Application of fluorescence in situ hybridization combined with chromosomal karyotyping analysis in children with disorders of sex development due to sex chromosome abnormalities / 中华医学遗传学杂志

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

Clinical and genetic analysis of a case of Turner syndrome with rapidly progressive puberty and a literature review / 中华医学遗传学杂志

OBJECTIVE@#To investigate the clinical features and genetic etiology of a case of Turner syndrome (TS) with rapidly progressive puberty.@*METHODS@#A child who had presented at the Pediatric Endocrinology Clinic of the Shenzhen People's Hospital on January 19, 2022 was selected as the study subject. Clinical data of the child were collected. Peripheral blood sample of the child was subjected to chromosomal microarray analysis (CMA) and multiple ligation-dependent probe amplification (MLPA). Previous studies related to TS with rapidly progressive puberty were retrieved from the CNKI, Wanfang Data Knowledge Service Platform, Boku, CBMdisc and PubMed databases with Turner syndrome and rapidly progressive puberty as the keywords. The duration for literature retrieval was set from November 9, 2021 to May 31, 2022. The clinical characteristics and karyotypes of the children were summarized.@*RESULTS@#The child was a 13-year-and-2-month-old female. She was found to have breast development at 9, short stature at 10, and menarche at 11. At 13, she was found to have a 46,X,i(X)(q10) karyotype. At the time of admission, she had a height of 143.5 cm (< P3), with 6 ~ 8 nevi over her face and right clavicle. She also had bilateral simian creases but no saddle nasal bridge, neck webbing, cubitus valgus, shield chest or widened breast distance. She had menstruated for over 2 years, and her bone age has reached 15.6 years. CMA revealed that she had a 58.06 Mb deletion in the Xp22.33p11.1 region and a 94.49 Mb duplication in the Xp11.1q28 region. MLPA has confirmed monosomy Xp and trisomy Xq. A total of 13 reports were retrieved from the CNKI, Wanfang Data Knowledge Service Platform, Boku, CBMdisc and PubMed databases, which had included 14 similar cases. Analysis of the 15 children suggested that their main clinical manifestations have included short stature and growth retardation, and their chromosomal karyotypes were mainly mosaicisms.@*CONCLUSION@#The main clinical manifestations of TS with rapidly progressive puberty are short stature and growth retardation. Deletion in the Xp22.33p11.1 and duplication in the Xp11.1q28 probably underlay the TS with rapid progression in this child, which has provided a reference for clinical diagnosis and genetic counselling for her.

Genetic analysis of a child with mosaicism Turner syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic characteristics of a child with mosaicism Turner syndrome.@*METHODS@#A child who had presented at Linyi People's Hospital on May 19, 2022 due to short stature was selected as the study subject. The child was subjected to combined chromosomal karyotyping, fluorescence in situ hybridization (FISH), and chromosomal microarray analysis (CMA).@*RESULTS@#The child was found to have a 46,X,i(X)(q10)[94]/45,X[6] karyotype. The result of FISH was nucish(XYpter,XYqter)1[78]/(XYpter)1,(XYqter)3[122]. CMA result for her peripheral blood sample was arr[hg19]Xp22.33p11.1(168551_58526888)×1, and that for her oral mucosal cells was arr[hg19]Xp22.33p11.1(168551_58526888)1-2,Xq11.2q28(63000001_155233098)×2-3. By integrating the above findings, her molecular karyotype was determined as mos 46,X,i(X)(q10)[94]/45,X[6].arr[hg19]Xp22.33p11.1(168551_58526888)×1-2,Xq11.2q28(63000001_155233098)×2-3.nucish(XYpter)1,(XYqter)3[122]/(XYpter,XYqter)1[78], which has indicated mosaicism Turner syndrome.@*CONCLUSION@#The 46,X,i(X)(q10)/45,X mosaicism probably underlay the pathogenesis in this child.

Clinical phenotype and genetic analysis of twelve children with ring chromosomes / 中华医学遗传学杂志

OBJECTIVE@#To explore the prevalence and clinical manifestations of ring chromosomes among children featuring abnormal development.@*METHODS@#From January 2015 to August 2021, 7574 children referred for abnormal development were selected, and their peripheral blood samples were subjected to G-banded chromosomal karyotyping analysis.@*RESULTS@#Twelve cases of ring chromosomes were detected, which have yielded a prevalence of 0.16% and included 1 r(6), 2 r(9), 1 r(13), 1 r(14), 2 r(15), 1 r(21) and 3 r(X). The children had various clinical manifestations including growth and mental retardation, limb malformation, and congenital heart disease. For two children with r(9) and two with r(15) with similar breakpoints, one child with r(9) and one with r(15) only had growth retardation, whilst another with r(9) and another with r(15) also had peculiar facies and complex congenital heart disease. The r(X) has featured some manifestations of Turner syndrome.@*CONCLUSION@#Ring chromosomes are among the common causes for severe growth and mental retardation in children with diverse clinical phenotypes. Clinicians should pay attention to those with developmental anomalies and use chromosomal analysis to elucidate their genetic etiology.

