Clinical manifestations

Presentation and course

Development

The neurocognitive profile in Down syndrome is unique compared to other populations with intellectual disability and reflects underlying structural and functional neuroanatomic abnormalities and differences in brain development. Acquisition of early developmental milestones occurs in the typical progression, but at a slower rate, with wide variability. Cognitive neurodevelopment is impaired in nearly all individuals with Down syndrome, and most individuals with Down syndrome have cognitive impairment in the mild-moderate-severe range of intellectual disability, although some may have more profound impairments.

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 (206; 37) 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.

Although global cognition is affected, developmental domains develop unevenly, with language abilities disproportionately impacted. These patterns of development lead to distinct neurocognitive and neurobehavioral profiles in Down syndrome.

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 (126). As a group, children with Down syndrome demonstrate greater deficits in verbal-linguistic skills relative to visual-spatial skills (187), and many children demonstrate increasing deficits in verbal-linguistic skill with increasing chronological age (156). 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 (157).

Neurodevelopmental and behavioral disorders: children and adolescents

Most children with Down syndrome do not have a coexisting psychiatric or behavioral disorder, and the available estimates of psychiatric comorbidity range from 20% to 40% (87; 93; 163; 41; 64; 32; 62). These estimates are greater compared to neurotypical children, but lower compared to children with similar levels of intellectual disability (87). When considering specific psychiatric disorders, it is useful to distinguish conditions with a prepubertal onset from those typically presenting during or after puberty, as these are biologically distinct periods that may impart vulnerability to specific types of psychiatric disorder (238; 49).

Attention-deficit/hyperactivity disorder (ADHD). ADHD is diagnosed by the presence of inattention, impulsivity, or motor hyperactivity disproportionate to mental age, resulting in significant academic or social impairment. Children with Down syndrome may have an increased risk of ADHD; the prevalence is reported to be about 10% to 44% (68; 66; 169). Although hyperactivity and impulsivity without inattention may be seen in young children with Down syndrome before 36 months (99), ADHD can be difficult to diagnose in children with Down syndrome as many symptoms may be developmentally congruent or part of the behavioral phenotype typically seen in children with Down syndrome (74). However, children with hyperactivity and impulsivity often engage in dangerous behavior and are at risk for elopement, wandering, and accidental injury, so these symptoms should not be easily dismissed. Careful consideration of co-occurring ADHD is necessary as it may require specialized treatment. Additionally, many children with Down syndrome have a component of hyperactivity-impulsivity or inattention in the presence of other neurobehavioral or psychiatric symptoms; therefore, the importance of looking at associated features is important because they will inevitably complicate both the diagnostic formulation and treatment approach (32). When diagnosing ADHD, it is important to gather collateral information from teachers or therapists to assess whether symptoms are evident in different settings. Treatment for ADHD is most effective when a multimodal approach is taken. Therefore, treatment should involve environmental modifications and accommodations, behavioral approaches, as well as pharmacological treatment. Although medication is one of the mainstays of treatment for ADHD, there have only been a few studies of medication use specifically in individuals with Down syndrome (30; 186).

Oppositional-defiant and disruptive behavior disorders. Oppositional defiant disorder (ODD) and disruptive behavior disorder (DBD) are related conditions distinguished by the severity, intensity, and pattern of negativistic, destructive, or aggressive behavior. Children with Down syndrome and oppositional defiant disorder or Down syndrome and disruptive behavior disorder often have comorbid ADHD, but not always. Taken together, ADHD-oppositional defiant disorder- disruptive behavior disorder form a continuum of disruptive behavior or conduct disturbance in childhood. Oppositional behavior may develop in temperamentally vulnerable toddlers without obvious hyperactivity-impulsivity before 36 months. Aggression in young children with Down syndrome is often impulsive or attention-seeking rather than malicious. Children with mild to moderate intellectual disability are quite capable of manipulating their caretakers through the use of socially motivated disruptive behavior. Thus, a longstanding pattern of undesirable behavior may become established. Routine inquiry about the child’s environment (setting – home versus school, consistency across environments) and known triggers (escape demands) should provide clues about the factors maintaining such disruptive behaviors.

