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© Borgis - Postępy Nauk Medycznych 7/2010, s. 562-569
Marta Podralska1, Wojciech Cichy2, Tomasz Banasiewicz3, *Andrzej Pławski1
Hereditary predisposition for the occurrence of hamartomatous polyposis
Dziedziczne predyspozycje do występowania polipowatości hamartomatycznych
1Institute of Human Genetics, Polish Academy of Sciences
Head of Institute of Human Genetics: prof. dr hab. Jerzy Nowak
2Clinics of Children Gastroenterology and Metabolic Diseases, Medical University in Poznań
Head of Clinics of Children Gastroenterology and Metabolic Diseases: prof. dr hab. med. Wojciech Cichy
3Department of General, Gastroenterological and Endocrine Surgery, Karol Marcinkowski Medical University
Head of Department of General, Gastroenterological and Endocrine Surgery: prof. dr hab. med. Michał Drews
Polipowatości hamartomatyczne stanowią heterogenną grupę chorób dziedziczonych w sposób autosomalny dominujący. Do polipowatości hamartomatycznych zaliczamy między innymi: polipowatość młodzieńczą, zespół Peutza i Jeghersa, zespół Cowdena oraz zespół mieszanej polipowatości. Zespoły te są bardzo rzadkimi chorobami, a ich cechą charakterystyczną jest występowanie polipów hamartomatycznych w przewodzie pokarmowym. Liczebność, jak i rozmieszczenie polipów w przewodzie pokarmowym jest różna w poszczególnych zespołach. Również predyspozycje do rozwoju nowotworów przewodu pokarmowego i innych narządów są zróżnicowane. Polipowatości hamartomatycznych często wykazują nieznaczne różnice w objawach, a ich cechy kliniczne w większości nie pozwalają na ich rozróżnienie. Dlatego w przypadku tych zespołów bardzo ważna jest diagnostyka molekularna umożliwiająca właściwe rozpoznanie choroby, a tym samym przyczyniająca się do udoskonalenia stosowanej u chorych opieki medycznej.
Hamartomatous polyposis syndromes constitute a heterogenic group of diseases inherited in an autosomally dominant manner in which, among others, juvenile polyposis syndrome, Peutz-Jeghers syndrome, Cowden disease and hereditary polyposis syndrome are also included. The above syndromes are very rare diseases and their characteristic feature is the occurrence of hamartomatous polyps in the gastrointestinal tract. Both the amount and the distribution of polyps in the alimentary canal differ in individual syndromes just as the predispositions for the development of tumours of the gastrointestinal tract as well as other organs. In the case of the above syndromes, molecular diagnostics allowing disease recognition is very important because, at some stages of the disease development, the observed clinical characteristics fail to indicate unequivocally the occurrence of the disease.

The term "hamartoma” was introduced into medical vocabulary in 1904 by a German pathologist Eugen Albrecht (Ober 1978). At the present time in medicine, it refers to a change developed from improperly linked tissues. Hamartomatous polyps are observed in a number of pathological syndromes. Among others, they are characteristic for: juvenile polyposis syndrome (JPS), Peutz-Jeghers syndrome (PJS), Cowden disease (CD) and hereditary mixed polyposis syndrome (HMPS). All the above-mentioned syndromes are inherited in an autosomally dominant manner. Apart from the occurrence of hamartomatous polyps in the alimentary canal, these rare syndromes are also characterised by increased risk of neoplastic transformations. The development of neoplastic changes is, by no means, limited to the gastrointestinal tract but, depending on the hamartomatous polyposis syndrome, it can also be found in other organs. The advance of neoplastic transformations in this kind of polyps has not been fully recognised but it exhibits a different mechanism of neoplastic transformations in comparison with that observed in adenomas.
Individual hamartomatous polyposis syndromes are frequently characterised by the occurrence of similar symptoms; especially at the initial phase of disease development, clinical traits make it very difficult to distinguish them. The appropriate recognition of the disease with the assistance of molecular differentiation diagnostics allows faster and more effective treatment because organs which exhibit increased predispositions for neoplastic transformations may be monitored (2) (tab. 1 and 2).
Table 1. Risk of occurrence of a neoplastic disease in individual organs in cases of hamartomatous polyposis syndromes.
