PA11.1-3 | Genetic & Pediatric Diseases — Summary & Reflection

REFLECT

Take 3 minutes before moving on:

1. Without looking, trace the complete mechanism from glucocerebrosidase deficiency → Gaucher cell formation → hepatosplenomegaly → pancytopenia. Can you draw this chain?

1. A colleague asks: "Why does Tay-Sachs cause blindness in some patients?" What would you say — and what fundus finding would you demonstrate?

1. You are shown a histology slide with small round blue cells, Homer-Wright rosettes, and the clinical history of an abdominal mass crossing the midline in a 2-year-old. What is your diagnosis, and which urine test would you order next?

These three threads — storage disorder mechanism, ophthalmic sign, and SRBCT differentiation — represent the highest-frequency exam scenarios for this module.

KEY TAKEAWAYS

Genetic mutations disrupt protein function via missense, nonsense, frameshift, or trinucleotide repeat expansion; inheritance follows AD, AR, X-linked recessive, or mitochondrial patterns.

Numerical cytogenetic abnormalities arise from non-disjunction: Down syndrome (47+21, maternal meiosis I, 95% free trisomy) → flat facies, VSD, AML, early Alzheimer; Turner syndrome (45,X) → streak gonads, webbed neck, coarctation; Klinefelter (47,XXY) → azoospermia, gynaecomastia, hyalinised tubules. Structural abnormalities include Robertsonian translocations (Down, familial) and 5p- deletion (cri-du-chat). Diagnosed by karyotype (large rearrangements) or FISH (microdeletions).

Paediatric SRBCTs are distinguished by: site + molecular marker — neuroblastoma (adrenal, N-myc, catecholamines, Homer-Wright rosettes), Wilms tumour (kidney, WT1, triphasic histology), retinoblastoma (retina, RB1 two-hit, Flexner-Wintersteiner rosettes, leukocoria), Ewing sarcoma (diaphysis, t(11;22), EWSR1-FLI1), rhabdomyosarcoma (soft tissue, desmin/MyoD1, t(2;13) alveolar).

Lysosomal storage disorders follow a single template — enzyme defect → substrate accumulates in RES macrophages/neurons. Key quartet: Gaucher (glucocerebrosidase, wrinkled Gaucher cells), Niemann-Pick (sphingomyelinase, foam cells), Tay-Sachs (hexosaminidase A, cherry-red spot, neurons), Hurler (α-L-iduronidase, gargoylism, AR) vs. Hunter (iduronate sulfatase, X-linked). Pompe (acid maltase) bridges GSDs and LSDs — glycogen in myocardial lysosomes causes fatal cardiomegaly.