Those children with a perseverative or inflexible cognitive style, anxiety, or mood dysregulation are often episodically oppositional, disruptive, or aggressive. Individuals who become increasingly difficult to manage with age may exhibit such features (14; 58; 231). These features are difficult to tease out during routine clinical observation, hence, our reliance on caretakers and teachers to provide a detailed qualitative description of these behaviors and triggering events.

Autism spectrum disorder. Autism spectrum disorder is a neurodevelopmental disorder characterized by difficulties with social interaction and communication and by certain characteristic patterns of behavior. The term “spectrum” refers to the wide range of symptoms that individuals can have, which varies greatly between individuals. Autism is more common in individuals with Down syndrome, although prevalence rates vary depending on diagnostic practices and study methodology (57; 161; 185).

Social communication is particularly impaired in children with both autism and down syndrome, and social disinterest, lack of sustained joint attention, and inability to communicate using gestures are symptoms that help distinguish autism spectrum disorder in children with Down syndrome. Behaviors often seen prior to 36 months include body rocking, arm/hand waving or flapping, dangling belts or strings, staring at lights, episodic ocular deviation, extreme food refusal, and unusual play with toys or other objects. Auditory processing impairments may cause the child to appear not to hear, and use of nonverbal gestural communication is often impaired.

In other children, symptoms suggesting an autistic spectrum disorder have a slow and insidious onset, appearing after 36 months with symptom intensification over many months or years. Preexisting repetitive behaviors, fearfulness, and sensory aversions may intensify. Peculiar sensory responding, fearfulness, anxiety, behavioral refusal, and sleep disturbance are often present (90; 110). Sometimes there is a distinct regression in speech, language, and social skills after 36 months (159). When frank developmental regression is well documented, even in the absence of clinical seizures, it may be useful to obtain overnight or extended EEG and a sleep study in the search for a treatable etiology. Neuroimaging and metabolic studies are rarely informative but may be considered.

Autism spectrum disorder may be difficult to diagnose in children with Down syndrome due to many overlapping symptoms. Additionally, medical conditions that are common in Down syndrome can mimic or precipitate symptoms that are often seen in autism spectrum disorder. Formal evaluation using standardized tests is important so that social communication skills can be considered in the context of the child’s overall developmental functioning. Some screening and diagnostic tools have been studied in Down syndrome and autism spectrum disorder, but this is an active area of research. The mainstays of treatment for autism spectrum disorder are educational and behavioral therapies, such as applied behavioral analysis, which is a data-driven approach to breaking down complex skills into smaller steps and can be an effective strategy for teaching skills and reducing maladaptive behaviors.

Stereotypic movement disorders. Stereotypic movement disorders can present similarly to autism spectrum disorders, and they are frequently confused with one another. When considered together, stereotypy movement disorders–autistic spectrum disorders align along a continuum of cognitive-language-social impairment and repetitive movements (33). Some children display unusual or atypical behaviors during infancy or the toddler years (27).

Children diagnosed with stereotypic movements are often regarded as “autistic-like” because of their frequently intense repetitive behaviors, unusual attention, and peculiar sensory features. However, when pressed many will demonstrate functional social communication and reciprocity, thus, excluding them from a label of autism spectrum disorder. Nevertheless, their symptom profile suggests a high burden of functional impairments similar to children who meet full diagnostic criteria for an autism spectrum disorder.

Psychiatric mental health disorders: adolescents and adults

By some estimates 20% to 30% of adults with Down syndrome have psychopathology (139; 145). Childhood maladaptive behavior and low levels of function are somewhat predictive of later psychopathology by young adulthood (146; 145).

Functional regression. There is an increasingly recognized phenomenon of unexplained regression occurring most commonly in adolescence that is sometimes referred to as unexplained regression in Down syndrome, Down syndrome disintegrative disorder, or Down syndrome regression disorder. This phenomenon involves a rather precipitous decline in previously stable social, language, cognitive-executive, and adaptive skills. It can accompany any of the major psychiatric disorders but appears most often in disorders with internalizing features, such as depression (01; 247; 158; 237; 197; 195). In some cases, regression appears to possibly be precipitated by a life stressor (199). The role of neuroimmune and inflammatory etiologies is an active area of investigation, with some recent success using immunological therapies in some patients (35; 104; 196). Functional adaptive skills may recover in some patients with successful pharmacologic treatment, including psychopharmacological or immunological treatment; however, the functional loss is permanent for others (44; 89; 01; 158). In rare instances, marked regression with functional decline occurs in the absence of any recognizable psychiatric disorder, except perhaps negative symptoms (173). Symptoms may manifest over weeks to months but are nonprogressive and appear relatively resistant to pharmacologic treatment. Catatonia is now established as a cause of functional regression in adolescents and young adults with Down syndrome (155). Its proper recognition is critical as symptoms may be responsive to benzodiazepines or electroconvulsive therapy (117; 91). For any cases of regression, other medical comorbidities, such as severe sleep apnea, seizures, or systemic illness, should also be sought. Thus, evaluation in a specialized center with expertise in this phenomenon may be important (198; 217).

