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© Borgis - Postępy Nauk Medycznych 1/2015, s. 11-18
Paweł Boruń1, Kacper Sałanowski2, Jarosław Walkowiak3, Marta Kaczmarek-Ryś1, Wojciech Cichy3, *Andrzej Pławski1
Zespoły polipowatości hamartomatycznych
Hamartomous polyposis syndromes
1Institute of Human Genetics, Polish Academy of Sciences, Poznań
Head of Institute: prof. Jerzy Nowak, MD, PhD
2Faculty of Agronomy and Bioengineering, University of Live Sciences, Poznań
Head of Faculty: prof. Wiesław Koziara, MD, PhD
3Department of Pediatric Gastroenterology and Metabolic Diseases, Poznań University of Medical Sciences
Head of Department: prof. Jarosław Walkowiak, MD, PhD
Streszczenie
Polipy hamartomatyczne są rodzajem malformacji błony śluzowej zbudowanych ze zdrowej, zdezorganizowanej tkanki. Ich rodzinne występowanie jest charakterystyczne dla zespołu polipowatości młodzieńczej, zespołu Peutza-Jeghersa, zespołu polipowatości mieszanej oraz zespołów guzów hamartomatycznych związanych z mutacjami PTEN. Wszystkie wyżej wymienione zespoły są dziedziczone w sposób autosomalnie dominujący i tworzą grupę chorób heterogennych pod względem liczebności i miejsca występowania polipów, a także ryzyka wystąpienia nowotworów układu pokarmowego i innych narządów. Poszczególne polipowatości często objawiają podobne symptomy, szczególnie we wczesnych etapach rozwoju, co w wielu przypadkach nie pozwala na ich rozróżnienie. Ich poprawna diagnoza, z wykorzystaniem metod z zakresu biologii molekularnej, pozwala na zastosowanie efektywnego leczenia na wczesnych etapach choroby oraz monitoring narządów, które zagrożone są rozwojem nowotworu.
Badania nad dziedzicznymi predyspozycjami do występowania polipowatości hamartomatycznych prowadzone są przez autorów pracy w Instytucie Genetyki Człowieka PAN w Poznaniu. W banku DNA polskich pacjentów z polipowatościami zgromadzono materiał 81 rodzin z polipowatościami hamartomatycznymi.
Summary
Hamartomas are malformations of mucosa, consisting of disorganized normal tissues. The manifestation of hamartomatous polyps is characteristic of juvenile polyposis syndrome, Peutz-Jeghers’ syndrome, hereditary mixed polyposis syndrome and PTEN hamartoma tumour syndrome. All the aforementioned syndromes are inherited in an autosomal dominant manner. They form a rather heterogeneous group of disorders both in respect to the number and localization of polyps and the risk of cancer in the alimentary tract and other organs. Individual syndromes frequently manifest similar symptoms, particularly during the early stage of the diseases when in several cases their clinical pictures do not allow to make a differential diagnosis. The correct diagnosis of the disease using molecular methods allows to implement early treatment and therefore more effectively since it is followed by a strict monitoring of organs that manifest a predisposition to neoplastic transformation.
Research on the inherited hamartomatous polyposis has been conducted by the authors of this article at the Institute of Human Genetics, Polish Academy of Sciences in Poznań. In the DNA bank of Polish patients with polyposis material from 81 families with hamartomatous polyposis has been collected.



