Peutz-Jeghers Syndrome


Article Author:
Marlyn Wu


Article Editor:
Karthik Krishnamurthy


Editors In Chief:
David Wood
Andrew Wilt
Hajira Basit


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
12/17/2018 5:27:19 PM

Introduction

Peutz-Jeghers syndrome (PJS) is a hereditary cancer syndrome characterized by gastrointestinal (GI) polyposis, mucocutaneous pigmented macules, and cancer predisposition. Patients with Peutz-Jeghers syndrome are at an increased risk for developing GI cancers of the colorectal, pancreatic, and gastric organs in addition to a wide variety of non-GI epithelial malignancies such as breast, uterine, and cervical cancers, lung cancer, and tumors of the ovaries and testicles. Among the various malignancies, colorectal is most common with a lifetime risk of 39%. Followed by breast cancer in females with a lifetime risk of 32% to 54%. Females with Peutz-Jeghers syndrome are also at risk for gynecological cancers such as benign ovarian sex cord tumors with annular tubules (SCTATs) and mucinous tumors of the ovaries and fallopian tubes. Males with Peutz-Jeghers syndrome are at risk of Sertoli cell tumors of the testes, which are often hormonally active, secreting estrogen. Males present with gynecomastia, advanced bone age, and rapid growth with short stature. Due to the increased risk for various malignancies, diligent surveillance is recommended.[1]

Etiology

The clinical course of Peutz-Jeghers syndrome manifests when germ-line STK11 mutations are accompanied by an acquired defect in the second STK11 allele in somatic cells. The STK11/LKB1 gene functions as a tumor suppressor which play an important role in regulating the cell cycle.[2]

Epidemiology

Peutz-Jeghers syndrome is a relatively rare disorder with an estimated incidence of about 1 in 25,000 to 300,000 births. The syndrome can occur in any ethnic group with males and females affected equally. Patients with Peutz-Jeghers syndrome are at an increased risk for developing malignancies; the average age of developing cancer is 42 years.

Pathophysiology

Peutz-Jeghers syndrome is an autosomal dominant inherited disorder. It is most often due to germ-line mutations in the STK11 (LKB1) on chromosome 19p13.3. STK11 is a tumor suppressor gene that regulates cell polarity. The gene encodes serine/threonine kinase 11 which play an important role in regulating the cell cycle. Mutations in STK11 are detected in 50% to 80% of families with PJS; for the remaining patients, PJS likely resulted from de novo mutations.[3]

History and Physical

The 2, classic, clinical manifestations of Peutz-Jeghers syndrome are mucocutaneous pigment macules and hamartomatous GI polyps. The average age of diagnosis is 23; the first presentation is often from bowel obstruction due to intussusception from the hamartomatous polyps in the GI tract.

Pigmented mucocutaneous dark blue, brown, to black macules, are present in over 95% of individuals with Peutz-Jeghers syndrome. Most commonly distributed on the lips, perioral areas, buccal mucosa, eyes, nostrils, fingertips, palms, soles, and perianal areas. The macules are rarely present at birth but appear in childhood usually before the age of 5 with oral pigmentation being the first to appear during the first year of life. The macules may fade during puberty and adulthood, except for those on the buccal mucosa which remain into adulthood. No malignant transformation is associated with the melanocytic macules.

Benign hamartomatous polyps with low malignancy-risk develop within the first decade of life and are found anywhere along the GI tract, most commonly the jejunum and extraintestinal sites including but not limited to the bronchus, renal pelvis, and urinary bladder.

Complications of Peutz-Jeghers syndrome include intussusception or obstruction of the GI lumen by the polyps. This may result in abdominal pain or ulceration of the bowels. Up to 69% of patients experience intussusception of the small intestine, with the first event occurring between the ages of 6 and 18 years. GI polyps can also cause chronic bleeding leading to anemia.

Evaluation

Peutz-Jeghers syndrome is based on clinical findings of having at least 2 of the 3 listed clinical criteria for a positive diagnosis:

  1. Family history 
  2. Multiple dark blue to brown pigmented (macules) lesions on the mucous membranes and skin are most often intraoral on the buccal mucosa or gingiva, lips, perioral, fingertips, palms, and soles
  3. Hamartomatous intestinal polyps

Mucocutaneous findings are non-specific for Peutz-Jeghers syndrome; other differentials must be considered. Molecular and genetic testing can aid in confirming the diagnosis

Treatment / Management

The mainstay of management of patients with Peutz-Jeghers syndrome includes surveillance, prevention of manifestations of the condition, and treatment of complications.[1][2][3]

Surveillance

Peutz Jeghers patients may develop GI polyposis as early as 10 years old, with the small intestine as the most common site. Therefore, it is imperative to evaluate the small intestine with upper endoscopy in addition to colonoscopy beginning at early adolescence.

