In the general population, epidemiological studies (2
) have shown that the risk ratio of developing IHPS is higher for twins than nontwins. By examining hereditary patterns of the disease, it is known that siblings of affected individuals are at a higher risk of developing IHPS than second- or third-degree relatives (7
). There is also a preference of the disease to occur concordantly in monozygotic twins compared with dizygotic twins (2
). These data suggest that infants with a high probability of developing IHPS would be co-twins of affected twins, as is presented in the current report.
It remains disputed whether IHPS is truly a congenital disorder, although, it is not typically present until at least three weeks after birth (1
) and rarely found past 12 weeks of age (8
). Rollins et al (8
) demonstrated through pylorus measurements that in infants who eventually develop IHPS, pyloric muscle hypertrophy is not visible immediately after birth. Thus, it is a disease of infancy, but its apparent lag in progression suggests that it is an acquired condition. Even if not a congenital disorder, epidemiological trends implicate a genetic etiology to the development of IHPS. The predominance in males, concordance in twins and familial clustering all suggest its hereditary nature (1
). However, IHPS does not follow classic Mendelian modes of inheritance, which have led researchers to posit other inheritance models. Two of these are the MFT model and the SML model. The MFT model proposes that IHPS has a polygenic inheritance involving several different genes; it discounts the genetic etiology from being autosomal recessive or sex-linked recessive (3
). Because IHPS is four to five times more prevalent in males than females (1
), the MFT model accounts for this by proposing that the inheritance is sex modified (9
). In this manner, females are ‘protected’ by their sex from developing the disease. Alternatively, the SML model proposes that only one two-allele locus is involved, which is likely to be a very rare but dominant allele (6
). Despite this difference, both models attribute a role to environmental modification on the genes involved. Trends in twins have shown a higher concordance rate in monozygotic twins than dizygotic twins; however, within the monozygotic group, approximately 50% of twin pairs are not affected (3
). This inconsistency in inheritance among genetically identical siblings is problematic for Mendelian genetics, but can be justified by a MFT model. Carrying the gene(s) only increases the propensity for IHPS development, while environmental variables are needed for the disorder to manifest (3
Acknowledging that neither model can explain all cases of IHPS, several potential environmental modifiers have been proposed. Erythromycin use during early infancy has been suggested as a risk factor for IHPS development (10
). An association has also been established between high intrauterine and early postnatal androgen levels in infants and IHPS, possibly accounting for its higher prevalence in males (5
It has also been proposed that during the perinatal period, low gastric acidity may cause the gut to be more susceptible to infections (12
). Such infections may disrupt the wall integrity, leading to muscle hypertrophy and IHPS. Using a similar rationale, hypergastrinemia has also been implicated as a risk factor for IHPS development (7
). A genetic predisposition toward hyperacidity may augment sensitivity of the fetus toward gastrin, possibly leading to gastrin-induced changes to the architecture of the immature, and potentially susceptible, stomach wall in the postnatal period (13
The documented hypertrophy of the smooth muscle cells of the pylorus in IHPS has led many to postulate neuronal nitric oxide (nNO) synthase dysfunction as a potential cause (14
). NO is a known nonadrenergic and noncholinergic inhibitory neurotransmitter (16
). As an inhibitory neurotransmitter, NO results in relaxation of the smooth muscle cells of the gastrointestinal tract; thus, its deficiency may lead to prolonged constriction and hypertrophy of the smooth muscle cells, as seen in IHPS. Vanderwinden et al (14
) demonstrated reduced expression of nNO synthase in the hypertrophied circular muscle layer in IHPS. They, and others, have also noted the presence of enlarged, distorted enteric nerve fibres in which reduced nNO synthase activity may be found (14
). Recent advances (16
) in genetic research tools have enabled the finding of a specific nNO synthase exon that is altered in IHPS patients. The exact mutation is unknown; however, a promoter sequence within the nNO synthase exon 1c has been identified as a risk factor for IHPS development (16
). Saur et al (16
) suggested that the functional changes that occur after birth may be accompanied by a change in gene expression, leading to mutations in the nNO synthase exon. The outcome of altered gene expression is, therefore, a decreased amount of nNO synthase exon 1c mRNA in neurons innervating the pyloric sphincter, impairing NO production.
Aided by technological advancements, Capon et al (4
) have recently mapped some IHPS cases to chromosome 16. There is inconsistency in this finding, suggesting that IHPS may be caused by more than one gene locus (4
). This may add credence to Carter’s MFT model that proposed polygenic inheritance of IHPS, although this requires further study.
Although it is not certain whether genetic or environmental causes are the more important factor, it is possible that both play a role in the etiology of IHPS. In monozygotic twins, because they share an identical genetic makeup, they also share genetic anomalies, such as an IHPS gene or mutation. If the gene is environmentally modified, twins (monozygotic and dizygotic) also share very similar pre- and postnatal conditions, which may explain the high concordance rates among twin children. One can conclude, therefore, that although the etiology of IHPS is still incompletely understood, empirical studies provide credence to adopt a lower threshold for examining and screening the co-twin when one twin is diagnosed with IHPS.