Peutz-Jeghers syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hamid Qazi, MD, BSc [2]

Peutz-Jeghers, also known as Hereditary Intestinal Polyposis Syndrome, is an autosomal dominant genetic disorder caused by a mutation in the STK11 (LKB1) tumor suppressor gene. It is characterized by the appearance of multiple benign hamartomatous polyps in the gastrointestinal tract, which increase the risk of cancer in the gastrointestinal tract. Peutz–Jeghers syndrome ia also associated with hyperpigmented macules on the lips and oral mucosa (melanosis). The incidence of Peutz-Jeghers syndrome is approximately 0.03 to 4 per 100,000 individuals worldwide. If left untreated, patients with Peutz-Jeghers syndrome may progress to develop rectal bleeding, anemia, intussusception, bowel obstruction. Abdominal CT and MRI may help in the diagnosis of Peutz-Jeghers disease. Screening for intestinal and extraintestinal cancers is recommended for patients with Peutz-Jeghers disease. Surgery is the mainstay of treatment.

In 1998, STK11 (LKB1) mutations were first identified in the pathogenesis of Peutz-Jeghers syndrome. The syndrome is named after Jans Peutz (1886-1957), a Dutch physician, and Harold Jeghers (1904-1990), an American physician who had successively described the association between polyposis and the mucocutaneous macules.

Peutz-Jeghers syndrome is transmitted in an autosomal dominant pattern. Polyps of Peutz-Jeghers syndrome are usually non-neoplastic hamartomas. It is thought that Peutz-Jeghers syndrome is the result of deletion or partial deletion of STK11 (LBK1) gene, located on chromosome 19p13.3. Mucutaneous pigmentation (macules) are caused by pigment-laden macrophages in the dermis.

Peutz-Jeghers syndrome is caused by a mutation in the STK11 (LKB1) tumor suppressor gene.

Peutz-Jeghers syndrome must be differentiated from other diseases that cause hamartomatous polyps and mucocutaneous pigmentation, such as Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome, and juvenile polyposis.

The prevalence of Peutz-Jeghers syndrome is estimated to be in the range of 0.8 to 2.8 in 100000 and it affects individuals between the ages of 10 to 30 years.

Common risk factor in the development of Peutz-Jeghers syndrome is the presence of family history of Peutz-Jeghers syndrome.

Screening for cancerous lesions by small intestine radiography, esophagogastroduodenoscopy (EGD), colonoscopy, pancreatic ultrasound, pelvic ultrasound, mammography, and Papanicolaou test (Pap test) is recommended among patients with Peutz-Jeghers syndrome.

If left untreated, patients with Peutz-Jeghers syndrome may progress to develop rectal bleeding, anemia, intussusception, bowel obstruction, and abdominal pain. Common complications of Peutz-Jeghers syndrome include colon cancer and cachexia. Prognosis is generally good with treatment.

The diagnosis of Peutz-Jeghers syndrome is made when at least 2 of the following 3 diagnostic criteria are met: positive family history, mucocutaneous pigmentation, and presence of hamartomatous polyps.

The hallmark of Peutz-Jeghers syndrome is hamatomatous polyps. A positive history of mucucutaneous hyperpigmentation and rectal bleeding is suggestive of Peutz-Jeghers syndrome. The most common symptoms of Peutz-Jeghers syndrome include abdominal pain, fatigue, and weight loss.

Common physical examination findings of Peutz-Jeghers syndrome include mucocutaneous hyperpigmentation, abdominal tenderness due to intussusception, bowel obstruction, and pallor due to anemia.

Some patients with Peutz-Jeghers syndrome may have positive stool guaiac test and anemia, which are usually suggestive of colon cancer.

On chest x-ray, Peutz-Jeghers syndrome is characterized by a mass with widening of the mediastinum, atelectasis, consolidation, and pleural effusion.

Abdominal CT scan may be helpful in the diagnosis of Peutz-Jeghers syndrome. Findings on CT scan suggestive of Peutz-Jeghers syndrome include multiple polyps, intussusception, and bowel obstruction.

Abdominal MRI scan may be helpful in the diagnosis of Peutz-Jeghers syndrome. Findings on MRI suggestive of Peutz-Jeghers syndrome include multiple polyps along the distribution of the gastrointestinal tract.

Abdominal ultrasound may be helpful in the diagnosis of Peutz-Jeghers syndrome. Findings on abdominal ultrasound suggestive of Peutz-Jeghers syndrome include multiple polyps and small bowel distention. Abdominal ultrasound is also used to exclude pregnancy in young females with Peutz-Jeghers syndrome presenting with abdominal pain.

Barium x-ray maybe helpful in the diagnosis of Peutz-Jeghers syndrome. Findings on barium x-ray suggestive of Peutz-Jeghers syndrome include multiple polyps.

