Evaluation of Constipation in Pediatric Patients with Osteogenesis Imperfecta

Abstract

Background. Osteogenesis imperfecta (OI) is a genetic disorder of connective tissue that often presents with fractures and bone bowing. Constipation is a common symptom in OI and is likley multifactorial. To our knowledge no assessment of the relationship between OI type, OI complications, and constipation has been conducted in this vulnerable patient population. Methods. A retrospective chart and radiographic review was conducted to assess the relationship between constipation and OI type, age, gender, GI symptoms, mobility scores and overall functionality. A total of 98 children with OI were included. Radiographs were analyzed to determine the presence of acetabular protrusio and the degree of fecal loading. Results. Fifty-three female (54%) and 45 male (46%) OI children with a median age of 85.8 months were analyzed. OI types were 30.6% Type I, 30.6% Type III, 27.6% Type IV, and 11.2% other. Constipation was reported in 60%, 26.7%, 11.1%, and 54.5% of children with types III, I, IV, and other, respectively. There was a statistically significant association between the severity of OI and the report of constipation (P < .001). Participants who reported weakness had a higher percentage of constipation, 55.6% versus 21.1%, (P = .001). Sixty percent of children with acetabular protrusion reported constipation, while only 27.4% of children without acetabular protrusion reported constipation (P < .01). Conclusion. Our study demonstrates a potential link between constipation and severity of OI, with weakness as a likely contributing factor. This study also affirmed an association between acetabular protrusion and constipation. Constipation warrants further investigation in OI as to cause and treatment.

Introduction

Osteogenesis imperfecta (OI) is a genetic disorder of connective tissue most often characterized by qualitative or quantitative errors in the production of Type I collagen. Specific pathogenic variants, most commonly in COL1A1 or COL1A2, affect an individual’s ability to synthesize normal Type I collagen. The result of these changes includes the production of a weakened bone matrix, which leads to bone fragility with frequent fractures, long bone bowing, and scoliosis, among other complications. Manifestations of OI typically include skeletal abnormalities such as increased fracture susceptibility, low bone mineral density, scoliosis, hyperlaxity of ligaments and skin, and short stature. ¹ Other findings can include hearing loss, blue sclera, chest wall abnormalities, and motor skill delays. ¹

OI is commonly grouped via the Sillence classification system into Types I-IV. Type I OI is both the mildest form and the most common. Type I OI is related to a quantitative deficiency of structurally normal collagen, characterized by blue sclerae and minimal bone deformities. Type II OI is the most severe—most infants die in utero or shortly after birth. Type III OI is characterized by extremely fragile bones that are prone to fractures and malformation. This is the most severe form observed in children who survive the neonatal period. Individuals with OI often have scoliosis and are short in stature. Type IV OI has the most variable degree of deformity of the long bones, including an affected spine and normal sclerae.^2,3

Constipation, or a decrease in the frequency of stool or bowel movements, is often caused by stool withholding, insufficient dietary fiber, dehydration, lack of physical activity, colonic obstruction, medications, and other illnesses. Constipation is also a common sequela of OI for many children and adults with OI and has been reported in 26% to 58% of children with OI.^4,5 Literature suggests constipation is common in people with Type III OI; however, short stature and acetabular protrusion have been identified as contributing factors to constipation symptoms. ⁵ Uncontrolled constipation may lead to fecal impaction which can lead to fecal incontinence (encopresis), difficulty with potty training, and negative social stigma.

When individuals with OI present with signs and symptoms of constipation there are some specific history and exam considerations to include. History of present illness should assess stool frequency, consistency size, or ignoring the urge to defecate followed by physical examination of the abdomen, perineum, and anorectum. Due to the fragility of children with OI, x-ray should be considered to help assess stool load while circumventing the increased risk of injury or fracture from physical examination.

Despite proposed associations between constipation, acetabular protrusion, and OI severity, the multifactorial etiology is unclear due to limited investigation in individuals with OI.^4,6,7 Due to the prevalence of constipation in OI, this study aims to characterize the relationship between constipation incidence and OI disease severity, age, sex, and mobility to assist with the early identification and potential treatment of constipation in children with OI. We hypothesize that constipation in OI is associated with demographic and clinical characteristics. Elucidation of these relationships may provide clinicians with valuable insight while guiding recommendations for mitigating and preventing constipation in this population.

