Down syndrome
By George T Capone MD (Dr. Capone of the Johns Hopkins University and Director of the Down Syndrome Clinic at Kennedy Krieger Institute
received a research grant from LuMind, and an hororaium from Roche for serving on an advisory board.)
Originally released October 29, 1995; last updated May 12, 2016; expires May 12, 2019
Introduction
This article includes discussion of Down syndrome, Down's syndrome, Downs syndrome, trisomy 21, trisomy 21
mosaicism, and chromosome 21 translocation. The foregoing terms may include synonyms, similar disorders,
variations in usage, and abbreviations.
Overview
In addition to congenital birth defects, persons with Down syndrome are at risk for acquired medical conditions during
childhood, throughout adulthood, as well as premature onset of aging-related conditions beginning in the 3rd to 4th
decades of life. Some of the comorbid medical conditions associated with Down syndrome have atypical presentations
that require a high index of suspicion for diagnosis. Healthcare guidelines for persons with Down syndrome are
designed to detect occult conditions in asymptomatic individuals and to guide physicians evaluating medically
complex or difficult-to-diagnose patients. Successful recognition and treatment of medical conditions is paramount to
managing patients with decline in functional skills.
Key points
• Lower cervical spondylosis with osteophytes and disc herniation increases with age and
may pose more of a neurologic threat in persons of advanced age than atlantoaxial instability.
• The most significant medical disorders related to mortality are dementia, declining motor
function, epilepsy, and respiratory infections.
Historical note and terminology
The first comprehensive description of this condition was provided by Dr. John Langdon Down in
1866.{embed="pagecomponents/media_embed" entry_id="8717"} Down served as Superintendent of the Earlswood
Asylum for Idiots in Surrey, England from 1858 to 1868 and had ample opportunity to observe and examine large
numbers of individuals with mental retardation. Influenced by the evolutionary teachings of that period, his intellectual
pursuits led him to propose an ethnic classification of "congenital idiocy," based on physiognomy and racial
stereotypes (Down 1866). In his classification, he proposed 5 different varieties: (1) Caucasian, (2) Malaysian, (3)
Ethiopian, (4) American-native, and (5) Mongolian. He called special attention to the Mongolian group because he was
struck by their close physical and mental resemblance to one another. In his report of 1866, Down highlighted some of
the salient aspects of the physical appearance and behavioral attributes of individuals with this syndrome. He also
speculated, incorrectly, that the condition was caused by tuberculosis in the parents. Although his ethnic classification
scheme was never accepted by his medical peers, Down's major contribution was to distinguish this condition from
congenital hypothyroidism, or "cretinism," which was also prevalent at that time.
Also writing in 1866, Seguin apparently described persons with Down syndrome but refers to them as having a subtype
of cretinism called "furfuraceous cretinism" (Seguin 1866). By 1877, Ireland clearly delineated between the 2
conditions and distinguished the "Mongolian idiot" from the "cretinoid idiot" (Ireland 1877). The first illustrations in the
medical literature of an individual with Down syndrome appeared in 1876 in a classic paper by Fraser and Mitchell, in
which they provided marvelous illustrations of the face, foot, and skull (Fraser and Mitchell
1876).{embed="pagecomponents/media_embed" entry_id="8718"}{embed="pagecomponents/media_embed"
entry_id="8719"} They were also the first to publish a pathologic description of the brain at
autopsy.{embed="pagecomponents/media_embed" entry_id="8720"} Apparently unaware of Langdon Down's paper
10 years earlier, Fraser and Mitchell also called attention to the oriental-like appearance of the condition and proposed
the term "Kalmuk idiocy" after the Mongolians (Kalmuk) who migrated into the lower Voltar region of Russia.
Fortunately, this term was never accepted by the medical community. The term "Mongolian idiocy," or "Mongolism,"
was used widely throughout the latter part of the 19th and first half of the 20th century. The chromosomal etiology
(trisomy 21) for Down syndrome has been known since 1959 (Lejeune et al 1959). In 1961, sparked by the discovery 2
years earlier of trisomy 21 in persons with Down syndrome as well as by complaints from Chinese and Japanese
scientific investigators, it was proposed that the term "Down syndrome" or "trisomy 21" be adopted to replace the
inaccurate and anachronistic designation "Mongolism" (Allen et al 1961). The complete DNA sequence of human
chromosome 21 (long-arm) was determined in 2000 and is revolutionizing our genetic understanding of this condition
(Gardiner 2000; Hattori 2000).
Clinical manifestations
Presentation and course
The clinical manifestations of Down syndrome are best categorized according to chronological age. In addition to the
well-recognized phenotypic features that are characteristic of this condition, it is paramount that physicians be aware
of the variety of congenital and acquired medical problems associated with Down syndrome (American Academy of
Pediatrics 2011).
Newborn: (0 to 1 month).
Diagnosis. A presumptive diagnosis of Down syndrome is usually made by the physician or hospital staff shortly after
birth. The 10 most common physical features that may aid in diagnosis were outlined by Hall (See Table 1) (Hall 1966).
No single phenotypic finding is diagnostically significant, but rather it is the association of 3 or more of these features
together that warrants suspicion. A definitive diagnosis requires cytogenetic testing (karyotype) to confirm either
complete or partial trisomy 21.
Table 1. Diagnostic Features of Down Syndrome in the Newborn Period
• Flat facial profile
• Poor Moro reflex
• Hypotonia
• Hyper flexible joints
• Excessive skin on neck
• Slanted palpebral fissures
• Pelvic dysplasia
• Anomalous auricles
• Dysplastic midphalanx of the fifth finger
• Single palmar crease
• Down syndrome newborns who demonstrate at least 4 features
• Down syndrome newborns who demonstrate 6 or more features
90%
85%
80%
80%
80%
80%
70%
60%
60%
45%
100%
90%
Adapted from (Hall 1966).
Cardiac. Congenital heart disease occurs in 40% to 60% of Down syndrome newborns. The most common cardiac
lesions are atrioventricular canal (60%); isolated ventricular septal defect, atrioseptal defect, or patent ductus
arteriosus (30%); and tetralogy of Fallot (7%). Isolated congenital valve disease or coarctation of the aorta is seen
occasionally (Marino et al 1990). Cardiac defects are responsible for significant morbidity and mortality during the first
2 years of life (Baird and Sadovnick 1987).
Gastrointestinal. Anatomic gastrointestinal tract anomalies are seen in 6% to 12% of Down syndrome newborns,
including duodenal stenosis or atresia (2.5%), imperforate anus (less than 1%), Hirschsprung disease (less than 1%),
tracheoesophageal fistula esophageal atresia, bile duct atresia, malrotation, and pyloric stenosis. Physiologic
complications such as oral motor dysfunction or gastroesophageal reflux are also commonly seen (Buchin et al 1986).
Ophthalmologic. Congenital cataracts are seen in about 2% to 4% of newborns with Down syndrome, which represents
a 10-fold increase compared to the general population (Roizen et al 1994).
