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Dowlut-McElroy T, Long JR, Mayhew AC, Lawson A, Fei YF, Smith AK, Shankar RK, Gomez-Lobo V. Gonadal Tumors in Individuals with Turner Syndrome and Y-Chromosome Mosaicism: A Retrospective Multisite Study. J Pediatr Adolesc Gynecol 2025; 38:154-160. [PMID: 39577758 DOI: 10.1016/j.jpag.2024.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 10/20/2024] [Accepted: 11/14/2024] [Indexed: 11/24/2024]
Abstract
STUDY OBJECTIVE To evaluate the prevalence of germ cell tumors and the clinical monitoring practices for those who deferred prophylactic gonadectomy in a large North American cohort of individuals with Turner syndrome with Y-chromosome mosaicism (TS+Y). METHOD A query of the medical records at multiple North American children's hospitals was done using ICD codes related to Turner Syndrome. A retrospective chart review was conducted on those patients between ages 0 to 30 years with Y-mosaicism. RESULTS The data of 57 participants were analyzed. Eight (25.8%, n = 31) ≥ 13 years underwent spontaneous thelarche. One (3.2%) had spontaneous menarche. Forty-seven (82.5%) had gonadectomy at a median age of 8 years (IQR 11.0, range <1 to 19 years). Sixteen (34%) had growth hormone therapy exposure prior to gonadectomy. Fourteen (29.8%) had gonadoblastoma. Two (4.3%) had dysgerminoma. Differences in age at gonadectomy, presence of the entire Y-chromosome, and exposure to growth hormone when comparing those with vs without gonadal tumor were not statistically significant. Gonadectomy had not been performed in 10 individuals, median age 6.5 (IQR 9.0, range <1 to 14 years). There was no consistency in the plan for ultrasound and/or tumor markers for follow-up. CONCLUSIONS Our data shows a prevalence of 24.6% of gonadal tumors in individuals with TS +Y and a relatively low risk of malignant transformation (3.5%). Prior exposure to growth hormone was not predictive of the presence of gonadal tumor. Future cytogenetic studies are needed to better understand the factors involved in the development of gonadal tumors.
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Affiliation(s)
- Tazim Dowlut-McElroy
- Pediatric and Adolescent Gynecology, Department of Surgery, Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri.
| | - Jessica R Long
- Pediatric and Adolescent Gynecology, Department of Obstetrics and Gynecology and Minimally Invasive Surgery, The University of Chicago, Pritzker School of Medicine, Chicago, Illinois
| | - Allison C Mayhew
- Pediatric and Adolescent Gynecology, Department of Surgery, Children's National Hospital, Washington, District of Columbia
| | - Ashli Lawson
- Pediatric and Adolescent Gynecology, Department of Surgery, Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
| | - Yeuyang Frances Fei
- Section of Pediatric and Adolescent Gynecology Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus, Ohio
| | - Anne K Smith
- Pediatric and Adolescent Gynecology, Gynecology & Reproductive Sciences, Yale School of Medicine, Yale New Haven Children's Hospital, New Haven, Connecticut
| | - Roopa Kanakatti Shankar
- Department of Endocrinology, Children's National Hospital, George Washington University School of Medicine, Washington, District of Columbia
| | - Veronica Gomez-Lobo
- Pediatric and Adolescent Gynecology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland
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van der Coelen S, van der Velden J, Nadesapillai S, Braat D, Peek R, Fleischer K. Navigating fertility dilemmas across the lifespan in girls with Turner syndrome-a scoping review. Hum Reprod Update 2024; 30:383-409. [PMID: 38452347 PMCID: PMC11215162 DOI: 10.1093/humupd/dmae005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 01/17/2024] [Indexed: 03/09/2024] Open
Abstract
BACKGROUND Girls with Turner syndrome (TS) lack a partial or complete sex chromosome, which causes an accelerated decline of their ovarian reserve. Girls have to deal with several dilemmas related to their fertility, while only a limited number of them are referred to a fertility specialist and counselled about options of family planning on time. OBJECTIVE AND RATIONALE This scoping review provides an update of the literature on fertility in girls with TS throughout their lifespan and aims to propose a clinical practice guideline on fertility in TS. SEARCH METHODS Databases of PubMed, Embase, and Web of science were searched using the following key terms: Turner syndrome, fertility, puberty, pregnancy, sex-hormones, karyotype, fertility preservation, assisted reproductive techniques, and counselling, alongside relevant subject headings and synonymous terms. English language articles published since 2007 were critically reviewed. Pregnancies after using donated oocytes and data about girls with TS with Y-chromosomal content were excluded. OUTCOMES This search identified 1269 studies of which 120 were extracted for the review. The prevalence of natural conception ranged from 15% to 48% in women with 45,X/46,XX, 1% to 3% in women with 45,X, and 4% to 9% in women with other TS karyotypes. When assessing a girl's fertility potential, it was crucial to determine the karyotype in two cell lines, because hidden mosaicism may exist. In addition to karyotype, assessment of anti-Müllerian hormone (AMH) played a significant role in estimating ovarian function. Girls with AMH above the detection limit were most likely to experience spontaneous thelarche, menarche, and ongoing ovarian function during the reproductive lifespan. Fertility preservation became more routine practice: vitrification of oocytes was reported in 58 girls with TS and a median of five oocytes were preserved per stimulation. Ovarian tissue cryopreservation has demonstrated the presence of follicles in approximately 30% of girls with TS, mostly in girls with mosaic-TS, spontaneous puberty, and AMH above the detection limit. Although girls and their parents appreciated receiving counselling on fertility in TS, only one in ten girls with TS received specialized counselling. Unfamiliarity with fertility preservation techniques or uncertainties regarding the eligibility of a girl for fertility preservation constituted barriers for healthcare professionals when discussing fertility with girls with TS. WIDER IMPLICATIONS There currently is a high demand for fertility preservation techniques in girls with TS. A reliable prognostic model to determine which girls with TS might benefit from fertility preservation is lacking. Only a minority of these girls received comprehensive fertility counselling on the full spectrum of fertility, including uncertainties of fertility preservation, pregnancy risks, and alternatives, such as adoption. Fertility preservation could be a viable option for girls with TS. However, the question remains whether enough oocytes can be obtained for a realistic prospect of a live birth. It is important that girls and parents are empowered with the necessary information to make a well-informed decision.
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Affiliation(s)
- Sanne van der Coelen
- Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Janielle van der Velden
- Department of Paediatrics, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Sapthami Nadesapillai
- Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Didi Braat
- Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ronald Peek
- Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Kathrin Fleischer
- Department of Reproductive Medicine, Nij Geertgen Center for Fertility, Elsendorp, The Netherlands
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Kalfa N, Nordenström J, De Win G, Hoebeke P. Adult outcomes of urinary, sexual functions and fertility after pediatric management of differences in sex development: Who should be followed and how? J Pediatr Urol 2024; 20:367-375. [PMID: 38423920 DOI: 10.1016/j.jpurol.2024.01.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 12/19/2023] [Accepted: 01/21/2024] [Indexed: 03/02/2024]
Abstract
The management of Differences of Sex Development (DSD) has evolved considerably in recent years. The questioning of systematic early childhood treatment of DSD requires a better understanding of the outcomes of such treatments and long-term studies are therefore essential to better evaluate the prognosis of DSD. Unfortunately, limitations are numerous including the limited size of the series, the absence of standardized methodology, the evaluation of managements that no longer take place today and the absence of prospective and comparative studies. Despite these difficulties, the purpose of this paper is to present the current data on the long-term follow-up of patients with DSD from the urological, sexual and fertility points of view. Even if it remains difficult at present to establish precise recommendations, we recapitulate the most important points that should drive follow-up of these patients especially the constitution of a multidisciplinary team with a holistic approach, the organization of the transition between adolescence and adulthood, a particular attention to psychological care, a careful communication with the patients and his/her family and the use of standardized data collection systems.
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Affiliation(s)
- Nicolas Kalfa
- Département de Chirurgie Infantile, Service de Chirurgie Viscérale et Urologie Pédiatrique, CHU de Montpellier, Montpellier, France; Centre de Référence Maladies Rares DEVGEN Constitutif Sud, CHU de Montpellier, Montpellier, France; UMR 1302 Institute Desbrest of Epidemiology and Public Health, INSERM, Univ Montpellier, Montpellier, France.
| | - Josefin Nordenström
- Department of Pediatric Surgery/Urology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Gunter De Win
- Department of Urology, University Hospital Antwerp, Edegem, Belgium; Astarc, Faculty of Medicine and Health Science, University of Antwerp, Belgium; Adolescenty Urology, University College London Hospitals, London, UK
| | - Piet Hoebeke
- Department of Urology, Ghent University Hospital, Gent, Belgium
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Nadesapillai S, van der Velden J, van der Coelen S, Schleedoorn M, Sedney A, Spath M, Schurink M, Oerlemans A, IntHout J, Beerendonk I, Braat D, Peek R, Fleischer K. TurnerFertility trial: fertility preservation in young girls with Turner syndrome by freezing ovarian cortex tissue-a prospective intervention study. Fertil Steril 2023; 120:1048-1060. [PMID: 37549836 DOI: 10.1016/j.fertnstert.2023.08.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 07/26/2023] [Accepted: 08/01/2023] [Indexed: 08/09/2023]
Abstract
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.
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Affiliation(s)
- Sapthami Nadesapillai
- Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, Gelderland, the Netherlands.
| | - Janielle van der Velden
- Department of Pediatrics, Amalia's Children's Hospital, Radboud University Medical Center, Nijmegen, Gelderland, the Netherlands
| | - Sanne van der Coelen
- Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, Gelderland, the Netherlands
| | - Myra Schleedoorn
- Emergency Department, County Hospital Lohr am Main, Am Sommerberg, Lohr am Main, Germany
| | - Amy Sedney
- Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, Gelderland, the Netherlands
| | - Marian Spath
- Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, Gelderland, the Netherlands
| | - Maarten Schurink
- Department of Pediatric Surgery, Amalia's Children's Hospital, Radboud University Medical Center, Nijmegen, Gelderland, the Netherlands
| | - Anke Oerlemans
- IQ Healthcare, Radboud University Medical Center, Nijmegen, Gelderland, the Netherlands
| | - Joanna IntHout
- Department for Health Evidence, Radboud University Medical Center, Nijmegen, Gelderland, the Netherlands
| | - Ina Beerendonk
- Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, Gelderland, the Netherlands
| | - Didi Braat
- Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, Gelderland, the Netherlands
| | - Ronald Peek
- Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, Gelderland, the Netherlands
| | - Kathrin Fleischer
- Department of Reproductive Medicine, Nij Geertgen Center for Fertility, Ripseweg, Elsendorp, the Netherlands
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Ossama HM, Kholeif S, Elhady GM. The Use of Fluorescence In situ Hybridisation in the Diagnosis of Hidden Mosaicism in Egyptian Patients with Turner Syndrome. J Hum Reprod Sci 2023; 16:286-298. [PMID: 38322635 PMCID: PMC10841934 DOI: 10.4103/jhrs.jhrs_128_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 12/01/2023] [Accepted: 12/01/2023] [Indexed: 02/08/2024] Open
Abstract
Background Turner syndrome (TS) is the most common chromosomal abnormality in females. The diagnosis of TS is based on karyotyping of 30 blood lymphocytes. This technique does not rule out tissue mosaicism or low-grade mosaicism in the blood. Because of the associated risk of gonadoblastoma, mosaicism is especially important in case this involves a Y chromosome. Aims This study was set to determine the value of additional genetic studies such as fluorescent in situ hybridisation and the inclusion of buccal cells in search for mosaicism in TS patients. Settings and Design This cross-sectional, descriptive study was performed in Human Genetics Department, Medical Research Institute, Alexandria University. Materials and Methods Fluorescence in situ hybridisation technique was applied to lymphocyte cultures as well as buccal smears using centromeric probes for X and Y chromosomes. Genotype phenotype correlation was also evaluated. Statistical Analysis Used Descriptive study where categorical variables were described using number and percentage and continuous variables were described using mean and standard deviation. Results Fluorescence in situ hybridisation technique study detected hidden mosaicism in 60% of studied patients; 20% of patients had a cell line containing Y material, while 40% had variable degrees of X, XX mosaicism, and in the remaining 40% no second cell line was detected. Fluorescence in situ hybridisation study helped identify the origin of the marker to be Y in all patients. The introduction of an additional cell line helped in identifying mosaicism in patients with monosomy X. Virilisation signs were only observed among TS patients with Y cell line mosaicism. The clinical manifestations were more severe in patients with monosomy X than other mosaic cases. Conclusions Molecular cytogenetic investigation for all suspected cases of TS should be considered for appropriate treatment plan and genetic counselling.
