Case Of Mixed Gonadal Dysgenesis Research Articles

Clinical characteristics and surgical treatment of children with 45, X/46, XY differences of sex development

This study retrospectively analyzes the clinical data of 18 children with 45,X/46,XY differences of sex development (DSD), summarizes their clinical features and explores gonadal and Müllerian duct remnants surgical treatment methods. The clinical data of 18 children with karyotype 45,X/46,XY diagnosed in the Department of Urology of Hunan Children's Hospital from March 2011 to October 2021 were collected. All children underwent HCG stimulation testing, laparoscopic exploration, urethroscopy and bilateral gonadal biopsy. After DSD multidisciplinary team (MDT) meeting, some children underwent gonadectomy and genitalia reconstructive surgeries. The median age at first diagnosis was 1 year and 4 months (range: 10 months ∼ 16 years and 3 months). 5 children presented with female gender; they all maintained their gender assignment. The external masculinisation score (EMS) of patients raised as female was 1 (0∼3) [median (range)]. 13 children presented with male gender, 10 maintained a male gender, 3 were assigned a neutral gender. The EMS of the children raised as male was 5 (2-8) [median (range)], the EMS of the children raised as neutral gender was 4 (3.5-9.5) [median (range)]. The HCG stimulation test was positive in 11 cases, partially positive in 2 case, and negative in 5 cases. There was no relationship between the percentage of chimerism (45X ratio) and the appearance and severity of genital abnormalities. (t=-1.08, P=0.298). There was 1 case of complete gonadal dysgenesis (CGD), 10 cases of mixed gonadal dysgenesis (MGD), 5 cases of partial gonadal dysgenesis (PGD), 1 case of bilateral normal testes and 1 case of ovotesticular DSD (split-lateral type). No gonadal specimen showed germ cell tumor changes. Five cases selected to maintain the female gender, among which 3 cases underwent bilateral gonadectomy and genitalia reconstructive surgeries. Among the 10 children who chose to maintain the male gender, unilateral streak gonadectomy was performed in 4 (57.1%) with MGD, unilateral dysgenetic orchiectomy in 1 (25%) with PGD, and right ovariectomy in 1 with OTDSD. Nine of them underwent genitalia reconstructive surgeries. Four of them preserved their uterus and vagina did not have any complications during the follow-up period. Hypospadias combined with cryptorchidism and residual Müllerian duct structures is the most common phenotype of children with 45, X/46, XY DSD. Mixed gonadal dysgenesis (MGD) is the most common gonadal type. Gender assignment should be carefully selected after a thorough evaluation, while genitalia reconstructive surgery can be considered in selected patients. In children who choose the male gender, the Müllerian duct can be preserved.

#332 : A Rare Case Report of Mixed Gonadal Dysgenesis with MOS 46, XY, 47,XY+21, 45,X Karyotype

Background and Aims: Mixed gonadal dysgenesis is a condition of unusual and asymmetrical gonadal development leading to an unassigned sex differentiation. A number of differences have been reported in the karyotype, most commonly a mosaicism 45, X/46, XY. We herein report an interesting case of mixed gonadal dysgenesis. Method: We present a rare patient case with mixed gonadal dysgenesis as a disorder of sex development (DSD) and a new pattern of chromosome in the karyotype, undergoing laparoscopic procedure for sex correction. Results: A 20-year-old person, reared as female presented with complaints of genital ambiguity and primary amenorrhoea along with lack of secondary sexual characters, but without short stature and Turner’s stigmata.Karyotype analysis revealed Mos 46, XY, 47,XY+21, 45,X karyotypeLuteinizing hormone (LH) was 18.3 mIU/ml and follicle-stimulating hormone (FSH) was 70,07 mIU/ml. Serum estradiol level was 35,9 pg/ml and prolactin was 25,8 ng/ml). Magnetic resonance imaging (MRI) pelvis with contrass (with ultrasonogrphy correlation) revealed uterus hypoplasia with right ovarian-like structures. View of corpus uteri measuring 1× 1.5× 0.8 cm with cervix building length 1 × 0.5 cm were visualized laparoscopically. The right tube and left tube (include bilateral fimbare) appear to be normal in shape and size. Right gonad with base in corpus uteri, white color, elongated ligament-like shape 0.5 × 0.3 × 0.8 cm, no follicle visible. The left gonad was seen with its base at the corpus uteri, white in color and elongated like a ligament uk 0.5 × 0.4 × 0.8cm, no follicles visible. Both gonads biopsied. Conclusion: Histopathology is still awaiting results. The patient was managed with a multidisciplinary approach and fertility issues discussed with the patient’s family.

