ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Down syndrome: Management

Down syndrome: Management
Literature review current through: Jan 2024.
This topic last updated: Oct 06, 2022.

INTRODUCTION — Down syndrome (DS) is the most common chromosome abnormality among live-born infants. It is the most frequent form of intellectual disability caused by a microscopically demonstrable chromosomal aberration.

The Committee on Genetics of the American Academy of Pediatrics (AAP) has provided recommendations to assist primary care clinicians in the care of children with DS (table 1) [1]. The Down Syndrome Medical Interest Group is another resource for clinicians. Management requires an organized approach to the initial and ongoing evaluation and monitoring for associated abnormalities and prevention of common disorders [2,3]. Some patients are also followed by specialists in a Down syndrome clinic, where they may have additional health care needs related to DS addressed.

The management and life expectancy of children with DS are presented here. The epidemiology, clinical features, and diagnosis are discussed separately. (See "Down syndrome: Overview of prenatal screening" and "Congenital cytogenetic abnormalities", section on 'Trisomy 21 (Down syndrome)' and "Down syndrome: Clinical features and diagnosis".)

General issues related to management of adults with intellectual disability, and problems related to DS specifically, are discussed in detail separately. (See "Primary care of the adult with intellectual and developmental disabilities".)

GROWTH — Patients with DS should be monitored for disturbances of growth associated with other disorders, such as hypothyroidism or celiac disease, and for excessive weight gain.

Growth charts — DS-specific growth charts based upon populations in the United States [4-6], the United Kingdom and Ireland [7], Italy [8], the Netherlands [9], and Sweden [10] have been published. The 2015 DS-specific US growth charts [6], which are consistent with the more contemporary charts based upon data from European populations [7,10,11], will most likely supplant the Centers for Disease Control (CDC) and World Health Organization (WHO) growth charts for assessing growth and nutritional status in children with DS. The updated 2015 DS-specific growth charts are optimal for assessment of height, weight, and head circumference and should be used, if available, rather than the old DS growth charts. The one exception is the body mass index (BMI) measurement. The 2015 US charts include weight-for-length and corresponding BMI charts that are needed to adequately assess nutritional status, although optimal weight-for-length and BMI levels for individuals with DS are not yet established. In addition, one study showed that the CDC BMI growth chart using the 85th percentile was more sensitive for excess adiposity than the new DS-specific BMI chart [12]. (See "Measurement of growth in children".)

Obesity prevention — A goal of growth monitoring is the prevention of obesity. Interventions beginning at 24 months of age should include attention to diet and promotion of physical activity. Caloric intake should be less than the age-specific recommendations for unaffected individuals [13]. Calcium and vitamin D intake should be monitored closely to minimize bone loss since adults with DS have lower bone mineral density than controls [14,15].

CARDIAC DISEASE — All newborns with DS should be evaluated for congenital heart disease in consultation with a pediatric cardiologist. An echocardiogram is recommended to detect abnormalities that may not be symptomatic or apparent on physical examination. Continued clinical cardiac evaluation is needed because of the high risk of mitral valve prolapse and aortic regurgitation in adolescents and young adults [2]. In a large, retrospective cohort study of congenital heart surgery, patients with DS had similar mortality, but higher morbidity, compared with patients without DS [16]. (See "Identifying newborns with critical congenital heart disease" and "Isolated atrial septal defects (ASDs) in children: Management and outcome" and "Management of isolated ventricular septal defects (VSDs) in infants and children" and "Management of patent ductus arteriosus (PDA) in term infants, children, and adults" and "Tetralogy of Fallot (TOF): Management and outcome".)

HEARING — Newborns should have a newborn hearing screening with brainstem auditory evoked response (BAER) or otoacoustic emission (OAE) [1]. Infants with DS should have repeat hearing screening at six months of age. Hearing should be evaluated regularly throughout childhood, typically every six months until four to five years of age and then yearly. Any child who fails screening should be referred to an otolaryngologist for further evaluation and management. (See "Screening the newborn for hearing loss" and "Hearing loss in children: Screening and evaluation" and "Screening tests in children and adolescents", section on 'Hearing screen'.)

