Ehlers-Danlos syndrome (EDS) is a rare heterogeneous group of inheritable connective tissue disorders characterized by articular hypermobility, skin extensibility, and tissue fragility. Type IV EDS, also known as the vascular or ecchymotic type, is unique for its associated vascular and gastrointestinal catastrophes. In this variant, megacolon has been reported, manifesting as progressive constipation typically beginning in adolescence and causing intestinal perforation, which may be spontaneous or may occur after trivial trauma (1,2). Unfortunately, this syndrome is often unrecognized despite a characteristic history and clinical course, and as a result, in many circumstances the diagnosis is considered only after its life-threatening complications have occurred (3-6).
Constipation, the most common digestive problem in the United States (7,8), is commonly treated with over-the-counter dietary supplements, laxatives, and enemas. The use of enema preparations to relieve acute constipation in children is also common in emergency departments (9). We present two adolescent patients in whom the diagnosis of EDS type IV was established only after the catastrophic complications of the disorder had developed. Both had chronic constipation for several months before seeking attention emergently for abdominal pain initially attributed to obstipation. Sigmoid perforations subsequently developed in temporal proximity to the enema treatments that were administered to help relieve the obstipation. There is only one previous report of a fatal colon perforation after a self-administered enema in an adult who in retrospect is thought to have had EDS (6). Ideally, the diagnosis of EDS should be considered in patients who have the suggestive physical features. In addition, a focused medical history with subsequent histologic and biochemical studies will aid in early diagnosis. We also recommend that enema therapy for constipation be avoided if a patient has known or suspected EDS.
A 14-year-old boy with intermittent constipation had acute abdominal pain that was not responsive to home enema treatment. Further evaluation and enema treatment in the emergency department did not relieve his discomfort. Hours later, the pain worsened with onset of signs and symptoms of peritonitis. At laparotomy an isolated pinpoint rectosigmoid perforation was found that was oversewn. A proximal diverting colostomy was performed. No other findings were reported at laparotomy except a stool-filled, dilated colon. The patient had an uncomplicated postoperative recovery and was discharged home within a week. The cause of the perforation was not determined. Four months later he had elective colostomy takedown and colon re-anastomosis. He did well during the first 4 postoperative days but then became persistently febrile with temperatures of 102°F and abdominal distension. Broad-spectrum antibiotics were instituted. However, on postoperative day 7 he had symptoms of anemia, hypotension, and sepsis, and an enterocutaneous fistula developed that was caused by breakdown of the transverse colon anastomosis. He was then transferred to the Children's Hospital of Philadelphia for further treatment.
On admission, computed tomographic (CT) scan of his abdomen demonstrated the presence of free intraperitoneal air, multiple fluid collections, and a subcapsular hematoma of the liver. At exploratory laparotomy, three perforations were seen in the jejunum, the anastomosis site was noted to have broken down, and numerous adhesions were seen in several areas. The perforated small bowel was resected and repaired by primary anastomosis, and the area of anastomotic breakdown was exteriorized as a colostomy. Histopathology of the resected bowel revealed disrupted aggregates of elastic fibers in the submucosa and mesentery blood vessels, in addition to diffuse ischemic injury in the muscularis propria. These findings were suggestive of vasculitis or elastic tissue abnormality, and a more detailed review of his history was therefore undertaken.
He had had bilateral inguinal hernias and hypospadias at birth, had been prone to chronic, easy, severe bruising since infancy, and had prominent superficial veins visible through his skin. He had had in-toeing and toe contractures since infancy and at age 11, was noted to have unusually flexible hips. There was also a history of a cruciate ligament tear in one knee. He had a thin nose and lips with tight facial skin. His eyes remained partially opened while he was asleep. There was a prominent venous pattern visible through his translucent skin over the abdomen, chest, and lower extremities. There were also wide papyraceous scars and areas of ecchymoses. He had high plantar arches and his toes were contracted. This history, clinical course, and physical findings were suggestive of the clinical diagnosis of type IV Ehlers-Danlos syndrome.
