Case Study # 37

Peutz-Jeghers Syndrome and Genetic Analysis
- Dr David Ramsay MD
- Dr Marie L. Borum, MD, EdD, MPH
- Dr David Jager MD

Learning Objectives

1. Explain the epidemiology of Peutz-Jeghers syndrome (PJS)
2. Describe the typical presentation and disease progression of Peutz-Jeghers syndrome
3. Review the diagnosis of Peutz-Jeghers syndrome
4. Review the mode of inheritance and the genes involved with Peutz-Jeghers syndrome
5. Create a plan for genetic counseling of family members for patients with Peutz-Jeghers syndrome
6. Review the recommended screening for malignancy in Peutz-Jeghers patients
7. Review the differences between Peutz-Jeghers syndrome and Juvenile Polyposis syndrome

Pretest Questions

1. What are the characteristic lesions found along the gastrointestinal tract of Peutz-Jeghers patients?
   a. Teratomas
   b. Medulloblastomas
   c. Osteomas
   d. Hamartomas
   e. Hemangiomas
   f. Hemangioblastomas
2. At what age should women who are diagnosed with Peutz-Jeghers Syndrome start having annual screening mammograms to evaluate for breast cancer in patients with no family history or other risk factors for breast cancer?
   a. 25
   b. 30
   c. 35
   d. 40
   e. at the same age as recommended to the general population
3. What is the mode of inheritance seen in Peutz-Jeghers Syndrome?
   a. autosomal dominant
   b. autosomal recessive
   c. X-linked dominant
   d. X-linked recessive
4. Which of the following genes is believes to play a role in the development of    Peutz-Jeghers Syndrome?   
   a. BRCA 1 and BRCA 2
   b. BMPR1A and SMAD4
   c. LKB1 (STK11)
   d. P53
   e. IPF1
   f. HFE
5. At which of the following anatomical sites does the classic Peutz-Jeghers mucocutaneous pigmentation persist while tending to fade at other locations?
   a. Nasal mucosa
   b. Lips
   c. Buccal mucosa
   d. Axilla
   e. Palms and soles

Answers:  1) d, 2) a, 3) a, 4) c, 5) c

Case Study
 
A 17 year old male presents to your office worried about his risk for cancer.  His father passed away last month from cancer and he is concerned he could be at risk, although he states he is in good health at this time.  He reports he has not had many doctor visits because he has not had any major illnesses and never had surgery.  His review of systems is positive only for occasional abdominal pain and constipation.  Family history is significant for several family members dying of cancer.  The patient states his father died of colon cancer last month at the age of 49.  He states his paternal uncle also died of colon cancer when he was 55, and he was told his paternal grandmother died of breast cancer when she was 46.  He also reports several cousins either have died of been diagnosed with various types of cancer.  During the physical exam you notice freckling on the patient’s buccal mucosa.  The patient states he had many more freckles around his mouth and on his hands and feet, but they have faded as he has gotten older.  The rest of the physical exam is normal.  The fecal occult blood test is positive.  How should you proceed? 

Explain the epidemiology and prevalence of Peutz-Jeghers Syndrome:

          Peutz-Jeghers Syndrome is autosomal dominant disease estimated to have a prevalence of 1:60,000 to 1:280,000.  The disease affects all races and all socioeconomic levels.   The mean age of diagnosis of PJS ranges between 22 and 26 years.  PJS affects males and females at an equal rate. 

What is the typical presentation of a patient with Peutz-Jeghers Syndrome?

          The presentation can be quite variable.  The classic findings in PJS are mucosal freckling and hamartomas found along the GI tract.  The hallmark freckling tends to be absent at birth and will begin to develop in early childhood around age 5-6.  The freckles tend to be perioral but can also appear on the eyes, hands, and feet.  During the teenage years, many of the freckles will tend to fade.  One location with preserved freckling is the buccal mucosa.  Since the hamartomas along the GI tract are small, many patients will be asymptomatic at initial presentation.  Diarrhea, constipation, GI bleeding, abdominal pain or bloating, weight loss, lack of energy, anemia, nausea, and precocious puberty can occur.  In addition, men occasionally develop gynecomastia.  If the polyps enlarge and block the lumen, severe constipation or intussusception may occur.  One-third of Peutz-Jeghers patients will experience symptoms before age 10, and 50–60% of patients will experience symptoms before age 20 (1).

