Case 33-2005 — A 43-Year-Old Man with Lower Gastrointestinal Bleeding
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《新英格兰医药杂志》
Presentation of Case
Dr. Joshua D. Moss (Department of Medicine): A 43-year-old man was admitted to the hospital because of blood in his stool.
When the patient was a child of about three and half years of age, his mother first noted bright red blood in his stool, without other symptoms. He was evaluated at this hospital. On examination, two areas of telangiectasia were present on the buccal mucosa. Examinations of the child's heart, lung, and abdomen revealed no abnormalities. Iron-deficiency anemia had been present. Sigmoidoscopy performed under general anesthesia revealed a 1-cm pedunculated polyp 18 cm from the rectum, and two smaller polyps were visible distally, with no active bleeding. Examination of biopsy specimens disclosed features of juvenile polyps. The patient continued to have guaiac-positive stools throughout his hospital course but required no blood transfusions. He was discharged on day 14 and his care was continued at another hospital.
The patient continued to have intermittent rectal bleeding over the next 40 years, often requiring transfusions, and he had regular evaluations of both the small and large bowels at the other hospital, with annual esophagogastroduodenoscopy, sigmoidoscopy, or colonoscopy. Polyps were removed at intervals from the esophagus, stomach, duodenum, and colon; the majority were found to be either juvenile or hamartomatous polyps. Subtotal colectomy for intractable rectal bleeding was performed when the patient was 25 years of age.
During the patient's first decade of life, epistaxis developed and recurred, with nosebleeds resulting in 15 to 50 ml of blood loss per day. When he was in his early teens, resection and reconstruction of the right mandible were performed at the other hospital to remove a vascular malformation.
At 31 years of age, the patient resumed his care at this hospital. Clubbing of the fingers was noted, and a chest radiograph disclosed several nodular densities suggestive of arteriovenous malformations. An air-contrast upper gastrointestinal series with small-bowel follow-through disclosed marked thickening of the gastric folds with multiple filling defects in the antrum that was consistent with the presence of polyps and irregularity in the duodenal bulb that might represent additional polyps.
The patient continued to have episodes of epistaxis, and severe maxillary gingival hyperplasia developed. When he was 32 years of age, he underwent an angiographic study of the external carotid arteries that revealed multiple telangiectatic lesions involving all portions of the nasal mucosa, the hard and soft palates, portions of the gingivae (particularly over the superior alveolar ridges), and the tongue; the facial arteries did not supply these lesions. Several distal branches of the bilateral internal maxillary arteries were successfully embolized, and laser gingivoplasty was performed three days later.
At 33 years of age, the patient had had an episode of right upper quadrant abdominal pain; an abdominal ultrasonographic study disclosed abnormal vascular channels in the liver that were consistent with the presence of vascular malformations. Abdominopelvic computed tomography (CT) one month later disclosed a lobulated mass in the posterior left lower lung; the mass enhanced brightly with contrast material, and there were two vessels feeding it — features consistent with the presence of an arteriovenous malformation. There were also multiple tortuous vascular channels in the liver. CT scanning of the chest when the patient was 38 years of age revealed multiple bilateral pulmonary arteriovenous malformations, 2 to 4 cm in diameter. CT scanning of the abdomen when he was 40 years of age showed innumerable arteriovenous malformations in the liver.
Three years later, on the evening before the current admission, the patient had four to five bowel movements containing bright red blood. He had no abdominal or rectal pain, nausea, vomiting, or fever. He came to the emergency department of this hospital, where he was evaluated. His temperature was 36.4°C, the blood pressure 110/68 mm Hg, the pulse 94 beats per minute, the respiratory rate 20 breaths per minute, and the oxygen saturation 94 percent while he was breathing room air. The hematocrit was 31.1 percent, with a mean corpuscular volume of 68 μm3. The patient was admitted to the hospital for further evaluation and treatment.
The patient's birth had followed a full-term pregnancy, and delivery was normal. An episode of Escherichia coli sepsis and a subdural hematoma had occurred when he was 15 days old, resulting in residual left-sided weakness and mild mental retardation. He subsequently had recurrent complex partial seizures, which were controlled with phenobarbital. CT scanning of the head five years before the current admission, when the patient was 38 years of age, which was performed because of a fall, revealed porencephaly affecting most of the right temporal and occipital lobes; repeated scanning three months before admission showed no change from earlier examinations. There was no evidence of a vascular malformation. He had undergone a laparotomy for reduction of intussusception when he was 23 years of age and exploratory laparotomy and lysis of adhesions for small-bowel obstruction at 26 years of age and again at 42 years of age (8 months before the current hospitalization). His medications at the time of admission included phenobarbital and iron supplements.
The patient's mother had undergone a subtotal colectomy when she was 13 years of age because of rectal bleeding and the presence of telangiectatic lesions and polyps in the colon, and several duodenal polyps had been excised. She had been hospitalized on multiple occasions for lower gastrointestinal bleeding and recurrent severe epistaxis. Duodenal adenocarcinoma arising in a polypoid lesion was resected when she was 43 years of age; she died of sepsis with multiple liver abscesses at 45 years of age. No other members of the patient's immediate family, including his grandparents and three sisters, were known to have bleeding problems.
On examination, the patient appeared comfortable; he was conversant and his behavior appropriate, although mildly mentally retarded. Multiple telangiectatic lesions were present on his tongue, buccal mucosa, and nasal mucosa. An examination of the lungs, heart, and abdomen revealed no abnormalities. Multiple well-healed surgical scars were present on the abdomen. A rectal examination revealed no masses; the stool was guaiac-positive. The hematocrit was 32.6 percent; the hemoglobin, 10.5 g per deciliter.
Normal saline was administered intravenously. The hematocrit, measured twice daily, remained stable. On the day after admission, diagnostic procedures were performed.
Differential Diagnosis
Dr. Joshua Korzenik: May we review the radiologic studies?
Dr. Subba Digumarthy: Anteroposterior and lateral views of the angiogram of the right external carotid artery (Figure 1A), obtained 11 years before the patient's current admission, showed multiple small tortuous vessels in the region of the nasal cavity, gingivae, palate, and tongue. The supply is predominantly from internal maxillary arteries. These findings are consistent with the presence of telangiectasia.
Figure 1. Radiologic Studies.
Anteroposterior and lateral views of the right external carotid artery (Panel A) show multiple telangiectatic lesions in the nasal mucosa, palate, gingivae, and tongue, predominantly supplied by branches of internal maxillary arteries (arrows). A contrast-enhanced CT study of the chest (Panel B) shows a lobulated mass in the left lower lobe with tortuous serpiginous vessels consistent with a pulmonary arteriovenous malformation (arrow). A contrast-enhanced CT study of the upper abdomen (Panel C) shows multiple tortuous vessels in the right lobe of the liver, consistent with vascular malformations (arrow).
A CT scan of the chest (Figure 1B) performed with contrast material 10 years before admission shows multiple tortuous enhancing blood vessels at the left lung base and superior segment of the left lower lobe, consistent with the presence of vascular malformations. A contrast-enhanced CT scan of the abdomen (Figure 1C) obtained at that time showed abnormal vascularity in the right lobe of the liver, with abnormal communications among the branches of the hepatic vein, portal vein, and hepatic arteries — consistent with the presence of a vascular malformation. An upper gastrointestinal examination with small-bowel follow-through after oral administration of barium contrast (Figure 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org) performed the same year shows filling defects in the antrum of the stomach and along the greater curvature.