Prenatal diagnosis and genetic analysis of two cases of Turner syndrome due to isodicentric Xp11.22 / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic characteristics of idic(X)(p11.22) in Turner syndrome (TS).@*METHODS@#Two fetuses suspected for sex chromosome abnormalities or ultrasound abnormalities were selected from Chengdu Women's and Children's Central Hospital in October 2020 and June 2020, and amniotic fluid samples were collected for G-banded chromosomal karyotyping analysis, chromosomal microarray analysis (CMA), and fluorescence in situ hybridization (FISH).@*RESULTS@#The two fetuses were respectively found to have a karyotype of 45,X[47]/46,X,psu idic(X)(p11.2)[53] and 46,X,psu idic(X)(p11.2). CMA found that both had deletions in the Xp22.33p11.22 region and duplications in the p11.22q28 region. FISH showed that the centromeres in both fetuses had located on an isochromosome.@*CONCLUSION@#The combination of karyotyping analysis, FISH, and CMA is useful for the delineation of complex structural chromosomal aberrations. High-resolution CMA can accurately identify chromosomal breakpoints, which can provide a clue for elucidating the mechanism of chromosomal breakage and rearrangement.

Turner syndrome associated with Down syndrome: about a case / Síndrome Turner asociado a síndrome Down: a propósito de un caso

The coexistence of double aneuploidy of Down and Turner syndromes is rare; most cases have been due to double mitotic errors. The objective of the study was to report a case with monosomy of the X chromosome and trisomy of chromosome 21, in mosaic variety, highlighting the phenotypic effect that the presence of different chromosomal abnormalities can produce and compare with those reported in the literature. A 10-year-old Ecuadorian female, born to a multipregnant mother with 46 years at conception, is seen in consultation with a predominant clinical phenotype of Down syndrome, associated with menarche, presence of pubic and axillary villu, where a karyotype is verified 45 X[7]/47XX+ 21 [3]/46, X, der (X)(: p11.1-> q11.1)[1]/46,XX [1]. The present case is a double Turner-Down aneuploidy, with predominantly X monosomy cell line, who shows important mental retardation and some signs of puberal development not usually in Turner syndrome. These features highlight the clinical importance of doing a karyotype in mental retardation cases and searching low mosaics of another aneuploidies in atypical cases. Its complex chromosomal formula and support with molecular cytogenetics allowed diagnostic confirmation and genetic counseling.

La coexistencia de doble aneuploidía de los síndromes de Down y Turner es rara; la mayoría de los casos se han debido a dobles errores mitóticos. Reportar un caso con trisomía del cromosoma 21 y monosomía del cromosoma en X, en variedad mosaico, que curiosamente presenta un despertar puberal precoz y comparar con los reportados en la literatura. Paciente ecuatoriana de sexo femenino, de 10 años de edad, nacida de madre multigesta con 46 años a la concepción, que es vista en consulta con fenotipo clínico predominante de Síndrome Down, asociado a menarquia y telarquia, donde se constata un cariotipo. El presente caso es el primero informado de mosaicismo de doble aneuploidía de Turner-Down asociado con un despertar puberal precoz. Su fórmula cromosómica compleja y el apoyo con la citogenética molecular permitió la confirmación diagnostica y la asesoría genética.

Variantes citogenéticas en pacientes con síndrome de Turner diagnosticadas en un hospital de tercer nivel de atención en Ecuador / Cytogenetic variants in patients with Turner syndrome diagnosed in a third level care hospital in Ecuador

Resumen Introducción: El Síndrome de Turner (ST) es una alteración cromosómica sexual causada por la ausencia parcial o completa del cromosoma X, además de mosaicismos y otras alteraciones estructurales del cromosoma X o Y; está presente en 1 de 2500 nacidas vivas. Objetivo: Describir las variantes citogenéticas de pacientes con síndrome de Turner y evaluar su asociación con el fenotipo de presentación y la edad del diagnóstico. Método: Estudio retrospectivo de corte transversal de una serie de 82 casos de síndrome de Turner. Los cariotipos fueron realizados utilizando el medio RPMI-1640; las preparaciones de cromosomas se obtuvieron utilizando técnicas estándar y se analizaron mediante bandas GTG con una resolución de 400-450 bandas, donde se contó con 20-50 metafases para reducir la probabilidad de no detección de mosaicismo. Resultados: 45 (55.6%) fueron diagnosticadas, con monosomía clásica del cromosoma X, mientras 29 (35,8%) mostraron anomalías estructurales del cromosoma X y 7 (8,6%) se asociaron a mosaicos numéricos del cromosoma X. Solo 21 (26%) pacientes fueron diagnosticadas por debajo de los 12 años, mientras el resto 60 (74%) se detectaron entre la adolescencia y la adultez. La baja estatura fue una característica universal en todos los grupos de estudio. Conclusiones: Las fórmulas cromosómicas en el síndrome de Turner pueden ser muy variadas y tener diversas implicaciones en el fenotipo; se destaca la baja talla como un criterio clínico relevante en la sospecha clínica.