OrganCumulative risk (%) of tumour development in individual hamartomatous polyposis syndromes
Juvenile polyposis syndromePeutz-Jeghers syndromeHamartomatous syndromes associated with gene mutations PTEN
Thyroid gland3-7
Pancreas Two cases36
Small intestine13
Large intestineFrom 39 to over 5039
Kidneys 2
Uterine cervix103
Ovaries 212
Table 2. Genes preconditioning occurrence of hamartomatous polyposis syndromes.
Hamartomatous polyposis syndromesGene preconditioning occurrence of diseaseGene location
Juvenile polyposisSMAD418q21.1
Peutz-Jeghers syndromeSTK1119p13.3
Cowden syndromePTEN10q23.31
Bannayan-Riley-Ruvalcab syndromePTEN10q23.31
Proteus syndromePTEN10q23.31
Juvenile polyposis (JPS, MIM # 174900) was described for the first time by McColl in 1964. It is a rare disease inherited in an autosomally dominant manner (3). JPS occurs in 1 out of 100 000 cases of births (4). In majority of the recorded cases, JPS is a family disease. The diagnosis of juvenile polyposis is based on the occurrence of polyps which are classified histopathologically as juvenile. Juvenile polyps are characterised by: normal epithelium and a lamina propria markedly expanded by dilated glands, abundant stroma, and an inflammatory infiltrate. The diameter of polyps ranges from 1 mm to several centimetres. Polyps usually occur in the large intestine and in the colon (80%) although they can also appear in the upper part of the gastrointestinal tract, in the stomach and small intestine. Single polyps occur in 75% of patients but they can also occur as multiple polyps. The intensity of intestinal symptoms can vary quite considerably. Single juvenile polyps were observed in about 2% of children and maturing youths but they were not found to have malignant potentials (5). According to different literature data, risks of neoplastic transformations in the intestine in the case of JPS ranges from several to several dozen percent.
Criteria of the PS diagnosis:
? More than 5 juvenile polyps in the colon and large intestine,
? Juvenile polyps in the entire gastrointestinal tract,
? Any number of juvenile polyps in the case of familial history of the disease.
Moreover patients with diagnosed disease are classified into one of the following three categories (6):
? Infant juvenile polyposis,
? Juvenile polyposis of the large intestine,
? General form of juvenile polyposis.
Juvenile polyposis of the large intestine and general form of juvenile polyposis were defined arbitrarily on the basis of the place of their occurrence.
It is estimated that in about 20% of JPS patients, congenital defects are determined in different organs. Meckel's diverticulum manifested by an umbilical fistula as well as small intestine malrotations were observed in the alimentary canal. In the urinary-sexual system, cases of testicle non-descent, one-sided kidney agenesis and uterus cleavage were registered. Reported congenital chest defects included: atrial septal defect, lung arteriovenous hemangiomas, pulmonary stenosis, Fallot tetralogy, aortic stenosis and persisting arterial duct. In the case of the central nervous system, the following defects were reported: macrocephaly, communicating hydrocephalus and vertebral cleft. In addition, cases of: osteomas, mesentery lymphangiomas, hereditary telagiectasia, hypertelorism, congenital amniotony, additional fingers of the lower limb as well as acute intermittent porphyria were also reported.
Mutations in SMAD4 and BMPR1A genes (4, 7, 8) are responsible for the occurrence of JPS. One of them is the Bone Morphogenetic Protein Receptor, Type IA) – BMPR1A (OMIM *601299) gene is localized in the q22-23 region of chromosome 10 and consists of 11 exons. It encodes the 532 amino acid polypeptide which belongs to the TGF-β/BMP protein family and is a type I receptor of serine-threonine kinase properties (9). A BMPR1A gene transcript encompasses 3613 nucleotides (10, 11). Its expression is observed in almost all tissues, including skeletal muscles and, to a lesser degree, in the heart and in placenta.
