History

Fact Explanation
Typical physical appearance Flat occiput, flat nasal bridge, small mouth with large tongue, low set ears, upward slanting eyes, single palmer crease, sandal gap between first toe web. [1]
Vomiting Due to intestinal obstruction caused by duodenal/ ileal atresia (3.9% of children with trisomy 21[2]) or annular pancreas. Presents within 24-48 hours of birth; but if the obstruction is incomplete may present after a few months[4]; usually with associated constipation. Maybe also occur due to another infection such as Otitis media, for which they are also predisposed. Exclude this by doing an auroscope examination.
Constipation Due to Hirschsprung disease[3] (0.8% of children with trisomy 21)[2], hypothyroidism, anal atresia (1% of children with trisomy 21)[2] or intestinal obstruction caused by duodenal/ ileal atresia or annular pancreas. All of these conditions are common in Down syndrome.
Hemetemesis Has been reported in association with intestinal obstruction. Thought to be due to associated duodenitis/ gastritis. [4]
Abnormal head posture and restricted neck movements, abnormal gait, deteriorating skilled movements of hand, bowel/ bladder incontinence. These symptoms may occur due to atlanto-axial instablility, which is common in Down syndrome, leading to acute or progressive spinal cord lesions.[7] Caregivers should be warned regarding these symptoms and the patient should be immediately referred to an orthopedic or a neurosurgeon if symptoms arise. [6]
Mild to moderate learning disability. [5] IQ of children with Down syndrome is lower than that of general population and is further deteriorated if there is associated hypothyroidism. Children with Down syndrome but normal levels of TSH and T4 levels have mean IQ of 55.3 whereas those with low TSH and low T4 levels have a mean IQ of 41.7. [16]
Fits 1-13% of patients with trisomy 21 have epilepsy. [8] Seems to have a bimodal distribution with some having seizures at less than one year of age, with infantile spasms or tonic-clonic seizures with myoclonus or else starting seizures after 40 years of age with simple partial or partial complex seizures or tonic-clonic seizures. [9]
Difficulty in breathing, syncopal attacks Congenital heart diseases (Atrioventricular septal defect-39%, secundum atrial septal defect-42%, ventricular septal defect-43%, tetralogy of Fallot-6%) [10]
Small stature People with trisomy 21 attain a lesser height than normal population. Thus the growth should be monitored with a Down syndrome specific chart.
Visual impairment/ Ophthalmic disorders. Refractive errors-hypermetropia, astigmatism, strabismus, nasolacrimal duct obstruction, cataracts or nystagmus. [11]
Memory loss. Early dementia/ Alzheimer's is a known entity in trisomy 21. [12] The amyloid precursor protein which is a known risk factor for Alzheimer's disease is coded in chromosome 21 and available in triplicate in trisomy 21. This is thought to be the cause of dementia in trisomy 21. [5]
Autism spectrum disorder This is higher in patients with trisomy 21 than in the general population. [13]
Snoring, sleep disturbance. mouth breathing, restless sleep, chronic rhinorrhea, odd sleep positions, recurrent upper respiratory tract infections, daytime sleepiness. [14] This may occur due to upper airway obstruction due to a large tongue, narrow nasopharynx, laryngomalacia, congenital subglottic stenosis, tracheobronchomalacia or tracheal stenosis. Tonsilar hyperplasia in already compromised airway may worsen the symptoms. [15]
References
  1. DEVLIN L, MORRISON P. Accuracy of the clinical diagnosis of Down syndrome. Ulster Medical Journal. May 2004, Volume 73. Issue 1. Pages 4–12. Available from: PMCID: PMC2475449 Viewed on: 21/03/2014 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2475449/
  2. FREEMAN SB, TORFS CP, ROMITTI PA, ROYLE MH, DRUSCHEL C, HOBBS CA, SHERMAN SL. Congenital gastrointestinal defects in Down syndrome: a report from the Atlanta and National Down Syndrome Projects. Clinical Genetics. 2009 Feb; Volume 75, Issue 2, Pages 180-4. Available from: doi: 10.1111/j.1399-0004.2008.01110 Viewed on: 18/ 03/ 2014. http://www.ncbi.nlm.nih.gov/pubmed/19021635