Neurologic. Neuromotor dysfunction, defined by generalized hypotonia and absent or diminished primitive and deep
tendon reflexes, is characteristic of most newborns with Down syndrome (Yessayan and Pueschel 1984).
Endocrine. An increased incidence of congenital hypothyroidism due to absence or aplasia of the thyroid gland occurs
in about 1% to 2% of newborns (Cutler et al 1986). A randomized clinical trial of thyroxine treatment in neonates with
Down syndrome demonstrated a mild benefit in motor and mental development at 24 months (van Trotsenburg et al
2005).
Infancy (1 to 12 months).
Hematologic. A transient myeloproliferative disorder is sometimes seen in the first few months of life. Elevated
peripheral blood leukocyte count with a predominance of "blasts" forms may make this condition difficult to distinguish
from true congenital leukemia (Weinberg et al 1982). Newborns with transient myeloproliferative disorder are at
increased risk to develop acute megakaryoblastic leukemia (Barnett et al 1990). Approximately 3% to 10% of
newborns with Down syndrome are diagnosed with transient myeloproliferative disorder (Seewald et al 2012).
Neonatal treatment of transient myeloproliferative disorder with cytarabine has a favorable impact on 5-year survival
rates (Klusmann et al 2008).
Ophthalmologic. A number of ophthalmologic conditions may present during or shortly after the first year of life,
including strabismus (23% to 44%), refractive errors (35% to 40%), nystagmus (5% to 30%), astigmatism (18% to
25%), amblyopia (10% to 12%), blepharitis (9% to 32%), keratoconus (5% to 8%), ptosis (5%), nasolacrimal duct
obstruction (4% to 6%), and cataracts (4%) (Roizen et al 1994).
Infectious. Infants with Down syndrome are more susceptible to both viral and bacterial infections, particularly of the
respiratory tract. Recurrent otitis media, sinusitis, and rhinitis are frequent problems, as are bronchiolitis and
pneumonia. Lower respiratory tract infections may be a significant cause of morbidity and mortality during infancy
(Chaney et al 1985). The increased predisposition to infections is probably the result of anatomic, immunologic, and
cardiac factors. Respiratory infections tend to become less common with age and subsequent growth of craniofacial
and respiratory structures (Dahle and Baldwin 1992).
Neurodevelopmental. Brain size is often normal throughout gestation and the first 6 months of postnatal life before
decelerating during the second half of the first year of postnatal life (Schmidt-Sidor et al 1990; Palmer et al 1992).
Some degree of neuromotor dysfunction (hypotonia, hyporeflexia, and diminished primitive reflexes) is characteristic
of all infants with Down syndrome. Dysgenesis of the cerebral cortex and cerebellum, as well as delays in myelination
during the first years of life, probably constitutes the primary neurologic substrate of neuromotor dysfunction. Delays
in the acquisition of gross motor milestones are usually obvious to physicians and parents during the first 6 months of
life. There is, however, considerable individual variation in the attainment of early motor milestones (Zausmer and
Shea 1984). A number of factors may account for this variability, including associated medical conditions (congenital
heart disease, seizures, or hypothyroidism), degree of hypotonia, and delayed sensory-motor reaction times (Shea
1990).
Seizures. The incidence of seizures during the first year of life is probably under 5%. Infantile spasms are not
uncommon in the first year of life (Stafstrom and Konkol 1994). Occasionally, tonic-clonic seizures, myoclonus, or
febrile seizures are encountered (Pueschel et al 1991). Infants with difficult-to-control infantile spasms or those in
whom recognition and treatment is delayed frequently have a poorer developmental outcome (Goldberg-Stern 2001;
Eisermann 2003). Severe intellectual disability and autism-like behaviors are not an uncommon outcome, even in
children who respond successfully to anticonvulsant medications (Sanmaneechai et al 2013).
Childhood (1 to 12 years).
Endocrine. Disorders of thyroid function are particularly common in children with Down syndrome. There is a trend for
thyroid-stimulating hormone values to increase and for thyroxine to decrease with advancing chronological age.
Acquired hypothyroidism is seen in between 2% to 7% of children (Cutler et al 1986; Selikowitz 1993). Both
compensated (elevated thyroid-stimulating hormone or normal thyroxine) and uncompensated (elevated thyroidstimulating hormone or decreased thyroxine) hypothyroidism are seen. A transient elevation in thyroid-stimulating
hormone is sometimes noted in infants and children less than 2 years of age, which may be due to hypothalamic and
pituitary dysregulation or end-organ insensitivity. This condition often resolves spontaneously. Compared to their
unaffected siblings, total body fat and serum leptin levels are elevated in prepubertal children with Down syndrome
(Magge et al 2008).
Growth. All children and adolescents with Down syndrome demonstrate reduced linear growth rates between 2 and 4
standard deviations below the mean for the general population (Cronk et al 1988). However, studies indicate
improvements in weight gain and linear growth in young children, suggesting an association with general
improvement in medical care (Zemel et al 2015).
Audiologic. There is a high incidence of hearing loss among children with this condition (Balkany et al 1979; Dahle and
McCollister 1986). Some degree of conductive loss is found in up to 50% and is usually the result of otitis media,
middle ear effusions, or impacted cerumen. Sensory-neural hearing loss, particularly for the higher frequencies, may
be seen in up to 5% to 10% and may result from congenital anomaly of the inner ear or from cholesteatoma. A
combination of conductive and sensory neural loss (mixed) is also seen in about 10% to 15% of children.
ENT/Pulmonary. Obstructive sleep apnea is noted in up to 31% of children with Down syndrome (Stebbens et al 1991).
One study reported abnormalities in overnight polysomnograms in 100% of Down syndrome subjects (hypoventilation
81%, obstructive sleep apnea 63%, and desaturation 56%) (Marcus et al 1991). More than 95% of non-obese children
with Down syndrome and snoring were found to have obstructive sleep apnea on overnight polysomnograms
(Fitzgerald et al 2007). Symptoms of obstructive sleep apnea may include snoring, restless sleep, unusual sleep
position, excessive mouth breathing, daytime somnolence, or behavioral changes. Factors that predispose Down
syndrome children to obstructive sleep apnea include a small oral cavity with relative macroglossia, narrowing of the
upper airway, hypotonia of the pharyngeal muscles, chronic rhinitis, obesity, and enlarged tonsils or adenoids.
Adenotonsillectomy often results in a significant reduction in CO2 retention and the severity of both obstructive and
central apneas (Thottam et al 2015). Even children who have undergone adenotonsillectomy may have persistent
symptoms secondary to glossoptosis, hypopharyngeal collapse, recurrent adenoid tonsils, enlarged lingual tonsils, and
macroglossia (Donnelly et al 2004).
