Peutz-Jeghers Syndrome

Etiology

PJS is caused by mutations in the STK11 gene, located on chromosome 19, which encodes a serine/threonine kinase that plays a key role in regulating cell growth, polarity, and metabolism. These mutations, typically inherited in an autosomal dominant manner, lead to a loss of function in the STK11 gene. Consequently, affected individuals are more likely to develop hamartomatous polyps and various cancers. The types and severity of cancers associated with PJS vary based on the specific mutation and other genetic or environmental factors. Genetic testing is strongly recommended for individuals who have a family history of PJS or exhibit its characteristic features.[2]

Most PJS cases result from germline mutations in STK11, typically nonsense or frameshift mutations that produce truncated or nonfunctional proteins. These mutations disrupt cellular signaling and impair tumor suppressor activity, promoting polyp formation and increasing cancer risk. Clinical manifestations of PJS vary widely and may be influenced by genetic factors, including mutation type and location. While most cases are inherited from an affected parent, spontaneous (de novo) mutations can also occur. In rare instances, mosaicism may be responsible, with some cells carrying the mutation while others are not.[3]

Epidemiology

PJS is a rare inherited disorder with an estimated incidence ranging from 1 in 8,300 to 1 in 200,000 live births. The condition's prevalence is approximately 1 in 50,000 to 1 in 200,000 people. PJS affects both male and female individuals.[4]

Pathophysiology

Pathological changes in PJS are primarily driven by mutations in STK11, a tumor suppressor gene on chromosome 19p13.3 that encodes a serine/threonine kinase. STK11 regulates essential cellular processes, including cell polarity, metabolism, and apoptosis, through the activation of AMP-activated protein kinase (AMPK) family members. Loss of STK11 function disrupts these processes, leading to abnormal cell proliferation, particularly in the gastrointestinal tract. This loss of function occurs through germline mutations in STK11, followed by somatic mutations in the 2nd STK11 allele within affected cells, resulting in the formation of hamartomatous polyps—the hallmark of PJS.

The hamartomatous polyps in PJS are benign growths caused by disorganized but noncancerous tissue proliferation. Unlike the adenomatous polyps in familial adenomatous polyposis (FAP), these lesions do not follow the adenoma-to-carcinoma sequence. However, these polyps contribute to significant gastrointestinal morbidity, including bleeding, obstruction, and intussusception. Polyp development is thought to result from impaired regulation of cell division, apoptosis, and tissue repair—processes normally controlled by STK11.

Individuals with PJS have an increased risk of developing malignant gastrointestinal tumors, including colorectal, stomach, and pancreatic cancers. Neoplasms in nongastrointestinal sites, such as the breasts, ovaries, and uterus, are also common. The tumor-suppressive role of STK11 is crucial for protecting against these malignancies, and mutations in STK11 increase the likelihood of 2nd-hit mutations in other oncogenes and tumor suppressor genes, including KRAS, TP53, and PTEN. These genetic alterations drive carcinogenesis, though the sequence of events varies between individuals and tumor types.

STK11 mutations are detected in 50% to 80% of families with PJS, with the remainder likely resulting from de novo mutations. Emerging research suggests that immune-regulatory pathways, particularly in T cells, may also contribute to PJS pathogenesis. Animal models have shown that STK11 deletion in T cells leads to gastrointestinal polyp formation, highlighting the complex interplay of cellular dysregulation, tumor suppressor loss, and immune system involvement in PJS.[5]

History and Physical

Clinical Presentation

PJS presents with a wide range of clinical manifestations, and the age at diagnosis often depends on symptom severity and the presence of characteristic features such as mucocutaneous pigmentation and gastrointestinal polyps. Symptoms typically appear in childhood or adolescence, with patients developing skin pigmentation or gastrointestinal problems, such as abdominal pain, nausea, vomiting, and rectal bleeding, due to polyps. Polyps are most commonly found in the small intestine but can occur throughout the gastrointestinal tract, including the stomach and colon.

Gastrointestinal Manifestations

The hallmark of PJS is the presence of hamartomatous polyps, which are typically benign but can cause significant clinical issues, including intestinal obstruction, intussusception, bleeding, and pain. These polyps are often large and numerous, sometimes requiring surgical intervention due to complications, as mentioned. Small bowel polyps, particularly in the jejunum and ileum, are more likely to cause intussusception severe enough to warrant emergency surgery.