A rare case of mixed gonadal dysgenesis in adulthood: diagnostic delay and unique outcomes

Mixed gonadal dysgenesis (MGD) is a rare sex development disorder, diagnosed by mosaic karyotype of 45,X/46,XY (classical form) with the presence of Müllerian structures, unilateral testis and contralateral streak gonad. MGD expresses diverse phenotypes, from female phenotype with virilization or turner stigmata, to ambiguous genitalia or male phenotype. Early diagnosis is crucial for effective correction of height, sexual development and cancer prevention. The study reports on a case of a 25-year-old patient, reared as female, presenting a large abdominal mass later confirmed as a mixed germ cell tumor. Associated findings were primary amenorrhea, ambiguous genitalia, short statue, gender dysphoria and hyperlipidemia. The study is the first to report on hyperlipidemia in MGD.

A rare case of mixed gonadal dysgenesis: 45, X0/ 46, X, mar 1/ 46, X, mar 2

This study aims to report a rare case of mixed gonadal dysgenesis with mosaicism pattern 45 X0 / 46, X, +mar 1/ 46, X, +mar 2. Patient referred to the pediatric urology service with 2 months of age. Right after the baby was born it was not possible do determine the baby's gender. The karyotype was inconclusive: 45, X0. Contrast genitography and uretrocystogram showed a single perineal orifice below the micropenis and between the bifid scrotum, opacification of the bladder with male aspect urethra during urination and short penile urethra. There was also opacification of the posterior vaginal cavity with low junction to the posterior urethra and a linear opacity image suggesting uterine canal. Laparoscopy revealed bilateral gonadal bands and spermatic elements entering the inguinal canal. Mlerian derivatives were absent. Gonadal biopsy was performed and concluded that these were abnormal infantile testes. Microarray testing took a few months and resulted in: 45 X0 / 46, X, +mar 1/ 46, X, +mar 2. Patient was kept on topic androstenedione for 6 months and then underwent penoscrotal hypospadias correction. Mosaic chromosomal pattern is a rare condition that can present with a wide variety of phenotypes. Early recognition has important implications on these patients social and psychological life and also for their proper management.

Clinical and cytological aspects of sex chromosome activity.

The first known example of a human female with more than one euchromatic X chromosome in somatic cells is presented, viz. a child with 2 normal X chromosomes and the long arm of a third X translocated onto one of the No. 22 chromosomes. In cultured lymphocytes there occurred, in addition to the ordinary Lyon pattern of X chromosome inactivation, 2 other patterns in which (1) 2 normal X chromosomes, and (2) one X and the t(X;22) were euchromatic. As the inactivation within the translocation chromosome did not spread onto chromosome 22, the clinical symptoms of the child had to be attributed to the excess of active X material, not to monosomy 22. Contrary to this, absence of heterochromaty of the Y chromosome does not influence the phenotype, as shown by the case of mixed gonadal dysgenesis with non-fluorescing Y presented. Possible reasons for this difference include: (1) The differences between facultative X and constitutive Y heterochromatin; (2) Different cytologic criteria for heterochromatin may not mean the same kind of inactivity; (3) Differences in phenotypic expression may be due to different chromosomal behaviour among tissues; (4) Late replication and decondensation may not equate genetic inactivity in terms of transcriptional inactivity.