Feeding-swallowing. Difficulties with feeding have long been recognized in infants and young children with Down
syndrome, including food refusal, food selectivity by type or texture, oral motor delay, and dysphagia (Field et al
2003). The presence of a small-crowded oral cavity, gastro-esophageal or tracheo-laryngeal anomalies, oral hypotonia,
and impaired sensory-motor skills may be predisposing factors. A pharyngeal phase type of swallow dysfunction has
been well documented in Down syndrome (Frazier and Friedman 1996; O'Neill and Richter 2013) and is thought to
contribute to the increased rates of silent aspiration and respiratory infections in the first years of life (McDowell and
Craven 2011).
Hematologic. Numerous abnormalities or variation in red cell, white cell, and platelet lines have been reported in Down
syndrome (Ganick 1986). Of greatest clinical significance is the increased risk in leukemia seen in Down syndrome
children. Compared to typical children, acute megakaryoblastic leukemia is 500 times more likely to develop in
children with Down syndrome under 3 years of age, whereas acute lymphocytic leukemia is 20 times more common in
children with Down syndrome over 3 years of age (Seewald et al 2012). Overall, Down syndrome is associated with
approximately 2% of all cases of acute leukemia in children (Ganick 1986; Fong and Brodeur 1987).
Orthopedic. Children with Down syndrome are susceptible to subluxation of the hips, patella, and C-spine. Atlantoaxial
subluxation may result in either acute trauma or slow chronic compression to the spinal cord (Pueschel et al 1984;
Chaudhry et al 1987). Up to 14% of children show x-ray evidence of C1/C2 instability (atlantodens interval 3 mm to 5
mm) and are asymptomatic. Less than 1% of children demonstrate neurologic symptoms that may require treatment.
Symptomatic children usually have an atlantodens interval greater than 8 mm. Symptoms may include brisk deep
tendon reflexes with up-going plantar response, stumbling gait or inability to walk, loss of bowel or bladder control,
and torticollis. Sensory findings are not usually present and are unreliable. In addition to C1/C2 instability, a higher
incidence of atlanto-occipital instability and congenital anomalies of the craniovertebral junction and cervical spine
have been reported (Pueschel et al 1984; Gabriel et al 1990; Tredwell et al 1990; Menezes and Ryken 1992).
Ligamentous laxity with or without accompanying vertebral anomaly (hypoplastic dens) is thought to predispose Down
syndrome children to cervical subluxation.
Immunology. Immune dysfunction is proposed to account for the increased incidence of infections, hepatitis B sAg
carrier status, and frequent autoimmune phenomena in children with Down syndrome (Nespoli et al 1993). Both B- and
T-lymphocyte populations are often markedly reduced in young children (de Hingh et al 2005). Several alterations of
humoral immunity have been reported. Children under the age of 6 appear to have a normal serum immunoglobulin
profile. After 5 or 6 years, hypergammaglobulinemia of the IgG and IgA type is often seen. Serum IgG1 and IgG3 are
usually elevated, whereas IgG2 and IgG4 are decreased. Serum IgM levels also start to decline during adolescence,
becoming lower than normal by adulthood. Altered cellular immunity is also apparent, as evidenced by decreased
numbers of lymphocytes and leukocytes. Evaluation of T-cell function indicates decreased mitogen and antigeninduced proliferation and interleukin-2 production.
Gastrointestinal. Celiac disease is more common and may or may not be associated with clinically significant
gastrointestinal symptoms. Several studies have reported an increase prevalence of IgA-antigliadin antibody (nonspecific), IgA-antiendomysium antibody, IgA-tissue transglutaminase antibody, and total serum IgA levels. Between 5%
and 40% of children may have 1 or more abnormally high antibody levels, whereas the rate of intestinal biopsy
confirmed celiac disease is closer to 7% (Bonamico et al 1996; Carlsson et al 1998; Zachor et al 2000). Screening for
celiac disease is best done using combined IgA-antiendomysium antibody and IgA-tissue transglutaminase antibody
determination (Bonamico 2005), although IgA-tissue transglutaminase antibody appears to be the most specific
(Shamaly et al 2007).
Neurodevelopmental. The brain in Down syndrome is said to have a characteristic morphologic appearance that
permits it to be easily identified at autopsy. Decreased size and weight with foreshortening of the anterior-posterior
diameter, flattening of the occiput, and narrowing of the superior temporal gyrus are most characteristic. Primary
cortical gyri may appear wide, whereas secondary gyri are often poorly developed or absent with shallow sulci
(Davidoff 1928). The cerebellum and brainstem are often markedly reduced in size compared to forebrain structures
(Crome et al 1966). Dysplasia of the brain is probably best reflected by changes in head growth and circumference
during the first few years of life (Palmer et al 1992). Detailed neuropathologic studies reveal a generalized
hypocellularity of the brain. Reduction in neuronal number and density has been demonstrated for most regions
examined (Wisniewski et al 1986). In the cerebral cortex, there is neuronal reduction in all cortical layers, with striking
paucity of small interneurons from cortical layers II and IV (Ross et al 1984). These interneurons use the
neurotransmitter GABA and provide primary inhibitory influence to the pyramidal neurons. Reductions in this cell
population may have particular significance for understanding the co-occurrence of spasms during infancy.
Ultrastructural studies of pyramidal neurons from the cerebral cortex reveal abnormalities of dendritic arborization and
reduced numbers of postsynaptic spines (Marin-Padilla 1976; Suetsugu and Mehraein 1980; Becker et al 1986).
Surviving spines are often abnormally long, thin, or irregular in contour and appearance (Marin-Padilla 1972). As would
be predicted, reductions in synaptic density and surface area are also present (Wisniewski et al 1986). During the first
year of life, decreased myelination is noted throughout the cerebral hemispheres, basal ganglia, cerebellum, and
brainstem (Wisniewski and Schmidt-Sidor 1989). After the first year, myelination delays primarily affect those fiber
tracks with a late beginning and slow myelination cycle. The intracortical fibers and U-fibers of the frontal and
temporal cortices are especially vulnerable.
Cognitive function. As expectations for language and cognitive growth increase during the second year of life, delays
usually become apparent to both parents and professionals alike. Although it is difficult to determine what constitutes
"typical" cognitive development, numerous studies have revealed a specific developmental trend in children with
Down syndrome. A nonlinear rate of cognitive growth is often seen during the first decade of life (Share et al 1964;
Carr 1988) and manifests as slowing in the rate of cognitive development with age. Reduced neuronal number in the
cerebral cortex in conjunction with decreased synaptic number and density, as well as altered dendritic spine
morphology, probably constitutes the major neurobiological substrate of cognitive impairment seen in these children.
Like cognitive development, it is difficult to define what constitutes "typical" speech and language development in
children with Down syndrome. There are large individual differences in the onset and complexity of spoken language
(LaVeck and Brehm 1978). As a group, children with Down syndrome demonstrate greater deficits in verbal-linguistic
skills relative to visual-spatial skills (Rohr and Burr 1978), and many children demonstrate increasing deficits in verballinguistic skill with increasing chronological age (Miller 1985). Asynchrony of language development has been well
documented in this population. Language comprehension and production develop at significantly different rates, with
production skills showing the greatest delays (Miller 1988).
