Individuals with 46,XY complete gonadal dysgenesis (CGD) are at high risk of developing gonadal neoplasms. Chromosome 9p monosomy with deletion of the DMRT1 gene, a key transcription factor in testicular development, is one of the known causes of 46,XY CGD. Noninvasive prenatal testing (NIPT) is being increasingly used, and can identify disorders of sexual development (DSDs).
Case Report EARLY-ONSET GONADOBLASTOMA IN A 13-MONTH-OLD INFANT WITH 46,XY COMPLETE GONADAL DYSGENESIS IDENTIFIED WITH PRENATAL TESTING: A CASE OF CHROMOSOME 9p DELETION Meghan E Fredette, MD1,2; Katelyn Cusmano, MD3; Chanika Phornphutkul, MD2,4; Jennifer Schwab, MS, CGC2,4; Anthony Caldamone, MD, MMSc2,5; Lisa Swartz Topor, MD, MMSc1,2 ABSTRACT Objective: Individuals with 46,XY complete gonadal dysgenesis (CGD) are at high risk of developing gonadal neoplasms Chromosome 9p monosomy with deletion of the DMRT1 gene, a key transcription factor in testicular development, is one of the known causes of 46,XY CGD Noninvasive prenatal testing (NIPT) is being increasingly used, and can identify disorders of sexual development (DSDs) Methods: We report the case of a 46,XY infant with phenotypically female external genitalia, müllerian structures including uterus and fallopian tubes, and bilateral streak gonads who was found to have unilateral gonadoblastoma at 13 months 46,XY DSD was suggested prenatally when discordance between NIPT and fetal ultrasound was noted Results: Genetic investigation revealed a deletion of 12.5 million base pairs at chromosome 9p24.3, which includes the doublesex and MAB-3-related transcription factor-1 (DMRT1) gene Submitted for publication June 17, 2019 Accepted for publication August 8, 2019 From the 1Division of Pediatric Endocrinology, Hasbro Children’s Hospital, Providence, Rhode Island, 2Warren Alpert Medical School of Brown University, Providence, Rhode Island, 3Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, 4Division of Genetics and Metabolism, Hasbro Children’s Hospital, Providence, Rhode Island, and 5Division of Pediatric Urology, Hasbro Children’s Hospital, Providence, Rhode Island Address correspondence to Dr Meghan E Fredette, 111 Plain Street, 3rd Floor, Providence, RI 02903 E-mail: meghan_fredette@brown.edu DOI:10.4158/ACCR-2019-0285 To purchase reprints of this article, please visit: www.aace.com/reprints Copyright © 2019 AACE Conclusion: Current guidelines recommend gonadectomy at the time of diagnosis in cases of 46,XY CGD, and our patient had gonadoblastoma at 13 months 46,XY DSD, including rare disorders such as CGD, will be increasingly identified before birth with more widespread use of NIPT, raising the question about the appropriate timing of gonadectomy in prenatal diagnoses Our case supports the current recommendation to perform gonadectomy as early as possible after diagnosis (AACE Clinical Case Rep 2019;5:e380-e383) Abbreviations: CGD = complete gonadal dysgenesis; DMRT1 = doublesex and MAB-3-related transcription factor-1; DSD = disorder of sexual development; NIPT = noninvasive prenatal testing INTRODUCTION Individuals with 46,XY complete gonadal dysgenesis (CGD) are at increased risk of developing gonadal neoplasms, most commonly gonadoblastoma, as dysgenetic gonads with Y chromosome present are at increased risk of malignancy (1) Chromosome 9p monosomy is a cause of 46,XY CGD due to deletion of region 9p24, which includes the doublesex and MAB-3-related transcription factor-1 (DMRT1) gene, a key transcription factor in testicular development The 9p deletion syndrome was first described in 1973 by Alfi et al (2) with a reported incidence of in 50,000 newborns Patients with 9p deletion syndrome have distinct physical characteristics including trigonocephaly, midface hypoplasia, long philtrum, a thin upper lip, anteverted nares, high palate, short palpebral fissures, low-set ears, and a short neck (3) Additional medical complications include