Dr. Korzenik: The diagnosis in this case rests on considering two different elements of this patient's presentation: gastrointestinal bleeding and polyps. I will address the first issue, and Dr. Chung will discuss the second. Both Dr. Chung and I are aware of the diagnosis.
Chronic gastrointestinal bleeding can have many causes. The bleeding in this case spanned decades, beginning at an early age, so that causes of bleeding in childhood as well as problems more common in adults should be considered. In children, chronic bleeding can be caused by milk allergy, Meckel's diverticulum, congenital vascular abnormalities, and juvenile polyposis. Common causes in adults include hemorrhoids, diverticula, neoplasms, and vascular ectasia. In both groups, ulcerative colitis and Crohn's disease could produce chronic bleeding, although other symptoms associated with these diseases were absent in this case. Polyps are common in both children and adults, whereas less common vascular lesions, such as the blue rubber bleb nevus syndrome or Klippel–Trénaunay–Weber syndrome, both of which normally would be associated with other findings, are not present in this patient. The presence of vascular abnormalities outside the gastrointestinal tract in this patient, as well as symptoms of chronic epistaxis, made the diagnosis likely to be hereditary hemorrhagic telangiectasia (also known as Osler–Weber–Rendu disease).
Hereditary hemorrhagic telangiectasia is a syndrome that results in arteriovenous malformations that affect numerous organs, including the nose (in >95 percent of the cases), skin (in >80 percent), gastrointestinal tract (in 30 percent), lungs (in 30 percent), brain (in 10 percent), and liver (in 30 percent); this patient had arteriovenous malformations of all these organs except the brain.1 Two of the identified genetic defects implicated in the disorder involve the protein endoglin, which is associated with transforming growth factor receptors I and II and which is expressed predominantly on endothelial cells, and activin-receptor–like kinase I.2,3,4 Establishing the diagnosis is critical, since screening for pulmonary and cerebral arteriovenous malformations can identify lesions and permit treatment before catastrophic bleeding or other complications occur. The diagnosis of hereditary hemorrhagic telangiectasia is based on the presence of three of the four Cura?ao criteria (Table 1).5 This patient's symptoms meet the criteria for hereditary hemorrhagic telangiectasia.
Table 1. Cura?ao Criteria for the Diagnosis of Hereditary Hemorrhagic Telangiectasia (HHT).
Gastrointestinal bleeding in hereditary hemorrhagic telangiectasia occurs in 30 to 40 percent of patients and usually becomes evident in the fourth or fifth decade of life.6 Bleeding is typically from telangiectatic areas in the stomach or proximal small bowel. This patient's gastrointestinal bleeding began at a very early age, raising the concern that it had another cause, and in fact, intestinal polyps were found. Dr. Chung will discuss this problem.
Dr. Daniel C. Chung: The presence of a personal and family history of multiple gastrointestinal polyps in childhood indicates that this patient had a type of polyposis syndrome. These syndromes are distinguished by their histologic features and categorized in two major groups as either adenomatous or hamartomatous (Table 2). On the basis of the predominantly hamartomatous histologic findings in this case, the considerations were juvenile polyposis syndrome, Cowden's disease, the Bannayan–Ruvalcaba–Riley syndrome, and the Peutz–Jeghers syndrome.
Table 2. Inherited Gastrointestinal Polyposis Syndromes.
Juvenile polyps, the predominant type of hamartomatous polyp identified in this patient, are observed in three of the four syndromes. The type of polyps associated with the Peutz–Jeghers syndrome is seen only in that disease, and such polyps were not seen in this case. A few adenomatous polyps were described, raising the possibility of the so-called hereditary mixed polyposis syndrome. However, the adenomatous changes were mainly seen within juvenile polyps. Furthermore, there were multiple gastric and duodenal polyps, and the hereditary mixed polyposis syndrome typically involves only the colon.7
The pattern of extraintestinal findings can help us distinguish among these hamartomatous syndromes: thyroid and breast cancer, facial trichilemmomas, and macrocephaly are seen in Cowden's disease, and mental retardation, macrocephaly, lipomas, and genital pigmentation in the Bannayan–Ruvalcaba–Riley syndrome. This patient has mild mental retardation, but this was attributed to brain injury in infancy. In classic forms of juvenile polyposis, there are no consistent extraintestinal findings, so this condition emerges as the most likely diagnosis.8
Juvenile polyps can arise sporadically as the most common type of colonic polyp in childhood, but these polyps are typically solitary.9 The diagnosis of juvenile polyposis can be established by any of the following clinical criteria: more than five juvenile polyps of the colorectum, juvenile polyps throughout the gastrointestinal tract, or any number of juvenile polyps in a patient with a family history of juvenile polyposis.10 This patient's condition fulfills all three of these criteria. Affected persons typically present in childhood, as this patient did, with rectal bleeding or with a prolapsed rectal polyp, anemia, diarrhea, or abdominal pain. The average age of a patient at diagnosis ranges from 9.5 years11 to 18.5 years.12 The disease is inherited in an autosomal dominant manner, but as many as 22 percent of affected persons may not report a family history of polyposis, suggesting that de novo mutations occur frequently.
A long-term concern in the case of this patient is the risk of gastrointestinal cancer. Polyps can develop adenomatous components, which are precursors of adenocarcinoma. The lifetime risk of colon cancer is estimated at between 17 percent and 38 percent among persons with juvenile polyposis,13,14 and the mean age at the diagnosis of colon cancer is 34 years.10 There is also a 15 to 21 percent lifetime risk of upper gastrointestinal tract cancers.14 Overall, the lifetime risk of any gastrointestinal cancer occurring in this patient is 46 to 55 percent.
Approximately 23 percent of patients with juvenile polyposis carry a germ-line mutation in MADH4 (a tumor-suppressor gene on chromosome 18q21),15,16 and 20 percent have a germ-line mutation in BMPR1A (the type I receptor for bone morphogenetic protein)17 — both of which are involved in signaling by transforming growth factor .18 The genetic basis of more than 50 percent of cases remains unknown. Some cases of juvenile polyposis may be caused by mutations in MADH4 or BMPR1A that cannot be detected by current techniques, but the existence of additional disease-causing genes is probable. No mutations have been identified in a number of other candidate genes from the transforming growth factor family.18
There are two features that appear to be more common in carriers of MADH4 mutations: gastric polyposis,19 which is seen in 57 to 86 percent of those with MADH4 mutations, as compared with 10 to 20 percent of those with BMPR1A mutations, and hereditary hemorrhagic telangiectasia.20 Thus, this patient and his mother, both of whom probably had juvenile polyposis and hereditary hemorrhagic telangiectasia, would be likely to have a mutation in the MADH4 gene, which is responsible for both clinical syndromes.
The diagnostic procedures performed in this case were esophagogastroduodenoscopy, sigmoidoscopy, and MADH4 genetic testing.
Clinical Diagnosis
Hereditary hemorrhagic telangiectasia.
Juvenile polyposis syndrome.
Dr. Joshua Korzenik and Dr. Daniel C. Chung's Diagnosis
Combined syndrome of juvenile polyposis and hereditary hemorrhagic telangiectasia due to a germ-line mutation in MADH4.
