Turner Stigmata Research Articles

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.

Atypical genotype in a typical phenotype

Introduction: Usually, onset of thelarche heralds puberty. Delayed puberty is worrisome and needs medical attention. Our patient in her late adolescence presented with primary amenorrhea, whose evaluation left us surprised. Case report: An eighteen-year-old scholastically backward girl, presented with complaints of not attaining menarche. Physical examination included a height of 156 cm(10th-25thcentile),weight 51 kg(50th centile), wide carrying angle, multiple nevi and a broad chest, however no other Turner stigmata was noted. Her sexual maturity rating (SMR) was A2P2B1 Laboratory investigations revealed increased gonadotropins (FSH:77mIU/ml; LH:25.4mIU/ml), low estradiol (14 pg/ml) and vitamin-D deficiency (21ng/ml). Ultrasonography of abdomen-pelvis showed small infantile uterus with streak ovaries. Karyotype (50 metaphases) demonstrated mosaicism [47,XXX (29)/45,X(19)/46,XX(2)]. Hormone replacement therapy and vitamin D replacement was initiated. Conclusion: 30-40% of the Turner syndrome are mosaics, the most common being 45,X/46,XX. Mosaicism is the presence of 2 or more cell lines with different chromosomal constitutions. The cell lines are derived due mostly to postzygotic mitotic nondisjunction. X/XX/XXX can present with or without classical turner stigmata. Trisomy X has a spectrum of presentation from normal menses and fertility to recurrent abortions and primary/secondary amenorrhea (primary ovarian insufficiency). Varied clinical phenotype due to three cell lines in a Turner mosaic makes this case unique.

Atypical genotype in a typical phenotype

Introduction: Usually, onset of thelarche heralds puberty. Delayed puberty is worrisome and needs medical attention. Our patient in her late adolescence presented with primary amenorrhea, whose evaluation left us surprised. Case report: An eighteen-year-old scholastically backward girl, presented with complaints of not attaining menarche. Physical examination included a height of 156 cm(10th-25thcentile),weight 51 kg(50th centile), wide carrying angle, multiple nevi and a broad chest, however no other Turner stigmata was noted. Her sexual maturity rating (SMR) was A2P2B1 Laboratory investigations revealed increased gonadotropins (FSH:77mIU/ml; LH:25.4mIU/ml), low estradiol (14 pg/ml) and vitamin-D deficiency (21ng/ml). Ultrasonography of abdomen-pelvis showed small infantile uterus with streak ovaries. Karyotype (50 metaphases) demonstrated mosaicism [47,XXX (29)/45,X(19)/46,XX(2)]. Hormone replacement therapy and vitamin D replacement was initiated. Conclusion: 30-40% of the Turner syndrome are mosaics, the most common being 45,X/46,XX. Mosaicism is the presence of 2 or more cell lines with different chromosomal constitutions. The cell lines are derived due mostly to postzygotic mitotic nondisjunction. X/XX/XXX can present with or without classical turner stigmata. Trisomy X has a spectrum of presentation from normal menses and fertility to recurrent abortions and primary/secondary amenorrhea (primary ovarian insufficiency). Varied clinical phenotype due to three cell lines in a Turner mosaic makes this case unique.

Kadın Cinsiyet Disforisinin Nadir Bir Nedeni: Düşük Yüzdeli Turner Mozaisizmli Üç Olgu Raporu

Gender dysphoria is a condition caused by a mismatch between the gender assigned at birth and gender identity. Gender development disorders include situations where congenital chromosomal, gonadal, or anatomically gender-related physical features are atypical. In the studies conducted mostly by karyotype analysis, it is reported that the rate of chromosomal abnormality is very low in people with gender dysphoria. In Turner mosaicism, gender dysphoria is not a common finding. In this case series, we examined the phenotype and genotype characteristics of the three cases identified as Turner mosaicism, who applied with gender dysphoria. The patients’ complaints were feeling like a male, negative thoughts about being a female, being uncomfortable with feminine body image, wanting to have a male body. None of our 3 cases had Turner stigmata however their chromosomal or FISH analyses showed that one of them was 45,X/46 XX/47,XXX and two of them were 45 X/46 XX karyotype.