Children should be evaluated and treated for otitis media, which occurs commonly [1]. (See "Acute otitis media in children: Epidemiology, microbiology, and complications".)

OPHTHALMOLOGIC DISORDERS — An ophthalmologic assessment should be performed in the newborn period or at least before six months of age to detect strabismus, nystagmus, and cataracts. The risk of refractive errors is approximately 50 percent between three and five years of age [1]. Affected children should have annual assessments of vision. Unaffected children should be examined annually before age five years to detect refractive errors that may occur during childhood and every two years after age five (every three years after age 13) to screen for disorders, including keratoconus and lens opacities, that may develop in adolescents or adults. The examination should be performed by a pediatric ophthalmologist or ophthalmologist with expertise in infants with disabilities. (See "Vision screening and assessment in infants and children" and "Evaluation and management of strabismus in children", section on 'Evaluation' and "Overview of nystagmus" and "Cataract in children".)

THYROID FUNCTION — Thyroid function testing (both total thyroxine [tT4] and thyroid-stimulating hormone [TSH]) should be obtained in the newborn period [17]. The American Academy of Pediatrics (AAP) recommends that screening should be repeated at 6 and 12 months and then annually [1]. However, there is debate regarding the optimal frequency of laboratory screening [18-21]. Height and weight should be measured yearly since the combination of deceleration of linear growth associated with weight gain is a sensitive indicator of hypothyroidism [20]. (See "Clinical features and detection of congenital hypothyroidism".)

CELIAC DISEASE — Screening for symptoms of celiac disease should begin at one year of age [1]. Laboratory screening is recommended if signs or symptoms develop. (See "Diagnosis of celiac disease in children".)

HEMATOLOGY — A complete blood count and differential should be obtained at birth to evaluate for myeloproliferative disorders and polycythemia. Infants with transient myeloproliferative disorders should be followed with a complete blood count and differential every three months until three years of age and then every six months until six years of age. This monitoring protocol is modified from that used in the prospective study of transient leukemia in DS conducted by the Pediatric Oncology Group [22]. Children with DS are at increased risk for leukemia. Thus, there should be vigilance for signs of leukemia, such as anemia, increased infections, and excessive bruising. (See "Down syndrome: Clinical features and diagnosis", section on 'Hematologic disorders' and "Neonatal polycythemia" and "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children" and "Primary care of the adult with intellectual and developmental disabilities", section on 'Down syndrome'.)

A complete blood count with differential and either a combination of ferritin and C-reactive protein (CRP) or a combination of serum iron and total iron-binding capacity (TIBC) should be obtained annually from 1 to 13 years of age to screen for anemia [1]. The anemia is usually due to iron deficiency secondary to the restricted diet that many children with DS develop as a result of delayed oral motor skills and dysphagia. However, anemia may also be a sign of leukemia. Low ferritin has been associated with restless sleep. Iron supplementation should be considered for children with DS who have a ferritin level <50 mcg/L and sleep concerns [1].

PERIODONTAL DISEASE — Periodontal disease is common in children and adults with DS and involves inflammation, periods of acute infection, and pain [23]. The increased frequency is thought to be due in part to alterations in mouth flora, with a higher frequency of Actinobacillus actinomycetemcomitans compared with controls [24]. Overlapping teeth, poor oral hygiene, and immunodeficiency may also play a role [25]. (See "Gingivitis and periodontitis in children and adolescents", section on 'Periodontitis' and "Periodontal disease in children: Associated systemic conditions", section on 'Down syndrome'.)

Routine brushing should be encouraged. Dental visits are recommended every six months. Orthodontic problems, which occur in the majority of DS patients, should be evaluated and treated, if possible. However, the cooperation necessary for many orthodontic procedures may make them impractical in this population.

ATLANTOAXIAL INSTABILITY — The American Academy of Pediatrics (AAP) Committee on Genetics and the AAP Committee on Sports Medicine and Fitness recommend careful neurologic evaluation for signs and symptoms consistent with spinal cord injury (eg, loss of motor skills, loss of bowel or bladder control, neck pain, neck stiffness) as the most important clinical predictor of symptomatic atlantoaxial instability (AAI) and dislocation [1,26]. The evaluating clinician should take a careful history and perform a thorough physical examination, looking for evidence of neurologic involvement. This clinical screening process should be done at least annually. Caution regarding contact sports and trampoline use should be discussed with parents/caregivers.