Transfer of surgical competences in the treatment of intersex disorders in Togo

To evaluate the impact of scientific seminar on the sexual ambiguity on patients and paediatric surgeons in French-speaking African countries. This was a report of the proceeding of a teaching seminar on intersex management, which was held from December 4 th to 8 th , 2006, in the Paediatric Surgery Department of Tokoin Teaching Hospital and the Surgery Department of "Saint Jean de Dieu" Hospital of Afagnan, Togo. There were 107 participants [five professors of paediatric surgery, 62 African paediatric surgeons (including 15 from African French-speaking countries), and 40 general surgeons]. The workshop involved a two-day theoretical teaching session (aimed at understanding, recognising, and treating the sexual ambiguities), and practical session; during these sessions different intersexes (one case of mixed gonadal dysgenesis, two of female pseudohermaphroditism, and two of male pseudohermaphroditism), were operated free of charge. Participants expressed satisfaction and confidence with regard to the management of intersex after the seminar. This scientific forum allowed possible exchange of competence among the paediatric surgeons with regard to efficient treatment of sexual ambiguities.

Gender assignment and hormonal treatment for disorders of sexual differentiation

To study the gender assignment and hormonal treatment advocated for disorders of sexual differentiation (DSD). A study was done on patients who were reviewed in the Pediatric Intersex Clinic to evaluate the pattern of gender assignment and hormonal treatment advocated. The patients included male pseudohermaphrodite (MPH) 169; congenital adrenal hyperplasia (CAH) 91; mixed gonadal dysgenesis (MGD) 29; true hermaphrodite (TH) 25; pure gonadal dysgenesis (PGD) 2; persistent mullerian duct syndrome (PMDS) 2 and others (micropenis, severe hypospadias with cryptorchidism, 46XX male) 39. Out of 91 cases of CAH, 70 (76.9%) were on steroids (prednisolone, hydrocortisone) and/or mineralocorticoids (fluoricortisone) for adrenal suppression. Out of 146 cases of male pseudohermaphrodite and 21 cases of true hermaphrodite and 3 cases of mixed gonadal dysgenesis reared as males, testosterone was given for local application for phallic growth in 101 and/or as systemic injection for mental makeup after puberty in 41 cases. Systemic testosterone injection was also given for 7 cases of CAH reared as males. Out of 26, 15 cases with mixed gonadal dysgenesis and one out of 2 cases of pure gonadal dysgenesis that attained puberty after being reared as females, after female genitoplasty, were given conjugated oestrogen (Premarin) supplemented with progesterone, as the uterus was preserved. For 12 post-pubertal cases of complete androgen insensitivity syndrome (AIS), only premarin was given as there was no uterus. Growth hormone and Gn RH analogue was given in 2 patients with CAH to tide over the early bone maturation induced by hormones with equivocal results. Thus judicious hormonal supplementation based upon type of DSD and gender assigned can provide a psychological and cosmetic benefit to patients with DSD.

Mixed gonadal dysgenesis associated with an isodicentric Y chromosome

Authors report a case of mixed gonadal dysgenesis with a karyotype containing an isodicentric Y chromosome in mosaic form, which was diagnosed in an infant. They emphasize the necessity of the special investigations of newborn with perineoscrotal hypospadia and bilateral or unilateral maldescent testes immediately after birth. The result of accurate evaluation provides correct sex assignment and the prevention of the neoplastic degeneration of a dysgenetic gonad.

Limitations of G-banding Karyotype Analysis with Peripheral Lymphocytes in Diagnosing Mixed Gonadal Dysgenesis