After surgery, the patient had multisystem complications. Forty-eight hours after surgery, dyspnea developed, and a right-side pleural effusion required a chest tube. Computed tomographic scan on postoperative day 8 revealed air fluid levels in what had previously been identified as a hepatic hematoma, suggesting an abscess. When this lesion was drained percutaneously, several hundred milliliters of foul-smelling liquefied hematoma was obtained. Intractable sepsis, hypotension, and coagulopathy developed. On postoperative day 9, he became acutely dyspneic and hypotensive, and the wound showed extensive dehiscence. At emergency laparotomy a freely bleeding superior mesenteric artery was seen, with extensive intra-abdominal blood and a new jejunal perforation. The bleeding artery was ligated and the jejunal perforation stapled. He had an extensively friable bowel with multiple bleeding sites that required that multiple sponge packs be left in place. After surgery, he remained in critical condition, did not respond to prolonged therapy with pressor agents and volume expanders, and died shortly thereafter.
At autopsy, the hepatic hematoma was confirmed to be caused by a right hepatic artery rupture. Fibroblast studies showed type III collagen deficiency consistent with type IV Ehlers-Danlos syndrome. Only 10% of the normal amount of collagen III was secreted by the cell; the remainder was retained within the cells. Molecular studies showed a point mutation that resulted in substitution of serine for glycine at amino acid 37 in the triple helical region of α-1(III) chain of collagen III. This mutation was not found in his parents and sister.
A 15-year-old girl with several months of chronic constipation was treated with large doses of mineral oil and occasional enemas. The constipation worsened acutely with no bowel movement for more than a week, and the patient came to the emergency department with abdominal pain and vomiting after a phosphate enema had failed to initiate a bowel movement. On initial examination she was febrile (39.3°C) and had a nonrigid but tender abdomen with a supine radiograph revealing a distended colon filled with feces. Two additional phosphate enemas followed by one large saline enema did not result in a bowel movement, and shortly thereafter signs and symptoms developed of an acute abdomen requiring an emergency laparotomy.
At surgery, a longitudinal tear of the antimesenteric wall of the sigmoid colon was seen, with fecal soiling and severe peritonitis. Adjacent to the tear there were two circumscribed perforations where the surrounding bowel wall appeared to consist of only mucosa denuded of serosa and muscle. These two areas leaked repeatedly despite several attempts to suture them. Therefore, the affected bowel was excised, and a colostomy was performed. Copious irrigation of the peritoneal cavity was performed, and multiple drains were left in place.
Seven days after surgery, bilateral pleural effusions and right lower lobe pneumonia developed. The pneumonia improved with antibiotic treatment; however, the effusions required repeated needle aspirations over the next several days. During one of the aspiration procedures, she reported severe right-side shoulder pain and had a precipitous drop in hemoglobin. A CT scan revealed a large right-side hepatic hematoma that was successfully managed with conservative therapy. Three weeks after surgery, signs and symptoms of peritonitis developed suddenly. At surgery, a ruptured inferior epigastric artery and necrotizing fascitis involving the anterior abdominal wall were found. Hemostasis was achieved, and the necrotic tissue was débrided.
These events led to the heightened awareness that she had thin, semitransparent delicate skin with a visible generalized prominent superficial venous network on her chest and abdomen. Her fingers were hyperextensible and there was a history of recurrent disease of the patella. She had been born prematurely at 33 weeks' gestation after the amnion had ruptured at 29 weeks. Her parents described her as having always been a "skinny child" with skin that one "could see through." There was a long history of severe, easy bruising, and on two occasions during her infancy and adolescence, she had been evaluated for a possible underlying clotting disorder (both evaluations were inconclusive). None of her immediate family members had a similar history or physical findings. This history, physical findings, and clinical course characterized by sigmoid perforation and rupture of a medium-sized artery suggested a generalized collagen tissue disorder such as type IV Ehlers-Danlos syndrome. She eventually recovered without further surgical complications and was discharged home after a 2-month hospital stay.
Examination of fibroblast cultures showed a deficiency of type III collagen synthesis confirming the diagnosis of type IV Ehlers-Danlos syndrome. Nine months later, she was electively admitted for a subtotal colectomy with an ileosigmoid anastomosis. She is now in her third decade of life. Since the surgery, constipation has not been noted.
More than 10 clinical types of EDS have been identified and classified on the basis of the modes of inheritance, predominant clinical signs, and in some types, the specific inborn error in collagen biosynthesis. This rare syndrome manifests with variable degrees of joint hypermobility, skin hyperextensibility, poor wound healing, blue sclerae, thin papyraceous scars, easy bruising, and occasionally, cardiac valve prolapse and bone fractures. Most types of EDS are inherited in an autosomal dominant pattern with intrafamilial and interfamilial variability in clinical expression.
