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PE29.1-5 | Chromosomal Abnormalities — PBL Case

CLINICAL SETTING

District Government Medical College, Genetics and Paediatrics outpatient clinic. It is a busy Monday morning. Mr. and Mrs. Sharma, both in their early thirties, arrive with their 4-month-old daughter Priya. The infant was referred from the primary health centre after the ANM noted 'unusual features' at the 4-month immunisation visit. Mrs. Sharma, a schoolteacher, is visibly anxious. She carries the infant's discharge summary from the newborn period, which records 'poor feeding, hypotonia — reassured'. The couple's first child, a 4-year-old son, is normal. Mrs. Sharma's maternal aunt has an adult son with intellectual disability who 'never went to school'. Three generations of the family have lived in the same village.

Trigger 1: The Newborn Who Was 'Just Sleepy'

On examination, Priya (4 months, weight 4.1 kg [<3rd centile], length 56 cm [<3rd centile]) has: - Upslanting palpebral fissures, epicanthal folds, flat nasal bridge - Small, low-set ears - Protruding tongue, small mouth - Single transverse palmar crease (bilateral) - Hypotonia (frog-leg posture, head lag on pull-to-sit) - Gap between first and second toes - Harsh pansystolic murmur grade 3/6 at lower left sternal border with a mid-diastolic flow rumble The mother recalls that pregnancy was uneventful. She is 31 years old. No antenatal karyotyping was done. Triple screen was offered but declined. The newborn had poor feeding requiring nasogastric tube for 3 weeks. A paediatric consultation noted 'hypotonia, possible sepsis' and the infant was discharged after improvement with no further investigation.

DISCUSSION POINTS

  • What is the most likely clinical diagnosis? What specific features in the examination support this diagnosis?
  • The mother says the newborn doctor told them the baby was 'just sleepy' and would grow out of it. What went wrong in the initial management and how would you handle the family's current understanding?
  • What is the significance of the murmur findings described? Which cardiac defect should be highest on your differential, and why is it associated with this diagnosis?
Click to reveal Trigger 2: The Karyotype Result and a Family Secret (discuss previous trigger first!)

Trigger 2: The Karyotype Result and a Family Secret

You arrange an urgent echocardiogram: it shows a complete atrioventricular septal defect (AVSD) with left-to-right shunting. Pulmonary arterial pressure is moderately elevated. Karyotype result: 46,XX,rob(14;21)(q10;q10),+21 While explaining this result, Mrs. Sharma's mother (the maternal grandmother) who has accompanied them, quietly tells you: 'My sister's son — the one who never went to school — he also had this kind of face when he was a baby. They said it was nothing.' You arrange karyotyping for both parents. Results: - Father: 46,XY (normal) - Mother: 45,XX,rob(14;21)(q10;q10) — balanced Robertsonian translocation carrier TSH at 4 months: 22 mIU/L (normal <5); free T4: low.

DISCUSSION POINTS

  • What is the exact mechanism causing Down syndrome in Priya? How does this differ from the most common mechanism? Write the correct ISCN notation for Priya and for her mother.
  • The grandmother mentions the affected cousin. How does this family history change the clinical picture? What is the probability that Priya's mother inherited the translocation from the grandmother's sister?
  • The karyotype shows a Robertsonian translocation. Calculate the recurrence risk for the next pregnancy and compare it to what the risk would have been if Priya had free trisomy 21. What counselling points would you prioritise?
  • What is the significance of the TSH result at 4 months? What action is required immediately and what is the long-term surveillance plan for thyroid disease in Down syndrome?
Click to reveal Trigger 3: Counselling Session — Managing the Information Cascade (discuss previous trigger first!)

