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Hypertrophic Pyloric Stenosis –
Familial and Genetic Correlates
Cordelie Witt
• 4 week old male monozygotic twins born
at 35-4/7 weeks via planned C-section
• Both twins simultaneously evaluated at
OSH; workup diagnosed hypertrophic
pyloric stenosis
• Transferred to Seattle Children’s Hospital
for management
• Twin A: 2.87 kg. 2 days nonbloody,
nonbilious projectile emesis with every feed
– No other medical problems, good weight gain
since birth. No known family history of pyloric
– Bottle fed; using soy-based formula
– Palpable epigastric mass
– Na 143, K 4.6, Cl 104, CO2 26, glucose 63
– US: 3.77 mm wall thickness, channel length 15
• Twin B: 2.51 kg. 4 days nonbloody,
nonbilious projectile emesis with almost all
– h/o periodic desaturations and apnea in the first
2 weeks of life, poor weight gain since birth
– Na 143, K 3.9, Cl 102, CO2 28, glucose 41
(corrected to 96 preop)
– Palpable epigastric mass
– US: 4.51 mm wall thickness, channel length 14.9
• Twins were taken to the operating room
sequentially; each underwent:
– Suctioning
– Rapid sequence intubation
– Ramstedt pyloromyotomy
• Twin A: 23 mm pyloromyotomy
• Twin B: 21 mm pyloromyotomy
• Both did well postoperatively and were
discharged home on POD1
Risk factors for pyloric stenosis
Male > female; 4-5x
Family history of pyloric stenosis
First-born child
Younger maternal age
Genetic syndromes
Bottle feeding
Macrolide antibiotic exposure (erythromycin)
?Prostaglandin exposure
?Acid exposure
Risk factors for pyloric stenosis
Male > female; 4-5x
Family history of pyloric stenosis
First-born child
Younger maternal age
Genetic syndromes
Bottle feeding
Macrolide antibiotic exposure (erythromycin)
?Prostaglandin exposure
?Acid exposure
Familial pyloric stenosis
• Familial aggregation described since 1934 (Cockayne)
• Multitude of case studies of both monozygotic and
dizygotic twins with pyloric stenosis
– Gezer et al (Clinical Genetics 2014) – monozygotic male
twins , presented at age 4.5 and 5 weeks
– Kundal et al (BMJ 2013) – dizygotic male twins, presented
at day of life 45
– Yang et al (Pediatric Child Health 2008) – 3 sets of
dizygotic twins, one set of monozygotic twins. Monozygotic
twins were female; one dizygotic twin was female.
Presented between 3.5 and 8 weeks of life
– Sheldon (1938) – 23 pairs of twins amongst 1000 cases of
pyloric stenosis
– Many more!
Familial Aggregation and
Heritability of Pyloric Stenosis
Krough et al, JAMA 2010
• Cohort study of all children born in Denmark
between 1977 and 2008
– Civil Registration System, Danish Family Relations
Database, and Danish National Patient Registry (all
hospital discharge diagnoses and operations)
– Followed for first year of life
– Cohort size: 1,999,738 (1,948,616 person-years)
– 3362 children had surgery for pyloric stenosis
• Overall rate 1.7 /thousand person-years
• Rate in singletons: 1.8 /thousand person-years
• Rate in twins: 3.1 /thousand person-years
– 81.5% of patients with pyloric stenosis were male
Familial Aggregation and
Heritability of Pyloric Stenosis
• Rate ratios
Krough et al, JAMA 2010
– Monozygotic twins: 182
• 46% of children with an affected monozygotic twin
developed pyloric stenosis!
Dizygotic twins: 29.4
Siblings: 18.5
Half-siblings: 4.99
Cousins: 3.06
Half-cousins: 1.60
• Rate ratios were NOT affected by sex
• Heritability: 87%
PS - heritability theories
• Carter ( 1961 and
1969) and Falconer
(1965): polygenic
inheritance with a
threshold effect
– Sex-modified risk
PS - heritability theories
• Single Major Locus model – Kidd and
Spence, 1976
– Single heritable gene, modified by
environmental factors
Identifying genetic loci
• Common Variants near MBNL1 and NKX2-5 are Associated
with Infantile Hypertrophic Pyloric Stenosis (Feenstra et al,
Nature Genetics, June 2013)
– Genome-Wide Association Study
– 1001 surgery-confirmed cases, 2401 controls from Denmark
• All cases were surgery-confirmed, singletons, and without major
congenital malformations
– Identified 3 SNPs that reached significance
• rs11712066, near MBNL1 (chromosome 2)
• rs573872, near MBNL1
• rs29784, near NKX2-5 (chromosome 5)
– The 3 SNPs showed no heterogeneity of effects between sexes
• Study findings supported by replication analysis on an
additional 796 cases and 876 controls by Everett and Chung
Genetic loci
• MBNL1: encodes “musclebind” proteins; these proteins
regulate alternative splicing in early postnatal period;
involved in muscle tissue remodeling
• NKX2-5: encodes homeobox transcription factor involved in
cardiac formation and development and embryonic gut
development including pyloric sphincter muscle tissue
– Chicken and mice: Nkx2-5 expression occurs in a ring of
mesenchyme at the foregut-midgut junction during development
– Suppression of Nkx2-5 activity in pyloric sphincter results in loss
of the sphincter endodermal phenotype
– Ectopic expression of Nkx2-5  pyloric sphincter-like structure
in chicken gizzard
More genetic loci
• Genome-wide linkage analysis in families
with infantile hypertrophic pyloric stenosis
indicates novel susceptibility loci
(Svenningsson et al, Journal of Human
Genetics, December 2011)
– Genome-wide linkage analysis in 37 Swedish
families with 2-5 affected individuals each; total
94 affected and 184 total
• Added 31 British families where linkage favored
– Genotyping and linkage analysis
• 2q24, 7p22 were significant; 6p21 and 12q24 were
Candidate genes identified
• GLP-2 (2q24) – GI hormone, stimulates
epithelial cell proliferation, inhibits
apoptosis, regulates motility
• NPY (7p22) – inhibitory effect on smooth
muscle cells
• NOS1 (12q24) – smooth muscle relaxation
• MLN (12q24) – encodes motilin, which
induces GI contraction. (*erythromycin is
a motilin agonist)
Nitric Oxide
• Chung et al (American Journal of Human
Genetics, Feb 1996) studied 27 families (21 had at
least 3 affected individuals). There were 229
individuals total; 87 had pyloric stenosis.
– Analyzed 2 NOS1 polymorphisms; found significant
transmission disequilibrium between one allele
(NOS1a) and PS
• Serra et al (Journal of Pediatric Surgery, May
2011) investigated NOS1 sequence variations in a
case control study of 43 patients and 47 controls;
19 polymorphisms were found but none were
significantly associated
Nitric oxide
• NOS1 gene (12q24) encodes neuronal
nitric oxide synthase; NO contributes to
smooth muscle relaxation
– NOS1 gene expression reduced in pyloric
stenosis muscle tissue
– NOS1 knockout mouse model: pyloric
stenosis-like phenotype with distended
stomach, thickened pylorus
Other identified sites
• Other studies have identified additional
candidate sites, including: 16p12-p13,
11q14-q22, Xq23, 16q24…
• There are also a multitude of studies
investigating environmental factors
associated with hypertrophic pyloric
• Pyloric stenosis is highly, but not
completely, heritable
• A multitude of studies suggests a strong
genetic basis for hypertrophic pyloric
stenosis; however, inheritance appears
polygenic and may be heterogeneous
across different populations. It also
appears to be influenced or triggered by
multiple environmental factors
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Thank you!