Introduction

Hirschsprung’s disease (HSCR) is a congenital disorder of bowel motility which arises in approximately 1 in 5000 newborns per annum. It is characterised by the absence of ganglion cells in the enteric nervous system extending for a variable distance from the internal anal spincther, due to failure of neural crest derived precursor cell migration or survival during early development [1]. The resulting loss of colonic motility leads to bowel obstruction necessitating corrective surgery to resect the affected segment of colon with pullthrough of normally ganglionated bowel to the anal margin [2].

The functional outcome after surgery for affected children can be influenced by the extent of aganglionosis as well as the presence of co-morbidities [3]. Poor outcomes particularly occur in patients with total colonic aganglionosis (TCA), which accounts for 9 % of all HSCR cases [4]. Disease burden on families can be heightened by the recurrence of HSCR in multiple siblings as well as the inheritance of HSCR in offspring of affected patients. Counseling requires the availability of accurate information for families.

HSCR is a multi-genetic condition with complex aetiology [5]. Mutations in RET proto-oncogene and endothelin receptor B (ENDRB) are the most frequent genetic insults [6]. HSCR usually occurs in isolation but can arise in association with Trisomy 21 (up to 10 % of all HSCR) and many other syndromes [7]. Familial recurrence of syndromic forms of HSCR has been reported, for example in multiple endocrine neoplasia (MEN) 2A resulting from RET mutation and in Shah-Waardenburg (WS4) syndrome due to ENDRB mutation [8, 9]. However, the majority of HSCR cases are sporadic and are lack definite genetic cause (>80 %). Families of patients with sporadic HSCR are also reported to have an increased risk of HSCR compared to the population risk. In some of these families, genetic screening can identify genetic susceptibility for the disease [10].

Single centre cohort studies report familial recurrence rates for sporadic HSCR ranging from 1 to 10 % [11, 12], illustrating a need for large volume patient data analysis. It was the purpose to this study to review the existing literature in a systematic fashion to identify the rate and patterns of familial recurrence of HSCR.

Methods

The Pubmed ® database was searched using the terms “Hirschsprung’s” and “familial” for studies published between 1980 and 2015. Articles yielded using this search were identified as relevant by abstract review followed by full text analysis. Additional studies of interest were identified by examination of reference lists in relevant articles. Studies including a minimum cohort of 10 index patients with sporadic HSCR were included for the main analysis. Only studies that gave the total number of sporadic HSCR at that centre and reported on familial recurrence were permitted. Studies of multicentre survey data were excluded to avoid duplicated patient cohorts in the analysis. The rate of familial HSCR was calculated as a percentage of the overall number of HSCR cases included in the analysis. Cohorts of patients with TCA were analysed separately. Familial HSCR occurring in association with syndromes or specific genetic mutations was excluded from the main analysis and reported on separately and permitted data from case reports. Patterns of familial HSCR were extracted and categorized as parent–child, sibling or other relative and were reported as a percentage of the total number of families for which recurrence patterns were available. The gender as well as extent of aganglionic segment (long or short) in familial cases were also recorded.

Results

The database search yielded 244 articles. Following abstract review and full text analysis, 38 studies were identified for inclusion in the main analysis (Table 1). In 4331 index cases of HSCR, there were 330 cases in which a family history of HSCR was recorded, giving an overall rate of 7.6 % for familial recurrence. In children with total colonic aganglionosis (n = 525), 20 % of cases were reported to have familial recurrence (Table 2). Recurrence of HSCR within families predominantly occurred in siblings (62 %) and was reported between parent and child in 22 % and in other relatives in 16 %. Multiple generations (>2) were affected in 15 % of families. The gender of familial cases was reported in 202 cases and exhibited a ratio of 1.65:1 male:female. Disease segment length was available in 141 cases of familial HSCR only. 39 % of cases were classified as long segment (defined in most studies as proximal to the midpoint of the transverse colon), and 61 % of cases were classified as short segment disease. Recurrence of syndromic HSCR in families was infrequent and is summarised in Table 3. RET mutation or MEN2A association were the most widely reported [13, 14]. An extended family of Mennonite kindred in the US with a 1 in 500 incidence of HSCR with a susceptibility locus mutation in ENDRB and features of Waardenburg syndrome also featured prominently in the literature [8].

Table 1 Familial recurrence in Hirschsprung’s Disease
Full size table
Table 2 Familial recurrence in total colonic aganglionois
Full size table
Table 3 Familial recurrence in syndromic HSCR
Full size table

Discussion

Our analysis suggests that familial recurrence of HSCR occurs at a higher rate than previously reported by multi-centre survey data from the EU (2.6 %) [15] and Japan [16] (2.8–6 %), but our results are similar to a US study which included survey data [17]. We observed high variability in rates of familial recurrence between different centres (Table 3). Nonetheless, this analysis most likely underestimates the rate of familial recurrence of HSCR. In general, the studies included have not been specifically designed to report comprehensive familial data. Recurrence in potential future siblings or other relatives of index patients was not captured. In addition, recurrence in offspring of affected patients is not addressed in any of these studies by long-term follow-up with some exceptions [18]. A relative risk of recurrence of 4 % (200 times the population risk) in siblings has previous been suggested using predictive models [19]; however, further data are required to predict recurrence risk for the future offspring of index patients. These findings reinforce the need for comprehensive follow-up of these and other patients with congenital disorders on a long-term basis to enhance understanding of disease mechanisms for aetiological and clinical purposes.

We found that HSCR recurred at a higher rate in families of patients with TCA (in 1 of every 5 cases). These findings are consistent with reports suggesting that TCA represents a distinct entity in terms of aetiology, displaying increased penetrance and dominant inheritance in families of affected patients rather than the multifactorial or recessive patterns of inheritance in other HSCR [6]. Cases of familial recurrence of syndromic HSCR are predominantly limited to RET mutation together with MEN2A or ENDRB mutation together with Shah-Wardenburg syndrome. Other syndromic associations recur within families only very rarely according to the case report literature.

Models analysing the gender and the length of the aganglionic segment in index patients have been reported to predict risk of recurrence of HSCR in siblings [19]. We noted that the proportion of female familial cases differed from sporadic HSCR which normally has a male preponderance of 4:1. We additionally noted that a higher number of long segment cases were reported in the familial cases (40 %) than would be expected for sporadic HSCR (15 %).

In conclusion, familial recurrence of HSCR is frequent and should be discussed with families of index patients. Genetic counseling should be offered in these families and in particular for those patients with long segment and total colonic aganglionosis.