Type IV EDS also known as the vascular or ecchymotic type, arises from a mutation in the COL3A1 gene resulting in abnormalities in the structure, synthesis, or secretion of type III procollagen. It is inherited in an autosomal dominant fashion and has an estimated prevalence varying from 1 in 100,000 to less than one in 1 million. It is not uncommon for the patient proband to be the first affected person in a family (10). Type III collagen is normally distributed in the vascular system, dermis, and the supporting connective tissue of the viscera. This explains the susceptibility of people with type IV EDS to rupture of medium-sized arteries, aneurysms, bowel perforations, uterine rupture, and tissue friability, possibly including the amnion. On account of these complications, the life expectancy of the affected person is shorter than with other types of EDS, which are more benign.
In a mailed questionnaire assessing gastrointestinal disorders and bowel habits in 613 people with Ehlers-Danlos syndrome, 24.5% of the respondents (total 208) reported that they were usually or always constipated (11). Constipation (2,12-14), obstipation (3), and fecal impaction (14) are frequently present in EDS syndrome. These symptoms usually appear in later childhood (15) and adolescence (2). On the contrary, childhood functional constipation, which is considered a transient disorder, has a peak incidence in the first 2 years of life and during the period of toilet training and subsides by the second decade of life (7,15). The possibility of type IV EDS should always be considered in patients with later onset of intractable constipation and easy bruising because of the life-threatening complications that could arise from routine enema therapy.
The more commonly cited complications related to administration of therapeutic phosphate enemas are metabolic derangements, which include hyperphosphatemia, hypocalcemia, hypokalemia, metabolic acidosis, and dehydration. Tetany and fatal cardiac arrest have also been reported (9). The people at greatest risk for these complications are children under the age of 5 years. Those especially at risk include patients with premorbid medical conditions predisposing them to alterations in the absorption and excretion of phosphate: renal disease, Hirschsprung's disease, and imperforate anus (9). Other less-frequent complications are related to the localized tissue irritation and reactions caused by the enema contents (16) and also to the trauma from the catheter tips or rectal tubes used to instill the enema. The latter two have resulted in injuries ranging from laceration of the perianal tissue (17) to perforation of the rectum (18) and sigmoid (19). Traumatic perforation of the rectum or colon that occurs while administering an enema for constipation is rare and has seldom been reported in children.
The sigmoid perforations in our patients were presumed to have been caused by a mechanism related to Laplace's law in an inherently premorbid colon. Laplace's law states that in a given tubular structure P = T/R, where P is the distending pressure, R is the radius and T is the tension in the wall, which is both active from contraction and passive from distension. This law implies that at a given pressure, a much higher tension is exerted in a larger tube compared with a smaller tube. Early studies by Burt (20) ascertained the applicability of this law in biological systems by demonstrating that less pressure was required to rupture the transverse colon and cecum than other parts of the gastrointestinal tract because of their larger diameters.
Chronic constipation is considered to be one of the most important predisposing factors to spontaneous perforations of the colon (21). This along with the sudden increase in colonic volume after the enema instillation with an inherently weak bowel wall such as occurs in type IV EDS is likely to have constituted the factors that caused the perforations in our patients. This mechanism of colonic perforation is rare in the absence of an inherent weakness in the bowel wall except in extreme conditions such as were seen in a 14-month-old previously healthy infant who had a fatal transverse colon perforation after serial administration of water enemas with a total volume of 1500 ml (22).
Spontaneous perforation of the colon with and without a characteristic preceding history of constipation has often been the manifestation that led to the clinical and biochemical diagnosis of type IV EDS (1,3,4,6,23). Because perforation of the colon occurs infrequently in normal patients, its occurrence should always prompt a detailed evaluation for type IV EDS. Patients with type IV EDS may have severe chronic constipation that develops in later childhood and adolescence and may comprise a high-risk group in whom enema therapy or any other bowel instrumentation could be lethal. These cases highlight the need for further inquiry into the cause of later onset of constipation before instituting routine therapy. Patients with known or suspected type IV EDS who have constipation should be treated with dietary fiber and laxatives; enema therapy should be avoided.
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