  3. CANIANO Donna A., TEITELBAUM Daniel H., QUALMAN Stephen J. Management of Hirschsprung's disease in children with trisomy 21. The American Journal of Surgery. April 1990,Volume 159, Issue 4, Pages 402–404. Viewed on: 18/ 03/ 2014. http://www.sciencedirect.com/science/article/pii/S0002961005812814
  4. SHAHWANI Noora Al, MANDHAN Parkash, ELKADHI Abdelrahman, ALI Mansour J., LATIF Abdel. Congenital duodenal obstruction associated with Down's syndrome presenting with hematemesis. Oxford Journals, Medicine Journal of Surgical Case Reports. 2013. Volume 2013, Issue 12. Viewed on: 18/ 03/ 2014. http://jscr.oxfordjournals.org/content/2013/12/rjt108.full
  5. WISEMAN Frances K., ALFORD Kate A., TYBULEWICZ Victor L.J., FISHER Elizabeth M.C. Down syndrome—recent progress and future prospects. Human Molecular Genetics 2009, Volume 18, Issue R1, Pages R75-R83 Available from: doi:10.1093/hmg/ddp010 Viewed on: 19/ 03/ 2014 http://hmg.oxfordjournals.org/content/18/R1/R75.full
  6. MARDER.E, DENNIS J. Medical management of children with Down’s syndrome. Current Paediatrics. 2001 Harcourt Publishers Ltd Available from: doi:10.1054/cupe.2000.0143 Viewed on: 20/03/2014. http://www.dsmig.org.uk/library/articles/medman-cup.pdf
  7. NADER-SEPAHI A, CASEY AT, HAYWARD R, CROCKARD HA, THOMPSON D. Symptomatic atlantoaxial instability in Down syndrome. Journal of Neurosurgery. 2005 Sep, Volume 103, Issue 3, Pages 231-7. Viewed on: 18/ 03/ 2014. http://www.ncbi.nlm.nih.gov/pubmed/16238076
  8. ARYA R, KABRA M, GULATI S. Epilepsy in children with Down syndrome. Epileptic Disorder 2011 Mar; Volume 13, Issue 1, Pages:1-7. Available from: doi: 10.1684/epd.2011.0415. Viewed on: 19/ 03/ 2014 http://www.ncbi.nlm.nih.gov/pubmed/21398208
  9. PUESCHEL SM, LOUIS S, McKNIGHT P. Seizure disorders in Down syndrome. Archieves of Neurology. 1991 Mar; Volume 48. Issue 3 Pages:318-20. Viewed on: 19/ 03/ 2014 http://www.ncbi.nlm.nih.gov/pubmed/1825777
  10. FREEMAN SB, BEAN LH, ALLEN EG, TINKER SW et al. Ethnicity, sex, and the incidence of congenital heart defects: a report from the National Down Syndrome Project. Genetics in Medicine 2008 Mar; Volume 10, Issue 3, Pages 173-80. Available from: doi: 10.1097/GIM.0b013e3181634867. Viewed on: 19/ 03/ 2014 http://www.ncbi.nlm.nih.gov/pubmed/18344706
  11. STEPHEN Elma, DICKSON Jennifer, KINDLE A David, SCOTT Christopher C,CHARELTON Patricia M. Surveillance of vision and ocular disorders in children with Down syndrome. Developmental Medicine & Child Neurology. July 2007 Volume 49, Issue 7, pages 513–515 Available from: DOI: 10.1111/j.1469-8749.2007.00513.x Viewed on: 20/03/2014. http://onlinelibrary.wiley.com/doi/10.1111/j.1469-8749.2007.00513.x/abstract
  12. HOLLAND A.J., HUPPERT J.F.A., STEVENS F., WATSON P. Population-based study of the prevalence and presentation of dementia in adults with Down's syndrome. The British Journal of Psychiatry (1998) Volume 172, Pages 493-498 Available from: doi: 10.1192/bjp.172.6.493 Viewed on: 19/ 03/ 2014 http://bjp.rcpsych.org/content/172/6/493
  13. DIGUISEPPI C, HEPBURN S, DAVIS JM, FIDLER DJ et al. Screening for autism spectrum disorders in children with Down syndrome: population prevalence and screening test characteristics. Journal of Developmental and Behavioural Pediatrics. 2010 Apr; Volume 31, Issue 3, Pages 181-91. Available from: doi: 10.1097/DBP.0b013e3181d5aa6d. Viewed on: 19/ 03/ 2014 http://www.ncbi.nlm.nih.gov/pubmed/20375732
  14. SAMUELS Martin, Sleep-related upper airway obstruction in Down’s syndrome, More Medical Issues in Down’s Syndrome. Learning Disability and The Down’s Syndrome Medical Interest Group. Royal Society of Medicine, London, Thursday 26th April 2001. Viewed on: 20/03/2014. http://www.dsmig.org.uk/library/articles/summary-samuels.pdf
  15. JACOBS IN, GRAY RF, TODD NW. Upper airway obstruction in children with Down syndrome. Archives of Otolaryngology Head and Neck Surgery. 1996 Sep, Volume 122, Issue 9, Pages 945-50. Viewed on: 20/03/2014. http://www.ncbi.nlm.nih.gov/pubmed/8797558
  16. PUESCHEL SM, PEZZULLO JC. Thyroid dysfunction in Down syndrome. American Journal of Diseases in Children. 1985 Jun; Volume 139, Issue 6, Pages:636-9. Viewed on: 24/03/2014. http://www.ncbi.nlm.nih.gov/pubmed/3159255

