Hereditary chronic intestinal pseudo-obstruction caused by a rare MYH11 mutation: A case report

Abstract

BACKGROUND

Chronic intestinal pseudo-obstruction (CIPO) is a rare and debilitating disorder, characterized by severe impairments in gastrointestinal motility. The affected sites include the enteric/intrinsic autonomic nerves (neuropathy), intestinal smooth muscle cells (myopathy), and interstitial cells of Cajal (mesenchymopathy). The etiology can be genetic, idiopathic, or acquired. Owing to its nonspecific clinical presentation and lack of definitive diagnostic methods, misdiagnosis of CIPO is common.

CASE SUMMARY

This case involved an older male with insidious onset in adolescence who presented with postprandial bloating, intermittent diarrhea, and weight loss. During the disease course, the patient experienced two episodes of intestinal obstruction. Imaging revealed multisegmental digestive tract abnormalities (gastric emptying disorder, significant duodenal dilatation, and segmental jejunal dilatation). Whole-exome sequencing revealed a rare MYH11 mutation [NM_001040113.2: C.5819del (p.Pro1940HisfsTer91)], confirming hereditary myopathic CIPO.

CONCLUSION

This report adds to our current understanding of CIPO etiology by reinforcing the role of MYH11 variants in the pathogenesis of the CIPO phenotype.

Key Words: Rare disease; Chronic intestinal pseudo-obstruction; Gastrointestinal motility disorder; MYH11; Case report

Core Tip: Chronic intestinal pseudo-obstruction (CIPO) is a rare disorder, characterized by severe impairments of gastrointestinal motility. This case involves an elderly male with an insidious onset during adolescence and a disease course spanning several decades, who experienced two episodes of intestinal obstruction requiring ileocecal resection. The histopathological findings confirmed the diagnosis of CIPO. Whole-exome sequencing identified a rare heterozygous MYH11 mutation [NM_001040113.2: C.5819del (p.Pro1940HisfsTer91)], confirming the diagnosis of hereditary myopathic CIPO. This case provides evidence to support the role of MYH11 variants in the CIPO phenotype.

INTRODUCTION

Chronic intestinal pseudo-obstruction (CIPO) is characterized by severely impaired gastrointestinal motility. Owing to their nonspecific clinical manifestations and a lack of definitive diagnostic methods, patients are often diagnosed at an advanced stage, with many undergoing unnecessary surgical procedures and experiencing high rates of misdiagnosis, delayed diagnosis, and inappropriate treatment. CIPO management is challenging, requiring a multidisciplinary approach involving experienced specialists in radiology, gastrointestinal motility, nutrition, and surgery. This case involved an older male with insidious onset in adolescence; however, the diagnosis was made decades later. Genetic analysis through whole-exome sequencing (WES) revealed a rare MYH11 gene. To our knowledge, this is the sixth reported case of CIPO with a heterozygous MYH11 mutation [NM_001040113.2: C.5819del (p.Pro1940HisfsTer91)].

CASE PRESENTATION

Chief complaints

A 77-year-old male patient presented to the Department of Geriatric Medicine, Peking Union Medical College Hospital in November 2024.

History of present illness

Over the past year, the patient had experienced increased frequency and severity of postprandial abdominal distension, intermittently accompanied by nausea and vomiting. The abdominal distension was relieved after vomiting. However, the effectiveness of prokinetic medications had become less pronounced. The episodes of diarrhea also became more frequent, occurring several times per month and presenting as watery stools without fever, mucus, or blood. The symptoms improved with antibiotics and anti-diarrheal medications. The bowel movements were normal in the absence of diarrhea. During this period, the patient’s weight decreased from 50 kg to 40 kg, with reported significant fatigue and decreased mobility. The patient became increasingly bedridden but remained capable of self-care. Two months previously, the patient had required a urinary catheter because of recurrent urinary retention.

History of past illness

The patient had a history of intermittent abdominal bloating and diarrhea for > 60 years, which had worsened in the past year and was accompanied by significant weight loss. The patient reported having experienced postprandial bloating since adolescence, which was attributed to “indigestion”. The patient often experienced episodes of diarrhea triggered by the consumption of unhygienic food, which was relieved by anti-diarrheal medication. In 2001, the patient developed severe abdominal distension with reduced bowel movements, and abdominal computed tomography (CT) imaging findings suggested partial intestinal obstruction, which improved with conservative management. In 2008, the patient had another episode of severe abdominal distension with a 1-week cessation of bowel movements, leading to a diagnosis of “intestinal obstruction”. The patient underwent ileocecal resection with ileocolic anastomosis at a local hospital. The patient’s medical history was negative for diabetes and toxin exposure; however, the patient reported a history of heavy alcohol consumption for > 40 years.

