Gastrointestinal symptoms and quality of life in adults with Silver-Russell syndrome: a cross-sectional study

Abstract

Background and objective

Most children with the rare disorder Silver-Russell syndrome (SRS) have feeding difficulties and/or gastrointestinal symptoms such as vomiting and constipation, worsening their postnatal growth. Whether the complaints remain in adult life has not been evaluated by large specialised national centres.

Design/setting/patients

All 28 individuals who were referred to the national centre for SRS as children were approached at an adolescent or adult age. We used the validated Gastrointestinal Symptom Rating Scale (GSRS) questionnaire to assess gastrointestinal symptoms during the last week. Individuals with the most bothersome gastrointestinal symptoms completed the Rome IV Diagnostic Questionnaires online, General Anxiety Disorder-7, the Patient Health Questionnaire-9, the Patient Health Questionnaire-12 Somatic Symptom scale and the Patient-Reported Outcomes Measurement Information System Global-10.

Results

The GSRS questionnaires were completed by 18 individuals from the age of 14 years. There was at least one gastrointestinal symptom of moderate severity reported by 11 (61%) individuals. The most frequent symptom domain was related to ‘Indigestion’ (27%), ‘Reflux’ (22%) and ‘Constipation’ (22%). Among 11 individuals with at least one gastrointestinal symptom of moderate severity, six completed the Rome IV Diagnostic Questionnaires and five were diagnosed with a disorder of gut-brain interaction.

Conclusion

Short-term gastrointestinal symptoms are common in young adults diagnosed with SRS. This needs to be further evaluated in prospective studies assessing the chronicity of the symptoms.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Children with Silver-Russell syndrome (SRS) frequently experience feeding difficulties and gastrointestinal (GI) symptoms, which may compromise growth. However, little is known about the persistence or clinical significance of GI symptoms in adolescence and adulthood.

WHAT THIS STUDY ADDS

• This study shows that short-term GI symptoms are common in adolescents and adults with SRS, with 61% reporting at least one moderate symptom, most often indigestion. Half of those with symptoms met diagnostic criteria for a disorder of gut–brain interaction.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• Our findings emphasise the importance of continued GI follow-up in individuals with SRS beyond childhood and adolescence. Prospective longitudinal studies are needed to determine symptom persistence and underlying mechanisms, which could guide clinical management and improve long-term outcomes.

Introduction

Silver-Russell Syndrome (SRS) is a rare and complex disorder characterised by small for gestational age, postnatal growth retardation, asymmetry of body proportions, facial dysmorphism (relative macrocephaly at birth and protruding forehead), feeding difficulties leading to underweight during early life and short stature.¹ The most prevalent underlying mechanisms include loss of methylation on chromosome 11p15 (11p15 LOM), observed in up to 60% of patients and maternal uniparental disomy for chromosome 7 (mUPD7), seen in 5%–10% of patients.²

The early nutritional history of children with SRS can be highly diverse, with varying feeding approaches during infancy and childhood as shown by our group³ and others.^{4 5} Several studies have reported a correlation between impaired fetal growth and gastrointestinal (GI) disorders, including coeliac disease and inflammatory bowel disease (IBD).^{6 7} Among individuals with SRS, more than 70% experience digestive problems or malnutrition, with around 55% developing severe gastro-oesophageal reflux after their first year of life, and 20% developing constipation, particularly after their second year.⁴

Feeding experiences may play a pivotal role in shaping long-term GI health in SRS. Early life GI problems (infantile colic and functional constipation) may correlate with later disorders.^{8 9} A Swedish registry-based cohort study found that females had the highest risk for irritable bowel syndrome (IBS), while preterm birth was protective in young women.¹⁰ Conversely, being born small for gestational age is associated with a greater impact of GI symptoms on daily functioning in adulthood.¹¹ GI symptoms in adults have periodically been mentioned in the literature regarding SRS, but not specifically linked to the syndrome.^{12 13} Furthermore, individuals with SRS face psychosocial difficulties throughout childhood, adolescence and adulthood.¹⁴ Psychological stress is recognised as a risk factor for the development of a disorder of gut-brain interaction (DGBI). The aim of this study was to evaluate the presence and severity of GI symptoms in adults and adolescents with SRS, considering their diverse nutritional history during childhood.