The second gene responsible for JPS is, the mothers against decapentaplegic, drosophila, homolog of 4 SMAD4 (OMIM *600993) gene is located in the q21.1. region of chromosome 18 and is made up of 11 exons. The genomic sequence of the gene comprises 50 000 base pairs and mRNA consists of 3197 nucleotides coding a protein composed of 552 amino acids. SMAD4is a tumor suppressor gene and participates in the signal transduction on the transforming growth factor β (TGF β) pathway and its ligands (9). SMAD4, classified as a "common” SMAD, possesses two conservative Mad Homology domains: MH1 and MH2. The MH1 domain, with a hairpin structure, is situated at the end of the SMAD amine protein and shows DNA binding activity. The MH2 domain is situated at the carboxyl end of SMAD proteins and is highly conservative. It is responsible for the interaction with proteins participating in the translocation of the complex to the nucleus as well as with DNA binding cofactors (12). Co-SMAD linker has a leucine rich NES ( nuclear export signal) recognised by CMR1. SMAD4 interaction with phosphorylated Co-SMAD masks NES and protects SMAD4 against its recognition by CMR1 and export from the nucleus. It is only after dephosphorylation of receptor SMADs and dissociation of the complex that SMAD export becomes possible. The import of SMAD proteins into the nucleus takes place without the participation of nuclear transport factors. Such import-independent transport was also described in the case of constituents participating in other transformations, for example of β-catenin on the Wnt pathway. This is possible thanks to the direct SMAD interaction with nucleoporins in the result of the contact of the hydrophobic corridor in the MH2 domain with the repeat region of FG nucleoporins (13).
Phosphorylated receptor SMADs bind with Co-SMADs, i.e. SMAD4. The complex developed in this way passes to the nucleus where it participates in the expression control of numerous genes as a positive or negative regulator of changes (14, 15). Both activation and repression requires participation of the same SMAD proteins and cell-specific interaction with factors acting as co-activators and co-repressors leads to the appropriate response. The SMAD complex with R- SMAD binds with DNA via the MH1 domain which recognises the palindromic DNA GTCTAGAC sequence. Such sequence binding SMAD (SBE) is frequently observed among genes which undergo expression as a result of the presence of TGF β/BMP ligands. On average, SBE GTCTAGAC occurs every 1024 base pairs or at least one such place is found in the regulatory region of each medium-size gene (13). In literature, three mechanisms of transcription regulation in the promoter or enhancer by SMAD and other transcription factors were described (12). The first of them is associated with the binding of the active R-SMAD and Co-SMAD complex with the transcription factor and such a multi-molecule complex binds with the recognised DNA sequence. The second mechanism involves separate binding of the SMAD and cofactor with DNA but it is only the interaction of these proteins that stabilises enhancer properties. The last regulation mechanism consists in independent binding of SMAD and an additional factor to a definite DNA site. They act separately but in a synergistic manner.
Mutations in the SMAD4gene are observed in 20% patients with familial juvenile polyposis (7). Mutations in gene BMPR1A are identified with similar frequency. In total, more than 120 mutations leading to the development of polyps associated with the juvenile polyposis syndrome were identified in both genes. The discovered mutations included, mainly, small changes, point mutations and small deletions. Also large changes constituted significant proportions of changes found in patients with juvenile polyposis; large deletions were observed in the q22-q23 region in chromosome 10. Those changes encompass two adjacent genes PTEN and BMPR1A. Mutations in those genes are involved in the development of different hamartomatous polyposis syndromes. Mutations described so far are of heterogenic character with the exception of one mutation – c.1244-1247delAGAC in exon 9 of the SMAD4gene. The mutation is situated in a hot site in the region containing four dinucleotide AG repeats, where unlooping of the DNA strand fragment probably takes place which undergoes deletion.
Certain correlations were observed between phenotypes and genotypes in patients with JPS and with a mutation in the SMAD4 gene; higher frequency of occurrence of large gastric polyps was recorded. Germinal mutations in the SMAD4 gene are responsible for the more aggressive phenotype of intestinal juvenile polyposis appearing as vessel malformations within stroma constituents when the mutation was situated before codon 423. It was also noticed that polyps with a mutation in the SMAD4 gene can be found both in the upper and lower sections of the gastrointestinal tract, whereas polyps with mutations in the BMPR1A gene are limited to the region of the colon and anus. Simultaneous deletions of BMPR1A and PTEN genes were initially attributed to patients with severe course of infant juvenile polyposis but now the deletions of the 10q22-q23 region containing both genes are associated with severe or medium phenotype of the disease (16).
The Peutz-Jeghers syndrome (PJS; OMIM 175200) was first described in 1921 by J.L.A. Peutz and later in 1948 by H. Jeghers.