Methods

Study Population

A retrospective review of 98 children within our OI registry who were dual enrolled in the Brittle Bone Disorders Consortium treated at our hospital was performed. Approval for this study was obtained from our local Institutional Review Board. Inclusion criteria include: clinical or genetic diagnosis of OI. Exclusion criteria include the inability to return for yearly clinic visits or another genetic diagnoses besides OI. Collected demographic data included gender, age in months, and type of OI. OI types outside of the I-IV range were aggregated into Other type, to protect confidentiality. Additionally, data related to constipation and quality of life were collected, including gastrointestinal symptoms reported by children or their parents, Functionality & Mobility Scale (FMS), ⁸ and Gillette Functional Assessment Questionnaire (GFAQ). ⁹ All of this data is routinely collected as a part of the yearly multidisciplinary OI clinic and for subjects who are enrolled in the Brittle Bone Disorders Consortium.

Analysis of Constipation

Medical records as part of their annual routine visit were reviewed for the clinical appearance of constipation. Radiographs including the spine and lower extremities are routinely obtained as a part of patients yearly assessment in the clinic. We utilized spine anteroposterior (AP) spine radiographs to assess constipation using the Blethyn method to determine what degree of fecal load was present. Grade 0 represents stool only in the rectum, while Grade I include stool in the rectum and cecum but discontinuous elsewhere. Grade II is defined as feces in the rectum and cecum, continuously affecting all segments. Grade III is the most severe, defined as feces in the rectum and cecum, and continuous with dilation of the colon and impaction of the rectum. ¹⁰

Radiographic Evaluation of Acetabular Protrusio

All AP pelvis or lower extremity radiographs were evaluated for the presence of acetabular protrusio. Intrapelvic displacement of the medial wall of the acetabulum is often seen in the diagnosis of acetabular protrusio. The medial displacement of the femoral head past the ilioischial line of the pelvis was used to determine if protrusio was present. ⁵

Statistical Analysis

The primary outcome of this study was investigating relationships between OI type and the incidence of reported constipation. Descriptive statistics for continuous data are presented as medians and interquartile ranges (IQRs); categorical variables are presented as frequencies and percentages. Associations between categorical variables of interest and constipation status were assessed using Chi-Square tests or Fisher’s exact tests when expected cell sizes were low. If a categorical variable had ordered categories, a Cochran-Armitage trend test was used. Wilcoxon Rank Sum tests were used to examine differences in distributions of skewed or ordinal scaled variables of interest between children with and without reported constipation. All analyses were performed using SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA).

Results

Study Population

Fifty-three female (54%) and 45 male (46%) children with OI with a median age of 85.8 months (range: 1.2, 268 months) were included in this analysis. There were 30 (30.6%) Type I, 30 (30.6%) Type III, 27 (27.6%) Type IV, and 11 (11.2%) Other OI type children. See Table 1 for subject details. Overall, constipation was reported in 35 individuals (35.7%). No statistically significant differences in age or gender distribution were observed between constipation groups. The median age of children with and without reported constipation was 67.5 months (IQR: 39.9, 117.6) and 87.7 months (IQR: 44.4, 160.4), respectively (P = .16). Eighteen males (40%) and 17 females (32.1%) reported constipation (P = 0.42).

Table 1.

Subject Gender, Age, and OI Type.

Subject identifiers	All patients (n = 98)n, (%)
Gender
Female	53 (54.1%)
Male	45 (45.9%)
Age (in months)
Median (IQR)	85.8 (40.7, 148.2)
Subtype of OI
I	30 (30.6%)
III	30 (30.6%)
IV	27 (27.6%)
Other	11 (11.2%)

There was a significant association between constipation and OI type (P < .001), see Table 2; constipation was reported in 3 (11.1%) children with type IV, 8 (26.7%) children with type I, 18 (60%) children with type III, and 6 (54.5%) of the children classified as having an other OI type.

Table 2.

Gender, Age, and OI Type in Relation to Constipation.

	Reported constipation		P-value
Patient Gender, Age and OI Type	No (n = 63)n (%)	Yes (n = 35)n (%)
Gender			.42
Female	36 (67.9%)	17 (32.1%)
Male	27 (60.0%)	18 (40.0%)
Age (in months)			.16
Median (IQR)	87.7 (44.4, 160.4)	67.5 (39.9, 117.6)
Subtype of OI			<.001
I	22 (73.3%)	8 (26.7%)
III	12 (40.0%)	18 (60.0%)
IV	24 (88.9%)	3 (11.1%)
Other	5 (45.5%)	6 (54.5%)

Constipation, Functionality, and Mobility

Perceptions of mobility limitations of both children with OI and their guardians were assessed using the FMS. A significantly higher percentage of children reported constipation among those who reported weakness related to walking compared to those who did not report weakness (55.6% vs 21.1%, P = .001). Those who reported endurance as a limiting factor for their walking ability had significantly higher constipation (48.1%) compared to those who did not (25.8%), P = .045. There was no significant difference in the percentage of participants who reported constipation between those who reported pain related to mobility (40.0%) and those who did not (39.5%) (P = .97). Safety concerns, balance, and mental ability were possible limitations to walking abilities, each of which showed no significant association with reported constipation (P = .65, P = .83, P = 1.00). All patients’ mobility was further assessed via the GFAQ; the proportion of children with GI issue tended to decrease with increases in typical walking ability, P = .02.

