A 18-month-old boy presents with severe growth retardation (height −3.2 SD), relative macrocephaly (head circumference −0.5 SD), prominent forehead, and triangular facies with micrognathia. Birth weight was −2.8 SD for gestational age. Genetic testing reveals the abnormality marked **A** in the diagram. Which of the following best explains the pathophysiology of growth failure in this patient?
A. Hypomethylation of paternal IC1 at 11p15.5 with decreased IGF2 expression
B. Loss of imprinted MEST/GRB10 gene expression due to maternal uniparental disomy of chromosome 7
C. Paternal disomy of chromosome 11 with loss of maternally expressed growth-suppressing genes
D. Biallelic expression of normally imprinted genes on chromosome 15 causing excessive growth factor signaling
Explanation
Why "Loss of imprinted MEST/GRB10 gene expression due to maternal uniparental disomy of chromosome 7" is right
The structure marked A is maternal UPD chromosome 7 (mUPD7), which accounts for 5–10% of Russell-Silver syndrome cases. In mUPD7, both chromosome 7 copies are inherited from the mother, resulting in loss of paternal gene expression and abnormal silencing of imprinted genes MEST and GRB10 on chromosome 7. These paternally expressed genes are critical for normal fetal and postnatal growth; their loss leads to the characteristic severe pre- and postnatal growth retardation with relative macrocephaly seen in this patient. The clinical presentation—birth weight ≤−2 SD, postnatal height ≤−2 SD, relative macrocephaly, prominent forehead, and triangular facies—matches the Netchine-Harbison Clinical Scoring System criteria for RSS and is consistent with mUPD7 etiology (Nelson Textbook of Pediatrics 22e; 2017 RSS International Consensus).
Why each distractor is wrong
Hypomethylation of paternal IC1 at 11p15.5 with decreased IGF2 expression: This is the molecular mechanism of the most common form of RSS (~30–60%), not mUPD7. While both cause growth retardation, this distractor represents a different chromosomal locus (11p15.5 vs. chromosome 7) and a different imprinting defect (IC1 hypomethylation vs. uniparental disomy).
Biallelic expression of normally imprinted genes on chromosome 15 causing excessive growth factor signaling: This describes Beckwith-Wiedemann syndrome (BWS), which is caused by paternal UPD15 or IC2 hypermethylation at 11p15.5. BWS presents with overgrowth and macrosomia—the opposite phenotype of RSS—and is not associated with chromosome 7 abnormalities.
Paternal disomy of chromosome 11 with loss of maternally expressed growth-suppressing genes: This describes paternal UPD11 (marked D in the diagram), which is not associated with Russell-Silver syndrome. Paternal UPD11 is rare and not a recognized cause of RSS.
High-YieldNEET PG
Maternal UPD7 (mUPD7) causes RSS via loss of paternally expressed imprinted genes MEST and GRB10; accounts for 5–10% of RSS cases; presents with severe growth retardation and relative macrocephaly.
Nelson Textbook of Pediatrics 22e; 2017 RSS International Consensus
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