developmental delay, hypotonia, cardiac anomalies, e380 AACE CLINICAL CASE REPORTS Vol No November/December 2019 Copyright © 2019 AACE Copyright © 2019 AACE Gonadoblastoma in 9p Deletion, AACE Clinical Case Rep 2019;5(No 6) e381 epilepsy, inguinal hernias, omphaloceles, choanal atresia, as well as 46,XY disorder of sexual development (DSD) Genital anomalies in patients with chromosome 9p deletions can vary from cryptorchidism and/or hypospadias to CGD The critical region for 46,XY CGD in 9p monosomy localizes between 9p24.3 and 9pter, with DMRT1 identified as the likely causative gene (4) The DMRT1 gene is located at 9p24.3, and is a transcription factor that is important in the sex determination pathway Two functional copies of DMRT1 are needed for testicular development (5) It is well known that patients with 46,XY CGD are at high risk of developing gonadal neoplasms with the incidence ranging from 38 to 45% (6) The most common neoplasm is gonadoblastoma (1,7), and of those with malignancy, dysgerminoma was present in 22 to 66% of cases (6) Gonadoblastoma is considered to be a benign in situ germ cell neoplasm composed of a mixture of germ cells at varying maturational stages, as well as supportive sex cord stromal cells Gonadoblastoma is rarely found in typical males or females, and is usually seen only in dysgenetic gonads containing a Y chromosome It has been speculated that the Y chromosome has a locus that acts as an oncogene, and a region near the centrosome referred to as gonadoblastoma locus on the Y chromosome (GBY) may have significance, with testis-specific protein on the Y chromosome (TSPY) serving as a possible candidate gene (8) Though benign, the natural history of gonadoblastoma results in 50% developing into invasive germ cell tumors such as dysgerminoma (8) We describe a patient with 46,XY CGD due to a 12.5 Mb deletion on 9p24.3p23 involving the DMRT1 gene, as well as a duplication of 13.15 Mb on the 9p23p21.2 region Prophylactic gonadectomy was recommended and performed at age 13 months, and she was found to have unilateral gonadoblastoma with bilateral streak gonads This case is one of the earliest reports of gonadoblastoma in children with 9p24.3 DMRT1 deletion, and affirms the importance of early evaluation and timing of gonadectomy in children with this form of CGD CASE REPORT A diagnosis of 46,XY DSD was suggested after noninvasive prenatal screening obtained due to advanced maternal age demonstrated the presence of a Y chromosome, and prenatal ultrasound at 20 weeks gestation did not visualize male genitalia Parents were non-consanguineous, and the family declined invasive diagnostic testing during pregnancy After delivery at full term via elective cesarean section to a 35-year-old mother, clinical examination showed phenotypically female external genitalia There were no palpable gonads Pelvic ultrasound demonstrated a normal prepubertal uterus with a gonad consistent with an ovary on the left, and without visualization of a gonad on the right Fluorescence in situ hybridization confirmed the presence of a Y chromosome, and karyotype was 46,XY She had sequencing, deletion, and duplication analyses of the genes SRY, DHH, NR5A1, and NROB1, which were within normal limits Adrenocorticotropic hormone stimulation testing was performed to rule out adrenal hypoplasia congenita and was normal with post-stimulation cortisol of 49 µg/dL (normal range is >18 µg/dL) At months, alpha-fetoprotein was elevated at 41 ng/ mL (normal range is to 10 ng/mL) At months, she had repeat pelvic ultrasound with a normal uterus without visualization of gonads At her to 9-month evaluation, she was found to have hypotonia with global developmental delay, mild to moderate conductive hearing loss, as well as failure to thrive A gastrostomy tube was placed, with improvement in her weight gain She did not have any dysmorphic features Based on developmental delay, further