Megacystis Microcolon Intestinal Hypoperistalsis Syndrome: A Case Series With Long-term Follow-up and Prolonged Survival

Abstract

Objectives:

Describe clinical characteristics, management, and outcome in a cohort of megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) patients.

Methods:

We conducted a retrospective chart review of MMIHS patients followed at a large transplant and intestinal rehabilitation center over a period of 17 years.

Results:

We identified 25 patients with MMIHS (68% girls, 13 transplanted). One transplanted and 1 nontransplanted patient were lost to follow-up. We estimated 100, 100, and 86% for 5-,10-, and 20-year survival, respectively, with only 1 death. Of the 22 patients alive at the time of study (11 transplanted, 11 nontransplanted), median age was 9.2 years (range 2.7–22.9 years). Longest posttransplant follow-up was 16 years. Seventeen patients had available prenatal imaging reports; all showed distended bladder. Eight had genetic testing (5, ACTG2; 2, MYH11; 1, MYL9). Almost all patients had normal growth with median weight z-score −0.77 (interquartile range −1.39 to 0.26), height z score −1.2 (−2.04 to −0.48) and body mass index z-score 0.23 (−0.37 to 0.93) with no statistical difference between transplanted and nontransplanted patients. All nontransplanted patients were on parenteral nutrition with minimal/no feeds, and all except 1 of the transplanted patients were on full enteral feeds. Recent average bilirubin, INR, albumin, and creatinine fell within the reference ranges.

Conclusions:

This is the largest single-center case series with the longest duration of follow-up for MMIHS patients. In the current era of improved intestinal rehabilitation and transplantation, MMIHS patients have excellent outcomes in survival, growth, and liver function. This observation contradicts previous reports and should alter counselling and management decisions in these patients at diagnosis.

Megacystis microcolon intestinal-hypoperistalsis syndrome (MMIHS) is a rare congenital disorder of smooth muscles, characterized mainly by enlarged bladder without mechanical obstruction, decreased intestinal motility, and microcolon (1,2). Around 450 cases have been reported in the literature (3,4) since Berdon et al (5) first described the disease in 1976 in a series of 5 female patients. Diagnosis commonly occurs prenatally or within the first year of life. The most common prenatal findings include enlarged bladder with normal or increased amniotic fluid on ultrasound (6,7).

MMIHS occurs more commonly in girls, with a reported female-to-male ratio of 2.3 : 1 (3). Most cases arise from sporadic de-novo mutations. The majority follow autosomal dominant inheritance because of mutations in ACTG2 (8–11) and constitute one of the most severe forms of ACTG2-related disorders (12). Less commonly, autosomal recessive cases because of mutations in LMOD1 (13), MYH11 (14–16), MYL9 (17), MYLK (18) have been reported, occasionally with confirmed parental consanguinity (3,19).

Historically, prognosis and survival rates of this disease have been poor, often regarded as a fatal condition (4). Death occurs because of sepsis with multiorgan failure, malnutrition, and complications from parenteral nutrition (PN) including catheter-related sepsis and chronic liver failure (1). The reported survival rates have, however, improved compared with historical data (1,20) with advances in intestinal rehabilitation and transplantation. There is limited current data on the long-term follow-up and survival of these patients. We aimed to describe the clinical characteristics, management, outcome, and survival of the MMIHS patients followed at a large transplant and intestinal rehabilitation center.

METHODS

We conducted a retrospective chart review of all patients with a clinical diagnosis of MMIHS who were followed by the Intestinal Care and Rehabilitation (ICARE) team and the Abdominal Transplant Team at the UPMC Children’s Hospital of Pittsburgh. We identified the MMIHS patient cohort from the patient database maintained by the ICARE team at our hospital since 1996 (21). Data was collected by review of the electronic medical record of each patient from the earliest available records until November 15, 2019, which was roughly about 17 years (2002–2019). Demographics, clinical characteristics, genetic testing, nutritional status, imaging studies, laboratory values, and surgical data were collected and analyzed for both transplanted and nontransplanted patients.