Examination

Fact Explanation
Examnation of face Brachycephaly, flat nasal bridge, small mouth with large, protruding tongue, upslanting eyes, epicanthal folds, Brushfield's spots, low-set ears. Up to 90% could be accurately diagnosed by careful clinical examination alone. [1]
Examination of hands Short broad hands, simian crease, hypoplasia of middle phalanx with single flexion crease and clinodactyly of fifth finger.
Examination of feet Sandal gap (wide space between first and second toes) and deep vertical crease.
Hypotonia; elicited by presence of head lag, positive scarf sign and by holding the baby in ventral suspension. Normally baby's elbow can be taken up to the middle of baby's chest. In positive scarf sign it can move beyond mid point indicating hypotonia. When the baby is carried from underneath the shoulder, a baby with hypotonia tends to slip through the examiner's hand. When ventrally suspended, baby assumes a curved posture resembling fetal posture depending on gravity.[3]
Cryptochidism. Acquired undescended testis is common in Down syndrome. [4]
Cardiac lesions. In first few weeks of life may be difficult to diagnose by examination alone, thus all children with Down syndrome should undergo early echocardiogram. [5]
Growth parameters plotted in Down syndrome specific growth charts. Children with Down syndrome are known to attain lesser height than normal population. Further suppression can be caused by congenital heart disease, upper airway obstruction, celiac disease and hypothyroidism which are common associations. Thus, plotting in Down syndrome specific growth chart helps to identify further deterioration of growth. [5]
References
  1. DEVLIN L, P. J. MORRISON. Accuracy of the clinical diagnosis of Down syndrome. Ulster Medical Journal. May 2004, Volume 73. Issue 1. Pages 4–12. Available from: PMCID: PMC2475449 Viewed on: 21/03/2014 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2475449/
  2. DEY A, BHOWMIK K, CHATTERJEE A, CHAKRABARTY PB, SINHA S, MUKHOPADHYAY K. Down Syndrome Related Muscle Hypotonia: Association with COL6A3 Functional SNP rs2270669. Frontier of Genetics. 2013 April. Volume 22. Issue4. Page57. Available from: doi: 10.3389/fgene.2013.00057 Viewed on: 21/03/2014 http://www.ncbi.nlm.nih.gov/pubmed/23626599
  3. BODENSTEINER John B. The Evaluation of the Hypotonic Infant. Seminars in paediatric neurology. Elsevier. Volulme 15. 2008. Pages 10-20. Viewed on: 21/03/2014 http://www.mc.vanderbilt.edu/documents/neurology/files/The%20Evaluation%20of%20the%20Hypotonic%20Infant%20(Seminars%20in%20Pediatric%20Neurology,%202008).pdf
  4. CHEW G, HUTSON JM. Incidence of cryptorchidism and ascending testes in trisomy 21: a 10 year retrospective review. Pediatrtric Surgery International. 2004 Oct; Volume 20, Issue 10, Pages 744-7. Viewed on: 21/03/2014 http://www.ncbi.nlm.nih.gov/pubmed/15517292
  5. MARDER.E, DENNIS J. Medical management of children with Down’s syndrome. Current Paediatrics. 2001 Harcourt Publishers Ltd Available from: doi:10.1054/cupe.2000.0143 Viewed on: 20/03/2014. http://www.dsmig.org.uk/library/articles/medman-cup.pdf

