Peutz-Jeghers Syndrome

Synonyms: Polyposis, Hamartomatous Intestinal polyps-and-spots syndrome

Peutz-Jeghers syndrome is an autosomal dominant disorder characterised by mucosal pigmentation of the lips and gums with multiple intestinal hamartomatous polyps and an increased risk of various cancers compared to the general population.
The syndrome is co-named after Peutz who first recognised the association of gastrointestinal polyposis and mucocutaneous pigmentation in 1921 and Jeghers who wrote the definitive descriptive reports and drew more wide-spread attention to the condition in 1949.

Prevalence - rare, around 1/50 000 ¹.

Autosomal dominant condition with high penetrance. In up to two thirds of cases, mutations can be identified in the serine/threonine kinase gene STK11(LKB1)². STK11 is thought to be a tumour suppressor gene.

• Family history - asymptomatic but requesting investigation/counselling.
• Deeply pigmented lesions on the lips (cross the vermillion border) and buccal mucosa. May also be present on hands and feet (particularly palms and soles) and around anus and genitalia. These lesions may be most prominent in infancy and fade after puberty.
• Repeated bouts of abdominal pain in a young patient (due to obstruction or intussusception)
• Unexplained intestinal bleeding in a young patient or iron-deficiency anaemia.
• Rectal prolapse
• Precocious puberty
• Nasal, bronchial, biliary tract, uterine or bladder polyps

Peutz-Jeghers Syndrome belongs to group of single gene disorders that carry a greatly increased risk of colorectal and other cancers.
Hamartomatous Polyposis Syndromes³ include:

• Juvenile polyposis syndrome - multiple hamartomatous polyps of the colon and rectum, usually manifesting during childhood.
• Cowden Syndrome - multiple hamartomas usually presenting as mucocutaneous lesions; also associated with neurodevelopmental abnormalities and gastrointestinal polyposis.
• Lhermitte-Duclos syndrome - very rare, slow-growing unilateral cerebellar mass of hamartomatous origin.

Previously, phenotypic features were the only way to identify a particular disease which was difficult when the different syndromes overlapped. Now, it is possible to categorise more accurately using molecular analysis and to give individuals a better assessment of their potential cancer risk and need for surveillance.

Other non-hamartomatous autosomal dominant disorders that increase risk of colorectal cancers are:

• Familial adenomatous polypolis - characterised by large numbers of adenomas (>100) of the colon and rectum. The development of large bowel cancer is virtually certain without prophylactic surgery.
• Hereditary non-polyposis colorectal cancer - result of mutation in a DNA mismatch repair gene. Disorder is defined empirically by family history (3 or more family members affected by colorectal cancer or more than 2 with colorectal cancer and one with endometrial cancer in 2 or more generations where one affected relative is under 50 at diagnosis and at least one must be a first degree relative) or by demonstration of a gene mutation.

• FBC
• Imaging - OGD, small bowel follow-through or capsular endoscopy⁴, colonoscopy to determine presence and location of intestinal polyps.
• Genetic analysis

If Peutz-Jeghers is suspected on the basis of clinical criteria, the patient should be referred to a regional genetics centre for formal counselling and mutation analysis of the relevant gene¹.
Surgical excision of lesions may be required - endoscopic polypectomy for diagnosis and control of symptoms; laparotomy and resection reserved for repeated intussusception or persistent intestinal bleeding⁵.

• High cancer risk. Most common cancers are gastroesophageal, small bowel, colorectal and pancreatic. Also risk of ductal breast cancer, thyroid, lung, uterine, sertoli cell testicular tumours or ovarian sex cord tumors. The cancer-susceptibility is thought to arise from mutation activating serine/threonine kinase.
• GI bleeding
• intussusception
• Rectal prolapse
• Adhesions and obstructions from repeated surgeries

Benefits of surveillance are uncertain but cancer risk is high so current recommendations (British Society of Gastroenterology)¹ are:

• Colonoscopy or flexible sigmoidoscopy from age 18 years at 3 yearly intervals.
• OGD from age 25 years at 3 yearly intervals.

Members of the family of an affected family where a causative gene has been identified should be referred for gene counselling and predictive gene testing. Where they test negative, there is no indication for their continued surveillance¹.