Review Pyloric stenosis a 100 years after Ramstedt Christina Georgoula,1 Mark Gardiner2 1Starlight Children’s Unit, SUMMARY Homerton University Hospital, Conrad Ramstedt performed the fi rst pyloromyotomy London, UK 2General & Adolescent for what is now called idiopathic hypertrophic pyloric Paediatrics Unit, Institute stenosis 100 years ago. The intervening century has of Child Health, University seen the management of this condition transformed College London, London, UK but the underlying cause remains a mystery. This article reviews the treatment of this condition before and after Correspondence to Christina Georgoula, Starlight the introduction of pyloromyotomy and the advances Children’s Unit, Homerton made subsequently towards understanding its cause. University Hospital, London E9 6SR, UK; christina. [email protected] Accepted 4 April 2012 INTRODUCTION Published Online First The clinical scenario is familiar and gratifying. 9 June 2012 An infant a few weeks old presents with vomit- ing of gradually increasing severity. Examination reveals mild dehydration and careful inspection identifi es visible peristalsis. Opinions differ as to whether a pyloric mass is palpable. Investigation shows hypokalaemia and a raised bicarbonate. An ultrasound scan duly confi rms a diagnosis of pyloric stenosis and after correction of any fl uid and electrolyte imbalance pyloromyotomy is performed as a minor and trivial procedure. The infant disappears from the ward and you meet by Figure 1 Infant with pyloric stenosis (reproduced chance a few weeks later. A happy infant with an from Rankin W. Lessons on the Surgical Diseases of invisible abdominal scar beams at you from the Childhood. Alex Macdougall, Glasgow 1933). lap of a delighted parent. How different from a 100 years ago when most infants with this condition died in an emaciated at age 10 days. She lost weight and died at age 30 state after months of misery (fi gure 1). Just 30 years days weighing less than at birth. Autopsy revealed after Ramstedt introduced pyloromyotomy, Mack a fi rm, cylindrical thickening of the pyloric canal could write with justifi cation in 1942 that ‘Present consisting of hypertrophy of all layers, particularly day methods of diagnosis and treatment of hyper- the muscularis. The second case, also a girl born at trophic pyloric stenosis of infants may well be term, was complicated by the coexistence of mil- classed among modern medical miracles’.1 iary tuberculosis. Vomiting began by 14 days and Yet despite this triumphant advance, the exact she died at age 6 months. At autopsy, there were cause of what is now designated idiopathic hyper- miliary tubercles in various organs, the stomach trophic pyloric stenosis (IHPS) remains a mystery. was dilated, the pyloric canal was elongated to 3 In this short review, we consider the early history cm and its wall was hypertrophied, particularly of recognition of this condition, how management the muscle layer. Case reports multiplied rapidly evolved in the last century and what advances after this and by 1910 there were 598 published in our understanding of IHPS have taken place. cases. Lastly, we ask whether further advances could one day relegate Ramstedt’s pyloromyotomy to Epidemiology the history books. IHPS has attracted much attention from epidemi- ologists and MacMahon provides a very useful EARLY DESCRIPTIONS recent review of the literature.3 Certain obser- Hirschsprung is credited with the fi rst unequivo- vations appear consistent. It has occurred in the cal modern description of IHPS in 1888.2 There Western world throughout the last century with are at least seven earlier case reports published in an incidence of between 2 and 5 per 1000 live the preceding 300 years including those of Blair births but is less common elsewhere. The latter (1717), Armstrong (1777) and Beardsley (1788), may of course refl ect under ascertainment but it the latter report being discovered and reported by is clearly less common in black and Asian ethnic Sir William Osler.1 groups in the USA where such bias is excluded. Hirschsprung reported two cases. The fi rst, a A fourfold to fi vefold higher risk of the disease in girl, was born at term and began violent vomiting boys than girls appears in all studies. Still was the Arch Dis Child 2012;97:741–745. doi:10.1136/archdischild-2011-301526 741 Review fi rst to record (in 1927) that it was more common in fi rst-born be identifi ed. A genome-wide single nucleotide polymor- children.4 However, MacMahon’s analysis of a series of cases phism (SNP)-based high-density linkage scan carried out providing information on birth order suggested a general on 81 small nuclear pedigrees identifi ed IHPS3 on chro- decline in risk with increasing birth order rather than a unique mosome 11q14–q22 