Explain the disease progression of Peutz-Jeghers Syndrome:

          The most common location for polyps is the small intestine.  One large series found the incidence of polyps in the small intestine to be 78%, colon 42%, stomach 38%, and rectum 28% (2).  The jejunum has the highest incidence of polyps in the small bowel followed by the ileum, and then the duodenum.  The polyps vary in size from less than 0.1cm to several cm in diameter.  Gastric polyps tend to be more sessile, whereas small and large intestinal polyps are generally pedunculated.  The largest polyps tend to cause the most severe symptoms of intussusception and constipation.  One series found 47% of patients experiences intussusception (1).  Initially, it was believed the polyps of PJS were adenomas, however, additional studies showed the polyps were in fact hamartomas that often contained adenomatous changes.  This finding has led to continuous debate over the rate of progression to malignancy in PJS.  One recent study found the risk for developing a cancer at ages 20, 30, 40, 50, 60, and 70 years was 2%, 5%, 17%, 31%, 60%, and 85% respectively (3).

Patients with Peutz-Jeghers Syndrome are at increased risk for what types on cancer?

There are many different reviews and series providing statistics on various cancer rates in patients with PJS.  The most common cancers represented were gastrointestinal in origin; gastroesophageal, small bowel, colorectal, and pancreatic.  Almost 50% of patients with Peutz-Jeghers syndrome who develop cancer will die by age 57.  In a large collected series there was an observed  93% cumulative lifetime risk of cancer.  The mean age at first diagnosis of cancer is 42.9 years, add or subtract 10.2 years. One report states the cumulative risk for developing any cancers associated with Peutz-Jeghers syndrome in patients aged 15–64 years is 93%. The cumulative risks of developing a particular cancer from ages 15-64 years are as follows: esophagus 0.5%, stomach 29%, small intestine 13%, colon 39%, pancreas 36%, lung 15%, testes 9%, breast 54%, uterus 9%, ovary 21%, and cervix 10% (4).  Another study has found the risk for developing gastrointestinal cancers at ages 30, 40, 50, and 60 years was 1%, 9%, 15%, and 33%, respectively.  In women with PJS, the risk of breast cancer was substantially increased, being 8% at age 40 and 31% at age 60 (3).  In a recent meta-analysis of 210 PJS patients, the relative risk of stomach, small bowel, and large bowel cancer developing in Peutz-Jeghers male patients was estimated at 235, 279, and 98, respectively, compared to that in the general population.  The relative risk for women with Peutz-Jeghers syndrome developing breast, uterine or ovarian cancer was 8.8, 8.0, and 13, respectively, compared to the general population (1).  Also, women were at increased risk for developing sex cord tumors with annular tubules (SCTAT), a benign neoplasm of the ovaries.  In all of the reviewed studies, patients with PJS have a much higher rate of multiple types of cancer.

Explain the diagnosis of Peutz-Jeghers syndrome:

          The diagnosis of PJS is made if a patient has polyps in the gastrointestinal tract and two of any of the following: polyps in the small intestine, melanin spots, or a family history of PJS.  However, in patients without a significant family history of cancer, early suspicion and a detailed physical exam including inspection of the buccal mucosa are essential in making the diagnosis.
If all exams are normal by age 24, then an at-risk patient most likely does not have PJS.  If an at-risk patient undergoes genetic testing for a mutation known to exist in a family member with PJS and is found to be negative, then the at-risk patient can follow screening recommendation for the general population. 

Describe the genetic component of Peutz-Jeghers syndrome and discuss the role of genetic counseling and testing in the diagnosis and treatment of the disease:

