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).

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 49^th and 309^th 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).

Cowden disease (CD, OMIM #158350) described in 1963 by Lloyd and Dennis is an even rarer illness than the hamartomatous polyposis syndromes presented above. The occurrence frequency of this syndrome is estimated at 1/200 000 new births. Its characteristic features include various hamartomatous tissue changes derived from three blastodermic layers: endoderm, ectoderm and mesoderm. Apart from the gastric-intestinal region (71% patients), these changes also appear on skin, mucous membranes as well as other organs. An international consortium dealing in CD elaborated diagnostic criteria which comprise: mucocutaneous changes, including fibroma of mouth mucous membrane as well as papillose and hyperkerototic changes on the face and limbs (26). Mucocutaneous changes were found to develop in nearly 99% patients before they turned 30. Hamartomatous changes within the alimentary tract occur along its entire length, although they are most frequent in the stomach, colon and esophagus. In the esophagus, they assume the form of glycogen keratoses. Hamartomatous changes in this syndrome include, primarily, polyps, adipose tumours and ganglioneromas. In the Cowder syndrome, polyps are characterised by the presence of nerve elements which are not observed in other hamartomatous polyposis syndromes.

In addition, in the case of CD, defects of the central nervous system are also diagnosed such as: macrocephaly (38%), mental retardation, Lhermitte-Dulclos disease (LDD) and cerebellar ganglioneuromas. Eye defects as well as developmental arteriovenous anomalies also occur (27-29). Defects of skull, spinal column and arm bones are diagnosed in one third of patients. In this syndrome, there is also an increased risk of development of both benign and malignant neoplasms of the thyroid gland, lung, kidney, retina, breasts, uterus and skin. In the case of women diagnosed with CD, 30 to 50% developed breast cancer and in 25%, it was bilateral. Breast cancer in these women appears at a very young age, approximately 10 years earlier in comparison with general population (27). Again, in comparison with general population, the risk of occurrence of the thyroid gland neoplasm is 10% higher in women and men with CD. From histopathological point of view, the most frequent thyroid gland cancer is papillose and follicular carcinoma, although single cases of medullar thyroid gland carcinoma also occur (30). The Phosphatase and Tensin Homolog – PTEN (OMIM*601728) gene mapped in 1997 in chromosome 10 in the q23 region is responsible for CD development. It is a suppressor gene which codes protein made up of 403 amino acids which are phosphatase, an enzyme responsible for the removal of the phosphate group. PTEN is characterised by properties allowing dephosphorylation of both proteins as well as lipids of the cell membrane. It removes the phosphate group from the D3 position of the inositol ring from the 3,4,5 triphosphate phosphatidinositol and 3,4-diphosphate phosphatidinositol which are manufactured in the course of cell signal transfer as a result of the activity of the phosphoinositol kinase 3' (PI3K) (31). PTEN acts as a specific switch of the signal transfer on the PI3K pathway, and therefore, it leads to the arrest of the cell cycle in the G1 phase. The action of the PTEN gene, consisting in the antagonising action of the phosphoinositol kinase 3' inhibits the activity of many oncoproteins exerting their impact exactly via kinase PI3K. PTEN-PI3K regulates fundamental cellular processes associated with the mechanism of neoplastic transformations. PTEN participates in the cell cycle regulation via Act kinase. Substrates of Act kinase that play a significant role in the cell cycle include such transcription factors as: FKHR (Forkhead transcription factor), AFX, FKHRL1or GSK3. Moreover, PTEN also controls cell divisions. Reduction of the response to stimulations of the apoptosis process following increased transcription of proapoptotic genes, i.e. FAS and Bim, takes place in pten-/- fibroblasts. The activity of the PTEN protein phosphatase leads to the inhibition of focal adhesion kinase (FAK) responsible for cell adhesion and cell migration capability (32). In addition, PTEN protein also plays an important role in the angiogenesis process and participates in the mTOR pathway control. In D melanogaster, the loss of dpten gene function causes cells and organs to increase their dimensions, whereas in yeasts hyperexpression of dpten causes that the phenotype effect is reverse. In mice, the absence of dpten gene in neuron cells results in the development of a complex of traits similar to those that are characteristic for the Lhermitte-Duclos disease which constitutes one of the clinical features of the Cowden syndrome (33).

Somatic mutations in the PTEN gene lead to the development of a number of various types of neoplasms and are observed in 80% of patients with the Cowden syndrome. PTEN gene mutations are also identified in other hamartomatous polyposis syndromes, among others in the Bannayan-Riley-Ruvalcab syndrome. Detectability of changes in the PTEN gene is close to 60%. Investigations in this field are also conducted at the Institute of Human Genetics of Polish Academy of Sciences in Poznań (34). In the computer database of 208 PTEN gene mutations, a significant majority comprised sense type and nonsense mutations (87 mutations) as well as small deletions and insertions (75 mutations). In patients with the Cowden syndrome, PTEN gene mutations were observed in the promotor region, whereas deletions of part or the entire gene were usually observed in patients with the Bannayan-Riley-Ruvalcab syndrome.

