Gastrointestinal Hamartomatous Polyposis Syndrome - Types and Management

Introduction:

For a better understanding of the syndrome, one should start learning about each term. Hamartoma is a benign tumor made up of an abnormal mixture of cells and tissues found in areas of the body where growth occurs. It is a developmental error. Polyps are tissue growths that look like small bumps or mushroom stalks. A syndrome is a group of symptoms or conditions together that are characteristic of a particular disorder.

What Are the Types of Gastrointestinal Hamartomatous Polyposis Syndrome?

A hamartomatous polyposis syndrome is a group of rare inherited conditions that are autosomal dominant and are characterized by hamartomatous polyps of the gastrointestinal tract. It includes three syndromes:

• Juvenile polyposis.

• Peutz-Jeghers syndrome.

• PTEN hamartoma tumor syndrome.

These syndromes are grouped together because they exhibit hamartomatous instead of epithelial polyp histology. Hamartomatous polyps arise from the over-proliferation of subepithelial cells native to the tissue of origin. They can contain cellular components from any of the three germinal layers (mesoderm, ectoderm, and endoderm) forming the intestines.

What Is Juvenile Polyposis Syndrome?

Juvenile polyposis syndrome is characterized by numerous benign growth in the gastrointestinal tract, typically the colon (the large intestine). Around 15 % of the people with juvenile polyposis syndrome have other conditions like cleft palate, polydactyly (extra fingers or toes), heart or brain abnormalities, twisting of the intestines, and abnormalities of the genitalia or urinary tract. However, people with juvenile polyposis syndrome develop polyps before the age of 20 years. The name of the condition, ‘juvenile,’ relates to the characteristics of the tissues that make up the polyp and is not related to age.

Juvenile polyposis syndrome is an inherited autosomal dominant disease, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In about 75 % of cases, an affected person inherits the mutation from one affected parent. The remaining 25 % of cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

What Is the Cause of Juvenile Polyposis Syndrome?

The cause of this syndrome is mutations in the BMPR1A and SMAD4 genes. These genes work together to help regulate the activity of particular genes and the growth and division of cells. Mutations in these genes disrupt cell signaling and interfere with their roles in gene-regulating and cell proliferation. This lack of regulation causes cells to grow and divide in an uncontrolled way, which can lead to polyp formation. The number of polyps varies from a few to hundreds, even among affected members of the same family.

What Are the Signs and Symptoms of Juvenile Polyposis Syndrome?

Polyps may cause anemia (lack of red blood cells), abdominal pain, gastrointestinal bleeding, and diarrhea. Juvenile polyposis syndrome has the following diagnostic signs:

• If more than five polyps are present in the rectum or colon.

• If polyps are present in any other part of the GI tract.

• If polyps are present along with an affected family member.

Single juvenile polyps are not characteristic of juvenile polyposis syndrome and are common in children.

What Are the Types of the Juvenile Polyposis Syndrome?

There are three types of juvenile polyposis syndrome based on signs and symptoms:

• Juvenile Polyposis of Infancy - In this, polyps occur throughout the gastrointestinal tract during infancy. Children with this condition may develop protein-losing enteropathy (excess loss of protein in the gastrointestinal tract). This leads to severe diarrhea, failure to gain weight and grow at the expected rate (failure to thrive), and general wasting and weight loss (cachexia).

• Generalized Juvenile Polyposis - In this type, polyps are diagnosed throughout the gastrointestinal tract. Usually, the affected people develop polyps during childhood.

• Juvenile Polyposis Coli - In this type, the affected individuals develop polyps only in the colon and develop during childhood.

Most juvenile polyps are benign (noncancerous), and there are chances of them turning malignant (cancerous).

What Is Peutz-Jeghers Syndrome?

Peutz-Jeghers syndrome is characterized by the development of mucocutaneous pigmentation and hamartomatous polyps throughout the digestive system. This syndrome has increased the risk of malignancy of several types. It is an autosomal dominant genetic condition. This syndrome is caused by mutations in the STK11/LKB1 gene.

The affected person can either inherit the abnormal gene from the affected parent or can because of the new mutation in the affected person. The probability of passing the abnormal gene from the affected parent to an offspring is 50 % for each pregnancy, and the risk is the same for females and males. Around 60 to 80 % of affected people have an affected relative. STK11 gene produces a protein that is involved in the regulation of cell division and programmed cell death. Mutations in this gene can lead to either stoppage or dysfunction of protein production by the gene and uncontrolled cell growth, leading to the development of benign polyps and cancer.

What Are the Signs and Symptoms of Peutz-Jeghers Syndrome?