The AAP Committee on Genetics recommends obtaining lateral plain cervical spine radiographs in the neutral position with odontoid and anterior-posterior (A-P) views to examine for evidence of AAI or subluxation in patients with myelopathic signs or symptoms [1]. Radiologic screening is also suggested in children with DS prior to procedures that require extremes of head position during induction of anesthesia or surgery [27]. Of note, children do not have adequate vertebral mineralization and epiphyseal development for accurate radiographic evaluation of the cervical spine until at least three years of age.

The patient should be placed in a collar and referred immediately to a pediatric neurosurgeon or pediatric orthopedic surgeon if significant radiographic abnormalities are noted. Flexion and extension radiographs may be performed prior to referral if no significant radiographic abnormalities are present. The AAP Committee on Sports Medicine and Fitness recommends that symptomatic children have magnetic resonance imaging (MRI) to clarify the extent of spinal cord compression and that appropriate surgical consultation be obtained to evaluate the need for definitive treatment [26].

Nearly all people with AAI who have suffered a catastrophic injury to the spinal cord have had preceding neurologic symptoms [26]. Asymptomatic AAI is more common than symptomatic AAI in patients with DS, occurring in 14 versus 3 percent, respectively, in one study [28]. Despite this, the Special Olympics requires screening neck radiographs in children with DS before participation. Children who are found to have AAI on these radiographs but who lack neurologic symptoms should be followed closely with repeat neurologic examinations (at least annually) [26].

BEHAVIOR AND PSYCHIATRIC PROBLEMS — Assessment and treatment of behavior and psychiatric problems should be expeditious and should include evaluation of the problem at school and at home, behavior management techniques, and medication as needed. (See "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis", section on 'Evaluation' and "Developmental-behavioral surveillance and screening in primary care", section on 'Children ≥4 years'.)

SLEEP APNEA — Children with DS have an increased risk of obstructive sleep apnea (OSA) because of soft tissue and skeletal alterations that lead to upper-airway obstruction. Symptoms related to sleep apnea (snoring, restless sleep, and sleep position) should be discussed at health supervision visits beginning at age one year and continuing throughout childhood [1]. Polysomnography or pulse oximetry monitoring during sleep is recommended in all children with DS by four years of age [1]. A predictive model using questions from a validated sleep questionnaire, medication history, patient age, anthropometric measurements, vital signs, and physical exam findings had a negative predictive value of 73 percent for mild OSA and 90 percent for moderate-to-severe OSA [29]. If confirmed in validation studies, this tool could be used to determine which patients may not need a diagnostic sleep study. (See "Mechanisms and predisposing factors for sleep-related breathing disorders in children" and "Evaluation of suspected obstructive sleep apnea in children".)

Management of OSA in DS is similar as for other patients. Adenotonsillectomy is the treatment of choice but is effective in only up to one-third of children with DS. Many patients require continuous positive airway pressure (CPAP) support after adenotonsillectomy, but it is often poorly tolerated. An alternative under investigation is upper-airway hypoglossal nerve stimulation [30]. (See "Management of obstructive sleep apnea in children" and "Adenotonsillectomy for obstructive sleep apnea in children", section on 'Hypoglossal nerve stimulation'.)

FERTILITY AND REPRODUCTION — Ages for the onset and completion of puberty are typical for individuals with DS. However, the mean stretched penile length and the mean testicular volumes are significantly below average among adult males with DS compared with unaffected males. Fertility is impaired in individuals with DS, most likely secondary to primary gonadal deficiency [31]. Most published data, however, suggest that 15 to 30 percent of females with DS are capable of becoming pregnant, and their risk of having a child with DS is approximately 50 percent [32]. Offspring without trisomy 21 seem to have an increased risk for other congenital and developmental abnormalities. Limited research also suggests that females with DS may have an increased risk for miscarriages, premature births, and difficult labor [33]. Males with DS are generally thought to be infertile. However, there have been various published case reports of males with DS fathering children [34-36].

