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Peutz-Jeghers Syndrome

  • Author: Thomas M Attard, MD, FAAP, FACG; Chief Editor: Julian Katz, MD  more...
 
Updated: Mar 06, 2015
 

Overview

Peutz-Jeghers syndrome (PJS) is an autosomal dominant inherited disorder characterized by intestinal hamartomatous polyps in association with a distinct pattern of skin and mucosal macular melanin deposition. Patients with Peutz-Jeghers syndrome have a 15-fold increased risk of developing intestinal cancer compared with the general population.[1, 2, 3, 4, 5, 6, 7, 8, 9]

See the images below.

Upper endoscopy image showing multiple gastric pol Upper endoscopy image showing multiple gastric polyps.
Facial photograph of a patient with Peutz-Jeghers Facial photograph of a patient with Peutz-Jeghers syndrome. Note the mucocutaneous pigmentation that crosses the vermilion border.
Photo of oral pigmented lesion from a patient with Photo of oral pigmented lesion from a patient with Peutz-Jeghers syndrome.

See Clues in the Oral Cavity: Are You Missing the Diagnosis?, a Critical Images slideshow, to help identify the causes of abnormalities of the oral cavity.

The syndrome was described in 1921 by Jan Peutz (1886-1957), a Dutch physician who noted a relationship between the intestinal polyps and the mucocutaneous macules in a Dutch family. The dermatologic component had previously been reported by John McHutchinson in 1896 in identical twins, one of who subsequently died from intussusception.

Harold Jeghers (1904-1990), an American physician, is credited with the definitive descriptive reports of the syndrome when he published "Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits," in 1949, with McKusick and Katz. The eponym Peutz-Jeghers syndrome was introduced by the radiologist Andre J. Bruwer in 1954.

The gastrointestinal polyps found in Peutz-Jeghers syndrome are typical hamartomas. Their histology is characterized by extensive smooth muscle arborization throughout the polyp. This may give the lesion the appearance of pseudoinvasion, because some of the epithelial cells, usually from benign glands, are surrounded by the smooth muscle.

Cancer develops in the gastrointestinal tract of patients with Peutz-Jeghers syndrome with a higher frequency than it does in the general population.[8] Forty-eight percent of patients with Peutz-Jeghers syndrome develop and die from cancer by age 57 years. Others may have a normal life span. The mean age at first diagnosis of cancer is 42.9 years, ±10.2 years.[10, 11, 12]

During the first 3 decades of life, anemia, rectal bleeding, abdominal pain, obstruction, and/or intussusception are common complications in patients with Peutz-Jeghers syndrome.[13, 14] Nearly 50% of the patients experience an intussusception during their lifetime, most commonly in the small intestine.[15]

See the image below.

Barium enema shows intussusception in the descendi Barium enema shows intussusception in the descending colon.

Peutz-Jeghers syndrome should be diagnosed in patients as early as possible. Genetic counseling should also be provided. Many of the gastrointestinal lesions start developing early in life, even if the syndrome is not clinically apparent until the second and third decades of life. Proper screening for intestinal cancers and extraintestinal cancers should be implemented.

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Genetics

The cause of Peutz-Jeghers syndrome (PJS) in most cases (66-94%) appears to be a germline mutation of the STK11/LKB1 (serine/threonine kinase 11) tumor suppressor gene, located on band 19p13.3.

STK11 is a tumor suppressor gene, in that its overexpression can induce a growth arrest of a cell at the G1 phase of the cell cycle and that somatic inactivation of the unaffected allele of STK11 is often observed in polyps and cancers from patients with Peutz-Jeghers syndrome.

STK11/LKB1 encodes a 433 amino acid ubiquitously expressed protein with a central catalytic domain and regulatory N- and C-terminal domains. The biologic function of LKB1 includes the regulation of downstream kinases, including AMPK and the related kinases MARK1 through MARK4 and Brsk/SAD, which are involved in cellular metabolic regulation–stress response and cellular polarity, the latter through tubulin stabilization, tight junction formation, and E-cadherin localization. See the figure below.

Role of STK11/LKB1 in neoplasia: Regulation of cel Role of STK11/LKB1 in neoplasia: Regulation of cell polarity and metabolism. Abbreviations: STRAD, STE20-related kinase adaptor; MO25, calcium-binding protein 39; MARK, microtube affinity-regulating kinases; SAD, synapses of the amphid-defective kinase; SIK, salt-induced kinase; MRLC, myosin regulatory light chain; mTOR, mammalian target of rapamycin.

