Down Syndrome — Viva · MBBS viva

Q1: A neonate is "floppy" with upslanting palpebral fissures and a single palmar crease. Discuss your diagnosis and approach. (3 min)

The clinical picture is Down syndrome (trisomy 21) — hypotonia, upslanting palpebral fissures, epicanthal folds, flat facial profile, protruding tongue, single transverse palmar crease, and clinodactyly, in a child often born to an older mother. [1]

My approach:

Confirm with a karyotype — never on clinical grounds alone; I must distinguish non-disjunction (47,+21) from Robertsonian translocation and mosaicism, because the cytogenetic type changes genetic counselling.
Anticipatory screening: echocardiogram by 2 weeks (AVSD is the most characteristic lesion; 40 to 60% have congenital heart disease); thyroid at birth, 6 and 12 months, then annually; FBC at birth for transient abnormal myelopoiesis; audiology and ophthalmology; plot on Down syndrome-specific growth charts.
Refer for early intervention (physiotherapy, speech and language, occupational therapy) and to the multidisciplinary team; counsel the family supportively and signpost to support organisations. [1]

Q2: What are the three cytogenetic types, and why does the distinction matter? (3 min)

Non-disjunction (95%): 47,+21; sporadic meiotic error, usually maternal meiosis I; risk rises with maternal age; recurrence about 1%.
Robertsonian translocation (3 to 4%): extra 21q fused to another acrocentric chromosome, usually t(14;21); 25% inherited from a balanced-carrier parent. The distinction matters because both parents must be karyotyped to counsel recurrence — mother t(14;21) ~10 to 15%, father t(14;21) under 1%, t(21;21) carrier up to 100%.
Mosaicism (1 to 2%): two cell lines from post-zygotic non-disjunction; phenotype often milder; IQ higher; recurrence low. [1]

Clinically and phenotypically, the three types are indistinguishable — the distinction is cytogenetic and is the reason every diagnosis needs a karyotype, not just a clinical impression or a microarray (which can miss a balanced translocation). [1]

Q3: Discuss the haematological complications of Down syndrome. (2 min)

Transient abnormal myelopoiesis (TAM) — a leukaemiaoid reaction in about 10% of neonates, driven by trisomy 21 plus an acquired GATA1 mutation; usually resolves spontaneously by 3 months, but low-dose cytarabine is given if there is organ dysfunction.
Leukaemia — a 10 to 20-fold increased risk. Acute lymphoblastic leukaemia (ALL) is the commonest. Acute megakaryoblastic leukaemia (AMKL, FAB M7) is 500 times more common than in the general population; TAM is the obligatory precursor. Treatment uses modified, reduced-intensity protocols because DS blasts are more chemo-sensitive but the patients tolerate more toxicity. [1]

The mechanism links to extra copies of haematopoietic genes on chromosome 21 (ERG, ETS2, JAK2) cooperating with the GATA1s mutation in fetal liver haematopoiesis. [1]

Q4: What is atlantoaxial instability, and how do you manage it? (2 min)

Atlantoaxial instability is excessive movement at the C1-C2 joint due to ligamentous laxity, which can compress the spinal cord. It affects a minority but is a classic exam topic. [1]

Management (AAP 2022):

Counsel all families to avoid high-risk activities — trampolining, diving, contact/collision sports, gymnastics tumbling, cervical manipulation.
Routine screening cervical radiographs are no longer recommended — asymptomatic atlanto-dens interval widening does not reliably predict cord injury. This is a major change from older guidance.
Investigate if symptomatic (neck pain, torticollis, gait change, pyramidal signs, bladder/bowel dysfunction): cervical spine immobilisation, lateral flexion/extension X-rays (atlanto-dens interval over 5 mm is abnormal), and MRI; refer for surgical C1-C2 fusion if there is cord compression or significant instability with neurological signs. [1]

Q5: What is the prognosis and long-term outlook? (2 min)