Differential Diagnoses

Fact Explanation
Mosaic trisomy 21[1] This is when an error in division occurs after fertilization but during early division. There will be 2 cell lines, one normal and the other with trisomy 21. Percentage of normal and trisomy 21 cell line varies. Children with mosaic trisomy 21 have better IQ than children with Down syndrome. [1]
References
  1. BUCKLEY SJ, BIRD G. What do we know about the needs of children with Mosaic Down syndrome and their families?. Down Syndrome News and Update. 2002 Volume 2, Issue 3, Pages 97-99. Available from: doi:10.3104/practice.179 http://www.down-syndrome.org/practice/179/

Investigations - for Diagnosis

Fact Explanation
Chromosomal analysis It could be due to non disjunction[1], translocation or mosaicism.[2]
References
  1. OLIVER Tiffany Renee, Eleanor FEINGOLD, Kai YU, Vivian CHEUNG, Stuart TINKER, Maneesha Yadav-SHAH, Nirupama MASSE, Stephanie L. SHERMAN. New Insights into Human Nondisjunction of Chromosome 21 in Oocytes. PLOS Genetics. March 14, 2008 Available from: DOI: 10.1371/journal.pgen.1000033 Viewed on: 21/03/2014 http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000033
  2. HIGURASHI M, I MATSUI, Y NAKAGOME, and M NAGANUMA. Down's syndrome: chromosome analysis in 321 cases in Japan. Journal of Medical Genetics. Dec 1969; Volume 6, Issue 4, Pages 401–404. Available from: PMCID: PMC1468774 Viewed on: 21/03/2014 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1468774/?page=1

Investigations - Followup

Fact Explanation
Thyroid function test Should be done at birth and repeated 2 yearly when proven to be normal and yearly in cases of subclinical hypothyroidism. [1] Hypothyroidism is more common than hyperthyroidism in patients with Down syndrome and may occur as congenital or acquired disease. [1]
2D echocardiogram Should be done within the first few weeks and at early adulthood by a pediatric cardiologist since they are at risk of having both congenital and acquired heart diseases. 40-60 % have cardiac defects and may not be evident by examination in early days, diagnosis of cardiac lesion earlier aids in avoidance of irreversible pulmonary vascular damage which occurs earlier in children with Down syndrome than in general population. [1] Subacute endocarditis prophylaxis should be advised where necessary.[2]
Auditory Brainstem Response (ABR) To be performed within the first six months of life. [3]
Pediatric opthalmological evaluation Should be done at 6 months and annually thereafter. [4]
In cases of sleep related upper airway obstruction sleep study with polysomnogram, barium swallow, CT/MRI, fibre-optic endoscopy, ECG/echocardiogram, Hb(hemoglobin) will be useful. Sleep study helps to find abnormal chest in-drawing, hypoxia, carbon dioxide, breathing patterns during sleep. Barium swallow will detect vascular rings causing large airway compromise and fiber optic endoscopy finds multiple obstructive sites in the respiratory system. ECG/echocardiogram excludes any cardiac cause which might be causing sleep disturbances and Hb is done if severe hypoxemia is suspected.[5]
References
  1. PRASHER Vee. Down Syndrome and Thyroid Disorders: A Review. Down Syndrome Research and Practice. 1999 Volume 6 Issue 1 Pages 25-42. Available from: doi:10.3104/reviews.95 Viewed on: 20/03/2014. http://www.down-syndrome.org/reviews/95/
  2. MARDER.E, J. DENNIS. Medical management of children with Down’s syndrome. Current Paediatrics. 2001 Harcourt Publishers Ltd Available from: doi:10.1054/cupe.2000.0143 Viewed on: 20/03/2014. http://www.dsmig.org.uk/library/articles/medman-cup.pdf
  3. ROIZEN Nancy J., WOLTERS Cheryl, NICOL Trent , BLONDIS Thomas A. Hearing loss in children with Down syndrome. The Journal of Pediatrics. 1993. Volume 123, Issue 1 , Pages S9-S12. Viewed on: 20/03/2014. http://www.jpeds.com/article/S0022-3476(05)81588-4/abstract
  4. ROIZEN NJ, METS MB, BLONDIS TA. Ophthalmic disorders in children with Down syndrome. Developmental Medicine and Child Neurology. 1994 July, Volume 36, Issue 7, Pages 594-600. Viewed on: 20/03/2014. http://www.ncbi.nlm.nih.gov/pubmed/8034121
  5. SAMUELS Martin, Sleep-related upper airway obstruction in Down’s syndrome, More Medical Issues in Down’s Syndrome. Learning Disability and The Down’s Syndrome Medical Interest Group. Royal Society of Medicine, London, Thursday 26th April 2001. Viewed on: 20/03/2014. http://www.dsmig.org.uk/library/articles/summary-samuels.pdf