There is evidence of interaction between the LKB1 pathway along with other tumor suppressor pathways p53 and PTEN. Abrogation of LKB1 function results in both polyposis along with, probably a separate process, resulting in tumorigenesis.

Penetrance of the gene mutation is variable, resulting in a spectrum of phenotypic manifestations among patients with Peutz-Jeghers syndrome (eg, inconsistent number, localization of polyps, differing presentation of the macules) and allowing for a variable presentation of cancer.[9, 16, 17, 18, 19, 20, 21, 22, 23]

Data on the impact of LKB1 mutation type and localization on disease expression are conflicting.Schumacher and colleagues reported a higher risk of malignancy with missense mutations involving the C-terminus or exons encoding for protein domains involved in substrate recognition.[24, 25, 26] Another report described a worse prognosis with greater polyp burden and higher risk of malignancy in individuals harboring a truncating mutation of LKB,[27] whereas another group failed to correlate the risk of (polyp-associated) intussusception with mutational characteristics. Overall opinion is divided on the usefulness of genotype-phenotype correlations in Peutz-Jeghers syndrome, and they are not, at present, routinely used in defining prognosis and management of the disease.

Mutation in the MYH11 gene may be implicated in a minority of patients without the LKB1 gene mutation. Hyperactivation of mammalian target of rapamycin (mTOR) signaling has also been associated with Peutz-Jeghers syndrome.[23]

Other genes may also play a role in Peutz-Jeghers syndrome, such as those that encode for the MARK protein, homologues of the Par 1 polarity protein that associates with LKB1. However, de Leng et al performed direct sequencing and probe amplification in 23 families with Peutz-Jeghers syndrome and were unable to identify any mutations in the MARK genes.[21] This again supports the evidence that LKB1 defects remain the major cause of Peutz-Jeghers syndrome, and, although other mechanisms are involved, they remain to be elucidated.[22]

An interesting study by Tobi et al demonstrated that Adnab-9, a premalignant marker found in Paneth cells, was more common in Peutz-Jeghers syndrome patients. The authors evaluated 8 patients with Peutz-Jeghers syndrome, 8 patients with juvenile polyposis, and 36 hyperplastic polyp sections (as controls).[28] The investigators found that 89% of Peutz-Jeghers syndrome polyps were labeled with Adnab-9, compared with 88% of familial juvenile polyposis sections and 11% of hyperplastic polyps.[28] This study suggested Adnab-9 labeling may identify polyps at higher risk of malignant degeneration.

Mehenni et al, reporting on the molecular and clinical characteristics of 46 families with Peutz-Jeghers syndrome, demonstrated an increase in the mutational spectrum of LKB1/STK11 allelic variants worldwide. They suggested that this new information would be helpful for clinical diagnosis and genetic counseling.[18]

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Epidemiology

Peutz-Jeghers syndrome (PJS) is rare in the United States, with a frequency of encounter from polyposis registries one tenth that of familial adenomatous polyposis. This would place the frequency between 1 case per 60,000 people and 1 case per 300,000 people.

The international frequency of Peutz-Jeghers syndrome is unknown, but given the rarity of this condition, the frequency is probably similar to that reported in the United States. Specific mutations of the STK11/LKB1 gene, however, may be more common in certain ethnic groups. For example, Zuo et al reported 2 new mutations in 3 Chinese families that had not been previously described in white families.[13, 14, 29, 30, 31, 32, 33, 34]

Age-related demographics

Polyps found in Peutz-Jeghers syndrome commonly present in adolescence and early adulthood.[35] One third of the affected individuals experience symptoms during the first 10 years of life.[36] The median time of first presentation with polyps is age 11-13 years; approximately 50% of individuals have experienced symptoms by age 20 years.[14, 29, 37]

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Cancer in Peutz-Jeghers Syndrome

Peutz-Jeghers syndrome (PJS) entails a significant overall increased lifetime risk of intestinal and extraintestinal malignancy (see the Table below), as well as increased risk of malignancy in younger individuals. Small bowel adenocarcinoma has been diagnosed in a child as young as 13 years,[38] with patients aged through 30 years harboring a 5% cumulative risk of cancer that rises to 85% by age 70 years. The overall relative risk for cancer is greater in females than in males and greatest for gastrointestinal, pancreatic, and gynecologic-cervical cancers.[39]

