INTRODUCTION

Peutz-Jeghers Syndrome (PJS) is an autosomal dominant hereditary polyposis syndrome. The main characteristics are hamartomatous polyps, mucocutaneous pigmentations, and increased vulnerability to malignancies.¹ The frequency of PJS is estimated to be 1 in 25.000-300.000 individuals, which makes such syndrome is rare in the general population.²

GENETICS ABNORMALITIES

In more than 90% of PJS cases, the genetic defect involves the Serine/threonine kinase (STK11) (previously known as Liver kinase B1/LKB1) gene locus,³ which is mapped to chromosome 19p13.3.^4,5 STK11 is a tumor suppressor gene that plays a role in the induction of the cell cycle’s growth arrest at G1 phase.⁶ This enables rapid regeneration of the cells without significant risk to develop a malignancy.¹ Therefore a defect in the STK11 gene often promotes the development of polyps and cancers in people with PJS.⁶ Moreover, the mutation is also linked to hypoactivity of p53 tumor suppressor pathways.⁷ The type of mutation the STK11 gene may give different severity of clinical manifestations. Truncating (nonsense) variants are associated with earlier onset of symptoms and cancers, compared to non-truncating (missense) and deletion variants.^1,8,9

Although PJS is fundamentally of hereditary origin, de novo mutations without family history of PJS can occur in about 25% cases.^4,10 Two case reports of two patients with PJS by Zhao et al uncover a new truncating mutation in the STK11 gene locus, resulting in a premature codon termination not previously reported in their respective family.^11,12 Similar to the two Zhao et al reports, a case report by Gao et al also described a new missense mutation in a Chinese patient with PJS, of which was not found in the patient’s family members.¹³

A recent retrospective study involving 15 patients with PJS in Taiwan has identified a normal STK11 gene in 4 patients; another 1 patient had a mutation in mTOR gene locus.¹⁴ It is not known whether the mTOR defect was an up- or downregulation-yielding in the study. It is described that a mutation in STK11 apparently disables mTOR gene locus inhibition, resulting in its activation and causes an increase in a cell’s size and mass, a phenotype that frequently occurs in a polyp pathogenesis.^15,16 Hence it is suspected that the mTOR defect in the study’s patient was an upregulation type.

CLINICAL MANIFESTATIONS AND HISTOLOGY

Mucocutaneous pigmentations are the main sign of PJS in 95% of cases.² The lesions are generally black- or brownish macules, round or oval in shape (about 1-5 mm in diameter), and mostly found on the buccal mucosa and lips (Figure 1).¹⁷ Other locations of the pigmented lesions can be observed around the mouth, eyes, nostrils, and perianal area, as well as fingers and toes (Figure 2).^2,18 These spots usually appear during infancy or early childhood, with inclination to increase in size during adolescence.¹⁷ The spots may fade away as the child grows however, but the spots in the buccal mucosa tend to persist.¹⁸

Figure 1. Macules on buccal mucosa and lips of a child with Peutz-Jeghers Syndrome.

Figure 2. Black-brownish spots on the fingers and toes.

The main clinical manifestations of Peutz-Jeghers Syndrome are the hamartomatous polyps. The majority of cases have polyps in the gastrointestinal tract, especially in the jejunum of the small intestine (Figure 3, box A), but polyps can be found in the large intestine and in the stomach. In rare cases, the polyps can be identified outside the gastrointestinal tract (extraintestinal) such as in the gallbladder and its tracts, bronchi, urinary bladder, and ureter.¹⁹

Histologically, the polyps in the small intestine are typically sessile, pedunculated or lobulated, with arborizing pattern, composed of nondysplastic epithelial cells and bundles of smooth muscle tissues originating from the muscularis mucosa layer (Figure 3, box B).²⁰ In some PJS cases, dilated mucinous cysts²¹ and dysplastic epithelial cells²² can be recognized in the polyps on examination. The lamina propria layer is usually normal without signs of inflammation.²² However, it can be identified otherwise.²¹ People with PJS have an increased risk of adenomas in their digestive tract.²²

In a minority of PJS polyps (around 10% of cases), a pseudoinvasion phenomenon, which exclusively develops in the small bowel, may be seen on histology examination (Figure 3, box C).²⁰ This must be thoroughly inspected due to a resemblance with a more invasive adenocarcinoma. A polyp with a pseudoinvasion trait has the following microscopic features: lack of atypical glands, normal composition of the epithelial cell types, hemosiderin deposition, and presence of mucinous cysts.²⁰

When presented in the large bowel, hamartomatous polyp may appear similar to a polyp from a mucosal prolapse (Figure 3, box F).²² On the other hand, the PJS polyp in the stomach is often indistinguishable from the juvenile polyps or other types of hamartomatous hyperplastic polyps (Figure 3, box D and E).²² In this case, the other characteristics are important to differentiate between the two, i.e. patient’s age, number of polyps and their locations. The clinical contexts also play a role in the discrimination, in that the other traits associated with the PJS (mucocutaneous pigmentations, history of surgery due to polyp complications, personal and/or family history of PJS and PJS-related malignancies) should assist in the diagnosis of PJS. The lobular organization of the colonic crypts and desmin-positive smooth muscle fibers around the lobules aid in PJS diagnosis when the polyps are found in the large intestine.²² Table 1 compares histological traits between PJS and juvenile polyps identified in the small intestine, colon, and stomach.

DIAGNOSTIC CRITERIA

The diagnosis of PJS can be established when at least one of the following four criteria is satisfied in the patient: ^1,3,6

1.     Discovery of three or more polyps confirmed histologically to be a PJS-type.

2.     Any number of PJS-type polyp found, with a positive history of PJS in patient’s family.

3.     Characteristic, prominent mucocutaneous pigmentations with a positive family history of PJS.

Characteristic, prominent mucocutaneous pigmentations with any number of PJS-type polyps.

Table 1. Polyp comparisons between Peutz-Jeghers Syndrome and Juvenile Polyposis Syndrome.²²

The histological confirmation of the polyps is essential to ensure that the polyps identified are actually PJS polyps, since there are not any specific macroscopic features of a PJS polyp when visualized endoscopically.²³ Furthermore, patients with PJS may present with both mucocutaneous pigmentations and polyps but can also present with either the polyps or the pigmentations alone.²² Thus the presence of just one out of the four criteria above is sufficient enough to establish a PJS diagnosis. 

            In addition to the conditions above, some of the following signs and symptoms may present in patients with PJS to support the diagnosis:⁶

• Recurrent abdominal pain
• Hematochezia and/or melena
• Feeling of weakness (due to anemia)
• Rectal prolapse
• Precocious puberty
• Irregular menstruation (in females) or gynecomastia (in males)

The menstruation irregularities are induced by the hyperestrogenism status which is generated from the sex cord tumors with annular tubules.⁶ In chronic cases, long-term high estrogen exposure could affect the cervix and lead to malignant cervical adenoma.¹⁸ Meanwhile, the male’s gynecomastia may be due to estrogen production by the Sertoli cell testicular tumors as the result of higher aromatase expression and thus higher rate of testosterone conversion to estradiol.^6,23 The most recent 2019 European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) guideline emphasizes to undertake testicular ultrasound to check the presence of Christmas tree-like pattern appearance in the testes, which is a pathognomonic for this kind of tumor.²³