The study was approved by the University of Pittsburgh Institutional Review Board (Protocol # STUDY18120118). Study data were collected and stored in REDCap (Research Electronic Data Capture), a secure web-based platform designed to support data capture for research studies, hosted at the University of Pittsburgh (22,23).

All patients, either transplanted or not transplanted, with a clinical diagnosis of MMIHS were included in the final patient cohort. Patients who died or were lost to follow-up during the study period were excluded from the descriptive statistical analysis (see Figure, Supplemental Digital Content 1, http://links.lww.com/MPG/C97, which demonstrates the patient selection flowchart). Data collected on the transplanted patients included age at the time of transplant, type of transplant, and time since transplant. The age and time since transplant were calculated as of November 2019. For the nontransplanted patients, we collected the average gastrointestinal output including gastrostomy tube output and ileostomy output from the most recent outpatient clinical encounter. We determined mode of nutrition and nutritional status, defined by growth parameters from the most recent clinical encounter. We collected laboratory values as a 3-month average before April 2019 if there was no known admission for sepsis during that period, as the infection and medications can possibly alter the lab values. If a patient had an admission for sepsis during that period, we collected the average laboratory values 3 months before the admission.

Our primary aim was to summarize the clinical and demographic characteristics including the cumulative survival of all the patients. Our secondary aim was to describe the outcomes of organ function and nutritional status (comparing transplanted and non-transplanted patients). Descriptive statistics were used to summarize the data as mean with standard deviation and median with interquartile range for normally and nonnormally distributed data, respectively. Comparison of growth parameters and laboratory values between transplanted and nontransplanted patients were done using Mann-Whitney U test, and the statistical significance was defined as a P value of <0.05. Overall survival was described using the Kaplan-Meier method. Stata v15 (College Station, TX) was used for data analysis.

RESULTS

We identified 25 patients with MMIHS followed at UPMC Children’s Hospital of Pittsburgh. Table 1 details their baseline demographic and clinical characteristics.

TABLE 1.

Baseline demographics and clinical characteristics of the megacystis microcolon intestinal hypoperistalsis syndrome patients

Total number of MMIHS patients	25
Included in the analysis	22 (non-Tx: 11, Tx: 11)
Lost to follow-up	2 (non-Tx: 1, Tx: 1)
Deceased	1 (Tx: 1)
Demographics
Age at diagnosis in months, median (range)	<1 (0–48)
Female sex, n (%)	17 (68)
Transplant status
Transplanted	13 (1, retransplanted)
Types of transplant
MVT	3
MVT + colon	5
Mod MVT	1
Mod MVT + colon	1
Small bowel, pancreas, liver	2
Small bowel + colon	1
Listed	11
Evaluated	1
Age at transplant in years, median (range)	3.1 (1.1–18.6)
Clinical characteristics
Genetic testing
Tested, n (%)	8 (32)
ACTG2	5
MYH11	2
MYL9	1
Malrotation, n (%)
Present	15 (60)
Absent	6 (24)
Unknown	4 (16)

MMIHS = megacystis microcolon intestinal hypoperistalsis syndrome; Mod MVT = modified multi-visceral transplant; MVT = multi-visceral transplant; non-Tx = nontransplanted; Tx = transplanted.

Baseline Characteristics

The median age of diagnosis was <1 month (range: prenatally/at birth to 48 months). Prenatal imaging reports were available on 17, and all had abnormal imaging, which showed distended urinary bladder. All 8 patients who had genetic testing were identified to have a known mutation described in MMIHS: 5, ACTG2; 2, MYH11; 1, MYL9. Upper gastrointestinal series showed malrotation in 14 of 20 patients with an available study.