Patients with PJS appear to have an increased risk for pancreatic-biliary cancer.[40] In a cohort study by Korsse et al that included 144 patients with PJS, 7 patients (5%) developed pancreatic cancer (median age, 54 y), 2 patients (3%) developed distal bile duct cancer, and 2 developed or ampullary cancer (median age, 55 y). The cumulative risk for pancreatic cancer was 26% at age 70 years; the relative risk was 76 (P < .001). The investigators reported a cumulative risk for pancreatic-biliary cancer of 32% at age 70 years, with a relative risk of 96 (P < .001).[40]

Table. Risk Ratio Compared to the General Population, Lifetime Frequency, Mean Age, and Age Range of Malignancies Related to Peutz-Jeghers Syndrome[3] (Open Table in a new window)

Organ Risk Ratio Frequency, % Mean Age (Range), Years
Esophagus 57 0.5 67
Stomach 213 29 30.1 (10-61)
Small Intestine 520 13 41.7 (21-84)
Colon 84 39 45.8 (27-71)
Pancreas 132 36 40.8 (16-60)
Lung 17 15  
Testis 4.5 9 8.6 (3-20)
Breast 15.2 54 37 (9-48)
Uterus 16 9  
Ovary 27 21 28 (4-57)
Cervix 1.5 10 34.3 (23-54)

In addition, other reproductive site cancers have been associated with Peutz-Jeghers syndrome, including adenoma malignum of the cervix, Sertoli cell tumors, and sex cord tumors with annular tubules.[41, 42, 43]

Breast cancer in patients with Peutz-Jeghers syndrome may occur at a young age, and it may also be bilateral.[5] Owing to the increased risk of pancreatic adenocarcinoma in Peutz-Jeghers syndrome, screening with endoscopic ultrasonography has emerged as a relatively new tool for early diagnosis.[44, 45]

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Additional Complications

Gastrointestinal complications

In a series of 222 patients with Peutz-Jeghers syndrome (PJS), Utsunomiya et al noted the following distribution of presenting gastrointestinal symptoms[10] :

  • Obstruction - 42.8% of patients
  • Abdominal pain caused by infarction - 23% of patients
  • Rectal bleeding caused by ulceration - 13.5% of patients
  • Extrusion of polyp - 7% of patients

Gastric outlet obstruction can be an early presenting complaint in Peutz-Jeghers syndrome, including in the neonatal period.[46] Recurrent abdominal pain is often reported with increased frequency and intensity as small intestinal polyp growth evolves into subtotal obstruction. Gastrointestinal hemorrhage may not be apparent and may present as iron deficiency anemia.

Polyps

Polyps in the Utsunomiya study’s patients occurred as follows:

  • Small intestine - 64% of patients
  • Colon - 63.2% of patients
  • Stomach - 48.6% of patients
  • Rectum - 32% of patients

The incidence of polyps within the small intestine is greatest in the jejunum and progressively decreases in the ileum and duodenum.[14, 37, 47, 48, 49, 50]

Other rare reported complications include gastrointestinal obstruction and vomiting secondary to gastric polyps.[10, 51, 52] Extraintestinal polyps are also reported, although they are rare; they include nasal polyps,[53] gall bladder polyps,[54] ureteric polyps,[55] and respiratory tract polyps.[56]

The principal causes of morbidity in Peutz-Jeghers syndrome stem from the intestinal location of the polyps (ie, small intestine, colon, stomach). Morbidity includes small intestinal obstruction and intussusception (43%), abdominal pain (23%), hematochezia (14%), and prolapse of a colonic polyp (7%); these typically occur in the second and third decades of life.

Intestinal obstruction can occur in about 50% of patients, and it is usually localized in the small bowel. Obstruction can be complete or incomplete and is caused by the polyp itself or by the subsequent intussusception that may occur, as seen in the images below.

Barium enema shows intussusception in the descendi Barium enema shows intussusception in the descending colon.
Computed tomography scan reveals the classic yin-y Computed tomography scan reveals the classic yin-yang sign of an intussusceptum inside an intussuscipiens.
Abdominal ultrasonography reveals the classic targ Abdominal ultrasonography reveals the classic target sign of an intussusceptum inside an intussuscipiens.
Postevacuation image from part of a double-contras Postevacuation image from part of a double-contrast barium enema study in a 47-year-old man presenting with features of small-bowel obstruction. The image shows a coiled-spring appearance in the region of the cecum suggestive of an intussusception. At laparotomy, an ileocecal intussusception was found in association with a carcinoid tumor of the terminal ileum.