SAT-301 Mixed Gonadal Dysgenesis: A Case Report

INTRODUCTION: An ambiguous genitalia is a birth defect of the sex organs that makes it unclear whether an affected newborn is a girl or a boy. This condition occurs approximately 1 in every 4,500 births. Defects of the external genital organs (penis, testes, or clitoris) usually result from abnormal levels of sex hormones in the fetus before birth. Here we present a case report of an 18year old girl with ambiguous genitalia. CLINICAL CASE: An 18-year-old girl presented with complaints of primary amenorrhea along with lack of secondary sexual characters. Her mother also gave history of genital ambiguity. No history of recent change in sexual identity. Past history, family history, antenatal history, perinatal history and developmental history were non contributory. On examination, anthropometric measurements were appropriate for her age. She was normotensive. General and systemic examination were unremarkable and there were no Turner stigmata. Genital examination revealed phallic structure of 5cm length and two seperate perineal openings. Minimal posterior fusion of labial margins and a palpable mass were noted in left inguinal region. Prader staging was 3/5. Sexual maturity rating was A0P1B2. Her basal serum cortisol 14.53μg/dL,[5-25μg/dL], 17-OH-progesterone (17-OHP) 1.51ng/mL,[0.09-2.19ng/ml] and serum estradiol level 37 pg/ml [13.6-54.4pg/ml] were normal while basal androstenedione 2.23 ng/ml[0.29-1.44 ng/ml], serum testosterone 1ng/mL [ lt 0.6ng/ml]and gonadotrophins Pooled LH 22 IU/L [5-15IU/ml] and FSH 76.37 IU/L [5-20IU/ml] were elevated. Karyotype analysis was 46XY. MRI pelvis revealed absent mullerian structures and ovaries, presence of seminal vesicle and left inguinal subcutaneous sac, containing gonad, suggestive of testis was noted. Intra abdominal right gonad was detected on diagnostic laparoscopy. No vas deferens noted in entire deep inguinal ring. Left gonad noted in its entirety in left deep inguinal ring. Rudimentary uterus was also noted. Histopathological examination of gonadal biopsy revealed presence of testicular tissue showing atrophic seminiferous tubules with hyperplasia of Leydig cells. No ovarian tissue was seen. Based on these results a diagnosis of 46XY mixed gonadal dysgenesis was made, which is rare and is difficult to distinguish from 46XY ovotesticular disorder of sexual differentiation. The patient underwent feminizing genitopasty after discussion with the patient’s caregivers. CONCLUSION: Mixed Gonadal Dysgenesis represents an intermediate between pure gonadal dysgenesis and ovotesticular disorder of sexual differentiation (DSD). The external genitalia, internal genitalia, and gonadal phenotype are highly variable. The most common genotype in these patients is 46XO/XX, however 46XY genotype has also been described, which can be difficult to distinguish from 46XY ovotesticular DSD.

Karyotype - Phenotype Associations in Patients with Turner Syndrome.

Variation in karyotype may be associated with the phenotype of patients with Turner syndrome (TS). Our objective was to identify these associations between karyotype and phenotype in TS patients. This study was part of the European multicentre dsd-LIFE study. We evaluated the associations between different karyotypes of TS patients and age at diagnosis, Turner stigmata, cardiac/renal involvement and gonadal function. Information was available for 328 TS patients. Participants had a monosomy 45,X (46%), mosaicism 45,X/46,XX (10%), karyotype with isochromosome (18%), or other karyotype (26%). The clinical signs of TS were the most severe in patients with monosomy 45,X and the least severe in patients with mosaicism 45,X/46,XX. Patients with isochromosome and y-material showed an intermediate phenotype. Despite the more severe features in patients with monosomy 45,X, the median age at diagnosis was only slightly lower compared to patients with other karyotypes, which suggests opportunities for improvement of knowledge and diagnostics.