genetic investigation was performed Microarray was obtained demonstrating a deletion of 12.5 Mb on 9p24.3p23, including the DMRT1 gene which explained the 46,XY DSD, as well as duplication of 13.15 Mb on the 9p23p21.2 region Given the known risk for gonadoblastoma in children with CGD, she underwent prophylactic gonadectomy at 13 months On laparoscopic approach, a normal uterus with bilateral fallopian tubes and bilateral streak gonads were visualized The bilateral streak gonads were removed Pathology demonstrated dense stroma reminiscent of ovarian stroma, without primordial follicles The stroma was inhibin negative Elongated tubular structures reminiscent of seminiferous tubules were also seen There were gonadoblastoma-like structures noted in the right gonad only She recovered well from surgery, and has not required further intervention She continues to follow up with pediatric endocrinology, and will require pubertal induction at the appropriate age DISCUSSION As seen with other forms of XY CGD, including mutations of the genes SRY, SOX9, and WT1, the chromosome 9p deletion in 46,XY CGD also confers an increased risk of gonadal neoplasms, with some reports in very young children We performed a review of the literature and summarized all published reports of neoplasia in individuals with 9p deletion in Table (3,4,9-14) The consistent recommendation is for bilateral gonadectomy to be performed as soon as possible after the diagnosis of XY CGD is made due to the high risk of malignancy (6,7) NIPT uses cell-free DNA in maternal plasma and evaluates short segments of DNA Of the cell-free DNA in maternal blood, to 13% consists of fetal DNA which is released into the circulation after apoptosis of placental e382 Gonadoblastoma in 9p Deletion, AACE Clinical Case Rep 2019;5(No 6) Copyright © 2019 AACE Table Published Reports of 9p Deletion and Gonadal Neoplasia Present case Genetic mutation Type of neoplasia Age of neoplasia diagnosis 46,XY 9p del(24.3p23) dup 23p21.2 Right gonadoblastoma Onesimo et al (3) 46,XY,del(9)(p24.1) Left gonadoblastoma Quinonez et al (4) 45X/46,XY,del(9)(p24.1)mat.ishdel(22)(q11.21q11.21) (b135h6-) Unclear, referred at months Bilateral gonadoblastoma year 46,XY,del(9)(p24.1).ish del(9)(wcp+,tel 9p-) Bilateral gonadoblastoma 3.2 years de Ravel et al (11) 45,X,der(Y;9) (Ypter-Yq12::9p21.1–9p22.2::9p22.2–9qter) Left dysgerminoma 12 years Muroya et al (13) 46,XY,der(9)t(4;9) (p15;p23) Left gonadoblastoma 15 months Del Rey et al (9) Ledig et al (10) Livadas et al (12) McDonald et al (14) 46,XY,del(9)(p24.3-p23) Dysgerminoma 46,XY,del(9)(p22) Bilateral gonadoblastoma 46,XY,der(9)t(8;9)(p21;p24)pat Bilateral gonadoblastoma cells (15) Screening for aneuploidy using cell-free DNA can be performed as early as 10 weeks NIPT can also determine fetal sex Although previously recommended as a screening option only for high-risk pregnancies, guidelines now recommend counseling all patients regardless of risk level about screening options including primary screening with cell-free DNA (15,16) Surveys of obstetricians report that NIPT is thought to be clinically superior to traditional methods of screening, with >80% of providers surveyed reporting that if insurance coverage was provided, they would utilize NIPT as a first-line screening test (17) There have been reports of sex chromosome genotype/phenotype discordance identified by prenatal testing including reports of prenatal diagnosis of 46,XY DSDs due to androgen insensitivity and rarely other forms of sex reversal such as campomelic dysplasia, Smith-Lemli-Opitz syndrome (18), as well as 9p deletion (19) We have presented the case of an infant female with 46,XY CGD discovered incidentally after NIPT revealed a 46,XY genotype in the setting of a phenotypic female fetus No other abnormalities were detected prenatally Guidelines suggest that gonadectomy should be performed at the time of diagnosis, and in this case