Psychiatric. About 18% to 38% of children and adolescents with Down syndrome may be diagnosed with a comorbid
psychiatric disorder (Gath and Gumley 1986; Myers and Pueschel 1991). Disruptive behaviors (attention deficit
hyperactivity disorder, conduct or oppositional, and aggression) are seen in about 16%, whereas repetitive-stereotypic
movements and autistic features are seen in about 5% to 7%. A characteristic neurobehavioral profile permits children
with Down syndrome plus autism-spectrum disorders to be distinguished from those with stereotypic movements or
moderate to severe mental retardation (Capone et al 2005). Similarly, children with Down syndrome plus disruptive
behaviors are also neurobehaviorally distinct from those with autism-spectrum disorders (Capone et al 2006; Carter et
al 2007).
Adolescence (13 to 18 years).
Growth. The adolescent growth spurt also occurs later compared to the general population (Rarick et al 1975). There is
tendency toward excessive weight gain relative to height throughout childhood and adolescence. Final adult heights
for males range between 140 cm and 160 cm, whereas the typical range for adult females is between 136 cm and 155
cm.
Reproductive endocrine. The onset and progression of puberty are the same or only slightly delayed for adolescent
males with Down syndrome compared to the general population. Males typically show decreased penile length and
testicular volume (Hsiang et al 1987). Serum testosterone levels appear normal throughout puberty (Pueschel et al
1985a; Hsiang et al 1987). Reports of histologically abnormal testes, reduced sperm counts, and lack of mature sperm
in males lead to the conclusion that most males with this condition are infertile. There is, however, 1 report of a male
with Down syndrome who fathered a child; thus, questions about fertility remain unanswered (Sheridan et al 1989).
The onset and duration of menstruation cycles are generally the same for females with Down syndrome compared to
the general population (Goldstein 1988). Reduced ovarian follicular size and number have been reported, and other
histologic abnormalities have also been described (Hojager et al 1978).
Cognitive function. A safety and efficacy study of donepezil for cognitive function in older children with Down
syndrome (10 to 17 years of age) has been published (Kishnani et al 2010). In the largest random controlled trial of its
kind involving children with Down syndrome, 129 subjects received either placebo or donepezil at 2.5 mg starting
dose, which was escalated in 2.5 mg increments every 14 days until reaching 10 mg. Using the Vineland-II Adaptive
Behavior Scales (VABS-II) Parent-Caregiver Rating Form (PCRF) as the primary outcome, improvement in both
treatment and placebo groups was observed. Given the brevity of the trial, and the need for re-test, a practice-effect
may have contributed to the improvements observed. Average daily dosing was 5.0 mg in the donepezil group and 5.6
mg in the placebo group, with greater than 90% compliance in both groups. The most common adverse events in the
treatment group resulting from expected cholinergic overstimulation included diarrhea (12.5%) and vomiting (6.3). The
majority of adverse events were mild or transient, with no serious adverse events reported. Only 1 subject receiving
donepezil discontinued the study because of moderately disturbing urinary retention.
Adulthood (18-40 years).
Growth. Excessive weight gain and obesity are common in adults with Down syndrome and may have a significant
impact on coexisting medical conditions and quality of life (Melville et al 2005).
Endocrine. There is an increasing risk for developing hypothyroidism with advancing age, as evidenced by higher
thyroid-stimulating hormone and declining thyroxine levels (Pueschel and Pezzullo 1985b). Persons with Down
syndrome and hypothyroidism are also more likely to have elevated antithyroglobulin or antimicrosomal antibody
titers, indicative of a Hashimoto-type thyroiditis.
Cardiac. Acquired mitral valve prolapse, tricuspid valve prolapse, and aortic regurgitation are frequently seen in early
adulthood, irrespective of whether congenital heart disease was present at birth (Goldhaber et al 1987; Geggel et al
1993). Typically, clinical symptoms are mild or absent. The actual prevalence of mitral valve prolapse in adults with
Down syndrome is uncertain, but may approach 60%. The prevalence of aortic regurgitation and tricuspid valve
prolapse is estimated to be 11% and 17%, respectively.
Orthopedic. The only longitudinal study of atlantoaxial relationships over time indicates that the atlantodens (C1/C2)
interval remains relatively stable (less than 1.5 mm change) over a 10- to 12-year period in most adults (Pueschel et al
1992). Eight percent showed changes in C1/C2 interval measurement between 2 mm and 4 mm.
Reduction in bone mass (BMD) has been documented in middle-aged adults with Down syndrome. When adjusted for
bone and body size, adults with Down syndrome demonstrated a lower volumetric BMD in lumbar spine and
diminished bone strength relative to the loads that the femoral neck must bear (Baptista et al 2005). Factors related to
reduced BMD may include hypogonadism, hypotonia, low muscle strength, reduced mobility, male gender, and
reduced sunlight exposure (Sakadamis et al 2002; Guijarro et al 2008). Evidence suggests that diminished osteoblastic
bone formation and inadequate accrual of bone mass, without differences in bone resorption, may be an underlying
mechanism regardless of gender or other risk factors (McKelvey et al 2013).
Cervical spondylosis and degenerative changes increase with age in adults with Down syndrome (Ali et al 2006). Lower
cervical spondylosis associated with osteophytic outgrowths and disc degeneration occurs at a higher rate than in the
general population and may predispose Down syndrome adults to cervical myelopathy presenting as gait deterioration
or loss of upper extremity use (Olive et al 1988).
Audiologic. Persons with Down syndrome experience presbycusis or progressive bilateral sensorineural hearing during
adulthood (Buchanan 1990). Approximately two thirds of Down syndrome adults aged 35 years or older have a
component of sensorineural hearing loss greater than 20 dB with relatively low rates (5%-10%) of isolated conductive
hearing loss (Evenhuis et al 1992; Van Buggenhout et al 1999). Almost half of all adults showed evidence of mixed
conductive and sensorineural loss. Additionally, severity appears to increase with age, with about three fourths of
older adults estimated to have moderate-profound hearing loss.
Ophthalmologic. Aging persons with Down syndrome have a high risk of developing visual impairment, cataracts, and
keratoconus. Mild visual impairment is estimated to affect over 50% of older adults. Moderate vision impairment is
seen in 21% whereas severe impairment affects 9% (Van Buggenhout et al 1999). Cataracts contribute to the high
rates of visual impairment and are experienced by 30% to 68%, compared to the general population (17%) (Hesmes et
al 1991). In addition to the classic “senile cataracts,” there is an increased prevalence of “coronary cerulean
cataracts,” which are flake-like lens opacities scattered throughout the peripheral cortex of the lens (Lowe 1949;
Ingersheim 1951). Finally, keratoconus (degeneration of the cornea) also contributes to vision problems. Keratoconus
also increases in prevalence with age, occurring in 20% to 37% of elderly Down syndrome individuals compared to
11% in middle-aged Down syndrome patients (Hesmes et al 1991; van Allen et al 1999).