The spectrum of 45,X/46,XY mosaicism in Taiwanese children: The experience of a single center.

45,X/46,XY mosaicism is a rare sex chromosome abnormality. Here, we present our experience in the management of 45,X/46,XY Taiwanese children. We enrolled 19 patients from January 1981 to September 2016. The diagnosis of 45,X/46,XY mosaicism was made by karyotyping peripheral blood lymphocytes. All medical records were thoroughly reviewed. Of the 19 patients, 16 were reared as females and 3 as males. The age at diagnosis ranged from 1 month to 15 years and 9 months. Atypical genitalia, short stature, and Turner stigmata were common manifestations. No patient exhibited a cardiac malformation but 29% had renal malformations and 12.5% had autoimmune thyroid disease who developed thyroid dysfunction later. Nine girls with short stature received growth hormone therapy and their height standard deviation score rose from -3.4±1.1 to -1.4±0.9 in adulthood (P<0.01). The gonadal phenotypes included bilateral streak gonads in nine patients, a streak gonad with contralateral gonadal agenesis in one, mixed gonadal dysgenesis in five, bilateral dysgenetic testes in two, and bilateral gonadoblastomas in one. The 45,X/46,XY phenotype varies widely and a high index of suspicion is important to ensure early diagnosis. Cardiac and renal malformations should be screened ultrasonically at diagnosis and thyroid status should be monitored annually. Growth hormone effectively improves adult height in short girls. Prophylactic gonadectomy is indicated for those with intra-abdominal streaks or dysgenetic gonads to prevent the development of a malignancy.

Association of Parental Origin with Phenotypic Profile in Turner Syndrome

Abstract Objective: The objective of the study is to report the association between the phenotype of the Turner syndrome with that of its karyotype and the parental origin of the X. 181 female referred to division of human genetics, St. John’s Medical College with different referral reasons are included in 1st phase of the study to observe the karyotype, upon obtaining the consent. Families of probands with confirmed pure or mosaic (more than 10% of mosaic status) karyotype of Turner stigmata are requested to participate in 2nd phase of study to determine the parent of origin. 20 families agreed and gave the consent for the study. Material and Method: The Karyotype analsyis was carried by GTG banding method automated karyotyping system. The parental origin was determined by X chromosome specific short tandem repeat (STR) markers. 23 Turner stigmata features were listed in the proforma. The secondary measure is to observe the associated Turner stigmata with the determined karyotype and the parental origin. Results: In 11 female probands, one had X structural abnormality (45,X/46,X,i(Xq)); 2 had X-mosaicism (45,X/ 46,XX) and 8 had 45,X. The determined parental origin of X was maternal in 8 (72.7%) and paternal in 3 (27.2%). 23 phenotypic features of Turner stigmata were tabulated. The features were further categorized as general observations, classical features of TS, features based on ultrasound findings and behavior. Percentage analysis indicated that a higher concordance of phenotype and behavior in proband with maternal X. Conclusion: In the present study, the Turner syndrome features were seemed to be associated with the maternal origin of X in Turner syndrome.

