Early screening the small bowel is key to protect Peutz-Jeghers syndrome patients from surgery: a novel mutation c.243delG in STK11 gene

Peutz-Jeghers Syndrome (PJS, OMIM 175200), an autosomal dominant disorder, is characterized by three major clinical features, which are mucocutaneous pigmentation (MP), gastrointestinal (GI) hamartomatous polyps and an increased risk for GI and extra-GI malignancies [1]. Germline mutations in STK11 gene are believed to be the causative reason of this syndrome, and hundreds of them recognized in PJS patients have been documented (http://​www.​hgmd.​cf.​ac.​uk).

Among recorded PJS cases, more than 30% of them develop polyp-related manifestations by age 10 years and 50% by 20 years [2]. In children with PJS, intussusception due to GI polyps is the most critical symptom, while in adults, the dominant threaten are PJS-associated tumors [3]. van Lier et al. [4] described cumulative intussusception risk in PJS of 15% by age 10 years and 50% by age 20 years. Because of these circumstances, making a set of strategies for screening and surveillance is important to young patients with PJS. Hinds et al. [5] reported the natural history of PJS in the St. Mark’s Hospital Polyposis Registry and showed 68% (23/34) of the adults with PJS had undergone a laparotomy for intestinal obstruction/ intussusception before 18 years old.

Here we displaced a novel mutation in STK11 causing PJS in a 9 year-old boy without a positive family history. The mutation was neither documented nor identified in unrelated control individuals. The fraction of de novo mutations (sporadic cases) is 49.21% (62/126) based on our database, and 63.0% (29/46) in our recent published cohort [9]. Since evolutionary conservation analysis together with structure prediction show the pathological effect of it, we are sure of that this mutation is a causative one.

In 1895, Dr. Connor first reported this syndrome in the literature, and Dr. Bruwer finally named it in 1954 after two investigators who made great contributions to it [10]. The pathogenic gene was finally believed as STK11 and cloned in 1997 [11]. STK11 encodes a 433-amino-acid-residue protein and it acts as a tumor suppressor. STK11 protein comes into play by participating in several pathways. For example, we noticed that impaired P53 activity caused by STK11 mutations in PJS patients is significantly related to cancer risk [12]. Multiplex ligation–dependent probe amplification (MLPA) together with direct sequencing raise the mutation detection rate to over 60% in most instances [13]. Though frameshift and nonsense mutations are most common types, large deletions and missense mutations are also disease-causing. Interestingly, we have found significantly more splice errors in Chinese PJS patients [9]. Among reported STK11 mutations (HGMD), most variants are in the region of catalytic kinase domain (amino acids 49–309) which cause the loss of kinase activity [14]. Through sequence alignment, the mutant protein loses main functional domains, so the novel mutation is probably a pathogenic one and the causative one to this boy, which broadens the spectrum of pathological STK11 gene mutations.

For children without a family history, PJS is often diagnosed when they suffer from intestinal obstruction and comes to the surgical emergency [15]. Under the circumstances, it is hard to implement preventive measures to avoid a open surgery. But when the possibility of PJS is predicted based on family history or typical MPs, a screening test for high risk individuals is necessary. According to the recommendations for management 2010, baseline colonoscopy and upper GI endoscopy should be performed at the age of 8 (Table 2), and extra-intestinal part needed screening for tumors include pancreas, breast, ovary, endometrium, cervix, testis and lung [2]. This is the current and comprehensive recommendations for PJS screening, surveillance and PJS-related cancer prevention. However, we notice the baseline age is worthy of discussion. Goldstein et al. [16] reviewed the charts of 14 children with a diagnosis of PJS at Children’s Hospital Colorado from 2000 to 2011, and 5 children suffered from intussusception events at the median age of 5 years for the first screening test. They suggested revised guidelines should consider initial screening at age 4 to 5 with capsule endoscopy and upper and lower endoscopy. The onset age in this case also supports the suggestion to advance the screening baseline. While it’s not convincing enough to revise the current recommendations merely based on these clues, and more evidences are needed to address this issue clearly. For endoscopic screening in children, it’s hard to keep the balance between advantages and disadvantages. Though we find early screening may reduce PJS complications like bowel obstruction, there are many potential side effects due to technical difficulty and anesthesia risk.

Once GI polyps were detected before they cause severe GI complications, enteroscopy is the effective method to avoid the open surgery [17]. Belsha et al. [18] set and followed up a prospective cohort for 6 years to examine the effectiveness of double-balloon enteroscopy (DBE) polypectomy for children with PJS. After 22 DBEs for 16 pediatric PJS patients, large polyps (>/=1 cm) were confirmed in 14 of them. Successful polypectomy were achieved by DBE or laparoscopically assisted DBE (Lap-DBE) in all patients. Besides only one patient suffered from post-Lap-DBE pelvic abscess, all other patients remained. Intervention free during follow-up (median 26 months). By analyzing the data of own 11 years’ experience, we notice DBE is effective for intestinal polyps management, and we have finished 153 DBEs in 53 pediatric patients. And when compared with DBE in adults, the incidence of perforation was higher in children (5/53 vs 4/150, P < 0.05) [19]. We believe with the progress of the equipment and technique, updating information is still needed to bring new recognitions. In the case reported here, ileal polyp was detected only when the symptoms happened again. If DBE were available, this patient might receive GI examination thoroughly when symptoms occurred firstly, and regular follow-up would surely protect him from severe GI complications. In our experience, within 131 PJS patients who had abdominal surgeries for intestinal obstruction before, 113 patients (86.3%) avoid a second open surgery after receiving regular follow-up by DBE [20].