Abstract Introduction: Turner Syndrome (TS) is a sexual chromosomal alteration caused by the partial or complete absence of the X chromosome, in addition to mosaicisms and other structural alterations of the X or Y chromosome; It is present in 1 in 2,500 live births. Objective: To describe the cytogenetic variants of Turner syndrome patients and to evaluate their association with the phenotype at presentation and age at diagnosis. Methods: Retrospective cross-sectional study of a series of 82 cases of Turner syndrome. Karyotypes were performed using RPMI-1640 medium; Chromosome preparations were obtained using standard techniques and analyzed by GTG banding with a resolution of 400-450 bands where 20-50 metaphases were counted to reduce the probability of missing mosaicism. Results: 45 (55.6%) were diagnosed with classic monosomy of the X chromosome, while 29 (35.8%) showed structural abnormalities of the X chromosome and 7 (8.6%) were associated with numerical mosaics of the X chromosome. Only 21 (26%) patients were diagnosed under 12 years of age, while the rest 60 (74%) were detected between adolescence and adulthood. Short stature was a universal characteristic in all study groups. Conclusions: The chromosomal formulas in Turner syndrome can be variable and have different implications in the phenotype; short stature stands out as a relevant clinical criterion in clinical suspicion.

Searching chromosome mosaicisms in 45, X Turner syndrome: how relevant is it?

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). Materials and 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. Conclusions: 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.

Association between cytogenetic alteration and the audiometric profile of individuals with Turner syndrome / Relação entre alteração citogenética e o perfil audiométrico de indivíduos com síndrome de Turner

Abstract Introduction: Turner syndrome is a frequent genetic disorder that affects female individuals and covers a large phenotypic variability. Scientific literature suggests an association between hearing loss and Turner syndrome, but it remains a controversial topic. Objective: To associate the cytogenetic alteration with the audiometric profile of individuals with Turner syndrome. Methods: Cross-sectional study, with a hospital-based, convenience sample. Patients diagnosed with Turner syndrome were included and those with difficulty understanding the audiometry and/or other associated syndromes were excluded. The participants were studied with pure tone audiometry. Results: Of the 65 patients included, 36.9% had X chromosome monosomy and 63.0% had other alterations. Regarding the audiometry, 64.6% had normal thresholds and 35.3% had hearing impairment. Of these, 30.4% had hybrid hearing loss, 26.0% alteration at 6 and/or 8 kHz, 17.3% had conductive hearing loss, 13.0% sensorineural loss and 13.0% had mixed hearing loss. We observed that the mild degree was the most frequent one. There was no statistically significant association between the cytogenetic type of Turner syndrome and the presence or absence of hearing loss, or with the type and degree of hearing loss. Conclusion: The cytogenetic alteration in Turner syndrome was not associated with the audiometric profile, which showed variability regarding the type and degree of hearing loss.

Resumo Introdução: A síndrome de Turner é uma alteração frequente e genética que acomete indivíduos do sexo feminino e abrange grande variabilidade fenotípica. A literatura científica sugere uma relação entre perda auditiva e síndrome de Turner, porém ainda é um tema controverso. Objetivo: Relacionar a alteração citogenética com o perfil audiométrico de indivíduos com síndrome de Turner. Método: Estudo transversal, com amostra de conveniência, de base hospitalar. Foram incluídas pacientes com diagnóstico de síndrome de Turner e excluídas as com dificuldade para compreender a audiometria e/ou outras síndromes associadas. As participantes foram submetidas à audiometria tonal. Resultados: Das 65 pacientes incluídas, 36,9% apresentaram monossomia do cromossomo X e 63,0%, outras alterações. Com relação à audiometria, 64,6% apresentaram limiares dentro da normalidade e 35,3% alteração auditiva. Dessas, 30,4% apresentaram perda auditiva híbrida, 26,0% alteração em 6 e/ou 8 KHz; 17,3% perda auditiva condutiva, 13,0% perda neurossensorial e 13,0% perda auditiva mista. Observamos que o grau leve foi o mais frequente. Não foi observada associação estatiscamente significativa entre o tipo citogenético da síndrome de Turner e a presença ou não perda auditiva, ou com o tipo e grau de perda auditiva. Conclusão: A alteração citogenética na síndrome de Turner não teve associação com o perfil audiométrico, o qual apresentou variabilidade quanto ao tipo e grau da perda auditiva.

