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 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, et al. 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, et al. 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