Approach

Around 88% to 100% of patients with Peutz-Jeghers syndrome (PJS) will develop polyps.[18] Polyp-related symptoms usually arise in childhood and are seen by the age of 10 years in 33% and by 20 years in 50% to 70% of patients.[3][19]​ Some patients present for a presymptomatic evaluation based on family history of the disease. 

History and family history

Any history of intestinal polyposis, extraintestinal polyposis, mucocutaneous pigmentation, or malignancies in the patient and in the family should be noted. Gastric, small bowel, and colorectal polyposis occur in 88% to 100% of patients, with the majority appearing in the small bowel (60% to 90%) and colon (50% to 64%).[18] Polyp growth begins in childhood by age 10 years, with most people experiencing symptoms such as bleeding, abdominal pain, intussusception, or obstruction by age 18 years.[18] Bleeding may be occult or overt and can result in iron-deficiency anemia and fatigue. Mucocutaneous pigmentation affects >95% of individuals and may often have been present in infancy but fades with time.[8]

Physical exam

PJS is recognizable by the characteristic pigmented macules (flat, blue-gray to brown spots 1 to 5 millimeters in size) which occur most commonly in the perioral region and buccal mucosa (94%). They can also occur on the digits, palms, soles, face, forearms, perianal region, and rarely on the intestinal mucosa.[8][20]​ The macules on the lips are distinctive as they cross the vermillion border and are typically darker and more densely clustered than freckles.[8] Pigmented macules on the skin increase in intensity from infancy and early childhood and often fade in adult life with complete disappearance in some patients. Accordingly, in adult patients, a lack of cutaneous findings does not exclude PJS. The buccal lesions usually persist.[17]

Although uncommon, anemia may arise as a consequence of gastrointestinal bleeding secondary to polyps; pallor, fatigue, and tachycardia may be present.

Males should be examined for signs of testicular tumors, and should be encouraged to perform regular testicular self-exams. Mildly enlarged testicles (without masses) or features of feminizing precocious puberty (for example, bilateral gynecomastia) may suggest an underlying Sertoli cell tumor. The average age of diagnosis for testicular cancer is ages 9 years, with a range of 3-20 years.[21] Occasionally polyp prolapse per anus may be present in both sexes. [Figure caption and citation for the preceding image starts]: Characteristic pigmentation present on lips and buccal mucosaFrom the collection of Dr Carol A. Burke, used with permission [Citation ends].com.bmj.content.model.Caption@2bdaab5c

Diagnostic criteria

A diagnosis of PJS should be considered in a person who satisfies any one of the following:[3][22]

  • Two or more histologically confirmed Peutz-Jeghers-type hamartomatous polyps (PJ-type polyps)

  • Any number of PJ-type polyps with a family history of PJS in a first-degree relative

  • Characteristic mucocutaneous pigmentation with a family history of PJS

  • Any number of PJ-type polyps and characteristic mucocutaneous pigmentation

Individuals who meet the clinical criteria should undergo genetic evaluation.

Genetic testing

Genetic testing should be utilized to confirm the clinical diagnosis in those patients who satisfy the diagnostic criteria for PJS or with a family history of PJS.[18][22]​ Genetic testing is also recommended for those with a pathogenic or likely pathogenic (P/LP) STK11 variant detected by tumor genomic testing on any tumor type in the absence of germline analysis.[22]​ Sequencing of STK11 on chromosome 19p13.3, which encodes for the serine-threonine kinase LKB1, will detect 30% to 69% of mutations, and deletion/duplication analysis will find another 30% of germline alterations.[16][23][24]​ The large majority of genetic testing for inherited cancer risk predisposition is performed using multigene panel testing.[18]​ A positive result confirms the diagnosis. Small and large deletions, insertions, splice site, and missense mutations in the STK11 gene have all been reported.[6][7]

A negative result significantly reduces the likelihood that the patient has PJS, although variant mutations may be missed. A variant of uncertain significance (VUS) could also be identified.