Other diagnostic studies for Peutz-Jeghers syndrome include colonoscopy, which demonstrates multiple polyps in the colon, and capsule endoscopy, which demonstrates multiple polyps in the small intestine.

There is no medical treatment for Peutz-Jeghers syndrome. Depending on the associated cancer, radiotherapy or chemotherapy may be considered.

Surgery is the mainstay of treatment for Peutz-Jeghers syndrome. Surgical options include polypectomy, laparotomy in case of intussusception, and laser cosmetic therapy may be considered for mucocutaneous pigmentation.

There are no primary preventive measures available for Peutz-Jeghers syndrome. However, if there is a positive family history, intrauterine genetic testing may help in early diagnosis.

Secondary prevention strategies to detect intestinal and extraintestinal malignancies in Peutz-Jeghers syndrome include enteroscopy and colonoscopy.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hamid Qazi, MD, BSc [2]

In 1998, STK11 (LKB1) mutations were first identified in the pathogenesis of Peutz-Jeghers syndrome. The syndrome is named after Jans Peutz (1886-1957), a Dutch physician and Harold Jeghers (1904-1990), an American physician who had successively described the association between polyposis and the mucocutaneous macules.

• In 1895, Peutz-Jeghers syndrome was first discovered by Dr. Connor, a British physician, in identical twin sisters.^[1][2]

• In 1921, the association between gastrointestinal polyposis with distinctive pigmentation of the skin and Peutz-Jeghers syndrome was made by Dr. Johannes Peutz of Holland.
• In 1949, Dr. Harold Jeghers of United States was the first to discover the association between combination of intestinal polyposis and skin pigmentation, and the development of Peutz-Jeghers syndrome.
• In 1954, A. Bruwer used the eponym Peutz-Jeghers syndrome.
• In 1998, serine/threonine–protein kinase 11 alias LKB1 (STK11/LKB1) gene mutations were first implicated in the pathogenesis of Peutz-Jeghers syndrome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hamid Qazi, MD, BSc [2]

There is no established classification system for Peutz-Jeghers syndrome.

There is no established classification system for Peutz-Jeghers syndrome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hamid Qazi, MD, BSc [2]

Peutz-Jeghers syndrome is transmitted in an autosomal dominant pattern. Polyps of Peutz-Jeghers syndrome are usually non-neoplastic hamartomas. It is thought that Peutz-Jeghers syndrome is the result of deletion or partial deletion of STK11 (LBK1) gene, located on chromosome 19p13.3. Mucutaneous pigmentation (macules) are caused by pigment-laden macrophages in the dermis.

• It is thought that Peutz-Jeghers syndrome is the result of deletion or partial deletion of STK11 (LBK1) gene, located on chromosome 19p13.3.^[1][2]
• STK11 protein plays an important role in second messenger signal transduction and is found to regulate cellular proliferation, controls cell polarity, and responds to low energy states.

• In Mammalian studies, STK11 is shown in the inhibition of AMP-activated protein kinase (AMPK), and signals downstream to inhibit the mammalian target of rapamycin (mTOR).
  • The mTOR pathway is dysregulated in Peutz-Jeghers syndrome.

• Pathogenesis of mucutaneous pigmentation (macules)
  • Caused by pigment-laden macrophages in the dermis.

• Peutz-Jeghers syndrome is inherited in an autosomal dominant pattern.

Conditions associated with Peutz-Jeghers syndrome include:

• Breast Cancer
• Colon Cancer
• Pancreatic cancer
• Ovarian cancer
• Cervical cancer
• Testicular cancer

• On gorss pathology, Peutz-Jeghers syndrome associated polyps have a unique smooth muscle core that arborizes throughout the polyp.^[1]
  • These polyps can only be differentiated from other polyp types by histopathology.

• Polyps of Peutz-Jeghers syndrome are usually non-neoplastic hamartomas.^[3]
• On microscopic histopathological analysis, polyps have the following characteristic findings:^[2]

• Frond-like polyp with all three components of mucosa:
  • Muscosal epithelium (melanotic mucosa, goblet cells)
  • Lamina propria
  • Muscularis mucosae

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hamid Qazi, MD, BSc [2]

Peutz-Jeghers syndrome must be differentiated from other diseases that cause hamartomatous polyps and mucocutaneous pigmentation, such as Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome, juvenile polyposis, and McCune-Albright syndrome.