A retrospective study by Burkhart et al examined the incidence of sporadic Peutz-Jeghers syndrome polyps over a 22-year period.[57] The investigators reported that sporadic Peutz-Jeghers syndrome polyps are very rare; however, individuals who may have even a single Peutz-Jeghers syndrome polyp may have an accumulative lifetime risk of cancer that is similar to those with the syndrome.

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Patient Education

The patient with Peutz-Jeghers syndrome (PJS) should be educated on the potential symptoms of intestinal obstruction and instructed on the need for cancer surveillance.

In wake of the discovery of the genetic cause(s) of Peutz-Jeghers syndrome, genetic counseling by someone knowledgeable in this disease should be provided if genetic testing is being considered, particularly as high penetrance autosomal dominant alleles has been described. Genetic counseling relays the risks, benefits, and consequences of genetic testing to the patient. It also informs the patient of the consequences of a positive, negative, or inconclusive genetic test result.

Genetic counseling also includes information on the risk of transmission to offspring and may provide guidance for the patient regarding testing of other family members.[9, 58]

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Patient History

Peutz-Jeghers syndrome (PJS) is characterized by the combination of pigmented lesions in the buccal mucosa and gastrointestinal polyps. The number, as well as the size and the location, of the polyps may vary from patient to patient. Isolated melanotic mucocutaneous pigmentation without gastrointestinal polyps has also been described, because of the genetic variability of the syndrome. Pigmented lesions on the extremities may fade, in time and by adulthood, although buccal mucosal lesions tend to persist.

Well-established clinical diagnostic criteria are noted for Peutz-Jeghers syndrome. One set includes the following elements: 3 histopathologically proven Peutz-Jeghers syndrome polyps with classic mucocutaneous pigmentation and a positive family history.[59]

The diagnostic criteria for Peutz-Jeghers syndrome proposed by the Johns Hopkins Registry include histopathologically verified hamartomatous polyps with at least 2 of the following: small-bowel location for polyposis, mucocutaneous melanotic pigmentation, and a family history of Peutz-Jeghers syndrome.[1]

The following patient characteristics may be noted in the Peutz-Jeghers syndrome[13, 14] :

  • Family history of Peutz-Jeghers syndrome
  • Repeated bouts of abdominal pain in patients younger than 25 years
  • Unexplained intestinal bleeding in a young patient
  • Prolapse of tissue from the rectum
  • Menstrual irregularities in females (due to hyperestrogenism from sex cord tumors with annular tubules)
  • Gynecomastia in males (possible due to the production of estrogens from Sertoli cell testicular tumors) [60]
  • Precocious puberty
  • Gastrointestinal intussusception with bowel obstruction
  • Mucocutaneous pigmentation, which may have faded
  • Melena or rectal bleeding
  • Hematemesis
  • Weakness due to anemia

The most frequent symptom is recurrent colicky abdominal pain caused by obstruction and transient intussusceptions.[61] Melena and rectal bleeding occur less frequently, and hematemesis is uncommon.[62] Certain reports suggest that nearly 50% of the patients experience an intussusception during their lifetime, most often in the small intestine.[15]

Protein-losing enteropathy should be considered as a possible clinical manifestation or presentation of significant gastrointestinal, especially colorectal, polyp burden.

Hyperpigmented mucocutaneous macules may be present on the lips and buccal mucosa and around the mouth, eyes, and nostrils, as well as sparsely on the fingers, soles of the feet, palms, anal area, and intestinal mucosa. The macules are flat, blue-gray to brown-black spots 2-4 mm in size. They tend to develop by age 5 years, but are rarely present at birth. Some may fade during the onset of puberty, but buccal mucosa lesions tend to persist.[36, 47, 63, 64, 65]

See the images below.

Facial photograph of a patient with Peutz-Jeghers Facial photograph of a patient with Peutz-Jeghers syndrome. Note the mucocutaneous pigmentation that crosses the vermilion border.
Photo of oral pigmented lesion from a patient with Photo of oral pigmented lesion from a patient with Peutz-Jeghers syndrome.
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Physical Examination

Mucocutaneous pigmentation and melanin spots (1- to 5-mm macules) are typical of patients with Peutz-Jeghers syndrome (PJS), and they are present in more than 95% of cases. They appear as small, flat, brown or dark-blue spots similar to freckles, most commonly around the mouth crossing the vermilion border (94%), nostrils, perianal area, digits, and the dorsal and volar aspects of hands and feet (62-74%). They may fade after puberty but tend to persist in the buccal mucosa.