Individuals with various disabilities are at an increased risk for sexual abuse. It is important for parents/caregivers to discuss matters of sexuality, social skills training, and measures to prevent pregnancy routinely with older children and adults with DS.

ALZHEIMER DISEASE — Dementia that resembles Alzheimer disease (AD) is more common and occurs at an earlier age in patients with DS. DS is now considered a genetically determined form of AD because the amyloid precursor protein (APP) gene is found on chromosome 21. This gene, thought to be involved in the production of brain plaques leading to AD, is overexpressed in DS given the three copies of chromosome 21 [37,38]. Estimated age at onset (53.8 years) and age at death (58.4 years) are similar to that seen in autosomal-dominant AD [39]. A medical evaluation should be performed, including testing for thyroid disease, when the diagnosis of AD is considered. Possible depression should also be excluded.

Patients with DS should be monitored for cognitive decline, particularly after age 40 years. In one series of 632 adults with DS and different levels of intellectual disability (436 asymptomatic, 69 with prodromal AD, and 127 with AD dementia) followed for five years, progression to AD dementia was seen in 17.1 percent of asymptomatic patients and was age dependent (0.6 percent for age <40 years, 21.1 percent for 40 to 44 years, 41.4 for 45 to 49 years, and 57.5 for ≥50 years) [40]. Nearly all patients with prodromal AD progressed to AD dementia. Cognitive decline was most common among those who progressed to symptomatic AD, although no association was seen between longitudinal cognitive decline and baseline intellectual disability.

The progressive cognitive deficits, along with impaired fertility and olfaction, seen in patients DS are similar to findings associated with a postpubertal decrease in hypothalamic and extrahypothalamic (eg, hippocampus, cortex) gonadotropin-releasing hormone (GnRH) expression and loss of GnRH neurons and fibers seen in a mouse model of DS. Measures that restored GnRH expression in the mouse model of DS abolished cognitive and olfactory deficits in adult mice [41]. Similar findings were previously seen in a mouse model of AD [42]. A six-month pilot study of pulsatile GnRH treatment administered via a minipump implanted under the skin in seven adult males with DS found improvements in both cognitive performance and functional brain connectivity but no change in olfaction or reproductive hormone levels except for a decrease in follicle-stimulating hormone [41]. Further study is needed to confirm these findings.

The general approach to diagnosis and treatment of dementia, including in patients with DS, is discussed in detail separately. (See "Down syndrome: Clinical features and diagnosis", section on 'Dementia/Alzheimer disease' and "Evaluation of cognitive impairment and dementia" and "Treatment of Alzheimer disease".)

LIFE EXPECTANCY — Life expectancy in DS is shorter than that in the general population or in persons with other causes of intellectual disability. However, survival has improved substantially [43-46]. In a Swedish study using national birth and death registries, the median age at death increased from 3.6 years from 1969 to 1973 to 56.8 years from 1999 to 2003 [46]. The most common main or contributing cause of death was pneumonia and other infections, followed by congenital malformations, circulatory disease, and dementia. In a similar study using United States death certificates from 1983 to 1997, the improvement in survival was thought to be due to increased placement of infants in homes rather than institutions, and to changes in treatment for common causes of death, especially congenital heart disease [43].

In a retrospective cohort study conducted on 16,506 infants with DS born in the United States between 1983 and 2003, the overall one-month and 1-, 5-, and 20-year survival probabilities were 98, 93, 91, and 88 percent, respectively [47]. Survival improved modestly over the course of the study in all but the neonatal period.

In the study using death certificate data, malignancies other than leukemia were much less frequent in those with than without DS (standardized mortality odds ratio 0.07) [43]. Possible mechanisms suggested for the low rate of cancer include tumor suppressor genes on chromosome 21, a slower rate of replication or higher rate of apoptosis in DS cells, or less exposure to environmental risks.

Predictors of survival in DS may include race, sex, birth weight, gestational age at birth, and presence of heart defects and other structural anomalies [43,47-49]. In the death certificate study noted above, the median age at death was higher among White Americans than other races [43]. In contrast to the greater longevity of females in most populations, males with DS appear to have a survival advantage [50,51]. In a series from Western Australia, life expectancy was 58.6 years for the population and 3.3 years longer for males than females [50].