Clinical and cytogenetic characteristics of patients diagnosed with Turner syndrome in a clinical genetics service: cross-sectional retrospective study

ABSTRACT BACKGROUND: Turner syndrome (TS) is a rare genetic disease. Understanding its clinical findings contributes to better management of clinical conditions. OBJECTIVE: To investigate the clinical and karyotypic characteristics of patients diagnosed with TS at two reference services for clinical genetics in southern Brazil. DESIGN AND SETTING: Retrospective cross-sectional study conducted in two clinical genetics services in Porto Alegre (RS), Brazil. METHODS: The sample consisted of 59 patients with TS diagnosed from 1993 to 2019. A review of their medical records was performed and a standard protocol was filled out. RESULTS: The average age of the patients at diagnosis was 15.9 years, and 40.7% were over 13 years old. The largest proportion of them (42.4%) had been referred from an endocrinology department and their constitution was 45,X (40.7%). The most common clinical findings were short stature (85.7%), hypoplastic/ hyperconvex nails (61.2%), low posterior hairline (52.1%) and cubitus valgus (45.8%). There was no difference regarding the presence of short stature (P = 0.5943), number of dysmorphia (P = 0.143), anatomical regions affected and malformations identified through imaging examinations (P = 1.0000), regarding the presence or absence of 45,X constitution. Only 6% of the patients had used growth hormone and 43%, estrogen. CONCLUSION: We found that, in general, patients with TS were being diagnosed late. This has important implications for their treatment. In addition, only a small proportion of the patients were undergoing further examination or evaluation, which appeared to be leading to underdiagnosis of many abnormalities.

Actualización en el manejo del síndrome de Turner en niñas y adolescentes: revisión de la literatura e Incorporación de recomendaciones de las nuevas guías clínicas / Update on the management of Turner syndrome in girls and adolescents: review of the literature and incorporation of recommendations of the new clinical guidelines

Turner syndrome (TS) is a common disorder (1/2.000 women) that affects multiple organs at different stages of life and needs a multidisciplinary approach. It can be present in women of all ethnicities and is caused by a monosomy of the X chromosome that causes a haploinsufficiency of certain genes. Its main features consist of specific but variables physical characteristics, congenital heart defects, renal anomalies, middle and inner ear diseases, skeletal alterations, and from the endocrinological point of view, short stature and ovarian insufficiency. Given the comorbidities associated with TS, it has been estimated that they have an increased risk of mortality (up to 3 times more) and a reduction in life expectancy of approximately 13 years. Depending on the genotype, the abnormalities can become very subtle, in these cases the diagnosis is late, when the adolescent consults, for example, for primary amenorrhea or an adult woman for infertility. Once the diagnosis is confirmed by a karyotype, these patients must remain in pediatric control in a continuous way to investigate associated pathologies in a timely manner, with periodic evaluations by specialists, such as otolaryngologists, cardiologists, neurologists and endocrinologists, among others. Numerous advances in the care of these patients gave rise to new guidelines published in 2017. In this article we will comment on the main conditions associated with TS and its specific etiology, we will mention what is relevant regarding the genotype-phenotype relationship in this syndrome and we will discuss the fundamental aspects of the control of the TS patient, with emphasis on the treatment of short stature and ovarian insufficiency, as well as the cardiovascular aspects and those related to fertility.

El Síndrome de Turner (ST) es una patología frecuente (1/2.000 mujeres) que afecta múltiples órganos en distintas etapas de la vida y necesita un enfoque multidisciplinario. Se produce por una monosomía del cromosoma X que provoca una haploinsuficiencia de determinados genes. Sus características principales consisten en un fenotipo característico pero variable, con presencia de cardiopatías congénitas, anomalías renales, enfermedades del oído medio e interno, alteraciones esqueléticas, y del punto de vista endocrinológico, talla baja e insuficiencia ovárica. Dadas las comorbilidades asociadas al ST, principalmente cardiovasculares (CV), presentan mayor mortalidad con respecto a la población general (hasta 3 veces más). Dependiendo del genotipo, las anomalías pueden llegar a ser muy sutiles, realizándose en estos casos el diagnóstico en forma tardía, cuando la adolescente consulte, por ejemplo, por amenorrea primaria o una mujer adulta por infertilidad. Una vez confirmado el diagnóstico mediante un cariotipo, estas pacientes deben permanecer en control endocrinológico pediátrico en forma continua hasta la transición hacia adultos, con el fin de pesquisar patologías asociadas en forma oportuna. Por ello requieren evaluaciones periódicas por especialistas, tales como otorrinolaringólogos, cardiólogos, neuropsiquiatras, entre otros. Numerosos avances en el cuidado de estas pacientes, dieron origen a nuevas guías publicadas el 2017. En este artículo comentaremos sobre las principales condiciones asociadas al ST y su etiología específica, mencionaremos lo relevante respecto a la relación genotipo-fenotipo en este síndrome y discutiremos los aspectos fundamentales del control de la paciente con ST, haciendo énfasis en el tratamiento de la talla baja y la insuficiencia ovárica, así como los aspectos CV y los relacionados a fertilidad.

