A 3-year-old boy presents with accelerated linear growth, height and head circumference >97th percentile, and a characteristic facial appearance with dolichocephalic macrocephaly, frontal bossing, and downslanting palpebral fissures. Developmental assessment reveals mild intellectual disability and motor delay. Skeletal survey shows advanced bone age. The genetic defect marked **A** in the diagram (5q35 NSD1 deletion) is confirmed by sequencing. Which of the following best explains the pathophysiological mechanism of overgrowth in this condition?
A. Loss of LIS1 function on chromosome 17p13.3, impairing neuronal migration and secondary growth dysregulation
B. Biallelic inactivation of IGF2 imprinting on chromosome 11p15.5, leading to increased growth factor signaling
C. Paternal uniparental disomy of chromosome 15q11-q13, resulting in loss of paternally expressed growth-suppressing genes
D. Haploinsufficiency of NSD1, a histone H3 lysine 36 methyltransferase, causing dysregulated transcription during development
Explanation
Why "Haploinsufficiency of NSD1, a histone H3 lysine 36 methyltransferase, causing dysregulated transcription during development" is right
NSD1 encodes a histone H3 lysine 36 methyltransferase that regulates transcription during development. Loss of one functional copy (haploinsufficiency) due to point mutations (60–80% in Western populations) or microdeletions of 5q35 causes dysregulated gene expression, leading to the characteristic overgrowth phenotype of Sotos syndrome (cerebral gigantism). This is the established molecular mechanism underlying the accelerated linear growth, advanced skeletal maturation, and macrocephaly seen in this patient. (Nelson Textbook of Pediatrics 22e; GeneReviews — Sotos Syndrome)
Why each distractor is wrong
Biallelic inactivation of IGF2 imprinting on chromosome 11p15.5, leading to increased growth factor signaling: This describes Beckwith-Wiedemann syndrome (marked B in the diagram), which presents with hemihypertrophy, omphalocele, and macroglossia—features absent in this patient. The chromosomal locus is different (11p15 vs. 5q35).
Paternal uniparental disomy of chromosome 15q11-q13, resulting in loss of paternally expressed growth-suppressing genes: This mechanism is characteristic of Prader-Willi syndrome (marked C in the diagram), which presents with hypotonia, hypogonadism, and obesity—not the overgrowth and advanced bone age seen in Sotos syndrome.
Loss of LIS1 function on chromosome 17p13.3, impairing neuronal migration and secondary growth dysregulation: This describes Miller-Dieker syndrome (marked D in the diagram), a severe lissencephaly syndrome characterized by profound developmental delay and seizures, not the mild intellectual disability and accelerated growth of Sotos syndrome.
High-YieldNEET PG
Sotos syndrome = NSD1 haploinsufficiency → histone methyltransferase defect → dysregulated transcription → overgrowth + macrocephaly + advanced bone age + mild ID. Differentiate from Beckwith-Wiedemann (hemihypertrophy, omphalocele), Prader-Willi (hypotonia, obesity), and Miller-Dieker (lissencephaly).
Nelson Textbook of Pediatrics 22e; GeneReviews — Sotos Syndrome
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