Turner’s Syndrome in Adulthood and Cytogenetics

Aims: Turner’s syndrome is a chronic disease of chromosomal aberration. The purpose of the study was to find out the accurate identification of cell line, which is critical for cytogenetic studies, genetic counseling, phenotypic studies carried out with few reconstructive procedures to plan future sexual and reproductive life. Methods: This study design was a prospective hospital based clinical study. In this study, ninety six patients were studied with secondary sex characters with relevant ultrasonogram findings and hormonal assay who underwent karyotyping in Bangabandhu Sheikh Mujib Medical University, Dhaka for a study period of ten years from October 1997 to October 2007. Results: Among 96 patients, 62.5 % of the patients were from 15-18 years. Four girls who were less than 15 years came with Turner’s and testicular stigmata. Twenty women aged more than 26 years presented with coital problems. Around 72.9% had no secondary sexual character, 20.83% had normal female type of secondary sex character, and 6.25% had virilizing type of secondary sexual character. Karyotyping of the cases revealed 72.9% (n = 70) had 45XO pattern, which belong to the Turner's stigmata and correlated well with the hormone profile. Whereas, 20.83% (n = 20) had 46XX pattern and 6.25% (n = 6) had 46XY pattern with testicular feminization syndrome with inguinal testis. Conclusions: About 60% of cases were in the 15-18 years age group. Most of the patients presented with no secondary sexual characteristics. 45XO chromosomal pattern was the most common presenting in 72.9% cases. DOI: http://dx.doi.org/10.3126/njog.v9i2.11744

A rare case report of 46XY mixed gonadal dysgenesis

A 16-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. She was taking steroids after being misdiagnosed as congenital adrenal hyperplasia (CAH). Karyotype analysis revealed 46XY karyotype. There was no evidence of hypocortisolemia (cortisol 9.08 μg/dl, adrenocorticotropic hormone [ACTH] 82.5 pg/ml) or elevated level of 17-OH-progesterone (0.16 ng/ml). Pooled luteinizing hormone (LH) was 11.79 mIU/ml and follicle-stimulating hormone (FSH) was 66.37 mIU/ml. Serum estradiol level was 25 pg/ml (21-251). Basal and 72 h post beta-human chorionic gonadotropin (hCG) levels of androstenedione and testosterone levels were done (basal testosterone of 652 ng/dl and basal androstenedione of 1.17 ng/ml; 72 h post hCG testosterone of 896 ng/dl and androstenedione of 1.34 ng/ml). Magnetic resonance imaging (MRI) pelvis (with ultrasonogrphy [USG] correlation) revealed uterus didelphys with obstructed right moiety and bilateral ovarian-like structures. Right sided gonads and adjacent tubal structures were visualized laparoscopically and removed. Left sided gonads were not visualized and Mullerian remnants were adhered to sigmoid colon. Histopathological examination revealed presence of testicular tissue showing atrophic seminiferous tubules with hyperplasia of Leydig cells. No ovarian tissue was seen. Based on these results a diagnosis of 46XY mixed gonadal dysgenesis (MGD) was made, which is rare and is difficult to distinguish from 46XY ovotesticular disorder of sexual differentiation (OT-DSD). The patient was managed with a multidisciplinary approach and fertility issues discussed with the patient's caregivers.

Parental origin and mechanism of formation of a 46,X,der(X)(pter→q21.1::p11.4→pter)/45,X karyotype in a woman with mild Turner syndrome

To describe the parental origin and the mechanism of formation of a 46,X,der(X)(pter-->q21.1::p11.4-->pter)[23]/45,X[8] karyotype in a patient with mild Turner syndrome. Case report. A university hospital. A 23-year-old woman with normal height, gonadal dysgenesis, and mild Turner stigmata. Genotype-phenotype correlation, array-based copy number analysis, fluorescence in situ hybridization with locus-specific probes, and microsatellite marker-mediated haplotype analysis subsequent to whole genome amplification of microdissected chromosomes. Genotype-phenotype correlation, mechanism of formation, and parental origin. Formation in paternal meiosis by refolding in itself and unequal recombination between Xp and Xq were found as the most likely mechanism of formation. Formation of der(X) chromosomes in females can be more complex than previously thought. The nearly normal height of this patient could be explained by a combination of trisomy of the Xp-located SHOX gene and mosaicism with a 45,X cell line.

