Gonadoblastoma associated with pure gonadal dysgenesis in monozygous twins

doi:10.1016/S0022-3476(64)80622-3

The Journal of Pediatrics

Volume 64, Issue 5, May 1964, Pages 740-745

https://doi.org/10.1016/S0022-3476(64)80622-3 Get rights and content

Monozygous twins with pure gonadal dysgenesis and associated gonadoblastoma are presented. There were no signs of Turner's syndrome and chromosome analysis revealed a 44A-XY karyotype. The literature regarding gonadoblastoma is reviewed. The association between gonadal tumors and abnormalities of gonadal differentiation is emphasized.

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50 Years Ago in THE JOURNAL OF PEDIATRICS: Fifty Years from Syndrome to Gene
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Systematic Review of Genotype-Phenotype Correlations in Frasier Syndrome
2021, Kidney International Reports
Citation Excerpt :
Although statistical analysis could not be conducted because only a single sample from each variant was available for analysis, all analyzed variants including the newly detected variant c.1432+3 G>T showed almost the same +/−KTS ratio in RNA sequencing. Genetic and clinical data were obtained from a total of 126 cases: 115 cases described in previous reports6,11,12,17–58 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, χ2 test).
Frasier syndrome (FS) is a rare inherited kidney disease caused by intron 9 splicing variants of WT1. For wild-type WT1, 2 active splice donor sites in intron 9 cause a mixture of 2 essential transcripts (with or without lysine-threonine-serine [+/KTS or −KTS]), and imbalance of the +KTS/−KTS ratio results in the development of FS. To date, 6 causative intron 9 variants have been identified; however, detailed transcript analysis has not yet been conducted and the genotype-phenotype correlation also remains to be elucidated.
We conducted an in vitro minigene splicing assay for 6 reported causative variants and in vivo RNA sequencing to determine the +KTS/−KTS ratio using patients’ samples. We also performed a systematic review of reported FS cases with a description of the renal phenotype.
The in vitro assay revealed that although all mutant alleles produced −KTS transcripts only, the wild-type allele produced both +KTS and −KTS transcripts at a 1:1 ratio. In vivo RNA sequencing showed that patients’ samples with all heterozygous variants produced similar ratios of +KTS to −KTS (1:3.2−1:3.5) and wild-type kidney showed almost a 1:1 ratio (1:0.85). A systematic review of 126 cases clarified that the median age of developing ESKD was 16 years in all FS patients, and there were no statistically significant differences between the genotypes or sex chromosome karyotypes in terms of the renal survival period.
Our study suggested no differences in splicing pattern or renal survival period among reported intron 9 variants causative of FS.
Genotype-Phenotype Correlation in WT1 Exon 8 to 9 Missense Variants
2021, Kidney International Reports
WT1 missense mutation in exon 8 or 9 causes infantile nephrotic syndrome with early progression to end-stage kidney disease (ESKD), Wilms tumor, and 46,XY female. However, some patients with missense mutations in exon 8 or 9 progress to ESKD in their teens or later. Therefore, we conducted a systematic review and functional analysis of WT1 transcriptional activity.
We conducted a systematic review of 174 cases with WT1 exon 8 or 9 missense variants from our cohort (n=13) and previous reports (n=161). Of these cases, mild and severe genotypes were selected for further in vitro functional analysis using luciferase assay.
The median age of developing ESKD was 1.17 years. A comparative study was conducted among three WT1 genotype classes: mutations of the DNA-binding site (DBS group), mutations outside the DNA-binding site but at sites important for zinc finger structure formation by 2 cysteines and 2 histidines (C2H2 group), and mutations leading to other amino acid changes (Others group). The DBS group showed the severest phenotype and the C2H2 group was intermediate, whereas the Others group showed the mildest phenotype (developing ESKD at 0.90, 2.00, and 3.92 years, respectively, with significant differences). In vitro functional analysis showed dominant-negative effects for all variants; in addition, the DBS and C2H2 mutations were associated with significantly lower WT1 transcriptional activity than the other mutations.
Not only the DNA-binding site but also C2H2 zinc finger structure sites are important for maintaining WT1 transcriptional activity, and their mutation causes severe clinical symptoms.
Dysgerminoma in a Prepubertal Girl with Complete 46XY Gonadal Dysgenesis: Case Report and Review of the Literature
2020, Journal of Pediatric and Adolescent Gynecology
Citation Excerpt :