Methods

Study population

The potential study population of this single-centre study conducted at Sahlgrenska University Hospital, Gothenburg, consisted of 28 individuals diagnosed with SRS between 1986 and 2010 of whom 19 (68%) were males: 24 adults (≥ 18 years) and four adolescents (the latter defined as near adult height if age ≥14 years, Tanner stage ≥4 and a height gain <3 cm/year). These patients had been longitudinally followed at the national and regional centre for SRS at the Queen Silvia Children’s Hospital from early childhood, which allowed us to collect clinical data from medical records. The initial diagnosis of SRS was made by a senior endocrinologist (JD) based on characteristic clinical features and subsequently confirmed by multiplex ligation-dependent probe amplification (MLPA). In cases where MLPA results were negative, whole-genome sequencing of the proband and both parents was performed to identify potential genetic variants associated with SRS. Syndromes with phenotypic overlap with SRS, such as Temple syndrome, Floating-Harbor syndrome, maternal uniparental disomy of chromosome 20, 3-M syndrome, Mulibrey nanism, Bloom syndrome, 12q14 microdeletion syndrome and heterozygous IGF1R defects were excluded based on genetic testing results.

Study protocol

The individuals with SRS for this cross-sectional study with retrospective elements were contacted via regular mail and asked to fill out the validated Gastrointestinal Symptom Rating Scale (GSRS) questionnaire regarding GI symptoms if consenting to participate.¹⁵ To those not responding, a reminder was sent after 4 weeks. All questionnaires completed between 1 February 2023, and 30 November 2023 were reviewed. The GSRS is a disease-specific instrument, developed on the basis of reviews of GI symptoms and clinical experience, to evaluate common GI symptoms in diseases and disorders during the last 7 days. The questionnaire consists of 19 items that can be divided into five symptom domains as follows: abdominal pain syndrome (abdominal pain, hunger pains and nausea); reflux syndrome (heartburn and acid regurgitation); indigestion syndrome (borborygmus, abdominal distension, eructation and increased flatus); diarrhoea syndrome (diarrhoea, loose stools and urgent need to defecate); and constipation syndrome (constipation, hard stools and feeling of incomplete evacuation). The severity of each symptom is rated on a Likert scale: 1=none; 2=insignificant; 3=mild; 4=moderate; 5=quite severe; 6=severe; and 7=very severe. Individuals with at least one moderate GI symptom severity were contacted by mail and phone and asked to fill out the following questionnaires online: the Rome IV Diagnostic Questionnaire,¹⁶ the General Anxiety Disorder-7 (GAD-7) questionnaire,¹⁷ the Patient Health Questionnaire-9 (PHQ-9),¹⁸ the PHQ-12 questionnaire¹⁹ and the Patient-Reported Outcomes Measurement Information System (PROMIS) Global-10.²⁰ The GAD-7 is used as a screening tool and severity measure for generalised anxiety disorder. Each item is rated on a 4-point Likert scale ranging from 0 (‘not at all’) to 3 (‘nearly every day’), giving a total score ranging from 0 to 21. Severity is categorised as minimal (0–4), mild (5–9), moderate (10–14) and severe (15–21). A score of ≥10 is commonly used as a cut-off for identifying probable cases of generalised anxiety disorder. The PHQ-9 is used for assessment of depression. Depression severity was categorised as minimal (0–4), mild (5–9), moderate (10–14), moderately severe (15–19) and severe (20–27). A cut-off score of ≥10 is typically used to identify clinically significant depressive symptoms. The PHQ-12 is a modified version of the PHQ-15 where the three items related to GI symptoms are excluded. Each item is rated on a 3-point scale from 0 (‘not bothered at all’) to 2 (‘bothered a lot’), giving a total score ranging from 0 to 24. The maximum total score is 22 for men (excluding the question on menstrual problems) and 24 for women, where 0–4 represent minimal, 5–9 low, 10–14 medium and ≥15 high somatic symptom severity. Higher scores indicate greater somatic symptom severity. PROMIS Global-10 assesses physical and mental quality of life. Higher scores indicate better overall patient health. Finally, a video consultation was made by a gastroenterologist for clinical assessment of GI symptoms (HT).