Radiographic Analysis of Fecal Load and Acetabular Protrusion

Investigation of x-rays using the Blethyn Scale was used to determine any differences between grade of fecal loading and type of OI. The percentage of reported constipation increased with increasing grade, from 20% within grade 0, to 52% within grade III (P = .02). Twenty-five (25.5%) demonstrated radiographic evidence of acetabular protrusion, and constipation was more commonly observed in children with acetabular protrusion compared to those without pelvic deformity (60.0% vs 27.4%, P = .003). A representative example of a child with type III OI with radiographically evident constipation and acetabular protrusion is displayed in Figure 1. Table 3 indicates the position the child was in during image acquisition.

Figure 1.

Example of a 7-year-old female with type III OI, note significant acetabular protrusion (A) on AP bilateral lower extremity x-ray, and large stool and gas burden (B) on seated scoliosis x-ray, indicative of significant constipation.

Table 3.

X-Ray Image Participate Position.

x-ray position
Unknown	1 (1.0%)
Sitting	20 (20.4%)
Standing	20 (20.4%)
Supine	57 (58.2%)

Discussion

Constipation is a reoccurring comorbidity in children and adults with OI which may be due to physical inactivity, bowel stasis secondary to fracture pain and/or medication use, or pelvic deformity causing obstruction; however, these etiologies are purely speculative. Literature specific to this population is limited,^4,6,11 yet there are numerous studies of constipation in pediatric populations.

The global prevalence of pediatric functional constipation is estimated to be between 0.3% and 29.6%. ¹¹ Constipation frequency has been shown to be increased in children and adults with musculoskeletal diseases. A cross-sectional observational study of constipation in 152 children with severe cerebral palsy by Veugelers et al ¹² reported a constipation rate of 57%, a laxative utilization rate of 55%, and continued constipation in 36% of patients taking laxatives. As expected, both were correlated with the severity of neuromuscular disease and concomitant use of medications that slow gastrointestinal mobility. More recently, Martins et al ⁶ conducted a descriptive study of 31 pediatric patients with OI and reported a functional constipation rate of 38%. Further, 26% of the parents reporting difficulties with their child’s toilet training noted severe constipation and multiple fractures as the principal reasons for unsuccessful toilet training, suggesting constipation is associated with neuromuscular impairments, immobility, and pain. We found higher reported constipation rates among our children with OI (35.7%) compared to the general pediatric population, similar rates to investigations of children with OI, and lower rates than those with cerebral palsy. Sixty percent and 11% of children with type III and type IV OI, respectively, reported constipation which may be a product of decreased mobility and increased pain associated with a more severe OI type.

These findings suggest there is a significant association between OI severity and constipation, yet all etiologies in this population have yet to be investigated. Previous authors have identified pelvic deformities, pelvic narrowing, and aberrant bone remodeling as contributory factors.^4,5,7 More severe OI types have a higher risk of acetabular protrusion, which may result in medial encroachment of the colon and subsequent disruption of normal bowel function or motility. Reports of acetabular protrusion in individuals with OI range between 33% and 55%, with an estimated 70% in individuals with type III OI. ⁵ Lee et al ⁴ conducted a single institution retrospective study of 43 subjects with type III OI and reported chronic constipation and abdominal pain more frequently in individuals with OI and acetabular protrusion than those without acetabular protrusion. These trends were similar in the present study as constipation was reported in 15 of the 25 children with radiographic evidence of acetabular protrusio. This patient cohort includes 70% of children with type III, IV or other which is skewed to more severe types based on enrolled patients in the Brittle Bone Disorders Consortium at our institution. In light of this the findings in this cohort may not be able to be generlized across all OI subtypes. Early identification and management of acetabular protrusion in individuals with OI with subsequent referral to gastroenterology should be pursued to minimize complications and reoccurrence of constipation.

