Pathogenesis of the proband
The proband was born in 1966. At the age of three, he was examined in a county hospital and had symptoms of diarrhoea, spontaneous polyp-elimination, and rectal bleeding. In the same hospital in 1970, he was diagnosed with ileus and treated with conservative, non-invasive methods that ended the symptoms, thus no further examinations followed. In 1971 he was again hospitalized due to ileus caused by intussusceptions; six hamartomatous polyps were removed from the colon by sigmoidoscopy. During the patient’s childhood, abdominal pain and spontaneous polyp-elimination were typical symptoms, nonetheless, serious bleeding and gravis anaemia were not observed and the patient’s general clinical status was good. During his teenage years, spontaneous polyp-amputations were observed together with rectal bleeding monthly or bimonthly; yet, the patient did not develop anaemia. During a continuous 18 years of care, 107 polyps were eliminated by endoscopy from the proband’s colon. Histological analyses showed hamartomatous lesions in each case without adenomatous elements (). The accessible relatives were examined while researching the family anamnesis; however, no typical alteration was found. The inheritance of familial colorectal cancer could be excluded; the colonoscopy done on the proband’s elder, symptom-free brother was negative.
Figure 1 Hamartomatous polyp from proband’s colon. A. Cystosus glands and regular colonic epithelial glands are visible (organotypic structure) (Hemtaoxilin & eosin (HE) staining). B. Higher magnification of (HE staining; 80× (more ...)
In 1985 several hamartomatous polyps with coloured cystic dilatation were removed from the proband’s colon by colonoscopy, whereas the results of gastroscopy and duodenoscopy were negative.
Although the proband was in a generally good condition, he was followed up yearly. In 1989, hamartomatouos polyps were found in the stomach and in the small intestine for the first time ().
Juvenile polyp from proband’s small intestine. The submucosa is visible along the axis of the polyp. The epithelial glands are proliferating (HE staining)
The colonoscopy performed at that time revealed mucoid, glove shaped, and soft, mostly pedunculated polyps in the rectum and proximal sigmoid colon, whereas the other parts of the sigmoid and descending colon were polyp free. Furthermore, some polyps were also observed in the transversal colon. Two polypectomies were performed; one of them was a juvenile polyp and the other was characterized as adenomatous with second degree dysplasia (). A year later, some polyps were detected in the rectosigmoid and even more in the stomach. Despite our yearly call, the proband did not come for controls between 1990 and 1997. The Hungarian political and economical changes as well as a significant growth in the proband’s and his family’s financials might have played a role in the insufficient compliance. The patient got married in 1993; his daughter was born in 1995. According to a follow up report, the proband did not show any signs or symptoms of the disease.
Figure 3 A. Hyperplastic polyp with adenomatous transformation from proband’s colon. (framed region) (HE staining); B. Adenomatous glands, some of them next to a cystous gland from proband’s colon (HE staining; 80× magnificiation); C. Real (more ...)
In April 1997 the proband checked into the local hospital with symptoms of grave anaemia and weight-loss. Gastroscopy revealed severe polyposis in the stomach, thus total gastrectomy was suggested by the local gastroenterologist. A month later, when the proband checked in our hospital, the total gastrectomy was rejected due to severely progressed polyposis which expanded to the duodenum. Four polypectomies were performed; histological analyses did not show malignancy. Colonoscopy was performed and revealed large polyps in the rectum which were suspected to be malignant. 15-20 polyps were removed; however, during the procedure arterial bleeding occurred that could not be controlled by coagulation. As a result, per rectum surgical intervention was needed; after the bleeding was under control, the colonoscopy was repeated and it revealed neoplastic tissue growth causing obstruction in the transversal colon. Staging tests, gastric ultrasonography and CT including the scan of the chest unveiled multiple hepatic metastases and a pulmonal metastasis in the right lobe. The patient was inoperable and was treated with palliative chemotherapy. In the same year, in 1997, he died at the age of 31 of a disease that was previously thought to be benign.
Pathogenesis of the proband’s brother
The proband’s elder brother (II.1., born in 1958) was first examined in 1971 when the proband was diagnosed with multiple polyposis. Endoscopy did not show any alteration in either the gastroduodenal or the colorectal tract. In January 1990 endoscopy detected several small polyps in the sigmoid colon as well as a larger (6 mm) polyp which was endoscopically removed; histological analysis confirmed it was hamartomatous. In the gastroduodenal tract, alterations were not detected. Despite our calls for regular, yearly controls, the brother did not check into our hospital until 1997 when he finally came in accompanying the seriously ill proband. The stomach ultrasonography and panendoscopy performed at that time showed no alterations in the elder brother, whereas during colonoscopy 6 small, villous polyps were removed from the rectosigmoid. Furthermore, the most part of an apple-sized, soft, villous polyp was removed from the descending colon in pieces. Due to the remaining tissue growth, repeated endoscopy and polypectomy were suggested. Histological analyses revealed hamartomatous lesions. Two months later a repeated colonoscopy was performed; due to the family anamnesis and the presence of an extremely large polyp in the border of the descending colon and the lienal flexure, subtotal colectomy was suggested ().
