An N-terminal WT1 mutation (P181S) in an XY patient with ambiguous genitalia, normal testosterone production, absence of kidney disease and associated heart defect: enlarging the phenotypic spectrum of WT1 defects.

OBJECTIVE: This study reports the clinical and molecular data of an XY patient with a very unusual phenotype due to a Wilms' tumor-suppressor (WT1) gene mutation. The genotype-phenotype relationship of different WT1 mutations is then discussed. PATIENT: The patient presented at birth with micropenis, severe hypospadias and cryptorchidism. Normal androgen production and an absence of clinical response to a testosterone treatment trial suggested partial androgen resistance. Eventually, female sex of rearing was chosen. At the beginning of puberty, normal male androgen production occurred, and subsequent gonadectomy did not show gonadal dysgenesis. It is notable that the patient, now 20 years of age, has not developed kidney disease. In addition to the genital malformation, the patient displayed an associated congenital heart defect, consisting of a coarctation of the aorta and a patent ductus arteriosis (PDA). RESULTS: No mutations were detected in the androgen receptor or 5alpha-reductase genes. Direct sequencing of the WT1 gene identified a heterozygous proline to serine substitution at position 181 (P181S). The same heterozygous mutation was found in the mother. Interestingly, the mother shows no signs of kidney disease at her present age of 49. CONCLUSION: This is the first germline missense mutation in the N-terminal part of WT1 identified in a patient with the very particular phenotype of ambiguous genitalia with absence of gonadal dysgenesis and kidney disease. The possible molecular mechanisms leading to the patient's phenotype are considered. The high frequency of PDA in newborns and the absence of heart abnormalities in XX females carrying the P181S mutation, however, suggest that the heart defect was most likely a coincidental association. This case enlarges the clinical spectrum of WT1 defects and may provide new insights into the complex functions of WT1 in genital and kidney development.

Large cell neuroendocrine carcinoma of the lung: pathological study and clinical outcome of 18 resected cases.

Large cell neuroendocrine carcinoma of the lung (LCNEC) has been recently redefined by the World Health Organisation (WHO) classification but the appropriate treatment remains unclear. We reviewed 18 consecutive resected cases of LCNEC. Two pathologists assessed diagnosis by applying rigorously the last WHO criteria. We reported the pathological features and the clinical outcome of this particular tumour. All patients were men with a median age of 63 years. Clinicopathologic stages corresponded to stage I (n = 8), II (n = 8) and IIIA (n = 2). All patients were treated as non-small cell lung carcinoma (NSCLC) and underwent surgery without any adjuvant treatment except four post-operative radiotherapy for N2 or T3 disease. The evolution was pejorative for 14 patients: one patient died of post-operative complications and 13 patients relapsed with distant metastases that occurred in 10 cases within 6 months after surgery. One-year survival rate was 27% and survival rate at the end of follow-up was 22%, which were both less than expected for stage-comparable NSCLC. Survival was neither influenced by lymph node status nor by pathological or molecular findings. Among the 10 evaluable patients with metastatic disease that received palliative platin-etoposide chemotherapy only two had partial tumour regressions (20%). Our study suggests that applying to LCNEC the NSCLC standard treatment lead to poor prognosis even in localised disease with a high incidence of early metastatic spread and a low response rate to chemotherapy. This way of relapse underlies the necessity of an efficient chemotherapy in order to improve survival.

Ovarian germ cell tumors in children. Management, survival and ovarian prognosis. A report of 75 cases.

BACKGROUND/PURPOSE: The aims of this study were to evaluate survival and ovarian prognosis in patients treated for ovarian germ cell tumor (OGCT) and to propose a decision-making protocol. METHODS: Charts of girls operated on for OGCT from 1976 up to 2009 were reviewed retrospectively. Tumor characteristics were assessed by tumor markers, imaging, and pathology. RESULTS: Charts were available in 71 children presenting 75 OGCT. Tumors were benign in 58 cases and malignant in 17 cases. The average of the largest diameter of benign OGCT was significantly lower than that of malignant OGCT (76.5 +/- 49 mm versus 169 +/- 54 mm, P < .0001). Ovarian-sparing tumorectomy was carried out in 27 benign OGCT; 23 (85%) preserved ovaries were follicular. Malignant OGCTs were managed according to the protocols of the French Society for Pediatric Oncology. Bilateral oophorectomy had to be performed in 2 children. One patient presented a recurrence and 1 died. CONCLUSIONS: In our series, both benign and malignant OGCTs have a good prognosis. A 75-mm cutoff size is proposed as an important criterion to preoperatively differentiate between benign and malignant tumors. In benign OGCT, ovarian-sparing tumorectomy leads to preserve ovaries in approximately 85% of cases, and in malignant OGCT, high survival rate has been obtained.

Ovarian torsion. Management and ovarian prognosis: a report of 45 cases.

BACKGROUND/PURPOSE: Ovarian torsion in childhood and adolescence is a rare entity. Traditionally, treatment is oophorectomy. The aim of this study was to evaluate ovarian outcome and to propose a decision-making protocol for suspected ovarian torsion. METHODS: Between January 1986 and December 2007, 45 ovarian torsion cases in 40 girls were operated on. In all the cases, when the ovary was preserved, patients were clinically and ultrasonographically followed up for several months. RESULTS: Median age was 11 years. Median delay between the first symptoms and surgical procedure was 3 days. There was a statistical difference (P = .0003) between the mean of the largest diameter of twisted normal ovary and the mean of the largest diameter of twisted diseased ovary. Underlying pathology was benign in 22 cases and low-grade malignancy in 2 (one grade II immature teratoma and one steroid cell tumor). Conservative management was performed in 26 cases. At follow-up, 17 ovaries were follicular, 7 being black-bluish during surgery. CONCLUSIONS: Conservative approach after detorsion of black-bluish ovaries is safe and effective in children. Although very unlikely, the fear of missing malignancy must incite to proceed with caution and can lead, when the size of the twisted ovary is greater than 75 mm, to prefer laparotomy to laparoscopy.