Depression and depression-like disorders. Depression and depression-like disorders are common in adults with Down syndrome (42) but may not be more common when compared to adults with intellectual disability of other etiologies (139). Depressed mood, crying, anhedonia, decreased interest, psychomotor slowing, fatigue, appetite/weight change, and sleep disturbance are the most common criteria observed in Down syndrome with major depression. Poor concentration, reduced speech, and agitation are also common, whereas feelings of guilt or worthlessness are less often reported (43; 164). Previously independent self-care routines may deteriorate over time, requiring more frequent prompting by caretakers and additional time allowed for completion. Symptom exacerbation may occur in conjunction with menstrual cycles in vulnerable females. Increasing awareness of being different, lack of acceptance by peers, or negative life events resulting in bereavement may predate the onset of symptoms, which then evolve into a recognizable depression in vulnerable persons (59). Intrusive, obsessional thoughts and perseveration can be seen as an accompanying feature in major depression (164; 148). Subtle extrapyramidal symptoms, tremor, adventitial movements, tics, stuttering, and other vocalizations may also be present (39; 249).

In some Down syndrome individuals, depression is characterized less by mood disturbance (melancholy, crying, or irritability) and more by extreme affective blunting, apathy, cognitive-executive disorganization, psychomotor slowing, and reduced speech or mutism. Changes in appetite or sleep pattern may predate the onset of deterioration in mental status, and self-care skills may be greatly impacted. These internalizing features or “negative symptoms” raise the question of catatonia or a pseudodementia syndrome (29).

Depression is often misdiagnosed as dementia in 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, small-crowded oropharynx, macroglossia) who fail to respond to antidepressant medications (32). Because depression and sleep apnea often coexist, an incorrect diagnosis of dementia in a young adult may lead physicians and caretakers to abandon the search for effective treatments prematurely (28).

Rarely Down syndrome individuals present with hypomanic or mixed-mood states suggestive of a bipolar or atypical mood disorder (172; 171). There are often delays in making this diagnosis until irritability, agitation, or psychosis have steadily intensified over a period of years despite multiple medication trials.

Obsessive-compulsive disorders. Anxiety, phobias, panic episodes, obsessional thinking, motor slowing, or freezing and thought perseveration may be seen in the absence of significant mood disturbance in persons with Down syndrome (39). Obsessive thinking can be difficult to ascertain in persons with intellectual disability and limited speech but thought intrusion or verbal perseveration may represent a behavioral equivalent. Perseveration on past relationships or events, or a need to ask about upcoming scheduled activities, can be annoying to caretakers. Repetitive, compulsive acts, by its very nature, are easier to appreciate than obsessive thought (166; 174). Ordering and tidiness compulsions are quite common, especially rearranging personal belongings and opening/closing doors, cabinets, blinds, and light switches. Hoarding of seemingly trivial objects (clips, pens, or papers) and repetitive doodling or list-making is also observed. Agitation may occur when such seemingly insignificant objects are moved or appear out-of-place. If the compulsion to perform an action is so strong that anxiety or agitation typically ensues when the person is prohibited from carrying it out, then criteria for obsessive-compulsive disorder may be met.

Caretakers sometimes report the sudden appearance of compulsions, accompanied by changes in affect, mood, and sociability (166; 215). Life events such as changes at school or the workplace; loss of a friend, family member, or teacher; and physical-emotional trauma are commonly cited occurrences (73; 240). If physical or emotional trauma can be substantiated, a diagnosis of post-traumatic stress disorder may be considered. Sometimes, there is an intensification in preexisting compulsions accompanied by extreme motor slowing, freezing, or “obsessional slowness” (39), which raises concerns about catatonia or atypical parkinsonism.