Investigations - Screening/Staging

Fact Explanation
Maternal serum triple marker Triple test consist of maternal serum levels of alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG) and unconjugated estriol.[1] This is an effective method of screening and is more accurate in older(maternal age is more than 35 years) than younger mothers. [2]
Ultrasound scan Presence of abnormal nuchal translucency is an effective method in diagnosing Down syndrome in early pregnancy. In second trimester serum testing has higher sensitivity(72%) than measurement of nuchal translucency(56%) [3]
Amniocentesis Pregnant mothers at high risk of having a baby with Down syndrome are offered invasive methods such as amniocentesis for diagnosis of Down syndrome.[4]
References
  1. GRAVES J. CHRISTOPHER, MILLER Karl E, SELLERS D Angela, BAXLEY, GEORGIA. Maternal Serum Triple Analyte Screening in Pregnancy. American Family Physician. 2002 Mar 1; Volume 65, Issue5, Pages:915-921. Viewed on: 25/03/2014 http://www.aafp.org/afp/2002/0301/p915.html
  2. CONDE-AGUDELO A, KAFURY-GOETA AC. Triple-marker test as screening for Down syndrome: a meta-analysis. Obstetrical and Gynecological Survery. 1998 Jun; Volume 53, Issue 6, Pages 369-76. Viewed on: 25/03/2014 http://www.ncbi.nlm.nih.gov/pubmed/9618713
  3. SAUCEDO MC, DeVIGAN C, VODOVAR V, LELONG N, GOFFINET F, KHOSHNOOD B. Measurement of nuchal translucency and the prenatal diagnosis of Down syndrome. Obstetrics and Gynecolegy. 2009 Oct; Volume 114, Issue 4, Pages 829-38. Available from: doi: 10.1097/AOG.0b013e3181b6f251. Viewed on: 25/03/2014 http://www.ncbi.nlm.nih.gov/pubmed/19888042
  4. ALFIREVIC Zarko, NEILSON James P. Antenatal screening for Down's syndrome. 7 October 2004 BMJ 2004; 329 Available from: doi: http://dx.doi.org/10.1136/bmj.329.7470.811, BMJ 2004;329:811 Viewed on: 25/03/2014 http://www.bmj.com/content/329/7470/811