Mixed gonadal dysgenesis (MGD) is an abnormal sexual differentiation syndrome usually presenting with ambiguous genitalia. Karyotype analysis is one of the essential components in the diagnosis of MGD and is conventionally done with peripheral lymphocytes by the G-banding technique. It is speculated that this conventional karyotype analysis has limitations since there are often difference in gonadal tissue analysis. Here we present four cases of MGD, in which karyotype analysis were performed by peripheral lymphocytes fluorescence in situ hybridization (FISH), gonad fibroblasts FISH and gonad fibroblasts G-banding technique, in addition to the conventional peripheral lymphocytes G-banding technique. In Case 1, the percentage of the 45,X cell line in lymphocytes decreased after birth and detection of mosaicism could only be done by karyotype of gonads at 7 mo of age. In Case 2, FISH analysis with peripheral lymphocytes was more useful for detecting low frequency mosaicism. In all cases, phenotype of gonads and external genitalia were more consistent with karyotype of gonads than that of the peripheral lymphocytes G-banding technique. In conclusion, conventional G-banding karyotype analysis with peripheral lymphocytes has limitations in the diagnosis and evaluation of MGD. Karyotype analysis by FISH or by using gonads is useful for diagnosing MGD and understanding of the phenotype of gonadal tissue.

A heterozygous mutation in the desert hedgehog gene in patients with mixed gonadal dysgenesis

Aetiology of mixed gonadal dysgenesis (MGD) has not been completely elucidated. Molecular analyses have failed to demonstrate the presence of mutations in sex-determining region on Y chromosome (SRY); it has been suggested that these individuals may bear mutations in other genes involved in the testis-determining pathway. Desert hedgehog's (DHH) importance regarding male sex differentiation has been demonstrated in various studies we describe here, for the first time, two cases of MGD in which a monoallelic single base deletion in DHH is associated with the disorder. Genomic DNA was isolated from paraffin-embedded gonad tissue from 10 unrelated patients with MGD and three controls; in addition to, DNA from peripheral blood leukocytes in 100 controls. Coding sequence abnormalities in DHH were assessed by exon-specific PCR, single-stranded conformation polymorphism (SSCP) and direct sequencing. In two patients, a heterozygous 1086delG in exon 3 was found. Comparing previously described mutations in DHH to the one observed in this study, we can affirm that the phenotypic spectrum of patients with gonadal dysgenesis due to mutations in DHH is variable. This study continues to demonstrate the importance that DHH has in mammalian male sexual differentiation, providing extended evidence that DHH constitutes a key gene in gonadal differentiation.

Ectopically located gonads in a patient with mixed gonadal dysgenesis: detection by diffusion-weighted MRI

We report a case of mixed gonadal dysgenesis in which diffusion-weighted magnetic resonance imaging played a major role in the detection of ectopically located gonads. Magnetic resonance imaging may have a potential in detecting ectopically located gonads and may provide important information for the management of patients with mixed gonadal dysgenesis.

Sry gene detection in gonads of intersex patients using FISH.

A candidate gene for sex determination was localized within a 35 kb region of the Y chromosome immediately adjacent to the pseudoautosomal boundary. Here, we describe a study of Sry detection in the gonads of intersex patients including 5 male pseudohermaphrodite (MPH), 4 XX true hermaphrodite (TH) and each 1 mixed gonadal dysgenesis (MGD) and XX sex reversal, and in the clitoris of 3 female pseudohermaphrodite (FPH) by fluorescent in situ hybridization (FISH). Sry gene was observed in all cases of MPH and each case of MGD and sex reversal in contrast to bare expression in all cases of FPH and most of TH. To our knowledge, the Sry gene itself functions testicular determination in almost all intersex cases except true hermaphrodite, a distinguished type of intersex in a different pathogenesis. In addition, FISH might be useful to detect the translocated Sry gene and localize the signal with ease.

Mixed gonadal dysgenesis and dysgenetic male pseudohermaphroditism--a critical analysis.

