[Manifestations of Turner syndrome: don't miss the diagnosis]. / Uitingsvormen van Turner-syndroom.

Turner syndrome (TS) is one of the most common sex chromosomal abnormalities affecting girls and women. Diagnosis of this condition can be delayed due to a variation in clinical presentation, although an early age at diagnosis is important for several reasons. It enables psychosocial support for girls and their parents; early initiation of growth hormone therapy; puberty induction at an appropriate age; early recognition of comorbidities, such as cardiac or renal abnormalities; and timely removal of the gonads in girls with Y-chromosomal material, who are at risk for gonadoblastoma. By increasing the knowledge of health care professionals and implementing screening programs for girls with short stature, delayed puberty and/or congenital heart disease such as coarctation of the aorta, more girls might be diagnosed at an early age. This allows for lifelong follow up, which is indicated to prevent morbidity and mortality in the long term.

Relationships among maternal monosomy X mosaicism, maternal trisomy, and discordant sex chromosome aneuploidies.

OBJECTIVE: To explore the impact of maternal factors on the false-positive fetal sex chromosome aneuploidies (SCAs) results obtained through noninvasive prenatal screening (NIPS). METHODS: We retrospectively analyzed pregnant women with high-risk SCAs as revealed using NIPS between January 2017 and December 2022. Clinical data such as results of invasive prenatal diagnoses, copy number variation sequencing (CNV-seq) and pregnancy outcomes were analysed. RESULTS: Overall, 177 (0.6 %) women with SCA-positive results were collected from 27,941 patients who had undergone NIPS. Among them, 110 (62.2 %) pregnant women chose prenatal diagnosis and 39 (35.5 %) cases were confirmed. For the women with monosomy X false-positive results from the NIPS, 53.1 % (17/32) were found to be maternal mosaicism monosomy X. In cases with 47, XXX false-positive results, 60 % (6/10) of them were maternal 47,XXX (5 cases) or maternal mosaicism 47,XXX (1 case). One (1/6, 16.7 %) case of maternal mosaicism monosomy X was detected in the false positive results of 47, XXY/47, XYY revealed. The incidence rate of maternal sex chromosome abnormalities was positively correlated with the Z-score of ChrX. When the Z-score of ChrX ≥ 15, more than 50 % of pregnant women were found to be maternal sex chromosome abnormalities, and when Z-score ≥ 30, the incidence rate was as high as 100 %. CONCLUSIONS: Maternal monosomy X mosaicism and trisomy X respectively played an important role in the discordance of 45, X and 47, XXX revealed by NIPS. CNV-seq was recommended for the pregnant women at risk of maternal sex chromosome abnormalities, which could help clinicians to provide more accurate and efficient advice during genetic counseling and to guide appropriate prenatal diagnosis strategy for the next pregnancy.

Inspiring New Science to Guide Healthcare in Turner Syndrome: Rationale, design, and methods for the InsighTS Registry.

Inspiring New Science to Guide Healthcare in Turner Syndrome (InsighTS) Registry is a national, multicenter registry for individuals with Turner syndrome (TS) designed to collect and store validated longitudinal clinical data from a diverse cohort of patients with TS. Herein, we describe the rationale, design, and approach used to develop the InsighTS registry, as well as the demographics of the initial participants to illustrate the registry's diversity and future utility. Multiple stakeholder groups have been involved from project conceptualization through dissemination, ensuring the registry serves the priorities of the TS community. Key features of InsighTS include recruitment strategies to facilitate enrollment of participants that appropriately reflect the population of individuals with TS receiving care in the US, clarity of data ownership and sharing, and sustainability of this resource. The registry gathers clinical data on diagnosis, treatment, comorbidities, health care utilization, clinical practices, and quality of life with the goal of improving health outcomes for this population. Future directions include multiple patient-centered clinical-translational research projects that will use the InsighTS platform. This thorough and thoughtful planning will ensure InsighTS is a valuable and sustainable resource for the TS community for decades to come.

45,X/46,XY mosaicism: Clinical manifestations and long term follow-up.