Introduction
The term of hamartoma corresponds to a non-neoplastic tumour, consisting of disorganized normal tissues and characteristic of the site of manifestation of the tumour. This term was introduced in 1904 by a German pathologist, Eugen Albrecht (1). Familial manifestation of hamartomatous polyps can be observed in a number of syndromes. The following are hamartomatous diseases: juvenile polyposis syndrome (JPS), Peutz-Jeghers syndrome (PJS), Hereditary Mixed Polyposis Syndrome (HMPS) and the syndrome of hamartomatous tumours linked to the PTEN gene mutations (PTEN hamartoma tumour syndrome – PHTS). Among others, the following were classed as belonging to PHTS: Cowden syndrome (CS), Bannayan--Riley-Ruvalcaba syndrome (BRRS) and Proteus syndrome (PS). All the above mentioned syndromes are inherited in an autosomal dominant manner. Apart from the manifestation in the alimentary tract of the hamartomatous polyps these syndromes are also characterized by an increased risk of neoplastic transformation. The development of neoplasms is not restricted to the alimentary tract, but they can also be manifested in other organs. Progression of neoplastic lesions in this type of polyps has not been fully researched, but it shows a different mechanism of formation than the one observed in adenomas.
Particular syndromes of hamartomatous polyposis are often characterized by the manifestation of similar symptoms, especially at the initial stage of the development of the disease the clinical pictures in many cases do not make it possible to differentiate them (2). Proper diagnosis of the disease by means of molecular differential methods makes it possible to begin faster and more efficient treatment since those organs are monitored which show an increased predisposition to neoplastic transformastion (3).
Juvenile polyposis
Juvenile polyposis syndrome (JPS) (MIM # 174900) is a rare disease inherited in an autosomal dominant manner as described by McColl in 1966 (4). JPS incidence is 1 per 100 000 births (5). In most of the noted cases it is a familial disease. Its diagnosis is based on finding the presence of polyps, which histopathologically are described as juvenile ones. Juvenile polyps are distinguished by hyperplasia of mucous glands, retention cysts accompanied by oedema, emboli in gland openings, rich lamina propria and an absence of smooth muscles, inflammatory infiltrates and a dominance of stroma (6). The diameter of polyps is between 1 millimeter to several centimeters. Polyps are most common in the colon and the anus (80%), although they can also be found in the upper parts of alimentary tract such as the stomach and the small intestine. Single polyps are manifested in 75% of the patients while in the rest of the cases multiple polyps are noted. As far as the number of polyps is concerned their different numbers were found even among members of a single family. Single juvenile polyps are found in about 2% of children and adolescents, however, they have no malignant potential (7). Meanwhile among patients with juvenile polyposis the risk of neoplasms is significantly higher. According to different data from literature the risk of neoplasms in the colon is between several to several dozen percent – from 9 to 50%.
Juvenile polyposis is diagnosed based on the following criteria (tab. 1) (8):
– at least three polyps detected on colonoscopy,
– juvenile polyps in the entire digestive tract,
– any number of juvenile polyps in cases of family history of the disease.
Three be distinguished (9, 10):
– juvenile polyposis of infants,
– juvenile polyposis coli,
– general form of juvenile polyposis.
Table 1. Diagnostic criteria for recognition of hamartomatous polyposis syndrome.
Hamartomatous polyposis syndromeDiagnostic criteria
Juvenile polyposis syndrome – Numerous juvenile polyps (3-10 polyps) in colon and rectum
– Any number of juvenile polyps in patients with family history of the disease
– Juvenile polyps beyond colon (in stomach or small intestine)
Peutz-Jeghers syndrome – Three or more polyps histologically confirmed
– Any number of polyps characteristic of PJS in patients with family history of disease
– Characteristic dermomucosal pigment lesions in patients with family history of disease
– Any numer of PJS-specific polyps and characteristic dermomucosal pigment lesions
Cowden syndrome
 