and IHPS4 on Xq23.11The two linked position for fi rst born. chromosomal regions each harbour functional candidate Epidemiological studies have provided several important genes that are members of the canonical transient receptor clues to aetiology as described below. Recurrence risk in fami- potential (TRPC) family of ion channels and have a poten- lies and twin studies provide unequivocal evidence of a genetic tial role in smooth-muscle control and hypertrophy: TRPC6 contribution and maternal smoking and postnatal erythro- and TRPC5. Further analysis provided suggestive evidence mycin administration have been suggested as environmental for a third locus on chromosome 3q12–q25, a region which factors. Sharp declines in the incidence of IHPS in Denmark harbours a third TRPC gene, TRPC1.12 Fine mapping of all and Sweden during the 1990s, coincident with successful cam- three genes using a tagSNP approach and re-sequencing paigns to discourage the prone sleeping position, led to the identifi ed a SNP in the promoter region of TRPC6 and a mis- hypothesis that sleeping prone may be a risk factor. sense variant in exon 4 of TRPC6, which may be putative It is amusing to note in retrospect that IHPS was regarded causal variants. as a disease of children of the intellectual classes. In fact, early progress in the study of IHPS depended to an unusual degree Environmental factors on infant offspring of physicians with the disease: Dent’s suc- Recent evidence suggested two factors for which plausible cessful pyloroplasty (1902) and Ramstedt’s pyloromyotomy biological explanations exist: infant sleeping position and (1912) were both performed on children of physicians. postnatal erythromycin exposure. A recent striking decline in the incidence of IHPS in Aetiology Denmark and Sweden appears to have coincided with an It is well established that IHPS arises from a genetic predisposi- increase in numbers of infants placed in the supine rather tion interacting with environmental factors. As yet, however, than prone sleeping position after the realisation that prone no causal gene or sequence variant has been identifi ed and the sleeping was a risk factor for sudden unexplained death in pathophysiology at a molecular level remains unknown. infancy and the consequent ‘back to sleep’ public health interventions.13 14 However, although a recent study of the Genetics incidence of IHPS and sudden infant death syndrome (SIDS) Armstrong (1777) was the fi rst to report familial occurrence of in Scotland in the period 1981–2004 showed a similar decline pyloric stenosis, but clear evidence for a genetic predisposition and linear correlation between rates for the two conditions, 15 required more affected individuals to survive to reproductive the decline in IHPS rates preceded that for SIDS by 2 years. age. Carter’s classic studies established non-syndromic pyloric The observation that the prone position is associated with stenosis as a complex, multifactorial, sex-modifi ed threshold pooling of milk in the gastric antrum rather than the fun- trait.5 6 A later re-analysis of data from several studies concluded dus could provide a biological basis for the effect of sleeping that IHPS is determined by two or three loci of moderate effect position if such pooling exacerbated pyloric smooth muscle conferring individual genotype relative risks of up to 5.7 contraction. IHPS has also been associated with several genetic syn- Several studies have reported a small increase in risk of IHPS dromes, such as Cornelia de Lange and Smith-Lemli-Opitz in infants exposed to erythromycin in the postnatal period, syndromes, and chromosomal abnormalities, including trans- although maternal ingestion either prenatally or during breast 16 17 location of chromosome 8 and 17 and partial trisomy of chro- feeding does not seem to alter risk. Erythromycin has gas- mosome 9. Autosomal-dominant monogenic forms of IHPS trokinetic effects mediated by its action as a motilin receptor have also been reported in several extended pedigrees. agonist which could lead to abnormal or excessive pyloric/gas- A recent population-based cohort study of 2 million children tric motility. born in Denmark between 1977 and 2008 has provided further evidence that familial aggregation among the 3362 infants Pathophysiology with IHPS is mostly due to shared genes rather than mater- Measurements of blood hormone levels and detailed exami- nal factors operating during in utero development or a com- nation of pyloric biopsy material has been undertaken. 8 mon family environment. Segregation was not mendelian but The latter is of course ‘end-stage’ tissue and the distinc- the data did not allow a particular model of inheritance to be tion between primary and secondary changes is diffi cult to determined.