Genetic Screening and Analysis of LKB1 Gene in Chinese Patients with Peutz-Jeghers Syndrome.

BACKGROUND Peutz-Jeghers syndrome (PJS) is an autosomal dominant genetic disease. It severely decreases patient quality of life and leads elevated cancer risk. Germline mutation of LKB1 is the leading cause of familial PJS. MATERIAL AND METHODS To characterize the germline mutation of LKB1 gene in Chinese familial and sporadic PJS patients, 14 PJS families, 5 sporadic PJS patients, and 250 healthy adults were collected and genomic DNAs of peripheral blood were extracted. Mutation screenings of LKB1 were performed using MLPA (multiplex ligation-dependent probe amplification), PCR, direct sequencing, and PCR-DHPLC (denaturing high-performance liquid chromatography). RESULTS A total of 12 kinds of germline mutations were found in 9 familial PJS patients, most of which were point mutations (7/12); 4 large deletions of LKB1 were also observed. Of the 12 mutations, 7 were pathogenic (2 were de novo), 4 were just polymorphisms, and 1 was indefinitely pathogenic. No pathogenic mutation in exons of the LKB1 gene was detected in the 5 sporadic PJS patients. The mutation detection rate for the LKB1 gene was 85.7% in our Chinese familial PJS and 63.2% in all Chinese PJS patients. Eight familial PJS patients were identified with pathogenic germline mutations in 14 unrelated families (57.1%). Further methylation detection and analysis showed promoter methylation in carcinomatous polyps. CONCLUSIONS LKB1 gene germline mutation with pathogenic effect is a common cause of familial PJS in Chinese patients; however, it is not the only molecular pathogen of PJS. Methylation in the LKB1 gene promoter region may cause carcinomatous change in intestinal polyps.

Management of prepubertal gynecomastia in two monozygotic twins with Peutz-Jeghers syndrome: from aromatase inhibitors to subcutaneous mastectomy.

BACKGROUND: Prepubertal gynecomastia is characterized by the presence of palpable uni- or bilateral breast tissue in boys without other signs of sexual maturation. It may be the endocrine expression of rare syndromes such as Peutz-Jeghers syndrome (PJS). This study aimed to evaluate the effectiveness of anastrozole and to describe an innovative surgical approach. METHODS: This report presents twins with PJS, bilateral prepubertal gynecomastia, and testicular multifocal calcifications. Both twins were treated with anastrozole for 2 years. After finishing treatment, both were followed before subcutaneous mastectomy was performed by the "modified" Webster technique. RESULTS: Growth velocity decreased and gynecomastia diminished during anastrozole treatment. After discontinuation of therapy due to a sharp reduction in growth velocity, both twins showed regrowth of gynecomastia, with painful and strained breasts. A significant reduction in breast volume with glandular removal was achieved. CONCLUSIONS: The findings of this study showed a multidisciplinary approach to prepubertal gynecomastia due to the synergy of pediatricians, radiologists, and plastic surgeons. The follow-up evaluation after the anastrozole treatment showed it to be an efficacious medical treatment, as an alternative to orchidectomy, to control the effects of circulating estrogens. Moreover, the results observed in the patients confirmed the validity and feasibility of the "modified" Webster technique in terms of aesthetic and functional results, patient satisfaction, and absence of complications.

A novel mutation in STK11 gene is associated with Peutz-Jeghers Syndrome in Indian patients.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare multi-organ cancer syndrome and understanding its genetic basis may help comprehend the molecular mechanism of familial cancer. A number of germ line mutations in the STK11 gene, encoding a serine threonine kinase have been reported in these patients. However, STK11 mutations do not explain all PJS cases. An earlier study reported absence of STK11 mutations in two Indian families and suggested another potential locus on 19q13.4 in one of them. METHODS: We sequenced the promoter and the coding region including the splice-site junctions of the STK11 gene in 16 affected members from ten well-characterized Indian PJS families with a positive family history. RESULTS: We did not observe any of the reported mutations in the STK11 gene in the index patients from these families. We identified a novel pathogenic mutation (c.790_793 delTTTG) in the STK11 gene in one index patient (10%) and three members of his family. The mutation resulted in a frame-shift leading to premature termination of the STK11 protein at 286th codon, disruption of kinase domain and complete loss of C-terminal regulatory domain. Based on these results, we could offer predictive genetic testing, prenatal diagnosis and genetic counselling to other members of the family. CONCLUSION: Ours is the first study reporting the presence of STK11 mutation in Indian PJS patients. It also suggests that reported mutations in the STK11 gene are not responsible for the disease and novel mutations also do not account for many Indian PJS patients. Large-scale genomic deletions in the STK11 gene or another locus may be associated with the PJS phenotype in India and are worth future investigation.