PJS is a rare disease inherited in an autosomally dominant manner which is characterised, primarily, by the occurrence of hamartomatous polyps and skin colour changes. The occurrence frequency of the Peutz-Jeghers syndrome fluctuates between 1/29 000 and 1/120 000 of new births. Polyps appear in the gastrointestinal tract in 80-100% patients during the second and third decades of life and can occur along the entire length of the alimentary canal, although their frequency rate varies and depends on the section of the canal. They appear most frequently in the small intestine (90%), next in the colon and stomach. In their histopathological picture, polyps remind tree-like branching buds of smooth muscles. The core of polyps is made up of stromatal tissue and smooth muscles. Colon polyps remind more of adenomal polyps which increases their neoplastic transformational potentials. The entire growth is covered by properly looking epithelium.
Benign polyps can also be found in patients outside the alimentary canal; in the nose, bronchi, gallbladder and urinary bladder. They are abundant and their size ranges from 1 to 3 cm. The risk of occurrence of intestinal tumours in patients with PJS is slightly higher than in the case of general population. Nevertheless, it should be said that hamartomatous polyps, especially multiple, can lead to many ailments of the gastrointestinal tract. They result in intestinal obstruction (caused by intussusceptions) and bleeding from the lower part of the gastrointestinal tract due to easy polyp self-amputation (17, 18). In literature, there are case descriptions of PJS patients with parenteral neoplasms. Increased risks of occurrence of pancreas, mamma, lung, ovary and vagina tumours were reported (19). The second characteristic symptom of this hamartomatous polyposis syndrome is the occurrence of mucous-skin discolourations which can appear both already in infancy and in early childhood. Dark-brown, black or blue spots ranging in size from 1 to 5 mm occur in more than 90% of patients. They can develop around lips, nostrils, eyes, cheeks, on the tongue or palate. Cases were also reported when these pigmentations appeared on hands, feet as well as in the umbilical or perirectal areas. The mucocutaneous may turn pale during the puberty period and adult years. Diagnostic criteria adopted for this disease in cases of persons with a familial course of the disease are confined only to the identification of melanin deposits. On the other hand, at the absence of family history, confirmation of the occurrence of at least two hamartomatous polyps is required.
PJS is preconditioned by the occurrence of mutation in the Serine/Threonine Protein Kinase 11 ( STK11) (OMIM*602216) gene located on the short arm of chromosome 19 in the 13.3 region. The gene consists of 10 exons of which 9 code protein of serine-threonine kinase properties. It undergoes universal expression in the course of embryonal development but it also occurs on organs of adult people, especially in the pancreas, liver and skeletal muscles. The STK11 protein consists of the following three main domains: N-terminal, non-catalytic domain which contains two signals of nuclear location; highly conservative kinase domain and regulatory domain located at the carboxyl end. The kinase domain of this 433 amino acid protein is situated between the 49th and 309th amino acids and it is there that most mutations leading to PJS is located. The STK11 protein contains several places which undergo phosphorilation and prenylation as well as a nuclear location signal (NLS). In the result of kinase activity, serines in positions 31 and 325 as well as threonine in position 363 are phosphorylated. STK11 is also capable of threonine autophosphorilation in positions 185, 189 and 336 as well as serine in position 402. STK11 autophosphorilation in position Thr 189 is very important for the kinase activity of this protein. On the other hand, the prenylation motif Cys430-Lys-Gln-Gln433 is located at the carboxyl end of the protein. The loss of function by the STK11 protein is accompanied by the occurrence of a number of disturbances because STK11 protein in involved in the regulation of many cellular processes. It takes part in the embryonal development control. Loss of its functionality in the heterozygous state is sufficient for polyp development. (20, 21). STK11 protein controls the TGF β pathway and forms a complex with SMAD4 and LIP1 proteins, interacts with the PTEN protein and participates in p53-dependent apoptosis (22). Germinal mutations of the STK11 gene are identified in 60% patients with the inherited form of this disease. In the case of patients with no familial history of the disease, the detectibility amounts to approximately 50% (23). So far, 221 mutations, including 70 point mutations, have been discovered in gene STK11with small deletions (54) and small insertions (33) making up a considerable part of these mutations. In addition, large deletions comprising individual exons as well as deletions of the entire gene are also frequent in PJS patients (24, 25).

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otrzymano: 2010-05-26
zaakceptowano do druku: 2010-06-30

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

Postępy Nauk Medycznych 7/2010
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