Data analysis and statistics

The individual GSRS symptom domain scores were calculated based on the mean of the sum of the GSRS items included in each symptom domain, and the median for each domain was used for the whole group, with higher scores indicating more severe GI symptoms. As there is no defined ‘cut-off’ for when the GSRS score becomes clinically relevant, a response of ≥4 (at least moderate symptom severity) on one or more questions or a median score of ≥4 in any symptom domain is used to define patients with bothersome GI symptoms.

The data are expressed as frequencies (percentages) for categorical data and as the median (range) for continuous non-normally distributed data. The CI was set to 95%. The non-parametric Mann-Whitney U test was used to compare continuous variables between two groups. The associations between categorical variables were assessed using the χ2 test for independence. The level of significance was set to p <0.05. The statistical analysis was performed using the IBM Statistical Package for Social Sciences (SPSS) Statistics 29 software (SPSS Inc., Chicago, IL, USA).

Results

Study cohort

Of the 28 individuals invited to participate, 18 (64%) responded by returning the GSRS questionnaire. Among the responders, 12 (67%) were males, while among the non-responders, seven (70%) were males. The median responder age was 28.5 years (range: 14–39) compared with 29.5 years (range: 14–36) for non-responders. Two individuals (20%) among the non-responders required enteral feeding during childhood, whereas 7 (39%) of the responders had a history of enteral feeding during their childhood.

Eleven individuals had at least one GI symptom of moderate severity and six (3 males) accepted the request to further characterise their GI complaints.

Baseline characteristics of responders

All individuals were born small for gestational age; two had low birth weight only, and 16 had both low birth weight and length. A gestational age of less than 37 weeks was observed in 10 (56%) individuals. Throughout childhood, seven out of 18 individuals required nutritional support through enteral feeding, with percutaneous endoscopic gastrostomy (PEG) feeding in five and nasogastric tube feeding in two of the children. The median duration of nasogastric tube placement was 6 months (range: 4–7), and 12.4 years (range: 1.2–17) for PEG. One individual still had partial nutritional support (PEG) despite being an adult. Eleven showed hypomethylation of 11p15, one had mUPD7, while the remaining six had neither (clinical SRS according to Netchine-Harbison clinical scoring system¹ and negative results from whole-genome sequencing). Clinical characteristics of the 18 individuals, according to the Netchine-Harbison clinical scoring system, are presented in online supplemental table 1. All but two received GH treatment with the median duration of 12.6 years (range: 2.0–15.1). Table 1 summarises the baseline characteristics of the study group by feeding method, and table 2 presents detailed individual data for all 18 individuals.

Table 1. Baseline characteristics among responders to the GSRS questionnaire, divided by feeding group and expressed as medians (range) or numbers (%).

	Total (n=18)	Orally fed (n=11)	Enterally fed (n=7)	P*
Age, years	28.5 (14-39)	33 (14–39)	23 (15–38)	0.15
Male, n (%)	12 (67)	7 (64)	5 (71)	1.00
Female, n (%)	6 (33)	4 (36)	2 (29)
Gestational age, weeks+days	36+2 (25+6–41+0)	38+6 (28+2–41+0)	36+0 (25+6–38+0)	0.15
Birth weight, SD score	−3.3 (−4.7 to −2.0)	−3.3 (−4.7 to −2.1)	−3.5 (−4.4 to −2.0)	0.84
Birth length, SD score	−4.1 (−6.8 to −0.9)	−4.1 (−6.8 to −2.6)	−4.3 (−7.3 to −0.9)	0.96
†BMI, SD score	0.6 (−4.5 to −3.5)	1.0 (−4.5 to −3.5)	−0.9 (-3.0 to −2.5)	0.17

^*P value for the comparison between orally fed and enterally fed groups.