Symptomatic criteria:
Dermomucosal lesions
– Trichilemmal cyst
– Acral papilla
– Pappilary lesions
– Mucosa lesions
The major criteria:
Breast cancer
Thyroid cancer (especially the follicular thyroid cancer)
Macrocephaly
Lhermitte-Duclos disease
Uterine (endometrial) cancer
The minor criteria:
Other changes in thyroid (e.g. augmentation of thyroid gland)
Mental retardation (IQ ≤ 75) hamartomatous polyps
Fibromatic-cystic dysplasia of the nipple
Lipomas
Fibromas
Neoplasms of the genito-urinary organs
Mixed polyposis syndrome Lack of definite diagnostic criteria for this syndrome
Diagnosis is based on the incidence of numerous polyps which differ histopathologically
The division into juvenile polyposis of the colon and the general form of juvenile polyposis has been conventionally assumed on the basis of the site where polyps are located. It is estimated that in more than 20% of JPS patients’ inborn defects are found in various organs (tab. 2). In the alimentary tract Meckel’s diverticula with umbilical fistula and malrotations of small intestine are found. In the urogenital system cases are registered of undescended testes, unilateral renal agenesia and split uterus. Inborn errors in the chest include a defect in the interatrial septum, arterionevous haemangiomas, and stenosis of the pulmonary valve, Fallot’s tetralogy, aortal stenosis, and persisting arterial duct. And within the central nervous system macrocephaly, a communicating hydrocephalus and rachischisis were found. Moreover, osteomas, mesenteric haemangioma, inherited telangiectasia, hypertelorism, inborn amniotony, supernumerary toes and acute intermittent porphyria have also been observed. Mutations in the SMAD4 and BMPR1A genes (5, 11, 12) are responsible for the manifestations of juvenile polyposis. The BMPR1A gene (OMIM *601299; Bone Morphogenetic Protein Receptor, Type IA) is found in chromosome 10 in the q22-23 region (tab. 3). This gene consists of 11 exons and codes 532 amino acids protein of belonging to the TGF-β/BMP family, representing a type I receptor of properties of serine-threonine kinase (13). The transcript of the BMPR1A gene consists of 3613 nucleotides (14, 15). It is submitted to expression in the majority of tissues including skeletal muscles and to a lesser degree in the heart and placenta.
Table 2. Risk of incidence of neoplastic disease in the hamartomatous polyposis in particular organs.
OrganCumulative risk (%) of the development of neoplasm in particular syndromes of hamartomatous polyposis
Juvenile polyposis syndromePeutz-Jeghers syndromePHTS 
Thyroid   3-7
Breasts  5419-28
Stomach    
Pancreas Two cases36 
Small intestine  15 
Colon 9-68 (17th-22nd to 25th year of life)57 (9th to 40th year of life) 
Kidneys   2
Urinary bladder   3
Uterus  96
Cervix  103
Ovaries  212
Testes  9S
Table 3. Genes preconditioning manifestation of the hamartomatous polyposis syndromes.
GeneBMPR1ASMAD4PTENSTK11
Name Bone morphogenetic protein receptor, type Ia Mothers against decapentaplegic, drosophila, homolog of, 4Phosphatase and tensin homologSerine/threonine protein kinase 11
Protein function ReceptorSignal proteinPhosphataseKinase
MIM*601299*600993*601728*602216
Chromosome10q22.318q2110q23.3119q13.3
Size 168.5 kb38.5 kb108 kb23 kb
Exons1311910
Amino acids 532552403433
Transcript 3613 nt8365 nt9007 nt3276 nt
Protein mass 60 kDa60 kDa47 kDa48.6 kDa
The SMAD4 (OMIM*600993 gene, mothers against decapentaplegic, drosophila, homolog of, 4) is located in chromosome 18, in the q21.1 region. It consists of 11 exons. The genomic sequence of this gene consists of 50 thousand base pairs and its respective mRNA consists of 3.197 nucleotides. SMAD4 is a suppressor gene and it codes for a protein including 552 amino acids and this protein participates in the transmission of signal on the pathway of the transforming growth factor β (TGF β) and its ligands (13). The SMAD4 protein included into „the common” SMAD has two conserved domains of MH1 and MH2 (Mad Homology domain). At the amine terminus of the protein there is the hair-pin domain MH1, which shows DNA binding activity. At the carboxyl terminus of SMAD proteins there is a much conserved MH2 domain. It is responsible for the interaction with proteins involved in the translocation of the complex to cell nucleus as well as interaction with DNA-binding factors (16). Linker Co-SMAD has a leucine rich NES (nuclear export signal) recognized by CMR1. Interaction of SMAD4 with phosphorylated Co--SMAD masks NES, protecting SMAD4 from recognition by CMR1 and from export to the cell nucleus. It is only dephosphorylation of the receptor SMAD and dissociation of the complex that makes export of SMAD4 possible. The import of SMAD proteins to the nucleus takes place without involvement of nuclear transport factors. Such transport, independent of import, has also been described in the case of components taking part in other transformations, e.g. β-catenin along the Wnt pathway. This is possible due to the direct influence of interaction of SMAD with nucleoporins and due to the interaction of hydrophobic corridor in the MH2 domain with the region of repetitions of FG nucleoporins (17).
The phosphorylated receptor SMAD bind with Co-SMAD. The complex created in this way is transferred into the nucleus where is involved in the control of expression of numerous genes as either positive or negative regulator (18, 19). Activation as well as repression requires participation of the same SMAD proteins and the cell-specific interaction with factors which are coactivators and corepressors creates the appropriate response. The complex of SMAD4 with R-SMAD binds to DNA through the MH1 domain, which recognizes the palindrome DNA sequence of GTCTAGAC. Such a SMAD (SBE) binding sequence is often observed in genes which are submitted to expression as a result of the presence of TGF β/BMP ligands. GTCTAGAC SBE is present in every 1.024 base pairs in the genome or at least one such place is in a control region of every moderate size gene (17). In the literature of the subject three mechanisms of control of transcription in either a promotor or an enhancer by SMAD and other transcription factors have been described (16). The first mechanism is binding of the active R-SMAD and Co-SMAD complex to a transcription factor and binding of such a complex to a recognized DNA sequence. The second mechanism consists in a separate binding of SMAD and of a cofactor to DNA, but it is only the interaction of these proteins that stabilizes the enhancer properties. The last way of control includes the independent binding of SMAD and the additional factor to a specific DNA site. Their activity is separate, however, they act synergistically.

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otrzymano: 2014-12-10
zaakceptowano do druku: 2015-01-05

Adres do korespondencji:
*Andrzej Pławski
Institute of Human Genetics PAS
ul. Strzeszyńska 32, 60-479 Poznań
tel. +48 (61) 657-92-15
andp@man.poznan.pl

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