Patients with PJS often have a history of abdominal discomfort, bloody stools, and anemia due to intermittent or less overt gastrointestinal bleeding. Polyps in the small intestine can be difficult to detect on routine imaging, complicating diagnosis without appropriate surveillance. Upper gastrointestinal symptoms, such as vomiting or recurrent abdominal pain, may indicate gastric polyps or obstructive lesions.

Extracolonic Manifestations

Mucocutaneous pigmentation is one of the most characteristic features of PJS, present in nearly all affected individuals. These pigmented macules, typically blue to dark brown, appear around the lips, oral and buccal mucosa, palms, and soles. The pigmentation often emerges in infancy or early childhood and may fade with age.

PJS is also significantly associated with various cancers, including those of the gastrointestinal tract, pancreas, breast, ovaries, and genitals. Breast cancer, particularly in women, and pancreatic cancer pose major concerns, with affected individuals facing a significantly higher lifetime risk than the general population. Ovarian and uterine cancers may present with abnormal menstrual cycles or pelvic pain.

Evaluation

Clinical Criteria

A clinical diagnosis of PJS can be made based on the following criteria:

• Presence of 2 or more Peutz-Jeghers-type hamartomatous polyps in the gastrointestinal tract
• Characteristic mucocutaneous hyperpigmentation (eg, on the mouth, lips, nose, eyes, genitalia, or fingers) in a person with a family history of PJS
• The presence of any number of Peutz-Jeghers polyps in an individual with a 1st-degree relative affected by PJS
• The presence of any number of Peutz-Jeghers polyps in a person with the characteristic mucocutaneous pigmentation associated with PJS [6]

Meeting any of these criteria supports a clinical diagnosis of PJS, informing further genetic evaluation and surveillance. Genetic testing for STK11 mutations can further confirm the diagnosis and guide family counseling.

Genetic Testing and Diagnosis

Identifying mutations in STK11 confirms the diagnosis of PJS. Genetic testing is the most reliable diagnostic method and is recommended for individuals with characteristic features, such as mucocutaneous pigmentation and multiple gastrointestinal polyps. Testing is also essential when an individual has a family history of PJS, or clinical findings suggest the syndrome, even in the absence of a known family history.

However, not all mutations associated with PJS have been identified. The diagnosis should not be ruled out if genetic testing does not detect a pathogenic STK11 mutation in an individual who meets the clinical criteria for PJS and has no known family history. In such cases, affected individuals and at-risk family members should still undergo routine endoscopic surveillance for gastrointestinal polyps and regular screening for extraintestinal cancers.[7]

Imaging and Surveillance

Once the diagnosis is confirmed, regular surveillance and imaging are essential due to the increased malignancy risk. Upper gastrointestinal endoscopy, video capsule endoscopy, and colonoscopy are recommended between ages 8 and 10 to screen for gastric, duodenal, and small bowel polyps. If polyps are detected on baseline screening, endoscopic evaluation should be repeated every 2 to 3 years. If polyps are absent, screening should resume every 2 to 3 years beginning at age 18.

Magnetic resonance imaging (MRI) or computed tomography (CT) scans may be used for abdominal imaging, particularly to monitor desmoid tumors or other solid organ tumors. Small bowel polyps are often best evaluated with video capsule endoscopy or double-balloon enteroscopy.[8]

Treatment / Management

Gastrointestinal Disease Management

Polyposis is the most prominent clinical issue for individuals with PJS. Treating gastrointestinal polyps generally focuses on symptom management and preventing complications, such as obstruction, bleeding, and intussusception. Polypectomy is the most common approach when polyps cause symptoms, particularly obstruction or bleeding. Endoscopic polypectomy is often preferred for accessible lesions, though more extensive surgical resection may be required for larger, symptomatic, or difficult-to-remove polyps.

Intussusception is a significant concern in individuals with PJS, particularly in childhood. If this condition occurs, surgical intervention may be necessary to reduce the bowel or remove the obstructing polyps. Surgical resection may also be considered if polyps cause repeated episodes of intussusception or other complications.[9] Preventive management involves close monitoring with regular endoscopic evaluations to assess for the emergence of new polyps, high-grade dysplasia, or malignancies.

Extracolonic Disease Surveillance

Cancer surveillance is essential due to the significantly elevated risk of breast, pancreatic, and gastrointestinal cancers in individuals with PJS. Regular screenings, with the use of imaging tests like mammography, MRI, and endoscopic ultrasound, help detect early signs of cancer. For pancreatic neoplasms, endoscopic ultrasound is considered the most effective early detection method, though recommendations for routine screening remain under discussion.