A 10 year prospective study of 14 patients with mixed gonadal dysgenesis (MGD) and six patients with dysgenetic male pseudohermaphroditism (DMP) is reported. All of them had internal mullerian structures, along with unilateral or bilateral dysgenetic testes, ambiguous external genitalia. Twelve had been brought up as male, nine of whom had a unilateral descended testis. Eight had been reared as females, as they had bilaterally undescended gonads, and ambiguous genitalia. Clinical examination, retrograde genito-urethrography and cytogenetic studies suggested the diagnosis in 16 patients, while four were diagnosed on inguino-abdominal exploration for undescended testis. This report delineates more clearly the clinical profile of these orders. All the patients reared as male were assigned the male gender following abdominal gonadectomy, retention of scrotal testis and male genitoplasty. The eight patients who were reared as females underwent bilateral salpingo-gonadectomy and female genitoplasty. This management differs from the usual recommendation that all such children should be reared as females. Ten patients (50%) had maternal history of previous abortion/stillbirth, or drug intake in the first trimester of pregnancy suggesting a role of these factors in the etiology. All cases of DMP had a 46,XY karyotype, while eight of 14 cases of MGD had mosaicism with 45X/46,XY cell lines in blood or gonadal cultures. The clinicopathological features of patients of MGD and DMP were similar. It is suggested that these two disorders represent different spectra of the same disorder. A unifying concept of etiopathogenesis is proposed.

Surgical management of ambiguous genitalia in the infant and child

Proper gender assignment to a neonate born with ambiguous genitalia is a social emergency of the newborn period. Once an appropriate sex assignment has been made, the next critical step is performance, if needed, of a reconstructive procedure in a timely fashion. In an attempt to evaluate our experience with this unique group of patients, we have retrospectively reviewed the course of 69 children with ambiguous genitalia managed surgically at this institution between 1974 and 1989. This series consists of 32 genotypic females with congenital adrenal hyperplasia (CAH), 10 children with mixed gonadal dysgenesis (MGD), 10 male pseudohermaphrodites, 3 true hermaphrodites, 8 genotypic females with urogenital sinus anomalies (UGS), and 6 genotypic males with bilateral undescended testes and penoscrotal hypospadius. All newborns initially seen at this institution received proper sex assignment within the first week of life. Prior to 1980, 17 of the children with CAH underwent clitorectomy and vaginoplasty and three underwent clitoral recession and vaginoplasty. After 1980, 10 patients with CAH were managed with clitoral recession and vaginoplasty and 2 with vaginoplasty alone. Eight of 10 cases of MGD were given a female sex assignment and all 8 underwent gonadectomy due to the high risk of gonadoblastoma; the other 2 children were raised as males. There were 3 true hermaphrodites of which 2 were assigned female gender roles and were managed with a clitoral recession and vaginoplasty. All 10 male pseudohermaphrodites were raised as females and all underwent bilateral orchidectomy. The 8 children with UGS were raised as females and underwent vaginal reconstruction. Six genotypic males with penoscrotal hypospadius and bilateral undescended testes were raised as males and underwent hypospadius repair and bilateral orchidopexy. This retrospective review underscores the complexities of assessment and management of ambiguous genitalia in infants and children. It also reconfirms the data from other series showing that the vast majority of infants born with the four most common forms of ambiguous genitalia (CAH, MGD, male pseudoher-maphroditism, and true hermaphroditism) must be raised as females because of inadequacy of the phallus.

Mixed Gonadal Dysgenesis: Case Reports and a Review of 65 Japanese Cases

Four cases of mixed gonadal dysgenesis encountered in our institute are described here, and 65 cases of mixed gonadal dysgenesis in the Japanese literature, including our cases, are reviewed. Of the four cases reported here, three had a chromosomal structure of 46,XY and one of 45,XO/46,XYq-. A chromosomal structure of 45,XO/46,XY accounts for 35% of all cases of mixed gonadal dysgenesis reported in the Japanese literature, 46,XY for 31%, and other types for 24%. Two of our cases (50%) also had a gonadal tumor. The overall incidence of gonadal tumor occurring after onset of puberty and reported in the Japanese literature is 17%.

Dicentric Y Chromosome and Mixed Dysgenesis

We report 4 cases of mixed gonadal dysgenesis with a karyotype containing a dicentric Y chromosome. All cases were mosaic with 45X and 46X, dic(Y) cell lines. Of the patients 1 had ambiguous genitalia and some features of Turner’s syndrome, 2 had classical features of Turner’s syndrome with normal female external genitalia and 1 had no features of Turner’s syndrome but he presented with penoscrotal hypospadias, inguinal hernia and cryptorchidism. Female gender assignment and early total gonadectomy should be considered when a dicentric Y chromosome is present in cases of mixed gonadal dysgenesis.