^†Values at the time of the study.

BMI, body mass index; GSRS, Gastrointestinal Symptom Rating Scale.

Table 2. Baseline characteristics and Gastrointestinal Symptom Rating Scale questionnaire findings of the 18 individuals with Silver-Russell syndrome.

No/sex/ age	Birth data					Clinical characteristics					Gastrointestinal Symptom Rating Scale questionnaire
	GA weeks+days	BW SDS	BL SDS	BHCF SDS	Epi- genetics	Enteral feeding	GH treatment	Weight SDS	Height SDS	BMI SDS	≥ Moderate GI symptom*	Abdominal pain syndrome	Reflux syndrome	Constipation syndrome	Diarrhoea syndrome	Indigestion syndrome	≥ Moderate GSRS domain
1/M/39	35+0	−3.2	−3.5	0.0	11p15.5	N	Y	3.1	0.5	3.0	N	1.3	1.0	2.0	1.3	1.5	N
2/F/24	36+3	−4.2	−5.1	−1.0	11p15.5	Y†	N	−3.2	−3.0	−2.9	N	2.0	1.0	1.3	1.0	1.9	N
3/M/28	39+0	−3.9	−4.7	−1.5	11p15.5	N	Y	−2.0	−2.1	0.0	N	1.0	1.0	1.0	1.0	1.0	N
4/F/34	38+6	−3.3	−5.0	2.0	11p15.5	N	Y	−4.8	−2.5	−4.5	Y‡	3.0	1.0	2.7	6.7	5.0	Y
5/M/32	33+0	−3.6	−0.9	−1.0	11p15.5	Y	Y	−1.0	−0.7	−0.7	Y‡	1.0	1.0	1.3	1.3	2.5	N
6/F/36	37+0	−2.8	−3.4	−0.5	Normal	N	Y	−0.5	−2.4	1.0	Y	2.0	1.0	1.0	1.3	3.0	N
7/M/38	36+0	−2.9	−3.4	0.2	11p15.5	Y	Y	1.0	0.0	1.0	N	1.0	1.0	1.0	1.0	1.0	N
8/M/33	40+0	−3.0	−3.3	−0.8	mUPD7	N	Y	−0.5	−1.0	0.0	Y‡	4.3	4.5	4.0	1.7	4.0	Y
9/M/34	41+0	−2.1	−2.6	0.0	Normal	N	Y	0.5	−1.0	1.0	Y	1.3	1.0	2.0	2.3	1.6	N
10/F/22	28+2	−3.6	−5.1	−1.0	Normal	N	Y	0.0	−1.8	1.0	Y‡	2.3	1.0	3.7	1.0	4.0	Y
11/M/25	32+3	−4.7	−6.8	−1.8	Normal	N	Y	0.5	−2.0	2.0	Y‡	2.7	4.0	4.3	1.7	4.3	Y
12/M/29	39+0	−4.0	−4.1	0.5	11p15.5	N	Y	0.0	−0.5	0.5	N	1.0	1.0	1.0	1.0	1.0	N
13/F/36	40+0	−2.5	−4.0	0.9	11p15.5	N	Y	2.8	−0.8	3.5	Y‡	3.0	4.5	4.7	2.7	4.1	Y
14/M/22	38+0	−3.0	−4.5	0.0	11p15.5	Y†	Y	−3.2	−3.9	−1.0	N	1.0	1.0	1.3	1.0	1.0	N
15/M/21	25+6	−3.3	−6.5	n/a§	Normal	Y†	Y	0.5	−0.3	0.8	Y	3.0	4.0	2.3	1.0	1.0	Y
16/M/14	29+5	−3.8	−4.7	−2.0	11p15.5	N	Y	−3.1	−1.0	−1.8	Y	1.7	1.0	1.7	4.0	1.9	Y
17/F/15	36+2	−2.0	−1.8	n/a§	11p15.5	Y†	N	−2.0	−1.3	−2.0	N	1.0	1.5	1.0	1.0	1.0	N
18/M/16	32+6	−4.4	−4.1	−2.0	Normal	Y†	Y	−2.8	0.0	−3.0	Y	1.3	1.5	2.3	1.3	2.5	N

^*A response of ≥4 GSRS score (at least moderate symptom severity) on one or more questions.