Pathological Discussion
Dr. Kamran Badizadegan: The patient had undergone numerous upper and lower gastrointestinal biopsies and polypectomies. Since a complete description of the specimens that were obtained is not possible here, I will focus on the evolution of several representative polyps over the course of 40 years and the findings in his most recent specimens.
The patient's first pathological diagnoses were made by two of the founders of modern academic pathology. The first sigmoid polyp, removed when the patient was three and a half years of age, was diagnosed as a juvenile polyp by Dr. Benjamin Castleman; rectosigmoid polyps that were removed when the patient was five years of age were diagnosed as retention polyps by Dr. Sidney Farber. Representative photomicrographs (Figure 2A) show an inflamed epithelial polyp with irregular and variably dilated glands. The polyp is not dysplastic and does not contain a prominent mesenchymal component. In addition, prominent cystically dilated glands and subsurface granulation tissue, which are typical features of solitary juvenile polyps, are not present.
Figure 2. Morphologic Progression of the Patient's Rectosigmoid Polyps from Early Childhood to the Present.
Histologic sections of representative polyps from when the patient was 5 years of age (Panel A and inset), 13 years of age (Panel B and inset) and 38 years of age (Panel C and inset are shown). Comparison of the three polyps at low magnification (Panels A, B, and C) shows a progression in the glandular architectural complexity, characterized by an overall increase in the epithelial component and the development of more crowded and more complex glandular patterns with age (hematoxylin and eosin). An examination of the surface of each polyp at higher magnification shows an inflamed stroma with mildly dilated glands reminiscent of typical juvenile polyps at 5 years of age (Panel A, inset), a more prominent epithelial component with focally villiform architecture at 13 years of age (Panel B, inset), and a diffusely dysplastic epithelium at 38 years of age (Panel C, inset).
Over the ensuing years, the patient's intestinal polyps gradually evolved into a more proliferative and eventually dysplastic phenotype. As represented in Figure 2B, the patient's polyps during the teenage years were dominated by a prominent epithelial component with a variably villiform surface architecture. The polyps did not contain a prominent inflammatory or mesenchymal component and were not dysplastic. In sharp contrast, a rectal polyp removed when the patient was 38 years of age (Figure 2C) shows small, crowded glands that are uniformly lined by low-grade dysplastic epithelium. At no point was a vascular lesion present on the biopsy specimens or resected polyps. However, several upper endoscopic studies described the presence of areas of mucosal telangiectasias in the stomach.
The diagnostic procedure at the time of this patient's admission was upper gastrointestinal endoscopy with polypectomy. An endoscopically resected duodenal polyp measured approximately 2.1 cm in its largest dimension and was diffusely dysplastic (Figure 3). The overall growth pattern of this polyp is similar to the adenomatous rectal polyp described above (Figure 2C), although the duodenal polyp shows more severe dysplasia, with marked nuclear atypia and irregular, back-to-back glands consistent with high-grade dysplasia and intramucosal carcinoma (Figure 3, inset). An examination of multiple sections showed no invasive component. It is notable that the patient's mother presented at a similar age (mid-40s) with an invasive duodenal carcinoma arising in a polypoid lesion, with metastases to regional lymph nodes.
Figure 3. Dysplastic Duodenal Polyp with Focal Intramucosal Carcinoma.
Histologic sections of the patient's duodenal polyp at the time of the current admission show an architecturally complex epithelial polyp with crowded glands and diffusely dysplastic epithelium. At higher magnification (inset), the polyp shows small, irregular, back-to-back glands with marked nuclear atypia and prominent mitotic activity, features that are consistent with high-grade dysplasia and intramucosal carcinoma.
Overall, the patient's gastrointestinal lesions are consistent with an atypical juvenile polyposis with progression to dysplasia and intramucosal carcinoma. Although classic juvenile polyps are round to oval with irregular, often dilated, glands in a highly inflamed stroma, rare atypical forms characterized by increased glandularity and a lobulated growth pattern have been reported in patients with polyposis in whom clinically significant dysplasia and adenocarcinoma developed.10,21,22,23 In addition, recent comparative studies have described the presence of subtle histologic features, including "long, elongated crypts replacing round cysts," in patients with juvenile polyposis who carry germ-line mutations in the MADH4 gene.24
Dr. Chung: This patient was one of 15 patients in seven families in a recent report who had a combined syndrome of juvenile polyposis and hereditary hemorrhagic telangiectasia associated with MADH4 mutations.20 Testing for MADH4 mutations disclosed a truncating germ-line MADH4 mutation at codon 534 in this patient.
Discussion of Management
Dr. Korzenik: The care of patients with hereditary hemorrhagic telangiectasia principally involves the prevention of complications from the arteriovenous malformations and management of gastrointestinal bleeding and epistaxis. Patients with hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations, as in this case, can present with a variety of problems including cerebrovascular accidents, cerebral abscesses, and dyspnea; 50 percent of such patients are asymptomatic. It is possible that this patient's neurologic problem in infancy could have been hemorrhage due to a cerebral arteriovenous malformation or a brain abscess due to E. coli sepsis, as a complication of his pulmonary arteriovenous malformation — although a clinically significant pulmonary arteriovenous malformation at birth would be very unusual. Interventional radiologic techniques can be used to obliterate pulmonary arteriovenous malformations, eliminating the need for surgery. Screening can be performed effectively with contrast echocardiography, which is positive in as many as 70 percent of patients. This study can then be followed up with angiography to treat malformations that are 3 mm in diameter or larger.25 I would recommend treating this patient's pulmonary arteriovenous malformations to avert future complications.
Hepatic arteriovenous malformations, which this patient also had, are present in as many as 30 percent of persons with hereditary hemorrhagic telangiectasia, but clinically significant lesions are much less common. Three distinct clinical presentations have been identified: congestive heart failure from high output, biliary involvement with multiple strictures, and portal hypertension.26 Transcatheter embolization therapy for hepatic arteriovenous malformations has a poor success rate, with a high morbidity and mortality. Consequently, liver transplantation is the preferred treatment for patients with hereditary hemorrhagic telangiectasia and severe hepatic complications. This patient's hepatic arteriovenous malformations do not appear to require treatment.
Dr. Chung: The management of polyposis depends on the size, number, and location of the polyps. Colonoscopic surveillance should begin by the time a patient is 15 years of age, with resection of all polyps, and examinations should be repeated every two to three years once the patient is free of polyps. Colonoscopic surveillance with polypectomy is an option if the polyp burden is deemed to be low and manageable; otherwise, colectomy is indicated, as it was in this patient. A subtotal colectomy is the most commonly performed operation, as long as the rectum can be cleared of all polyps.
Management of the upper intestinal polyps in this patient is more problematic. Affected persons should have an upper endoscopic examination by the time they reach 15 years of age, with resection of all polyps, and these examinations should be repeated every two to three years once the patient is free of polyps. However, if the polyp burden is large or dysplasia or cancer is identified, partial or total gastrectomy may be necessary. In this case, because there have been two diagnoses of intramucosal carcinoma in the duodenum, a Whipple procedure should be strongly considered. It is possible that the early duodenal cancer has been completely excised, but the patient remains at high risk for additional unrecognized cancers. He will also require annual upper endoscopic as well as sigmoidoscopic examinations, given the persistence of polyps in the stomach and rectum. Finally, genetic counseling is an integral component of management. Genetic testing for MADH4 mutations can be offered to this patient's relatives.