Personal and family history

The patient’s father had a history of intestinal obstruction, and one of the patient’s six siblings had died of intestinal obstruction, although the others had no related symptoms.

Physical examination

On admission, the patient appeared emaciated, with a body mass index of 14 kg/m². The cardiopulmonary examination results were unremarkable. The patient exhibited generalized muscle atrophy, grade IV proximal limb muscle strength, and decreased pinprick sensation below the knees.

Laboratory examinations

Laboratory tests revealed mild anemia [hemoglobin (HGB), 106 g/L] and normal urinalysis, cardiac enzyme levels, and liver and kidney functions. The patient’s serum albumin level was 33 g/L, the prealbumin level was 140 mg/L, and inflammatory marker levels were within normal limits. The folate and vitamin B12 levels were normal with regular vitamin B12 supplementation over the past 6 months. Abdominal ultrasonography revealed multiple dilated small bowel loops with an aortomesenteric angle of approximately 36°.

Imaging examinations

Renal ultrasonography revealed dilation of the left renal collecting system with mild upper ureteral dilatation. Abdominal radiography (Figure 1A) showed right hemidiaphragm elevation and dilated bowel loops with air-fluid levels. The findings of the upper gastrointestinal barium study (Figure 1B) demonstrated mild esophageal dilation, as well as marked duodenal bulb and descending segment dilation with contrast retention. Abdominal CT (Figure 2) revealed duodenal sac-like dilatation with positional changes, narrowing of the horizontal segment, segmental jejunal dilatation, reduced bladder tone, and an indwelling urinary catheter. Abdominal magnetic resonance imaging (Figure 3) revealed significant duodenal and multiple small intestinal dilatations. Gastroscopy revealed reflux esophagitis (LA-B), gastric retention and deformation, and duodenal dilatation with villous atrophy. Colonoscopy revealed a polyp located in the descending colon, which showed an unremarkable anastomotic site.

Figure 1 Abdominal imaging findings. A: Upright abdominal radiograph showing an elevated right diaphragm, with dilated intestinal loops below the diaphragm containing significant content. Small bowel distension in the lower abdomen with multiple gas-fluid levels are also visible; B: Upper gastrointestinal contrast study showing marked dilatation of the duodenal bulb, and descending and horizontal segments, with the widest area measuring approximately 6 cm. No duodenal folds are observed.

Figure 2 Abdominal computed tomography imaging with barium contrast showing marked dilatation of the duodenum with contrast retention, displaced between the right lobe of the liver and diaphragm. The jejunum, ileum, and colon show varying degrees of widening, along with decreased bladder tension and visible ureter.

Figure 3  Abdominal magnetic resonance imaging (T2 coronal view) showing marked dilatation of the duodenum and varying degrees of widening of the jejunum and ileum.

Additional examinations

Nerve conduction studies showed that peripheral neuropathy predominantly affected sensory fibers in both lower limbs. A pathological specimen of the resected intestinal segment obtained in 2008 was submitted to the pathology department of our hospital for consultation. The examination revealed muscle fiber atrophy in the muscular layer of the colon, no significant reduction in ganglion cell number, nerve fiber proliferation and disorganization, partial ganglion cell degeneration, or eosinophilic infiltration (Figure 4).

Figure 4 Surgical resection of intestinal pathological specimens in 2008. The colonic mucosa shows muscular layer atrophy of the smooth muscle fibers, no significant reduction in ganglion cells, nerve fiber hyperplasia and disorganization, partial ganglion cell degeneration, and eosinophil infiltration.

FINAL DIAGNOSIS

CIPO was diagnosed based on gastrointestinal dysmotility and histopathological findings. Further screening for secondary causes revealed normal glycated HGB levels, thyroid function, and blood cortisol levels. The findings of serum protein and immunofixation electrophoresis, as well as tumor marker levels, were also normal. Antinuclear and anti-double-stranded DNA antibody levels were normal. The celiac disease-related autoantibody panel findings and testing for anti-neuronal antigen antibodies (Ri, Hu, Yo) were negative. Blood tests for tuberculosis infection T-cells, cytomegalovirus, and Epstein–Barr virus were also negative. The hydrogen-methane-carbon dioxide breath test revealed no evidence of bacterial overgrowth in the small intestine. WES identified a heterozygous MYH11 mutation [NM_001040113.2: C.5819del (p.Pro1940HisfsTer91)] (Figure 5). According to the guidelines of American College of Medical Genetics and Genomics, this variant was classified as likely pathogenic (PVS1moderate + PS4 + PM2_Supporting + PP4). Based on the patient’s phenotype, the MYH11 mutation was determined to be the causative factor for CIPO. Genetic testing of the patient’s son showed no gene mutation.

