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PA11.1-3 | Genetic & Pediatric Diseases — SDL Guide (Part 2)

Structural Cytogenetic Abnormalities & Karyotype/FISH

A multi-panel cytogenetics diagram shows translocation, deletion, inversion, duplication, Robertsonian translocation, 5p deletion in cri-du-chat syndrome, and karyotype/FISH diagnostic methods. — **Panel A:** Translocation, deletion, inversion, duplication, normal chromosome segment, moved segment, lost segment, reversed segment, duplicated segment. **Panel B:** Balanced reciprocal translocation, chromosome A, chromosome B, exchanged segments, no net gain or loss, clinically silent carrier. **Panel C:** Chromosome 14, chromosome 21, acrocentric chromosomes, centromeric fusion, derivative chromosome t(14;21), extra chromosome 21 material, Down syndrome risk. **Panel D:** Chromosome 5, short arm deletion, 5p-, cri-du-chat syndrome, high-pitched cat-like cry, microcephaly, intellectual disability, hypertelorism. **Panel E:** Karyotype, paired chromosomes, metaphase chromosome, FISH probe, fluorescent signal, normal two-signal pattern, abnormal missing or fusion signal pattern.

Structural rearrangements arise from chromosome breakage and abnormal repair:

Translocation: segment moves from one chromosome to another. Balanced translocations carry no net gain/loss — often clinically silent in the carrier but risk unbalanced offspring. Robertsonian translocation: two acrocentric chromosomes (13, 14, 15, 21, 22) fuse at centromere; a carrier of t(14;21) risks Down syndrome children.
Deletion: loss of a chromosomal segment. Cri-du-chat syndrome: deletion of short arm of chromosome 5 (5p-); high-pitched cat-like cry (laryngeal hypoplasia), microcephaly, intellectual disability, hypertelorism.
Inversion: segment reverses orientation. Pericentric (includes centromere) vs. paracentric.
Duplication: extra copy of a segment; often better tolerated than deletion.

Diagnostic tools:

Tool	Resolution	Best for
Karyotype (G-banding, 400–550 bands)	~5–10 Mb	Numerical abnormalities, large deletions, translocations
FISH (Fluorescence In Situ Hybridisation)	~100 kb	Targeted microdeletion (DiGeorge 22q11), confirmation of translocation
Array CGH / SNP array	5–50 kb	Genome-wide copy number variants (CNVs)
PCR/sequencing	Single nucleotide	Specific point mutations (BRCA, TP53)

Exam tip: FISH is ordered when you suspect a microdeletion too small for karyotype but too large for routine sequencing.

Paediatric Tumours — Hamartoma, Choristoma & Overview

A multi-panel educational diagram shows structural chromosomal abnormalities including translocation, deletion, inversion, duplication, Robertsonian fusion, and their diagnosis by karyotype and FISH. — **Panel A:** Overview of chromosome breakage and abnormal repair leading to translocation, deletion, inversion, and duplication.. **Panel B:** Balanced translocation and Robertsonian translocation with acrocentric chromosomes 14 and 21 fusing at the centromere, indicating risk of Down syndrome offspring.. **Panel C:** Deletion of the short arm of chromosome 5 causing Cri-du-chat syndrome, with key clinical features shown as small icons.. **Panel D:** Pericentric inversion, paracentric inversion, and duplication shown with orientation arrows, centromere position, and duplicated chromosomal segment.. **Panel E:** Karyotype with G-banding and FISH with fluorescent probes demonstrating detection of deletion and translocation..

Before examining specific tumours, two important developmental lesions:

Hamartoma: disorganised but normal tissue elements native to that site (e.g., pulmonary hamartoma with cartilage + epithelium + fat). Not a true neoplasm. Grows slowly, proportionate to body growth, does not metastasise.

Choristoma: normal tissue in an abnormal location (e.g., gastric mucosa in a Meckel's diverticulum causing peptic ulceration). Also called heterotopia.

The dominant paediatric malignancies are the small round blue cell tumours (SRBCT) — a group named for their shared histological appearance: sheets of small cells with scant cytoplasm and round hyperchromatic nuclei. The challenge — and the exam test — is distinguishing them using ancillary features.