Talla baja en varones con fenotipo normal y mosaicismo 45,X/46,XY

There is wide variation in the clinical expression of 45,X/46,XY mosaicism. Ninety percent of prenatally diagnosed boys have normal male phenotype at birth, while those diagnosed postnatally show a wide spectrum of phenotypes, ranging from Turner syndrome, mixed gonadal dysgenesis, and male pseudohermaphroditism to apparent normality. We report the clinical, cytogenetic, endocrinologic and histologic findings in three boys with an apparently normal male phenotype and 45,X/46,XY mosaicism who were diagnosed postnatally because of their short stature. With the exception of one patient with Turner stigmata, no other abnormal features were found. No correlation between the proportion of 45,X/46,XY cell lines in blood, gonads and phenotype was found. Both prenatally and postnatally diagnosed boys with normal male phenotype must be followed-up because they can develop late-onset abnormalities, such as dysgenetic testes leading to infertility or neoplastic transformation, and short stature, which could be improved with growth hormone therapy.

Effects of transmission of Y chromosome AZFc deletions

Deletions of specific regions on the Y chromosome cause male infertility. Recent advances in infertility treatment allow Y chromosome deletions to be transmitted to male offspring with the assumption that there will be no clinical consequences other than infertility in adult life. We screened 12 patients, who had a 45X/46XY karyotype and presented with Turner stigmata or sexual ambiguities, or both, for Y chromosome microdeletions with PCR. A third of these patients had Y chromosome microdeletions of distal Yq, the most common microdeletion seen in infertile men with azoospermia or severe oligozoospermia. Transmission of Y chromosome microdeletions could potentially have severe clinical consequences other than male infertility, such as the development of sexual ambiguities and Turner stigmata.

P-14. Y chromosome AZFc deletions present in 45X/46,XY chromosomal mosaic patients with Turner stigmata and sexual ambiguities: consequences for ICSI?

P-14. Y chromosome AZFc deletions present in 45X/46,XY chromosomal mosaic patients with Turner stigmata and sexual ambiguities: consequences for ICSI?

Del Xq23 in a Mosaic Turner Female: Molecular and Cytogenetic Studies

We report a Turner patient aged 22 years with a 45,X/46,X,del(X)(q23) karyotype. Late replication studies showed preferential inactivation of the deleted X chromosome; FISH studies with a probe for total human telomeres showed hybridisation signal in the telomeres on both the normal and the deleted X chromosomes. Microsatellite analysis in the proposita and her family permitted us to conclude to the maternal origin of the deleted X chromosome, and to detect using the marker DXS1106 (Xq22) a probable meiotic recombination event above the breakage point suggesting that the deletion occurred underneath this point. The mild Turner stigmata may be explained by the 45,X cell line, and the gonadal dysgenesis probably by a partial deletion of the gonadal dysgenesis region Xq13-q23 (excluding Xq22).

Molecular definition of Xq common-deleted region in patients affected by premature ovarian failure.

High-resolution cytogenetic analysis of a large number of women with premature ovarian failure (POF) identified six patients carrying different Xq chromosome rearrangements. The patients (one familial and five sporadic cases) were negative for Turner's stigmata and experienced a variable onset of menopause. Microsatellite analysis and fluorescent in situ hybridization (FISH) were used to define the origin and precise extension of the Xq anomalies. All of the patients had a Xq chromosome deletion as the common chromosomal abnormality, which was the only event in three cases and was associated with partial Xp or 9p trisomies in the remaining three. Two of the Xq chromosome deletions were terminal with breakpoints at Xq26.2 and Xq21.2, and one interstitial with breakpoints at Xq23 and Xq28. In all three cases, the del(X)s retained Xp and Xq specific telomeric sequences. One patient carries a psu dic(X) with the deletion at Xq22.2 or Xq22.3; the other two [carrying (X;X) and (X;9) unbalanced translocations, respectively] showed terminal deletions with the breakpoint at Xq22 within the DIAPH2 gene. Furthermore, the rearranged X chromosomes were almost totally inactivated, and the extent of the Xq deletions did not correlate with the timing of POF. In agreement with previous results, these findings suggest that the deletion of a restricted Xq region may be responsible for the POF phenotype. Our analysis indicates that this region extends from approximately Xq26.2 (between markers DXS8074 and HIGMI) to Xq28 (between markers DXS 1113 and ALD) and covers approximately 22 Mb of DNA. These data may provide a starting point for the identification of the gene(s) responsible for ovarian development and folliculogenesis.