          PJS is acquired through autosomal dominant inheritance.  A gene called LKB1 (or STK11) on chromosome 19p was found to be mutated in a significant number of PJS patients.  This gene was expressed in all tissues examined at the time, and the mutations found were predicted to decrease the kinase activity of the protein.  It was therefore believed that LKB1 was a tumor suppressor gene.  In a study of nine Peutz-Jeghers families, all LKB1 mutations led to a loss in kinase activity (1).  This belief was later confirmed by demonstrating that 11 of 12 hamartomas or adenocarcinomas from 4 PJS patients had loss of the wild-type allele with retention of the mutated allele (2).   It should be noted that many patients with PJS do not have the identified LKB1 mutation and therefore other mutations may exists.   PJS patients with undetectable mutations appear to have a similar risk for developing GI malignancies as those patients with the LKB1 mutation (1).
            Genetic counseling is recommended for all patient diagnosed with PJS.   At-risk family members are also advised to undergo genetic counseling as well as to have yearly physicals to evaluate for melanin spots, and signs of testicular and ovarian cancer until the family members are 24.  It is also recommended by Johns Hopkins Hospital that at risk family members have genetic testing, or combination of upper and lower endoscopy as well as a small bowel series at ages 12, 18, and 24.  At-risk family members are considered first degree relatives of affected patients. Gene testing for PJS is becoming more available and involves direct sequencing of the entire gene for probands followed by directed mutation screening of other at-risk individuals once a mutation is found in the family.  As always with genetic testing, all of the implications need to be discussed with the patient and family before they consent to testing.  There are well known psychological and financial risks to any type of genetic testing.  However, those found to be gene carriers can be educated regarding their risk for developing cancer, be given surveillance recommendations, and be counseled about the possibility of passing their mutation to their offspring.  Testing of at-risk individuals from families with known LKB1 mutations will help those found not to have the mutation by excluding them from the risks and costs of additional procedures included in the surveillance recommendations and will allow them to return to the screening recommendations of the general population.    

What are the surveillance screening and treatment recommendations for patients with Peutz-Jeghers syndrome?

         
          Patients with PJS are at risk for numerous malignancies, therefore they are recommended to have earlier and more frequent evaluations for various types of cancer.  They are also at risk for complications due to intestinal blockage and intussusception.   Screening should begin as soon as the diagnosis of PJS has been made.  Although there is no consensus on a screening timetable, Table 1 provides a general outline gathered from two sets of screening guidelines (1,5). 

Table 1

Treatment involves removal of all polyps.  Multiple resections are often necessary for malignancy, obstruction, and intussusception.  Additional small bowel examination and endoscopy can be performed if necessary during laparotomy.     

What are the similarities and differences between Peutz-Jeghers syndrome and Juvenile Polyposis syndrome (JPS)?

Both PJS and JPS are inherited in an autosomal dominant manner.  Both PJS and JPS have hamartomas located throughout the GI tract.  Both syndromes carry and increased risk for developing tumors along the GI tract.  However, only patients with PJS are more likely to develop tumors outside of the GI system.  Therefore, patients diagnosed with JPS will need increased surveillance for GI malignancies but would not need to follow the additional surveillance recommended to patients with PJS.   It must also be remembered Juvenile refers to the polyps and not the age of the patient at the time of presentation. 
The difference in diagnosis between PJS and JPS is dependent on the histological evaluation of the polyps.  Also, evidence of malignancy outside of the GI tract, mucosal freckling, and known LKB1 mutation of an affected family member strongly suggests the diagnosis of PJS.  Many patients with Juvenile Polyposis syndrome are known to carry mutations of the BMPR1A and SMAD4 genes.   

Patient Resources

The Johns Hopkins Guide for Patients and Families: Peutz-Jeghers Syndrome. 
http://hopkins-gi.org/multimedia/database/hccIntro_42_PJS-Book.pdf

The Peutz-Jeghers Syndrome on-line Support Group
http://listserv.acor.org/SCRIPTS/WA-ACOR.EXE?SUBED1=pjs&A=1

The Peutz-Jeghers Syndrome Support Group Home Page
http://www.peutz-jeghers.com/default.htm

References

1. McGarrity T, Kulin H, Zaino R. Peutz-Jeghers Syndrome, Am J Gastroenterol; 95 (2000), pp. 596–604

2. Merg A, Lynch HT, Lynch JF, et al. Hereditary colorectal cancer-part II. Current Problems in Surgery. 42(5):267-333, 2005 May

3. Hearle N, Schumacher V, Menko FH, Et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clinical Cancer Research. 12(10):3209-15, 2006 May 15

4. Duchini A, Carethers J. Peutz-Jeghers Syndrome. Emedicine.com.  Last updated August 21, 2006.

5. Giardiello FM; Trimbath JD. Peutz-Jeghers Syndrome and Management Recommendations. Clin Gastroenterol Hepatol. 2006 Apr; 4(4):408-415.