If an individual meets the clinical diagnostic criteria for PJS but has a negative or VUS result on genetic testing, they should be managed as though they have PJS or evaluated further for another genetic syndrome.[18]​ Repeated genetic testing is generally unneeded unless there is uncertainty about an existing result: for example, the result is inconsistent with the patient’s clinical presentation or the test methodology has changed or significantly advanced.[25][26]

Once a mutation is identified in a proband, at-risk family members can be tested for this family-specific alteration. It should be recognized that, while most patients will have an affected parent, approximately 25% of patients have de novo mutations.[8] Even if the mutation is thought to be de novo, the first-degree relatives of patients with PJS should be carefully evaluated for features of PJS (gastrointestinal polyps or mucocutaneous pigmentation), and they should be offered genetic testing.

Whether inherited or de novo, all children of the proband have a 50% risk of inheriting the mutation and should be offered genetic testing. After appropriate genetic counseling and informed consent, testing for any at-risk family members should be performed. Given the pediatric manifestations of PJS, genetic testing of at-risk children should not be delayed until adulthood. Gene reviews: Peutz-Jeghers syndrome Opens in new window

Endoscopic evaluation

Endoscopic evaluation is indicated for three groups of individuals:

  • Asymptomatic individuals with PJS undergoing surveillance.

  • Symptomatic individuals or patients with laboratory or radiographic abnormalities suggestive of PJS.

  • At-risk first-degree relatives who meet the phenotypic criteria (i.e., colonic polyps or mucocutaneous pigmentation) when the family mutation is not identified.

Surveillance of the colon, stomach, and duodenum by esophagogastroduodenoscopy (EGD) and colonoscopy should begin by age 8 years in affected asymptomatic individuals (and earlier in those with symptoms).[17][22][27]​​​​ Small bowel surveillance with video capsule endoscopy (VCE) or computed tomography/magnetic resonance enterography (CTE or MRE) should also begin by ages 8 years (and earlier if the patient is symptomatic).[3][17][18][22]​​[27][28]​​​​​ Capsule endoscopy is safe to use in individuals with PJS and small bowel polyposis who lack obstructive symptoms. If a concern for capsule retention is present, a patency capsule should be utilized. In general, adverse events associated with diagnostic EGD are rare (reported rates: infection <0.3%, bleeding <0.1%, cardiopulmonary events <0.1%, perforation <0.01%).[29]

The most common endoscopic finding is diffuse hamartomatous polyposis. Gastric, small bowel, and colorectal polyposis occur in 88% to 100% of patients, with the majority appearing in the small bowel (60% to 90%) and colon (50% to 64%).[18] In rare cases, polyps have also occurred in the renal pelvis, urinary bladder, lungs, and nares. Polyps may be small or large, sessile, or pedunculated. They often have a characteristic cerebriform appearance due to smooth muscle arborization within the polyps. Multiple polyps are typical; usually the total number is below 20. Individual polyps vary in size from a few millimeters to several centimeters. Pathologically the polyp is hamartomatous in nature; smooth muscle core is covered by lamina propria and mature glandular epithelium. [Figure caption and citation for the preceding image starts]: Small bowel hamartomatous polyp identified on capsule endoscopyFrom the collection of Dr Carol A. Burke, used with permission [Citation ends].com.bmj.content.model.Caption@6248c378[Figure caption and citation for the preceding image starts]: Polypoid mass in the small bowelFrom the collection of Dr James Church, used with permission [Citation ends].com.bmj.content.model.Caption@5731e405[Figure caption and citation for the preceding image starts]: Characteristic serosal dimpling resulting from a pedunculated hamartoma in the small bowel of a patient with PJSFrom the collection of Dr James Church, used with permission [Citation ends].com.bmj.content.model.Caption@673f1285[Figure caption and citation for the preceding image starts]: Histology of a hamartomatous polypFrom the collection of Dr Carol A. Burke, used with permission [Citation ends].com.bmj.content.model.Caption@e6159d0

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