Localization in the oral mucosa is typical of patients with Peutz-Jeghers syndrome and does not happen with other types of dermatologic pigmented lesions, such as common lentigo (see image below). Freckles do not localize in the buccal mucosa. An important differential diagnosis for freckling and pigmented macules involving the glans penis is PTEN-hamartoma syndrome, which is a distinct, rare, hereditary intestinal polyposis and cancer-predisposing condition.

Woman with solar lentigo. Woman with solar lentigo.

A rectal mass (rectal polyp) may be found during a rectal examination. In rare cases (7% of cases), the polyp can prolapse outside the anus if it reaches a significant size.

Gynecomastia and growth acceleration (due to Sertoli cell tumor), as well as testicular mass, may also be noted in Peutz-Jeghers syndrome.[57, 66, 67]

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Approach Considerations

2015 ACG guidelines on genetic testing and management of hereditary gastrointestinal cancer syndromes

The American College of Gastroenterology (ACG) released the following recommendations for the management of patients with hereditary gastrointestinal cancer syndromes—and they specifically discuss genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer[68] :

  • The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer.
  • Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives.
  • When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives.
  • Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making.
  • Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers.

Laboratory Studies

Laboratory studies include the following:

  • Complete blood cell (CBC) count - The polyps of Peutz-Jeghers syndrome (PJS) may ulcerate and be a source of blood loss and anemia; gastrointestinal bleeding may be massive but also microscopic, with subsequent iron deficiency, so cell counts and iron studies should be monitored
  • Iron studies
  • Fecal occult blood - Hemoccult, a type of fecal occult blood test, should be performed to check for blood in the stool
  • Carcinoembryonic antigen (CEA) - This test has been used by some physicians for screening and monitoring of cancer degeneration
  • Cancer antigen (CA)–19-9 and CA-125 – CA-125 testing is indicated every year starting at age 18 years, and CA 19-9 is indicated every 1-2 years starting at age 25 years [69]

Genetic testing is available; however, not all families with Peutz-Jeghers syndrome map to the STK11/LKB1 locus.[16, 18, 70, 71] Thus, a negative genetic test does not exclude the diagnosis.

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Imaging Studies

Imaging studies in Peutz-Jeghers syndrome (PJS) include the following:

  • Capsule endoscopy
  • Magnetic resonance imaging (MRI) enteroclysis
  • Computed tomography (CT) scanning with oral contrast
  • Colonoscopy
  • Push enteroscopy
  • Intraoperative enteroscopy (IOE)
  • Double-balloon enteroscopy
  • Endoscopic ultrasonography
  • Endoscopic retrograde cholangiopancreatography [72]

Enteroclysis and dedicated small-bowel follow-through radiographs have traditionally been used to determine the presence and the location of small intestinal polyps in individuals with Peutz-Jeghers syndrome. Capsule endoscopy appears to be safe and as sensitive as barium enterography in the detection of significant small intestinal polyps in children with Peutz-Jeghers syndrome.[73] More recently, MRI enterography has emerged as potentially superior to capsule endoscopy in the assessment of polyp size in adult patients with Peutz-Jeghers syndrome.[74]

Imaging studies of the liver and the pancreas are indicated because of the risk of pancreatic cancer as well as of gallbladder polyps and cancer. These imaging studies may include ultrasonography and CT scanning with pancreatic details or magnetic resonance cholangiopancreatography (MRCP).

Endoscopy and wireless capsule endoscopy (WCE)

Symptoms such as abdominal pain or anemia/melena require investigation with upper and lower endoscopy. Traditionally, primary surgical resection and IOE were the only available options for treating polyps in the mid small bowel in patients with Peutz-Jeghers syndrome[75, 76, 77, 78] ; this strategy did not allow for a preventive approach to recurrent small intestinal obstruction. WCE may improve the likelihood of detection of small intestinal polyps[79] ; however, definitive management may, given the availability of suitable expertise, depend on advanced enteroscopic techniques, including push-enteroscopy, spiral enteroscopy, and double-balloon enteroscopy with polypectomy.[80] Small intestinal polyps may be removed as part of a “clean-sweep” strategy for disease surveillance or because they are resulting in symptoms, including bleeding.