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Affiliation(s)
- Heba Mohamed Ossama
- Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Soha Kholeif
- Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Ghada Mohamed Elhady
- Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt
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Karila D, Donadille B, Léger J, Bouvattier C, Bachelot A, Kerlan V, Catteau-Jonard S, Salenave S, Albarel F, Briet C, Coutant R, Brac De La Perriere A, Valent A, Siffroi JP, Christin-Maitre S. Prevalence and characteristics of gonadoblastoma in a retrospective multi-center study with follow-up investigations of 70 patients with Turner syndrome and a 45,X/46,XY karyotype. Eur J Endocrinol 2022; 187:873-881. [PMID: 36305565 DOI: 10.1530/eje-22-0593] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 10/27/2022] [Indexed: 11/08/2022]
Abstract
INTRODUCTION A gonadectomy is currently recommended in patients with Turner syndrome (TS) and a 45,X/46,XY karyotype, due to a potential risk of gonadoblastoma (GB). However, the quality of evidence behind this recommendation is low. OBJECTIVE This study aimed to evaluate the prevalence of GB, its characteristics, as well as its risk factors, according to the type of Y chromosomal material in the karyotype. METHODS Our study within French rare disease centers included patients with TS and a 45,X/46,XY karyotype, without ambiguity of external genitalia. Clinical characteristics of the patients, their age at gonadectomy, and gonadal histology were recorded. The regions of the Y chromosome, the presence of TSPY regions, and the percentage of 45,X/46,XY mosaicism were evaluated. RESULTS A total of 70 patients were recruited, with a median age of 29.5 years (21.0-36.0) at the end of follow-up. Fifty-eight patients had a gonadectomy, at a mean age of 15 ± 8 years. GB was present in nine cases. Two were malignant, which were discovered at the age of 14 and 32 years, without metastases. Neither the percentage of XY cells within the 45,X/46,XY mosaicism nor the number of TSPY copies was statistically different in patients with or without GB (P = 0.37). However, the entire Y chromosome was frequent in patients with GB (6/9). CONCLUSIONS In our study, including a large number of patients with 45,X/46,XY TS, the prevalence of gonadoblastoma is 12.8%. An entire Y chromosome appears as the main risk factor of GB and should favor early gonadectomy. SIGNIFICANT STATEMENT About 10% of patients with TS have a karyotype containing Y chromosomal material: 45,X/46,XY. Its presence is related to the risk of GB. Therefore, a prophylactic gonadectomy is currently recommended in such patients. However, the quality of evidence is low. Our objective was to evaluate the prevalence of GB according to the type of Y-chromosomal material. We found a prevalence of GB of 12.8% in a cohort of 70 TS patients. No sign of hyperandrogenism was observed. The entire Y chromosome was the most frequent type of Y-material in patients with GB. As the prognosis of these tumors was good, a delay of surgery might be discussed.
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Affiliation(s)
- Daphné Karila
- Sorbonne University, Endocrine Unit, Reproductive Medicine, Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du Développement (CRMERC), Endo-ERN (id 739527), Saint-Antoine Hospital, AP-HP, Paris, France
| | - Bruno Donadille
- Sorbonne University, Endocrine Unit, Reproductive Medicine, Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du Développement (CRMERC), Endo-ERN (id 739527), Saint-Antoine Hospital, AP-HP, Paris, France
| | - Juliane Léger
- Pediatric Endocrinology and Diabetology, Robert-Debré Hospital, Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du Développement (CRMERC), Endo-ERN Paris, France
| | - Claire Bouvattier
- Pediatric Endocrinology and Diabetology, Bicêtre Hospital, Centre de référence des maladies rares du développement (DEVGEN), Endo-ERN Le Kremlin Bicêtre, France
| | - Anne Bachelot
- Sorbonne University, Department of Endocrinology and Reproductive Medicine, Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du Développement, CRMERC, Endo-ERN, Pitié-Salpêtrière Hospital, AP-HP, Paris, France
| | | | | | - Sylvie Salenave
- Endocrinology and metabolism, Bicêtre Hospital, Le Kremlin Bicetre, APHP, France
| | - Frédérique Albarel
- Department of Endocrinology, Assistance Publique-Hôpitaux de Marseille (AP-HM), Hôpital de la Conception, Centre de référence des Maladies Rares de l'hypophyse HYPO, 13005 Marseille, FRANCE
| | - Claire Briet
- Endocrinology, Diabetology, and Nutrition, Centre de référence des maladies rares de la Thyroïde et des Récepteurs Hormonaux, ENDO ERN CHU Angers, Angers, France
| | - Regis Coutant
- Pediatric Endocrinology and Diabetology, Centre de référence des maladies rares de la Thyroïde et des Récepteurs Hormonaux Endo-ERN CHU Angers, Angers, France
| | | | - Alexander Valent
- Department of Molecular Pathology, Cytogenetics and Medical Biology, Institut Gustave Roussy, Villejuif, France
| | - Jean-Pierre Siffroi
- Sorbonne University, Genetic unit, Trousseau Hospital, Paris, APHP, France
- INSERM UMR-833, Trousseau Hospital, Paris, France
| | - Sophie Christin-Maitre
- Sorbonne University, Endocrine Unit, Reproductive Medicine, Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du Développement (CRMERC), Endo-ERN (id 739527), Saint-Antoine Hospital, AP-HP, Paris, France
- INSERM UMR-833, Trousseau Hospital, Paris, France
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Schleedoorn MJ, Fleischer K, Braat D, Oerlemans A, van der Velden A, Peek R. Why Turner patients with 45, X monosomy should not be excluded from fertility preservation services. Reprod Biol Endocrinol 2022; 20:143. [PMID: 36138432 PMCID: PMC9494871 DOI: 10.1186/s12958-022-01015-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 08/10/2022] [Indexed: 11/10/2022] Open
Abstract
In this case report, we highlight the practical dilemma, i.e. to perform ovarian tissue cryopreservation surgery in a 45, X Turner Syndrome patient or not, by reporting on the presence of follicles in a 13-year-old female diagnosed with 45, X monosomy and an unmeasurable anti-müllerian hormone serum level. We compare our results with previous research, highlight the challenges we faced in this case and provide recommendations for daily practice. Hereby, we demonstrate that excluding certain subgroups of Turner Syndrome patients (e.g. monosomy patients, and/or girls with an anti-müllerian hormone level below 2.0 ng/l) may be premature, especially based on the current state of published research data. This practical example of a challenging dilemma in the counselling of Turner Syndrome patients for fertility preservation is of interest for clinicians involved in fertility counselling and Turner Syndrome care.
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Affiliation(s)
- M J Schleedoorn
- Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, the Netherlands.
| | - K Fleischer
- Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, the Netherlands
| | - Ddm Braat
- Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, the Netherlands
| | - Ajm Oerlemans
- Medical Ethics, Radboud University Medical Centre, Nijmegen, the Netherlands
| | - Aaem van der Velden
- Paediatric Endocrinology, Radboud University Medical Centre Amalia Children's Hospital, Nijmegen, the Netherlands
| | - R Peek
- Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, the Netherlands
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Abstract
PURPOSE OF REVIEW Turner syndrome is the most common sex chromosome abnormality in female individuals, affecting 1/2000-1/2500 female newborns. Despite the high incidence of this condition, the mechanisms underlying the development of multiorgan dysfunction have not been elucidated. RECENT FINDINGS Clinical features involve multiple organ systems and include short stature, dysmorphic facial features, delayed puberty and gonadal failure, cardiac and renal abnormalities, audiologic abnormalities, and a high prevalence of endocrine and autoimmune disorders. Paucity of available genotype/phenotype correlation limits the ability of clinicians to provide accurate guidance and management. Given the advent of robust genetic testing and analysis platforms, developments in the genetic basis of disease are materializing at a rapid pace. SUMMARY The objective of this review is to highlight the recent advances in knowledge and to provide a framework with which to apply new data to the foundational understanding of the condition.
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Dejonckheere C, Moyson C, de Zegher F, Antonio L, Van Buggenhout G, Decallonne B. Neoplasia in Turner syndrome: a retrospective cohort study in a tertiary referral centre in Belgium. Acta Clin Belg 2022; 77:86-92. [PMID: 32780684 DOI: 10.1080/17843286.2020.1805237] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVES Patients with Turner syndrome (TS), the most common sex chromosome abnormality in women, can suffer from a variety of well-researched reproductive, cardiovascular, metabolic, and autoimmune comorbidities. Few studies investigate the neoplasia risk. We assessed the general neoplasia risk in TS women, and more specifically, the gonadoblastoma/dysgerminoma risk in the subgroup with Y chromosome mosaicism, and evaluated potential risk factors for neoplasia development, such as karyotype, metabolic and autoimmune comorbidity, and treatment with growth hormone and/or estrogen replacement. DESIGN 10-year retrospective cohort study in a tertiary referral centre in Belgium. RESULTS 105 TS women were included (median age 29; range 2-69). Six malignant tumours were detected in 5 (4.8%) patients (SIR = 0.6, 95% CI 0.2-1.0). In addition, 2 benign meningiomas were observed, resulting in 3 (2.9%) tumours of the central nervous system (CNS; SIR = 19.9, 95% CI 4.0-35.8). No breast cancer was noted. Benign neoplasms occurred in 22 women (21.0%), with skin lesions being the most frequent. All patients with Y chromosome mosaicism (n = 9; 8.6%) underwent prophylactic gonadectomy, but gonadoblastoma/dysgerminoma was not detected. A weak association was found between any tumour type and autoimmune comorbidity (r = 0.24; p = 0.02). CONCLUSION The overall malignancy risk was not increased, but a different pattern of occurrence is apparent, with an increased risk of CNS and skin tumours and a decreased breast cancer risk. Gonadoblastoma/dysgerminoma was not reported. There is a need for centralised multidisciplinary care and prospective research to unravel and predict the neoplasia risk.