Trigger 3: Counselling Session — Managing the Information Cascade

You conduct a formal genetic counselling session with the couple. Mrs. Sharma is tearful and asks: 'Did I cause this? I teach children all day — did I do something wrong?' Mr. Sharma is silent but asks: 'Can this happen again? We want one more child.' You explain: - The recurrence risk - The need to test their 4-year-old son for carrier status - The availability of prenatal diagnosis (CVS/amniocentesis) in future pregnancies - Priya's immediate medical needs: AVSD surgery is planned for age 4–6 months, levothyroxine started today The maternal aunt (grandmother's sister) is subsequently karyotyped at your advice and found to be 45,XX,rob(14;21)(q10;q10) — she is also a carrier. Her affected son (the cousin) has translocation Down syndrome.

DISCUSSION POINTS

  • How would you address Mrs. Sharma's guilt ('Did I cause this?') using accurate, empathetic, non-directive language? Draft the key sentences you would say.
  • The son (4-year-old sibling) needs karyotyping. How do you explain this to the parents? What are the ethical considerations of testing a healthy child?
  • What prenatal diagnosis options would you offer for the next pregnancy and when? Compare CVS versus amniocentesis in terms of timing, accuracy, and risk.
  • List ALL comorbidity surveillance Priya requires from birth through school age, with the recommended schedule.
Click to reveal Trigger 4: Follow-up at 18 Months — Developmental and Educational Planning (discuss previous trigger first!)

Trigger 4: Follow-up at 18 Months — Developmental and Educational Planning

Priya is now 18 months old. She underwent AVSD repair at 5 months; the cardiac surgeon reports successful correction with good haemodynamic result. TSH has normalised on levothyroxine 25 mcg/day. She is walking with support, has 3 words, and can follow simple two-step commands. On examination: height and weight tracking on Down syndrome-specific growth chart at 25th centile. Cervical spine X-ray in flexion and extension: atlanto-dens interval = 5.5 mm. Audiology: mild bilateral sensorineural hearing loss. Ophthalmology: small refractive error, no cataracts. The parents ask whether Priya can attend a mainstream school and what additional support she will need.

DISCUSSION POINTS

  • The atlanto-dens interval is 5.5 mm. What is the significance? What activity restrictions are advised and when would surgical stabilisation be considered?
  • Priya has mild bilateral sensorineural hearing loss. How does this affect her developmental plan, and what interventions are recommended?
  • The parents ask about intellectual ability and school placement. Based on current evidence for Down syndrome, how would you counsel them about cognitive development and inclusive education? What early intervention services should be in place?
  • Design a 5-year surveillance plan for Priya covering cardiac, thyroid, atlantoaxial, audiology, ophthalmology, dental, haematological (ALL risk), and developmental domains.

Group Task Assignments

Group 1: Collaborative Task

Group 2: Collaborative Task

Group 3: Collaborative Task

Learning Issues

Research these questions and bring your findings to the discussion.

  1. [PE29.1] What are the genetic basis, risk factors, clinical features, complications, prenatal diagnosis options, management principles, and genetic counselling approach for Down syndrome? How does the mechanism (non-disjunction vs Robertsonian translocation vs mosaicism) alter recurrence risk?
  2. [PE29.2] How do you interpret a normal karyotype and recognise trisomy 21 in a karyotype report? What is the correct ISCN notation for free trisomy 21, translocation Down syndrome, and Down syndrome mosaicism?
  3. [PE29.3] How do you counsel parents of a child with Down syndrome regarding recurrence risk in the next pregnancy, differentiating between non-disjunction (~1% + age-specific risk) and Robertsonian translocation (maternal carrier ~10–15%, paternal ~5%)? What prenatal diagnosis options are available and when?
  4. [PE29.4] What is the genetic basis, clinical presentation, cardiovascular risk profile, hormonal management (GH for short stature, estrogen for pubertal induction), fertility implications, and surveillance protocol for Turner syndrome (45,X)? Why is the notation 45,XO incorrect?
  5. [PE29.5] What is the genetic basis, clinical features, endocrine profile (hypergonadotropic hypogonadism), and management of Klinefelter syndrome (47,XXY)? Why must TESE be attempted before testosterone replacement when fertility is desired?