Dr. Nancy Lee Harris (Pathology): Two generations of this family have been cared for by many physicians at this hospital.
Dr. Harland Winter (Pediatric Gastroenterology): Management of this patient's recurrent gastrointestinal bleeding was a challenge when he was a child, and his problems have continued into adulthood. We never could remove all his polyps, and probably because of the hereditary hemorrhagic telangiectasia, he continued to bleed more than most patients with juvenile polyposis.
Dr. Stephen Goldfinger (Gastroenterology): The patient's mother was a patient of mine for many years. It is scary to see the recapitulation of her disease in her son, both in the extensive gastrointestinal bleeding and in the development of cancer when he was in his early 40s. His mother required nearly weekly blood transfusions until we started intravenous infusions of 500 mg of iron dextran, after which she never again required red cells. We did not know at that time that juvenile polyps had the potential to be malignant. For that reason she was not screened, and an invasive cancer developed. I hope that screening of her son will result in a better outcome.
Dr. Li Tso (Internal Medicine): I have been this patient's primary care physician for the past 10 years. He has not had any symptoms from his pulmonary arteriovenous malformations, but I will try to convince him to undergo a pulmonary angiogram and elective treatment for them.
Dr. Kenneth Hung (Gastroenterology): This patient's fear of cancer and his reluctance to discuss surgery makes the management of his case very difficult. Discussions are ongoing with the family about whether to perform a Whipple procedure. Currently we have increased the frequency of his endoscopic surveillance to every six months.
Addendum
Dr. Digumarthy: Eight months after the admission described here, pulmonary angiography with embolization of the largest arteriovenous malformations was performed successfully (Figures 2A and 2B of the Supplementary Appendix). Surveillance endoscopy around that time showed no polyps or telangiectasia in the colon, distal ileum, or stomach.
Dr. Hung: One year after this admission, a Whipple procedure was performed, which showed multiple duodenal polyps with dysplasia and intramucosal carcinoma, but no invasive carcinoma. The patient has had recurrent epistaxis and continues to have iron-deficiency anemia.
Anatomical Diagnosis
Hereditary hemorrhagic telangiectasia and atypical juvenile polyposis with dysplasia and intramucosal carcinoma, associated with a germ-line mutation in the MADH4 gene.
Dr. Korzenik reports having received consulting fees from Isis Pharmaceuticals, Cytokine Pharmaceuticals, Berlex, and Synta Pharmaceuticals; lecture fees from Procter & Gamble, Centocor Pharmaceuticals, and Berlex; and grant support from Danisco. Dr. Chung reports having received research grants from Sugen, the Verto Foundation, and the Caring for Carcinoid Foundation; he reports having received consulting fees from Myriad Genetics.
We are indebted to the pathology department of Children's Hospital, Boston, for providing some of the pathological materials presented in this case.
Source Information
From the Gastrointestinal Unit (J.K., D.C.C.) and the Departments of Radiology (S.D.) and Pathology (K.B.), Massachusetts General Hospital; and the Departments of Medicine (J.K., D.C.C.), Radiology (S.D.), and Pathology (K.B.), Harvard Medical School.
References
Guttmacher AE, Marchuk DA, White RI Jr. Hereditary hemorrhagic telangiectasia. N Engl J Med 1995;333:918-924.
McAllister KA, Baldwin MA, Thukkani AK, et al. Six novel mutations in the endoglin gene in hereditary hemorrhagic telangiectasia type 1 suggest a dominant-negative effect of receptor function. Hum Mol Genet 1995;4:1983-1985.
Johnson DW, Berg JN, Baldwin MA, et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 1996;13:189-195.
Berg JN, Guttmacher AE, Marchuk DA, Porteous ME. Clinical heterogeneity in hereditary haemorrhagic telangiectasia: are pulmonary arteriovenous malformations more common in families linked to endoglin? J Med Genet 1996;33:256-257.
Shovlin CL, Guttmacher AE, Buscarini E, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet 2000;91:66-67.
Kjeldsen AD, Kjeldsen J. Gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia. Am J Gastroenterol 2000;95:415-418.
Rozen P, Samuel Z, Brazowski E. A prospective study of the clinical, genetic, screening, and pathologic features of a family with hereditary mixed polyposis syndrome. Am J Gastroenterol 2003;98:2317-2320.
McColl I, Bussey HJ, Veale AM, Morson BC. Juvenile polyposis coli. Proc R Soc Med 1964;57:896-897.
Nugent KP, Talbot IC, Hodgson SV, Phillips RK. Solitary juvenile polyps: not a marker for subsequent malignancy. Gastroenterology 1993;105:698-700.
Jass JR, Williams CB, Bussey HJ, Morson BC. Juvenile polyposis -- a precancerous condition. Histopathology 1988;13:619-630.
Grotsky HW, Rickert RR, Smith WD, Newsome JF. Familial juvenile polyposis coli: a clinical and pathologic study of a large kindred. Gastroenterology 1982;82:494-501.
Coburn MC, Pricolo VE, DeLuca FG, Bland KI. Malignant potential in intestinal juvenile polyposis syndromes. Ann Surg Oncol 1995;2:386-391.
Howe JR, Mitros FA, Summers RW. The risk of gastrointestinal carcinoma in familial juvenile polyposis. Ann Surg Oncol 1998;5:751-756.
Scott-Conner CE, Hausmann M, Hall TJ, Skelton DS, Anglin BL, Subramony C. Familial juvenile polyposis: patterns of recurrence and implications for surgical management. J Am Coll Surg 1995;181:407-413.
Howe JR, Roth S, Ringold JC, et al. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 1998;280:1086-1088.
Xu X, Brodie SG, Yang X, et al. Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric polyposis and cancer in mice. Oncogene 2000;19:1868-1874.
Howe JR, Bair JL, Sayed MG, et al. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet 2001;28:184-187.
Howe JR, Sayed MG, Ahmed AF, et al. The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J Med Genet 2004;41:484-491.
Sayed MG, Ahmed AF, Ringold JR, et al. Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis. Ann Surg Oncol 2002;9:901-906.
Gallione CJ, Repetto GM, Legius E, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 2004;363:852-859.
Gilinsky NH, Elliot MS, Price SK, Wright JP. The nutritional consequences and neoplastic potential of juvenile polyposis coli. Dis Colon Rectum 1986;29:417-420.
Ramaswamy G, Elhosseiny AA, Tchertkoff V. Juvenile polyposis of the colon with atypical adenomatous changes and carcinoma in situ: report of a case and review of the literature. Dis Colon Rectum 1984;27:393-398.
Jarvinen H, Franssila KO. Familial juvenile polyposis coli: increased risk of colorectal cancer. Gut 1984;25:792-800.
Woodford-Richens KL, Rowan AJ, Poulsom R, et al. Comprehensive analysis of SMAD4 mutations and protein expression in juvenile polyposis: evidence for a distinct genetic pathway and polyp morphology in SMAD4 mutation carriers. Am J Pathol 2001;159:1293-1300.
White RI Jr, Pollak JS, Wirth JA. Pulmonary arteriovenous malformations: diagnosis and transcatheter embolotherapy. J Vasc Interv Radiol 1996;7:787-804.