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Affiliation(s)
- Cas Dejonckheere
- Faculty of Medicine, Catholic University Leuven, Leuven, Belgium
| | - Carolien Moyson
- Department of Adult Endocrinology, University Hospitals Leuven, Leuven, Belgium
| | - Francis de Zegher
- Department of Paediatrics, University Hospitals Leuven, Leuven, Belgium
| | - Leen Antonio
- Department of Adult Endocrinology, University Hospitals Leuven, Leuven, Belgium
| | | | - Brigitte Decallonne
- Department of Adult Endocrinology, University Hospitals Leuven, Leuven, Belgium
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Barbosa LG, Siviero-Miachon AA, Souza MA, Spinola-Castro AM. Recognition of the Y chromosome in Turner syndrome using peripheral blood or oral mucosa tissue. Ann Pediatr Endocrinol Metab 2021; 26:272-277. [PMID: 34634867 PMCID: PMC8749017 DOI: 10.6065/apem.2142026.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 05/31/2021] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Turner syndrome is defined as total or partial loss of the second sex chromosome in a phenotypically female patient. Due to the possibility of hidden mosaicism of fragments of the Y chromosome and development of gonadoblastoma, we evaluated the presence of such fragments in 2 tissues with different embryonic origins, peripheral blood lymphocytes (mesoderm), and oral mucosal cells (ectoderm) using multiplex polymerase chain reaction. METHODS DNA samples were collected from 109 patients, and primers for the SRY, TSPY, and AMELX genes were used. RESULTS We found 14 patients (12.8%) with positive molecular markers for the Y chromosome. The study of tissues of different embryological origin showed the same degree of agreement, sensitivity, and specificity. CONCLUSION Oral mucosa cells have a simpler method of collection that is less invasive and requires less time for DNA extraction at a lower cost.
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Affiliation(s)
- Lene Garcia Barbosa
- Division of Pediatric Endocrinology, Department of Pediatrics in Federal University of Sao Paulo (UNIFESP-EPM), Sao Paulo, Brazil,Address for correspondence: Lene Garcia Barbosa Division of Pediatric Endocrinology, Department of Pediatrics in Federal University of Sao Paulo (UNIFESPEPM), Sao Paulo, Brazil,340 José de Magalhães Street, São Paulo 04026- 090, Brazil
| | | | | | - Angela Maria Spinola-Castro
- Division of Pediatric Endocrinology, Department of Pediatrics in Federal University of Sao Paulo (UNIFESP-EPM), Sao Paulo, Brazil
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11
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Soares JS, da Silva Lago RMR, Toralles MBP, Mota LR, Alves ES, de Carvalho AFL. Searching chromosome mosaicisms in 45,X Turner syndrome: how relevant is it? ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2021; 65:739-746. [PMID: 34762780 PMCID: PMC10065388 DOI: 10.20945/2359-3997000000403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Objective To investigate the presence of chromosome mosaicism, especially for the presence of Y derived material in 45,X women with Turner syndrome (TS). Methods FISH and PCR were performed for the presence of chromosome mosaicism and Y-derived-material and genetic findings were correlated to clinical data. Results Thirty-one participants were enrolled: 18 (58%) had chromosome mosaicisms (FISH), Y-derived material was found in 2. Yet, SRY primer was found with PCR in only one of them and DYZ3 was not found. The most frequent clinical findings were short or webbed neck (81,82%), high-arched palate (78%), breast hypertelorism, e cubitus valgus and genu valgus (57.6%, both), short fourth metacarpals (46.9%), epicanthic folds (43.8%), shield chest (43.8%), lymphedema (37.5%), and low set ears (34.4%). Both patients with Y-derived-material had primary amenorrhea, dyslipidemia and reached the height of 150 cm despite not treated with recombinant growth hormone (GHr). One of them showed 26% of leukocytes with Y-derived material and few clinical findings. Conclusion FISH techniques proved efficient in detecting chromosome mosaicisms and Y-derived material and searching in different tissues such as mouth cells is critical due to the possibility of tissue-specific mosaicism. Phenotypical variance in TS may be a signal of chromosome mosaicisms, especially with the presence of Y-derived material.
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Affiliation(s)
- Jéssica Silva Soares
- Laboratório de Genética Humana e Mutagênese, Instituto de Biologia, Universidade Federal da Bahia, Salvador, BA, Brasil
| | | | - Maria Betânia Pereira Toralles
- Departamento de Genética Médica, Hospital Universitário Edgard Santos, Universidade Federal da Bahia, Salvador, BA, Brasil
| | - Laís Ribeiro Mota
- Laboratório de Genética Humana e Mutagênese, Instituto de Biologia, Universidade Federal da Bahia, Salvador, BA, Brasil
| | - Esmeralda Santos Alves
- Departamento de Genética Médica, Hospital Universitário Edgard Santos, Universidade Federal da Bahia, Salvador, BA, Brasil
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12
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Noordman ID, Fejzic Z, Bos M, Duijnhouwer AL, Weijers G, Kempers M, Merkx R, van der Velden JAEM, Kapusta L. Cardiac abnormalities in girls with Turner syndrome: ECG abnormalities, myocardial strain imaging, and karyotype-phenotype associations. Am J Med Genet A 2021; 185:2399-2408. [PMID: 33969942 PMCID: PMC8359841 DOI: 10.1002/ajmg.a.62259] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/09/2021] [Accepted: 04/24/2021] [Indexed: 12/13/2022]
Abstract
Turner syndrome (TS) is a chromosomal condition which is associated with an increased prevalence of cardiac morbidity and mortality. In this cross‐sectional study, Minnesota‐based electrocardiographic (ECG) abnormalities, aortic dimensions, routine‐ and myocardial strain echocardiographic parameters, and karyotype‐cardiac phenotype associations were assessed in girls with TS. In total, 101 girls with TS (0–18 years) were included. The prevalence of major ECG abnormalities was 2% (T‐wave abnormalities) and 39% had minor ECG abnormalities. Dilatation of the ascending aorta (z‐score > 2) was present in 16%, but the prevalence was much lower when using TS‐specific z‐scores. No left ventricular hypertrophy was detected and the age‐matched global longitudinal strain was reduced in only 6% of the patients. Cardiac abnormalities seemed more common in patients with a non‐mosaic 45,X karyotype compared with other karyotypes, although no statistically significant association was found. Lowering the frequency of echocardiography and ECG screening might be considered in girls with TS without cardiovascular malformations and/or risk factors for aortic dissection. Nevertheless, a large prospective study is needed to confirm our results. The appropriate z‐score for the assessment of aortic dilatation remains an important knowledge gap. The karyotype was not significantly associated with the presence of cardiac abnormalities, therefore cardiac screening should not depend on karyotype alone.
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Affiliation(s)
- Iris D Noordman
- Department of Pediatric Endocrinology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Zina Fejzic
- Department of Pediatric Cardiology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Melanie Bos
- Department of Pediatric Cardiology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | | | - Gert Weijers
- Medical Imaging, Medical UltraSound Imaging Center, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marlies Kempers
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Remy Merkx
- Medical Imaging, Medical UltraSound Imaging Center, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Janiëlle A E M van der Velden
- Department of Pediatric Endocrinology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Livia Kapusta
- Department of Pediatric Cardiology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands.,Pediatric cardiology unit, Dana-Dwek Children's Hospital, Tel-Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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13
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Graff A, Donadille B, Morel H, Villy MC, Bourcigaux N, Vatier C, Borgel A, Khodawardi A, Siffroi JP, Christin-Maitre S. Added value of buccal cell FISH analysis in the diagnosis and management of Turner syndrome. Hum Reprod 2021; 35:2391-2398. [PMID: 32810206 DOI: 10.1093/humrep/deaa197] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 07/05/2020] [Indexed: 12/17/2022] Open
Abstract
STUDY QUESTION Is there an added diagnosis value of buccal cell FISH analysis compared with blood lymphocyte chromosomal investigations in patients with Turner syndrome (TS)? SUMMARY ANSWER Buccal cell FISH analysis, a non-invasive technique, modified the chromosomal results obtained with the blood karyotype in 17 patients (12%) of our cohort. WHAT IS KNOWN ALREADY Few studies have evaluated buccal cell FISH analysis and compared them with blood karyotype in patients with TS. STUDY DESIGN, SIZE, DURATION A prospective, monocentric cohort study was conducted in a rare diseases centre (CMERC) between July 2017 and August 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS In total, 142 adult patients with TS, and at least 5% 45,X cells in a previous blood karyotype, were recruited. All the patients' files were included in the CEMARA database. This national database has been declared to the French data protection agency (CNIL approval number 1187326). In compliance with French law, consent regarding non-opposition to collect and use the data was obtained from each patient. A FISH analysis on a buccal smear was performed. MAIN RESULTS AND THE ROLE OF CHANCE The percentage of 45,X cells was identical between the two tissues in only 32.4% of cases. The discrepancy was higher than 41% for 12% of the cohort. The percentage of 45,X cells was higher in blood in 53 (37.3%) patients, and higher in buccal cells in 43 (30.3%) of cases. In 17 (12%) cases, the blood karyotype had to be reconsidered in regard to the buccal cell analysis. LIMITATIONS, REASONS FOR CAUTION It would have been interesting to evaluate karyotypes in cells from other tissues such as cells from skin biopsy or from the urinary tract and even from blood vessels or gonads in case of surgery and to compare them with each patient's phenotype. However, most of the time, these tissues are not available. WIDER IMPLICATIONS OF THE FINDINGS Although blood lymphocyte karyotype remains the gold standard for the diagnosis of TS, buccal cell FISH analysis is an efficient tool to evaluate the global chromosomal constitution in these patients, thus allowing them to have better care and follow-up. For instance, identifying a Y chromosome can prevent the occurrence of a gonadoblastoma, as gonadectomy should be discussed. On the other hand, finding normal XX cells in a patient with a previous diagnosis of homogenous 45,X TS, may be psychologically helpful and relevant for gynaecological care. STUDY FUNDING/COMPETING INTEREST(S) No specific funding was sought for the study. The authors declare no competing interests. TRIAL REGISTRATION NUMBER N/A.