The effects of mobility and physical activity on gastrointestinal motility are well known, irrespective of comorbidities. In an evaluation of the effects of a sedentary lifestyle on constipation in Chinese adolescents, Huang et al ¹³ reported a linear relationship between insufficient physical activity and sedentary behaviors and constipation frequency. However, this is further exacerbated in children without ambulatory capabilities due to severe chronic disabilities. ⁹ Regular physical activity decreases the likelihood of constipation, but individuals with OI may not be capable of meeting these requirements or may be confined to wheelchair use, significantly affecting their endurance and mobility. As such, we investigated the relationships between mobility, limitations to mobility, and constipation. In our sample of children with OI, those that reported weakness as a barrier to mobility were more likely to report constipation. This may be due to reduced bone quality and propensity to fracture, which leads to immobility and subsequent constipation. Interestingly, we found no significant difference in the reporting of safety concerns, pain, balance, or mental ability as limitations to mobility between those who reported constipation versus those who did not. However, endurance as a limitation to mobility was significantly more frequent in children with constipation than those without constipation. This may be attributed to increased weakness in OI patients as generalized weakness may impact endurance, resulting in limited physical activity which contributes to constipation.

While this analysis of constipation presents one of the largest cohort of children with OI (n = 98) in the literature, it is not without limitations. As this was a retrospective cohort we did not perform a sample size calculation prior to assessing the data. The retrospective nature of this study limited our ability to collect parameters that impact the risk of constipation such as dietary habits, fluid or fiber intake, and medication use. Additionally, this study defined constipation based on self- or parent reports of bowel habits rather than the ROME III criteria. ¹⁴ However, large-scale studies commonly use a single-item questionnaire in the assessment of bowel frequency. ¹⁵ Another limitation of the study is potential challenge of positioning the children during the imaging acquisition. We did not use abdominal specific radiographs for this study and instead utilized spine images, supine, seated, and standing that are a part of our yearly evaluation of the children with OI. Positioning for standard imaging alone can be challenging in this population and the images were not specifically obtained to assess for constipation and therefore validity of fecal load in the images cannot be discussed.

Radiographic evaluation of fecal load may be another limitation of the present study, as constipation is a clinical diagnosis and the presence of stool is expected in the colon, with an x-ray used only to detect fecal load and rectal impaction. Yet, the utility of radiographs in the evaluation of constipation is conflicting. An evaluation of abdominal x-ray in the acute care setting reported imaging shows the presence of stool in nearly as many individuals who meet clinical criteria for constipation as those who do not, suggesting it may not be useful in the diagnosis of constipation (49% positive predictive value, only 27% sensitive for the diagnosis of constipation). ¹⁵ In contrast, a review by Levy et al ¹⁶ noted that abdominal radiography may be beneficial in some clinical scenarios. For instance, x-ray would benefit the evaluation of constipation if digital rectal examination or abdominal palpation is limited (such as in suspicion of sexual abuse or in highly fearful/anxious children). Further, x-ray may provide clinical utility in the setting of extreme obesity when abdominal palpation is less reliable. Many children with OI cannot tolerate physical exam of the abdomen, and radiographic imaging of the spine was already conducted; thus, x-ray served as an additional assessment methodology in our study. Increases in x-ray grades II & III are more commonly seen in patients reporting constipation. ⁵

In the present study, there was a significant linear association between x-ray grade and fecal load; however, there were still several children with grade II and III x-rays without constipation. In comparison to other radiographic fecal loading scales, the Blethyn scale was found to have 79% sensitivity and 92% specificity ¹⁷ and few other reliable quantification systems exist. Radiographic quantification of fecal load is still inherently subjective and suboptimal sensitivity limits its ability to differentiate between symptomatic constipation and normal stool in some cases. Accuracy of abdominal assessment may be further limited by the fact that images in this series were taken for the analysis of osseous structures. Positioning for these films could also impact the ability to clearly visualize the pelvic region to assess distal colonic fecal impaction.

Conclusion

Our retrospective investigation is to our knowledge the largest cohort evaluating constipation in the setting of OI and indicated an association between constipation report and OI severity, with weakness a likely contributing factor. This study also affirmed an association between acetabular protrusion and constipation. This apparent risk factor for constipation deserves further attention in future studies, clinical management, and evaluation. Since constipation is reported by many children and parents in this study, the use of a standardized constipation survey in individuals with OI could increase provider awareness of this issue. Future directions for this research include expanding our sample size and exploring other variables that may contribute to constipation in this population. Providers caring for children and adults with OI should be aware of the predisposition for constipation, pursue early evaluation, and aggressively manage constipation to optimize outcomes in this especially vulnerable patient population.