Germ cell tumors are rare in female children and adolescents; therefore, if these are diagnosed, such patients should be further assessed with a karyotype for chromosomal abnormalities. Several studies have documented malignant germ cell tumors, including palpable abdominal or pelvic masses and acute abdominal pain as the presenting symptoms, and on further workup the patients were found to have 46XY karyotypes.12,13,15,16,18 Not unexpectedly, siblings appear to be at high risk for similar genetic abnormalities; therefore, karyotype analysis and ovarian imaging should be performed for prepubertal asymptomatic relatives of patients with Swyer syndrome.12,17
Complete 46XY gonadal dysgenesis (Swyer syndrome) is a rare and challenging diagnosis among prepubertal girls, as estrogen insufficiency becomes evident only during adolescence, with nonspecific symptoms such as primary amenorrhea and/or delayed puberty. Unfortunately, girls with Swyer syndrome are at high risk for malignancies in the dysgenetic gonads, which can be prevented only by performing prophylactic bilateral gonadectomy.
We present a 9-year-old patient with Swyer syndrome diagnosed with dysgerminoma in the right gonad and gonadoblastoma in the left gonad after prophylactic bilateral gonadectomy.
Concerning the high risk of early gonadoblastoma and its malignant transformation, we recommend performing prophylactic bilateral gonadectomy at the time of diagnosis, even if the patient is prepubertal.
Clinical heterogeneity in children with gonadal dysgenesis associated with non-mosaic 46,XY karyotype
2017, Journal of Pediatric Urology
Gonadal dysgenesis is unique in disorders of sex development (DSD), in that it can be associated with 46,XX, 46,XY or mosaic 45,X/46,XY karyotypes. Gonadal dysgenesis can be partial or complete. Gonadal dysgenesis associated with the Y-chromosome has increased risk of gonadal germ cell neoplasms. Most of the literature focus on 45,X/46,XY gonadal dysgenesis, while there are scanty data on the condition when the karyotype is non-mosaic 46,XY.
To investigate the diversity of clinical pictures of children presenting with 46,XY DSD due to gonadal dysgenesis.
A retrospective study on consecutive patients diagnosed with 46,XY gonadal dysgenesis at age ≤18 years in a tertiary center from 1985 to 2015. The clinical presentations, phenotypes, gonadal features and associated anomalies were investigated.
Twenty-eight patients with Y-chromosome gonadal dysgenesis were identified during the study period and six (21.4%) had non-mosaic 46,XY karyotype. Three had complete gonadal dysgenesis (CGD) with normal female phenotype, while the other three had partial gonadal dysgenesis (PGD). Of the three patients with CGD, two presented with the classical Swyer syndrome at adolescence, while the third presented at birth with multiple congenital anomalies. The three PGD patients presented with ambiguous genitalia at birth (n = 2), and isolated hypospadias (n = 1), which was associated with Frasier syndrome. Three patients had germ cell neoplasms: bilateral gonadoblastoma (n = 1), bilateral intratubular germ cell neoplasia unclassified (n = 1), and dysgerminoma + gonadoblastoma (n = 1). Two patients had global developmental delay with other congenital anomalies, and another patient had learning difficulties with borderline intelligence (Table).
The findings suggest that 46,XY gonadal dysgenesis is much rarer than 45,X/46,XY gonadal dysgenesis. Patients differed in their clinical presentations and well-established syndromes happened in half of them. Overall, the risk of germ cell neoplasms and the association with other somatic anomalies appeared to be high. The study was limited by: its small number, single-center experience, and the possibility of missing the diagnosis in some male patients with mild undervirilization.
Heterogeneity was noted in the clinical, phenotypic and gonadal features among pediatric patients with 46,XY gonadal dysgenesis.
Evidence for NR2F2/COUP-TFII involvement in human testis development
2024, bioRxiv

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^**: This work supported in part by United States Public Health Service Training Grant T1AM 5215.

^*: Postdoctoral trainee of the National Institute of Arthritis and Metabolic Diseases.

¹: Address, Department of Pediatrics, Center for the Health Sciences, Los Angeles, Calif. 90024.

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Gonadoblastoma associated with pure gonadal dysgenesis in monozygous twins**

Am. J. Obst. & Gynec.

Exper. Cell Res.

Gonadoblastoma

Cancer

Clinical and pathological survey of ovarian embryonal carcinomas, including so-called “mesonephromas,” (Schiller) and “mesoblastoma” (Telium), treated at the Radium-hemmit

Acta obst. et gynec. scandinav.

Dysgenetic gonadomas and other tumors in intersexes

Cancer

An unusual gonadal tumor (gonadoblastoma) in a male pseudohermaphrodite with testicular dysgenesis

J. Obst. & Gynaec. Brit. Emp.