Life expectancy is now 50 to 60 years (under 10 in the 1960s), improved by cardiac surgery, antibiotics, thyroid replacement, and anticipatory care. Intellectual disability is typically mild to moderate (IQ 25 to 75); many achieve functional literacy and semi-independent living. Females are usually fertile (30 to 50% chance of an affected child); males are almost always infertile. Alzheimer-type dementia develops in 50 to 70% by age 60, driven by APP gene triplication and amyloid deposition from the 40s. The disposition is to home with community multidisciplinary support, not institutional care. [1]

References

[1]Bull MJ. Down Syndrome. N Engl J Med, 2020.PMID 32521135
[2]Weijerman ME, de Winter JP. Clinical practice. The care of children with Down syndrome. Eur J Pediatr, 2010.PMID 20632187
[3]Bull MJ, Committee on Genetics. Health supervision for children with Down syndrome. Pediatrics, 2011.PMID 21788214
[4]Bittles AH, Bower C, Hussain R, Glasson EJ. The four ages of Down syndrome. Eur J Public Health, 2007.PMID 16857692
[5]Hitzler JK, Zipursky A. Origins of leukaemia in children with Down syndrome. Nat Rev Cancer, 2005.PMID 15630411
[6]Kucik JE, Shin M, Siffel C, Marengo L, Correa A. Trends in survival among children with Down syndrome in 10 regions of the United States. Pediatrics, 2013.PMID 23248222
[7]Bergström S, Carr H, Petersson G, Stephansson O, Bonamy AK, Ludvigsson JF, Dahlström A, Palmér M, Johansson S. Trends in congenital heart defects in infants with Down syndrome. Pediatrics, 2016.PMID 27252035
[8]Maris M, Verhulst S, Wojciechowski M, Van de Heyning P. Sleep problems and obstructive sleep apnea in children with down syndrome, an overwiew. Int J Pediatr Otorhinolaryngol, 2016.PMID 26857307
[9]Shin M, Besser LM, Kucik JE, Lu C, Siffel C, Correa A, Congenital Anomaly Multistate Prevalence and Survival (CAMPS) Collaborative. Prevalence of Down syndrome among children and adolescents in 10 regions of the United States. Pediatrics, 2009.PMID 19948627
[10]Van Cleve SN, Cannon S, Cohen WI. Part II: Clinical Practice Guidelines for adolescents and young adults with Down Syndrome: 12 to 21 Years. J Pediatr Health Care, 2006.PMID 16675381

Q1: A neonate is "floppy" with upslanting palpebral fissures and a single palmar crease. Discuss your diagnosis and approach. (3 min)

My approach:

Confirm with a karyotype — never on clinical grounds alone; I must distinguish non-disjunction (47,+21) from Robertsonian translocation and mosaicism, because the cytogenetic type changes genetic counselling.

Anticipatory screening: echocardiogram by 2 weeks (AVSD is the most characteristic lesion; 40 to 60% have congenital heart disease); thyroid at birth, 6 and 12 months, then annually; FBC at birth for transient abnormal myelopoiesis; audiology and ophthalmology; plot on Down syndrome-specific growth charts.

Refer for early intervention (physiotherapy, speech and language, occupational therapy) and to the multidisciplinary team; counsel the family supportively and signpost to support organisations. [1]

Q2: What are the three cytogenetic types, and why does the distinction matter? (3 min)

Non-disjunction (95%): 47,+21; sporadic meiotic error, usually maternal meiosis I; risk rises with maternal age; recurrence about 1%.

Robertsonian translocation (3 to 4%): extra 21q fused to another acrocentric chromosome, usually t(14;21); 25% inherited from a balanced-carrier parent. The distinction matters because both parents must be karyotyped to counsel recurrence — mother t(14;21) ~10 to 15%, father t(14;21) under 1%, t(21;21) carrier up to 100%.