Recién nacida normal con sospecha prenatal de monosomía del cromosoma X debido a mosaicismo confinado a la placenta / Normal newborn with prenatal suspicion of X chromosome monosomy due to confined placental mosaicism

La reciente introducción de las pruebas prenatales no invasivas (NIPT, por sus siglas en inglés) basadas en el ADN libre ofrece un método más preciso que los métodos tradicionales de detección en el suero materno para identificar aneuploidías fetales. La eficacia de las pruebas NIPT para detectar los síndromes de Down, Edwards y Patau se ha demostrado en ensayos clínicos. Sin embargo, los enfoques de las pruebas NIPT que aprovechan la información sobre el polimorfismo de un solo nucleótido (SNP, por sus siglas en inglés) tienen el potencial de identificar triploidías, síndromes de microdeleción cromosómica y otras variantes genéticas no habituales. Para destacar este enfoque de las pruebas NIPT, se presenta un caso poco frecuente de monosomía del cromosoma X debido a mosaicismo confinado a la placenta, del que había una sospecha prenatal por el resultado de una prueba prenatal no invasiva basada en el polimorfismo de un solo nucleótido. Los resultados de las pruebas invasivas (amniocentesis) mostraron una pequeña proporción de mosaicismo del cromosoma X (45, X[5]/46, XX[95]). Después del nacimiento, el cariotipo de la niña no reveló anomalías (46 XX), lo que confirmó que el mosaicismo se limitaba a la placenta. Estos resultados ponen de manifiesto la necesidad del consentimiento informado de la paciente, y del minucioso asesoramiento anterior y posterior a las pruebas, para garantizar que comprenda las limitaciones y las ventajas de dichas pruebas, y las repercusiones de los resultados.

The recent introduction of cell-free DNA (cfDNA)-based noninvasive prenatal testing (NIPT) offers pregnant women a more accurate method than traditional serum screening methods for detecting fetal aneuploidies. Clinical trials have demonstrated the efficacy of NIPT for Down, Edwards and Patau syndromes. However NIPT approaches that take advantage of single-nucelotide polymorphism (SNP) information potentially allow the identification of triploidy, chromosomal microdeletion syndromes and other unusual genetic variants. To highlight this approach of NIPT we present a rare case of confined placental X chromosome monosomy mosaicism that was prenatally suspected with a single-nucleotide polymorphism-based noninvasive prenatal test. The results of invasive tests (amniocentesis) showed small proportion of X chromosome mosaicism (45, X[5]/46, XX[95]). After birth karyotype of the girl revealed no abnormalities (46 XX), confirming that mosaicism was limited to the placenta. These results highlight the need of patient's informed consent and thorough pretest and postest counseling to ensure that they understand the limitations and advantages of the tests and the implications of the resultss.

45,X/46,XY mosaicism: report on 14 patients from a Brazilian hospital. A retrospective study / Mosaicismo 45,X/46,XY: relato de 14 pacientes de um hospital do Brasil. Um estudo retrospectivo

CONTEXT AND OBJECTIVE: 45,X/46,XY mosaicism, or mixed gonadal dysgenesis, is considered to be a rare disorder of sex development. The aim of our study was to investigate the clinical and cytogenetic characteristics of patients with this mosaicism. DESIGN AND SETTING: A retrospective study in a referral hospital in southern Brazil. METHODS: Our sample consisted of patients diagnosed at the clinical genetics service of a referral hospital in southern Brazil, from 1975 to 2012. Clinical and cytogenetic data were collected from the medical records. RESULTS: Fourteen patients were included in the sample, with ages at the first evaluation ranging from 2 days to 38 years. Nine of them had female sex of rearing and five, male. Regarding the external genitalia, most were ambiguous (n = 10). One patient presented male phenotype and was treated for a history of azoospermia, while three patients presented female phenotype, of whom two had findings of Turner syndrome and one presented secondary amenorrhea alone. Some findings of Turner syndrome were observed even among patients with ambiguous genitalia. None presented gonadal malignancy. One patient underwent surgical correction for genital ambiguity and subsequent exchange of sex of rearing. Regarding cytogenetics, we did not observe any direct correlation between percentages of cell lines and phenotype. CONCLUSIONS: 45,X/46,XY mosaicism can present with a wide variety of phenotypes resulting from the involvement of different aspects of the individual. All these observations have important implications for early recognition of these patients and their appropriate management. .

CONTEXTO E OBJETIVO: O mosaicismo 45,X/46,XY, ou disgenesia gonadal mista, é considerado uma doença rara do desenvolvimento sexual. O objetivo do nosso estudo foi verificar as características clínicas e citogenéticas de pacientes com este mosaicismo. TIPO DE ESTUDO E LOCAL: Estudo retrospectivo em um hospital de referência no sul do Brasil. MÉTODOS: Nossa amostra foi composta por pacientes diagnosticados em um serviço de genética clínica de um hospital de referência no sul do Brasil, no período de 1975 até 2012. Os dados clínicos e citogenéticos foram coletados a partir dos prontuários médicos. RESULTADOS: Catorze pacientes foram incluídos na amostra, idades na primeira avaliação variando de 2 dias a 38 anos. Nove deles apresentavam sexo feminino de criação e cinco, masculino. A genitália externa, na maioria, era ambígua (n = 10). O paciente com fenótipo masculino foi tratado por história de azoospermia, enquanto que das três pacientes do fenótipo feminino, duas apresentavam achados da síndrome de Turner e a outra, amenorreia secundária isolada. Alguns achados da síndrome de Turner foram observados mesmo entre pacientes com genitália ambígua. Nenhum deles apresentou neoplasia gonadal. Um paciente foi submetido à correção cirúrgica de ambiguidade genital e posterior troca de sexo de criação. Quanto à citogenética, não observamos correlação direta entre a porcentagem de linhas de células e o fenótipo. CONCLUSÕES: O mosaicismo 45,X/46,XY pode apresentar grande variedade de fenótipos resultantes do envolvimento de diferentes aspectos do indivíduo. Todas essas observações têm implicações importantes para o reconhecimento precoce desses pacientes e seu adequado manejo. .