Dental. Severe periodontal disease consisting of gingivitis with loss of attachment and loss of alveolar bone is
increased, whereas the prevalence of caries formation appears to be decreased in adults with Down syndrome (Ulseth
et al 1991). Dietary, oral hygiene, and other environmental factors may be important variables when trying to
determine the actual incidences of these oral health problems.
Gynecologic. Hypermenorrhea, menorrhagia, and premenstrual syndrome are reported to occur more frequently in
adult females with Down syndrome (Elkin 1992). Menopause typically occurs earlier in women with Down syndrome,
with a median age of onset 4 to 6 years earlier than the general population. In 1 study, 87% of women with Down
syndrome stopped menstruating by age 46 years and 100% had cessation by age 51 years (Schupf et al 1997). The
median age of menopause in Down syndrome (47.1 years) is 2 years younger than in women with ID (49.3 years) and
4 years earlier than the average age of menopause in the general population (51.3 years) (McKinlay et al 1992).
ENT/Pulmonary. It is now known that obstructive sleep apnea is more prevalent in adults with Down syndrome than
previously thought. In the few studies that examine this issue, an extraordinarily high prevalence of hypopnea and
apnea associated with desaturation were reported (Andreou et al 2002; Resta et al 2003). A relationship between
apnea score and performance on cognitive testing was also noted (Andreou 2002). The risk for obstructive sleep apnea
in adults is increased secondary to both upper airway anatomy and obesity. A study reported that 94% of adults with
Down syndrome had abnormal polysomnograms, with 70% indicating severe obstructive sleep apnea [apneahypopnea index (AHI) over 30] (Trois et al 2009). There was a clear correlation between BMI and AHI, but not for age
and AHI or hypothyroidism and AHI. Patients presenting with lethargy, fatigue, mood changes, and cognitive decline,
especially in early adulthood, should have overnight polysomnography as a routine part of their diagnostic evaluation
(Capone et al 2013).
Pneumonia and other lower respiratory infections are the most common cause of morbidity and mortality in adults and
may be related to microaspiration during feeding and drinking (Bittles et al 2007; Smith et al 2014).
Neurologic. Several studies have confirmed a bimodal peak in the prevalence of new-onset seizures in adults with
Down syndrome (Evenhuis 1990; Pueschel et al 1991; McVicker et al 1994). The first peak occurs between 20 and 30
years of age, with a second peak occurring around 45 years of age. Typically, partial complex and partial simple
seizures are seen in the early-onset group and are not associated with cognitive decline or diffuse EEG abnormalities.
Several important age-related changes in the brain have been described in association with Down syndrome. Basal
ganglia calcification seems to be a near universal finding in individuals with Down syndrome, although its pathogenesis
and clinical significance remain obscure (Wisniewski et al 1982; Takashima and Becker 1985). Typically the globus
pallidus and putamen are affected. Using computerized tomography, Wisnewski demonstrated that 27% of individuals
with Down syndrome of various ages showed basal ganglia calcification. In contrast, 100% of postmortem brains
showed basal ganglia calcification on histopathologic examination, yet only 11% of these brains showed basal ganglia
calcification when evaluated by CT prior to autopsy.
The neuropathologic stigmata of Alzheimer-type disease are another universal finding in Down syndrome. Possible
factors influencing the pathogenesis include APP production and metabolism, inflammatory mechanisms, cholesterol
metabolism, and APOE genotype (Lott and Head 2005).
Middle-aged and elderly individuals develop senile plaques, neurofibrillary tangles, and granulovacuolar bodies that
are virtually identical to the Alzheimer pathology seen in the general population (Burger and Vogel 1973; Ellis et al
1974). Alzheimer-type neuropathologic changes are most pronounced throughout the cerebral cortex and limbic
structures. Autopsy studies have convincingly demonstrated that senile plaques and neurofibrillary tangles are present
in all individuals with Down syndrome by the fourth decade of life (Wisniewski et al 1985), with some individuals
showing a much earlier onset (Rumble et al 1989). In addition to the histopathologic similarities, a similar pattern of
neurochemical deficits is seen. Presynaptic markers for cholinergic, noradrenergic, and serotonergic markers are all
reduced in the brains of aged individuals with Down syndrome (Yates et al 1983; Godridge et al 1987). These
neurochemical changes appear to be caused by degeneration and cell loss of the cortical projection neurons arising
from the nucleus basalis of Meynert (cholinergic), locus coeruleus (noradrenergic), and dorsal Raphae nuclei
(serotonergic). Progressive degeneration and loss of neurons from these nuclei are associated with the appearance of
senile plaques and neurofibrillary tangles within the cerebral cortex and hippocampus (See Table 2) (Mann et al 1984).
Table 2. Down Syndrome: Histopathology of Cortically Projecting Neurons
I
<30 years
(n=2)
II
30 to 50 years
(n=5)
III
>50 years
(n=15)
0
0
100%
100%
+
+
100%
100%
++++
++++
40% to 60%
70% to 80%
100%
100%
80%
100%
40%
80%
100%
100%
90%
90%
30%
90% to 95%
100%
100%
100%
95%
75%
75%
Temporal cortex
• Senile plaques
• Neurofibrillary tangles
• Cell number
• Nucleolar volume
Nucleus basalis
• Cell number
• Nucleolar volume
Locus coeruleus
• Cell number
• Nucleolar volume
Dorsal raphae
• Cell number
• Nucleolar volume
0 not present; + minimally present; ++++ abundant
(Adapted from Mann et al 1984)
Cognitive therapies. Reports from several small clinical trials using acetylcholinesterase inhibitors in elderly persons
with Down syndrome and clinical signs of dementia began to appear about 14 years ago (Lott et al 2002; Prasher et al
2002). Initially, mild improvement or slowing in the rate of cognitive deterioration was observed over a 3- to 6-month
period in treated subjects. Within a matter of several years, randomized clinical trials were being conducted as joint
investigator-initiated, industry-sponsored research. A study was designed to measure the safety and efficacy of
donepezil on cognitive function in young adults with Down syndrome (18 to 35 years of age); a 12-week, double-blind,
placebo-controlled trial was conducted in which 121 subjects received placebo or donepezil at 5 mg for 6 weeks and
10 mg for the remaining 6 weeks (Kishnani et al 2009). Using the Severe Impairment Battery Scales (SIB) as the
primary outcome, significant improvement on SIB score was noted in both groups after 12 weeks of the double-blind
phase. The Vineland Adaptive Behavior Scales (VABS) captured significant improvement only in donepezil-treated
subjects during the same period. Of the 121 subjects, 87 continued their participation for another 12 weeks in an
open-label extension study. Those subjects previously on placebo who then received donepezil showed an
improvement in SIB scores, whereas SIB scores for subjects previously on donepezil who continued on donepezil
remained stable. Adverse events were more likely in donepezil-treated subjects in both the double-blind and open-
label phases. No deaths or serious life-threatening events were reported in either group. Donepezil-treated subjects
reported abdominal pain, nausea, vomiting, and insomnia at twice the rate of the placebo group. Most adverse effects
were transient and only mildly or moderately impairing.