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Histologic Findings

Polyps in Peutz-Jeghers syndrome (PJS) can reliably be differentiated from other types of polyps only by histopathology.[81] Smooth-muscle hyperplasia, with an elongated, arborized pattern of polyp formation towards the epithelial layer, can be seen.[13, 58] This results in the formation of islands of epithelium within the underlying smooth muscle,[61, 82] which is best appreciated in Peutz-Jeghers syndrome small intestine polyps.[57]

See the image below.

Intestinal polypoid adenomas. Tubular adenoma, low Intestinal polypoid adenomas. Tubular adenoma, low-power view. Courtesy of George H. Warren, MD†.
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Surgical Care

Patients with Peutz-Jeghers syndrome usually undergo numerous surgeries during their lives. These surgeries include laparotomies and laparoscopies for both gastrointestinal involvement and extraintestinal complications. Surgical treatment of extraintestinal cancers detected through surveillance procedures is frequently required.

Laparotomy and resection may be necessary, as indicated, for small intestinal intussusception, obstruction, or persistent intestinal bleeding. Laparoscopic-assisted enteroscopy may offer a less invasive option for polyp removal.

Complications

Adhesions and intestinal obstruction or short bowel syndrome from repeated abdominal surgeries can be limited with the use of endoscopic methods for intestinal polyp resection, such as intraoperative endoscopy and push enteroscopy.

In a study consisting of 10 children with Peutz-Jeghers syndrome, Bizzarri et al reported that single-balloon enteroscopy is effective for treating small bowel polyps in children with Peutz-Jeghers syndrome.[83] The investigators suggested that well-timed polypectomy may prevent polyp-related complications and the need for emergency laparotomy.

Diet

Diet is unrestricted, except for those who have surgical resections and or strictures, wherein avoiding food with kernels (eg, popcorn) is indicated.

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Pharmacologic Management

Chemopreventive strategies for familial adenomatous polyposis syndrome management has led to investigation into cyclooxygenase (COX) inhibitors for Peutz-Jeghers syndrome (PJS). Rossi et al demonstrated that COX-2 was highly up-regulated in a murine model of Peutz-Jeghers syndrome LKB1 mutant mice.[84] Polyps recovered from patients with Peutz-Jeghers syndrome also showed a significant correlation between LKB1 staining and COX-2, suggesting COX-2 is integral to the tumorigenesis pathway in Peutz-Jeghers syndrome.[85]

A decrease in polyp burden was reported in COX-2 knockout LKB-1 mutant mice, analogous to LKB-1 mutant mice treated with celecoxib. In that report, Udd et al reported an uncontrolled, open-labeled pilot study in humans and noted reduced gastric polyposis in patients treated with celecoxib.[86] Celecoxib use in Peutz-Jeghers syndrome, although promising, remains to be tested and currently cannot be routinely recommended in any age group.

Given that modulation of PI3-kinase is critical to the function of STK11, and in turn, one of the major downstream mediators of PI3-kinase signaling is mammalian target of rapamycin (mTOR), inhibition of mTOR offers potential therapeutic possibilities in chemoprevention in Peutz-Jeghers syndrome. Rapamycin has been shown to be effective in reducing polyp burden in a murine model of Peutz-Jeghers syndrome.[87] In addition, RAD001 (everolimus) has been proposed as a potential chemopreventive agent and reportedly effective in achieving a partial remission in a patient with Peutz-Jeghers syndrome with advanced pancreatic cancer.[88] Currently, the use of mTOR inhibitors is not recommended as standard of care in adult and pediatric patients with Peutz-Jeghers syndrome.

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Consultations

Follow-up care of patients with Peutz-Jeghers syndrome (PJS) should be supervised by a primary physician familiar with this condition. Liaison with a tertiary center or registry-based team facilitates care. Gastroenterology involvement, genetic consultation and counseling, as well as urologic and gynecologic consultations, are required in the management of these patients.

Psychologist referral and psychiatric consultation should be borne in mind as patients with Peutz-Jeghers syndrome are more likely to suffer from mild depression, experience a poorer mental quality of life, and are susceptible to more limitations in daily functioning owing to emotional problems and a general health perception compared with the general population.[89, 90]

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Patient Monitoring

Ideally, patients with Peutz-Jeghers syndrome (PJS) should be followed by a multidisciplinary team that is familiar with the syndrome. The aim of the initial consultation and continued follow up is to educate the patient and family on the illness, outline a schema for continued disease surveillance, offer genetic counseling, and, if appropriate, offer genetic testing to the extended family. Support, including identification of psychologically at-risk individuals, needs to be factored in this holistic management approach.[91] Counseling and testing of asymptomatic but at-risk individuals is geared toward limiting the likelihood of Peutz-Jeghers syndrome patients presenting with complications, including malignancy, inherent to their disease, as well as advice regarding potential preventive strategies, including cancer-surveillance measures.