Garcia-Tsao G, Korzenik JR, Young L, et al. Liver disease in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2000;343:931-936.(Joshua Korzenik, M.D., Da)
Dr. Joshua D. Moss (Department of Medicine): A 43-year-old man was admitted to the hospital because of blood in his stool.
When the patient was a child of about three and half years of age, his mother first noted bright red blood in his stool, without other symptoms. He was evaluated at this hospital. On examination, two areas of telangiectasia were present on the buccal mucosa. Examinations of the child's heart, lung, and abdomen revealed no abnormalities. Iron-deficiency anemia had been present. Sigmoidoscopy performed under general anesthesia revealed a 1-cm pedunculated polyp 18 cm from the rectum, and two smaller polyps were visible distally, with no active bleeding. Examination of biopsy specimens disclosed features of juvenile polyps. The patient continued to have guaiac-positive stools throughout his hospital course but required no blood transfusions. He was discharged on day 14 and his care was continued at another hospital.
The patient continued to have intermittent rectal bleeding over the next 40 years, often requiring transfusions, and he had regular evaluations of both the small and large bowels at the other hospital, with annual esophagogastroduodenoscopy, sigmoidoscopy, or colonoscopy. Polyps were removed at intervals from the esophagus, stomach, duodenum, and colon; the majority were found to be either juvenile or hamartomatous polyps. Subtotal colectomy for intractable rectal bleeding was performed when the patient was 25 years of age.
During the patient's first decade of life, epistaxis developed and recurred, with nosebleeds resulting in 15 to 50 ml of blood loss per day. When he was in his early teens, resection and reconstruction of the right mandible were performed at the other hospital to remove a vascular malformation.
At 31 years of age, the patient resumed his care at this hospital. Clubbing of the fingers was noted, and a chest radiograph disclosed several nodular densities suggestive of arteriovenous malformations. An air-contrast upper gastrointestinal series with small-bowel follow-through disclosed marked thickening of the gastric folds with multiple filling defects in the antrum that was consistent with the presence of polyps and irregularity in the duodenal bulb that might represent additional polyps.
The patient continued to have episodes of epistaxis, and severe maxillary gingival hyperplasia developed. When he was 32 years of age, he underwent an angiographic study of the external carotid arteries that revealed multiple telangiectatic lesions involving all portions of the nasal mucosa, the hard and soft palates, portions of the gingivae (particularly over the superior alveolar ridges), and the tongue; the facial arteries did not supply these lesions. Several distal branches of the bilateral internal maxillary arteries were successfully embolized, and laser gingivoplasty was performed three days later.
At 33 years of age, the patient had had an episode of right upper quadrant abdominal pain; an abdominal ultrasonographic study disclosed abnormal vascular channels in the liver that were consistent with the presence of vascular malformations. Abdominopelvic computed tomography (CT) one month later disclosed a lobulated mass in the posterior left lower lung; the mass enhanced brightly with contrast material, and there were two vessels feeding it — features consistent with the presence of an arteriovenous malformation. There were also multiple tortuous vascular channels in the liver. CT scanning of the chest when the patient was 38 years of age revealed multiple bilateral pulmonary arteriovenous malformations, 2 to 4 cm in diameter. CT scanning of the abdomen when he was 40 years of age showed innumerable arteriovenous malformations in the liver.
Three years later, on the evening before the current admission, the patient had four to five bowel movements containing bright red blood. He had no abdominal or rectal pain, nausea, vomiting, or fever. He came to the emergency department of this hospital, where he was evaluated. His temperature was 36.4°C, the blood pressure 110/68 mm Hg, the pulse 94 beats per minute, the respiratory rate 20 breaths per minute, and the oxygen saturation 94 percent while he was breathing room air. The hematocrit was 31.1 percent, with a mean corpuscular volume of 68 μm3. The patient was admitted to the hospital for further evaluation and treatment.
The patient's birth had followed a full-term pregnancy, and delivery was normal. An episode of Escherichia coli sepsis and a subdural hematoma had occurred when he was 15 days old, resulting in residual left-sided weakness and mild mental retardation. He subsequently had recurrent complex partial seizures, which were controlled with phenobarbital. CT scanning of the head five years before the current admission, when the patient was 38 years of age, which was performed because of a fall, revealed porencephaly affecting most of the right temporal and occipital lobes; repeated scanning three months before admission showed no change from earlier examinations. There was no evidence of a vascular malformation. He had undergone a laparotomy for reduction of intussusception when he was 23 years of age and exploratory laparotomy and lysis of adhesions for small-bowel obstruction at 26 years of age and again at 42 years of age (8 months before the current hospitalization). His medications at the time of admission included phenobarbital and iron supplements.
The patient's mother had undergone a subtotal colectomy when she was 13 years of age because of rectal bleeding and the presence of telangiectatic lesions and polyps in the colon, and several duodenal polyps had been excised. She had been hospitalized on multiple occasions for lower gastrointestinal bleeding and recurrent severe epistaxis. Duodenal adenocarcinoma arising in a polypoid lesion was resected when she was 43 years of age; she died of sepsis with multiple liver abscesses at 45 years of age. No other members of the patient's immediate family, including his grandparents and three sisters, were known to have bleeding problems.
On examination, the patient appeared comfortable; he was conversant and his behavior appropriate, although mildly mentally retarded. Multiple telangiectatic lesions were present on his tongue, buccal mucosa, and nasal mucosa. An examination of the lungs, heart, and abdomen revealed no abnormalities. Multiple well-healed surgical scars were present on the abdomen. A rectal examination revealed no masses; the stool was guaiac-positive. The hematocrit was 32.6 percent; the hemoglobin, 10.5 g per deciliter.
Normal saline was administered intravenously. The hematocrit, measured twice daily, remained stable. On the day after admission, diagnostic procedures were performed.
Differential Diagnosis
Dr. Joshua Korzenik: May we review the radiologic studies?
Dr. Subba Digumarthy: Anteroposterior and lateral views of the angiogram of the right external carotid artery (Figure 1A), obtained 11 years before the patient's current admission, showed multiple small tortuous vessels in the region of the nasal cavity, gingivae, palate, and tongue. The supply is predominantly from internal maxillary arteries. These findings are consistent with the presence of telangiectasia.
Figure 1. Radiologic Studies.
Anteroposterior and lateral views of the right external carotid artery (Panel A) show multiple telangiectatic lesions in the nasal mucosa, palate, gingivae, and tongue, predominantly supplied by branches of internal maxillary arteries (arrows). A contrast-enhanced CT study of the chest (Panel B) shows a lobulated mass in the left lower lobe with tortuous serpiginous vessels consistent with a pulmonary arteriovenous malformation (arrow). A contrast-enhanced CT study of the upper abdomen (Panel C) shows multiple tortuous vessels in the right lobe of the liver, consistent with vascular malformations (arrow).
A CT scan of the chest (Figure 1B) performed with contrast material 10 years before admission shows multiple tortuous enhancing blood vessels at the left lung base and superior segment of the left lower lobe, consistent with the presence of vascular malformations. A contrast-enhanced CT scan of the abdomen (Figure 1C) obtained at that time showed abnormal vascularity in the right lobe of the liver, with abnormal communications among the branches of the hepatic vein, portal vein, and hepatic arteries — consistent with the presence of a vascular malformation. An upper gastrointestinal examination with small-bowel follow-through after oral administration of barium contrast (Figure 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org) performed the same year shows filling defects in the antrum of the stomach and along the greater curvature.