Psychosis and psychotic-like disorders. The prevalence and diagnosis of psychosis-NOS and depression with psychotic features appears to be increased in adolescents and adults with Down syndrome compared to those with other forms of intellectual disability (43% vs. 13%), as is the prevalence of marked motoric slowing and mutism (17% vs. 0%). No differences were noted in the rates of depression or anxiety; however, the rates of bipolar (29% vs. 4%) and impulse control disorder (38% vs. 20%) were higher in those with other intellectual disabilities compared to Down syndrome (63).

It is important not to interpret all self-talk, or interaction with imaginary characters during times of stress or isolation, as prima facia evidence of psychosis (112). Psychosis often occurs within the setting of major depression in persons with Down syndrome but can manifest as the primary disorder (psychosis-NOS) without significant disturbance in mood (61; 63). Positive symptoms of psychosis such as paranoia, delusions, and hallucinations along with anxiety may be prominent features, or psychotic disorganization may coexist in the setting of profound apathy, abulia, motor slowing, and sleep disturbance (162; 164; 120; 01). Psychosis can also represent the manic phase of a bipolar disorder, which is infrequent, but should be considered when a family history is confirmed (171).

Medical conditions

The associated medical manifestations of Down syndrome are often categorized according to age epoch. In addition to the well-recognized phenotypic features that are characteristic of this condition, physicians need to be aware of the variety of congenital, acquired, and age-related medical conditions associated with Down syndrome (04).

Newborn: (0 to 1 month)

Neurologic. Neuromotor dysfunction, defined by generalized hypotonia and absent or diminished primitive and deep tendon reflexes, is characteristic of most newborns with Down syndrome (251).

Cardiac. Congenital heart disease occurs in 40% to 60% of newborns with Down syndrome. The most common cardiac lesions are atrioventricular canal (60%); isolated ventricular septal defect, atrial septal defect, or patent ductus arteriosus (30%); and tetralogy of Fallot (7%). Isolated congenital valve disease or coarctation of the aorta is seen occasionally (143). Cardiac defects are responsible for significant morbidity and mortality during the first 2 years of life (08).

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 (21).

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 (188).

Endocrine. An increased incidence of congenital hypothyroidism due to absence or aplasia of the thyroid gland occurs in about 1% to 2% of newborns (48). A randomized clinical trial of thyroxine treatment in neonates with Down syndrome demonstrated a mild benefit in motor and mental development at 24 months (232).

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 (239). Newborns with transient myeloproliferative disorder are at increased risk to develop acute megakaryoblastic leukemia (12). Approximately 3% to 10% of newborns with Down syndrome are diagnosed with transient myeloproliferative disorder (203). Most will not require treatment. However, treatment with exchange transfusion, pheresis, or cytarabine can improve survival for those with life-threatening symptoms, such as hyperviscosity and very high blast counts, or those with severe organomegaly (123; 84).

Infancy (1 to 12 months)

Neurologic. 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, may constitute 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 (253). 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 (207).

Seizures. The incidence of seizures during the first year of life is probably under 5%. Infantile spasms are the most common epilepsy syndrome in Down syndrome in the first year of life (214). Occasionally, tonic-clonic seizures, myoclonus, or febrile seizures are encountered (178). Infants with difficult-to-control infantile spasms or those in whom recognition and treatment is delayed frequently have a poorer developmental outcome (96; 67). Severe intellectual disability and autism-like behaviors are not an uncommon outcome, even in children who respond successfully to anticonvulsant medications (194).

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%) (188).

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 (38). 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 (50).

Childhood (1 to 12 years)

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 (47). More contemporary studies indicate improvements in weight gain and linear growth in young children, suggesting an association with improvements in medical care (254).

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 (48; 204). Both compensated (elevated thyroid-stimulating hormone or normal thyroxine) and uncompensated (elevated thyroid-stimulating hormone or decreased thyroxine) hypothyroidism are seen. A transient elevation in thyroid-stimulating hormone is sometimes noted in infants and children, 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 (137).