^†Individuals with percutaneous endoscopic gastrostomy.

^‡Individuals who completed the Rome IV Diagnostic Questionnaires.

^§Data missing from medical records.

BHCF, birth head circumference; BL, birth length; BMI, body mass index; BW, birth weight; F, female; GA, gestational age; GH, growth hormone; M, male; mUPD7, maternal uniparental disomy of chromosome 7; N, no; n/a, not available; SDS, SD score; Y, yes.

Gastrointestinal symptoms

Of the 18 individuals, 11 (61%) reported at least moderate symptom severity for at least one GI symptom (figure 1), where abdominal bloating emerged as the most severe symptom, with a median score of 4 (range: 1–7) among the responders. When symptoms were analysed at the domain level, fewer individuals met the threshold for moderate severity. In total, seven individuals had at least one symptom domain with a score in the moderate range. Indigestion was the most frequently affected domain in five (27%) individuals, followed by reflux in four (22%) individuals and constipation in four (22%) individuals. Notably, three of the five individuals with indigestion also reported reflux and constipation. The corresponding values for the GSRS domains of abdominal pain, reflux, constipation, diarrhoea and indigestion for every individual are presented in table 2, while table 3 shows these data categorised by feeding group.

Figure 1. Distribution of the highest symptom score by individual. Note: Score scale severity—the highest reported level on a minimum of one question. - - - - threshold for clinically significant symptom severity (a response of ≥4 (at least moderate symptom severity)).

Table 3. GSRS summary for individuals with SRS, divided by feeding group and expressed as medians (range).

GSRS symptom domains	Total (n=18)	Orally fed (n=11)	Enterally fed (n=7)	P*
Abdominal pain syndrome	1.5 (1.0–4.3)	2.0 (1.0–4.3)	1.0 (1.0–3.0)	0.13
Reflux syndrome	1.0 (1.0–4.5)	1.0 (1.0–4.5)	1.0 (1.0–3.5)	0.93
Constipation syndrome	1.8 (1.0–4.7)	2.0 (1.0–4.7)	1.3 (1.0–2.3)	0.21
Diarrhoea syndrome	1.3 (1.0–6.7)	1.7 (1.0–6.7)	1.0 (1.0–1.3)	0.05
Indigestion syndrome	1.9 (1.0–5.0)	3.0 (1.0–5.0)	1.0 (1.0–2.5)	0.07

^*P value for the comparison between orally fed and enterally fed groups.

GSRS, Gastrointestinal Symptom Rating Scale; SRS, Silver-Russell syndrome.

The orally fed individuals reported a wider range of symptom scores in all domains, except for reflux syndrome, compared with the enterally fed individuals. Symptoms of indigestion were reported as more severe in orally fed individuals; however, they did not reach a significant difference compared with the enterally fed individuals (p=0.07).

There was no significant difference between males and females, although there was a tendency towards higher symptom scores among females in the indigestion syndrome domain. Symptom data divided by sex are shown in table 4.

Table 4. GSRS summary for patients with SRS based on sex and expressed as medians (range).

GSRS symptom domains	Female (n=6)	Male (n=12)	P
Abdominal pain syndrome	2.2 (1.0–3.0)	1.3 (1.0–4.3)	0.18
Reflux syndrome	1.0 (1.0–4.5)	1.0 (1.0–4.5)	1.00
Constipation syndrome	2.0 (1.0–4.7)	1.8 (1.0–4.3)	0.82
Diarrhoea syndrome	1.2 (1.0–6.7)	1.3 (1.0–3.7)	1.00
Indigestion syndrome	3.1 (1.0–5.0)	1.6 (1.0–4.3)	0.13

GSRS, Gastrointestinal Symptom Rating Scale; SRS, Silver-Russell syndrome.