Dr. Korzenik: The diagnosis in this case rests on considering two different elements of this patient's presentation: gastrointestinal bleeding and polyps. I will address the first issue, and Dr. Chung will discuss the second. Both Dr. Chung and I are aware of the diagnosis.
Chronic gastrointestinal bleeding can have many causes. The bleeding in this case spanned decades, beginning at an early age, so that causes of bleeding in childhood as well as problems more common in adults should be considered. In children, chronic bleeding can be caused by milk allergy, Meckel's diverticulum, congenital vascular abnormalities, and juvenile polyposis. Common causes in adults include hemorrhoids, diverticula, neoplasms, and vascular ectasia. In both groups, ulcerative colitis and Crohn's disease could produce chronic bleeding, although other symptoms associated with these diseases were absent in this case. Polyps are common in both children and adults, whereas less common vascular lesions, such as the blue rubber bleb nevus syndrome or Klippel–Trénaunay–Weber syndrome, both of which normally would be associated with other findings, are not present in this patient. The presence of vascular abnormalities outside the gastrointestinal tract in this patient, as well as symptoms of chronic epistaxis, made the diagnosis likely to be hereditary hemorrhagic telangiectasia (also known as Osler–Weber–Rendu disease).
Hereditary hemorrhagic telangiectasia is a syndrome that results in arteriovenous malformations that affect numerous organs, including the nose (in >95 percent of the cases), skin (in >80 percent), gastrointestinal tract (in 30 percent), lungs (in 30 percent), brain (in 10 percent), and liver (in 30 percent); this patient had arteriovenous malformations of all these organs except the brain.1 Two of the identified genetic defects implicated in the disorder involve the protein endoglin, which is associated with transforming growth factor receptors I and II and which is expressed predominantly on endothelial cells, and activin-receptor–like kinase I.2,3,4 Establishing the diagnosis is critical, since screening for pulmonary and cerebral arteriovenous malformations can identify lesions and permit treatment before catastrophic bleeding or other complications occur. The diagnosis of hereditary hemorrhagic telangiectasia is based on the presence of three of the four Cura?ao criteria (Table 1).5 This patient's symptoms meet the criteria for hereditary hemorrhagic telangiectasia.
Table 1. Cura?ao Criteria for the Diagnosis of Hereditary Hemorrhagic Telangiectasia (HHT).
Gastrointestinal bleeding in hereditary hemorrhagic telangiectasia occurs in 30 to 40 percent of patients and usually becomes evident in the fourth or fifth decade of life.6 Bleeding is typically from telangiectatic areas in the stomach or proximal small bowel. This patient's gastrointestinal bleeding began at a very early age, raising the concern that it had another cause, and in fact, intestinal polyps were found. Dr. Chung will discuss this problem.
Dr. Daniel C. Chung: The presence of a personal and family history of multiple gastrointestinal polyps in childhood indicates that this patient had a type of polyposis syndrome. These syndromes are distinguished by their histologic features and categorized in two major groups as either adenomatous or hamartomatous (Table 2). On the basis of the predominantly hamartomatous histologic findings in this case, the considerations were juvenile polyposis syndrome, Cowden's disease, the Bannayan–Ruvalcaba–Riley syndrome, and the Peutz–Jeghers syndrome.
Table 2. Inherited Gastrointestinal Polyposis Syndromes.
Juvenile polyps, the predominant type of hamartomatous polyp identified in this patient, are observed in three of the four syndromes. The type of polyps associated with the Peutz–Jeghers syndrome is seen only in that disease, and such polyps were not seen in this case. A few adenomatous polyps were described, raising the possibility of the so-called hereditary mixed polyposis syndrome. However, the adenomatous changes were mainly seen within juvenile polyps. Furthermore, there were multiple gastric and duodenal polyps, and the hereditary mixed polyposis syndrome typically involves only the colon.7
The pattern of extraintestinal findings can help us distinguish among these hamartomatous syndromes: thyroid and breast cancer, facial trichilemmomas, and macrocephaly are seen in Cowden's disease, and mental retardation, macrocephaly, lipomas, and genital pigmentation in the Bannayan–Ruvalcaba–Riley syndrome. This patient has mild mental retardation, but this was attributed to brain injury in infancy. In classic forms of juvenile polyposis, there are no consistent extraintestinal findings, so this condition emerges as the most likely diagnosis.8
Juvenile polyps can arise sporadically as the most common type of colonic polyp in childhood, but these polyps are typically solitary.9 The diagnosis of juvenile polyposis can be established by any of the following clinical criteria: more than five juvenile polyps of the colorectum, juvenile polyps throughout the gastrointestinal tract, or any number of juvenile polyps in a patient with a family history of juvenile polyposis.10 This patient's condition fulfills all three of these criteria. Affected persons typically present in childhood, as this patient did, with rectal bleeding or with a prolapsed rectal polyp, anemia, diarrhea, or abdominal pain. The average age of a patient at diagnosis ranges from 9.5 years11 to 18.5 years.12 The disease is inherited in an autosomal dominant manner, but as many as 22 percent of affected persons may not report a family history of polyposis, suggesting that de novo mutations occur frequently.
A long-term concern in the case of this patient is the risk of gastrointestinal cancer. Polyps can develop adenomatous components, which are precursors of adenocarcinoma. The lifetime risk of colon cancer is estimated at between 17 percent and 38 percent among persons with juvenile polyposis,13,14 and the mean age at the diagnosis of colon cancer is 34 years.10 There is also a 15 to 21 percent lifetime risk of upper gastrointestinal tract cancers.14 Overall, the lifetime risk of any gastrointestinal cancer occurring in this patient is 46 to 55 percent.
Approximately 23 percent of patients with juvenile polyposis carry a germ-line mutation in MADH4 (a tumor-suppressor gene on chromosome 18q21),15,16 and 20 percent have a germ-line mutation in BMPR1A (the type I receptor for bone morphogenetic protein)17 — both of which are involved in signaling by transforming growth factor .18 The genetic basis of more than 50 percent of cases remains unknown. Some cases of juvenile polyposis may be caused by mutations in MADH4 or BMPR1A that cannot be detected by current techniques, but the existence of additional disease-causing genes is probable. No mutations have been identified in a number of other candidate genes from the transforming growth factor family.18
There are two features that appear to be more common in carriers of MADH4 mutations: gastric polyposis,19 which is seen in 57 to 86 percent of those with MADH4 mutations, as compared with 10 to 20 percent of those with BMPR1A mutations, and hereditary hemorrhagic telangiectasia.20 Thus, this patient and his mother, both of whom probably had juvenile polyposis and hereditary hemorrhagic telangiectasia, would be likely to have a mutation in the MADH4 gene, which is responsible for both clinical syndromes.
The diagnostic procedures performed in this case were esophagogastroduodenoscopy, sigmoidoscopy, and MADH4 genetic testing.
Clinical Diagnosis
Hereditary hemorrhagic telangiectasia.
Juvenile polyposis syndrome.
Dr. Joshua Korzenik and Dr. Daniel C. Chung's Diagnosis
Combined syndrome of juvenile polyposis and hereditary hemorrhagic telangiectasia due to a germ-line mutation in MADH4.
