Down Syndrome — SAQ

Stem

A 2-day-old term infant is reviewed on the postnatal ward. The midwife notes that the baby feels "floppy" and has an unusual face. On examination: weight 2.9 kg (9th centile), head circumference on 2nd centile. There is generalised hypotonia with poor head control. Facial features include upslanting palpebral fissures, epicanthal folds, a flat nasal bridge, a protruding tongue, small low-set ears with overfolded helices, and excess nuchal skin. There is a single transverse palmar crease on the right and clinodactyly of both 5th fingers. A grade 2/6 systolic murmur is heard at the lower left sternal edge; pre- and post-ductal saturations are equal at 96%. Abdomen is soft; meconium has not yet been passed. The mother is 39 years old; antenatal scans were normal but she declined prenatal screening. [1]

Questions

a) What is the most likely diagnosis, and what is the definitive investigation to confirm it? (2 marks) [1]

Down syndrome (trisomy 21), based on the characteristic phenotype (upslanting palpebral fissures, epicanthal folds, flat facial profile, protruding tongue, hypotonia, single palmar crease, clinodactyly) in a baby born to a 39-year-old mother. The definitive investigation is a chromosomal karyotype (not microarray alone), which confirms trisomy 21 and — critically — distinguishes non-disjunction from Robertsonian translocation (which changes genetic counselling). [1]

b) Outline the three cytogenetic types and their genetic-counselling implications. (3 marks) [1]

1. Non-disjunction (95%): 47,XX/XY,+21; sporadic meiotic error (usually maternal meiosis I); risk rises with maternal age; recurrence about 1%.
2. Robertsonian translocation (3 to 4%): extra 21q material fused to another acrocentric chromosome (usually t(14;21)); 25% inherited from a balanced-carrier parent; both parents must be karyotyped — recurrence risk is about 10 to 15% if the mother carries t(14;21), under 1% if the father carries it, and up to 100% for a t(21;21) carrier.
3. Mosaicism (1 to 2%): two cell lines from post-zygotic non-disjunction; phenotype often milder; recurrence risk low. [1]

c) Describe the anticipatory investigations and their timing for this neonate. (3 marks) [1]

• Echocardiogram before discharge / by 2 weeks — the murmur mandates urgent cardiac imaging; AVSD is the most characteristic lesion in Down syndrome and 40 to 60% have congenital heart disease.
• Thyroid function (TSH, free T4) — at birth, 6 and 12 months, then annually (15% have hypothyroidism).
• Full blood count at birth — to detect transient abnormal myelopoiesis and to baseline for future leukaemia surveillance.
• Newborn hearing screen and ophthalmology review by 6 months (red reflex now to exclude cataract).
• Failure to pass meconium warrants review for Hirschsprung disease (contrast enema, rectal biopsy).
• Plot growth on Down syndrome-specific charts. [1]

d) List the four highest-yield complications to counsel the parents about. (2 marks) [1]

1. Cardiac — AVSD / congenital heart disease; early surgical repair to prevent pulmonary hypertension.
2. Gastrointestinal — duodenal atresia (double bubble), Hirschsprung disease, coeliac disease.
3. Haematology-oncology — transient abnormal myelopoiesis; leukaemia (ALL and AMKL, 10 to 20x risk).
4. Neurology/development — intellectual disability, atlantoaxial instability (avoid contact sports), and early-onset Alzheimer disease in adulthood. Also hypothyroidism (~15%). [1]

References

1. [1]Bull MJ. Down Syndrome. N Engl J Med, 2020.PMID 32521135
2. [2]Weijerman ME, de Winter JP. Clinical practice. The care of children with Down syndrome. Eur J Pediatr, 2010.PMID 20632187
3. [3]Bull MJ, Committee on Genetics. Health supervision for children with Down syndrome. Pediatrics, 2011.PMID 21788214
4. [4]Bittles AH, Bower C, Hussain R, Glasson EJ. The four ages of Down syndrome. Eur J Public Health, 2007.PMID 16857692
5. [5]Hitzler JK, Zipursky A. Origins of leukaemia in children with Down syndrome. Nat Rev Cancer, 2005.PMID 15630411
6. [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. [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. [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. [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. [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