Due to the increased risk of malignancy in Peutz-Jeghers syndrome surveillance recommendations includes the following:

Upper GI Tract 

Upper endoscopy 

  • Baseline screening beginning at 12 years old
  • If polyps found repeat annually 
  • In absence of polyps repeat every 2-3 years into adulthood

Colorectal

Colonoscopy

  • Baseline screening beginning at 12 years old or earlier if reported symptoms
  • If polyps found repeat annually
  • In absence of polyps repeat at 1-3 year intervals

Pancreatic

Magnetic resonance cholangiopancreatography (MRCP) and/or endoscopic ultrasound: Beginning at 25 to 30 years old; Repeat every 1 to 2 years

Breast

Breast examination: 6-month clinical breast examination beginning at age 25

Breast mammogram: Beginning at age 25Gynecologic

Papanicolaou smear: Annually

Transvaginal ultrasound: Consider yearly transvaginal ultrasound beginning at age 18

Testicular

Consider annual examination and yearly ultrasound beginning at age 10.

Prevention

Genetic counseling is recommended to individuals that have a family history of Peutz-Jeghers syndrome and are planning to have children

In female patients with Peutz Jeghers prophylactic mastectomy to manage the increased risk for breast cancer and hysterectomy and bilateral salpingo-oophorectomy after childbearing completion or age 35 to prevent gynecologic malignancy could be considered.[4][5]

Differential Diagnosis

Juvenile polyposis (JPS), is an autosomal dominant inherited condition which presents with hamartomatous polyps of the small intestine due to mutations in the BMPR1A, SMAD4 or ENG genes; however, dermatological findings of PJS are not appreciated.[6][7]

Peutz-Jeghers syndrome, Bannayan-Riley Ruvalcaba syndrome (BRRS), and Cowden Syndrome belong to a family of hamartomatous polyposis syndromes. Therefore, they share similar clinical features such as gastrointestinal polyposis, but they differ in genetic loci mutation. BRRS and Cowden syndromes belong to the PTEN1 gene mutations, with pigmented lesions most commonly on the glans penis. Bannayan-Riley Ruvalcaba patients present with macrocephaly, developmental delay, lipomas, and vascular abnormalities and Cowden syndrome patients present with trichilemmomas, facial papules/oral papillomas, and acral keratoses.

Pigmented intraoral mucocutaneous macules can be found in Laugier-Hunziker syndrome (LHS) but appear later in life after childhood. Additional dermatological findings of longitudinal hyperpigmented bands (melanonychia) on toe and fingernails are also present. Laugier-Hunziker syndrome is not associated with gastrointestinal polyposis.

Prognosis

Peutz-Jeghers syndrome patients are at an increased risk for malignancies. Earlier screening and surveillance is recommended.

Complications

  • Bowel obstruction
  • Rectal bleeding
  • Mesenteric ischemia
  • Gastric outlet obstruction
  • Iron deficiency anemia

Enhancing Healthcare Team Outcomes

An interprofessional approach to PJS is recommended. Peutz-Jeghers syndrome (PJS) is a hereditary cancer syndrome characterized by GI polyposis, mucocutaneous pigmented macules and cancer predisposition. Patients with PJS are at an increased risk for developing GI cancers of the colorectal, pancreatic, and gastric organs besides a wide variety of non- gastrointestinal epithelial malignancies such as breast, uterine and cervical cancer, lung and tumors of the ovaries and testicles. An interprofessional team consisting of a geneticist, gastroenterologist, general surgeon, dermatologist, urologist, and gynecologist is recommended to decrease the morbidity and mortality of this syndrome. The primary care provider and nurse practitioner should refer these patients to the appropriate specialist as soon as the diagnosis is made. The outlook for most patients is guarded. For those who remain cancer free, the long-term outlook is good, but once malignancies develop, the lifespan is shorter.[8][9][10]


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Peutz-Jeghers Syndrome - Questions

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In Peutz-Jeghers syndrome (PJS), small bowel polyps are characterized as which one of the following?



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Which is a feature of Peutz-Jeghers syndrome (PJS)?



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Which of the following conditions is characterized by hamartomas?



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What is the most common initial presentation of a patient with Peutz-Jeghers syndrome?



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Which of the following is not a feature of Peutz-Jeghers syndrome (PJS)?



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Which medical disorder is associated with mutation of the serine/threonine kinase gene and the presence of cancers of the intestine and ovaries?



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What inheritance pattern does Peutz-Jeghers syndrome (PJS) display?



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A child undergoing a full physical work up was found to have mucosal pigmentation of the lips and gums and hamartomas throughout the GI tract. What is the most likely diagnosis?



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A young man presents with recurring attacks of abdominal pain and multiple, two to five millimeter, brown macules on the lips, buccal mucosa, and the dorsum of the fingers. What is the most likely diagnosis?



