Peutz–Jeghers syndrome

Peutz–Jeghers syndrome (often abbreviated PJS) is an autosomal dominant genetic disorder characterized by the development of benign hamartomatous polyps in the gastrointestinal tract and hyperpigmented macules on the lips and oral mucosa (melanosis).[2] This syndrome can be classed as one of various hereditary intestinal polyposis syndromes[3] and one of various hamartomatous polyposis syndromes.[4] It has an incidence of approximately 1 in 25,000 to 300,000 births.[5]

Peutz-Jeghers syndrome
Manifestations of Peutz-Jeghers syndrome.[1]
SpecialtyMedical genetics 

Signs and symptoms

The risks associated with this syndrome include a substantial risk of cancer, especially of the breast and gastrointestinal tracts.[6][7] Colorectal is the most common malignancy, with a lifetime risk of 39 percent, followed by breast cancer in females with a lifetime risk of 32 to 54 percent.[8]

Patients with the syndrome also have an increased risk of developing carcinomas of the liver, lungs, breast, ovaries, uterus, testes, and other organs. Specifically, it is associated with an increased risk of sex-cord stromal tumor with annular tubules in the ovaries.[9]

Due to the increased risk of malignancies, direct surveillance is recommended.[7][8]

Micrograph of Peutz-Jeghers type colonic polyp. H&E stain.

The average age of first diagnosis is 23. The first presentation is often bowel obstruction or intussuseption from the hamartomatous gastrointestinal polyps.[8] Dark blue, brown, and black pigmented mucocutaneous macules, are present in over 95 percent of individuals with Peutz-Jeghers syndrome.[8] Pigmented lesions are rarely present at birth, but often appear before 5 years of age. The macules may fade during puberty. The melanocytic macules are not associated with malignant transformation.[8]

Complications associated with Peutz-Jeghers syndrome include obstruction and intussusception, which occur in up to 69 percent of patients, typically first between the ages of 6 and 18, though surveillance for them is controversial.[7][8] Anemia is also common due to gastrointestinal bleeding from the polyps.[8]

Genetics

In 1998, a gene was found to be associated with the mutation. On chromosome 19, the gene known as STK11 (LKB1)[10] is a possible tumor suppressor gene. It is inherited in an autosomal dominant pattern, which means that anyone who has PJS has a 50% chance of passing the disease on to their offspring.

Peutz–Jeghers syndrome is rare and studies typically include only a small number of patients. Even in those few studies that do contain a large number of patients, the quality of the evidence is limited due to pooling patients from many centers, selection bias (only patients with health problems coming from treatment are included), and historical bias (the patients reported are from a time before advances in the diagnosis of treatment of Peutz–Jeghers syndrome were made). Probably due to this limited evidence base, cancer risk estimates for Peutz–Jeghers syndrome vary from study to study.[11] There is an estimated 18–21% risk of ovarian cancer, 9% risk of endometrial cancer, and 10% risk of cervical cancer, specifically adenoma malignum.[9]

Diagnosis
Drawing from 1896 publication of twins thought to have Peutz-Jeghers Syndrome

The main criteria for clinical diagnosis are:

  • Family history
  • Mucocutaneous lesions causing patches of hyperpigmentation in the mouth and on the hands and feet. The oral pigmentations are the first on the body to appear, and thus play an important part in early diagnosis. Intraorally, they are most frequently seen on the gingiva, hard palate and inside of the cheek. The mucosa of the lower lip is almost invariably involved as well.
  • Hamartomatous polyps in the gastrointestinal tract. These are benign polyps with an extraordinarily low potential for malignancy.

Having 2 of the 3 listed clinical criteria indicates a positive diagnosis. The oral findings are consistent with other conditions, such as Addison's disease and McCune–Albright syndrome, and these should be included in the differential diagnosis. 90–100% of patients with a clinical diagnosis of PJS have a mutation in the STK11/LKB1 gene. Molecular genetic testing for this mutation is available clinically.[12]

Management

Resection of the polyps is required only if serious bleeding or intussusception occurs. Enterotomy is performed for removing large, single nodules. Short lengths of heavily involved intestinal segments can be resected. Colonoscopy can be used to snare the polyps if they are within reach.

Prognosis
Most people with Peutz-Jeghers syndrome will have developed some form of neoplastic disease by age 60

Most patients will develop flat, brownish spots (melanotic macules) on the skin, especially on the lips and oral mucosa, during the first year of life, and a patient's first bowel obstruction due to intussusception usually occurs between the ages of six and 18 years. The cumulative lifetime cancer risk begins to rise in middle age. Cumulative risks by age 70 for all cancers, gastrointestinal (GI) cancers, and pancreatic cancer are 85%, 57%, and 11%, respectively.[13]

A 2011 Dutch study followed 133 patients for 14 years. The cumulative risk for cancer was 40% and 76% at ages 40 and 70, respectively. 42 (32%) of the patients died during the study, of which 28 (67%) were cancer related. They died at a median age of 45. Mortality was increased compared with the general population.[14]

A family with sinonasal polyposis were followed up for 28 years. Two cases of sinonasal type adenocarcinoma developed. This is a rare cancer. This report suggested that follow up of sinus polyps in this syndrome may be indicated.[15]

Monitoring
Barium enema radiograph showing multiple polyps (mostly pedunculated) and at least one large mass at the hepatic flexure coated with contrast in a patient with Peutz–Jeghers syndrome.

