Which family history would the nurse recognize as a risk factor for an infant developing hypertrophic pyloric stenosis?

Paediatr Child Health. 2008 May; 13(5): 383–385.

Language: English | French

Abstract

BACKGROUND

The etiology of infantile hypertrophic pyloric stenosis (IHPS) remains a mystery. Some suspected risk factors include birth rank, maternal age, sex, family history and monozygosity in twins. Various theories attempt to explain the etiology of IHPS. Scientific research suggests that enteric neuronal damage and nitric oxide synthase dysfunction may be implicated, but the consensus is that environmental modification must exist to account for the variability in its occurrence.

METHOD

Four cases of concordant occurrences of IHPS in twins were examined to determine the history and outcome of IHPS development in twins. Three sets were dizygotic and one was monozygotic. Of the eight infants, three were female, including the one monozygotic pair. In all four cases, a time lag existed between the development of symptomatic onset of IHPS in twin A and twin B. In one set, sonographic confirmation, performed because of IHPS diagnosis in the twin sibling, occurred concurrently with onset of vomiting, leading to early surgery before fluid and electrolyte imbalances developed.

CONCLUSIONS

Despite the lack of agreement as to whether the cause of IHPS is genetic, environmental or both, the high concordance rate seen in twins is indisputable. Thus, the empirical evidence provides credence to consider examining the asymptomatic co-twin when one of the twins presents with IHPS.

Keywords: Genetic factors, Pyloric stenosis, Twins

Résumé

HISTORIQUE

L’étiologie de la sténose hypertrophique du pylore chez l’enfant (SHPE) demeure un mystère. Parmi les facteurs de risque présumés, soulignons le rang dans la famille, l’âge de la mère, le sexe, les antécédents familiaux et le monozygotisme chez les jumeaux. Diverses théories cherchent à expliquer l’étiologie de la SHPE. Selon les recherches scientifiques, les lésions neuronales entériques et le dysfonctionnement de la synthase de monoxyde d’azote pourraient être en cause, mais on s’entend pour croire en une modification environnementale qui en expliquerait la variabilité.

MÉTHODOLOGIE

Les auteurs ont examiné quatre cas d’occurrences concomitantes de SHPE chez des jumeaux pour déterminer l’historique et l’issue de l’évolution du SHPE chez les jumeaux. Trois couples étaient dizygotes et un, monozygote. Trois des huit nourrissons étaient de sexe féminin, y compris le couple monozygote. Dans les quatre cas, on remarquait un délai entre l’apparition symptomatique du SHPE chez le jumeau A et le jumeau B. Au sein d’un couple, la confirmation échographique effectuée en raison du diagnostic de SHPE chez le jumeau a concordé avec le début des vomissements et suscité une intervention chirurgicale rapide, avant l’apparition d’un déséquilibre de liquides et d’électrolytes.

CONCLUSIONS

Même si on ne s’entend pas pour déterminer si le SHPE est attribuable à des facteurs génétiques, environnementaux ou les deux, le taux de concordance élevé observé chez les jumeaux est incontestable. De plus, les données empiriques justifient l’examen du jumeau asymptomatique lorsque l’autre jumeau est atteint de SHPE.

Infantile hypertrophic pyloric stenosis (IHPS) is a disorder that can occur in neonates three to eight weeks after birth (1). Characterized by hypertrophy and hyperplasia of the pylorus muscles, IHPS causes functional gastric outlet obstruction leading to nonbilious projectile vomiting. The standard procedure to correct IHPS is a Ramstedt’s pyloromyotomy, which relieves the obstruction by longitudinal splitting of the pylorus muscle. Despite knowing how to treat IHPS, the etiology remains unclear.

The incidence rate for IHPS is between two and five per 1000 newborns, with a higher prevalence among the Caucasian population (1,2). Earlier birth rank and younger maternal age have both been deemed risk factors for IHPS development in neonates (2); however, the relationship is more likely associative than causal. Males have a higher risk (four to five times) of developing IHPS than females (1,3,4), a fact that has also been documented within a cohort of opposite sex twins (5). Familial clustering has also been reported, with an increased likelihood of a child being affected if there is a family history of the condition (2). Epidemiological studies (2,3) have calculated higher risk ratios for developing the disease in multiple births; there appears to be a higher concordance rate in monozygotic twins than dizygotic twins. Discordance is prevalent in twins (2,3), but comparisons between the two types favours co-occurrence in monozygotic cases.

This preferential development of IHPS in monozygotic twins and males strongly implicates it as a hereditary disorder. In 1961, Carter (3) proposed a genetic model to fit these findings – it was termed the multifactorial threshold (MFT) model of inheritance. This model suggests that IHPS is caused by polygenic inheritance of genes that are sex and environment modified. Alternatively, the single major locus (SML) model has also been proposed, which assumes the involvement of one gene subject to random environmental modifications (6). Despite the lack of agreement as to exactly which and how many genes are involved, there is consensus as to the environmental modifications that occur to account for the variability in IHPS occurrence.

The current report presents four cases of concordant IHPS in twins (Table 1) and a review of the literature to discuss the etiology of this enigmatic disorder.

TABLE 1

Four cases of concordant infantile hypertrophic pyloric stenosis (IHPS) in twins

CASE PRESENTATION

Case 1

Case 1 is described in detail for its more circuitous course of IHPS development. Dizygotic twins, with no significant family history, were born at 35 weeks’ gestational age. At four weeks of age, twin B (male) developed nonbilious vomiting after feeding. Workup included an ultrasound examination that revealed a normal-looking, nonobstructive pylorus. Gastroesophageal reflux was diagnosed, and because the infant was not dehydrated, no specific treatment was prescribed. One week later, twin A presented with nonbilious projectile vomiting. An ultrasound examination revealed IHPS, and an uneventful open pyloromytomy was performed with good recovery. A week later, twin B’s vomiting became projectile; a repeat ultrasound revealed IHPS, which was then remedied by an uneventful open pyloromyotomy.

DISCUSSION

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 (2,3,7). 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 (1–4,7,9). 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 (3,7,9). Because IHPS is four to five times more prevalent in males than females (1,3,4), 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 (3,6,7,9).

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 (5,11).

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 (7,13). 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 (14–16). 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 (14,17). 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.

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