Figure 5 Sanger sequencing validation of the mutation site in myosin (MYH11; NM_001040113.2: C.5819del (p.Pro1940HisfsTer91). The top and bottom plots show the verification for the patient and the patient’s son, respectively. The red arrow indicates the mutation location, at the C nucleotide at position 5819 of the gene coding sequence.

TREATMENT

The patient showed no signs of acute intestinal obstruction and was managed with nutritional support. Given the preserved digestive and absorptive functions, dietary modifications were combined with additional oral enteral nutrition supplementation (1000 mL/day, approximately 1500 kcal). The patient was also administered multivitamins, digestive enzymes, and probiotics.

OUTCOME AND FOLLOW-UP

At the 1- and 3-month follow-ups, the patient’s weight had increased by 1 kg and 3.5 kg, respectively, and the patient showed good compliance and tolerance with enteral nutrition, passing 1–2 soft stools daily.

DISCUSSION

CIPO is a rare disorder characterized by the severe impairment of gastrointestinal motility, leading to symptoms that mimic mechanical bowel obstruction in the absence of actual luminal blockage[1-3]. It can affect any part of the gastrointestinal tract, most commonly the small intestine and colon, and may result in severe gastrointestinal dysfunction with potentially life-threatening complications[2-4]. Despite its rarity, CIPO accounts for 15% of pediatric and 9.7% of adult cases of chronic intestinal failure cases[5]. Due to its nonspecific clinical presentation, CIPO is frequently misdiagnosed, with an average diagnostic delay of approximately 8 years[6,7]. The estimated prevalence in adults is approximately 1 per 100000 in males and 0.8 per 100000 in females, with annual incidences of 0.21 per 10000 and 0.24 per 100000 in males and females, respectively[8].

CIPO is a heterogeneous syndrome with multiple etiologies. Based on the pathological findings, this condition can be classified into neuropathic, myopathic, and mesenchymopathic types, with some patients exhibiting mixed features. CIPO can be categorized as hereditary, acquired, or idiopathic. CIPO predominantly affects children and follows autosomal dominant, autosomal recessive, or X-linked inheritance patterns. Acquired CIPO is typically associated with systemic pathophysiological conditions, and is more common in adults. Secondary causes of CIPO include malignancy, neurological disorders, endocrine dysfunction, and connective tissue diseases[9]. The patient in the present case experienced disease onset as an adolescent, with a progressive course over several decades. Despite extensive diagnostic evaluation, no secondary causes were identified. Given these genetic findings, hereditary myopathic CIPO was considered the most likely diagnosis.

Approximately 80% of pediatric pseudo-obstruction cases are hereditary or idiopathic; are often associated with genitourinary involvement, intestinal malrotation, or volvulus; frequently require surgical intervention or parenteral nutrition; and have a poorer prognosis than adult-onset cases[10]. Among them, 56.5% of pediatric patients develop symptoms during the neonatal period, and the incidence gradually decreases with age. Onset during adolescence has also been reported, with an incidence of 9.7%[11]. Currently, most of the reported pathogenic genes associated with pediatric pseudo-obstruction encode proteins related to smooth muscle contraction[12]. In a recent review, Fournier & Fabre summarized the mutation spectrum of genes implicated in visceral myopathy based on the results of 117 reported cases, including 112 postnatal patients and five prenatal terminations. The most frequently mutated genes were actin gamma 2 (ACTG2, 67%), MYH11 (14%), and filamin A (FLNA, 13%)[13]. Smooth muscle contraction depends on the interaction between actin and myosin filaments. MYH11 encodes the smooth muscle myosin heavy chain, a key component of the thick filaments essential for contraction[14]. Therefore, MYH11 mutations impair smooth muscle function, signaling, and motility. Homozygous MYH11 knockout mice exhibit an enlarged thin-walled bladder and abnormal intestinal motility, leading to death within 12-24 hour of birth. MYH11 mutations are associated with thoracic aortic aneurysm and dissection, as well as patent ductus arteriosus. Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare congenital disorder, characterized by urinary bladder enlargement, significant shortening of the colon, and severe hypoperistalsis of the small intestine. Gauthier et al[15] previously identified homozygous MYH11 variants in neonates with MMIHS, suggesting that MYH11 Loss-of-function mutations may contribute to the pathogenesis of this syndrome by impairing smooth muscle function across multiple organ systems.