Audiologic. There is a high incidence of hearing loss among children with this condition (09; 51). 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 (216). One study reported abnormalities in overnight polysomnograms in 100% of Down syndrome subjects (hypoventilation 81%, obstructive sleep apnea 63%, and desaturation 56%) (140). More than 95% of non-obese children with Down syndrome and snoring were found to have obstructive sleep apnea on overnight polysomnograms (78). 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 (221). Even children who have undergone adenotonsillectomy may have persistent symptoms secondary to glossoptosis, hypopharyngeal collapse, recurrent adenoid tonsils, enlarged lingual tonsils, and macroglossia (60). Additional treatments include continuous positive airway pressure or surgical interventions.

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 (77). The presence of a small-crowded oral cavity, gastro-esophageal or tracheo-laryngeal anomalies, oral motor hypotonia, and impaired sensory-motor skills are predisposing factors.

A pharyngeal phase type of swallow dysfunction has been well documented in Down syndrome (82; 168). High rates of both symptomatic and silent aspiration have been demonstrated in children with Down syndrome (168; 114). Many of these children had cardiac, gastrointestinal, pulmonary, and tracheal malformations requiring surgical repair in early childhood.

Hematologic. Numerous abnormalities or variation in red cell, white cell, and platelet lines have been reported in Down syndrome (85). 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 (203). Overall, Down syndrome is associated with approximately 2% of all cases of acute leukemia in children (85; 80). Children with Down syndrome are at risk for iron deficiency anemia, which is also harder to detect in Down syndrome due to macrocytosis. In addition to annual screening for anemia, annual screening for iron sufficiency and iron deficiency with specific iron studies has also been recommended (105; 22). Iron repletion should follow similar protocols as those for the general population.

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 (177; 40). Up to 14% of children show x-ray evidence of C1/C2 instability (atlantodens interval 3 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 (177; 83; 222; 153). 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 and frequent autoimmune phenomena in children with Down syndrome (165). Both B- and T-lymphocyte populations are often markedly reduced in young children (54). Several alterations of humoral immunity have been reported. Children under the age of 6 years 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 antigen-induced 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 (non-specific), IgA-antiendomysium antibody, IgA-tissue transglutaminase antibody, and total serum IgA levels. Between 5% and 40% of children may have one or more abnormally high antibody levels, whereas the rate of intestinal biopsy confirmed celiac disease is closer to 7% (18; 36; 252). Screening for celiac disease is best done using combined IgA-antiendomysium antibody and IgA-tissue transglutaminase antibody determination (17), although IgA-tissue transglutaminase antibody appears to be the most specific (205).

Adolescence (13 to 18 years)

Growth. The adolescent growth spurt is less robust and typically occurs later compared to the general population (182). There is tendency toward excessive weight gain relative to height throughout childhood and adolescence. Final adult heights for males range between 140 and 160 cm, whereas the typical range for adult females is between 136 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 (111). Serum testosterone levels appear normal throughout puberty (179; 111). 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, one report of a male with Down syndrome who fathered a child; thus, questions about fertility remain unanswered (208).

The onset and duration of menstruation cycles are generally the same for females with Down syndrome compared to the general population (98). Reduced ovarian follicular size and number have been reported, and other histologic abnormalities have also been described (108).

Adulthood (18-40 years)

As longevity continues to increase greater numbers of adults with Down syndrome will live to be of advanced age (16). This presents ongoing challenges to the primary care physicians expected to manage an array of acquired, chronic, and age-related conditions (15).

Of the health conditions typically mentioned in adulthood, visual and hearing impairment, thyroid disease, obesity, sleep apnea, cardiopulmonary function, respiratory infections, seizure disorder, psychiatric disorders, and dementia are likely to remain the major considerations (72; 94; 31; 34; 198). Evidence-based clinical guidelines have been created to support the screening and diagnosis of nine different health conditions in adults with Down syndrome, resulting in 14 recommendations and four statements of good practice (224).

Growth. Excessive weight gain and obesity are common in younger adults with Down syndrome and may have a significant impact on coexisting medical conditions and quality of life (152).