Uso da FISH em mucosa oral para investigação de mosaicismo com linhagem 45,X: estudo com homens saudáveis e pacientes com distúrbios da diferenciação do sexo / The use of FISH on buccal smear to investigate mosaicism with a 45,X cell line: study on healthy men and patients with disorders of sex development

Objetivo: Verificar se a hibridização in situ por fluorescência (FISH) em células de mucosa oral poderia ser empregada para detectar criptomosaicismo com linhagem 45,X em pacientes 46,XY. Sujeitos e métodos: Amostra de 19 jovens saudáveis 46,XY e cinco pacientes com distúrbios da diferenciação do sexo (DDS), quatro 45,X/46,XY e um 46,XY. FISH com sondas específicas para X e Y em núcleos interfásicos de linfócitos e mucosa oral para investigar a proporção de núcleos contendo apenas o sinal do cromossomo X. Resultados: A frequência de núcleos contendo apenas o sinal do X nos dois tecidos dos homens saudáveis não diferiu (p = 0,69). Em todos os pacientes com DDS essa frequência foi significativamente maior, e também não houve diferença entre os dois tecidos (p = 0,38). Conclusões: A investigação de mosaicismo com linhagem 45,X em pacientes com DDS 46,XY ou esterilidade pode ser feita por FISH diretamente em células de mucosa oral. .

Objective: To verify whether fluorescence in situ hybridization (FISH) of cells from the buccal epithelium could be employed to detect cryptomosaicism with a 45,X lineage in 46,XY patients. Subjects and methods: Samples of nineteen 46,XY healthy young men and five patients with disorders of sex development (DSD), four 45,X/46,XY and one 46,XY were used. FISH analysis with X and Y specific probes on interphase nuclei from blood lymphocytes and buccal epithelium were analyzed to investigate the proportion of nuclei containing only the signal of the X chromosome. Results: The frequency of nuclei containing only the X signal in the two tissues of healthy men did not differ (p = 0.69). In all patients with DSD this frequency was significantly higher, and there was no difference between the two tissues (p = 0.38), either. Conclusions: Investigation of mosaicism with a 45,X cell line in patients with 46,XY DSD or sterility can be done by FISH directly using cells from the buccal epithelium. .

Variedad de la presentación citogenética en el síndrome de turner, prenatal y postnatal / Cytogenetics variety of presentation turner syndrome, prenatal and postnatal

Antecedentes: El síndrome de Turner (ST) es causado por la ausencia total o parcial del cromosoma X y posee una gran variedad en su presentación citogenética. Objetivos: Determinar la variedad de presentación citogenética y la existencia de diferencias entre los casos diagnosticados in útero y los de diagnóstico postnatal, en pacientes con ST en dos laboratorios de referencia de Cali, Colombia. Métodos: Se realizó un estudio observacional descriptivo de corte transversal, se incluyeron pacientes con diagnóstico de ST, cuyo cariotipo se realizó entre los años 2000 y 2012, en los laboratorios de citogenética de la Universidad del Valle y un instituto de genética de Cali, Colombia. Se recolectó información del reporte del cariotipo, tipo de muestra y tiempo de realización del diagnóstico y se determinó frecuencias y asociaciones estadísticas entre las variables a estudiar. Resultados: Se incluyeron 181 pacientes con fórmula cromosómica compatible con ST; 69 fueron diagnosticados in útero, los demás, en recién nacidos vivos, infantes o adultos. La fórmula cromosómica 45 X0 se encontró en el 95,6 por ciento de los casos de diagnóstico prenatal y 58 por ciento de los de diagnóstico postnatal. Se aplicó la prueba del test exacto de Fisher, comparando los múltiples subgrupos de la variedad de presentación citogenética de diagnóstico prenatal y postnatal, encontrándose diferencias estadísticamente significativas en la distribución de las dos poblaciones evaluadas (p<0,001). Conclusiones: Existen diferencias significativas en los cariotipos de los pacientes con ST diagnosticados in útero, respecto a los diagnosticados en vida extrauterina. Se postula que esa diferencia tendría una explicación biológica sobre la posibilidad de muerte in útero por la ausencia total del cromosoma X.