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Affiliation(s)
- A Graff
- Sorbonne Université, Service d'Endocrinologie, diabétologie et médecine de la reproduction, Hôpital Saint-Antoine, AP-HP, Paris, France
| | - B Donadille
- Sorbonne Université, Service d'Endocrinologie, diabétologie et médecine de la reproduction, Hôpital Saint-Antoine, AP-HP, Paris, France
| | - H Morel
- Département de Génétique Médicale, Sorbonne Université, AP-HP, Hôpital d'Enfants Armand Trousseau, Paris, France
| | - M C Villy
- Département de Génétique Médicale, Sorbonne Université, AP-HP, Hôpital d'Enfants Armand Trousseau, Paris, France
| | - N Bourcigaux
- Sorbonne Université, Service d'Endocrinologie, diabétologie et médecine de la reproduction, Hôpital Saint-Antoine, AP-HP, Paris, France
| | - C Vatier
- Sorbonne Université, Service d'Endocrinologie, diabétologie et médecine de la reproduction, Hôpital Saint-Antoine, AP-HP, Paris, France
| | - A Borgel
- Département de Génétique Médicale, Sorbonne Université, AP-HP, Hôpital d'Enfants Armand Trousseau, Paris, France
| | - A Khodawardi
- Département de Génétique Médicale, Sorbonne Université, AP-HP, Hôpital d'Enfants Armand Trousseau, Paris, France
| | - J P Siffroi
- Département de Génétique Médicale, Sorbonne Université, AP-HP, Hôpital d'Enfants Armand Trousseau, Paris, France.,INSERM, Maladies génétiques d'expression pédiatrique UMR 933, Hôpital d'Enfants Armand Trousseau, Paris, France
| | - S Christin-Maitre
- Sorbonne Université, Service d'Endocrinologie, diabétologie et médecine de la reproduction, Hôpital Saint-Antoine, AP-HP, Paris, France.,INSERM, Maladies génétiques d'expression pédiatrique UMR 933, Hôpital d'Enfants Armand Trousseau, Paris, France
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Santi M, Graf S, Zeino M, Cools M, Van De Vijver K, Trippel M, Aliu N, Flück CE. Approach to the Virilizing Girl at Puberty. J Clin Endocrinol Metab 2021; 106:1530-1539. [PMID: 33367768 PMCID: PMC8063244 DOI: 10.1210/clinem/dgaa948] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Indexed: 11/19/2022]
Abstract
UNLABELLED Virilization is the medical term for describing a female who develops characteristics associated with male hormones (androgens) at any age, or when a newborn girl shows signs of prenatal male hormone exposure at birth. In girls, androgen levels are low during pregnancy and childhood. A first physiologic rise of adrenal androgens is observed at the age of 6 to 8 years and reflects functional activation of the zona reticularis of the adrenal cortex at adrenarche, manifesting clinically with first pubic and axillary hairs. Early adrenarche is known as "premature adrenarche." It is mostly idiopathic and of uncertain pathologic relevance but requires the exclusion of other causes of androgen excess (eg, nonclassic congenital adrenal hyperplasia) that might exacerbate clinically into virilization. The second modest physiologic increase of circulating androgens occurs then during pubertal development, which reflects the activation of ovarian steroidogenesis contributing to the peripheral androgen pool. However, at puberty initiation (and beyond), ovarian steroidogenesis is normally devoted to estrogen production for the development of secondary female bodily characteristics (eg, breast development). Serum total testosterone in a young adult woman is therefore about 10- to 20-fold lower than in a young man, whereas midcycle estradiol is about 10- to 20-fold higher. But if androgen production starts too early, progresses rapidly, and in marked excess (usually more than 3 to 5 times above normal), females will manifest with signs of virilization such as masculine habitus, deepening of the voice, severe acne, excessive facial and (male typical) body hair, clitoromegaly, and increased muscle development. Several medical conditions may cause virilization in girls and women, including androgen-producing tumors of the ovaries or adrenal cortex, (non)classical congenital adrenal hyperplasia and, more rarely, other disorders (also referred to as differences) of sex development (DSD). The purpose of this article is to describe the clinical approach to the girl with virilization at puberty, focusing on diagnostic challenges. The review is written from the perspective of the case of an 11.5-year-old girl who was referred to our clinic for progressive, rapid onset clitoromegaly, and was then diagnosed with a complex genetic form of DSD that led to abnormal testosterone production from a dysgenetic gonad at onset of puberty. Her genetic workup revealed a unique translocation of an abnormal duplicated Y-chromosome to a deleted chromosome 9, including the Doublesex and Mab-3 Related Transcription factor 1 (DMRT1) gene. LEARNING OBJECTIVES Identify the precise pathophysiologic mechanisms leading to virilization in girls at puberty considering that virilization at puberty may be the first manifestation of an endocrine active tumor or a disorder/difference of sex development (DSD) that remained undiagnosed before and may be life-threatening. Of the DSDs, nonclassical congenital adrenal hyperplasia occurs most often.Provide a step-by-step diagnostic workup plan including repeated and expanded biochemical and genetic tests to solve complex cases.Manage clinical care of a girl virilizing at puberty using an interdisciplinary team approach.Care for complex cases of DSD manifesting at puberty, such as the presented girl with a Turner syndrome-like phenotype and virilization resulting from a complex genetic variation.
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Affiliation(s)
- Maristella Santi
- Pediatric Endocrinology, Diabetology, and Metabolism, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Stefanie Graf
- Pediatric Endocrinology, Diabetology, and Metabolism, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Mazen Zeino
- Department of Pediatric Surgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Martine Cools
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | | | - Mafalda Trippel
- Institute of Pathology, Inselspital, University of Bern, Bern, Switzerland
| | - Nijas Aliu
- University Clinic for Pediatrics, Human Genetics, Inselspital, University of Bern, Bern, Switzerland
| | - Christa E Flück
- Pediatric Endocrinology, Diabetology, and Metabolism, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department of BioMedical Research, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Correspondence: Christa E. Flück, Pediatric Endocrinology and Diabetology, University Children’s Hospital, Freiburgstrasse 15 / C845, 3010 Bern, Switzerland. E-mail:
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15
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He MN, Zhao SC, Li JM, Tong LL, Fan XZ, Xue YM, Lin XH, Cao Y. Turner syndrome with positive SRY gene and non-classical congenital adrenal hyperplasia: A case report. World J Clin Cases 2021; 9:2259-2267. [PMID: 33869601 PMCID: PMC8026834 DOI: 10.12998/wjcc.v9.i10.2259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 01/10/2021] [Accepted: 01/27/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Co-morbidity of SRY gene turner syndrome (TS) with positive SRY gene and non-classical congenital adrenal hyperplasia (NCAH) is extremely rare and has never been reported to date.
CASE SUMMARY In this article, we present a 14-year-old girl who was referred to our hospital with short stature (weight of 43 kg and height of 143 cm, < -2 SD) with no secondary sexual characteristics (labia minora dysplasia). Laboratory tests indicated hypergonadotropic hypogonadism with significantly increased androstenedione and 17-hydroxyprogesterone (17-OHP) levels. This was accompanied by the thickening of the extremity of the left adrenal medial limb. The patient’s karyotype was 45,X/46,X, +mar, and cytogenetic analysis using multiplex ligation-dependent probe amplification and high-throughput sequencing indicated that the SRY gene was positive with compound heterozygous mutations in CYP21A2 as the causative gene for congenital adrenal hyperplasia. The sites of the suspected candidate mutations were amplified and verified using Sanger sequencing. The patient was finally diagnosed as having SRY positive TS with NCAH. The patient and her family initially refused medical treatment. At her most recent follow-up visit (age = 15 years old), the patient presented facial hair, height increase to 148 cm, and weight of 52 kg, while androstenedione and 17-OHP levels remained high. The patient was finally willing to take small doses of hydrocortisone (10 mg/d).
CONCLUSION In conclusion, upon evaluation of the patient mentioned in the report, we feel that 17-OHP measurement and cytogenetic analysis are necessary for TS patients even in the absence of significant virilization signs. This will play a significant role in guiding diagnosis and treatment.
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Affiliation(s)
- Mei-Nan He
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Shan-Chao Zhao
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Ji-Min Li
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Lu-Lu Tong
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Xin-Zhao Fan
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Yao-Ming Xue
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Xiao-Hong Lin
- Guangzhou KingMed Center for Clinical Laboratory Co., Ltd., Guangzhou 510005, Guangdong Province, China
| | - Ying Cao
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
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Noordman ID, Duijnhouwer AL, Coert M, Bos M, Kempers M, Timmers HJLM, Fejzic Z, van der Velden JAEM, Kapusta L. No QTc Prolongation in Girls and Women with Turner Syndrome. J Clin Endocrinol Metab 2020; 105:5896615. [PMID: 32838426 PMCID: PMC7518463 DOI: 10.1210/clinem/dgaa552] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 08/13/2020] [Indexed: 02/08/2023]
Abstract
CONTEXT Turner syndrome (TS) is a genetic condition that is reported to be associated with a prolonged rate-corrected QT (QTc) interval. OBJECTIVES To evaluate the prevalence of QTc prolongation in patients with TS, to compare their QTc intervals with healthy controls, and to investigate whether QTc prolongation is associated with a monosomy 45,X karyotype. METHOD Girls (n = 101) and women (n = 251) with TS visiting our center from 2004-2018 were included in this cross-sectional study. QT intervals of 12-leaded electrocardiograms were measured manually, using Bazett's and Hodges formulas to correct for heart rate. A QTc interval of >450 ms for girls and >460 ms for women was considered prolonged. Corrected QT (QTc) intervals of patients with TS were compared to the QTc intervals of healthy girls and women from the same age groups derived from the literature. RESULTS In total, 5% of the population with TS had a prolonged QTc interval using Bazett's formula and 0% using Hodges formula. Mean QTc intervals of these patients were not prolonged compared with the QTc interval of healthy individuals from the literature. Girls showed shorter mean QTc intervals compared with women. We found no association between monosomy 45,X and prolongation of the QTc interval. CONCLUSIONS This study shows that the QTc interval in girls and women with TS is not prolonged compared with the general population derived from the literature, using both Bazett's and Hodges formulas. Furthermore, girls show shorter QTc intervals compared with women, and a monosomy 45,X karyotype is not associated with QTc prolongation.
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Affiliation(s)
- Iris D Noordman
- Department of Pediatric Endocrinology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
- Correspondence and Reprint Requests: I.D. Noordman, MD, Department of Pediatric Endocrinology, Amalia Children’s Hospital, Radboud University Medical Center, P.O. Box 9101, Geert Grooteplein Zuid 10, 6500 HB Nijmegen (804), The Netherlands. E-mail:
| | | | - Misty Coert
- Department of Neonatology, Willem Alexander Children’s Hospital, Leiden University Medical Center, Leiden, The Netherlands
| | - Melanie Bos
- Department of Pediatric Cardiology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marlies Kempers
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Henri J L M Timmers
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Zina Fejzic
- Department of Pediatric Cardiology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Janiëlle A E M van der Velden
- Department of Pediatric Endocrinology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Livia Kapusta
- Department of Pediatric Cardiology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
- Pediatric Cardiology Unit, Dana-Dwek Children’s Hospital, Tel-Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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Abstract
Turner syndrome is a rare condition affecting 1 in 2500 female births and yet is the most common sex chromosome abnormality in women. Described as a cradle-to-grave condition, it requires life-long multidisciplinary management. Accelerated atresia of the primordial follicular pool leads to premature ovarian insufficiency, which is an almost inevitable feature of Turner syndrome, especially in 45XO karyotype. Many patients will have had their diagnosis made in childhood and require paediatric endocrinology management especially for induction of puberty. At the age of 18, patients may then be transitioned to an adult service. Continuation of multidisciplinary care for these women requires input from specialist services in menopause care, reproductive medicine and high-risk pregnancy, cardiology, endocrinology, bone health and psychosocial care. A gynaecologist may take on the mantle of lead clinician especially during the perceived reproductive years of a Turner syndrome patient's life, hinging together management input from other disciplines. This review attempts to summarise an overview of the involvement of such a multidisciplinary team in the management of a single but complex condition, through the lens of a gynaecologist.