Tumour	Age	Site	Key marker
Neuroblastoma	<5 yr	Adrenal/sympathetic chain	N-myc amplification, catecholamines
Wilms (nephroblastoma)	2–5 yr	Kidney	WT1 gene, triphasic histology
Retinoblastoma	<5 yr	Retina	RB1 gene, two-hit hypothesis
Ewing sarcoma	5–20 yr	Bone (diaphysis)	t(11;22), EWSR1-FLI1 fusion
Rhabdomyosarcoma	<10 yr (embryonal); teen (alveolar)	Soft tissue, head/neck, genitourinary	Desmin, MyoD1; t(2;13) alveolar

Neuroblastoma & Wilms Tumour

Neuroblastoma

Arises from neural crest-derived sympathetic neuroblasts; most common extracranial solid tumour of childhood. 70% arise in the adrenal medulla; rest from paraspinal sympathetic ganglia.

Clinical: abdominal mass crossing midline, hypertension (catecholamine excess → raised VMA/HVA in urine), opsoclonus-myoclonus syndrome (paraneoplastic), periorbital ecchymoses ("raccoon eyes" from retro-orbital metastases).

Morphology: small round blue cells with neuritic processes; Homer-Wright rosettes (tumour cells arranged around a central fibrillary core — not a true lumen).

Molecular: N-myc (MYCN) amplification → poor prognosis; >10 copies = high-risk. Deletion 1p, gain 17q also adverse.

Prognosis paradox: infants (<18 months) have excellent prognosis even with metastases (Stage 4S — spontaneous regression). Older children with N-myc amplification fare poorly.

A multi-panel cytogenetics diagram compares structural chromosome abnormalities and shows karyotype and FISH detection, with examples relevant to cri-du-chat syndrome, Wilms tumour, and neuroblastoma. — **Panel A:** Normal chromosome segment, translocation, deletion, inversion, duplication, moved segment, lost segment, reversed segment, duplicated segment. **Panel B:** Chromosome A, chromosome B, exchanged segments, balanced reciprocal translocation, no net gain or loss, clinically silent carrier. **Panel C:** Acrocentric chromosomes, centromere fusion, short arms lost, Robertsonian translocation, balanced carrier with 45 chromosomes. **Panel D:** 5p deletion in cri-du-chat syndrome, 11p13 WT1 deletion associated with Wilms tumour risk, MYCN amplification in neuroblastoma. **Panel E:** Metaphase karyotype for large structural changes, interphase FISH nuclei, fluorescent probes, normal control signal, abnormal deletion or amplification signal.

Wilms Tumour (Nephroblastoma)

Arises from metanephric blastema (primitive renal precursor cells). Linked to mutations in WT1 (Wilms tumour suppressor gene, 11p13) and WT2 (11p15).

Associations: WAGR syndrome (Wilms + Aniridia + Genitourinary anomaly + intellectual disability — all from 11p13 deletion); Beckwith-Wiedemann syndrome (gigantism, macroglossia, omphalocele — WT2 region).

Clinical: unilateral abdominal mass (does NOT cross midline — contrast with neuroblastoma), haematuria, hypertension.

Morphology — triphasic histology (pathognomonic): blastemal cells (small round blue cells) + stromal cells (spindle) + epithelial cells (tubules/glomeruli). All three components reflect the attempted — but disorganised — recapitulation of normal nephrogenesis.

Prognosis: excellent overall (90% cure with nephrectomy + chemo ± radiation); anaplastic variant = adverse.

SELF-CHECK

A 3-year-old has a large abdominal mass that does NOT cross the midline. Biopsy shows blastemal cells, stromal cells, and epithelial tubules. Which molecular alteration is most characteristically associated with this tumour?

A. N-myc amplification

B. WT1 gene mutation

C. RB1 gene loss (two-hit)

D. EWSR1-FLI1 fusion t(11;22)

Reveal Answer

Answer: B. WT1 gene mutation

This is Wilms tumour (nephroblastoma). The triphasic histology (blastemal + stromal + epithelial) is pathognomonic. WT1 (11p13) mutation is the characteristic association. N-myc is neuroblastoma; RB1 is retinoblastoma; EWSR1-FLI1 is Ewing sarcoma.