Endocrine. There is an increasing risk for developing hypothyroidism with advancing age, as evidenced by higher thyroid-stimulating hormone and declining thyroxine levels (180). 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. The long-term outcome of congenital heart defects in adults is a topic of growing interest. One study employed prospective cardiac screening in a subset of participants from a residential setting who were ascertained retrospectively (235). Up to 17% of those patients had undiagnosed congenital heart defects in addition to the 16% with previously confirmed congenital heart defects (33%). Regurgitation of the mitral, aortic, and tricuspid valves was present in 75% of subjects. In patients with atrioventricular septal defect repair, left atrioventricular valve insufficiency and left ventricle outflow tract obstruction are the most frequently reported long-term complications requiring surgical repair (144). The largest study used a case-control design, including hospitalized participants with congenital heart defects with and without Down syndrome (11). The patients with Down syndrome and congenital heart defects had an increased prevalence of pulmonary hypertension, cyanosis, and secondary erythrocytosis compared to those without the condition. Among all of the hospitalized patients with congenital heart defects, mortality was higher for those with Down syndrome. Bacterial and aspiration pneumonia were exclusively associated with higher mortality in Down syndrome. Cardiac procedures, however, were less often performed in patients with Down syndrome.

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 (97; 88). 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 atlantoaxial (C1/C2) interval remains relatively stable (less than 1.5 mm change) over a 10- to 12-year period in most adults (181). Eight percent showed changes in C1/C2 interval measurement between 2 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 (10). Factors related to reduced BMD may include hypogonadism, hypotonia, low muscle strength, reduced mobility, male gender, and reduced sunlight exposure (193; 100). 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 (149).

Cervical spondylosis and degenerative changes increase with age in adults with Down syndrome (02). 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 (167).

Audiologic. Persons with Down syndrome experience presbycusis or progressive bilateral sensorineural hearing during adulthood (20). 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 (76; 230). 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% (230). Cataracts contribute to the high rates of visual impairment and are experienced by 30% to 68%, compared to the general population (17%) (107). 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 (135; 113). Surgical outcomes for cataract surgery in adults is generally good, but visual outcomes may be suboptimal due to other ocular abnormalities (128).

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 patients with Down syndrome (107; 229). Corneal cross-linking under local anesthesia has now become the preferred treatment in select patients with promising results (213).

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 (226). Tooth loss and other dental problems can result in problems chewing.

Gynecologic. Hypermenorrhea, menorrhagia, and premenstrual syndrome are reported to occur more frequently in adult females with Down syndrome (69). 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 a study, 87% of women with Down syndrome stopped menstruating by age 46 years and 100% had cessation by age 51 years (202). 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) (150). Early menopause in women with Down syndrome has been associated with a 1.8-fold increased risk of dementia (hazard ratio 1.82) and with an increased risk of death (hazard ratio 2.05) (202; 45).

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 (06; 184). A relationship between apnea score and performance on cognitive testing was also noted (06). 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 [apnea-hypopnea index (AHI) over 30] (223). 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 (28).

The high rates of pneumonia in adults with Down syndrome may very well be related to micro-aspiration during feeding and drinking (15; 210). Clinical indicators of aspiration were seen in 70% of subjects in a young cohort of adults with Down syndrome, suggesting that they may be at a higher risk even at an early age (115).

Neurologic. Several studies have confirmed a bimodal peak in the prevalence of new-onset seizures in adults with Down syndrome (75; 178; 151). 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 young adult–onset group and are not always associated with cognitive decline or diffuse EEG abnormalities.

Cerebrovascular disorders related to cerebrovascular pathology are also implicated in the age-related neurologic morbidity seen in adults with Down syndrome (241). The prevalence of myocardial infarction and cerebrovascular accident in Down syndrome is incompletely understood (116). In one large case-control study of hospitalized patients, adults with Down syndrome were at a higher risk of cerebrovascular events but at a lower risk of coronary events (males only), compared with age-matched individuals without Down syndrome (212). Another study found that despite an increased risk of vascular amyloidosis, adults with Down syndrome may enjoy relative protection from intracerebral hemorrhage compared to other high-risk groups (25). Furthermore, adults with Down syndrome may be relatively resistant to developing atherosclerosis compared to the general population, possibly due to reduced heart-type fatty acid binding protein (233). Dysautonomia is very common as adults with Down syndrome generally have lower resting heart rates and blood pressures compared to the general population; furthermore, essential hypertension is uncommon (191). Chronic hypotension is often associated with other signs of autonomic dysfunction, including mottling or acrocyanosis of the peripheral extremities (23). In asymptomatic individuals, screening consists of monitoring heart rate and blood pressure for bradycardia and orthostatic hypotension. Symptomatic individuals will often have a history of syncope or pre-syncopal episodes, unusual spells, or falls. Preventive measures include maintenance of adequate hydration status, added salt to the diet, and caution on prolonged or sudden standing.