Pathological Discussion
Dr. Kamran Badizadegan: The patient had undergone numerous upper and lower gastrointestinal biopsies and polypectomies. Since a complete description of the specimens that were obtained is not possible here, I will focus on the evolution of several representative polyps over the course of 40 years and the findings in his most recent specimens.
The patient's first pathological diagnoses were made by two of the founders of modern academic pathology. The first sigmoid polyp, removed when the patient was three and a half years of age, was diagnosed as a juvenile polyp by Dr. Benjamin Castleman; rectosigmoid polyps that were removed when the patient was five years of age were diagnosed as retention polyps by Dr. Sidney Farber. Representative photomicrographs (Figure 2A) show an inflamed epithelial polyp with irregular and variably dilated glands. The polyp is not dysplastic and does not contain a prominent mesenchymal component. In addition, prominent cystically dilated glands and subsurface granulation tissue, which are typical features of solitary juvenile polyps, are not present.
Figure 2. Morphologic Progression of the Patient's Rectosigmoid Polyps from Early Childhood to the Present.
Histologic sections of representative polyps from when the patient was 5 years of age (Panel A and inset), 13 years of age (Panel B and inset) and 38 years of age (Panel C and inset are shown). Comparison of the three polyps at low magnification (Panels A, B, and C) shows a progression in the glandular architectural complexity, characterized by an overall increase in the epithelial component and the development of more crowded and more complex glandular patterns with age (hematoxylin and eosin). An examination of the surface of each polyp at higher magnification shows an inflamed stroma with mildly dilated glands reminiscent of typical juvenile polyps at 5 years of age (Panel A, inset), a more prominent epithelial component with focally villiform architecture at 13 years of age (Panel B, inset), and a diffusely dysplastic epithelium at 38 years of age (Panel C, inset).
Over the ensuing years, the patient's intestinal polyps gradually evolved into a more proliferative and eventually dysplastic phenotype. As represented in Figure 2B, the patient's polyps during the teenage years were dominated by a prominent epithelial component with a variably villiform surface architecture. The polyps did not contain a prominent inflammatory or mesenchymal component and were not dysplastic. In sharp contrast, a rectal polyp removed when the patient was 38 years of age (Figure 2C) shows small, crowded glands that are uniformly lined by low-grade dysplastic epithelium. At no point was a vascular lesion present on the biopsy specimens or resected polyps. However, several upper endoscopic studies described the presence of areas of mucosal telangiectasias in the stomach.
The diagnostic procedure at the time of this patient's admission was upper gastrointestinal endoscopy with polypectomy. An endoscopically resected duodenal polyp measured approximately 2.1 cm in its largest dimension and was diffusely dysplastic (Figure 3). The overall growth pattern of this polyp is similar to the adenomatous rectal polyp described above (Figure 2C), although the duodenal polyp shows more severe dysplasia, with marked nuclear atypia and irregular, back-to-back glands consistent with high-grade dysplasia and intramucosal carcinoma (Figure 3, inset). An examination of multiple sections showed no invasive component. It is notable that the patient's mother presented at a similar age (mid-40s) with an invasive duodenal carcinoma arising in a polypoid lesion, with metastases to regional lymph nodes.
Figure 3. Dysplastic Duodenal Polyp with Focal Intramucosal Carcinoma.
Histologic sections of the patient's duodenal polyp at the time of the current admission show an architecturally complex epithelial polyp with crowded glands and diffusely dysplastic epithelium. At higher magnification (inset), the polyp shows small, irregular, back-to-back glands with marked nuclear atypia and prominent mitotic activity, features that are consistent with high-grade dysplasia and intramucosal carcinoma.
Overall, the patient's gastrointestinal lesions are consistent with an atypical juvenile polyposis with progression to dysplasia and intramucosal carcinoma. Although classic juvenile polyps are round to oval with irregular, often dilated, glands in a highly inflamed stroma, rare atypical forms characterized by increased glandularity and a lobulated growth pattern have been reported in patients with polyposis in whom clinically significant dysplasia and adenocarcinoma developed.10,21,22,23 In addition, recent comparative studies have described the presence of subtle histologic features, including "long, elongated crypts replacing round cysts," in patients with juvenile polyposis who carry germ-line mutations in the MADH4 gene.24
Dr. Chung: This patient was one of 15 patients in seven families in a recent report who had a combined syndrome of juvenile polyposis and hereditary hemorrhagic telangiectasia associated with MADH4 mutations.20 Testing for MADH4 mutations disclosed a truncating germ-line MADH4 mutation at codon 534 in this patient.
Discussion of Management
Dr. Korzenik: The care of patients with hereditary hemorrhagic telangiectasia principally involves the prevention of complications from the arteriovenous malformations and management of gastrointestinal bleeding and epistaxis. Patients with hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations, as in this case, can present with a variety of problems including cerebrovascular accidents, cerebral abscesses, and dyspnea; 50 percent of such patients are asymptomatic. It is possible that this patient's neurologic problem in infancy could have been hemorrhage due to a cerebral arteriovenous malformation or a brain abscess due to E. coli sepsis, as a complication of his pulmonary arteriovenous malformation — although a clinically significant pulmonary arteriovenous malformation at birth would be very unusual. Interventional radiologic techniques can be used to obliterate pulmonary arteriovenous malformations, eliminating the need for surgery. Screening can be performed effectively with contrast echocardiography, which is positive in as many as 70 percent of patients. This study can then be followed up with angiography to treat malformations that are 3 mm in diameter or larger.25 I would recommend treating this patient's pulmonary arteriovenous malformations to avert future complications.
Hepatic arteriovenous malformations, which this patient also had, are present in as many as 30 percent of persons with hereditary hemorrhagic telangiectasia, but clinically significant lesions are much less common. Three distinct clinical presentations have been identified: congestive heart failure from high output, biliary involvement with multiple strictures, and portal hypertension.26 Transcatheter embolization therapy for hepatic arteriovenous malformations has a poor success rate, with a high morbidity and mortality. Consequently, liver transplantation is the preferred treatment for patients with hereditary hemorrhagic telangiectasia and severe hepatic complications. This patient's hepatic arteriovenous malformations do not appear to require treatment.
Dr. Chung: The management of polyposis depends on the size, number, and location of the polyps. Colonoscopic surveillance should begin by the time a patient is 15 years of age, with resection of all polyps, and examinations should be repeated every two to three years once the patient is free of polyps. Colonoscopic surveillance with polypectomy is an option if the polyp burden is deemed to be low and manageable; otherwise, colectomy is indicated, as it was in this patient. A subtotal colectomy is the most commonly performed operation, as long as the rectum can be cleared of all polyps.
Management of the upper intestinal polyps in this patient is more problematic. Affected persons should have an upper endoscopic examination by the time they reach 15 years of age, with resection of all polyps, and these examinations should be repeated every two to three years once the patient is free of polyps. However, if the polyp burden is large or dysplasia or cancer is identified, partial or total gastrectomy may be necessary. In this case, because there have been two diagnoses of intramucosal carcinoma in the duodenum, a Whipple procedure should be strongly considered. It is possible that the early duodenal cancer has been completely excised, but the patient remains at high risk for additional unrecognized cancers. He will also require annual upper endoscopic as well as sigmoidoscopic examinations, given the persistence of polyps in the stomach and rectum. Finally, genetic counseling is an integral component of management. Genetic testing for MADH4 mutations can be offered to this patient's relatives.