the diagnosis of CGD was suggested prenatally and confirmed after birth Further genetic analysis revealed a deletion of 12.5 Mb on 9p24.3p23, which includes the DMRT1 gene, explaining the diagnosis of CGD as well as her developmental delay and hypotonia She was found to have unilateral gonadoblastoma at 13 months of age and, due to early detection, no further treatment is indicated CONCLUSION This case highlights the importance of early surveillance and gonadectomy in children with gonadal dysgenesis due to chromosome 9p deletion It also raises the ques- 13 months Unclear years years tion of what timeline should be used for gonadectomy in children diagnosed prenatally or in early infancy, as NIPT is increasingly utilized Based on our experience and literature review, we recommend gonadectomy as soon as the diagnosis of 46,XY CGD is established and can safely be performed DISCLOSURE The authors have no multiplicity of interest to disclose REFERENCES Troche V, Hernandez E Neoplasia arising in dysgenetic gonads Obstet Gynecol Surv 1986;41:74-79 Alfi O, Donnell GN, Crandall BF, Derencsenyi A, Menon R Deletion of the short arm of chromosome no.9 (46,9p-): a new deletion syndrome Ann Genet 1973;16:17-22 Onesimo R, Orteschi D, Scalzone M, et al Chromosome 9p deletion syndrome and sex reversal: novel findings and redefinition of the critically deleted regions Am J Med Genet A 2012;158A: 2266-2271 Quinonez SC, Park JM, Rabah R, et al 9p partial monosomy and disorders of 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syndromic and non-syndromic XY gonadal dysgenesis: evaluation of array CGH as diagnostic tool and search for new candidate loci Hum Reprod 2010;25:2637-2646 Copyright © 2019 AACE Gonadoblastoma in 9p Deletion, AACE Clinical Case Rep 2019;5(No 6) e383 11 de Ravel TJ, Fryns JP, Van Driessche J, Vermeesch JR Complex chromosome re-arrangement 45,X,t(Y;9) in a girl with sex reversal and mental retardation Am J Med Genet A 2004;124A:259-262 12 Livadas S, Mavrou A, Sofocleous C, van Vliet-Constantinidou C, Dracopoulou M, Dacou-Voutetakis C Gonadoblastoma in a patient with del(9)(p22) and sex reversal: report of a case and review of the literature Cancer Genet Cytogenet 2003;143: 174-177 13 Muroya K, Okuyama T, Goishi K, et al Sex-determining gene(s) on distal 9p: clinical and molecular studies in six cases J Clin Endocrinol Metab 2000;85:3094-3100 14 McDonald MT, Flejter W, Sheldon S, Putzi MJ, Gorski JL XY sex reversal and gonadal dysgenesis due to 9p24 monosomy Am J Med Genet 1997;73:321-326 15 Committee on Practice Bulletins—Obstetrics, Committee on Genetics, and the Society for Maternal-Fetal Medicine Practice 16 17 18 19 Bulletin No 163: Screening for Fetal Aneuploidy Obstet Gynecol 2016;127:e123-e137 Gregg AR, Skotko BG, Benkendorf JL, et al Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics Genet Med 2016;18:1056-1065 Brewer J, Demers L, Musci T Survey of US obstetrician opinions regarding NIPT use in general practice: implementation and barriers J Matern Fetal Neonatal Med 2017;30:1793-1796 Chitty LS, Chatelain P, Wolffenbuttel KP, Aigrain Y Prenatal management of disorders of sex development J Pediatr Urol 2012;8:576-584 Richardson EJ, Scott FP, McLennan AC Sex discordance identification following non-invasive prenatal testing Prenat Diagn 2017;37:1298-1304 ... form of CGD CASE REPORT A diagnosis of 46 ,XY DSD was suggested after noninvasive prenatal screening obtained due to advanced maternal age demonstrated the presence of a Y chromosome, and prenatal. .. circulation after apoptosis of placental e382 Gonadoblastoma in 9p Deletion, AACE Clinical Case Rep 2019;5(No 6) Copyright © 2019 AACE Table Published Reports of 9p Deletion and Gonadal Neoplasia...Copyright © 2019 AACE Gonadoblastoma in 9p Deletion, AACE Clinical Case Rep 2019;5(No 6) e381 epilepsy, inguinal hernias, omphaloceles, choanal atresia, as well as 46 ,XY disorder of sexual development