All patients underwent transplant evaluation, the median age at transplant evaluation was 12 months (range: 2 months to 16.3 years) and 24 were ultimately listed. Thirteen patients received intestinal or multivisceral transplants, and the rest 11 patients are still actively listed. The 13 transplanted patients included 8 multivisceral transplants, 2 modified multivisceral transplants, 2 liver-small bowel transplants, and 1 isolated small bowel transplant. Five among the 13 patients underwent colon transplant. One patient required retransplant because of chronic graft rejection. The median age at the time of transplant was 3.1 years (range: 1.1–18.6 years).

Survival

One patient each from transplanted and nontransplanted group were lost to follow-up. Of the remaining 23 patients, only 1 transplanted patient died during the review period. Figure 1 shows the Kaplan-Meier survival curve for the entire cohort. Survival was estimated to be 100%, 100%, and 86% at 5, 10, and 20 years, respectively. The remaining 22 patients were included in the analysis of current clinical characteristics: 11 transplanted and 11 nontransplanted patients. The median age of the 22 patients at the time of analysis was 9.2 years (oldest 22.9 years). The longest duration of follow up post-transplant was 16.6 years (median 6.1 years).

FIGURE 1.

Kaplan-Meier survival curve for all patients with megacystis microcolon intestinal hypoperistalsis syndrome.

Current Clinical Characteristics

All 11 nontransplanted patients require PN with lipids (Intralipid: 1, SMOFlipid: 7, Omegaven: 3). Eight patients receive minimal oral feeds. The remaining 3 receive no oral feeds because of significant oral aversion or concern for aspiration. Excluding 1 patient who had been transplanted in the month before this analysis, all transplanted patients receive full enteral feeds without parenteral calories. Eight transplanted patients feed orally whereas 2 remain on enteral tube feeds because of significant oral aversion. Two of the transplanted patients require intravenous fluids (Table 2).

TABLE 2.

Current clinical characteristics of megacystis microcolon intestinal hypoperistalsis syndrome patients, as of November 2019

Current age in years, median (range)	9.2 (2.7–22.9)
Time since transplant in years (n = 11), median (range)	6.1 (2.3–16.6)
Nutritional management
Total parenteral nutrition dependence, n (%)	12 (55)
Non-Tx	11
Tx	1
Enteral autonomy, n (%)	10 (45)
Non-Tx	0
Tx	10
Oral feeds, n (%)
Full	8 (36)
Minimal	8 (36)
None	6 (27)
Surgical interventions
Gastrostomy tube, n
Non-Tx	11
Tx	4
Ileostomy present, n
Non-Tx	7
Tx	3

N = 22; non-Tx patients: 11, Tx patients: 11. MMIHS = megacystis microcolon intestinal hypoperistalsis syndrome; non-Tx = non-transplanted; Tx = transplanted.

Almost all the patients were noted to have nearly normal growth parameters, with a median weight z score of −0.77 (interquartile range [IQR] −1.39 to 0.26), median height z-score of −1.2 (IQR −2.04 to −0.48) and median body mass index z-score of 0.23 (IQR −0.37 to 0.93) with no statistical difference between transplanted and nontransplanted patients (Table 2). Recent laboratory results showed that both transplanted and nontransplanted patients had similar total bilirubin, direct bilirubin, and albumin. International normalized ratio (INR) and creatinine were significantly different amongst the groups but values were within the reference range (Table 3).

TABLE 3.

Growth parameters and average laboratory values of the megacystis microcolon intestinal hypoperistalsis syndrome patients