Peutz-Jeghers syndrome must be differentiated from the following diseases:^[1][2]

• Cowden syndrome
• Cronkhite-Canada syndrome
• Bannayan–Riley–Ruvalcaba syndrome
• Juvenile polyposis
• McCune-Albright syndrome

Differential diagnosis according to polys:

Diseases	History and Symptoms				Physical Examination			Laboratory Findings				Other Findings
	Abdominal Pain	Rectal Bleeding	Hyperpigmentation	Fatigue	Abdominal Tenderness	Hyperpigmentation	Anemia	Gene(s)	Sertoli Cell Tumors	Gastrointestinal Tumors	Cancers
Juvenile Polyposis Syndrome	+		–	+	–	–	–	SMAD4 BMPR1A	–	Adenoma+  Hamartoma+++	Colon
Cowden Syndrome	–	–	Axillary+ Inguinal+ Facial+	–	–	Axillary+ Inguinal+ Facial+	–	PTEN	–	Adenoma+  Hamartoma+++	Breast, Thyroid, Endometrium	Trichilemmoma, skin hamartoma, hyperplastic polyps, macrocephaly, breast fibrosis
Carney Syndrome	–	–	Facial+ Mucosal+	–	–	Facial+ Mucosal+	–	PRKAR1A	++		Thyroid	Myxomas of skin and heart
Familial Adenomatous Polyposis	+	+	–	+	+/-	–	+	APC	–	Adenoma+++	Colon, brain	Desmoid tumors, osteomas
Hereditary Non-Polyposis Colon Cancer	–	+	–	+	+/-	–	+	MLH1 MSH2 MSH3 MSH6 PMS1 PMS2	–	Adenoma+	Endometrial, gastric, renal pelvis, ureter, and ovarian	Sebaceous adenoma

Differential of gastrointestinal bleeding

Disease Clinical manifestations Diagnosis Comments Symptoms Signs Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Peutz-Jeghers syndrome Depends on location of polyps it maybe present ± – ± – ± ± ± Rectal bleeding may be present due to polyp – – – + Hamartomatous polyps present on endoscopy Iron deficiency anemia on CBC STK11 mutation Intra-operative enteroscopy (laparatomy with endoscopy Double balloon eneteroscopy Colonoscopy Barium Swallow Can lead to colon cancer, breast cancer, ovarian cancer, cervical cancer, and testicular cancer Peptic ulcer disease Diffuse ± − + − − − + Gastric ulcer- melena and hematemesis Duodenal ulcer- melena and hematochezia Positive if perforated Positive if perforated Positive if perforated N Ascitic fluid LDH > serum LDH Glucose < 50mg/dl Total protein > 1g/dl Air under diaphragm in upright CXR Upper GI endoscopy for diagnosis Gastritis Epigastric ± − + − − − Positive in chronic gastritis + − − − N H.pylori infection diagnostic tests Endoscopy H.pylori gastritis guideline recommendation Gastrointestinal perforation Diffuse + ± – ± − − − + + + ± Hyperactive/hypoactive WBC> 10,000 Air under diaphragm in upright CXR Hamman’s sign Acute diverticulitis LLQ + ± + − + ± − + Positive in perforated diverticulitis + + Hypoactive Leukocytosis CT scan Ultrasound History of constipation Inflammatory bowel disease Diffuse ± − − ± − + + + − − − Normal or hyperactive Anti-neutrophil cytoplasmic antibody (P-ANCA) in Ulcerative colitis Anti saccharomyces cerevisiae antibodies (ASCA) in Crohn’s disease String sign on abdominal x-ray in Crohn’s disease Extra intestinal findings: Uveitis Arthritis Infective colitis Diffuse + − ± − − + − + Positive in fulminant colitis ± ± Hyperactive Stool culture and studies Shiga toxin in bloody diarrhea PCR CT scan Bowel wall thickening Edema Colon carcinoma Diffuse/localized − − − − ± ± + + ± − − Normal or hyperactive if obstruction present CBC Carcinoembryonic antigen (CEA) Colonoscopy Flexible sigmoidoscopy Barium enema CT colonography  PILLCAM 2: A colon capsule for CRC screening may be used in patients with an incomplete colonoscopy who lacks obstruction Budd-Chiari syndrome RUQ ± − − ± − − − Positive in liver failure leading to varices − − − N Elevated serum aspartate aminotransferase and alanine aminotransferase levels may be more than five times the upper limit of the normal range. Elevated serum alkaline phosphatase and bilirubin levels, decreased serum albumin level. Findings on CT scan suggestive of Budd-Chiari syndrome include: Early enhancement of the caudate lobe and central liver around the inferior vena cava Delayed enhancement of the peripheral liver with accompanying central low density (flip-flop appearance) Peripheral zones of the liver show reversed portal venous blood flow In the chronic phase, there is caudate lobe enlargement and atrophy of the peripheral liver in affected areas Ascitic fluid examination shows: Total protein more than 2.5 g per deciliter White blood cells are usually less than 500/μL. Hemochromatosis RUQ − − − − − − − Positive in cirrhotic patients − − − N >60% TS >240 μg/L SF Raised LFT Hyperglycemia Ultrasound shows evidence of cirrhosis Extra intestinal findings: Hyperpigmentation Diabetes mellitus Arthralgia Impotence in males Cardiomyopathy Atherosclerosis Hypopituitarism Hypothyroidism Extrahepatic cancer Prone to specific infections Cirrhosis RUQ − − − + − − + + + − − N Hypoalbuminemia Prolonged PT Abnormal LFTs Hyponatremia Thrombocytopenia US Nodular, shrunken liver Ascites Stigmata of liver disease Cruveilhier- Baumgarten murmur Mesenteric ischemia Periumbilical Positive if bowel becomes gangrenous − + − − + + + Positive if bowel becomes gangrenous Positive if bowel becomes gangrenous − Hyperactive to absent Leukocytosis and lactic acidosis Amylase levels D-dimer CT angiography SMA or SMV thrombosis Also known as abdominal angina that worsens with eating Acute ischemic colitis Diffuse + ± + − − + + + + + + Hyperactive then absent Leukocytosis Abdominal x-ray Distension and pneumatosis CT scan Double halo appearance, thumbprinting Thickening of bowel May lead to shock Ruptured abdominal aortic aneurysm Diffuse ± − + − − − + + + − − N Fibrinogen D-dimer Focused Assessment with Sonography in Trauma (FAST)  Unstable hemodynamics Intra-abdominal or retroperitoneal hemorrhage Diffuse ± − ± − − − − + + − − N ↓ Hb ↓ Hct CT scan History of trauma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hamid Qazi, MD, BSc [2]