Psychiatric. The prevalence of certain psychiatric disorders also increases with age among persons with Down
syndrome. Overall, about 20% to 25% of adults have a psychiatric diagnosis, which is somewhat lower than the 30% to
60% prevalence rates cited for other groups of individuals with mental retardation (Myers and Pueschel 1991).
Specifically, the rates of depression and dementia are significantly increased (Collacott et al 1992). Obsessivecompulsive disorder is also increased (Prasher 1995) and may be accompanied by extreme slowing or catatonic
features (Charlot et al 2002). There are presently no randomized, double-blind clinical trials assessing the tolerability
or efficacy of commonly used psychotropic medication in adult persons with Down syndrome and comorbid anxiety,
depression, obsessive-compulsive or movement disorder.
Depression, which may be responsive to medication, is often misdiagnosed as dementia in young and middle-aged
adults with Down syndrome. Routine evaluation should include testing thyroid, vitamin B12, and folate levels.
Polysomnography should also be performed in subjects with or without obvious risk factors for obstructive sleep apnea
(obesity, narrow-crowded oropharynx, macroglossia) who fail to respond to medications for symptoms of depression,
or functional decline (Capone et al 2006). Because depression and sleep apnea often coexist, an incorrect diagnosis of
dementia in a younger adult may lead physicians to abandon the search for effective treatments prematurely (Capone
et al 2013).
Senescent adults (>40 years).
Spine. Cervical spondylosis associated with osteophytic outgrowths, disc degeneration, and spinal canal stenosis can
lead to the development of cervical myelopathy, which may present with gait disturbance, radicular symptoms, or loss
of upper extremity use (Olive et al 1988). In a study by van Allen and colleagues, 40% of elderly adults showed
evidence of lower cervical spondylosis and degenerative changes (van Allen et al 1999). The neurologic consequences
of these degenerative changes likely pose more of a neurologic threat than atlantoaxial instability among those of
advanced age (Ali et al 2006).
Neurologic. Seizure disorders among elderly Down syndrome individuals often forebode the onset of dementia. In
studies by Lott and Lai and McVicker and colleagues, 53% to 80% of adults with new-onset seizures also had
symptoms of dementia or experienced the onset of cognitive decline soon afterwards (Lott and Lai 1982; McVicker et
al 1994). The seizures associated with dementia are often myoclonic jerks that may be prominent upon or soon after
awakening, and are sometimes asymmetrical (De Simone et al 2010). Of the 18 patients that presented with
myoclonic jerks, 14 (78%) also developed generalized tonic-clonic seizures. In older adults over 50 years of age,
between 24% and 46% had seizures (McVicker et al 1994; McDermott et al 2005). One study comparing Down
syndrome individuals younger than 50 years of age to those individuals over 50 years of age documented increased
use of anticonvulsant use in the older group (16% vs. 38%) (Kerins et al 2008).
Extrapyramidal symptoms are frequently associated with dementia in persons with Down syndrome. In 1 study, 36% of
elderly Down syndrome individuals who had dementia had extrapyramidal symptoms, whereas none of the
nondemented patients showed any evidence of extrapyramidal symptoms (Vieregge et al 1991). Extrapyramidal
symptoms often occur late in the course of dementia, though occasionally are seen earlier. Extrapyramidal symptoms
are not seen in all cases of dementia, and when present are usually of the rigid-hypokinetic variety. Symptoms may
include tremor, rigidity in the extremities, shuffling gait, masked facies, orofacial dyskinesias, bradykinesia, and frontal
release signs.
Dysphagia is not well studied in adults with Down syndrome, although it appears to be a common occurrence in elderly
individuals with and without dementia (Smith et al 2014). Dysphagia may be subtle, and individuals will rarely report
difficulties with eating. However, choking, sputtering, gagging, or coughing are all concerning symptoms and should be
further evaluated. Some patients will merely avoid eating or appear to have loss of appetite. Even when swallowing
dysfunction is not apparent, silent aspiration may be occurring. The high rate of pneumonia in adults with Down
syndrome may very well be related to microaspiration during feeding and drinking (Bittles et al 2007; Smith et al
2014). Beyond concerns for aspiration, swallowing dysfunction and difficulty chewing may also contribute to weight
loss in elderly individuals.
Alzheimer dementia. In spite of the apparent universal finding of Alzheimer-type neuropathologic changes in all
individuals with Down syndrome by the fourth decade of life, the implications for the development of a clinical
dementia syndrome are less clear. In 1 retrospective review of 16 studies, both postmortem brain tissue and clinical
findings were used to support the diagnosis of Alzheimer-type dementia in 33 persons with Down syndrome between
the ages of 35 and 60 years (Dalton et al 1992). All individuals had evidence of senile plaques and neurofibrillary
tangles at autopsy and 1 or more clinical manifestations were found in 75%: seizures (58%), change in personality
(46%), focal neurologic signs (46%), apathy (36%), loss of conversational skills (36%), incontinence (36%), EEG
abnormalities (33%), loss of self-help skills (30%), tremors or myoclonus (24%), visual or auditory deficits (24%), gait
or mobility problems (21%), stubborn or uncooperative behavior (21%), depression (18%), memory loss (18%),
increased muscle tone (12%), disorientation (12%), and delusions or hallucinations (3%).
Prospective studies reveal a different clinical picture of Alzheimer-related changes. Memory loss, temporal
disorientation, and reduced verbal skills have been reported as the earliest signs of Alzheimer-type dementia in
higher-functioning individuals (Lai and Williams 1989). Those individuals in the severe-profound range of mental
retardation more often manifest apathy, inattention, and decreased social interaction. Motor impairments, new onset
of seizures, and loss of self-help skills have also been reported. The natural history of Alzheimer-type dementia in
Down syndrome indicates that the mean age of onset is 51.3 years in the moderately retarded and 52.6 years in the
severely retarded (Evenhuis 1990). In a another study, the prevalence of Alzheimer-type dementia increased from 11%
between 40 to 49 years to 77% between 60 to 69 years; and all subjects over 70 years had dementia (Visser et al
1997). It now appears that both the male gender and the apoE4 allele are associated with earlier onset of clinical
dementia, whereas the apoE2 allele provides some protective effect (Schupf et al 1998). Once recognized, the clinical
signs and symptoms of dementia progress rapidly in most subjects.