Background: Turner syndrome is caused by the complete or partial absence of chromosome X and has a great variety in their cytogenetic presentation. Objectives: To determine the variety of cytogenetic presentation and the presence of differences between cases diagnosed in uterus and postnatally, in patients with Turner syndrome at two reference laboratories of Cali, Colombia. Methods: A descriptive cross-sectional study was performed. We included patients with cytogenetic diagnosis of Turner syndrome performed between 2000 and 2012 at cytogenetic laboratories of Universidad del Valle and a genetic institute in Cali, Colombia. The information of karyotype result, type of sample and the diagnosis moment was collected, determining frequencies and statistical associations. Results: 181 patients with Turner's chromosomic presentation; 69 were diagnosed in uterus, the other as live newborns, infants or adults. Chromosomal formula 45X0 was found in 95.6 percent of cases with prenatal diagnosis and 58 percent of postnatal diagnosis. Fisher's test was applied, comparing the cytogenetic presentations of prenatal and postnatal diagnosis, statistically significant difference in the distribution of the two populations evaluated was found (p<0.001). Conclusions: There are significant differences in the karyotypes of patients with ST diagnosed in utero, compared to those diagnosed in postnatal life. We hypothesize that this difference would have a biological explanation due to a higher probability of death in utero by the complete absence of chromosome X.

Juvenile ankylosing spondylitis in Turner syndrome.

Juvenile ankylosing spondylitis (JAS) is a chronic autoimmune disorder which causes considerable morbidity when left untreated; it occurs predominantly in men. We describe an Asian Indian woman who had JAS with phenotypic features of Turner syndrome (TS) and was found to be a mosaic for 45, X/46, X, psu idic (X) (p11) by karyotyping and fluorescence in situ hybridization (FISH) studies of peripheral blood. The absence of Y chromosome material was confirmed by FISH. Haplo-insufficiency of the X chromosome can predispose to autoimmunity. To the best of our knowledge, this is the first report of JAS in association with mosaic Turner syndrome. This case highlights the possible effects of gene dosage in development of an autoimmune disease.

Body composition in Egyptian Turner syndrome girls.

OBJECTIVE: This cross-sectional study was undertaken to construct the new body fat % curve and provide body composition reference data for adolescent girls with Turner syndrome (TS). They diagnosed cytogenetically by blood karyotyping and not treated with growth hormone (GH). MATERIALS AND METHODS: The study included 70 TS girls from age 13 years to age 17 years. Body composition was measured by bioelectrical impedance. Smoothed centile charts were derived by using the least mean square (LMS) method. RESULTS: The new body fat curves reflect the increase of body fat mass (FM) from age 13 years to age 17 years. Body FM % of Egyptian TS girls was lower when compared with age-matched American untreated TS girls. CONCLUSION: This study presents the new body fat curves and reference values of body composition for untreated Egyptian TS adolescent girls. The present charts can be used for direct assessment of body FM % for Egyptian TS girls and evaluation for cases on GH treatment or other growth promoting therapy.

Síndrome de Turner con mosaicismo 45,X/46Xdel(X)(q21): Comunicación de un caso / Turner's syndrome 45,X/46Xdel(X)(q21): A case report

El síndrome de Turner fue descrito por Otto Ullrich en 1930 y por Henry Turner en 1938. Se estima que 1 de 2000 a 3000 niñas recién nacidas, y 1% de las concepciones de embriones y fetos femeninos portan esta patología, llegándose a abortar espontáneamente, en el primer trimestre, entre el 95% y el 99% de los fetos afectados. El caso que se presenta corresponde a una adolescente, nacida en 1995, que consultó por amenorrea primaria, con cariotipo 45,X[6]/46Xdel(X)(q21)[14]. Dado el resultado observado, se estudió a la madre, quien había experimentado una insuficiencia ovárica prematura y cuyo cariotipo era 46Xdel(X)(q21) [3]/ 46,XX[35].

Turner's syndrome was described by Otto Ullrich (1930) and Henry Turner (1938). An estimated 1 from 2,000 to 3,000 female babies and 1% of the conceptions of female embryos and fetuses have this condition, and 95 to 99% of them result in miscarriage during the first trimester. The case presented concerns a 15 y/o girl who consulted due to primary amenorrhea. The karyotype was 45,X[6]/46Xdel(X)(q21)[14]. Her mother had experienced premature ovarian failure and her karyotype was: 46Xdel(X)(q21)[3]/46,XX[35].

Spontaneous puberty in girls with early diagnosis of Turner syndrome / Puberdade espontânea em meninas com diagnóstico precoce de síndrome de Turner

OBJECTIVE: To verify if the frequency of spontaneous pubertal development among girls with Turner syndrome (TS) diagnosed in infancy and childhood is greater than that of patients diagnosed later. SUBJECTS AND METHODS: Thirty three girls aged < 10 years at the time of diagnosis were evaluated regarding pubertal development. The frequency of spontaneous puberty was compared with that of girls aged > 13 years diagnosed at the same service. RESULTS: Sixteen of 32 informative patients had signs of spontaneous puberty, a frequency greater than that of patients diagnosed later. In six patients, there was no progression of puberty; menarche occurred in six, and one became pregnant, but the fetus was a stillborn. Spontaneous puberty was absent in all cases with 45,X karyotype. CONCLUSIONS: The greater prevalence of spontaneous puberty in girls whose diagnosis was not based on pubertal delay suggests that, among those diagnosed later, there is a bias towards patients with hypogonadism. Arq Bras Endocrinol Metab. 2012;56(9):653-7.