The prevalence of Peutz-Jeghers syndrome is estimated to be in the range of 0.8 to 2.8 in 100000 and it affects individuals between the ages of 10 to 30 years.

The epidemiology and demographics are as follows:^[1][2]

• The prevalence of Peutz-Jeghers syndrome is estimated to be 0.8 to 2.8 in 100000.

• Peutz-Jeghers syndrome affects individuals between the ages of 10 to 30 years.
  • Average age of diagnosis of Peutz-Jeghers syndrome is 23 years for males and 26 years for females.

• There is no racial predilection to Peutz-Jeghers syndrome.

• Peutz-Jeghers syndrome affects men and women equally.
• Average age of diagnosis of Peutz-Jeghers syndrome is 23 years for males and 26 years for females.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hamid Qazi, MD, BSc [2]

Common risk factor in the development of Peutz-Jeghers syndrome is the presence of family history of Peutz-Jeghers syndrome.

Common risk factor in the development of Peutz-Jeghers syndrome is the presence of family history of Peutz-Jeghers syndrome.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hamid Qazi, MD, BSc [2]

Screening for cancerous lesions by small intestine radiography, esophagogastroduodenoscopy (EGD), colonoscopy, pancreatic ultrasound, pelvic ultrasound, mammography, and Papanicolaou test (Pap test) is recommended among patients with Peutz-Jeghers syndrome.

Patients who are at risk of developing Peutz-Jeghers syndrome are screened for the locations of the hamartomas by:^[1]

• Genetic testing
• Upper GI endoscopy
• Enteroclysis
• Colonoscopy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hamid Qazi, MD, BSc [2]

If left untreated, patients with Peutz-Jeghers syndrome may progress to develop rectal bleeding, anemia, intussusception, bowel obstruction, and abdominal pain. Common complications of Peutz-Jeghers syndrome include colon cancer and cachexia. Prognosis is generally good with treatment.

If left untreated, patients with Peutz-Jeghers syndrome may progress to develop rectal bleeding, anemia, intussusception, bowel obstruction, and abdominal pain.^[1][2][3]

Percentage of extraintestinal cancer in Peutz-Jeghers syndrome
Cancers	Percentage (%)
Breast	32 to 54
Ovary	21
Cervix	10
Testes	9

Percentage of gastrointestinal cancer in Peutz-Jeghers syndrome
Cancers	Percentage (%)
Colon	39
Stomach	29
Small Bowel	13
Pancraes	11 to 39

Complications that can develop as a result of Peutz-Jeghers syndrome are:^[4][5][6]

• Colon cancer
• Cachexia
• Anemia
• Intussusception
• Gastrointestinal tract adenocarcinoma, although the polyps themselves are not premalignant

• Extra-intestinal malignancies:

• Adenoma malignum (adenocarcinoma subtype of cervix)
• Breast cancer
• Pancreatic cancer
• Ovaries: sex cord tumors
• Testis: Sertoli cell tumors
• Lung cancer
• Uterine cancer
• Paraganglioma

• Prognosis is generally good with treatment.^[7]
  
• Almost half of Peutz-Jeghers patients die from cancer between age 50-60 years.
• The cumulative risk of developing a form of cancer associated with Peutz-Jeghers syndrome between ages 15-64 is 93%.

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