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.
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.
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.
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.
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.
Peutz-Jeghers syndrome is based on clinical findings of having at least 2 of the 3 listed clinical criteria for a positive diagnosis:
Mucocutaneous findings are non-specific for Peutz-Jeghers syndrome; other differentials must be considered. Molecular and genetic testing can aid in confirming the diagnosis
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
Magnetic resonance cholangiopancreatography (MRCP) and/or endoscopic ultrasound: Beginning at 25 to 30 years old; Repeat every 1 to 2 years
Breast examination: 6-month clinical breast examination beginning at age 25
Breast mammogram: Beginning at age 25
Papanicolaou smear: Annually
Transvaginal ultrasound: Consider yearly transvaginal ultrasound beginning at age 18
Consider annual examination and yearly ultrasound beginning at age 10.
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.
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.
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.
Peutz-Jeghers syndrome patients are at an increased risk for malignancies. Earlier screening and surveillance is recommended.
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. A consult should take place with a board-certified oncology pharmacist regarding the patient's medication regimen, for both cancer and non-cancer meds, and an oncology specialty nurse can assist in the monitoring, answer patient questions, and report any changes in status to the managing clinician immediately. 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.
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