45,X/46,XY chromosomal mosaicism presents a range of clinical manifestations, including phenotypes from Turner syndrome through genital abnormalities to apparently unaffected phenotypic males; however, the full clinical spectrum has not yet been fully delineated since prior studies on the clinical phenotype and associated risk of gonadal tumors included small cohorts and limited follow-up. To better describe the clinical manifestations and long-term outcome of patients with 45,X/46,XY mosaicism. We conducted a retrospective chart review of patients with 45,X/46,XY from three health centers (Hospital for Sick Children and Mount Sinai Hospital in Canada, and University of Pittsburgh Medical Center in United States). Of 100 patients with 45,X/46,XY karyotype, 47 were raised as females and 53 as males. Females were significantly shorter than males (p = 0.04) and height Z-score was significantly decreased with age for both genders (p = 0.02). Growth hormone (GH) treatment did not result in a significant height increase compared to the untreated group (p = 0.5). All females required puberty induction in contrast to majority of males. Five females were diagnosed with gonadal tumors, while no males were affected. Around 58% of patients exhibited at least one Turner syndrome stigmata. This study expands the clinical spectrum, long-term outcomes, and associated tumor risk in a large cohort of patients with 45,X/46,XY mosaicism. Additionally, it highlights our experience with GH therapy and prophylactic gonadectomy.

Lichen sclerosus associated with Turner syndrome treated with photodynamic therapy: A case report.

Turner syndrome (TS) is a rare clinical condition associated with a completely or partially absence, or structural abnormality of an X chromosome, mainly representing as short stature and skeletal anomalies, female hypergonadotropic hypogonadism and infertility. Skin is frequently involved in TS, especially autoimmune diseases like vitiligo and lichen sclerosus (LS). Here, we present a 10-year-old Chinese girl with TS combined with both vulvar LS (VLS) and extragenital LS, who had been misdiagnosed as eczema and vitiligo for years. In order to control LS sufficiently and allay the parents' concerns of potential side effects of topical corticosteroids, she was prescribed with tacrolimus ointment on the extragenital lesions, and photodynamic therapy (PDT) for vulvar lesions. For PDT regimen, we used 5-aminolevulinic acid (ALA) as photosensitizer and 633 nm red light to irradiate the lesion area at 60 mW / cm2 for 30 min each time. After 6 times of treatment at 2-week intervals, a satisfactory remission of both pruritus and lesion severity was achieved. So far, the guideline on TS did not include LS as a common comorbidity to raise attention. However, accurate diagnosis and effective treatment are essential for LS to avoid the possibilities of developing labial atrophy, adhesion, or even vulvar cancer. Based on our research, PDT can significantly relieve subjective symptoms, objective lesion severity and histopathological changes of VLS with good tolerance, and therefore can also be a safe and effective therapeutic alternative in such comorbidity in TS patients.

[Clinical characterization of girls with Turner syndrome]. / Caracterización de una cohorte de pacientes pediátricas con Síndrome de Turner.

Turner syndrome is a genetic disorder that occurs in women with partial or complete absence of an X chromosome. OBJECTIVE: To describe the clinical, laboratory, and genotypic characteristics of patients with Turner syndrome, treated at three health institutions in Medellin. PATIENTS AND METHOD: A retrospective study was carried out. A total of 97 patients with Turner syndrome (< 18 years) confirmed by karyotype between 2011 and 2018 were included. Patients whose karyotype did not meet the specification of the American College of Medical Genetics were excluded. Data on sociodemographic details, nutritional variables, phenotypic characteristics, and laboratory tests were collected. A descriptive analysis was performed in SPSS software version 20. RESULTS: Median age at diagnosis was 8.5 years (IQR 4-12). The main clinical characteristic was short stature (90%). Additionally, they presented cardiovascular malformations (35%), renal alterations (26%), hearing disorders, mainly hypoacusis (33%), and neuropsychiatric disorders (44%). The most frequent karyotype was 45,X (51%) followed by 45,X/46,XX (14%). The patients with 45,X karyotype had the most classic clinical characteristics. Patients > 5 years old had a higher proportion of weight excess than the general population. Dyslipidemia was found in 62% and hypothyroidism in 22%. 70% of patients > 11 years received pubertal induction; 23% presented spontaneous puberty and 44% of them required hormonal maintenance. 86% received somatropin. CONCLUSION: The patients with Turner syndrome in our study presented a high frequency of short stature and cardiovascular, renal, hearing, endocrine, and neuropsychiatric comorbidities. The diagnosis was delayed due to the lack of clinical suspicion given its variable presentation.

[A case of congenital hypothyroidism and Turner syndrome.] / Un caso di ipotiroidismo congenito e sindrome di Turner.