Most of the individuals (six of seven) who received enteral feeding and half of those (five of 11) who were orally fed reported no clinically relevant GI symptom domains. In one of the enterally fed individuals, medical records showed previous reflux symptoms despite no current GI symptoms being reported. At gastroscopy, biopsies showed reactive antral gastritis with intestinal metaplasia and a hiatal hernia, and the patient was treated with proton pump inhibitors. This patient was recommended annual follow-ups with gastroscopy. One patient who still received partial nutritional support via PEG reported intermittent dysphagia and was subsequently diagnosed with diffuse oesophageal spasm.

All but one of the seven individuals who reported moderate symptom severity in any of the GSRS domains had a history of GI disorders in childhood. In 6/18 (33%) individuals, no current GI symptoms were reported despite having experienced them during childhood. The prevalence of at least moderate GI symptoms severity in any GSRS domain during adulthood, along with the history of GI disorders during childhood, is shown in online supplemental figure 1.

Individuals fulfilling a DGBI diagnosis

Among the six individuals who completed the Rome IV Diagnostic Questionnaires, five met the Rome IV diagnostic criteria for at least one DGBI as shown in online supplemental table 2. The most common in these five individuals were functional dysphagia and functional dyspepsia with postprandial distress syndrome in three, followed by IBS and proctalgia fugax in two. Of those five diagnosed with at least one DGBI, four (80%) individuals had symptoms affecting multiple anatomical areas, and two were affected in all four. The overlaps between anatomical regions are demonstrated in online supplemental figure 2.

All self-reported cases of non-allergic asthma, one reported migraine; two were diagnosed with gastro-oesophageal reflux disease without oesophagitis. Three individuals reported using painkillers at least once a week; two used proton pump inhibitors, another two used sleeping pills, and one individual reported taking medication to manage diarrhoea.

Somatic symptoms and quality of life

The median PHQ-12 SS score among the six individuals was 7.5 (range: 0–14). Moderate anxiety disorder was observed in two individuals, one of whom reported using medication for anxiety symptoms. An additional individual had mild anxiety disorder. Half of individuals experienced moderate to severe depressive symptoms, with only one self-reporting the use of antidepressant medication. Additionally, one individual with minimal depressive symptoms reported taking antidepressant medication. The mean score in the General Quality of Life domain reflected a moderate overall quality of life; however, half of individuals reported a good quality of life.

Discussion

The present study explored short-term GI symptoms and quality of life experienced by adults and adolescents diagnosed with SRS and compared previously orally and enterally fed individuals. There was at least one GI symptom of moderate severity present in 61% of the individuals, and a trend indicating a higher prevalence of indigestion symptoms among females was observed. GI disorders during childhood were associated with the developing of GI symptoms later in life. Our data indicate that there is a need for GI follow-up in adults regardless of their way of feeding during childhood.

Approximately one-third of 18 individuals in our cohort reported at least moderate GSRS domain scores. The mean domain scores for abdominal pain, reflux and diarrhoea were comparable to a Swedish reference population. However, higher scores were observed for constipation (1.8 vs 1.5) and indigestion (1.9 vs 1.7), indicating that this might not be a gastroenterologically healthy population.²¹ Very little has been published on GI problems in adults with SRS. Lokulo-Sodipe et al¹² reported the presence of GI disease in 18.2% (6/33) in a cohort of SRS patients with the median age of 29 years, where five had gastro-oesophageal reflux disease and one had delayed gastric emptying. Additionally, one patient was diagnosed with IBS, while another patient showed symptoms that potentially indicated the same disorder. Although Lokulo-Sodipe et al¹² frequently mentioned childhood feeding difficulties, such as ‘poor appetite’ (27/32), nasogastric tube feeding (19/32) and gastrostomy feeding (3/33), no notable feeding issues were reported in adulthood. Several other studies, mostly case reports, described long-term outcomes in SRS, focusing mainly on metabolic syndrome factors such as hypertension, dyslipidaemia, insulin resistance and obesity.22,25