Management - General Measures

Fact Explanation
For sleep related upper airway obstruction, topical decongestants are used for intermittent problems; nasal CPAP(Continuous Positive Airway Pressure), nasopharyngeal tubes, ENT procedures according to the deformity (eg: tonsillo-adenoidectomy, uvulopalatopharyngoplasty, tonsillar pillar plication..) can be done. Tracheostomy may have to be used in cases of emergency or as a last resort. [1] Airway obstruction in Down syndrome could be due to multiple problems and surgery should be specific to each patient and residual symptoms are common after surgery.[2]
Education on safeguarding themselves from sexual abuse, usage of contraceptives and sexually transmitted diseases should be provided. [3] Sexual development of children with trisomy 21 would be largely equivalent to that of general population. [3]
Surgical interventions for Hirshsprung disease including Duhamel pull-through, Soave pull-through or anal myectomy. [4] Child should be referred to paediatric surgical unit upon diagnosis of Hirshsprung disesase where appropriate surgical interventions can be undertaken. Children with Hirschsprung and Down syndrome have higher mortality and high risk of development of surgical complications than children with Hirschsprung alone. [4][5]
Children with cardiac lesion should undergo appropriate surgery according to lesion. Child should be referred to paediatric cardio thoracic surgeon upon diagnosis of cardiac lesions. Early interventions made in children with Down syndrome with cardiac lesions helps to improve the quality of life. [6] There is no significant increase in post operative mortality but post operative morbidity is higher in children with Down syndrome. [7]
References
  1. SAMUELS Martin , Sleep-related upper airway obstruction in Down’s syndrome, More Medical Issues in Down’s Syndrome. Learning Disability and The Down’s Syndrome Medical Interest Group. Royal Society of Medicine, London, Thursday 26th April 2001. Viewed on: 20/03/2014. http://www.dsmig.org.uk/library/articles/summary-samuels.pdf
  2. JACOBS IN, GRAY RF, TODD NW. Upper airway obstruction in children with Down syndrome. Archives of Otolaryngology Head and Neck Surgery. 1996 Sep, Volume 122, Issue 9, Pages 945-50. Viewed on: 20/03/2014. http://www.ncbi.nlm.nih.gov/pubmed/8797558
  3. DYKE Don Van, Dianne McBRIEN and Andrea SHERBONDY. Issues of sexuality in Down syndrome. Down Syndrome Research and Practice. 1995. Volume 3. Issue 2 Pages 65-69. Available from: doi:10.3104/reviews.53 Viewed on: 20/03/2014. http://www.down-syndrome.org/reviews/53/
  4. CANIANO Donna A. MD, MD Daniel H. TEITELBAUM MD, Stephen J. QUALMAN MD. Management of Hirschsprung's disease in children with trisomy 21. The American Journal of Surgery. April 1990,Volume 159, Issue 4, Pages 402–404. Viewed on: 18/ 03/ 2014. http://www.sciencedirect.com/science/article/pii/S0002961005812814
  5. RESCORLA Frederick J. MD; Albert M. MORRISON MD; Drew ENGLES MD; Karen W. WEST MD; Jay L. GROSFELD MD. Hirschsprung's Disease-Evaluation of Mortality and Long-term Function in 260 Cases, JAMA Surgery, Formerly archives of surgery. August 1992, Vol 127, No. 8 Pages 934-942. Available from doi:10.1001/archsurg.1992.01420080068011. Viewed on: 18/ 03/ 2014 http://archsurg.jamanetwork.com/article.aspx?articleid=595452
  6. FIGUEROA Jesús de Rubens, Blanca del Pozzo MAGANAA, José L Pablos HACHA, Claudia Calderón JIMENEZA, Rocío Castrejón URBINNA. Heart Malformations in Children With Down Syndrome. Revista Espanola De Cardiologia. September 2003. Volume 56. Issue 09. Viewed on 21/03/2014 http://www.revespcardiol.org/en/heart-malformations-in-children-with/articulo/13051768/
  7. FUDGE James C,SHUANG LI , JAGGERS James et al., Congenital Heart Surgery Outcomes in Down Syndrome: Analysis of a National Clinical Database. Pediatrics. July 12, 2010 Vol./ 126 No. page 315 -322. Available from: doi: 10.1542/peds.2009-3245. Viewed on 22/03/2014

Management - Specific Treatments

Fact Explanation
No specific management for trisomy 21 itself. But regular assessment and necessary interventions should be done when necessary. The primary care physician should actively inquire about conditions common in Down syndrome, give routine care including routine examination and investigations, provide information about available community resources, coordinate with sub specialists, and refer patients appropriately and as soon as possible so that early intervention is made possible. [1]
Genetic counselling should be provided to the parents. There is an incresed risk of having a baby with Down syndrome as the maternal age increases. This is probably due to increased risk of non disjunction. But non disjunction is also common in younger mothers.[3] This age-related risk is further increased in mothers who have had a child with Down syndrome. [2] If there is a maternal balanced translocation of 14-21 the risk of next baby having Down syndrome is 12% and if its paternal the chances drop to 3%. In the rare occurrence of 21-21 translocation the recurrence rate is 100%. [3]
References
  1. DAVIDSON Melissa A. Primary Care for Children and Adolescents with Down Syndrome. Pediatric Clinics of North America. Elsevier. October 2008,Volume 55, Issue 5, Pages 1099–1111. Available from: http://dx.doi.org/10.1016/j.pcl.2008.07.001. Viewed on: 21/03/2014. http://www.sciencedirect.com/science/article/pii/S003139550800151X
  2. WARBURTON Dorothy, Louis Dallaire, THANGAVELU Maya, ROSS Lori, LEVIN Bruce, KLINE Jennie. Trisomy Recurrence: A Reconsideration Based on North American Data. American Journal on Human Genetics. Sep 2004; Volume 75, Issue 3, Pages 376–385. PMCID: PMC1182017 Viewed on: 21/03/2014. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1182017/
  3. BENKE Paul J., DONAHUE Roger, Risk and Recurrence Risk of Down Syndrome, October 1995, Down Syndrome: health issues, news and information for parents and professionals. Viewed on: 21/03/2014. http://www.ds-health.com/benke.htm