Down syndrome differential diagnosis

Jump to navigation Jump to search

Down syndrome Microchapters


Patient Information


Historical Perspective



Differentiating Down syndrome from other Diseases

Epidemiology and Demographics

Risk Factors


Natural History, Complications and Prognosis


History and Symptoms

Physical Examination

Laboratory Findings


X Ray



Echocardiography or Ultrasound

Other Imaging Findings

Other Diagnostic Studies


Medical Therapy


Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Sociological and Cultural Aspects

Case Studies

Case #1

Down syndrome differential diagnosis On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides


American Roentgen Ray Society Images of Down syndrome differential diagnosis

All Images
Echo & Ultrasound
CT Images

Ongoing Trials at Clinical

US National Guidelines Clearinghouse

NICE Guidance

FDA on Down syndrome differential diagnosis

CDC on Down syndrome differential diagnosis

Down syndrome differential diagnosis in the news

Blogs on Down syndrome differential diagnosis

Directions to Hospitals Treating Down syndrome

Risk calculators and risk factors for Down syndrome differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]


The diagnosis of Down syndrome should be suspected in pre-natal assessment of fetuses on ultrasound examination. Second quad screen showing decreased alfa-fetoprotein (AFP) should raise the suspicion of fetal chromosomal abnormlaity. Pre-natal differentials of low AFP include Down syndrome, Edwards syndrome and Patau syndrome. In the newborn, Down syndrome should be differentiated from other congenital conditions presenting with hypotonia, poor feeding, poor growth and dysmorphic facial features. The differentials include isolated hypotonia, congenital hypothyroidism and Zellweger syndrome.

Differential Diagnosis

Pre-natal differentials

The diagnosis of Down syndrome should be suspected in pre-natal assessment of fetuses on ultrasound examination during first trimester of pregnancy. Second trimester quad screen showing decreased alfa-fetoprotein (AFP) should raise the suspicion of fetal chromosomal abnormlaity. The following are the differential diagnosis of decreased AFP levels during a first trimester quad screen:[1][2][3][4][5][6][7]

Fetal chromosomal abnormality Quad screen results Pregnancy associated protein-A (PAPP-A)
Alfa-fetoprotein (AFP) Beta human chorionic gonadotrpin (B-hCG) Estriol Inhibin A
Down syndrome (trisomy 21)
Edwards syndrome (trisomy 18) ↓ or normal
Patau syndrome (trisomy 13)

Differentials in newborns and children

In the newborns and children, Down syndrome should be differentiated from other congenital conditions presenting with hypotonia, poor feeding, poor growth and dysmorphic facial features. The differentials include the following:[8][9][10][11][12][12][13][14]

Congenital condition Physical examination Karyotype examination Echocardiography
Hypotonia Poor feeding Poor growth Dysmorphic features (simian crease) Single palmar crease Epicanthal folds Flat occiput and face Seizures Dry skin Ophtalmologic examination Abundant neck skin Gap between first and second fingers (sandal gap) Protruding tongue Downward turned mouth Almond eyes Round face
Down syndrome + + + + + + + + - + Increased + + + +
  • Meiotic error:
    • 47,XX, +21 or 47, XY, +21 (meiotic I error leads to heterodisomy whereas meiotic II error leads to isodisomy)
  • Robertsonian translocation:
    • 46, XX, -14, +t(14q;21q) etc.
Congenital hypothroidism + + + + - - - + + - Increased + - - -
  • 46, XX or 46, XY
Zellwegger syndrome + + + + + + + + - - - - - - -
  • 46, XX or 46, XY
Isolated hypotonia + - - - - - - - - - - - - - - -
  • 46, XX or 46, XY

Down syndrome must be differentiated from other similar conditions which lead to multiple endocrine disorders such as autoimmune polyendocrine syndrome, POEMS syndrome, Hirata syndrome, Kearns–Sayre syndrome and Wolfram syndromes.[15][16][17][18][19]

Disease Addison's disease Type 1 diabetes mellitus Hypothyroidism Other disorders present
APS type 1 + Less common Less common Hypoparathyroidism
APS type 2 + + + Hypogonadism
APS type 3 - + + Malabsorption
Thymoma + - + Myasthenia gravis
Cushing syndrome
Chromosomal abnormalities
(Turner syndrome,
Down's syndrome)
- + + Cardiac dysfunction
Kearns–Sayre syndrome - + - Myopathy
Wolfram syndrome - + - Diabetes insipidus
Optic atrophy
POEMS syndrome - + - Polyneuropathy
Plasma cell dyscrasias