Cognitive therapies. A study designed to measure the safety and efficacy of antioxidant supplementation on cognitive
function in adults with Down syndrome over 40 years of age has been completed (Lott et al 2011). This randomized,
double-blind, placebo-controlled trial was conducted on 53 subjects receiving either placebo or antioxidant
supplements (900 IU alpha-tocopherol, 200 mg ascorbic acid and 600 mg of alpha-lipoic acid) over a 2-year treatment
period. Only 31 of the original 53 (58%) participants completed the study. No improvement or stabilization in cognitive
function was observed using the Severe Impairment Battery Scales (SIB) as the primary outcome measure.
A novel NMDA glutamate receptor partial-antagonist memantine was examined for safety and efficacy in adults over
40 years of age (Hanney et al 2012). A randomized, double-blind, placebo-controlled trial was conducted on 163
subjects receiving either memantine or placebo for 52 weeks. Both groups declined on measures of cognitive and
adaptive function using the Down's syndrome Attention, Memory and Executive Function Scales (DAMES) and the
Adaptive Behavior Scale (ABS). After adjustment for baseline scores, no group differences in the rate of decline were
observed. Serious adverse events were also observed in both groups.
Longevity. Longevity has been increasing rapidly in the Down syndrome population since around 1970. In 2007, the
median age (53 years) and the mean age (47.3 years) at death showed a 3.75-fold increase compared to 1970
(Presson et al 2013). Further, there is a notable increase in the number of ageing adults between 35 to 60 years (born
1947-1972) who require expert medical care. Although longevity in Down syndrome adults is increasing overall,
previous studies suggest that these increases have been substantially lower for some minority groups (Yang et al
2002).
Mortality. The most significant medical disorders related to mortality are dementia, declining motor function, epilepsy,
and respiratory infections (Bittles et al 2007; Coppus et al 2010; Glasson et al 2014). A study looking at the
relationship between hospitalization and mortality as a function of congenital heart disease in adults with and without
Down syndrome found that those with Down syndrome/congenital heart disease were more likely to have
hypothyroidism, dementia, heart failure, pulmonary hypertension, cyanosis, and secondary polycythemia. Individuals
with Down syndrome/congenital heart disease also experienced higher in-hospital mortality and were less likely to
undergo a cardiac procedure or surgery (Baraona et al 2013).
Prognosis and complications
A medical prognosis given during the newborn period should be determined on an individual basis, based on the
presence or absence of specific medical conditions. Caution should be exercised in issuing an overly positive or
negative developmental prognosis early in life because of the wide individual variation in developmental outcome.
Biological basis
Etiology and pathogenesis
Down syndrome most often results from complete trisomy of chromosome 21 due to nondisjunction during gamete
formation (Lejeune et al 1959). In about 95% of cases of trisomy 21, the nondisjunction is of maternal origin
(Antonarakis 1991). Such cases of nondisjunction appear to occur "randomly" during meiosis, as the extra
chromosome is not "inherited" per se. Rarely, nondisjunction will occur after fertilization is complete, resulting in 2
different cell lines. This condition is referred to as mosaicism because there exist 1 trisomic and 1 euploid cell line
within the same embryo-fetus. A small number of cases result from either complete or partial translocation of
chromosome 21 to another chromosome (usually in the G or D group). Some forms of translocation Down syndrome
are associated with a familial pattern of inheritance (Williams et al 1975). Overall, 90% to 95% of cases of Down
syndrome result from full trisomy 21; 2% to 4% result from translocation; and 2% to 4% are the result of mosaicism
(Mikkelsen 1977; Hook 1981).
In Down syndrome, as in other trisomic conditions, the developmental expression of normal genes present in triplicate
results in altered patterns of development and ultimately abnormal morphology and physiologic function (Epstein
1990; Capone 2001; Lubec 2002). Chromosome 21, the smallest autosomes, contains about 35 million base pairs of
DNA. The short arm (21p) contains multiple copies of genes coding for ribosomal RNA and a proximal region composed
of highly repetitive DNA sequences. All of the other genes on chromosome 21 map to the long arm (21q). The entire
DNA sequence for chromosome 21 was originally predicted to contain about 225 genes, although more recent
predictions based on mRNA transcript catalogues estimate approximately 550 possible genes (Hattori et al 2000;
Reeves 2000; Sturgeon and Gardiner 2011).
To view the most recent catalogue of known genes mapping to chromosome 21, visit the Online Mendelian Inheritance
in Man Web Site.
Epidemiology"
Data collected by the Centers for Disease Control regarding the prevalence of Down syndrome have been compiled in
the United States from 17 states (10 regions) with population-based birth defects surveillance programs (Morbidity and
Mortality Weekly Report 1994). During 1983 to 1990, the overall birth prevalence of Down syndrome was 9.2 cases per
10,000 liveborn infants (greater than 20 weeks' gestation). Rates differed significantly by racial or ethnic group for
Hispanic (0.12%), Caucasian (0.09%), and African-American (0.07%) infants. The prevalence rates for Down syndrome
increased with advancing maternal age in all racial and ethnic groups. For the periods of 1979 to 1983 and 1999 to
2003, the total number of cases at birth in the United States increased by 24.2% in these same 10 regions (Shin 2009).
Prevention
Advanced maternal age (greater than 35 years) constitutes the major associated risk factor for producing a child with
Down syndrome. When viewed as maternal age-specific rates, the rate of Down syndrome increases linearly until
about 32 years of age, then rises dramatically in an exponential fashion (Hook 1981). The exact reason for this change
in risk with advanced maternal age is poorly understood.
Differential diagnosis
In the newborn period, infants with Down syndrome may be difficult to distinguish from infants with other chromosome
anomalies.
Diagnostic workup
The karyotype performed on blood lymphocytes or skin fibroblasts is mandatory to confirm the diagnosis of Down
syndrome, even in cases where the phenotypic appearance is obvious. It is critical for purposes of genetic counseling
to distinguish complete trisomy 21 from trisomy 21 mosaicism and trisomy 21 due to an unbalanced translocation.
Management
Clinical management of specific medical conditions is generally no different in individuals with Down syndrome
compared to others in the general population. Because of the high incidence of certain conditions, preventive medical
screening of asymptomatic individuals at regular intervals is recommended (Table 3).