Periodic surveillance and removal of larger polyps aims to reduce the likelihood of complications in Peutz-Jeghers syndrome. Hence, surveillance for gastric and small-bowel polyposis should begin at age 8-10 years and continue at 2-year intervals.[92] When small bowel polyps are present, there is broad consensus amongst quaternary referral centers that they be removed before symptoms and obstruction become evident. A regular surveillance-based, clean-sweep enteroscopy (double-balloon or intraoperative assisted and push-enteroscopy) is suggested to decrease the risk of obstruction, surgical resection and, long term, the risk of short bowel syndrome.[93, 94, 95]

Follow-up care should be supervised by a gastroenterologist familiar with Peutz-Jeghers syndrome. Patients with Peutz-Jeghers syndrome should undergo an annual CBC count, as well as an annual physical examination that includes evaluation of the breasts, abdomen, pelvis, and testes. Lifelong cancer surveillance is advocated.[3]

A recent review by Beggs and coworkers summarized the current recommendations for cancer surveillance in patients with Peutz-Jeghers syndrome and pooled the published recommendations to date.[96, 97, 98] Recommendations were based on literature review, cohort studies, and systematic review. Recommendations focused on upper intestinal, colorectal, pancreatic, breast, and genitourinary (reproductive) organ surveillance.

  • Upper gastrointestinal tract - Annual hemoglobin concentration, esophagogastroduodenoscopy (EGD) every 2-3 years, small bowel series/enteroscopy (possible alternatives: wireless capsule endoscopy, magnetic resonance enterography) every 2 years, although there is no consensus on from what age (eg, 10 y, 18 y, 25 y) to start
  • Colorectal - Colonoscopy or flexible sigmoidoscopy and barium enema every 2-3 years from the time of first symptoms or in late teens/25 years onwards
  • Pancreatic - Annual abdominal ultrasound or annual/every-other-year endoscopic ultrasound from age 25-30 years onwards
  • Breast - Regular breast examination (monthly to 6 monthly) from age 18 years onwards, mammography (or MRI) every other year (annually after age 50 y)
  • Genitourinary in women - Annual pelvic examination, pelvic ultrasound, and cervical smears; some reviews recommend serum CA 125, endometrial biopsy annually from age 20 years onwards
  • Genitourinary in men - Annual testicular examination; ultrasound if symptomatic from birth

The Cancer of the Pancreas Screening (CAPS) Consortium summit in 2012 addressed pancreatic cancer screening recommendations in at-risk populations, including persons with Peutz-Jeghers syndrome. Periodic screening of all individuals with Peutz-Jeghers syndrome was recommended from age 50 years onwards. Suitable modalities for initial screening included endoscopic ultrasonography, MRI/magnetic resonance cholangiopancreatography (MRCP), CT scanning, abdominal ultrasound, and endoscopic retrograde cholangiopancreatography (ERCP). The ideal frequency for surveillance, however, was not defined.

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Contributor Information and Disclosures
Author

Thomas M Attard, MD, FAAP, FACG Associate Professor of Pediatrics, University of Malta; Consultant Pediatric Gastroenterologist, Mater Dei Hospital, Republic of Malta

Thomas M Attard, MD, FAAP, FACG is a member of the following medical societies: American Academy of Pediatrics, American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, Crohn's and Colitis Foundation of America

Disclosure: Nothing to disclose.

Coauthor(s)

Seth Septer, DO Pediatric Gastroenterologist, Children’s Mercy Hospital Clinics; Assistant Professor, University of Missouri-Kansas City School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD Clinical Professor of Medicine, Drexel University College of Medicine

Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law, Medicine & Ethics, American Trauma Society, Association of American Medical Colleges, Physicians for Social Responsibility

Disclosure: Nothing to disclose.

Acknowledgements

Ruchir Agrawal, MD Chief, Allergy and Immunology, Aurora Sheboygan Clinic

Ruchir Agrawal, MD, is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American College of Allergy, Asthma and Immunology, and American Medical Association

Disclosure: Nothing to disclose.