Some suggestions for surveillance for cancer include the following:

Follow-up care should be supervised by a physician familiar with Peutz–Jeghers syndrome. Genetic consultation and counseling as well as urological and gynecological consultations are often needed.

Eponym

First described in a published case report in 1921 by Jan Peutz (1886–1957), a Dutch Internist, it was later formalized into the syndrome by American physicians at Boston City Hospital, Harold Joseph Jeghers (1904–1990) and Kermit Harry Katz (1914–2003), and Victor Almon McKusick (1921–2008) in 1949 and published in the New England Journal of Medicine.[16]

See also

References
  1. Klimkowski S, Ibrahim M, Ibarra Rovira JJ, Elshikh M, Javadi S, Klekers AR; et al. (2021). "Peutz-Jeghers Syndrome and the Role of Imaging: Pathophysiology, Diagnosis, and Associated Cancers". Cancers (Basel). 13 (20). doi:10.3390/cancers13205121. PMC 8533703. PMID 34680270.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. p. 857. ISBN 0-7216-2921-0.
  3. Dean, PA (1996), "Hereditary intestinal polyposis syndromes", Rev Gastroenterol Mex, 61 (2): 100–111, PMID 8927912.
  4. Jelsig, AM; et al. (2014), "Hamartomatous polyposis syndromes: a review", Orphanet J Rare Dis, 9 (1): 101–111, doi:10.1186/1750-1172-9-101, PMC 4112971, PMID 25022750.
  5. Bouquot, Jerry E.; Neville, Brad W.; Damm, Douglas D.; Allen, Carl P. (2008). Oral and Maxillofacial Pathology. Philadelphia: Saunders. p. 16.11. ISBN 978-1-4160-3435-3.
  6. Boardman, Lisa A.; Thibodeau, Stephen N.; Schaid, Daniel J.; Lindor, Noralane M.; McDonnell, Shannon K.; Burgart, Lawrence J.; Ahlquist, David A.; Podratz, Karl C.; Pittelkow, Mark; Hartmann, Lynn C. (1998). "Increased Risk for Cancer in Patients with the Peutz-Jeghers Syndrome". Annals of Internal Medicine. 128 (11): 896–9. doi:10.7326/0003-4819-128-11-199806010-00004. PMID 9634427. S2CID 11373591.
  7. Beggs, A. D.; Latchford, A. R.; Vasen, H. F. A.; Moslein, G.; Alonso, A.; Aretz, S.; Bertario, L.; Blanco, I.; Bülow, S.; Burn, J.; Capella, G. (2010-07-01). "Peutz–Jeghers syndrome: a systematic review and recommendations for management". Gut. 59 (7): 975–986. doi:10.1136/gut.2009.198499. hdl:2445/18638. ISSN 0017-5749. PMID 20581245. S2CID 34417579.
  8. Wu, Marlyn; Krishnamurthy, Karthik (2021), "Peutz-Jeghers Syndrome", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 30570978, retrieved 2021-09-14
  9. Ring, Kari L.; Garcia, Christine; Thomas, Martha H.; Modesitt, Susan C. (November 2017). "Current and future role of genetic screening in gynecologic malignancies". American Journal of Obstetrics and Gynecology. 217 (5): 512–521. doi:10.1016/j.ajog.2017.04.011. ISSN 1097-6868. PMID 28411145. S2CID 29024566.
  10. Universal protein resource accession number Q15831 for "Serine/threonine-protein kinase STK11" at UniProt.
  11. Riegert-Johnson, Douglas; Gleeson, Ferga C.; Westra, Wytske; Hefferon, Timothy; Song, Louis M. Wong Kee; Spurck, Lauren; Boardman, Lisa A. (August 9, 2008). "Peutz-Jeghers Syndrome". In Riegert-Johnson, Douglas L; Boardman, Lisa A; Hefferon, Timothy; Roberts, Maegan (eds.). Cancer Syndromes. National Center for Biotechnology Information (US). PMID 21249755.
  12. McGarrity, Thomas J; Amos, Christopher I; Frazier, Marsha L; Wei, Chongjuan (July 25, 2013). "Peutz-Jeghers Syndrome". In Pagon, Roberta A; Adam, Margaret P; Bird, Thomas D; Dolan, Cynthia R; Fong, Chin-To; Smith, Richard JH; Stephens, Karen (eds.). GeneReviews. Seattle: University of Washington. PMID 20301443.
  13. Riegert-Johnson D, Gleeson FC, Westra W, et al. Peutz-Jeghers Syndrome. 2008 Jul 18 [Updated 2008 Aug 9]. In: Riegert-Johnson DL, Boardman LA, Hefferon T, et al., editors. Cancer Syndromes [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2009–. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1826/
  14. van Lier, Margot G. F.; Westerman, Anne Marie; Wagner, Anja; Looman, Caspar W. N.; Wilson, J. H. Paul; de Rooij, Felix W. M.; Lemmens, Valery E. P. P.; Kuipers, Ernst J.; Mathus-Vliegen, Elisabeth M. H. (2011-02-01). "High cancer risk and increased mortality in patients with Peutz-Jeghers syndrome". Gut. 60 (2): 141–147. doi:10.1136/gut.2010.223750. ISSN 1468-3288. PMID 21205875. S2CID 11627842.
  15. Chiang JM, Chen TC (2017) A Peutz-Jeghers syndrome family associated with sinonasal adenocarcinoma: 28 years follow up report. Fam Cancer doi: 10.1007/s10689-017-9983-z.
  16. Familial Cancer 2002; 1:181–185)
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