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Affiliation(s)
- Shehnaaz Jivraj
- Late Effects Clinic, Sheffield Teaching Hospitals NHS Trust, Sheffield, UK
| | - Susan Stillwell
- Menopause Service, Jessop Wing, Sheffield Teaching Hospitals NHS Trust, Sheffield, UK
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Peek R, Schleedoorn M, Smeets D, van de Zande G, Groenman F, Braat D, van der Velden J, Fleischer K. Ovarian follicles of young patients with Turner's syndrome contain normal oocytes but monosomic 45,X granulosa cells. Hum Reprod 2020; 34:1686-1696. [PMID: 31398245 PMCID: PMC6736193 DOI: 10.1093/humrep/dez135] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 06/21/2019] [Accepted: 06/27/2019] [Indexed: 12/12/2022] Open
Abstract
STUDY QUESTION What is the X chromosomal content of oocytes and granulosa cells of primordial/primary (small) follicles and stromal cells in ovaries of young patients with Turner's syndrome (TS)? SUMMARY ANSWER Small ovarian follicles were detected in one-half of the patients studied, and X chromosome analysis revealed that most oocytes were normal, granulosa cells were largely monosomic, while stromal cells showed a high level of mosaicism. WHAT IS KNOWN ALREADY Most women with TS experience a premature reduction or complete loss of fertility due to an accelerated loss of gametes. To determine whether fertility preservation in this group of patients is feasible, there is a strong need for information on the X chromosomal content of ovarian follicular and stromal cells. STUDY DESIGN, SIZE, DURATION Small follicles (<50 μm) and stromal cells were isolated from ovarian tissue of young TS patients and analysed for their X chromosomal content. In addition to ovarian cells, several other cell types from the same patients were analysed. PARTICIPANTS/MATERIALS, SETTING, METHODS After unilateral ovariectomy, ovarian cortex tissue was obtained from 10 TS patients (aged 2-18 years) with numerical abnormalities of the X chromosome. Ovarian cortex fragments were prepared and cryopreserved. One fragment from each patient was thawed and enzymatically digested to obtain stromal cells and primordial/primary follicles. Stromal cells, granulosa cells and oocytes were analysed by FISH using an X chromosome-specific probe. Extra-ovarian cells (lymphocytes, buccal cells and urine cells) of the same patients were also analysed by FISH. Ovarian tissue used as control was obtained from individuals undergoing oophorectomy as part of their gender affirming surgery. MAIN RESULTS AND THE ROLE OF CHANCE Ovarian follicles were detected in 5 of the 10 patients studied. A method was developed to determine the X chromosomal content of meiosis I arrested oocytes from small follicles. This revealed that 42 of the 46 oocytes (91%) that were analysed had a normal X chromosomal content. Granulosa cells were largely 45,X but showed different levels of X chromosome mosaicism between patients and between follicles of the same patient. Despite the presence of a low percentage (10-45%) of 46,XX ovarian cortex stromal cells, normal macroscopic ovarian morphology was observed. The level of mosaicism in lymphocytes, buccal cells or urine-derived cells was not predictive for mosaicism in ovarian cells. LIMITATIONS, REASONS FOR CAUTION The results are based on a small number (n = 5) of TS patient samples but provide evidence that the majority of oocytes have a normal X chromosomal content and that follicles from the same patient can differ with respect to the level of mosaicism of their granulosa cells. The functional consequences of these observations require further investigation. WIDER IMPLICATIONS OF THE FINDINGS The results indicate that despite normal ovarian and follicular morphology, stromal cells and granulosa cells of small follicles in patients with TS may display a high level of mosaicism. Furthermore, the level of mosaicism in ovarian cells cannot be predicted from the analysis of extra-ovarian tissue. These findings should be considered by physicians when offering cryopreservation of ovarian tissue as an option for fertility preservation in young TS patients. STUDY FUNDING/COMPETING INTEREST(S) Unconditional funding was received from Merck B.V. The Netherlands (Number A16-1395) and the foundation 'Radboud Oncologie Fonds' (Number KUN 00007682). The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER NCT03381300.
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Affiliation(s)
- Ronald Peek
- Department of Obstetrics and Gynecology, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Myra Schleedoorn
- Department of Obstetrics and Gynecology, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Dominique Smeets
- Department of Human Genetics, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Guillaume van de Zande
- Department of Human Genetics, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Freek Groenman
- Amsterdam UMC, Vrije Universiteit Amsterdam, Obstetrics and Gynecology, Amsterdam Reproduction and Development, De Boelelaan 1117 Amsterdam, The Netherlands
| | - Didi Braat
- Department of Obstetrics and Gynecology, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Janielle van der Velden
- Amalia Children's Hospital, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Kathrin Fleischer
- Department of Obstetrics and Gynecology, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands
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19
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Slowikowska-Hilczer J, Szarras-Czapnik M, Duranteau L, Rapp M, Walczak-Jedrzejowska R, Marchlewska K, Oszukowska E, Nordenstrom A. Risk of gonadal neoplasia in patients with disorders/differences of sex development. Cancer Epidemiol 2020; 69:101800. [PMID: 32905884 DOI: 10.1016/j.canep.2020.101800] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 08/12/2020] [Accepted: 08/17/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Patients with disorders/differences of sex development (DSD), especially those possessing the Y chromosome, have a higher risk of gonadal germ-cell tumours (GCTs). We aimed to examine the incidence of different types of gonadal neoplasia and associated risk factors. METHODS A total of 1040 DSD patients aged ≥16 years participated in a cross-sectional multicentre European study (dsd-LIFE). Data on medical history were gathered from the patients' archival medical documents. A web-based questionnaire was filled out individually by the participants. A physical examination was performed in all, while ultrasonography of gonads was carried out in 214 and semen analysis was performed for 53 patients. RESULTS Germ-cell neoplasia was present in 12 % of patients with DSD and in 14 % of those with XY DSD. The highest risk (36 %) was observed in 46,XY patients with gonadal dysgenesis (GD): complete GD (33 %) and partial GD (23 %), but also in mixed GD (8 %) and complete androgen insensitivity syndrome (AIS) (6%). It was not reported in partial AIS, XX male, 46,XX DSD and congenital adrenal hyperplasia, Turner and Klinefelter syndromes, or in androgen biosynthesis defects. Benign sex cord-stromal tumours (Sertoli- and Leydig-cell tumours) were noted only in patients with complete AIS (3.1 %) and Klinefelter syndrome (14.3 %). A relationship between risk factors for GCT and gonadal neoplasia appearance, other than the Y chromosome, was not found. CONCLUSION Adult patients with GD and the Y chromosome have the highest risk of GCT and should be kept under thorough medical control and receive special medical follow-up to prevent the development of gonadal tumours.
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Affiliation(s)
- Jolanta Slowikowska-Hilczer
- Department of Andrology and Reproductive Endocrinology, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland.
| | - Maria Szarras-Czapnik
- Department of Endocrinology and Diabetology, Children's Memorial Health Institute, Aleja Dzieci Polskich 20, 04-730 Warsaw, Poland
| | - Lise Duranteau
- Adolescent and Young Adult Gynaecology Unit and DSD Reference Centre, Bicêtre Hospital, AP.HP Université Paris Saclay, France
| | - Marion Rapp
- Clinic for Paediatric and Adolescent Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lubeck, Germany
| | - Renata Walczak-Jedrzejowska
- Department of Andrology and Reproductive Endocrinology, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland
| | - Katarzyna Marchlewska
- Department of Andrology and Reproductive Endocrinology, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland
| | - Elzbieta Oszukowska
- II Clinic of Urology, Medical University of Lodz, Pabianicka 62, 93-513 Lodz, Poland
| | - Anna Nordenstrom
- Department of Paediatric Endocrinology, Astrid Lindgren Children Hospital, Karolinska University Hospital, Stockholm, Sweden
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20
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Funck KL, Budde RPJ, Viuff MH, Wen J, Jensen JM, Nørgaard BL, Bons LR, Duijnhouwer AL, Dey D, Mortensen KH, Andersen NH, Roos-Hesselink JW, Gravholt CH. Coronary plaque burden in Turner syndrome a coronary computed tomography angiography study. Heart Vessels 2020; 36:14-23. [PMID: 32613319 DOI: 10.1007/s00380-020-01660-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 06/26/2020] [Indexed: 11/25/2022]
Abstract
Turner syndrome (TS) is associated with coronary artery disease (CAD), an important cause of premature death in TS. However, the determinants of CAD in women with TS remain unknown. In a cross-sectional study design, 168 women without clinical evidence of CAD (115 with TS and 53 without TS) were assessed for the presence and volume of subclinical CAD using coronary CT angiography. Karyotype, the presence of congenital heart defects and conventional cardiovascular risk factors were also registered. Comparative analyses were performed (1) between women with and without TS and (2) in the TS group, between women with and without subclinical CAD. The prevalence of CAD, in crude and adjusted analyses, was not increased for women with TS (crude prevalence: 40 [35%] in TS vs. 25 [47%] in controls, p = 0.12). The volume of atherosclerosis was not higher in women with TS compared with controls (median and interquartile range 0 [0-92] in TS vs. 0 [0-81]mm3 in controls, p = 0.29). Among women with TS, women with subclinical CAD were older (46 ± 13 vs. 37 ± 11 years, p < 0.001), had higher blood pressure (systolic blood pressure 129 ± 16 vs. 121 ± 16 mmHg, p < 0.05) and were more frequently diagnosed with type 2 diabetes (5 [13%] vs. 2 [3%], p < 0.05). Karyotype or congenital heart defects were not associated with subclinical CAD. Some women with TS show early signs of CAD, however overall, not more than women without TS. Conventional cardiovascular risk factors were the principal determinants of CAD also in TS, and CAD prevention strategies should be observed.ClinicalTrial.gov Identifier: NCT01678261 ( https://clinicaltrials.gov/ct2/show/NCT01678261 ).
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Affiliation(s)
- Kristian L Funck
- Department of Endocrinology and Internal Medicine and Medical Research Laboratories, Aarhus University Hospital, Palle Juul-Jensens, Boulevard 99, 8200, Aarhus N, Denmark. .,Diagnostic Center, Regional Hospital Central Jutland, Silkeborg, Denmark.
| | - Ricardo P J Budde
- Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Erasmus University, Rotterdam, The Netherlands
| | - Mette H Viuff
- Department of Endocrinology and Internal Medicine and Medical Research Laboratories, Aarhus University Hospital, Palle Juul-Jensens, Boulevard 99, 8200, Aarhus N, Denmark
| | - Jan Wen
- Department of Endocrinology and Internal Medicine and Medical Research Laboratories, Aarhus University Hospital, Palle Juul-Jensens, Boulevard 99, 8200, Aarhus N, Denmark
| | - Jesper M Jensen
- Department of Cardiology, Aarhus University Hospital, Århus, Denmark
| | - Bjarne L Nørgaard
- Department of Cardiology, Aarhus University Hospital, Århus, Denmark
| | - Lidia R Bons
- Department of Cardiology, Erasmus MC, Erasmus University, Rotterdam, The Netherlands
| | | | - Damini Dey
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Biomedical Imaging Research Institute, Los Angeles, CA, USA
| | - Kristian H Mortensen
- Centre for Cardiovascular Imaging Department, Cardiorespiratory Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, UK
| | - Niels H Andersen
- Department of Cardiology, Odense University Hospital, Odense, Denmark
| | | | - Claus H Gravholt
- Department of Endocrinology and Internal Medicine and Medical Research Laboratories, Aarhus University Hospital, Palle Juul-Jensens, Boulevard 99, 8200, Aarhus N, Denmark.,Department of Molecular Medicine, Aarhus University Hospital, Århus, Denmark
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21
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Dabrowski E, Johnson EK, Patel V, Hsu Y, Davis S, Goetsch AL, Habiby R, Brickman WJ, Finlayson C. Turner Syndrome with Y Chromosome: Spontaneous Thelarche, Menarche, and Risk of Malignancy. J Pediatr Adolesc Gynecol 2020; 33:10-14. [PMID: 31465855 PMCID: PMC7413626 DOI: 10.1016/j.jpag.2019.08.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 08/06/2019] [Accepted: 08/19/2019] [Indexed: 01/05/2023]
Abstract
STUDY OBJECTIVE Girls with Turner syndrome with Y-chromosome material (TS + Y) are assumed to have nonfunctional gonads with increased tumor risk, therefore prophylactic gonadectomy is recommended at diagnosis. In this study we aimed to determine rates of spontaneous thelarche (ST) and spontaneous menarche (SM), and prevalence of gonadal tumor and malignancy in girls with TS + Y, to further inform discussions about gonadectomy. DESIGN Retrospective review of clinical and pathology data. SETTING Multicenter study involving 4 United States children's hospitals. PARTICIPANTS Patients included those with a genetically proven diagnosis of TS + Y and phenotypically female genitourinary exam. INTERVENTIONS Demographic characteristics, pubertal development, and gonadal pathology data were abstracted from clinical records. Data for ST were analyzed for patients aged 13 years and older and SM for patients older than 15 years. MAIN OUTCOME MEASURES ST, SM, prevalence of gonadal tumor, and malignancy. RESULTS Forty-four patients met inclusion criteria. Nineteen patients were 13 years or older; 8/19 (42%) had ST and reached Tanner stages 2-4 and 2 (11%) had normal ovarian pathology. Nineteen patients were 15 years or older; 2/19 (11%) had SM. Thirty-seven patients underwent gonadectomy; 35 had available pathology results. Gonadoblastoma was identified in 35/7 patients (19%), 1 in situ germ cell neoplasia, and 1 dysgerminoma (3%). One patient with bilateral gonadoblastoma had ST and SM. CONCLUSION In this multicenter cohort, 42% of girls with TS + Y entered puberty spontaneously and 11% had SM, supportive of gonadal function. Risk of tumor was similar to previous reports. To achieve informed decision-making, discussions about gonadectomy should incorporate potential for gonadal function and tumor risk.