Desmoid tumors, though benign, can become locally invasive and are a hallmark feature of PJS. Surgical removal may be necessary for large or symptomatic desmoid tumors. However, medical management with tyrosine kinase inhibitors or hormonal therapies, such as tamoxifen, may help control tumor growth, particularly in the abdominal or mesenteric regions. Since surgical trauma can accelerate desmoid tumor growth, surgical intervention should be delayed when possible.

Breast cancer screening should begin early, typically by age 30, even earlier if the family has a significant history of breast cancer. Screening includes a clinical breast examination every 6 months, along with annual mammography and MRI.[10] Pancreatic cancer screening is not routinely recommended, but high-risk individuals may benefit from having imaging studies, such as MRI and endoscopic ultrasound, regularly performed starting at age 35.[11]

Ovarian and uterine cancer screening includes pelvic examinations, ultrasounds, and CA-125 blood tests starting in early adulthood. Testicular cancer screening involves an annual testicular examination beginning at age 10.[12](B3)

Surgical Management

Surgical resection may be necessary for patients with multiple complications from polyps or desmoid tumors. The extent of the surgery depends on disease severity and associated complications, which can range from partial small intestine resection to more extensive procedures. Prophylactic colectomy is generally not recommended unless significant polyps or intestinal malignancies develop.

Managing PJS requires an interprofessional approach that integrates regular surveillance for malignancies and polyps, medical management for symptom control, and surgical intervention when necessary. Given the complexity of PJS, early diagnosis and lifelong monitoring are essential to optimize outcomes and mitigate the elevated risk of cancer and other complications.

Differential Diagnosis

PJS may be distinguished from other conditions that also present with gastrointestinal polyps or mucocutaneous pigmentation based on specific skin findings, polyp types, and genetic mutations. For example, Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, both caused by PTEN gene mutations, share clinical features, such as lipomas and pigmented spots on the glans penis. However, Cowden syndrome lacks lip pigmentation, while Bannayan-Riley-Ruvalcaba syndrome is characterized by macrocephaly and developmental delay.

Juvenile polyposis syndrome, associated with mutations in SMAD4, BMPR1A, or ENG, differs from PJS by the absence of pigmented macules and the presence of multiple juvenile polyps without mucocutaneous pigmentation. Laugier-Hunziker syndrome, a sporadic condition, presents with intraoral pigmentation and longitudinal nail changes in adults but lacks gastrointestinal polyps and the STK11 mutation characteristic of PJS.[13]

Accurate differentiation between PJS and related syndromes is crucial, as each condition has unique treatment considerations and long-term prognoses. Understanding these distinctions allows for individualized management and optimized patient outcomes.

Prognosis

PJS is associated with an increased risk of various cancers, particularly gastrointestinal and extraintestinal cancers, but the prognosis can vary widely depending on early detection and management. The lifetime cancer risk ranges from 37% to 93%, with colorectal, pancreatic, and gastric cancers being the leading causes of morbidity and mortality. The average age at cancer diagnosis is approximately 42 years.[14]

Without proper surveillance and intervention, the risk of cancer-related death is significantly higher, especially from gastrointestinal malignancies. However, early cancer screening, close monitoring, and timely management of polyps can reduce cancer progression and substantially improve survival rates.

Duodenal cancer is a leading cause of death in individuals with PJS, especially in those with advanced polyposis. Extraintestinal malignancies, including breast, ovarian, and testicular cancers, also contribute to increased mortality risk and require vigilant screening.

Psychosocial support is crucial, as individuals with PJS often face emotional and psychological challenges due to the early onset of disease, frequent medical interventions, and heightened cancer risk. An interprofessional team, including genetic counselors, oncologists, gastroenterologists, and mental health professionals, is essential for optimizing care and maintaining long-term quality of life. Regular surveillance for both cancer and polyp management remains a cornerstone of improving life expectancy and reducing cancer-related mortality.

Complications

Complications associated with PJS include the following:

• Increased risk of gastrointestinal malignancies, particularly colorectal, pancreatic, gastric, and duodenal cancer
• Duodenal cancer, which is the most common cause of death in individuals with PJS
• Breast cancer, with a risk comparable to BRCA mutation carriers
• Ovarian and testicular cancers, including an increased risk of Sertoli cell tumors in male individuals
• Small bowel obstruction or intussusception due to hamartomatous polyps
• Desmoid tumors, particularly in the abdominal cavity
• Other extra-intestinal cancers, including thyroid and lung cancers
• Gastrointestinal bleeding and, potentially, anemia due to polyp-related complications

A structured approach to monitoring, evaluation, and timely treatment can significantly reduce the risk of complications, enhancing both quality of life and overall survival in patients with PJS.