When properly treated, congenital hypothyroidism (CH) allows normal growth. We describe the case of a girl followed-up for CH diagnosed upon newborn screening, with good adherence to L-T4 therapy, who had an impaired linear growth starting from 4 years of age. Diagnostic work-up allowed exclusion of inflammatory diseases and/or malabsorption and led to the diagnosis of Turner syndrome (TS). Recombinant GH (rGH) therapy was undertaken with satisfactory growth recovery. At the age of 8, a condition of autoimmune thyroiditis was detected, due to an increased risk in the context of her syndrome. Except for small adjustments in the dose of L-T4, hypothyroidism remained well-controlled even after starting rGH therapy.

High-level mosaicism for 45,X in 45,X/46,X,+mar at amniocentesis in a pregnancy associated with positive non-invasive prenatal testing for Turner syndrome, normal male external genitalia and positive SRY in the fetus, a favorable fetal outcome, postnatal decrease of the 45,X cell line and cytogenetic discrepancy in various tissues.

OBJECTIVE: We present high-level mosaicism for 45,X in 45,X/46,X,+mar at amniocentesis in a pregnancy associated with positive non-invasive prenatal testing (NIPT) for Turner syndrome, normal male external genitalia and positive SRY in the fetus, a favorable fetal outcome, postnatal decrease of the 45,X cell line and cytogenetic discrepancy in various tissues. CASE REPORT: A 35-year-old, gravida 2, para 1, woman underwent amniocentesis at 16 weeks of gestation because of positive NIPT for Turner syndrome (Z score = -11.72 for X chromosome) at 10 weeks of gestation. Amniocentesis revealed a karyotype of 45,X[13]/46,X,+mar[8]. Simultaneous molecular analysis on the DNA extracted from uncultured amniocytes revealed the results of arr (X) × 1, (Yp) × 0-1 (0.63), (Yq) × 0, (1-22) × 2 in array comparative genomic hybridization (aCGH) and rsa(X) × 1, Yp11.31 × 0-1, Yq11.21 × 0, (13, 18, 21) × 2 in multiplex ligation-dependent probe amplification (MLPA). The parental karyotypes were normal. Prenatal ultrasound revealed normal male external genitalia. She was referred for genetic counseling, and continuing pregnancy was advised. A 2875-g male baby was delivered at 38 weeks of gestation with normal male external genitalia. The karyotypes of cord blood, umbilical cord and placenta were 46,X,+mar[27]/45,X[13], 46,X,+mar[24]/45,X[16] and 45,X[22]/46,X,+mar[18], respectively. SRY testing on cord blood revealed a positive result. When follow-up at age two months, the neonate was normal in development. The karyotype of peripheral blood was 46,X,+mar[25]/45,X[13]/46,X,idic r(Y) [2]. Interphase fluorescence in situ hybridization (FISH) analysis on 103 buccal mucosal cells using Yp11.2-specific probe RP11-119E4 and Xp22.31-specific probe RP11-143E20 showed that 90 cells (90/103 = 87%) had double Yp signals, 3 cells (3/103 = 3%) had single Yp signal and 10 cells (10/103 = 10%) had no Yp signal. CONCLUSION: High-level mosaicism for 45,X in 45,X/46,X,+mar at amniocentesis with positive Yp and SRY can be associated with a favorable fetal outcome, postnatal decrease of the 45,X cell line and cytogenetic discrepancy in various tissues.

TurnerFertility trial: fertility preservation in young girls with Turner syndrome by freezing ovarian cortex tissue-a prospective intervention study.