Peutz-Jeghers syndrome is characterized by pigmented macules present on lips, buccal mucosa, and periorbital area. It also occurs on fingers, soles, palms, perianal area, labia, and intestinal mucosa. Pigmented lesions are benign and do not have malignant potential. Symptoms usually occur in the first decade of life. Numerous noncancerous polyps called hamartomas start to grow in the gastrointestinal tract. These polyps can cause pain in the abdomen, obstructions or blockage in the intestine, nausea, vomiting, and rectal bleeding leading to anemia. They can also lead to the folding of the intestine into itself (intussusception), which can lead to severe abdominal pain and emergency surgery.

The melanotic macules can appear as early as the first year of life and are present in most affected children under five years of age. Although they fade away with age, they persist in the oral mucosa. Polyps begin to grow within the first year of life, but associates arise between 10 to 30 years of age. Polyp tends to grow in the small intestine but also arises in the stomach and large intestine.

How to Diagnose Peutz Jeghers Syndrome?

Clinical diagnosis can be made on the basis of the following:

• Presence of at least two Peutz-Jeghers syndrome polyps.

• Any number of Peutz-Jeghers syndrome polyps and at least one close relative diagnosed with Peutz-Jeghers syndrome characteristic dark pigmented spots (melanotic macules) and at least one close relative diagnosed with the Peutz-Jeghers syndrome.

• Any number of Peutz-Jeghers syndrome polyps and characteristic dark-pigmented spots.

A physical examination can be done for identification with melanotic macules. Endoscopy, X-ray examination, or wireless capsule endoscopy and microscopic examination are done for the detection of Peutz-Jeghers syndrome polyps. Genetic testing for the identification of disease-causing mutations in the STK11 gene is recommended if one of the following criteria is present:

• Dark-pigmented spots.

• Presence of at least two Peutz-Jeghers syndrome polyps.

• Family history of the Peutz-Jeghers syndrome.

What Is PTEN Hamartoma Tumor Syndrome?

• PTEN (phosphatase tensin homolog) hamartoma tumor syndrome is a range of disorders caused by mutations of the PTEN tumor suppressor gene in egg or sperm cells. It is characterized by multiple hamartomas that can affect various areas of the body. People with a variety of clinical diagnoses who ultimately have been found to carry a germline PTEN mutation as the underlying cause are said to have PTEN hamartoma tumor syndrome. This is also an autosomal inherited dominant pattern.

• PTEN hamartoma tumor syndrome is caused by a mutation in the PTEN, a tumor suppressor gene. PTEN is an acronym for phosphatase tensin homolog. A tumor suppressor gene slows down the division of cells, does damage repair to the DNA of cells, and tells cells to die. The PTEN gene is responsible for the production of an enzyme that is believed to be important in stopping cell growth and starting apoptosis. Mutation in this gene often leads to cancer.

What Are the Signs and Symptoms of PTEN Hamartoma Tumor Syndrome?

The symptoms vary from patient to patient, even among individuals in the same family. In patients with PTEN hamartoma tumor syndrome, there is an increased risk for certain types of cancer, benign tumors, tumor-like malformations (hamartoma), and neurodevelopmental disorders.

How to Diagnose PTEN Hamartoma Tumor Syndrome?

Diagnosis of the PTEN hamartoma tumor syndrome is made through a clinical evaluation, detailed patient history, and the presence of characteristic findings. A mutation risk calculator is available that can calculate the risk for people having a PTEN mutation based on the attributes of their personal history.

What Is the Treatment of Gastrointestinal Hamartomatous Polyposis Syndrome?

• Treatment is focused on surveillance and control of symptoms at the time of diagnosis to detect the tumor at the earliest. There is no permanent cure for this syndrome.

• Any kind of treatment for this syndrome is symptomatic and supportive.

• Surgical interventions are required for polyp-related complications, and polypectomy (surgical removal of polyps) is performed through endoscopic techniques to avoid recurrence. For women, gynecologic and breast examination is recommended along with magnetic resonance imaging (MRI). Monthly breast self-examination is suggested.

• A testicular examination is recommended for men. Biannual renal imaging should be done for patients of age 40 years and above. Yearly, thyroid ultrasound and dermatologic evaluation should be done.

Conclusion:

The gastrointestinal hamartomatous polyposis syndrome represents a diverse group of inherited polyposis syndromes associated with high rates of benign and malignant complications, both gastrointestinal and extraintestinal. They are a result of a defect in the balance between cell growth inhibition and cell growth promotion. Though it is not fully established that hamartoma leads to malignancy, people suffering from this syndrome do have a higher risk of developing cancer. For the management of this syndrome, multiple specialists are needed in view of the benign complications and cancer risks, so early diagnosis and proper screening are really important.