Aspects of Hirschsprung disease

Abstract

Hirschsprung disease (HSCR) is a congenital defect of the enteric nervous system characterized by a lack of enteric neurons in the distal hindgut. Motility disturbances in the distal colon usually lead to neonatal intestinal obstruction. The birth prevalence of HSCR has been assessed to 1 in 5,000 live births. HSCR is known to be a multifactorial disease caused by both genetic and environmental factors. HSCR can be part of a syndrome, most commonly Down syndrome (trisomy 21). A majority of the patients undergo surgical treatment during the first year of life. There is a risk of impaired long-term functional outcome, with fecal incontinence and obstructive symptoms.

The aim of this thesis was to assess the functional outcome and quality of life (QoL) after surgery for HSCR. The aim was also to investigate environmental risk factors for HSCR as well as assessing it as a risk factor for a patient’s future socioeconomic life. An additional aim was to evaluate the molecular background in a family with HSCR combined with multiple sclerosis (MS).

In Study I, mutation screening was performed using exome sequencing in three females in a family; a girl with HSCR, and also her mother and grandmother, both with HSCR associated with MS. A novel heterozygote mutation in the endothelin receptor B gene was found changing arginine at position 133 into a premature stop codon (p.Arg>*).

Study II was conducted as a longitudinal assessment of bowel function with a three-year interval. Twenty-nine patients operated 1998-2009 with laparoscopic assisted pull-through surgery for HSCR in the Stockholm area were eligible for inclusion. Median age at surgery was 104 days (29 days-8 years) and median age at first follow-up was 4 (2-16) years. Soiling for loose stools was reported by 67% of the patients at the first interview and by 59% three years later, whereas soiling for solid stools was reported by 59% and 56% of the patients respectively. The number of patients suffering from constipation decreased significantly from 41% to 14% (p=0.023).

Study III was a cross-sectional study of bowel function and QoL in patients who underwent surgery for HSCR between 1969 and 1994. Validated questionnaires for bowel function and QoL were sent to 60 patients. Forty-eight responded, of who 39 were finally included. For each patient one age- and gender-matched control was selected. The median age at follow-up was 28 (20-43) years and most of the patients had undergone a Soave procedure. Patients with HSCR reported significantly more constipation symptoms and fecal incontinence than the control group. There were no differences in the generic QoL but the symptom-specific QoL showed significantly lower scores for patients with HSCR.

Studies IV and V were population-based register studies. In Study IV, maternal risk factors, perinatal characteristics and the birth prevalence of HSCR were investigated in a case-control study between 1982 and 2012. Study IV included 600 cases of HSCR and 3,000 controls and their mothers. The results showed that maternal obesity was associated with an increased risk of the child having HSCR (OR 1.74; CI 1.25-2.44) as well as maternal parity of three or more children (OR 1.25; CI 1.00-1.56). Patients with HSCR were born at an earlier gestational age (OR 1.60; CI 1.18-2.17). The birth prevalence in Sweden between 1987 and 2012 was 1.91/10,000. In Study V the impact of HSCR on future educational level and income was assessed in individuals born between 1964 and 2013. In the cohort, 739 individuals were exposed (having HSCR) and 3,847 individuals were unexposed. The median age of the cohort was 25 (16-49) years. The highest educational level did not differ between the groups (p=0.327). Median individual disposable income was 142,200 (0-817,200) Swedish krona (SEK) in the exposed group and 159,900 (0-3418,900) SEK in the non-exposed group (p=0.615).