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Affiliation(s)
- Elizabeth Dabrowski
- Division of Pediatric Endocrinology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
| | - Emilie K Johnson
- Division of Urology, Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Vrunda Patel
- Division of Adolescent Medicine and Pediatric Gynecology, Children's National Medical Center, Wilmington, Delaware
| | - YeoChing Hsu
- Division of Pediatric Endocrinology, Cohen Children's Medical Center, Northwell Health, Zucker School of Medicine at Hofstra/Northwell
| | - Shanlee Davis
- Division of Pediatric Endocrinology, University of Colorado, Denver, Colorado
| | - Allison L Goetsch
- Division of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Reema Habiby
- Division of Pediatric Endocrinology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Wendy J Brickman
- Division of Pediatric Endocrinology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Courtney Finlayson
- Division of Pediatric Endocrinology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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22
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Lin AE, Prakash SK, Andersen NH, Viuff MH, Levitsky LL, Rivera-Davila M, Crenshaw ML, Hansen L, Colvin MK, Hayes FJ, Lilly E, Snyder EA, Nader-Eftekhari S, Aldrich MB, Bhatt AB, Prager LM, Arenivas A, Skakkebaek A, Steeves MA, Kreher JB, Gravholt CH. Recognition and management of adults with Turner syndrome: From the transition of adolescence through the senior years. Am J Med Genet A 2019; 179:1987-2033. [PMID: 31418527 DOI: 10.1002/ajmg.a.61310] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 06/11/2019] [Accepted: 07/18/2019] [Indexed: 12/16/2022]
Abstract
Turner syndrome is recognized now as a syndrome familiar not only to pediatricians and pediatric specialists, medical geneticists, adult endocrinologists, and cardiologists, but also increasingly to primary care providers, internal medicine specialists, obstetricians, and reproductive medicine specialists. In addition, the care of women with Turner syndrome may involve social services, and various educational and neuropsychologic therapies. This article focuses on the recognition and management of Turner syndrome from adolescents in transition, through adulthood, and into another transition as older women. It can be viewed as an interpretation of recent international guidelines, complementary to those recommendations, and in some instances, an update. An attempt was made to provide an international perspective. Finally, the women and families who live with Turner syndrome and who inspired several sections, are themselves part of the broad readership that may benefit from this review.
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Affiliation(s)
- Angela E Lin
- Medical Genetics Unit, Mass General Hospital for Children, Boston, Massachusetts
| | - Siddharth K Prakash
- Division of Cardiology, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Niels H Andersen
- Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark
| | - Mette H Viuff
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Lynne L Levitsky
- Division of Pediatric Endocrinology, Department of Pediatrics, Mass General Hospital for Children, Boston, Massachusetts
| | - Michelle Rivera-Davila
- Division of Pediatric Endocrinology, Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Melissa L Crenshaw
- Medical Genetics Services, Division of Genetics, Johns Hopkins All Children's Hospital, St. Petersburg, Florida
| | - Lars Hansen
- Department of Otorhinolaryngology, Aarhus University Hospital, Aarhus, Denmark
| | - Mary K Colvin
- Psychology Assessment Center, Massachusetts General Hospital, Boston, Massachusetts.,Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts
| | - Frances J Hayes
- Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Evelyn Lilly
- Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts
| | - Emma A Snyder
- Medical Genetics Unit, Mass General Hospital for Children, Boston, Massachusetts
| | - Shahla Nader-Eftekhari
- Division of Endocrinology, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Melissa B Aldrich
- Center for Molecular Imaging, The Brown Institute for Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Ami B Bhatt
- Corrigan Minehan Heart Center, Adult Congenital Heart Disease Program, Massachusetts General Hospital, Boston, Massachusetts.,Yawkey Center for Outpatient Care, Massachusetts General Hospital, Boston, Massachusetts
| | - Laura M Prager
- Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts
| | - Ana Arenivas
- Department of Rehabilitation Psychology/Neuropsychology, TIRR Memorial Hermann Rehabilitation Network, Houston, Texas.,Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, Texas
| | - Anne Skakkebaek
- Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark
| | - Marcie A Steeves
- Medical Genetics Unit, Mass General Hospital for Children, Boston, Massachusetts
| | - Jeffrey B Kreher
- Department of Pediatrics and Orthopaedics, Massachusetts General Hospital, Boston, Massachusetts
| | - Claus H Gravholt
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
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23
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León NY, Reyes AP, Harley VR. A clinical algorithm to diagnose differences of sex development. Lancet Diabetes Endocrinol 2019; 7:560-574. [PMID: 30803928 DOI: 10.1016/s2213-8587(18)30339-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 11/27/2018] [Accepted: 11/27/2018] [Indexed: 12/15/2022]
Abstract
The diagnosis and management of children born with ambiguous genitalia is challenging for clinicians. Such differences of sex development (DSDs) are congenital conditions in which chromosomal, gonadal, or anatomical sex is atypical. The aetiology of DSDs is very heterogenous and a precise diagnosis is essential for management of genetic, endocrine, surgical, reproductive, and psychosocial issues. In this Review, we outline a step-by-step approach, compiled in a diagnostic algorithm, for the clinical assessment and molecular diagnosis of a patient with ambiguity of the external genitalia on initial presentation. We appraise established and emerging technologies and their effect on diagnosis, and discuss current controversies.
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Affiliation(s)
- Nayla Y León
- Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - Alejandra P Reyes
- Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Melbourne, VIC, Australia; Genetics Department, Children's Hospital of Mexico Federico Gómez, Mexico City, Mexico
| | - Vincent R Harley
- Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Melbourne, VIC, Australia.
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24
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Abstract
This review describes the germ cell neoplasms that are malignant and most commonly associated with several types of gonadal dysgenesis. The most common neoplasm is gonadoblastoma, while others including dysgerminomas, yolk-sac tumors and teratomas are rare but can occur. The purpose of this review is to evaluate the incidences of these abnormalities and the circumstances surrounding these specific tumors.According to well-established methods, a PubMed systematic review was performed, to obtain relevant studies published in English and select those with the highest-quality data.Initially, the first search was performed using gonadal dysgenesis as the search term, resulting in 12,887 PubMed papers, published, from 1945 to 2017. A second search using ovarian germ cell tumors as the search term resulted in 10,473 papers, published from 1960 to 2017. Another search was performed in Medline, using germ cell neoplasia as the search term, and this search resulted in 7,560 papers that were published between 2003 to 2016, with 245 new papers assessing gonadoblastomas.The higher incidence of germ cell tumors in gonadal dysgenesis is associated with a chromosomal anomaly that leads to the absence of germ cells in these gonads and, consequently, a higher incidence of neoplasms when these tumors are located inside the abdomen. Several hypotheses suggest that increased incidence of germ cell tumors involves all or part of the Y chromosome or different genes.
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Affiliation(s)
- Mauri José Piazza
- Departamento de TocoGinecologia, Universidade Federal do Parana, Curitiba, PR, BR
- Corresponding author. E-mail:
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25
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Duijnhouwer AL, Bons LR, Timmers HJLM, van Kimmenade RRL, Snoeren M, Timmermans J, van den Hoven AT, Kempers M, van Dijk APJ, Fleischer K, Roos-Hesselink JW. Aortic dilatation and outcome in women with Turner syndrome. Heart 2018; 105:693-700. [PMID: 30368486 DOI: 10.1136/heartjnl-2018-313716] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 09/13/2018] [Accepted: 09/27/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Women with Turner syndrome (TS) are at increased risk of aortic dissection, which is related to ascending aortic diameter. However, the relation between aortic diameter and outcome is not well determined. This study evaluates the prevalence of aortic dilatation, the growth rate of the aorta and the risk of aortic complications in adults with TS. METHODS Single centre, retrospective study of all women with TS followed with a strict protocol in an outpatient TS clinic. Aortic diameters were analysed using advanced imaging. The primary outcome was a combined endpoint of aortic-related mortality, aortic dissection and preventive aortic surgery. The secondary endpoint was aortic growth and prevalence of aortic dilatation, defined as an aortic size index >20 mm/m2 at baseline. RESULTS At least one cardiac MR/CT was available in 268 women with TS, having median age of 28.7 (IQR: 21.3-39.7) years. Aortic dilatation was present in 22%. Linear regression identified independent factors associated with larger aortic diameters: age (coefficient=0.23; p<0.001), hypertension (coefficient=2.7; p<0.001), bicuspid aortic valve (coefficient=3.3; p<0.001), 45XO karyotype (coefficient=1.7; p=0.002), weight (coefficient=0.075; p<0.001) and growth hormone treatment (coefficient=1.4; p=0.044). During follow-up (6.8±3.2 years), five women (2%) reached the primary endpoint (two dissections, three aortic surgery). Women withmore than one scan (n=171; 1015 patient-years follow-up), the median aortic growth was 0.20 (IQR: 0.00-0.44) mm/year. In multivariate analysis, aortic growth was not associated with baseline aortic diameter or other variables. CONCLUSIONS Aortic dilatation is common and known associations were confirmed in large adult TS cohort However, aortic dissection, related mortality and preventive aortic surgery are rare. Growth hormone treatment in childhood was associated with aortic dimensions.
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Affiliation(s)
| | - Lidia R Bons
- Department of Cardiology, Erasmus MC, Rotterdam, The Netherlands
| | - Henri J L M Timmers
- Department of Endocrinology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | | | - Miranda Snoeren
- Department of Radiology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Janneke Timmermans
- Department of Cardiology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | | | - Marlies Kempers
- Department of Medical Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands
| | | | - Kathrin Fleischer
- Department of Gynaecology, Radboud University Medical Centre, Nijmegen, Netherlands
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26
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Noordman I, Duijnhouwer A, Kapusta L, Kempers M, Roeleveld N, Schokking M, Smeets D, Freriks K, Timmers H, van Alfen-van der Velden J. Phenotype in girls and women with Turner syndrome: Association between dysmorphic features, karyotype and cardio-aortic malformations. Eur J Med Genet 2018; 61:301-306. [PMID: 29339108 DOI: 10.1016/j.ejmg.2018.01.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2017] [Revised: 12/23/2017] [Accepted: 01/01/2018] [Indexed: 01/15/2023]
Abstract
INTRODUCTION Turner syndrome (TS) is a genetic disorder characterized by the (partial) absence or a structural aberration of the second sex chromosome and is associated with a variety of phenotypes with specific physical features and cardio-aortic malformations. The objective of this study was to gain a better insight into the differences in dysmorphic features between girls and women with TS and to explore the association between these features, karyotype and cardio-aortic malformations. METHODS This prospective study investigated 14 dysmorphic features of TS girls and women using a checklist. Three major phenotypic patterns were recognized (severe phenotype, lymphatic phenotype and skeletal phenotype). Patient data including karyotype and cardio-aortic malformations (bicuspid aortic valve (BAV) and aortic coarctation (COA)) were collected. Associations between the prevalence of dysmorphic features, karyotype and cardio-aortic malformations were analysed using chi2-test and odds ratios. RESULTS A total of 202 patients (84 girls and 118 women) were analysed prospectively. Differences in prevalence of dysmorphic features were found between girls and women. A strong association was found between monosomy 45,X and the phenotypic patterns. Furthermore, an association was found between COA and lymphatic phenotype, but no association was found between karyotype and cardio-aortic malformations. CONCLUSION This study uncovered a difference in dysmorphic features between girls and women. Monosomy 45,X is associated with a more severe phenotype, lymphatic phenotype and skeletal phenotype. All patients with TS should be screened for cardio-aortic malformations, because in contrast to previous reports, karyotype and cardio-aortic malformations showed no significant association.