OBJECTIVE: To evaluate which girls with Turner syndrome (TS) could benefit from fertility preservation by ovarian tissue cryopreservation on the basis of karyotype, puberty status, and hormonal data. DESIGN: Prospective intervention study; participants were included between 2018 and 2020. SETTING: Tertiary hospital in the Netherlands. PATIENTS: In total, 106 girls with TS aged between 2 and 18 years were included. Girls with minor X chromosome deletions, Y chromosomal content, active infections, or contraindications for surgery were excluded. INTERVENTION: A laparoscopic unilateral ovariectomy was performed to obtain ovarian cortical tissue for cryopreservation. One tissue fragment per participant was used to determine the number of follicles per ovary by serial sectioning and staining. Chromosome analysis was performed on lymphocytes and buccal cells. A blood sample was taken before the ovariectomy for hormonal analysis. MAIN OUTCOME MEASURES: The presence of follicles in ovarian cortex tissue from girls with TS in relation to karyotype, puberty status, and hormonal data. RESULTS: A unilateral ovariectomy was performed on 93 girls with TS. Complications after surgery occurred in 5 girls, including luxation of psychological symptoms in 2 girls. In 13 (14%) girls, a 46,XX cell line was found in buccal cells that was absent in lymphocytes. Follicles were observed in 30 (32%) of the 93 girls and were found mainly in girls with a 46,XX cell line in lymphocytes or buccal cells (Phi coefficient = 0.55). Spontaneous onset of puberty (Phi coefficient = 0.59), antimüllerian hormone (AMH; point-biserial correlation [r] = 0.82), inhibin B (r = 0.67), and follicle-stimulating hormone (r = -0.46) levels were also correlated strongly with the presence of follicles. Furthermore, AMH levels had a significant correlation with the number of follicles per ovary (r = 0.66). CONCLUSION: Favorable predictive markers for the presence of follicles included either a 46,XX cell line, spontaneous onset of puberty, or a combination of measurable AMH and normal follicle-stimulating hormone levels. Karyotyping of two peripheral cell lines in girls with TS is recommended to reveal hidden mosaicisms. Ovarian tissue cryopreservation should be offered with caution in a research setting to those with a sufficient ovarian reserve, considering the significant loss of follicles after ovarian tissue cryopreservation and autotransplantation. Physicians should pay attention to the mental health of the girls during the whole process. CLINICAL TRIAL REGISTRATION NUMBER: Trial registration number: NCT03381300- Preservation of Ovarian Cortex Tissue in Girls With Turner Syndrome - Full Text View - ClinicalTrials.gov. Registered on: December 21, 2017. First patient recruited on January 1, 2018.

[Application of fluorescence in situ hybridization combined with chromosomal karyotyping analysis in children with disorders of sex development due to sex chromosome abnormalities].

OBJECTIVE: To retrospectively analyze sex chromosomal abnormalities and clinical manifestations of children with disorders of sex development (DSD). METHODS: A total of 14 857 children with clinical features of DSD including short stature, cryptorchidism, hypospadia, buried penis and developmental delay were recruited from Zhengzhou Children's Hospital from January 2013 to March 2022. Fluorescence in situ hybridization (FISH) and chromosomal karyotyping were carried out for such children. RESULTS: In total 423 children were found to harbor sex chromosome abnormalities, which has yielded a detection rate of 2.85%. There were 327 cases (77.30%) with Turner syndrome and a 45,X karyotype or its mosaicism. Among these, 325 were females with short stature as the main clinical manifestation, 2 were males with short stature, cryptorchidism and hypospadia as the main manifestations. Sixty-two children (14.66%) had a 47,XXY karyotype or its mosaicism, and showed characteristics of Klinefelter syndrome (KS) including cryptorchidism, buried penis and hypospadia. Nineteen cases (4.49%) had sex chromosome mosaicisms (XO/XY), which included 11 females with short stature, 8 males with hypospadia, and 6 cases with cryptorchidism, buried penis, testicular torsion and hypospadia. The remainder 15 cases (3.55%) included 9 children with a XYY karyotype or mosaicisms, with main clinical manifestations including cryptorchidisms and hypospadia, 4 children with a 47,XXX karyotype and clinical manifestations including short stature and labial adhesion, 1 child with a 46,XX/46,XY karyotype and clinical manifestations including micropenis, hypospadia, syndactyly and polydactyly, and 1 case with XXXX syndrome and clinical manifestations including growth retardation. CONCLUSION: Among children with DSD due to sex chromosomal abnormalities, sex chromosome characteristics consistent with Turner syndrome was most common, among which mosaicism (XO/XX) was the commonest. In terms of clinical manifestations, the females mainly featured short stature, while males mainly featured external genital abnormalities. Early diagnosis and treatment are particularly important for improving the quality of life in such children.

Turner syndrome: skin, liver, eyes, dental and ENT evaluation should be improved.