	All	Non-Tx	Tx	Non-Tx versus Tx P value
Growth parameters, median (IQR)
Weight z-score	−0.77 (−1.39 to 0.26)	0.66 (−0.99 to −0.28)	−1.06 (−2.01 to 0.36)	0.62
Height z-score	−1.20 (−2.04, −0.48)	−1.07 (−1.59 to −0.61)	−1.92 (−2.95 to 0.35)	0.45
BMI z-score	0.23 (−0.37 to 0.93)	0.23 (−0.37 to 0.94)	0.22 (−1.04 to 0.93)	0.85
Laboratory values (3-month average), median (IQR)
Total bilirubin	0.51 (0.32–0.68)	0.63 (0.47–0.68)	0.34 (0.28–1.38)	0.11
Direct bilirubin	0.23 (0.12–0.39)	0.3 (0.1–0.43)	0.2 (0.13–0.25)	0.31
Albumin	3.5 (3.0–3.9)	3.3 (2.9–3.9)	3.7 (3.2–4.03)	0.13
INR	1.1 (1.0–1.2)	1.2 (1.1–1.2)	1 (0.99–1.1)	0.01
Creatinine	0.4 (0.28–0.44)	0.37 (0.23–0.4)	0.43 (0.39–0.77)	0.01

INR = international normalized ratio; IQR = interquartile range; MMIHS = megacystis microcolon intestinal hypoperistalsis syndrome; non-Tx = nontransplanted; Tx = transplanted.

Statistical significance defined as P-value <0.05.

Gastrostomy tubes were present in all nontransplanted patients and in 4 transplanted patients. Ileostomy was present in 7 of the nontransplanted patients. Of the transplanted patients, 2 had ileostomy, 4 had colostomy, and 1 had both ileostomy and colostomy (Table 2). Of the nontransplanted patients, mean gastrointestinal output was 64 mL/kg (n = 11), with mean gastrostomy tube output of 62.5 mL/kg (n = 10), and mean ileostomy output of 11 mL/kg (n = 7).

DISCUSSION

We present one of the largest single-center case series of MMIHS patients describing the longest duration of follow-up for both transplanted and nontransplanted patients. The survival of MMIHS patients have improved significantly in the current era of intestinal rehabilitation and transplantation. Notably, both the transplanted and nontransplanted MMIHS patients had nearly normal growth parameters and liver function, and almost all patients achieved enteral autonomy after transplantation. Our study also provides one of the longest follow-up of the MMIHS patients after transplantation, providing data on the long-term outcome of these patients.

MMIHS is one of the rare and severe forms of hollow viscus myopathy reported to be associated with significant morbidity. Survival rates have improved with recent advances in management of PN complications and intestinal transplantation. Examples of these advances include: strict monitoring of PN, limiting glucose infusion rate, cycling PN, switching to different types of lipid emulsions, such as Omegaven or SMOFlipid to prevent PN cholestasis, multidisciplinary team approach, encouraging oral feeds, use of lock therapy to prevent central venous catheter-associated blood stream infection, strict monitoring of antirejection therapy. Puri et al had reported an overall survival rate of 19.7%, which had improved from 12.6% (1976–2004) to 55.6% (2004–2011) and Sohet al reported 5- and 10-year survival rates of 63% and 57%, respectively in a nationwide survey of MMIHS patients in Japan(1,2,20). Our study showed 100% 10-year survival, and the oldest patient in our study was 22.9 years of age. Data on long-term post-transplant follow-up on MMIHS patients are limited. In 1999, Masetti et al (24) reported outcomes of multivisceral transplants on 3 MMIHS patients, with 2 patients who survived 17 months post-transplant. Loinaz et al (25) described outcomes of multivisceral transplants of 12 patients with severe gastrointestinal dysmotility, including 6 MMIHS patients, and reported a 3-year survival of 50%, with longest follow-up of 7 years. In our study, the transplanted patients were followed for a median period of 6.1 years, with the longest post-transplant follow-up of 16.6 years. The collaborative management approach by experts in both intestinal rehabilitation and transplantation allowed for a reduction in PN complications and timely referral to transplant, likely contributing to the excellent outcomes.