BASIC SCIENCE RESEARCH AND FUTURE TREATMENT OPTIONS — The development of DS mouse models has provided an opportunity to study emerging pharmacotherapies that target intellectual disabilities common in DS [52-54]. The overexpression of many genes found on chromosome 21 contributes to learning deficits. Research has focused on hippocampus function related to memory and learning. Areas of interest include specific gamma-aminobutyric acid (GABA) receptor inhibitors, N-methyl-D-aspartic (NMDA) receptor antagonists, and hippocampal dentate gyrus neurogenesis. Preliminary basic science research shows medications such as pentylenetetrazole (PTZ), memantine, and fluoxetine may enhance learning in the DS mouse model. Further studies and clinical trials are needed to show efficacy and safety of these medications in children with DS.

ALTERNATIVE TREATMENTS — Oxidative stress, the imbalance between production and removal of oxygen-derived free radicals, may contribute to some features of DS, such as decreased immune function, premature aging, impaired mental function, and malignancy [55]. In particular, the activity of superoxide dismutase (the gene for which is located on chromosome 21) is increased [56]. Superoxide dismutase is usually regarded as a protective enzyme since it scavenges free superoxide molecules. However, in DS, the hydrogen peroxide generated by superoxide dismutase-1 may become toxic in the presence of ferrous iron (Fe2+). It forms the highly toxic hydroxyl radical (OH), which can result in profound cellular damage [57].

Supplementation with antioxidant nutrients has been proposed as potential therapy for DS. Treatments studied include supplementation with zinc, selenium, megavitamins and minerals, vitamin A, vitamin B6, 5-hydroxytryptamine, coenzyme Q10, and targeted nutritional intervention [55,58,59]. These studies have methodologic flaws and provide no convincing evidence that nutritional supplementation improves outcomes in DS [60]. One randomized, controlled trial evaluated psychomotor and language development in 156 infants treated for 18 months with daily oral supplementation with one of four programs: antioxidants (selenium, zinc, vitamin A, vitamin E, vitamin C), leucovorin (folinic acid), antioxidants and leucovorin combined, or placebo. This trial found no significant differences between the groups [59].

COUNSELING AND RESOURCES — Counseling may begin when a prenatal diagnosis of DS is made or suspected [1]. The discussion should include the wide range of variability in manifestations and prognosis. Medical and educational treatments and interventions should be discussed. Initial referrals should be made to early intervention, informative publications [61], parent/caregiver groups, and advocacy groups. In the early teen years, discussion and plans for transition to adulthood should include employment/volunteer work [62], place of residence, driving, and leisure activities.

Internet resources for parents/caregivers and patients include the following:

The Association for Children with Down Syndrome

National Down Syndrome Society

A brochure entitled, "A promising future together: A guide for new and expectant parents," available in English and Spanish, can be downloaded from the National Down Syndrome Society website.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Down syndrome".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Down syndrome (The Basics)")

Beyond the Basics topic (see "Patient education: Down syndrome (Beyond the Basics)")

SUMMARY

Approach to ongoing evaluation and monitoring – Management of Down syndrome (DS) requires an organized approach to ongoing evaluation and monitoring for associated abnormalities and prevention of common disorders. The Committee on Genetics of the American Academy of Pediatrics (AAP) has provided recommendations to assist clinicians in the care of children with DS (table 1).

The following evaluations for associated disorders and complications are recommended:

Growth – Plot growth on standard National Center for Health Statistics or World Health Organization (WHO) growth charts; monitor for disturbances of growth associated with other disorders, such as hypothyroidism or celiac disease, and for excessive weight gain.

Cardiovascular disease – Pediatric cardiology evaluation, including an echocardiogram, in the newborn period for congenital heart disease and continued clinical cardiac monitoring in adolescence and adulthood for mitral valve prolapse and aortic regurgitation.

Hearing – Newborn hearing screen and ongoing hearing screening throughout childhood, plus monitoring for otitis media, which is a common cause of hearing loss in children with DS.

Vision – An ophthalmologic assessment before six months of age and then approximately annually to screen for ophthalmologic disorders.

