IHPS: A Genetic Journey

Abstract

Infantile hypertrophic pyloric stenosis (IHPS) is a stricture of the pyloric sphincter, primarily affecting Caucasians. IHPS may be genetically inherited, environmental, or it may be a multifactorial trait. Throughout all of the research compiled and available to the public, the consensus is uneven- no two schools of thought agree on the exact cause. Research would indicate a higher prevalence of males inheriting the trait, especially first-born males. If pyloric stenosis is thought to be multifactorial, or even environmental, then what are these factors and when do they coalesce to express a hypertrophic pyloric sphincter? The average case of IHPS presents in infants within two to eight weeks after birth. That is an important detail, as there is no empirical rationale for the latency of IHPS manifestation. Is there a relationship between feeding methods and rates of incidence? Can sleeping positions be a possible factor, and if so, to what extent do they cause IHPS? One of the leading theories involves the concept of a mutation, which allows penetrance. In summation, if it is not multifactorial and linked to environmental factors, then the etiology must be genetic.

 

IHPS: A Genetic Journey

To begin with an inference that the condition is genetically inherited, one must take into account why signs and symptoms are not present directly at the moments after delivery. This latency of two to eight weeks indicates an unknown activator to those who harbor said gene. This unknown variable may very well be the cause of expression in infants who possess the gene for IHPS. Danish physician Mads Melbye conducted research, on IHPS, at Statens Serum Institut, in Denmark. Upon the conclusion of his findings, he reported the following:

The familial aggregation of pyloric stenosis is convincingly strong and suggests that specific genes determine who develops the condition. The infant is apparently not born with pyloric stenosis, but develops the disease after some weeks. There appears to be an external factor that triggers the disease in a genetically predisposed infant. We now seek to identify the genetic profile and if we succeed the disease
could potentially be prevented (Melbye, 2010).

One of Doctor Melbye’s students, Camilla Krogh M.D. wrote the following statement in her thesis on IHPS, “…with a heritability estimate of 87%, it seems that familial aggregation is primarily explained by shared genes that may affect responses to postnatal factors” (Krogh, 2010). IHPS is extremely common and the most prevalent condition, in newborns, requiring surgery (MacMahon, 2006). The etiology of the condition is unknown, and to date there exists no test to identify whether or not one’s offspring possesses it, other than the hallmark signs and symptoms, which often appear around the first eight weeks in newborns (Taylor, Cass, & Holland, 2012). The trait is characterized by projectile vomiting immediately after a feeding (MacMahon, 2006). IHPS occurs more often in males than females with a ratio of 4:1 (Krogh et al., 2010). Curiously, the manifestation is even greater in first-born males (Taylor, Cass, & Holland, 2012). In some instances, a child presents with symptoms that mimic colic, while the pathology is found to be IHPS (Onesimo, Giorgio, Monaco, & Fundarò, 2012). At the time of this writing, the only reversal for IHPS is pyloromyotomy (Everett et al., 2008).

MacMahon (2006) theorized that the practice of placing an infant on its stomach, which was thought to reduce sudden infant death syndrome (SIDS), was a possible factor in the development of IHPS (MacMahon, 2006). Other studies have focused on the sleeping positions of infants, but have found no substantial data to corroborate (Sommerfield et al., 2008). In both studies, SIDS and IHPS numbers declined without a definitive explanation. An unproved but compelling theorem is that IHPS is a secondary condition, with other abdominal and gastroinsestinal factors involved (Namini, Raisolsadat, Omid, & Mirzade, 2013).

IHPS may be genetically inherited on multiple accounts according to Peeters, Benninga, and Hennekam (2012). Various pathways and proteins are involved in the matrix of the molecular composition of smooth muscle tissue. In this delicate network lies the opportunity for mutation, thus leading to penetrance (Everett et al., 2008). The causative agent involved in IHPS expression may be located on chromosome 16q24 (Everett et al., 2008). Svenningsson (2012) presents evidence for the occurrence of IHPS as being multifactorial, and notes that neuronal nitric oxide synthase, otherwise known as the (NOS1) gene, as being recognized in the manifestation IHPS (Svenningsson et al., 2012). Incorporating the NOS1 gene as absolute proof of genetic causation, multiple locations on two chromosomes have been directly linked to the expression of IHPS- chromosomes 2q24 and 6p21(Svenningsson et al., 2012). Everett states:

We have mapped a second locus for monogenic IHPS through an SNP-based genome scan of a multigenerational pedigree. The sex-segregation male-to-female ratio in family IHPS078 is 1.7:1. In our resource, the IHPS male sex bias tends to be less pronounced in familial cases (2.2:1 in the 14 additional families used in this study) than in sporadic cases (5.2:1 in our resource of 358 trios; data not shown). This suggests that underlying sex-specific factors are of greater importance in sporadic cases, or that familial cases occur because of a more highly penetrant allele to which females do not have a sex-specific protection.

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