Elderly adults (> 40 years)

Neurologic. 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 (167). In a study by van Allen and colleagues, 40% of elderly adults showed evidence of lower cervical spondylosis and degenerative changes (229). The neurologic consequences of these degenerative changes likely pose more of a neurologic threat than atlantoaxial instability among those of advanced age (02).

During adulthood, the risk of seizures increases with advancing age and may herald the onset of dementia. In adults over 50 years of age, between 24% to 46% have seizures (151; 147). Two studies have documented abnormal EEG findings in approximately 70% of elderly adults with Down syndrome independent of seizure status (Tangye 1979; 234). There was no apparent relationship between severity of EEG changes and dementia.

The seizures associated with dementia are often myoclonic jerks that may be prominent soon after awakening and are sometimes asymmetrical (56). 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 (151; 147). 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%) (119).

No guidelines exist to aid in the selection of anticonvulsant therapy choices in elderly individuals with Down syndrome. However, a study by De Simone and colleagues found that valproic acid and levetiracetam seem to be most efficacious in treating myoclonic jerks and generalized tonic-clonic seizures (56). Gholipour found that a majority of patients with new-onset seizures achieve partial or complete seizure control (92).

Gait dyspraxia can be a subtle and early symptom of dementia that often leads to increased anxiety and fearfulness, which may impair functional ambulation prior to actual loss of walking ability (05).

Extrapyramidal symptoms are frequently associated with dementia in persons with Down syndrome. In one study, 36% of elderly individuals with Down syndrome who had dementia also had extrapyramidal symptoms, whereas none of the nondemented patients showed any evidence of extrapyramidal symptoms (234). Older studies estimated that 20% of demented middle-aged to elderly patients with Down syndrome displayed extrapyramidal symptoms (125). Other studies have reported both lower percentages (9%) and higher percentages (65%) (225). Possible mechanistic links between dementia and extrapyramidal symptoms include premature aging of substantia nigra neurons and subsequent decline in dopamine production (250). The contribution of basal ganglia calcifications to extrapyramidal symptoms has been examined, but these calcifications seem to be a near universal finding in adults with Down syndrome (243; 220); however, only a small percentage ever develop clinical extrapyramidal symptoms. Most often, extrapyramidal symptoms occur late in the course of dementia, though they are occasionally seen earlier. Extrapyramidal symptoms do not accompany all cases of dementia, and when present, they are usually of the rigid-hypokinetic variety (234). Symptoms may include tremor, rigidity in the extremities, shuffling gait, masked facies, orofacial dyskinesia, bradykinesia, and frontal release signs. Resting tremors and myoclonic jerks were not notable components of extrapyramidal symptoms in the Vieregge study. From a caregiver’s management perspective, extrapyramidal symptoms may be more impairing than the cognitive aspects of dementia. Gait can be markedly affected, requiring close supervision from caregivers. Extrapyramidal symptoms also interfere with a person’s ability to perform activities of daily living that require fine motor (dressing, toileting, grasping and holding utensils) and oral motor control (chewing, swallowing).

Dysphagia is also more common in adults with Down syndrome, although not well studied in elderly individuals (210). Beyond concerns for aspiration, swallowing dysfunction can also contribute to weight loss in elderly persons. It is likely that tooth loss and problems chewing also contribute to decreased oral intake. Symptoms of dysphagia may be subtle, and patients will rarely self-report difficulties with eating. However, choking, sputtering, gaging, or coughing are all concerning symptoms and should be further evaluated. Some patients will merely avoid eating or appear to have a loss of appetite. Even when swallowing dysfunction is not apparent, silent aspiration may be occurring.

Although obesity is common in young adults with Down syndrome, older adults often experience a decrease in BMI with advanced age compared to controls (174). In a study of 201 adults with Down syndrome, only 13 (7%) were found to be underweight; all were over 50 years of age (79). Indeed, one study suggests that unintentional weight loss in those over 36 years old may be related to the progression of Alzheimer-type pathology.

Alzheimer-type 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 a 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 (52). All individuals had evidence of senile plaques and neurofibrillary tangles at autopsy and one 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, however, 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 (125). Those individuals in the severe–profound range of intellectual disability more often manifest apathy, inattention, and decreased social interaction. Motor impairments, new onset of seizures, and loss of self-help skills. 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 (75). In 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 (236). 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 (201). Once recognized, the clinical signs and symptoms of dementia progress rapidly in most subjects.