The most common GI complaint in our cohort belonged to the GSRS indigestion domain (borborygmus, abdominal distension, eructation and increased flatus). These findings suggest that individuals with SRS may present with digestive symptoms that, if not due to organic GI disease, are part of the most common diagnoses classified under DGBI.²⁶ At least one-third of 18 adults with SRS in our study experienced symptoms compatible with DGBI. From this perspective, our results resemble those of a large Swedish population-based study, which found DGBI prevalence of 39.1% with the bowel disorders most common (31.6%).²⁷ Notably, in our cohort, the distribution of DGBI appeared to differ, with ‘upper’ DGBI (dysphagia and dyspepsia) more frequently reported.

We found a tendency towards higher GSRS indigestion scores in orally vs enterally fed patients. This may reflect differences in symptom perception, as those with prior enteral feeding might interpret GI sensations differently. However, no statistical significance was found, suggesting similar GI follow-up between the orally and enterally fed individuals. A history of GI disorders during childhood was linked to the presence of GI symptoms in adults. According to Jones et al,²⁸ 10% to 20% of children with DGBI continue experiencing symptoms in adulthood. Specifically, 11% of those diagnosed with IBS and 20% with functional dyspepsia in childhood retained their diagnosis. That study also suggested that in IBS, childhood anxiety and depression were stronger predictors of adult-onset IBS than recurrence of childhood IBS. Similarly, childhood asthma and recurrent abdominal pain emerged as significant risk factors for IBS later in life. Interestingly, we found that all those five with DGBI had a diagnosis of asthma.

Regarding gestational age, we found no association between preterm birth and adult GI symptoms (data not shown). Surprisingly, Olen et al¹⁰ showed that birth before 37 weeks was associated with reduced IBS risk in young adulthood, particularly in females. They hypothesise that significant neonatal morbidity might overshadow GI complaints, which could be perceived as minor in comparison. One might expect that antibiotic treatment during perinatal life of preterm infants would lead to increased risk of disrupting gut microbiota and maturation of the intestinal immune system,²⁹ thereby increasing the risk of GI symptoms. Scandinavian cohort data linked antibiotic use, particularly penicillin, before age one to higher IBD risk, though no association was found for exposure between ages 1 and 3 years.³⁰ Missing infection data limited those findings. On the other hand, several studies have found no significant association between early-life antibiotics and later IBD.^{31 32} Swedish cohort data also reported no overall association with abdominal pain at the age of 12, though infant girls exposed to antibiotics had higher risk.³³ Female predisposition was associated with psychological distress. In our study, half of those with DGBI also had anxiety symptoms, with a trend towards higher prevalence among females. Indigestion symptoms were likewise more common in females. Prior research shows women generally report poorer well-being than men.³⁴ In addition, Ballard et al¹⁴ also found that women with SRS, particularly over age 30, often reported pain, disability, fatigue and feeling generally unwell.

Although previous reports have indicated a decrease in feeding difficulties and GI problems with age during childhood in patients with SRS,^{4 12} there is still a risk of underestimating GI problems in adult life in this population.

We need to acknowledge that the strength of the study lies in its ability to collect data from individuals with the rare SRS disorder, made possible by centralised treatment and follow-up. Even so, we acknowledge that the sample size and lack of a control group are fundamental limitations that are difficult to overcome without multicentre collaboration. The true prevalence of GI disorders may be underestimated, as many individuals have experienced GI symptoms since early childhood and may perceive them as normal, expressing sentiments such as mentioned by one patient in our cohort, ‘Sometimes I feel unwell, but I’m not sure if this is typical or if others without SRS feel the same’. It is also advisable to follow-up GI symptoms in individuals with SRS prospectively during childhood, adolescence and adult life, to achieve a better understanding of their true prevalence, underlying causes and prognosis.

Data availability statement

Data are available upon reasonable request.