All of these patients begin life dependent on PN. Many ultimately undergo intestinal transplantation, and most of them achieve enteral autonomy after transplant (4). Loinaz et al (25) described post-transplant outcomes of MMIHS patients, all of whom tolerated enteral feeds and were weaned off PN. In our study, all of the transplanted patients except 1, who was <1-month post-transplant, achieved enteral autonomy. A recent study suggested that promoting safe oral feeds pre-transplant is one of the main predictors of successful eating after transplant, which can significantly impact the quality of life of these patients (26). In our study, we observed that among the transplanted patients who achieved enteral autonomy, 8 were on full oral feeds and among the 11 nontransplanted patients, 8 were on at least minimal oral feeds. We suspect that patients who were successfully transitioned to full oral feeds after transplant were the ones who were encouraged to take some oral feeds before transplant. The perceived positive impact of pre-transplant eating should encourage providers to start early feeding therapy to manage oral aversion even during the pre-transplant period.

Sepsis with multiorgan failure, malnutrition, catheter-related sepsis, and PN-associated liver disease have all been associated with the increased morbidity and mortality in MMIHS patients (1). Intestinal and multivisceral transplantation is considered an appropriate therapeutic option for patients with irreversible intestinal pathology, such as dysmotility (25). Care at experienced centers with multidisciplinary expertise has been known to improve the outcome of patients on PN (27). Innovations in PN management have reduced complications, improved growth, and increased survival of the patients with intestinal failure (21). Among the MMIHS patients followed at our center, both transplanted and nontransplanted patients were noted to have relatively normal growth and liver function. Management of our MMIHS patients by the ICARE and transplant teams, focusing on strategies to mitigate the complications of long-term PN, optimize the timing of transplantation, and deliver quality post-transplant care, likely contributed to the improved outcomes in our patients. We recommend early referral to an intestinal transplant center to allow for interdisciplinary coordination between the intestinal rehabilitation and transplant teams.

MMIHS patients frequently undergo surgical procedures early for bowel decompression including gastrostomy, ileostomy, jejunostomy, and colostomy. Some authors had suggested that most of these interventions are probably not necessary or helpful in the management of these patients (1,4,20). In our nontransplanted MMIHS patients, all of them had gastrostomy tubes and 7 had ileostomies. The average gastrointestinal output was 64 mL/kg and majority of that was gastrostomy tube output (62.5 mL/kg) and only minimal ileostomy output (11 mL/kg). MMIHS patients do not respond to prokinetic agents or gastrointestinal hormones and no curative treatments are known so far (1,28). In our center, we strongly believe that gastrostomy tubes are of great importance for these patients as they allow a nonfunctional stomach to decompress, reduce nausea and vomiting, and limit the development of oral aversion. Conversely, the minimal ileostomy output raises the question of the utility of an ileostomy for bowel decompression. We believe the need for these surgical interventions should be carefully evaluated and should be individualized to avoid unnecessary procedures.

Our study is limited as a retrospective analysis with a relatively small sample size, although one of the largest single-center samples in this population. Some might consider a risk of selection bias in our study as all these patients were cared for at a single tertiary center with longstanding experience in intestinal rehabilitation and transplant, which most likely positively impacted the outcome in these patients.

CONCLUSIONS

This study is one of the largest single case series describing long-term follow-up for both transplanted and nontransplanted MMIHS patients. Both long-term PN and transplantation are acceptable long-term management options in these patients and the improved outcome is likely linked to the multidisciplinary management approach. With the current era of improved intestinal rehabilitation and transplantation, patients with MMIHS shows excellent outcome in survival rates, normal growth, and liver function. This observation contradicts the bleak picture previously reported in the literature for these patients and should alter counselling and management decisions in these patients at the time of diagnosis.

What Is Known

• Megacystis microcolon intestinal hypoperistalsis syndrome is a rare smooth muscle myopathy mainly affecting the intestines and urinary bladder.

• These patients are managed by either total parenteral nutrition or intestinal transplant as no curative treatment is known.

• The previously reported survival rates of these patients are very poor.

What Is New

• Excellent survival rates are seen in megacystis microcolon intestinal hypoperistalsis patients with advances in management of intestinal failure and transplantation.

• Both transplanted and nontransplanted megacystis microcolon intestinal hypoperistalsis patients show nearly normal growth and liver function.