Sertoli cell tumor and gonadoblastoma in an untreated 29-year-old 46,XY phenotypic male with Frasier syndrome carrying a WT1 IVS9+4C>T mutation

Abstract

ObjEcTIvE: Frasier syndrome (FS) phenotype in 46,XY patients usually consists of female external genitalia, gonadal dysgenesis, high risk of gonadoblastoma and the development of end stage renal failure usually in the second decade of life. FS is caused by heterozygous de novo intronic splice site mutations of the Wilms' tumor suppressor gene 1 (WT1), although a few cases with typical exonic WT1 Denys-Drash mutations that resemble an FS phenotype have been described. The aim of this study was to present further data on the spectrum of FS phenotypes through the evaluation of a 29-year-old patient with a predominantly male phenotype and coexistence of Sertoli cell tumor and gonadoblastoma. rESulTS: Genetic analysis using standard methods for DNA sequencing confirmed FS due to a WT1 gene mutation, IvS9+4c>T. cONcluSIONS: This very rare case illustrates the natural course of FS over many years due to the neglect by the patient to address his need for follow-up, while adding further data on the spectrum of FS phenotypes associated with IvS9+4 c>T mutations. The coexistence of the rare Sertoli cell tumor and gonadoblastoma emphasizes that early clinical recognition and molecular identification facilitates appropriate patient management, especially with respect to the high risk of gonadal malignancy.

Long‐term outcomes and molecular analysis of a large cohort of patients with 46,XY disorder of sex development due to partial gonadal dysgenesis

“…Instead, our patient had a predominantly male phenotype, with normal penile length and perineal hypospadias resembling the Denys‐Drash phenotype. Even though there are five other cases of Frasier syndrome with a male phenotype, including one with a normal male phenotype, there are no reports of patients with spontaneous puberty.…”

Gonadal Tumor in Frasier Syndrome: A Review and Classification

“…Among the 46,XY Frasier syndrome cases, 32 (67%) had gonadal tumor, suggesting that the risk of gonadal tumor is higher than that reported in previous studies [60%; (ref. Eight cases of type 2 Frasier syndrome have been reported (8,12,(23)(24)(25)(26)(27)(28)(29). Although 5 of the cases initially visited clinics due to hypospadia or aplasia of testis (mean age at first visit: 1.0 AE 2.2 years), in most cases, these features did not lead to the diagnosis of Frasier syndrome.…”

Systematic Review of Genotype-Phenotype Correlations in Frasier Syndrome

“…Genetic and clinical data were obtained from a total of 126 cases: 115 cases described in previous reports 6 , 11 , 12 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 and 11 cases diagnosed at our institution ( Table 2 ). There were no significant differences in the proportions of patients with female external genitalia and XY chromosomes between the 2 major variants: c.1432+4 C>T (44/49, 90%) and c.1432+5 G>A (30/35, 86%) ( Table 2 , P = 0.57, χ 2 test).…”

“…The results showed that 85% of patients who were XY female and none with XX chromosomes developed a gonadal tumor. Interestingly, 40% (2 in 5) of patients who were XY male developed a gonadal tumor, both of whom had been diagnosed with bilateral cryptorchidism 36,45 .…”