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Affiliation(s)
- Iris Noordman
- Department of Paediatrics, Amalia Children's Hospital, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Anthonie Duijnhouwer
- Department of Cardiology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Livia Kapusta
- Department of Paediatrics, Amalia Children's Hospital, Radboud University Medical Centre, Nijmegen, The Netherlands; Pediatric Cardiology Unit, Tel-Aviv Sourasky Medical Centre, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Marlies Kempers
- Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Nel Roeleveld
- Department for Health Evidence, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Michiel Schokking
- Department of Paediatrics, Amalia Children's Hospital, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Dominique Smeets
- Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Kim Freriks
- Department of Internal Medicine, Tjongerschans Hospital, Heerenveen, The Netherlands
| | - Henri Timmers
- Department of Internal Medicine, Section of Endocrinology, Radboud University Medical Centre, Nijmegen, The Netherlands
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27
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Shankar RK, Backeljauw PF. Current best practice in the management of Turner syndrome. Ther Adv Endocrinol Metab 2018; 9:33-40. [PMID: 29344338 PMCID: PMC5761955 DOI: 10.1177/2042018817746291] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 10/24/2017] [Indexed: 01/15/2023] Open
Abstract
Turner syndrome (TS) is characterized by partial or complete loss of the second X-chromosome in phenotypic females resulting in a constellation of clinical findings that may include lymphedema, cardiac anomalies, short stature, primary ovarian failure and neurocognitive difficulties. Optimizing health care delivery is important to enable these individuals achieve their full potential. We review the current best practice management recommendations for individuals with TS focusing on the latest consensus opinion in regard to genetic diagnosis, treatment of short stature, estrogen supplementation, addressing psychosocial issues, as well screening for other comorbidities. A multidisciplinary approach and a well-planned transition to adult follow-up care will improve health care delivery significantly for this population.
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Affiliation(s)
- Roopa Kanakatti Shankar
- Assistant Professor, Division of Pediatric Endocrinology, Department of Pediatrics, Children's Hospital of Richmond at Virginia Commonwealth University, Richmond, VA, USA
| | - Philippe F Backeljauw
- Cincinnati Center for Pediatric and Adult Turner Syndrome Care, Professor, Division of Pediatric Endocrinology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
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28
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MacMahon JM, O'Sullivan MJ, McDermott M, Quinn F, Morris T, Green AJ, Betts DR, O'Connell SM. Early Bilateral Gonadoblastoma in a Young Child with Mosaicism for Turner Syndrome and Trisomy 18 with Y Chromosome. Horm Res Paediatr 2017; 87:130-135. [PMID: 27614983 DOI: 10.1159/000448172] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 07/01/2016] [Indexed: 12/11/2022] Open
Abstract
Mosaic Turner syndrome (TSM) commonly occurs in the form of 45,X/46,XX and 45,X/46,X,i(X)(q10). Mosaicism for a Y chromosome, 45,X/46,XY, has been well documented and is associated with increased risk of gonadoblastoma (GB). To date, there are only six reported cases of TSM with a trisomy 18 karyotype, and only two of these were phenotypically female with 45,X/47,XY,+18 karyotype. We present the case of a phenotypically female infant born with dysmorphic features. G-banded karyotype and interphase FISH of blood showed 45,X in 95% and 47,XY,+18 (trisomy 18) in 5% of cells analysed. However, interphase FISH of buccal cells showed only the presence of the 45,X cell line. Due to the presence of Y chromosome material, elective gonadectomy was performed at 13 months of age. There were bilateral streak ovaries with early evidence of GB bilaterally, a rudimentary uterus and bilateral fallopian tubes with unilateral ectopic adrenal tissue identified histologically. Interphase FISH of the gonadal tissue was similar to the blood findings with 45,X in 86% of cells and 47,XY,+18 in 14% of cells analysed. This case highlights a rare karyotype of TSM and trisomy 18 in the same patient and is the first reporting the associated finding of bilateral GB.
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Affiliation(s)
- Jayne M MacMahon
- Department of Paediatrics and Child Health, Cork University Hospital, Cork, Ireland
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Gravholt CH, Andersen NH, Conway GS, Dekkers OM, Geffner ME, Klein KO, Lin AE, Mauras N, Quigley CA, Rubin K, Sandberg DE, Sas TCJ, Silberbach M, Söderström-Anttila V, Stochholm K, van Alfen-van derVelden JA, Woelfle J, Backeljauw PF. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol 2017; 177:G1-G70. [PMID: 28705803 DOI: 10.1530/eje-17-0430] [Citation(s) in RCA: 643] [Impact Index Per Article: 80.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 06/07/2017] [Indexed: 12/14/2022]
Abstract
Turner syndrome affects 25-50 per 100,000 females and can involve multiple organs through all stages of life, necessitating multidisciplinary approach to care. Previous guidelines have highlighted this, but numerous important advances have been noted recently. These advances cover all specialty fields involved in the care of girls and women with TS. This paper is based on an international effort that started with exploratory meetings in 2014 in both Europe and the USA, and culminated with a Consensus Meeting held in Cincinnati, Ohio, USA in July 2016. Prior to this meeting, five groups each addressed important areas in TS care: 1) diagnostic and genetic issues, 2) growth and development during childhood and adolescence, 3) congenital and acquired cardiovascular disease, 4) transition and adult care, and 5) other comorbidities and neurocognitive issues. These groups produced proposals for the present guidelines. Additionally, four pertinent questions were submitted for formal GRADE (Grading of Recommendations, Assessment, Development and Evaluation) evaluation with a separate systematic review of the literature. These four questions related to the efficacy and most optimal treatment of short stature, infertility, hypertension, and hormonal replacement therapy. The guidelines project was initiated by the European Society for Endocrinology and the Pediatric Endocrine Society, in collaboration with The European Society for Pediatric Endocrinology, The Endocrine Society, European Society of Human Reproduction and Embryology, The American Heart Association, The Society for Endocrinology, and the European Society of Cardiology. The guideline has been formally endorsed by the European Society for Endocrinology, the Pediatric Endocrine Society, the European Society for Pediatric Endocrinology, the European Society of Human Reproduction and Embryology and the Endocrine Society. Advocacy groups appointed representatives who participated in pre-meeting discussions and in the consensus meeting.
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Affiliation(s)
- Claus H Gravholt
- Departments of Endocrinology and Internal Medicine
- Departments of Molecular Medicine
| | - Niels H Andersen
- Departments of Cardiology, Aarhus University Hospital, Aarhus, Denmark
| | - Gerard S Conway
- Department of Women's Health, University College London, London, UK
| | - Olaf M Dekkers
- Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Mitchell E Geffner
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, USA
| | - Karen O Klein
- Rady Children's Hospital, University of California, San Diego, California, USA
| | - Angela E Lin
- Department of Pediatrics, Medical Genetics Unit, Mass General Hospital for Children, Boston, Massachusetts, USA
| | - Nelly Mauras
- Division of Endocrinology, Nemours Children's Health System, Jacksonville, Florida, USA
| | | | - Karen Rubin
- Connecticut Children's Medical Center, Hartford, Connecticut, USA
| | - David E Sandberg
- Division of Psychology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA
| | - Theo C J Sas
- Department of Pediatric Endocrinology, Sophia Children's Hospital, Rotterdam, The Netherlands
- Department of Pediatrics, Dordrecht, The Netherlands
| | - Michael Silberbach
- Department of Pediatrics, Doernbecher Children's Hospital, Portland, Oregon, USA
| | | | - Kirstine Stochholm
- Departments of Endocrinology and Internal Medicine
- Center for Rare Diseases, Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark
| | | | - Joachim Woelfle
- Department of Pediatric Endocrinology, Children's Hospital, University of Bonn, Bonn, Germany
| | - Philippe F Backeljauw
- Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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Abstract
Post-zygotic variation refers to genetic changes that arise in the soma of an individual and that are not usually inherited by the next generation. Although there is a paucity of research on such variation, emerging studies show that it is common: individuals are complex mosaics of genetically distinct cells, to such an extent that no two somatic cells are likely to have the exact same genome. Although most types of mutation can be involved in post-zygotic variation, structural genetic variants are likely to leave the largest genomic footprint. Somatic variation has diverse physiological roles and pathological consequences, particularly when acquired variants influence the clonal trajectories of the affected cells. Post-zygotic variation is an important confounder in medical genetic testing and a promising avenue for research: future studies could involve analyses of sorted and single cells from multiple tissue types to fully explore its potential.
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Coyle D, Kutasy B, Han Suyin K, Antao B, Lynch SA, McDermott MB, O'Connell SM, Quinn F. Gonadoblastoma in patients with 45,X/46,XY mosaicism: A 16-year experience. J Pediatr Urol 2016; 12:283.e1-283.e7. [PMID: 27052295 DOI: 10.1016/j.jpurol.2016.02.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 02/14/2016] [Indexed: 11/30/2022]
Abstract
BACKGROUND It is recognised that individuals with a 45,X/46,XY karyotype, known as Turner mosaic syndrome with Y chromosome material (TMSY), have an increased risk of developing gonadoblastoma (GB), which may then devolve into one of a number of germ cell malignancies. Hence, children with TMSY are usually recommended to undergo prophylactic gonadectomy. OBJECTIVE We designed this study to describe the phenotypic features of our series of children with TMSY who underwent prophylactic gonadectomy in order to evaluate the prevalence of GB and germ cell malignancies in their resected specimens. STUDY DESIGN This is a retrospective case series wherein we comprehensively reviewed the clinical, histological, and cytogenetic features of all patients who underwent prophylactic gonadectomy at three tertiary paediatric referral centres over 16 years. Cases were identified from surgical logbooks and through the institutional histopathology database. Data were collected with particular reference to clinical phenotype, predominant karyotype cell line, operative management, anatomical findings and the presence of neoplastic changes. RESULTS Fourteen children ranging in age at the time of surgery from 2 weeks to 17 years were included in the series. Eleven children were reared as females. The three children who were reared as males had severe penoscrotal hypospadias. The 46,XY cell line was the predominant cell line in seven (50%) cases in blood lymphocytes. The resected specimens from four patients (28.6%) contained GB, with three patients having bilateral GB. This sub-group of patients with GB were aged 5 months, 48 months, 71 months, and 13 years. GB arose in one patient with and three patients without genital virilisation. There was no focus of invasive germ cell tumour in any specimen. DISCUSSION GB may be present in infants with TMSY as young as 5 months, even with low levels of Y chromosome material. The prevalence of GB in prophylactic gonadectomy specimens is similar to many previously reported series, although the absence of dysgerminoma in our series is reassuring. The exclusive presence of GB in intra-abdominal gonads is in keeping with the findings of several other series. CONCLUSION Owing to the presence of gonadoblastoma in the gonads of children with TMSY as young as 5 months, we recommend that all patients with intra-abdominal gonads in the context of TMSY should duly undergo prophylactic gonadectomy, although the timing of such surgery can be discussed with parents during counselling regarding the risk of malignancy.