The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome.

Turner syndrome is characterized by short stature and is frequently associated with a variable spectrum of somatic features including ovarian failure, heart and renal abnormalities, micrognathia, cubitus valgus, high-arched palate, short metacarpals and Madelung deformity. Madelung deformity is also a key feature of Leri-Weill syndrome. Defects of the pseudoautosomal homeobox gene SHOX were previously shown to lead to short stature and Leri-Weill syndrome, and haploinsufficiency of SHOX was implicated to cause the short stature phenotype in Turner syndrome. Despite exhaustive searches, no direct murine orthologue of SHOX is evident. SHOX is, however, closely related to the SHOX2 homeobox gene on 3q, which has a murine counterpart, Og12x. We analysed SHOX and SHOX2 expression during human embryonic development, and referenced the expression patterns against those of Og12x. The SHOX expression pattern in the limb and first and second pharyngeal arches not only explains SHOX -related short stature phenotypes, but also for the first time provides evidence for the involvement of this gene in the development of additional Turner stigmata. This is strongly supported by the presence of Turner-characteristic dysmorphic skeletal features in patients with SHOX nonsense mutations.

Two male patients with ring Y: definition of an interval in Yq contributing to Turner syndrome

Turner syndrome is thought to result from the haploinsufficiency of genes on the sex chromosomes, but these genes have not been identified yet. We describe two males with deleted ring...

An unusual case of pseudodicentric Xq and one possible mechanism

Structural abnormalities of the X chromosome are relatively common with isochromosome Xq being the most common. While isochromosome for Xp has been reported, its existence is questionable since true isochromosome Xp lacks the inactivation center and thus is presumed to be non-viable. Most of these cases are in fact believed to be pseudodicentric (having one active and one inactive centromere) and contain at least one inactivation center. We report an 18 year old female referred for primary gonadal failure (elevated FSH and LH; decreased estradiol). Cytogenetics revealed a 46,X,psu dic(X)(q24) karyotype suggesting trisomy for Xp and proximal Xq and monosomy for Xq distal to band q24. Fluorescent in situ hybridization (FISH) analysis using whole chromosome paint and XIST probes confirmed a structurally abnormal dicentric X chromosome containing two inactivation centers. Additional clinical history included oligoammenorrhea with menarche at age 12 and insulin dependent diabetes mellitus with onset at 14-15 years of age. No significant Turner stigmata were noted which may be attributable, in part, to an indeterminate X inactivation pattern. Mechanisms for the formation of pseudodicentric X chromosomes have been hypothetical thus far. One proposed mechanism is a U-type exchange between two chromatids or chromosomes following a break in each at a homologous site. This repair process would result in a dicentric inverted duplication or dicentric X chromosome. We propose another mechanism and suggest that the genetic constitution may have begun as trisomy X. Breaks in two of the X chromosomes at band q24 with subsequent fusion of the centric fragments would result in a pseudodicentric X chromosome. The remaining acentric fragments would be lost in continued cell division. Further investigation by microdissecting the dicentric X chromosome may help in understanding other atypical cytogenetic mechanisms for dicentric chromosome formation. These studies could determine whether the dicentric centromeres originated from homologous X chromosomes or are identical via duplication.

Presence of Turner stigmata in a case of dysgenetic male pseudohermaphroditism with 45,X/46,X+mar karyotype

A case is reported of dysgenetic male pseudohermaphroditism (DMPH) having Turner stigmata and 45,X/46,X+mar karyotype. The marker chromosome of this patient consisted of most if not all of the short...