Introduction: Turner syndrome association with multi-organ system comorbidities highlights the need for effective implementation of follow-up guidelines. We aimed to assess the adequacy of care with international guidelines published in 2007 and 2017 and to describe the phenotype of patients. Methods: In this multicenter retrospective descriptive cohort study, we collected growth and pubertal parameters, associated comorbidities, treatment, and karyotype in patients diagnosed at age <18 years between 1993 and 2022. We assessed age-appropriate recommendation follow-up (children, adolescents and adults) according to the 2007 guidelines if the last visit was before 2017 (18 recommendations) and the 2017 guidelines if the last visit was after 2017 (19 recommendations). Results: We included 68 patients followed at Lausanne University Hospital (n=64) and at Neuchatel Regional Hospital (RHNe) (n=4). 2.9% of patients underwent all recommended investigations.Overall, 68.9 ± 22.5% and 78.5 ± 20.6% of the recommendations were followed, before and after 2017 respectively. High implementation rates were found for height, weight and BMI (100%), cardiac (80 to 100%) and renal (90 to 100%) imaging. Low implementation rates were found for Ear, Nose and Throat (ENT) (56.5%), skin (38.5%), dental (23.1%), ophthalmological (10%) and cholestasis (0 to 29%) assessments, depending on age and time of visit. In adults (n=33), the mean proportion of followed recommendations was lower before than after 2017: 63.5 ± 25.8% vs. 78.7 ± 23.4%, p=0.039. Conclusion: Growth parameters, cardiac and renal imaging are well followed. However, efforts should be made for dental, ENT, ophthalmological, skin and cholestasis assessments. Adequacy of follow-up improved with the quality of transition to adult care.

Individuals with numerical and structural variations of sex chromosomes: interdisciplinary management with focus on fertility potential.

Diagnosis and management of individuals who have differences of sex development (DSD) due to numerical or structural variations of sex chromosomes (NSVSC) remains challenging. Girls who have Turner syndrome (45X) may present with varying phenotypic features, from classical/severe to minor, and some remain undiagnosed. Boys and girls who have 45,X/46,XY chromosomal mosaicism may have Turner syndrome-like features and short stature; therefore, unexplained short stature during childhood requires karyotype analysis in both sexes, particularly if characteristic features or atypical genitalia are present. Many individuals with Klinefelter syndrome (47XXY) remain undiagnosed or are only diagnosed as adults due to fertility problems. Newborn screening by heel prick tests could potentially identify sex chromosome variations but would have ethical and financial implications, and in-depth cost-benefit analyses are needed before nationwide screening can be introduced. Most individuals who have NSVSC have lifelong co-morbidities and healthcare should be holistic, personalized and centralized, with a focus on information, psychosocial support and shared decision-making. Fertility potential should be assessed individually and discussed at an appropriate age. Oocyte or ovarian tissue cryopreservation is possible in some women who have Turner syndrome and live births have been reported following assisted reproductive technology (ART). Testicular sperm cell extraction (TESE) is possible in some men who have 45,X/46,XY mosaicism, but there is no established protocol and no reported fathering of children. Some men with Klinefelter syndrome can now father a child following TESE and ART, with multiple reports of healthy live births. Children who have NSVSC, their parents and DSD team members need to address possibilities and ethical questions relating to potential fertility preservation, with guidelines and international studies still needed.

[A case of Turner syndrome associated with schizophrenia]. / Szkizofréniával társuló Turner-szindróma.

The authors present the case of a young woman with mosaic karyotype Turner's syndrome who was admitted to a partial hospitalization program due to comorbid schizophrenia. Psychiatric history of the patient included the diagnosis of mild mental retardation and an outpatient appointment due to depressive symptoms. Medical history included hormone replacement therapy due to primary ovarian insufficiency and autoimmune thyroiditis as well as a single case of physical polytrauma due to a road traffic accident years before her admission. On admission, the physical characteristics of Turner's syndrome, chronic phonemic hallucinations and paranoid delusion were found with secondary anger management and social adjustment problems. Brain imaging revealed global cerebral atrophy and a clinically not significant frontal meningioma. Neuropsychological tests confirmed the mild mental retardation and an imbalanced intelligence profile with better verbal than non-verbal functioning. Medication therapy was initiated with social skill training and outpatient follow-ups. Ten months after the initial admission, the antipsychotic monotherapy resulted in a good therapeutic response without a full remission of symptoms. We present our case in the context of a literature review. Orv Hetil. 2023; 164(19): 753-757.

Turner Syndrome with Mosaicism of X Chromosome: A Case Report.

Turners' syndrome, although common, is a complex syndrome that requires a multidisciplinary team to manage it. If undiagnosed prenatally or in childhood, Turners' syndrome females often present later to gynaecologists with premature ovarian insufficiency or infertility as their primary presenting complaint. Timely diagnosis and management are key to improving health outcomes in women with Turners' syndrome, as it is associated with multiple comorbidities which left untreated will result in excess morbidity and mortality. We hereby present a case of a 20-year-old female diagnosed to have Turner's syndrome with mosaicism of the X chromosome to highlight the wide array of clinical presentations it can have. Keywords: case reports; infertility; sex chromosome aberrations; Turner syndrome.