Thyroid function – Thyroid function testing to monitor for hypothyroidism in the newborn period with newborn state screens and repeated at 6 months of age, 12 months of age, and then yearly thereafter.

Celiac disease – Monitor for symptoms of celiac disease beginning at one year of age. Screening is recommended if signs or symptoms develop.

Myeloproliferative disorders – A complete blood count and differential at birth to evaluate for myeloproliferative disorders and polycythemia; ongoing monitoring for signs of leukemia.

Iron deficiency anemia – Check hemoglobin level annually starting at one year of age to screen for iron deficiency anemia.

Spinal cord compression – Neurologic evaluation for signs and symptoms consistent with spinal cord injury at each health supervision visit; symptomatic children should have magnetic resonance imaging (MRI) to clarify the extent of spinal cord compression.

Sleep apnea – Monitoring for symptoms related to sleep apnea at health supervision visits beginning at age one year; polysomnography or pulse oximetry during sleep is recommended in all children with DS by four years of age.

Survival – Life expectancy in DS is shorter than that in the general population or in persons with other causes of intellectual disability. However, survival has improved substantially in the past two to three decades.

Resources – Internet resources for parents/caregivers and patients include the following:

The Association for Children with Down Syndrome

National Down Syndrome Society

  1. Bull MJ, Trotter T, Santoro SL, et al. Health Supervision for Children and Adolescents With Down Syndrome. Pediatrics 2022; 149.
  2. Roizen NJ, Patterson D. Down's syndrome. Lancet 2003; 361:1281.
  3. Weijerman ME, de Winter JP. Clinical practice. The care of children with Down syndrome. Eur J Pediatr 2010; 169:1445.
  4. Cronk C, Crocker AC, Pueschel SM, et al. Growth charts for children with Down syndrome: 1 month to 18 years of age. Pediatrics 1988; 81:102.
  5. Palmer CG, Cronk C, Pueschel SM, et al. Head circumference of children with Down syndrome (0-36 months). Am J Med Genet 1992; 42:61.
  6. Zemel BS, Pipan M, Stallings VA, et al. Growth Charts for Children With Down Syndrome in the United States. Pediatrics 2015; 136:e1204.
  7. Styles ME, Cole TJ, Dennis J, Preece MA. New cross sectional stature, weight, and head circumference references for Down's syndrome in the UK and Republic of Ireland. Arch Dis Child 2002; 87:104.
  8. Piro E, Pennino C, Cammarata M, et al. Growth charts of Down syndrome in Sicily: evaluation of 382 children 0-14 years of age. Am J Med Genet Suppl 1990; 7:66.
  9. Cremers MJ, van der Tweel I, Boersma B, et al. Growth curves of Dutch children with Down's syndrome. J Intellect Disabil Res 1996; 40 ( Pt 5):412.
  10. Myrelid A, Gustafsson J, Ollars B, Annerén G. Growth charts for Down's syndrome from birth to 18 years of age. Arch Dis Child 2002; 87:97.
  11. Van Gameren-Oosterom HB, Van Dommelen P, Oudesluys-Murphy AM, et al. Healthy growth in children with Down syndrome. PLoS One 2012; 7:e31079.
  12. Hatch-Stein JA, Zemel BS, Prasad D, et al. Body Composition and BMI Growth Charts in Children With Down Syndrome. Pediatrics 2016; 138.
  13. Luke A, Sutton M, Schoeller DA, Roizen NJ. Nutrient intake and obesity in prepubescent children with Down syndrome. J Am Diet Assoc 1996; 96:1262.
  14. Sepúlveda D, Allison DB, Gomez JE, et al. Low spinal and pelvic bone mineral density among individuals with Down syndrome. Am J Ment Retard 1995; 100:109.
  15. Angelopoulou N, Souftas V, Sakadamis A, Mandroukas K. Bone mineral density in adults with Down's syndrome. Eur Radiol 1999; 9:648.