Mosaicism (1 to 2%): two cell lines from post-zygotic non-disjunction; phenotype often milder; IQ higher; recurrence low. [1]

Q3: Discuss the haematological complications of Down syndrome. (2 min)

Transient abnormal myelopoiesis (TAM) — a leukaemiaoid reaction in about 10% of neonates, driven by trisomy 21 plus an acquired GATA1 mutation; usually resolves spontaneously by 3 months, but low-dose cytarabine is given if there is organ dysfunction.

Leukaemia — a 10 to 20-fold increased risk. Acute lymphoblastic leukaemia (ALL) is the commonest. Acute megakaryoblastic leukaemia (AMKL, FAB M7) is 500 times more common than in the general population; TAM is the obligatory precursor. Treatment uses modified, reduced-intensity protocols because DS blasts are more chemo-sensitive but the patients tolerate more toxicity. [1]

The mechanism links to extra copies of haematopoietic genes on chromosome 21 (ERG, ETS2, JAK2) cooperating with the GATA1s mutation in fetal liver haematopoiesis. [1]

Q4: What is atlantoaxial instability, and how do you manage it? (2 min)

Atlantoaxial instability is excessive movement at the C1-C2 joint due to ligamentous laxity, which can compress the spinal cord. It affects a minority but is a classic exam topic. [1]

Management (AAP 2022):

Counsel all families to avoid high-risk activities — trampolining, diving, contact/collision sports, gymnastics tumbling, cervical manipulation.

Routine screening cervical radiographs are no longer recommended — asymptomatic atlanto-dens interval widening does not reliably predict cord injury. This is a major change from older guidance.

Investigate if symptomatic (neck pain, torticollis, gait change, pyramidal signs, bladder/bowel dysfunction): cervical spine immobilisation, lateral flexion/extension X-rays (atlanto-dens interval over 5 mm is abnormal), and MRI; refer for surgical C1-C2 fusion if there is cord compression or significant instability with neurological signs. [1]

Q5: What is the prognosis and long-term outlook? (2 min)

References

[1]Bull MJ. Down Syndrome. N Engl J Med, 2020.PMID 32521135
[2]Weijerman ME, de Winter JP. Clinical practice. The care of children with Down syndrome. Eur J Pediatr, 2010.PMID 20632187
[3]Bull MJ, Committee on Genetics. Health supervision for children with Down syndrome. Pediatrics, 2011.PMID 21788214
[4]Bittles AH, Bower C, Hussain R, Glasson EJ. The four ages of Down syndrome. Eur J Public Health, 2007.PMID 16857692
[5]Hitzler JK, Zipursky A. Origins of leukaemia in children with Down syndrome. Nat Rev Cancer, 2005.PMID 15630411
[6]Kucik JE, Shin M, Siffel C, Marengo L, Correa A. Trends in survival among children with Down syndrome in 10 regions of the United States. Pediatrics, 2013.PMID 23248222
[7]Bergström S, Carr H, Petersson G, Stephansson O, Bonamy AK, Ludvigsson JF, Dahlström A, Palmér M, Johansson S. Trends in congenital heart defects in infants with Down syndrome. Pediatrics, 2016.PMID 27252035
[8]Maris M, Verhulst S, Wojciechowski M, Van de Heyning P. Sleep problems and obstructive sleep apnea in children with down syndrome, an overwiew. Int J Pediatr Otorhinolaryngol, 2016.PMID 26857307
[9]Shin M, Besser LM, Kucik JE, Lu C, Siffel C, Correa A, Congenital Anomaly Multistate Prevalence and Survival (CAMPS) Collaborative. Prevalence of Down syndrome among children and adolescents in 10 regions of the United States. Pediatrics, 2009.PMID 19948627
[10]Van Cleve SN, Cannon S, Cohen WI. Part II: Clinical Practice Guidelines for adolescents and young adults with Down Syndrome: 12 to 21 Years. J Pediatr Health Care, 2006.PMID 16675381