Vivek Bansal Armed Forces Medical College, India

Disclosure: Nothing to disclose.

John M Carethers, MD Professor of Medicine, Chief, Division of Gastroenterology, Department of Medicine, University of California, San Diego, School of Medicine

John M Carethers, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Gastroenterology, American College of Physicians, and American Gastroenterological Association

Disclosure: Nothing to disclose.

Carmen Cuffari, MD Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine

Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, and Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Andrea Duchini, MD Associate Professor of Medicine and Surgery, Director of Hepatology, University of Texas Medical Branch School of Medicine; Medical Director of Liver Transplantation, Department of Surgery, The Methodist Hospital

Andrea Duchini, MD is a member of the following medical societies: American College of Physicians, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, and International Liver Transplantation Society

Disclosure: Nothing to disclose.

Robert J Fingerote, MD, MSc, FRCPC Consultant, Clinical Evaluation Division, Biologic and Gene Therapies, Directorate Health Canada; Consulting Staff, Department of Medicine, Division of Gastroenterology, York Central Hospital, Ontario

Robert J Fingerote, MD, MSc, FRCPC is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, Canadian Medical Association, Ontario Medical Association, and Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Rohit Kohli, MBBS, MS Assistant Professor of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center

Rohit Kohli, MBBS, MS is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, American Society of Transplantation, International Pediatric Transplant Association, and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

Disclosure: Johnson and Johnson Grant/research funds Consulting

Sandeep Mukherjee, MB, BCh, MPH, FRCPC Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center

Sandeep Mukherjee, MB, BCh, MPH, FRCPC is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada

Disclosure: Merck Honoraria Speaking and teaching; Ikaria Pharmaceuticals Honoraria Board membership

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Jorge H Vargas, MD Professor of Pediatrics and Clinical Professor of Pediatric Gastroenterology, University of California, Los Angeles, David Geffen School of Medicine; Consulting Physician, Department of Pediatrics, University of California at Los Angeles Health System

Jorge H Vargas, MD is a member of the following medical societies: American Liver Foundation, American Society for Gastrointestinal Endoscopy, American Society for Parenteral and Enteral Nutrition, Latin American Society of Pediatric Gastroenterology, Hepatology & Nutrition, and North American Society for Pediatric Gastroenterology and Nutrition

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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Upper endoscopy image showing multiple gastric polyps.
Facial photograph of a patient with Peutz-Jeghers syndrome. Note the mucocutaneous pigmentation that crosses the vermilion border.
Photo of oral pigmented lesion from a patient with Peutz-Jeghers syndrome.
Barium enema shows intussusception in the descending colon.
Computed tomography scan reveals the classic yin-yang sign of an intussusceptum inside an intussuscipiens.
Abdominal ultrasonography reveals the classic target sign of an intussusceptum inside an intussuscipiens.
Woman with solar lentigo.
Postevacuation image from part of a double-contrast barium enema study in a 47-year-old man presenting with features of small-bowel obstruction. The image shows a coiled-spring appearance in the region of the cecum suggestive of an intussusception. At laparotomy, an ileocecal intussusception was found in association with a carcinoid tumor of the terminal ileum.
Intestinal polypoid adenomas. Tubular adenoma, low-power view. Courtesy of George H. Warren, MD†.
Role of STK11/LKB1 in neoplasia: Regulation of cell polarity and metabolism. Abbreviations: STRAD, STE20-related kinase adaptor; MO25, calcium-binding protein 39; MARK, microtube affinity-regulating kinases; SAD, synapses of the amphid-defective kinase; SIK, salt-induced kinase; MRLC, myosin regulatory light chain; mTOR, mammalian target of rapamycin.
Table. Risk Ratio Compared to the General Population, Lifetime Frequency, Mean Age, and Age Range of Malignancies Related to Peutz-Jeghers Syndrome [3]
Organ Risk Ratio Frequency, % Mean Age (Range), Years
Esophagus 57 0.5 67
Stomach 213 29 30.1 (10-61)
Small Intestine 520 13 41.7 (21-84)
Colon 84 39 45.8 (27-71)
Pancreas 132 36 40.8 (16-60)
Lung 17 15  
Testis 4.5 9 8.6 (3-20)
Breast 15.2 54 37 (9-48)
Uterus 16 9  
Ovary 27 21 28 (4-57)
Cervix 1.5 10 34.3 (23-54)
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