  1. Benn PA, Ying J, Beazoglou T, Egan JF (January 2001). "Estimates for the sensitivity and false-positive rates for second trimester serum screening for Down syndrome and trisomy 18 with adjustment for cross-identification and double-positive results". Prenat. Diagn. 21 (1): 46–51. PMID 11180240.
  2. Yazdani S, Rouholahnejad R, Asnafi N, Sharbatdaran M, Zakershob M, Bouzari Z (2015). "Correlation of pregnancy outcome with quadruple screening test at second trimester". Med J Islam Repub Iran. 29: 281. PMC 4764288. PMID 26913244.
  3. Reynolds T (August 2010). "The triple test as a screening technique for Down syndrome: reliability and relevance". Int J Womens Health. 2: 83–8. PMC 2971727. PMID 21072301.
  4. Shaw SW, Lin SY, Lin CH, Su YN, Cheng PJ, Lee CN, Chen CP (March 2010). "Second-trimester maternal serum quadruple test for Down syndrome screening: a Taiwanese population-based study". Taiwan J Obstet Gynecol. 49 (1): 30–4. doi:10.1016/S1028-4559(10)60005-8. PMID 20466289.
  5. Cuckle H (May 2014). "Prenatal Screening Using Maternal Markers". J Clin Med. 3 (2): 504–20. doi:10.3390/jcm3020504. PMC 4449694. PMID 26237388.
  6. Shiefa S, Amargandhi M, Bhupendra J, Moulali S, Kristine T (January 2013). "First Trimester Maternal Serum Screening Using Biochemical Markers PAPP-A and Free β-hCG for Down Syndrome, Patau Syndrome and Edward Syndrome". Indian J Clin Biochem. 28 (1): 3–12. doi:10.1007/s12291-012-0269-9. PMC 3547446. PMID 24381414.
  7. Park SY, Jang IA, Lee MA, Kim YJ, Chun SH, Park MH (September 2016). "Screening for chromosomal abnormalities using combined test in the first trimester of pregnancy". Obstet Gynecol Sci. 59 (5): 357–66. doi:10.5468/ogs.2016.59.5.357. PMC 5028642. PMID 27668198.
  8. Devlin L, Morrison PJ (May 2004). "Accuracy of the clinical diagnosis of Down syndrome". Ulster Med J. 73 (1): 4–12. PMC 2475449. PMID 15244118.
  9. Kurtul BE, Ozer PA, Kabatas EU, Gürkan A, Aycan Z (2016). "Ophthalmic Manifestations in Children With Congenital Hypothyroidism". J Pediatr Ophthalmol Strabismus. 53 (1): 29–34. doi:10.3928/01913913-20160113-06. PMID 26836000.
  10. Mutton D, Ide RG, Alberman E (October 1998). "Trends in prenatal screening for and diagnosis of Down's syndrome: England and Wales, 1989-97". BMJ. 317 (7163): 922–3. PMC 28676. PMID 9756810.
  11. Ozturk, Banu T; Kerimoglu, Hurkan; Dikbas, Oguz; Pekel, Hamiyet; Gonen, Mustafa S (2009). "Ocular changes in primary hypothyroidism". BMC Research Notes. 2 (1): 266. doi:10.1186/1756-0500-2-266. ISSN 1756-0500.
  12. 12.0 12.1 Lee PR, Raymond GV (May 2013). "Child neurology: Zellweger syndrome". Neurology. 80 (20): e207–10. doi:10.1212/WNL.0b013e3182929f8e. PMC 3908348. PMID 23671347.
  13. Klouwer FC, Berendse K, Ferdinandusse S, Wanders RJ, Engelen M, Poll-The BT (December 2015). "Zellweger spectrum disorders: clinical overview and management approach". Orphanet J Rare Dis. 10: 151. doi:10.1186/s13023-015-0368-9. PMC 4666198. PMID 26627182.
  14. Reddy PA, Rajagopal G, Harinarayan CV, Vanaja V, Rajasekhar D, Suresh V, Sachan A (2010). "High prevalence of associated birth defects in congenital hypothyroidism". Int J Pediatr Endocrinol. 2010: 940980. doi:10.1155/2010/940980. PMC 2864451. PMID 20454578.
  15. Sherer Y, Bardayan Y, Shoenfeld Y (1997). "Thymoma, thymic hyperplasia, thymectomy and autoimmune diseases (Review)". Int. J. Oncol. 10 (5): 939–43. PMID 21533467.
  16. Nozza, Andrea (2017). "POEMS SYNDROME: AN UPDATE". Mediterranean Journal of Hematology and Infectious Diseases. 9 (1): e2017051. doi:10.4084/mjhid.2017.051. ISSN 2035-3006.
  17. Maceluch JA, Niedziela M (2006). "The clinical diagnosis and molecular genetics of kearns-sayre syndrome: a complex mitochondrial encephalomyopathy". Pediatr Endocrinol Rev. 4 (2): 117–37. PMID 17342029.
  18. Rigoli L, Di Bella C (2012). "Wolfram syndrome 1 and Wolfram syndrome 2". Curr. Opin. Pediatr. 24 (4): 512–7. doi:10.1097/MOP.0b013e328354ccdf. PMID 22790102.
  19. Husebye, Eystein S.; Anderson, Mark S. (2010). "Autoimmune Polyendocrine Syndromes: Clues to Type 1 Diabetes Pathogenesis". Immunity. 32 (4): 479–487. doi:10.1016/j.immuni.2010.03.016. ISSN 1074-7613.