Figure 4 Adenoma from the colon of the proband’s brother. A. Neoplastic tubular adenoma with irregular, dysplastic glands (HE staining; 160× magnification) B. Adenoma with severe dysplasia. The structure of the glands corresponds to an early malignant (more ...)
After the operation, regular endoscopic examinations were carried out in every two years. In 2001 a polyp was detected in the stomach and each time the patient was examined by endoscopy different numbers of polyps were detected in and removed from the remaining part of the colon. In March 2005, capsular endoscopy and colonoscopy were performed. Some adenomatous polyps were removed from the rectum. After treatment, the patient was free from lesions and symptoms. In 2006 the upper panendoscopy was negative, but six tiny polyps were eliminated from the rectum and five bigger polyps (the diameter of the largest one was 20 mm) were removed from the large intestine. Malignancy was not found based on histological data; at the same time, the amount of hamartomatous elements decreased whereas the adenomatous lesions and tubular architectures increased in the histological samples.
The family anamnesis of the two brothers is not typical. The patients’ father died at the age of 66, autopsy did not show any characteristics of JPS. The mother was thoroughly examined at the age of 42 years and was free of JPS; she is still alive and free of any symptoms. The proband’s paternal grandfather died of colon cancer at the age of 67 (his file is not accessible, autopsy was not performed). There are no data about the proband’s paternal grandmother. The proband’s daughter was first examined in 2006 after genetic analysis revealed positivity for JPS. She has been followed up every year since. Two children of the proband’s brother have also been examined in 2004. The proband’s niece was diagnosed with JPS and has been yearly followed up by endoscopy since 2006. Based on genetic analysis the nephew was negative for JPS.
Molecular diagnostic examination
The activity of the p53, c-MYC and H-ras genes was examined in blood samples derived from the proband, the proband’s daughter, his elder brother and one of his elder brother’s children. These results revealed increased activity of all three genes examined.
The increased expression of tumorsuppressor p53, c-MYC oncoprotein, and H-ras genes cannot be explained based on our current knowledge; even the latest publications can only hypothesize the possible causes of such aberrations (17
). The activity of these genes was only elevated, however, in those people’s blood samples that carried a mutation in genes playing a role in the development of JPS (19
James R. Howe and his colleagues examined the samples taken from the proband’s daughter, his brother, and the brother’s two children. The published genetic analyses revealed a mutation in the BMPR1A gene (21
). Two substitutions were found in consecutive nucleotides of exon 7 (735-6 TG>AT) of the BMPR1A gene. Interestingly, each of these substitutions would change the corresponding amino acid into a stop codon. This genetic aberration has been diagnosed in the proband, in his daughter, in his elder brother, and in his brother’s daughter, but was not detected in the proband’s son (21
After receiving the genetic results, the risk-specific care of the proband’s family was planned. The results of the first surveillance are the following:
II.1. Proband’s brother (53 year-old man) - Multiple polyps in the colon. Subtotal colectomy cue to the presence of an extremely large polyp in the border of the descending colon and the lienal flexure.
II.2. Proband (49 year-old man) - The stomach is free of polyps. Two adenomatous polyps without dysplasia were removed during colonoscopy. Capsule endoscopy did not show alterations in the small intestine.
III.1. Proband’s niece (25 year-old single, childless woman) - The gastroscopy was negative; colonoscopy revealed two small, flat polyps which were hyperplastic based on the histologycal analysis.
III.2. Proband’s nephew (24 year-old single, childless man) - Oesophago-gastro-duodenoscopy and colonoscopy were performed, both with negative results.
III.3. Proband’s daughter (13 year-old girl) - Pathological alterations were not detected by endoscopy in the upper gastrointestinal tract. Five polyps were removed endoscopically and several pinhead-sized polyps were detected by total colonoscopy. The removed polyps were hamartomatous and typical for JPS.
The proband’s risk-specific family tree is shown in .
Figure 5 Proband’s family tree. Patient II/2 (proband) clearly has JPS. Mutation of the BMPRA1 gene was shown in patients III/1 (proband’s niece) and III/3 (proband’s daughter), therefore they need strict endoscopic surveillance. Mutation (more ...)