Large Prostatic Utricles and Related Structures, Urogenital Sinus and Other Forms of Urethrovaginal Confluence

The urethrograms and clinical records of 106 children with a large prostatic utricle or related structures, urogenital sinus in intersex disorders and other types of urethrovaginal confluence were reviewed. There were 27 boys with normal external genitalia, 19 cases of male hypospadias, 1 case of male pseudohermaphroditism, 7 cases of mixed gonadal dysgenesis, 1 case of true hermaphroditism, 32 cases of female pseudohermaphroditism, 11 normal girls with urethrovaginal confluence and 8 cases of cloacal malformation. Among the patients of the first 2 groups 10 had an imperforate anus, 7 the prune belly syndrome, 6 Down’s syndrome and 2 posterior urethral valves.

Persistence of Müllerian ducts in male pseudohermaphroditism, and its relationship to cryptorchidism.

Twenty-two cases of male pseudohermaphroditism with persistence of Müllerian duct derivatives were reviewed. In 12 cases of mixed gonadal dysgenesis and five cases of dysgenetic male pseudohermaphroditism, testosterone-dependent steps of sex differentiation were also impaired, and testicular dysgenesis was prominent, even in the younger age group. The capacity of testes to inhibit the ipsilateral Müllerian duct was correlated with testicular descent: it is suggested that testicular dysgenesis explains both the functional and topographical testicular abnormalities observed in these male pseudohermaphrodites. Five other patients were cryptorchid but externally normally virilised, persistence of Müllerian derivatives representing their only abnormality of sex differentiation. Testicular structure was usually normal or showed changes attributable to long-standing cryptorchidism. It is suggested that in these patients, persistence of Müllerian derivatives is due to an inborn error of metabolism, affecting the binding of anti-Müllerian hormone to its receptor and that failure of testicular descent is caused by mechanical restraint by the abdominal Müllerian organs.

Dysgenesis of testicular and streak gonads in the syndrome of mixed gonadal dysgenesis: Perspective derived from a clinicopathologic analysis of twenty-one cases

The clinical and pathologic aspects of 21 cases of mixed gonadal dysgenesis (MGD) were studied. The gonads in 15 patients consisted of a macroscopic testis and a streak gonad; six patients had variants, including two with bilateral testes and four with bilateral streak gonads or tumors. Functionally, the gonads were incompetent. Testes 1) failed to completely inhibit müllerian development, 2) failed to support full differentiation of mesonephric duct structures, 3) failed to adequately masculinize development of the external genitalia, or 4) often failed to mediate their own descent, resulting in asymmetry of the internal and external genitalia. None of the streak gonads mediated normal female adolescent development or fertility. Microscopic examination revealed that every gonad, regardless of its gross appearance, was morphologically abnormal. Although gonads with seminiferous tubules usually developed to a moderately advanced state, macroscopically resembling testes, the hilar zone remained architecturally disorganized; the cortex invariably lacked more than a rudimentary tunica albuginea or exhibited partial ovarian differentiation, sometimes even with a rare primordial follicle. Over time, the seminiferous tubules atrophied and hyalinized. Gonads that grossly resembled streak gonads were observed microscopically to be composed of a stroma resembling that of normal ovarian cortex. In patients more than several years of age, the entire complement of germ cells in streak gonads disappeared. It is suggested that patients with MGD be raised as females. Early removal of gonads will prevent the development of gonadoblastoma and dysgerminoma. If the uterus is retained and the patient is subsequently given exogenous estrogen, care should be taken to detect early any signs of the development of endometrial carcinoma or its precursor, to which these patients may be prone.

Two cases of mixed gonadal dysgenesis in siblings

Two cases of mixed gonadal dysgenesis in siblings