First reports about the Hereditary Mixed Polyposis Syndrome 1 (MIM #610069; HMPS) go back to 1971 when a case was described of an 11-year-old girl with juvenile polyps and adenomas in the colon and small intestine. However, the name 'mixed polyposis' was proposed by Sarles in 1987 to describe a case of a father and a son with numerous different types of colon polyps. In the father, they were metaplastic polyps and adenomas, while in the son, additionally, juvenile polyps were also diagnosed. Clinical features of the mixed polyposis syndrome were best described in a case of a multi-generation family referred to as SM96 (35, 36). From among over 200 members of the family, 42 persons were diagnosed with various types of polyps beginning from tubular, through papillous to flat adenomas down to hyperplastic polyps or atypical juvenile polyps. Histologically, atypical juvenile polyps exhibited features of hyperplastic polyps and adenomas. Colonoscopic examinations usually showed several polyps in the colon and anus. Average age of diagnosis of patients with HMPS in the SM96 family was 40. Cao presented two three-generation families of a very similar course of the HMPS to that in the SM96 family. In most cases, polyps were located in the large intestine and no parenteral changes were observed in the family members affected by the disease.

The gene responsible for the development of HMPS has not been identified so far. Following the performed linkage analysis, a region strongly associated with the appearance of the disease symptoms was determined. It was called CRAC1 and is located on the long arm of chromosome 15. In a proband from one of the families described by Cao, a heterozygotic mutation, deletion of 11 nucleotides in exon 2 of the BMPR1A gene, was identified. The mutation was not identified in the remaining members of the family. HMPS is the least recognised disease from among hamartomatous polyposis syndromes and still requires further investigations which will allow its rapid and simple diagnosis. Diagnostic criteria for recognition of hamartomatous polyposis is prezented in table 3.

Pathological syndromes associated with hamartomatous polyposes comprise a fairly heterogenous group both from the point of view of the number and location of polyps as well as risks of the occurrence of neoplasms of the gastrointestinal tract and other organs. Although the diseases are by no means frequent, nevertheless they remain dangerous for patients not only because of predispositions for the occurrence of neoplastic diseases but also due to non-cancer symptoms including: bleeding and intestinal intussusceptions and obstructions. Each hamartomatous polyposis possesses its own organ-specific location of symptom occurrences and, therefore, each of them requires a different strategy of diagnostic approach. That is why appropriate allocation of patients to the correct pathogenic syndrome constitutes the basic step towards proper care of patients with such predispositions. However, recommendations of diagnostic examinations for the hamartomatous polyposis are based only on expert opinions. No randomised investigations were conducted which would assess the effectiveness of medical care programs in these diseases (37). In the case of PJS, diagnostic care comprises organs threatened by neoplastic transformations taking into account gender. Both for males and females, small intestine examination (small intestinal passage) is recommended every 2-3 years from the 8^th year of life, colonoscopy – every 2-3 years from the 18^th year of life and from the 24^th year of life – pancreas USG examination once in every 1-2 years. In women, breasts examination (self-control) from the age of 18 and from the age of 24 – annual mammography. Ovary examination is recommended once a year from birth up the 12^th year of life and later – from the age of 21. In the case of male patients, testicles should be examined up to the 12^th year of life (37, 38). In the case of JPS, patients' care is focused on the control of the gastrointestinal tract. However, in some families, co-occurrence of hemorrhagic multiple angiomas was observed in the case of mutations in the SMAD4gene, therefore possibilities of vessel malformations must be taken into consideration. Attention should be paid to the occurrence in patients of haemorrhages, anaemia, abdominal pains, diarrhea or changes in the shape and colour of the stool. The occurrence of the above-mentioned symptoms should be taken as an indication of the need of further examinations, including colonoscopy. In patients without complaints, endoscopic examinations (gastroduodenoscopy and colonoscopy) should begin at the age of 15. If polyps are identified during endoscopic examination, they should be removed and in such situation examination and removal ought to be repeated every year (37). On the other hand, if no polyps are visible, the examination should be carried out once every three years. In difficult cases, colectomy may be the only way of treatment (2). In mixed polyposis, endoscopic examination of the large intestine is recommended once a year and the occurring polyps should be removed by polypectomy (38, 39). CD poses of risk of a neoplastic disease in various organs and, therefore, prophylactic examinations include: thyroid gland, breasts and endometrium. There are no special recommendations regarding the alimentary canal, although some researchers recommend to examine it periodically using contrast (2, 37, 40). Breasts examinations should begin from the 30^th year of life. Self-control should be performed once a month with mammography carried out annually. Thyroid gland USG examinations should be supplemented with thin-needle aspiration biopsy of the identified tumours (2, 40).