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Affiliation(s)
- David Coyle
- Department of Paediatric Surgery, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.
| | - Balazs Kutasy
- Department of Paediatric Surgery, National Children's Hospital, Tallaght, Dublin, Ireland
| | - Kathleen Han Suyin
- Department of Histopathology, Temple Street Children's University Hospital, Dublin, Ireland
| | - Brice Antao
- Department of Paediatric Surgery, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
| | - Sally Ann Lynch
- National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
| | - Michael B McDermott
- Department of Histopathology, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
| | - Susan M O'Connell
- Department of Paediatrics and Child Health, Cork University Hospital, Cork, Ireland
| | - Feargal Quinn
- Department of Paediatric Surgery, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
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Identification of Y-Chromosome Sequences in Turner Syndrome. Indian J Pediatr 2016; 83:405-9. [PMID: 26634260 DOI: 10.1007/s12098-015-1929-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 10/15/2015] [Indexed: 10/22/2022]
Abstract
OBJECTIVES To investigate the presence of Y-chromosome sequences and determine their frequency in patients with Turner syndrome. METHODS The study included 23 patients with Turner syndrome from Brazil, who gave written informed consent for participating in the study. Cytogenetic analyses were performed in peripheral blood lymphocytes, with 100 metaphases per patient. Genomic DNA was also extracted from peripheral blood lymphocytes, and gene sequences DYZ1, DYZ3, ZFY and SRY were amplified by Polymerase Chain Reaction. RESULTS The cytogenetic analysis showed a 45,X karyotype in 9 patients (39.2 %) and a mosaic pattern in 14 (60.8 %). In 8.7 % (2 out of 23) of the patients, Y-chromosome sequences were found. This prevalence is very similar to those reported previously. The initial karyotype analysis of these patients did not reveal Y-chromosome material, but they were found positive for Y-specific sequences in the lymphocyte DNA analysis. CONCLUSION The PCR technique showed that 2 (8.7 %) of the patients with Turner syndrome had Y-chromosome sequences, both presenting marker chromosomes on cytogenetic analysis.
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de Marqui ABT, da Silva-Grecco RL, Balarin MAS. Prevalence of Y-chromosome sequences and gonadoblastoma in Turner syndrome. REVISTA PAULISTA DE PEDIATRIA (ENGLISH EDITION) 2016. [PMID: 26525685 PMCID: PMC4795730 DOI: 10.1016/j.rppede.2015.12.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Mohamed S, Roche EF, Hoey HMCV. Mode of initial presentation and chromosomal abnormalities in Irish patients with Turner syndrome: a single-centre experience. J Pediatr Endocrinol Metab 2015; 28:1215-8. [PMID: 25381945 DOI: 10.1515/jpem-2014-0287] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Accepted: 09/26/2014] [Indexed: 01/15/2023]
Abstract
BACKGROUND Age at diagnosis of girls with Turner syndrome (TS) is an important indicator of successful management. We determined the age, initial clinical presentation, and chromosomal abnormalities in patients with TS. METHODS This was a retrospective evaluation of the clinical and laboratory records of patients with TS. RESULTS Sixty-five patients with TS were identified; 40 (62%) were diagnosed after age 5 years. The main presenting features were short stature, delayed puberty, dysmorphic features, and neonatal lymphoedema. Chromosomal analysis of this cohort showed that 31 patients demonstrated mosaicism, while a 45,X karyotype was observed in 19. The remaining patients had variable abnormalities including deletion, translocation, isochromosome, and ring chromosome. Y-chromosome material was found in four cases. CONCLUSIONS Most patients with TS were diagnosed after age 5 years, had a varied clinical presentation, and had a wide range of chromosomal abnormalities.
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Milunsky JM. Prenatal Diagnosis of Sex Chromosome Abnormalities. GENETIC DISORDERS AND THE FETUS 2015:267-312. [DOI: 10.1002/9781118981559.ch5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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de Marqui ABT, da Silva-Grecco RL, Balarin MAS. [Prevalence of Y-chromosome sequences and gonadoblastoma in Turner syndrome]. REVISTA PAULISTA DE PEDIATRIA 2015; 34:114-21. [PMID: 26525685 DOI: 10.1016/j.rpped.2015.06.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Revised: 05/26/2015] [Accepted: 06/04/2015] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To assess the prevalence of Y-chromosome sequences and gonadoblastoma in patients with Turner syndrome using molecular techniques. DATA SOURCE A literature search was performed in Pubmed, limiting the period of time to the years 2005 to 2014 and using the descriptors: Turner syndrome and Y sequences (n=26), and Turner syndrome and Y-chromosome material (n=27). The inclusion criteria were: articles directly related to the subject and published in English or Portuguese. Articles which did not meet these criteria and review articles were excluded. After applying these criteria, 14 papers were left. DATA SYNTHESIS the main results regarding the prevalence of Y-chromosome sequences in Turner syndrome were: 1-about 60% of the studies were conducted by Brazilian researchers; 2-the prevalence varied from 4.6 to 60%; 3-the most frequently investigated genes were SRY, DYZ3 and TSPY; 4-seven studies used only PCR, while in the remaining seven it was associated with FISH. Nine of the 14 studies reported gonadectomy and gonadoblastoma. The highest prevalence of gonadoblastoma (33%) was found in two studies. In five out of the nine papers evaluated the prevalence of gonadoblastoma was 10 to 25%; in two of them it was zero. CONCLUSIONS according to these data, molecular analysis to detect Y-chromosome sequences in TS patients is indicated, regardless of their karyotype. In patients who test positive for these sequences, gonadoblastoma needs to be investigated.
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Jørgensen A, Lindhardt Johansen M, Juul A, Skakkebaek NE, Main KM, Rajpert-De Meyts E. Pathogenesis of germ cell neoplasia in testicular dysgenesis and disorders of sex development. Semin Cell Dev Biol 2015; 45:124-37. [PMID: 26410164 DOI: 10.1016/j.semcdb.2015.09.013] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 09/21/2015] [Indexed: 12/29/2022]
Abstract
Development of human gonads is a sex-dimorphic process which evolved to produce sex-specific types of germ cells. The process of gonadal sex differentiation is directed by the action of the somatic cells and ultimately results in germ cells differentiating to become functional gametes through spermatogenesis or oogenesis. This tightly controlled process depends on the proper sequential expression of many genes and signalling pathways. Disturbances of this process can be manifested as a large spectrum of disorders, ranging from severe disorders of sex development (DSD) to - in the genetic male - mild reproductive problems within the testicular dysgenesis syndrome (TDS), with large overlap between the syndromes. These disorders carry an increased but variable risk of germ cell neoplasia. In this review, we discuss the pathogenesis of germ cell neoplasia associated with gonadal dysgenesis, especially in individuals with 46,XY DSD. We summarise knowledge concerning development and sex differentiation of human gonads, with focus on sex-dimorphic steps of germ cell maturation, including meiosis. We also briefly outline the histopathology of germ cell neoplasia in situ (GCNIS) and gonadoblastoma (GDB), which are essentially the same precursor lesion but with different morphological structure dependent upon the masculinisation of the somatic niche. To assess the risk of germ cell neoplasia in different types of DSD, we have performed a PubMed search and provide here a synthesis of the evidence from studies published since 2006. We present a model for pathogenesis of GCNIS/GDB in TDS/DSD, with the risk of malignancy determined by the presence of the testis-inducing Y chromosome and the degree of masculinisation. The associations between phenotype and the risk of neoplasia are likely further modulated in each individual by the constellation of the gene polymorphisms and environmental factors.
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Affiliation(s)
- Anne Jørgensen
- Department of Growth & Reproduction and International Center for Research and Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Denmark.
| | - Marie Lindhardt Johansen
- Department of Growth & Reproduction and International Center for Research and Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Denmark.
| | - Anders Juul
- Department of Growth & Reproduction and International Center for Research and Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Denmark.
| | - Niels E Skakkebaek
- Department of Growth & Reproduction and International Center for Research and Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Denmark.
| | - Katharina M Main
- Department of Growth & Reproduction and International Center for Research and Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Denmark.
| | - Ewa Rajpert-De Meyts
- Department of Growth & Reproduction and International Center for Research and Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Denmark.
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Levitsky LL, Luria AHO, Hayes FJ, Lin AE. Turner syndrome: update on biology and management across the life span. Curr Opin Endocrinol Diabetes Obes 2015; 22:65-72. [PMID: 25517026 DOI: 10.1097/med.0000000000000128] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE OF REVIEW We review recent understanding of the pathophysiology, molecular biology, and management of Turner syndrome. RECENT FINDINGS Sophisticated genetic techniques are able to detect mosaicism in one-third of individuals previously thought to have monosomy X. Prenatal detection using maternal blood should permit noninvasive detection of most fetuses with an X chromosome abnormality. Disproportionate growth with short limbs has been documented in this condition, and a target gene of short stature homeobox, connective tissue growth factor (Ctgf), has been described. Liver disease is more common in Turner syndrome than previously recognized. Most girls have gonadal failure. Spontaneous puberty and menarche is more commonly seen in girls with XX mosaicism. Low-dose estrogen replacement therapy may be given early to induce a more normal onset and tempo of puberty. Oocyte donation for assisted reproduction carries a substantial risk, particularly if the woman has known cardiac or aortic disease. Neurodevelopmental differences in Turner syndrome are beginning to be correlated with differences in brain anatomy. SUMMARY An increased understanding of the molecular basis for aspects of this disorder is now developing. In addition, a renewed focus on health maintenance through the life span should provide better general and targeted healthcare for these girls and women.
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Affiliation(s)
- Lynne L Levitsky
- aPediatric Endocrine Unit, Department of Pediatrics, Massachusetts General Hospital bGenetics Residency Program, Harvard Medical School cBoston Children's Hospital dReproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital eGenetics Unit, Mass General Hospital for Children, Massachusetts, Boston, USA
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Davies W. Sex differences in attention Deficit Hyperactivity Disorder: candidate genetic and endocrine mechanisms. Front Neuroendocrinol 2014; 35:331-46. [PMID: 24680800 DOI: 10.1016/j.yfrne.2014.03.003] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 02/13/2014] [Accepted: 03/17/2014] [Indexed: 02/07/2023]
Abstract
Attention Deficit Hyperactivity Disorder (ADHD) is a developmental condition characterised by severe inattention, pathological impulsivity and hyperactivity; it is relatively common affecting up to 6% of children, and is associated with a risk of long-term adverse educational and social consequences. Males are considerably more likely to be diagnosed with ADHD than females; the course of the disorder and its associated co-morbidities also appear to be sensitive to sex. Here, I discuss fundamental biological (genetic and endocrine) mechanisms that have been shown to, or could theoretically, contribute towards these sexually dimorphic phenomena. Greater understanding of how and why the sexes differ with respect to ADHD vulnerability should allow us to identify and characterise novel protective and risk factors for the disorder, and should ultimately facilitate improved diagnosis, prognosis and treatment.
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Affiliation(s)
- William Davies
- Behavioural Genetics Group, Neuroscience and Mental Health Research Institute, Schools of Psychology and Medicine, Cardiff University, Tower Building, Park Place, Cardiff CF10 3AT, UK; Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Hadyn Ellis Building, Cardiff CF24 4HQ, UK.
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Turner syndrome revisited: review of new data supports the hypothesis that all viable 45,X cases are cryptic mosaics with a rescue cell line, implying an origin by mitotic loss. Hum Genet 2014; 133:417-24. [DOI: 10.1007/s00439-014-1420-x] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Accepted: 01/13/2014] [Indexed: 10/25/2022]
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Balitzki B, Laberke P, Jegge L, Kübler E. Geschlechtsbestimmung mit dem Amelogeninsystem. Rechtsmedizin (Berl) 2013. [DOI: 10.1007/s00194-013-0931-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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