In the present case, a heterozygous frameshift mutation, MYH11: c.5819del (p.Pro1940HisfsTer91), was identified. This mutation resulted from the deletion of a nucleotide at position 5819 within the gene’s coding sequence, resulting in a frameshift mutation. Consequently, the original stop codon was lost, and a new stop codon was generated at the 91^st downstream codon. This led to the addition of 90 extra amino acids at the C-terminus of the MYH11 protein, altering its local three-dimensional structure and contributing to disease pathogenesis[16]. To date, five case reports have identified heterozygous MYH11 mutations in patients with CIPO. In 2019, Dong et al[17] reported on a large 13-member family diagnosed with the CIPO phenotype. Most of the family members presented with megacystis and required long-term self-catheterization. WES analysis of the seven affected individuals revealed a shared MYH11 c.5819del (p.Pro1940HisfsTer91). This MYH11 frameshift allele is identical to the MYH11 allele reported by Gilbert et al[16] in their analysis of three generations of a family in which five individuals were affected. The proband was diagnosed with chronic constipation during infancy, and subsequently developed features of infantile pseudo-obstruction at the age of 11. By 20 years of age, anorectal manometry revealed motility abnormalities consistent with a diagnosis of smooth muscle myopathy. In 2022, Li et al[18] reported the case of a 43-year-old man with a history of lower abdominal distension lasting more than 10 years. WES of both the patient and his mother confirmed the diagnosis of primary familial visceral myopathy with CIPO, with both individuals carrying the same MYH11 gene mutation. Geraghty et al[19] screened the Genomics England 100000 Genomes Project rare diseases database for patients with visceral myopathy -related phenotypes. Among the 76 identified patients, four carried the same heterozygous MYH11 c.5819del (p.Pro1940HisfsTer91) frameshift allele. These four individuals also exhibited variable clinical phenotypes, with two diagnosed with CIPO. In summary, these cases contribute to accumulating evidence supporting the role of MYH11 variants in the CIPO phenotype.

The treatment of patients with CIPO is challenging and requires a multidisciplinary team. Unnecessary surgical interventions should be avoided in adults and children. Management strategies should focus on maintaining adequate fluid and electrolyte status, thereby ensuring sufficient caloric and nutrient intake, promoting intestinal motility coordination, and addressing potential complications such as sepsis and small intestinal bacterial overgrowth. The ability to maintain oral intake is a key independent factor for improved survival. Therefore, patients receiving parenteral nutrition should be encouraged to maximize their oral intake as tolerated[20,21]. As this patient presented without acute intestinal obstruction and was in disease remission, the primary treatment approach was dietary adjustments combined with enteral nutrition supplementation.

The role of surgery in CIPO remains controversial. While it can be used to obtain full-thickness intestinal biopsy samples, surgical interventions are generally reserved for emergencies such as severe bowel dilation, perforation, or ischemia. In one 13-year longitudinal study enrolling 59 adult patients with idiopathic CIPO, 88% were reported to have undergone an average of three unnecessary surgeries, highlighting the significant diagnostic and therapeutic challenges associated with this condition[6]. Another retrospective study of 63 adult patients reported an overall postoperative mortality rate of 7.9% and a 66% reoperation rate within 5 years due to CIPO-related complications[22,23]. For patients with end-stage CIPO, isolated small bowel transplantation or multivisceral transplantation may be considered as treatment options[24,25]. Although the patient in the present case underwent full-thickness intestinal histopathology in 2008, a definitive diagnosis was not made at that time because of the limited awareness of CIPO among physicians. Consequently, several decades passed before the patient finally received an accurate diagnosis.

CONCLUSION

In conclusion, CIPO is a rare condition leading to severe impairments of gastrointestinal motility. Owing to the limited awareness of this condition among clinicians, misdiagnosis, missed diagnosis, and inappropriate treatment are common. This case involved an older male with insidious onset in adolescence, and a disease course spanning several decades before a definitive diagnosis could be established. WES identified a rare heterozygous MYH11 mutation, confirming hereditary myopathic CIPO. Overall, this case suggests that inherited conditions can be diagnosed even in older patients.

ACKNOWLEDGEMENTS

We wish to express our gratitude to the patient and his family.