OBJETIVO: Verificar se a frequência de puberdade espontânea em meninas com síndrome de Turner (ST) diagnosticadas na infância é superior a de pacientes diagnosticadas posteriormente. SUJEITOS E MÉTODOS: Foram avaliadas 33 meninas < 10 anos ao diagnóstico quanto ao desenvolvimento puberal. A frequência de puberdade espontânea foi comparada com a de pacientes com mais de 13 anos diagnosticadas no mesmo serviço. RESULTADOS: Dezesseis das 32 pacientes informativas tiveram sinais puberais espontâneos, frequência superior a daquelas diagnosticadas posteriormente. Em seis delas, não houve progressão da puberdade; a menarca ocorreu em seis casos e uma paciente ficou grávida, porém o feto foi natimorto. Em todos os casos com cariótipo 45,X não ocorreu puberdade espontânea. CONCLUSÕES: A maior prevalência de puberdade espontânea em meninas cujo diagnóstico não se baseou em atraso puberal sugere que naquelas detectadas posteriormente haja distorção em favor de pacientes com hipogonadismo. Arq Bras Endocrinol Metab. 2012;56(9):653-7.

The use of fluorescence in situ hybridization in the diagnosis of hidden mosaicism: apropos of three cases of sex chromosome anomalies / O uso da hibridação in situ com fluorescência no diagnóstico de mosaicismo oculto: a propósito de três casos de anomalias de cromossomos sexuais

FISH has been used as a complement to classical cytogenetics in the detection of mosaicism in sex chromosome anomalies. The aim of this study is to describe three cases in which the final diagnosis could only be achieved by FISH. Case 1 was an 8-year-old 46,XY girl with normal female genitalia referred to our service because of short stature. FISH analysis of lymphocytes with probes for the X and Y centromeres identified a 45,X/46,X,idic(Y) constitution, and established the diagnosis of Turner syndrome. Case 2 was a 21-month-old 46,XY boy with genital ambiguity (penile hypospadias, right testis, and left streak gonad). FISH analysis of lymphocytes and buccal smear identified a 45,X/46,XY karyotype, leading to diagnosis of mixed gonadal dysgenesis. Case 3 was a 47,XYY 19-year-old boy with delayed neuromotor development, learning disabilities, psychological problems, tall stature, small testes, elevated gonadotropins, and azoospermia. FISH analysis of lymphocytes and buccal smear identified a 47,XYY/48,XXYY constitution. Cases 1 and 2 illustrate the phenotypic variability of the 45,X/46,XY mosaicism, and the importance of detection of the 45,X cell line for proper management and follow-up. In case 3, abnormal gonadal function could be explained by the 48,XXYY cell line. The use of FISH in clinical practice is particularly relevant when classical cytogenetic analysis yields normal or uncertain results in patients with features of sex chromosome aneuploidy. Arq Bras Endocrinol Metab. 2012;56(8):545-51.

FISH tem sido usado como um complemento para a citogenética clássica na detecção de mosaicismo em anomalias de cromossomos sexuais. O objetivo deste trabalho é descrever três casos nos quais o diagnóstico final só foi obtido por meio de FISH. O caso 1 é uma menina de 8 anos, 46,XY, com genitália feminina normal, encaminhada ao nosso setor devido à baixa estatura. A análise de linfócitos por FISH com sondas centroméricas de X e Y identificou a constituição 45,X/46,X,idic(Y) e estabeleceu o diagnóstico de síndrome de Turner. O caso 2 é um menino de 21 meses, 46,XY, com ambiguidade genital (hipospadia peniana, testículo à direita e gônada disgenética à esquerda). FISH de linfócitos e mucosa oral identificou o cariótipo 45,X/46,XY, levando ao diagnóstico de disgenesia gonadal mista. O caso 3 é um rapaz de 19 anos, 47,XYY, com atraso de desenvolvimento neuromotor, dificuldade de aprendizado, problemas psicológicos, alta estatura, testículos pequenos, gonadotrofinas elevadas e azoospermia. FISH de linfócitos e mucosa oral identificou a constituição 47,XYY/48,XXYY. Os casos 1 e 2 ilustram a variabilidade fenotípica do mosaico 45,X/46,XY e a importância da detecção da linhagem 45,X na avaliação e na condução dos casos. No caso 3, a função gonadal anormal pôde ser explicada pela linhagem 48,XXYY. O uso de FISH na prática clínica é particularmente relevante quando a análise citogenética clássica traz resultados normais ou incertos em pacientes com quadro sugestivo de uma aneuploidia de cromossomos sexuais. Arq Bras Endocrinol Metab. 2012;56(8):545-51.