Caring for adults with dementia requires nonmedicinal approaches to supporting the individual as well as medications to treat associated symptoms. Medications approved for the treatment of dementia in the general population have been found to have limited benefit in those with Down syndrome. A Cochrane analysis found insufficient evidence of benefit for treating people with Down syndrome and Alzheimer disease with acetylcholinesterase inhibitors (AChEI) or the NMDA receptor antagonist, memantine (129). An increase in behavioral symptoms was reported with donepezil. Eady and colleagues reported longer survival in those taking medications (donepezil), but the study group was younger and had other significant factors in their favor (65).

Elderly adults with Down syndrome without dementia demonstrate fewer and less severe maladaptive behaviors than those with early or mid-stage dementia. The maladaptive behaviors associated with progression into early stages of dementia may include aggression, fearfulness, sadness, sleep problems, and other regressive behaviors (227). Psychiatric symptoms are often apparent and may include delusions, hallucinations, and depression with associated appetite and sleep problems (228).

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 (176). 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 (248).

Mortality. The most significant medical disorders related to mortality are dementia, declining motor function, epilepsy, and respiratory infections (15; 45; 94). Approximately 13% of death certificates reviewed in New York in 2007 listed pneumonia due to aspiration or choking as the primary cause of death (255), and most bacterial pneumonias are likely linked to aspiration of pharyngeal contents. Another 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 (11).

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 neurodevelopmental outcome.

Biological basis

Etiology and pathogenesis

Down syndrome most often results from complete trisomy of chromosome 21 due to nondisjunction during gamete formation (127). In about 95% of cases of trisomy 21, the nondisjunction is of maternal origin (07). 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 two different cell lines. This condition is referred to as mosaicism because there exist one trisomic and one 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 (242). 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 (154; 109).

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 (71; 26; 136). 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 additional predictions based on mRNA transcript catalogues estimate approximately 550 possible genes (106; 183; 218).

To view the most recent catalogue of known genes mapping to chromosome 21, visit the Online Mendelian Inheritance in Man Web Site.

Neuropathology

Brain development. 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 (200; 170). 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 (53). The cerebellum and brainstem are often markedly reduced in size compared to forebrain structures (46). Dysplasia of the brain is probably best reflected by changes in head growth and circumference during the first few years of life (170). Detailed neuropathologic studies reveal a generalized hypocellularity of the brain. Reduction in neuronal number and density has been demonstrated for most regions examined (244). In the cerebral cortex, there is neuronal reduction in all cortical layers, with striking paucity of small interneurons from cortical layers II and IV (190). 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 (142; 219; 13). Surviving spines are often abnormally long, thin, or irregular in contour and appearance (141). As would be predicted, reductions in synaptic density and surface area are also present (244). During the first year of life, decreased myelination is noted throughout the cerebral hemispheres, basal ganglia, cerebellum, and brainstem (245). 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.

Brain aging

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 (243; 220). 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 (133).

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 (24; 70). 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 (246), with some individuals showing a much earlier onset (192). 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 (250; 95). 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 (Table 1) (138).

Table 1. Down Syndrome: Histopathology of Cortically Projecting Neurons

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 (160). 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 (209).

Prevention

Risk factors. 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 (109). 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

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 (Table 2) (101). No single phenotypic finding is diagnostically significant; rather, it is the association of three or more of these features together that warrants suspicion. Fluorescence in situ hybridization (FISH) may be used for rapid diagnosis of Down syndrome in the newborn period. However, a definitive diagnosis requires cytogenetic testing (karyotype) to confirm either complete or partial trisomy 21 or a translocation.

Table 2. Diagnostic Features of Down Syndrome in the Newborn Period

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

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 intellectual disability, and one-third appear to be normal (19). 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 (103). 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 (124).

There are several reports of spinal cord compression and narrowing of the neural canal intraoperatively in children with Down syndrome (124; 55). 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, x-rays 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.

Drug discovery and clinical trials

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 (121). 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 one subject receiving donepezil discontinued the study because of moderately disturbing urinary retention.

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 (134; 173). 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 (122). 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.

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 (132). 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 (102). 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.