Peutz-Jeghers syndrome: report of 6 cases in a family and management of polyps with intraoperative endoscopy.

BACKGROUND/AIMS: Peutz-Jeghers syndrome is an uncommon, autosomal dominantly inherited disorder characterized by mucocutaneous melanin pigmentation and gastrointestinal hamartomatous polyps. The purpose of this study was to present six cases of Peutz-Jeghers syndrome in a family. METHODS: Enteroclysis, upper and lower gastrointestinal endoscopy, and thyroid, abdominal, and testicular or breast ultrasonography were performed in all subjects. Tumor markers including CEA, alpha-FP, CA 19-9, CA 15-3, and CA 125 were measured. Management of polyps and complications were evaluated. RESULTS: History of the patients were as follows: patient 1 (40-year-old male) underwent surgery 20 years previously; patients 2 and 3 (19-year-old female and 17-year-old male) had undergone surgery three times between the ages of 11 and 18 years, and two times between the ages of 15 and 17 years, respectively; patient 4 (16-year-old male) had undergone surgery three times at the age of 13 years; patients 5 and 6 (14-year-old and 11-year-old males) had no history of surgery. All surgical procedures had been performed due to intestinal obstruction. Hyperpigmentation of the lips and oral mucosa were observed in all patients except patient 1, whose pigmentation disappeared 20 years previously. Patient 2 also had pigmentation of hands and feet. Enteroclysis showed small bowel polyps in all subjects except patients 1 and 6. During colonoscopy, different sizes of polyps were observed at different locations of the colon, and polyps larger than 1 cm were removed. Patients 2 and 3 underwent surgery due to complication of small bowel polyps; 69 polyps in patient 2 and 17 polyps in patient 3 were removed via intraoperative endoscopic procedure. Hamartomatous lesions were confirmed by histopathological examinations. Microscopic study of polyps of patients 2 and 3 revealed dysplastic changes. None of the patients had evidence of malignancy as of June 2003. Peutz-Jeghers syndrome demonstrated autosomal dominant inheritance in this family. CONCLUSIONS: The major problem during follow-up of patients with Peutz-Jeghers syndrome is the management of small bowel polyps. When encountered during surgery, intraoperative enteroscopic polypectomy should be performed.

Serum inhibin B concentration in a prepubertal boy with gynecomastia and Peutz-Jeghers syndrome.

Gynecomastia in boys with Peutz-Jeghers syndrome and Sertoli cell tumors of gonadal origin results from increased estrogen production due to increased aromatase activity within the testicular tumor. We present a prepubertal boy with Peutz-Jeghers syndrome, gynecomastia and bilateral neoplastic Sertoli cell proliferation in whom the only abnormal hormonal profile was increased concentration of inhibin B and Pro-alpha C in serum.

Peutz-Jeghers syndrome with feminizing sertoli cell tumor.

A case involving a 6-year-old boy with Peutz-Jeghers syndrome and an unilateral feminizing Sertoli cell tumor is described. Endocrinologic studies revealed consistently high plasma and urine levels of estrogens and normal levels of testosterone and dihydrotestosterone. The increased levels of estrogens did not show changes that could be correlated with exogenous gonadotropin administration, thus indicating an autonomous nature. The histopathologic studies of nontumorous testicular tissue revealed changes in the seminiferous tubules which suggested that estrogens, directly or indirectly, may have had both stimulating and atrophying effects. It is concluded that gonadal tumors are in additional manifestation of the Peutz-Jeghers syndrome gene in both male and female patients.