Dr. Nancy Lee Harris (Pathology): Two generations of this family have been cared for by many physicians at this hospital.
Dr. Harland Winter (Pediatric Gastroenterology): Management of this patient's recurrent gastrointestinal bleeding was a challenge when he was a child, and his problems have continued into adulthood. We never could remove all his polyps, and probably because of the hereditary hemorrhagic telangiectasia, he continued to bleed more than most patients with juvenile polyposis.
Dr. Stephen Goldfinger (Gastroenterology): The patient's mother was a patient of mine for many years. It is scary to see the recapitulation of her disease in her son, both in the extensive gastrointestinal bleeding and in the development of cancer when he was in his early 40s. His mother required nearly weekly blood transfusions until we started intravenous infusions of 500 mg of iron dextran, after which she never again required red cells. We did not know at that time that juvenile polyps had the potential to be malignant. For that reason she was not screened, and an invasive cancer developed. I hope that screening of her son will result in a better outcome.
Dr. Li Tso (Internal Medicine): I have been this patient's primary care physician for the past 10 years. He has not had any symptoms from his pulmonary arteriovenous malformations, but I will try to convince him to undergo a pulmonary angiogram and elective treatment for them.
Dr. Kenneth Hung (Gastroenterology): This patient's fear of cancer and his reluctance to discuss surgery makes the management of his case very difficult. Discussions are ongoing with the family about whether to perform a Whipple procedure. Currently we have increased the frequency of his endoscopic surveillance to every six months.
Addendum
Dr. Digumarthy: Eight months after the admission described here, pulmonary angiography with embolization of the largest arteriovenous malformations was performed successfully (Figures 2A and 2B of the Supplementary Appendix). Surveillance endoscopy around that time showed no polyps or telangiectasia in the colon, distal ileum, or stomach.
Dr. Hung: One year after this admission, a Whipple procedure was performed, which showed multiple duodenal polyps with dysplasia and intramucosal carcinoma, but no invasive carcinoma. The patient has had recurrent epistaxis and continues to have iron-deficiency anemia.
Anatomical Diagnosis
Hereditary hemorrhagic telangiectasia and atypical juvenile polyposis with dysplasia and intramucosal carcinoma, associated with a germ-line mutation in the MADH4 gene.
Dr. Korzenik reports having received consulting fees from Isis Pharmaceuticals, Cytokine Pharmaceuticals, Berlex, and Synta Pharmaceuticals; lecture fees from Procter & Gamble, Centocor Pharmaceuticals, and Berlex; and grant support from Danisco. Dr. Chung reports having received research grants from Sugen, the Verto Foundation, and the Caring for Carcinoid Foundation; he reports having received consulting fees from Myriad Genetics.
We are indebted to the pathology department of Children's Hospital, Boston, for providing some of the pathological materials presented in this case.
Source Information
From the Gastrointestinal Unit (J.K., D.C.C.) and the Departments of Radiology (S.D.) and Pathology (K.B.), Massachusetts General Hospital; and the Departments of Medicine (J.K., D.C.C.), Radiology (S.D.), and Pathology (K.B.), Harvard Medical School.
References
Guttmacher AE, Marchuk DA, White RI Jr. Hereditary hemorrhagic telangiectasia. N Engl J Med 1995;333:918-924.
McAllister KA, Baldwin MA, Thukkani AK, et al. Six novel mutations in the endoglin gene in hereditary hemorrhagic telangiectasia type 1 suggest a dominant-negative effect of receptor function. Hum Mol Genet 1995;4:1983-1985.
Johnson DW, Berg JN, Baldwin MA, et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 1996;13:189-195.
Berg JN, Guttmacher AE, Marchuk DA, Porteous ME. Clinical heterogeneity in hereditary haemorrhagic telangiectasia: are pulmonary arteriovenous malformations more common in families linked to endoglin? J Med Genet 1996;33:256-257.
Shovlin CL, Guttmacher AE, Buscarini E, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet 2000;91:66-67.
Kjeldsen AD, Kjeldsen J. Gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia. Am J Gastroenterol 2000;95:415-418.
Rozen P, Samuel Z, Brazowski E. A prospective study of the clinical, genetic, screening, and pathologic features of a family with hereditary mixed polyposis syndrome. Am J Gastroenterol 2003;98:2317-2320.
McColl I, Bussey HJ, Veale AM, Morson BC. Juvenile polyposis coli. Proc R Soc Med 1964;57:896-897.
Nugent KP, Talbot IC, Hodgson SV, Phillips RK. Solitary juvenile polyps: not a marker for subsequent malignancy. Gastroenterology 1993;105:698-700.
Jass JR, Williams CB, Bussey HJ, Morson BC. Juvenile polyposis -- a precancerous condition. Histopathology 1988;13:619-630.
Grotsky HW, Rickert RR, Smith WD, Newsome JF. Familial juvenile polyposis coli: a clinical and pathologic study of a large kindred. Gastroenterology 1982;82:494-501.
Coburn MC, Pricolo VE, DeLuca FG, Bland KI. Malignant potential in intestinal juvenile polyposis syndromes. Ann Surg Oncol 1995;2:386-391.
Howe JR, Mitros FA, Summers RW. The risk of gastrointestinal carcinoma in familial juvenile polyposis. Ann Surg Oncol 1998;5:751-756.
Scott-Conner CE, Hausmann M, Hall TJ, Skelton DS, Anglin BL, Subramony C. Familial juvenile polyposis: patterns of recurrence and implications for surgical management. J Am Coll Surg 1995;181:407-413.
Howe JR, Roth S, Ringold JC, et al. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 1998;280:1086-1088.
Xu X, Brodie SG, Yang X, et al. Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric polyposis and cancer in mice. Oncogene 2000;19:1868-1874.
Howe JR, Bair JL, Sayed MG, et al. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet 2001;28:184-187.
Howe JR, Sayed MG, Ahmed AF, et al. The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J Med Genet 2004;41:484-491.
Sayed MG, Ahmed AF, Ringold JR, et al. Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis. Ann Surg Oncol 2002;9:901-906.
Gallione CJ, Repetto GM, Legius E, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 2004;363:852-859.
Gilinsky NH, Elliot MS, Price SK, Wright JP. The nutritional consequences and neoplastic potential of juvenile polyposis coli. Dis Colon Rectum 1986;29:417-420.
Ramaswamy G, Elhosseiny AA, Tchertkoff V. Juvenile polyposis of the colon with atypical adenomatous changes and carcinoma in situ: report of a case and review of the literature. Dis Colon Rectum 1984;27:393-398.
Jarvinen H, Franssila KO. Familial juvenile polyposis coli: increased risk of colorectal cancer. Gut 1984;25:792-800.
Woodford-Richens KL, Rowan AJ, Poulsom R, et al. Comprehensive analysis of SMAD4 mutations and protein expression in juvenile polyposis: evidence for a distinct genetic pathway and polyp morphology in SMAD4 mutation carriers. Am J Pathol 2001;159:1293-1300.
White RI Jr, Pollak JS, Wirth JA. Pulmonary arteriovenous malformations: diagnosis and transcatheter embolotherapy. J Vasc Interv Radiol 1996;7:787-804.
Garcia-Tsao G, Korzenik JR, Young L, et al. Liver disease in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2000;343:931-936.(Joshua Korzenik, M.D., Da)