Table 3. Down Syndrome Medical Checklist
Infancy (birth to 12 months)
• Karyotype confirmation and genetic counseling, newborn period
• Cardiac evaluation and echocardiogram, newborn period
• Confirm red reflex, newborn period
• Ophthalmology evaluation, by 10 to 12 months
• Check thyroid screen, newborn period
• Complete blood-count, newborn period
• Subacute bacterial endocarditis prophylaxis in susceptible children
• Consider influenza vaccine
• Consider RSV prophylaxis
• Monitor cardiac, gastrointestinal, and neurodevelopmental function
• Obtain a swallow study when oral hypotonia is severe, or when feeding problems or
recurrent respiratory infections occur
• Audiology (hearing) evaluation, by 6 months
• Compile a medical information log
• Appointment at a Down syndrome clinic
Childhood (1 to 12 years)
• Recheck thyroid function tests, yearly
• Complete blood count and ferritin level annually
• Continue subacute bacterial endocarditis prophylaxis in susceptible children
• Consider influenza and pneumococcal vaccine
• Monitor ENT, cardiac, gastrointestinal, sleep, behavior, and neurodevelopmental function
• Obtain an overnight sleep study (r/o OSA) if symptoms or anatomical risk factors are
present
• Consider antibiotic prophylaxis, allergies, ventilation tubes, and ENT consultation
• Recheck hearing at least annually
• Ophthalmology (vision) evaluation, by 1 year
• Cervical spine x-ray if myelopathic symptoms are present. Lateral neck (neutral, flexion,
and extension views). Measure atlanto-dens interval and neural canal width.
• Regular physical exercise and recreational programs
• Continue medical information log
• Appointment at a Down syndrome clinic
Adolescence (12 to 18 years)
• Echocardiogram for mitral valve prolapse and aortic regurgitation, if new murmur is
present
• Continue subacute bacterial endocarditis prophylaxis in susceptible individuals
• Consider influenza vaccine
• Monitor sleep, behavior, and mental health function
• Recheck thyroid function tests, yearly
• Recheck hearing, at least every 2 years
• Recheck vision, at least every 2 to 3 years
• Cervical spine x-ray if myelopathic symptoms are present. Lateral neck (neutral, flexion,
and extension views). Measure atlanto-dens interval and neural canal width.
• Repeat polysomnography if risk-factors or symptoms are present despite previous T & A
• Menstruating females: consider gynecology evaluation (pelvic examination or ultrasound)
as required
• Dental evaluation, twice yearly
• Regular physical exercise and recreational programs
• Continue medical information log
• Appointment at a Down syndrome clinic
Adulthood (18 to 40 years)
• Echocardiogram for mitral valve prolapse and aortic regurgitation if new murmur is
present
• Monitor for syncope from bradycardia and low resting blood pressure
• Consider influenza vaccine
• Monitor sleep, behavior, and mental health function
• Recheck thyroid function tests, yearly
• Monitor Vitamin D, calcium, and endocrine studies
• Recheck hearing, at least every 2 years
• Recheck vision, at least every 2 to 3 years
• Cervical spine x-ray if myelopathic symptoms are present. Lateral neck (neutral, flexion,
and extension views). Measure atlanto-dens interval and neural canal width.
• Obtain overnight sleep study (r/o OSA) if symptoms or anatomical risk factors are present,
despite previous T & A
• Menstruating females: consider gynecology evaluation (pelvic exam or ultrasound) as
required
• Dental evaluation, twice yearly
• Regular physical exercise and recreational programs
• Continue medical information log
• Appointment at a Down syndrome clinic
Senescent adults (>40 years)
• As above
• Cervical spine x-ray and MRI if myelopathic or radicular symptoms present
• Monitor DXA bone density scan
• Monitor Vitamin D, calcium, and bone biomarkers
• Maintain high vigilance for cognitive decline, gait deterioration, seizures, and dysphagia
• Monitor safety during ambulation, feeding, bathing, and toileting
• Arrange in-home support for caretakers as required
Adapted from (American Academy of Pediatrics 2011; Smith 2001; Jensen and Bulova 2014).
Special considerations
Pregnancy
There are at least 31 reported cases of pregnancy in females with Down syndrome. Approximately one-third of
offspring also have trisomy 21, another one-third have major malformations or mental retardation, and one-third
appear to be normal (Bovicelli et al 1982). An increased rate of prematurity is also seen.
Anesthesia
The cholinergic antagonist atropine has been reported to result in greater cardio-acceleration in adults with Down
syndrome compared to controls (Harris and Goodman 1968). This needs to be considered whenever atropine is being
given as a preanesthetic agent. A review of 100 patients with Down syndrome requiring general anesthesia for surgical
procedures revealed no significant differences with inhaled anesthetics compared to normal children (Kobel et al
1982).
There are several reports of spinal cord compression and narrowing of the neural canal intraoperatively in children
with Down syndrome (Kobel et al 1982; DeLeon et al 1991). In children over 2 years of age, C-spine films in neutral,
flexion, and extension views should be obtained prior to general anesthesia in order to determine the propensity for
C1-C2 subluxation and spinal canal narrowing associated with hyperextension of the neck. In children under 2 years, xrays may not be informative. It is strongly recommended that anesthesiologists use caution when manipulating the
head and neck at the time of intubation and throughout the intraoperative period in all persons with Down syndrome.
There are no reports regarding the use of agents for conscious sedation in Down syndrome; however, it is mandatory
that all patients be carefully screened for a history of obstructive sleep apnea prior to administration of hypnotics or
sedatives because hypoventilation may occur. The physician or nurse anesthetist should be prepared to intervene in
such cases by repositioning the head and neck or by supplying supplemental oxygen.
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**References especially recommended by the author or editor for general reading.
Former authors
Hilary Gwynn MD
ICD and OMIM codes
ICD codes
ICD-9:
Down syndrome: 758.0
ICD-10:
Down syndrome: Q90
OMIM numbers
Down syndrome: #190685
Profile
Age range of presentation
prenatally
0-01 month
01-23 months
Sex preponderance
male=female
Family history
family history may be obtained
Heredity
heredity may be a factor in translocation
Population groups selectively affected
none selectively affected
Occupation groups selectively affected
none selectively affected
Differential diagnosis list
other chromosome anomalies
Associated disorders
ADHD
Alzheimer disease
Antithyroid antibodies
Anxiety
Aortic regurgitation
Articulation disorder
Atlantoaxial subluxation
Atrioventricular canal
Auditory impairment
Autism spectrum disorder
C1-C2 instability
C1-C2 subluxation
Cervical spondylosis
Chronic otitis media
Cognitive impairment
Congenital gastrointestinal anomaly
Congenital heart disease
Depression
Dementia
Duodenal atresia
Duodenal stenosis
Gross motor delays
Growth retardation
Hepatitis B carrier
Hirschsprung disease
Hyporeflexia
Hypothyroidism
Hypotonia
Imperforate anus
Infantile spasms
Intellectual disability
Leukemia
Ligamentous laxity
Mental retardation
Mitral valve prolapse
Neuromotor dysfunction
Obstructive sleep apnea
Obsessive-compulsive disorder
Osteoporosis
Presbycusis
Pyloric stenosis
Senile cataracts
Sleep disorders associated with encephalopathy and mental retardation
Transient myeloproliferative disorder
Tricuspid valve prolapse
Vertebral anomaly
Other topics to consider
Cerebral amyloid angiopathy
Impact of genomics on the practice of neurology
Intellectual disability
Microcephaly
Neuroproteomics
Sleep and intellectual disability
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