Lynch syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Lynch syndrome, often called hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited disorder that increases the risk of many types of cancer. This includes cancers of the colon and rectum, which are collectively referred to as colorectal cancer. People with Lynch syndrome also have an increased risk of cancers of the stomach, small intestine, liver, gallbladder ducts, urinary tract, brain, and skin. Additionally, women with this disorder have an increased risk of cancer of the ovaries and the lining of the uterus (endometrial cancer). Women with Lynch syndrome have a higher overall risk of developing cancer than men with the condition because of these cancers of the female reproductive system. In individuals with Lynch syndrome who develop cancer, the cancer typically occurs in their 40s or 50s.

People with Lynch syndrome may occasionally have noncancerous (benign) growths in the colon, called colon polyps. In individuals with this disorder, colon polyps occur at a younger age but not in greater numbers than they do in the general population.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants that cause a disease or increase the risk for a disease are sometimes called pathogenic variants. Pathogenic variants in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes can cause Lynch syndrome.

The MLH1, MSH2, MSH6, and PMS2 genes are involved in repairing the errors that occur when DNA is copied in preparation for cell division, a process called DNA replication. Because these genes work together to fix DNA errors, they are known as mismatch repair (MMR) genes. Pathogenic variants in any of these MMR genes can cause Lynch syndrome. People with pathogenic variants in the MLH1 or MSH2 genes tend to have a higher risk of developing cancer during their lifetime than people with pathogenic variants in the MHS6 or PMS2 genes.

Changes in the EPCAM gene can also disrupt DNA repair, although the gene itself is not directly involved in this process. The EPCAM gene lies next to the MSH2 gene on chromosome 2, and certain EPCAM gene variants cause the MSH2 gene to be turned off (inactivated). As a result, the MSH2 gene's role in DNA repair is disrupted, which can lead to accumulated DNA errors and cancer development.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Lynch syndrome is typically inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to increase the risk of cancer. Although people with Lynch syndrome have a higher risk of cancer, not all people with Lynch syndrome will develop cancer.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

In the United States, it is estimated that 1 in 279 individuals have a genetic variant (also known as a mutation) that is associated with Lynch syndrome.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abdominal pain · Very frequent (99-80%)

An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) and perceived to originate in the abdomen.

Adenoma sebaceum · Very frequent (99-80%)

The presence of a sebaceous adenoma with origin in the sebum secreting cells of the skin.

Constipation · Very frequent (99-80%)

Infrequent or difficult evacuation of feces.

Fatigue · Very frequent (99-80%)

A subjective feeling of tiredness characterized by a lack of energy and motivation.

Gastrointestinal hemorrhage · Very frequent (99-80%)

Hemorrhage affecting the gastrointestinal tract.

Glioblastoma multiforme · Very frequent (99-80%)

A tumor arising from glia in the central nervous system with macroscopic regions of necrosis and hemorrhage. Microscopically, glioblastoma multiforme is characterized by regions of pseudopalisading necrosis, pleomorphic nuclei and cells, and microvascular proliferation.

Malabsorption · Very frequent (99-80%)

Impaired ability to absorb one or more nutrients from the intestine.

Neoplasm of the skin · Very frequent (99-80%)

A tumor (abnormal growth of tissue) of the skin.

Weight loss · Very frequent (99-80%)

Reduction of total body weight.

Anxiety · Frequent (79-30%)

Intense feelings of nervousness, tension, or panic often arise in response to interpersonal stresses. There is worry about the negative effects of past unpleasant experiences and future negative possibilities. Individuals may feel fearful, apprehensive, or threatened by uncertainty, and they may also have fears of falling apart or losing control.

Attention deficit hyperactivity disorder · Frequent (79-30%)

Attention deficit hyperactivity disorder (ADHD) manifests at age 2-3 years or by first grade at the latest. The main symptoms are distractibility, impulsivity, hyperactivity, and often trouble organizing tasks and projects, difficulty going to sleep, and social problems from being aggressive, loud, or impatient.

Atypical behavior · Frequent (79-30%)

Atypical behavior is an abnormality in a person's actions that can be controlled or modulated by the will of the individual. While abnormal behaviors can be difficult to control, they are distinct from other abnormal actions that cannot be affected by the individual's will.

Death in early adulthood · Frequent (79-30%)

Death between the age of 16 and 40 years.

Death in infancy · Frequent (79-30%)

Death within the first 24 months of life.

Other findings in the same source

From: Orphanet

Additional reported features include Depression (Frequent (79-30%)); Hypertonia (Frequent (79-30%)); Hypotonia (Frequent (79-30%)); Increased intracranial pressure (Frequent (79-30%)); Irritability (Frequent (79-30%)); Migraine (Frequent (79-30%)); Nausea and vomiting (Frequent (79-30%)); Neoplasm of the stomach (Frequent (79-30%)); Seizure (Frequent (79-30%)); Colon cancer (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Lynch syndrome is Oncology, with a oncologist and relevant organ specialist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics; Relevant organ specialist / Surgical Oncology as indicated.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Has the exact tumour type been confirmed, and is staging relevant?
• What is the goal of each proposed treatment option?
• How will side effects, daily function and supportive care be addressed?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Lynch syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.