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An 8-year-old male with a past medical history of Peutz-Jeghers syndrome presents to the emergency department with his father. The patient reports a sudden onset of severe abdominal pain, fever, and diarrhea. The abdominal exam reveals the presence of bowel sounds, no guarding or rigidity, and a palpable “sausage-shaped” mass. Additional exam findings include four dark blue to brown pigmented macules on his lips, oral mucosa, and fingertips. Based on the history and exam what is the most likely diagnosis?



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A 13-year-old male presents to your office with his mother. He has a past medical history of intussusception a decade ago. On exam, you note multiple dark blue to brown pigmented macules on his lips, oral mucosa, and fingertips. His mother has similar lesions on her lips. What condition is associated with the past medical history and dermatologic findings?



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A 10-year-old female presents to your office with her father for fatigue and weakness for 3 months. Her vitals include a temperature of 37.2 C, blood pressure 120/80 mmHg, heart rate 90 beats/min, and respiratory rate 18/min. Additional exam findings include four dark blue to brown pigmented macules on her lips, oral mucosa, and fingertips similar to the lesions on her father's lips. What laboratory test should be ordered?



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A 10-year-old female presents to your office for a post-hospitalization checkup. She was hospitalized a week ago for intussusception and subsequently was diagnosed with Peutz-Jeghers syndrome. What extraintestinal malignancy is she most at risk of developing?



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A 10-year-old otherwise healthy female presents to the emergency department with her mother. The patient reports a sudden onset of severe abdominal pain, fever, and diarrhea. The pain has been present for a few hours and seems to come and go. The child appears to be in pain and pulls her knees to her chest. Her mother denies recent illness, changes to diet, sick contacts, or recent travel. The mother does, however, note that her daughter's stool has had some blood and mucus. The child's immunizations are up-to-date. Vitals reveal a temperature 37.2 C, blood pressure 102/70 mmHg, heart rate 105 beats/min, and respiratory rate 22/min. The gastrointestinal exam reveals that bowel sounds are present with no guarding or rigidity, and on palpation, a “sausage-shaped” abdominal mass is noted. Additional exam findings include dark blue to brown pigmented macules on her lips, oral mucosa, and fingertips similar to the lesions on her mother's lips. Which gene most often is mutated in Peutz-Jeghers Syndrome?



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Peutz-Jeghers Syndrome - References

References

Zhao HM,Yang YJ,Duan JQ,Ouyang HJ,Liu L,Yi LC,Attard TM,Li DY,You JY, Clinical and Genetic Study of children With Peutz-Jeghers Syndrome Identifies a High Frequency of STK11 De Novo Mutation. Journal of pediatric gastroenterology and nutrition. 2018 Oct 16     [PubMed]
Benzel J,Fendrich V, Familial Pancreatic Cancer. Oncology research and treatment. 2018     [PubMed]
Duan N,Zhang YH,Wang WM,Wang X, Mystery behind labial and oral melanotic macules: Clinical, dermoscopic and pathological aspects of Laugier-Hunziker syndrome. World journal of clinical cases. 2018 Sep 26     [PubMed]
Jaegle WT,Keyser EA,Messersmith L,Brady RO,Miller C, Extraovarian sex cord tumor with annular tubules discovered arising from a leiomyoma. Gynecologic oncology reports. 2018 Nov     [PubMed]
Pelit ES,Erol B,Zenginkinet T,Çaşkurlu T, Testis-sparing surgery of unilateral testicular large-cell calcifying Sertoli cell tumor: a sporadic case. Turkish journal of urology. 2018 Jul     [PubMed]
Signoretti M,Bruno MJ,Zerboni G,Poley JW,Delle Fave G,Capurso G, Results of surveillance in individuals at high-risk of pancreatic cancer: A systematic review and meta-analysis. United European gastroenterology journal. 2018 May     [PubMed]
Spoto CPE,Gullo I,Carneiro F,Montgomery EA,Brosens LAA, Hereditary gastrointestinal carcinomas and their precursors: An algorithm for genetic testing. Seminars in diagnostic pathology. 2018 May     [PubMed]
Yoshikawa T,Abe T,Amano H,Hanada K,Minami T,Kobayashi T,Yonehara S,Nakahara M,Ohdan H,Noriyuki T, Metachronous triple cancer associated with Peutz-Jeghers syndrome treated with curative surgery: a case report. Surgical case reports. 2018 Aug 1     [PubMed]
Shah J,Sunkara T,Xiao P,Gaduputi V,Reddy M,Razia S, Peutz-Jeghers Syndrome Presenting as Colonic Intussusception: A Rare Entity. Gastroenterology research. 2018 Apr     [PubMed]
Pittman ME,Brosens LA,Wood LD, Genetic Syndromes with Pancreatic Manifestations. Surgical pathology clinics. 2016 Dec     [PubMed]

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