No Established Genetic Link Between Hypertrophic Pyloric Stenosis and Lissencephaly
There is no recognized genetic link between hypertrophic pyloric stenosis (HPS) and lissencephaly in children—these are distinct conditions with separate genetic etiologies and pathophysiological mechanisms.
Distinct Genetic Architecture
Lissencephaly Genetics
Lissencephaly is considered an exclusively genetic disorder affecting neuronal migration, with 28 known causative genes and highly specific genotype-phenotype correlations 1:
- Primary genes: LIS1 (chromosome 17p13.3), DCX, TUBA1A, TUBG1, and ARX account for the majority of cases with diagnostic yields exceeding 90% for specific imaging patterns 1
- Inheritance patterns: Primarily autosomal dominant or X-linked, with some autosomal recessive forms 1
- Pathophysiology: Defects in neuronal migration causing cortical malformation with thickened cortex (>10 mm) and absent or reduced gyration 1
Hypertrophic Pyloric Stenosis Genetics
HPS is inherited as a complex sex-modified multifactorial trait with male preponderance 2:
- Linkage loci: Chromosomes 11q14-q22 and Xq23 identified through genome-wide SNP analysis 2
- Candidate genes: TRPC family ion channels involved in smooth muscle control and hypertrophy 2
- Familial aggregation: Family history present in 47.9% of siblings, but with considerable genetic heterogeneity 3, 4
- Pathophysiology: Acquired hypertrophy of pyloric smooth muscle causing gastric outlet obstruction 5, 4
Why These Conditions Are Unrelated
Different Tissue Systems
- Lissencephaly: Affects neuronal migration and cortical development in the central nervous system 1
- HPS: Affects smooth muscle hypertrophy in the gastrointestinal tract 2, 5
Different Molecular Pathways
- Lissencephaly pathways: Microtubule dynamics (tubulin genes), neuronal migration machinery, and cortical development regulators 1
- HPS pathways: Smooth muscle ion channels, intracellular signaling, and metabolic regulation 2, 4
No Syndromic Overlap
While HPS is associated with numerous clinical syndromes including neuromuscular disorders, connective tissue disorders, and metabolic conditions, lissencephaly is not among the recognized associations 4. Similarly, comprehensive guidelines on malformations of cortical development do not list HPS as an associated feature of any lissencephaly syndrome 1.
Clinical Implications
If Both Conditions Present in the Same Patient
This would represent a coincidental occurrence of two separate genetic conditions rather than a shared genetic etiology:
- Pursue independent genetic workup for each condition 1, 2
- For lissencephaly: Chromosomal microarray analysis followed by targeted gene panel or whole exome sequencing focusing on the 28 known lissencephaly genes 1
- For HPS: Consider genetic testing if familial aggregation is present, though surgical correction (pyloromyotomy) remains the standard treatment regardless of genetic findings 3, 5
Avoid This Pitfall
Do not assume a unifying genetic diagnosis when these conditions co-occur—each requires separate diagnostic evaluation and management 1, 4.