A novel missense mutation of the STK11 gene in a Chinese family with Peutz-Jeghers syndrome

Abstract

Background: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disease caused by mutations in the Serine-Threonine Kinase 11 (STK11) gene. This study aimed to diagnose a Chinese pedigree with PJS and to expand the spectrum of STK11 variants.

Methods: We performed an inductive analysis of clinical features, gastrointestinal endoscopy, radiologic imaging, and pathological findings in a Chinese family with PJS. Whole-exome sequencing (WES), Sanger sequencing, and STK11 protein 3D structure prediction were performed for establishing a molecular diagnosis.

Results: The proband, her mother, and grandfather presented with pigmentation spots on lips, oral mucosa, and fingers. Her mother and grandfather also had pigmentation spots on face and feet, while her brother had pigmentation spots only on the lower lip. On endoscopy, polyps were discovered in the proband, her mother, and grandfather. A novel heterozygous mutation (c.521A > C) in exon 4 of STK11 was identified in all four patients, leading to a change from histidine to proline in amino acid 174. The variable site p.H174 was highly conserved in different species on multiple sequence alignment analysis.

Conclusions: We diagnosed a Chinese pedigree with PJS based on clinical features, gastrointestinal endoscopy, and genetic testing results. Our results expanded the spectrum of STK11 variants, which will be helpful for genetic counseling.

Keywords: Gastrointestinal polyps; Mutation; Peutz-Jeghers syndrome; STK11.

Fig. 1

A genogram and clinicopathological features of the subject family with PJS. A Pedigree of the family with PJS. Roman numerals indicate generations and Arabic numbers indicate individuals. Squares = males, and circles = females. Filled and unfilled symbols denote affected and unaffected individuals, respectively. Slash indicates decedent. The proband is indicated by an arrow. B Endoscopic, histopathological, and radiologic imaging signs exhibited by the proband’s grandfather. Upleft, endoscopy showed polyps in the sigmoid colon; upper right, representative hematoxylin–eosin-stained tissue slices of the polyp specimens confirm hamartomatous polyps (left, × 40 magnification; right, × 100 magnification); middle, contrast enhanced CT and MRI, MRCP of lesions in the liver; bottom, well-differentiated adenocarcinoma in the hilar bile duct, nerve invasion, and focal invasion into the liver tissue were consistent with the pathology of cholangiocarcinoma (left, × 40 magnification; right, × 100 magnification). C PJS signs exhibited by the proband’s mother. Up, pigmentation on the lips, face, fingers, and feet; middle, contrast enhanced CT showed that the small intestine and mesentery gathered in a round shape, presenting a ‘target sign’; MPR showed that two moderately uneven and round enhanced masses were seen in the duodenal cavity; bottom, gastrointestinal tract polyps of the sigmoid colon and histopathology (left, × 40 magnification; right, × 100 magnification). D Signs exhibited by the proband and her brother. Upleft, pigmentation on the proband’s lips, oral mucosa, and fingers; upper right, pigmentation on the lower lip of the proband’s brother; bottom left, gastrointestinal endoscopy images showed polyps in the ascending colon; bottom right, histology of the resected polyps in the proband, with features of a juvenile polyp (left, × 40 magnification; right, × 100 magnification)

Fig. 2

Sequencing results and bioinformatic analysis of the gene mutation. A Sanger sequencing results of the variants. A heterozygous mutation c.521 A > C transition, causing the substitution of histidine by proline at codon 174 (NM_000455). B The gene structure of STK11. c. 521 A > C (p.H174P) is located in exon 4 within the kinase domain. C Score of the novel damaging mutation c.521 A > C (p.H174P) in PolyPhen-2. D Evolutionary conservation showed that the variable site p.H174P was highly conserved across different species. E Protein structure prediction of wild-type and mutant STK11 is displayed