  16. Fudge JC Jr, Li S, Jaggers J, et al. Congenital heart surgery outcomes in Down syndrome: analysis of a national clinical database. Pediatrics 2010; 126:315.
  17. Erlichman I, Mimouni FB, Erlichman M, Schimmel MS. Thyroxine-Based Screening for Congenital Hypothyroidism in Neonates with Down Syndrome. J Pediatr 2016; 173:165.
  18. Posner EB, Colver AF. Thyroid dysfunction in Down's syndrome: relation to age and thyroid autoimmunity. Arch Dis Child 1999; 81:283.
  19. Gibson PA, Newton RW, Selby K, et al. Longitudinal study of thyroid function in Down's syndrome in the first two decades. Arch Dis Child 2005; 90:574.
  20. Van Vliet G. How often should we screen children with Down's syndrome for hypothyroidism? Arch Dis Child 2005; 90:557.
  21. McGowan S, Jones J, Brown A, et al. Capillary TSH screening programme for Down's syndrome in Scotland, 1997-2009. Arch Dis Child 2011; 96:1113.
  22. Massey GV, Zipursky A, Chang MN, et al. A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children's Oncology Group (COG) study POG-9481. Blood 2006; 107:4606.
  23. Hennequin M, Faulks D, Veyrune JL, Bourdiol P. Significance of oral health in persons with Down syndrome: a literature review. Dev Med Child Neurol 1999; 41:275.
  24. Barr-Agholme M, Dahllöf G, Linder L, Modéer T. Actinobacillus actinomycetemcomitans, Capnocytophaga and Porphyromonas gingivalis in subgingival plaque of adolescents with Down's syndrome. Oral Microbiol Immunol 1992; 7:244.
  25. Kusters MA, Verstegen RH, Gemen EF, de Vries E. Intrinsic defect of the immune system in children with Down syndrome: a review. Clin Exp Immunol 2009; 156:189.
  26. Atlantoaxial instability in Down syndrome: subject review. American Academy of Pediatrics Committee on Sports Medicine and Fitness. Pediatrics 1995; 96:151.
  27. Hankinson TC, Anderson RC. Craniovertebral junction abnormalities in Down syndrome. Neurosurgery 2010; 66:32.
  28. Pueschel SM, Herndon JH, Gelch MM, et al. Symptomatic atlantoaxial subluxation in persons with Down syndrome. J Pediatr Orthop 1984; 4:682.
  29. Skotko BG, Macklin EA, Muselli M, et al. A predictive model for obstructive sleep apnea and Down syndrome. Am J Med Genet A 2017; 173:889.
  30. Yu PK, Stenerson M, Ishman SL, et al. Evaluation of Upper Airway Stimulation for Adolescents With Down Syndrome and Obstructive Sleep Apnea. JAMA Otolaryngol Head Neck Surg 2022; 148:522.
  31. Hsiang YH, Berkovitz GD, Bland GL, et al. Gonadal function in patients with Down syndrome. Am J Med Genet 1987; 27:449.
  32. Bovicelli L, Orsini LF, Rizzo N, et al. Reproduction in Down syndrome. Obstet Gynecol 1982; 59:13S.
  33. Issues of Sexualtiy in Down Syndrome. http://www.ds-health.com/issues.htm (Accessed on July 19, 2012).
  34. Johannisson R, Gropp A, Winking H, et al. Down's syndrome in the male. Reproductive pathology and meiotic studies. Hum Genet 1983; 63:132.
  35. Sheridan R, Llerena J Jr, Matkins S, et al. Fertility in a male with trisomy 21. J Med Genet 1989; 26:294.
  36. Pradhan M, Dalal A, Khan F, Agrawal S. Fertility in men with Down syndrome: a case report. Fertil Steril 2006; 86:1765.e1.
  37. Fortea J, Zaman SH, Hartley S, et al. Alzheimer's disease associated with Down syndrome: a genetic form of dementia. Lancet Neurol 2021; 20:930.
  38. Lott IT, Head E. Dementia in Down syndrome: unique insights for Alzheimer disease research. Nat Rev Neurol 2019; 15:135.
  39. Iulita MF, Garzón Chavez D, Klitgaard Christensen M, et al. Association of Alzheimer Disease With Life Expectancy in People With Down Syndrome. JAMA Netw Open 2022; 5:e2212910.
