How to recognise Peutz-Jeghers syndrome

Once in a lifetime: Continuing our series on conditions that GPs might only encounter once in their career, gastroenterology resident doctors Dr Kevin Jacob, Dr Aamna Tariq, Dr Emma Khoury, Dr Advaith Ravishankar and consultant gastroenterologist Dr Andrew Poullis describe the rare condition known as Peutz-Jeghers syndrome

What is Peutz-Jeghers syndrome?

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disorder characterised by the development of intestinal hamartomatous polyps, distinctive pigmented macules on the skin and mucous membranes, and an increased risk of both gastrointestinal and non-gastrointestinal cancers. It is caused by mutations in the STK11 (serine threonine kinase 11) gene, also known as LKB1 (liver kinase B1), a tumour suppressor gene located on chromosome 19.

Manifestations

Mucocutaneous pigmented macules: These are present in 95% of affected individuals and are typically flat, blue-grey to brown spots ranging from 1mm to 5mm in size. They most commonly occur on the lips and perioral region (94%), palms of the hands (74%), buccal mucosa (66%), and soles of the feet (62%). Pigmentation usually occurs in the first two years of life, increases in size and number over the following years, and fades after puberty, except for on the buccal mucosa. Malignant transformation is rare.
Gastrointestinal hamartomatous polyps: These most commonly occur in the small bowel (60-90% of patients), particularly the jejunum, but can be found throughout the gastrointestinal tract, including the stomach (15-30%) and colon (50-64%). They may also occur outside the gastrointestinal tract, including in the nasopharynx, lungs, bladder and renal pelvis. The polyps generally develop in the first decade of life.

Symptoms

Half of patients are asymptomatic at the time of diagnosis, with mucocutaneous pigmentation leading to the diagnosis. For those who do experience symptoms, the most frequent presentation is recurrent colicky abdominal pain caused by obstruction and transient intussusceptions (69% of patients). The typical age of symptom onset is between 10 and 30 years. There may also be melaena, rectal bleeding and, less commonly, haematemesis. Anaemia may result from either acute or chronic bleeding.

Cancer risks

Gastrointestinal cancer: Individuals with PJS have an estimated lifetime risk of gastrointestinal cancer of 38-66%, with colorectal being the most common (39%), followed by the stomach (29%) and small bowel (13%), and estimates of pancreatic lifetime risk ranging from 11% to 36%.
Non-gastrointestinal cancer: Women with PJS have an increased lifetime risk for cancers of the breast (32-54%), ovary (21%) and cervix (10%). Men with PJS have an increased lifetime risk of Sertoli cell testicular tumours (9%).

How rare is it?

PJS has an estimated prevalence of 1 in 25,000 to 300,000 births, meaning that GPs are likely to see only one or two cases in their career. Males and females are equally affected. PJS has a high penetrance of over 90% by 30 years of age, though 10-20% of individuals with PJS do not have a family history of the condition. They are thought to have PJS because of de novo mutations.

Not to be confused with…

PJS can present with pigmented mucocutaneous macules for which there is a relatively small differential. This includes Addison’s disease, Spitz nevus and Langier-Hinziker Syndrome (LHS). LHS is a rare syndrome, more commonly seen in the Asian population, that can present with mucocutaneous pigmentation of the lips, buccal mucosa and hard and soft palates. In LHS, these lesions are progressively acquired in young or middle-aged adults rather than in the first few years of life as in PJS. They may also have longitudinal hyperpigmented bands on their fingernails and toenails.

The differential for gastrointestinal hamartomatous polyps is also relatively small. Juvenile polyposis syndrome is characterized by multiple gastrointestinal hamartomas, but without mucocutaneous pigmentation. Patients with Cowden syndrome may also suffer from hamartomatous polyps of the small intestine along with pigmented spots on the glans penis in males, rather than the perioral region as occurs in PJS, and other skin and oral changes such as trichilemmomas, acral keratoses and facial papules/oral papillomas. If these diseases are suspected, patients should be referred to secondary care services.

Red flags

Red flags that should alert the GP to a possible diagnosis of PJS include:

Mucocutaneous pigmentation, particularly in the perioral region and in children.
Repeated episodes of unexplained abdominal pain.
Recurrent gastrointestinal intussusception with bowel obstruction.
Unexplained gastrointestinal bleeding in patients younger than 30 years of age.

A strong family history of gastrointestinal cancers or polyps should also raise the possibility of PJS and the need for referral to secondary care.

Diagnosis and management

Key features in the history include a family history of PJS or related cancers, early onset gastrointestinal symptoms such as abdominal pain or bleeding, often in childhood.

Examination findings of characteristic pigmented macules, especially in the perioral area and buccal mucosa, but also on the soles of feet and palms of hands, suggest the possibility of PJS.

Abdominal examination will most likely be normal, but acutely, there may be signs of gastrointestinal obstruction or palpable masses due to polyps.

Initial investigations for GPs should include blood tests with a full blood count and haematinics to investigate for anaemia. The gold standard is genetic testing to identify mutations of the STK11/LKB1 gene and confirm a diagnosis of PJS. This is often not available to GPs, and therefore, a referral to the local genetics service should be made. Once confirmed, endoscopic surveillance for direct visualisation and biopsy of polyps in the gastrointestinal tract can be performed.

Management and prognosis

The mainstay of management in PJS involves surveillance, with regular monitoring through gastroscopy, colonoscopy and capsule endoscopy. Screening should begin at 8 years of age, with endoscopic investigations repeated every 3 years if polyps are identified. If none are identified, investigations should be repeated at the age of 18, or earlier if symptomatic, and subsequently repeated every 2 to 3 years. Surveillance in older patients should balance the invasive nature of investigations against the potential benefits.

Given the increased risk of pancreatic cancers, some guidelines advise MRI surveillance to begin at 30 years of age, but this has not yet been incorporated into UK practice because of a lack of robust evidence. Male patients should be vigilant for new testicular lumps and examine themselves regularly, and GPs should have a low threshold for urgent referral. Female patients should be enrolled in the national breast and cervical cancer screening programmes between the ages of 30 and 60 and examine themselves regularly for lumps.

Genetic counselling, particularly about family planning, is also important, and the local genetics service should be involved.

The prognosis of patients with PJS depends on the severity of the condition and whether they develop symptoms from gastrointestinal polyps. There is an increased lifetime risk of various cancers, and they will need screening as discussed. However, with vigilant screening and appropriate management and support, many can lead normal lives.

Dr Andrew Poullis is consultant gastroenterologist and Dr Kevin Jacob, Dr Aamna Tariq, Dr Emma Khoury and Dr Advaith Ravishankarare gastroenterology resident doctors at St George’s University Hospital NHS Foundation Trust