) [104,105]. In another study, the estimated prevalence of type I diabetes in DS
children up to nine years of age was eight times greater than the age-matched controlpopulation (335 versus 40 per 100,000) [104].
REPRODUCTIONWomen with DS are fertile and may become pregnant. In oneseries, 30 pregnancies in 26 women resulted in 10 offspring with DS, 18 (including one set
of twins) without DS, and three spontaneous abortions [106]. Appropriate counseling
should be provided for management of menstruation and contraception [4].
Nearly all males with DS are infertile. The mechanism is impairment of spermatogenesis
[107]. However, cases have been reported of offspring from fathers with DS [108,109].
ATLANTOAXIAL INSTABILITYAtlantoaxial instability (AAI), defined as
excessive mobility of the articulation of the atlas (C1) and the axis (C2), may lead tosubluxation of the cervical spine [110]. Approximately 13 percent of individuals with DS
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have asymptomatic AAI, while spinal cord compression due to the disorder affects
approximately 2 percent [111]. The diagnosis is made by lateral neck radiographs taken in
neutral position, flexion, and extension.
Patients with symptomatic spinal cord compression may have neck pain, torticollis, gait
abnormalities, loss of bowel or bladder control, or signs of quadriparesis or quadriplegia,and require immediate stabilization. Asymptomatic individuals appear to remain
asymptomatic whether or not physical activity is restricted [112,113]. In one study, DSchildren with AAI were randomly assigned to participate or not in athletic activities
considered to be risky and evaluated after one year. The groups were similar in motor
function, frequency of neurologic signs, and changes in atlantoaxial distance, and were also
similar to children with DS and without AAI [112].
UROLOGIC ABNORMALITIESStudies suggest an increased incidence of urologic
abnormalities in individuals with DS. These include hypospadias (1 in 250 males),cryptorchidism (14 to 27 percent of males), testicular cancer, and renal malformations (3.5
percent) [114]. (See appropriate topic reviews).
ARTHROPATHYDown syndrome arthropathy has a prevalence of 8.7/1000, or six
times the prevalence of juvenile rheumatoid arthritis, in the general population. In a review
of 30 cases, 17 had polyarticular disease at symptom onset, and 13 had oligoarticulardisease at symptom onset but 7 of these progressed to polyarticular disease [115]. Average
delay from symptom onset to diagnosis was two years [115].
SLEEP APNEAObstructive sleep apnea occurs in at least 30 to 75 percent of children
with DS, including those who are not obese [116-122]. In a population of 65 unselected
3.5-year-olds with DS, polysomnograms were classified as abnormal with evidence ofobstructive sleep apnea in 57 percent. Among the 45 children whose parents reported no
sleep problems, 54 percent had abnormal results [121]. The mechanism includes soft tissue
and skeletal alterations that lead to upper airway obstruction. Intermittent hypoxemia may
lead to pulmonary hypertension and contribute to mental impairment.
SKIN DISORDERSThe majority of DS children have associated skin disorders, which
are considered benign. In one series, 62 of 71 children (87 percent) had skin abnormalitiesin the following proportions [123]:
Palmoplantar hyperkeratosis41 percent Seborrheic dermatitis31 percent Fissured tongue20 percent Cutis marmorata13 percent Geographic tongue11 percent Xerosis10 percent
In adolescents, dermatologic problems become particularly bothersome. The most common
condition in this age group is folliculitis, which affects 50 to 60 percent of patients [124],
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BEHAVIOR DISORDERSBehavior and psychiatric disorders are more common in
DS than typical children but less common than in those with other causes of mental
retardation [8]. In one report, psychiatric disorders affected 17.6 percent of individuals withDS less than 20 years of age [125]. Disruptive behavior disorders, such as attention deficit
hyperactivity disorder, conduct/oppositional disorder, or aggressive behavior, were most
common. In the same study, psychiatric disorders, most often consisting of majordepressive illness or aggressive behavior, affected 25.6 percent of DS adults.
Autism is a common comorbidity of DS, affecting as many as 7 percent of DS children
[126]. The diagnosis is often delayed compared to children without DS [127].
DIAGNOSIS OF DOWN SYNDROMEThe diagnosis of DS is often made by
prenatal screening.
When no prenatal diagnosis is available, DS is usually recognized from the characteristicphenotypic features present in the newborn (see'Dysmorphic features'above). Diagnosis
should be confirmed with a karyotype performed on a blood sample.
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