  40. Videla L, Benejam B, Pegueroles J, et al. Longitudinal Clinical and Cognitive Changes Along the Alzheimer Disease Continuum in Down Syndrome. JAMA Netw Open 2022; 5:e2225573.
  41. Manfredi-Lozano M, Leysen V, Adamo M, et al. GnRH replacement rescues cognition in Down syndrome. Science 2022; 377:eabq4515.
  42. Meethal SV, Smith MA, Bowen RL, Atwood CS. The gonadotropin connection in Alzheimer's disease. Endocrine 2005; 26:317.
  43. Yang Q, Rasmussen SA, Friedman JM. Mortality associated with Down's syndrome in the USA from 1983 to 1997: a population-based study. Lancet 2002; 359:1019.
  44. Strauss D, Eyman RK. Mortality of people with mental retardation in California with and without Down syndrome, 1986-1991. Am J Ment Retard 1996; 100:643.
  45. Irving CA, Chaudhari MP. Cardiovascular abnormalities in Down's syndrome: spectrum, management and survival over 22 years. Arch Dis Child 2012; 97:326.
  46. Englund A, Jonsson B, Zander CS, et al. Changes in mortality and causes of death in the Swedish Down syndrome population. Am J Med Genet A 2013; 161A:642.
  47. Kucik JE, Shin M, Siffel C, et al. Trends in survival among children with Down syndrome in 10 regions of the United States. Pediatrics 2013; 131:e27.
  48. Rasmussen SA, Wong LY, Correa A, et al. Survival in infants with Down syndrome, Metropolitan Atlanta, 1979-1998. J Pediatr 2006; 148:806.
  49. Rankin J, Tennant PW, Bythell M, Pearce MS. Predictors of survival in children born with Down syndrome: a registry-based study. Pediatrics 2012; 129:e1373.
  50. Glasson EJ, Sullivan SG, Hussain R, et al. The changing survival profile of people with Down's syndrome: implications for genetic counselling. Clin Genet 2002; 62:390.
  51. Glasson EJ, Sullivan SG, Hussain R, et al. Comparative survival advantage of males with Down syndrome. Am J Hum Biol 2003; 15:192.
  52. Wiseman FK, Alford KA, Tybulewicz VL, Fisher EM. Down syndrome--recent progress and future prospects. Hum Mol Genet 2009; 18:R75.
  53. Wetmore DZ, Garner CC. Emerging pharmacotherapies for neurodevelopmental disorders. J Dev Behav Pediatr 2010; 31:564.
  54. Bianchi P, Ciani E, Guidi S, et al. Early pharmacotherapy restores neurogenesis and cognitive performance in the Ts65Dn mouse model for Down syndrome. J Neurosci 2010; 30:8769.
  55. Ani C, Grantham-McGregor S, Muller D. Nutritional supplementation in Down syndrome: theoretical considerations and current status. Dev Med Child Neurol 2000; 42:207.
  56. Garcez ME, Peres W, Salvador M. Oxidative stress and hematologic and biochemical parameters in individuals with Down syndrome. Mayo Clin Proc 2005; 80:1607.
  57. Capone GT. Down syndrome: advances in molecular biology and the neurosciences. J Dev Behav Pediatr 2001; 22:40.
  58. Miles MV, Patterson BJ, Chalfonte-Evans ML, et al. Coenzyme Q10 (ubiquinol-10) supplementation improves oxidative imbalance in children with trisomy 21. Pediatr Neurol 2007; 37:398.
  59. Ellis JM, Tan HK, Gilbert RE, et al. Supplementation with antioxidants and folinic acid for children with Down's syndrome: randomised controlled trial. BMJ 2008; 336:594.
  60. Livingstone N, Hanratty J, McShane R, Macdonald G. Pharmacological interventions for cognitive decline in people with Down syndrome. Cochrane Database Syst Rev 2015; :CD011546.
  61. Babies with Down syndrome: A new parent's guide, 2nd ed, Stray-Gundersen K (Ed), Woodbine House, Bethesda 1995.
  62. Kumin L, Schoenbrodt L. Employment in Adults with Down Syndrome in the United States: Results from a National Survey. J Appl Res Intellect Disabil 2016; 29:330.
Topic 2938 Version 44.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