A Small Supernumerary Xp Marker Chromosome Including Genes NR0B1 and MAGEB Causing Partial Gonadal Dysgenesis and Gonadoblastoma

2021 ◽  
pp. 1-9
Author(s):  
Mirian Yumie Nishi ◽  
José Antônia Diniz Faria Júnior ◽  
Ana Cristina Victorino Krepischi ◽  
Daniela Rodrigues de Moraes ◽  
Silvia Souza da Costa ◽  
...  
Keyword(s):  
Gonadal Dysgenesis ◽  
Marker Chromosome ◽  
Copy Number Variations ◽  
Breast Development ◽  
Chromosomal Microarray ◽  
Primary Amenorrhea ◽  
Chromosomal Microarray Analysis ◽  
Fish Analysis ◽  
Sex Development ◽  
Partial Gonadal Dysgenesis

Copy number variations of several genes involved in the process of gonadal determination have been identified as a cause of 46,XY differences of sex development. We report a non-syndromic 14-year-old female patient who was referred with primary amenorrhea, absence of breast development, and atypical genitalia. Her karyotype was 47,XY,+mar/46,XY, and FISH analysis revealed the X chromosome origin of the marker chromosome. Array-CGH data identified a pathogenic 2.0-Mb gain of an Xp21.2 segment containing <i>NR0B1/DAX1</i> and a 1.9-Mb variant of unknown significance from the Xp11.21p11.1 region. This is the first report of a chromosomal microarray analysis to reveal the genetic content of a small supernumerary marker chromosome detected in a 47,XY,+der(X)/46,XY karyotype in a non-syndromic girl with partial gonadal dysgenesis and gonadoblastoma. Our findings indicate that the mosaic presence of the small supernumerary Xp marker, encompassing the <i>NR0B1/DAX1</i> gene, may have been the main cause of dysgenetic testes development, although the role of <i>MAGEB</i> and other genes mapped to the Xp21 segment could not be completely ruled out.

scholarly journals 46,XY Disorder of Sex Development Caused by 17α-Hydroxylase/17,20-Lyase Deficiency due to Homozygous Mutation ofCYP17A1Gene: Consequences of Late Diagnosis

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Giampaolo Papi ◽  
Rosa Maria Paragliola ◽  
Paola Concolino ◽  
Carlo Di Donato ◽  
Alfredo Pontecorvi ◽  
...  
Keyword(s):  
Ethinyl Estradiol ◽  
Tanner Stage ◽  
Pubic Hair ◽  
Breast Development ◽  
Normal Male ◽  
Primary Amenorrhea ◽  
Homozygous Mutation ◽  
Tall Stature ◽  
Disorder Of Sex Development ◽  
Sex Development

Context.Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease due to specific enzyme deficiencies in the adrenal steroidogenesis pathway.Case Description.A 40-year-old Chinese woman was referred to the Endocrine Unit for the work-up of a syndrome characterized by long-lasting and multidrug resistant high blood pressure, severe hypokalemia with metabolic alkalosis, and primary amenorrhea. The patient presented with sexual infantilism, lack of breast development, absence of axillary and pubic hair, tall stature, and slenderness. CT scan revealed enlarged adrenal glands bilaterally and the absence of the uterus, the ovaries, and the Fallopian tubes. Furthermore, diffuse osteopenia and osteoporosis and incomplete ossification of the growth plate cartilages were demonstrated. Chromosomal analysis showed a normal male 46,XY, karyotype, and on molecular analysis of theCYP17A1gene she resulted homozygous for the g.4869T>A; g.4871delC (p.Y329Kfs?) mutation in exon 6. Hydrocortisone and ethinyl-estradiol supplementation therapy led to incomplete withdrawal of antihypertensive drug and breast development progression to Tanner stage B2 and slight height increase, respectively.Conclusions.We describe a late-discovered case of CAH with 46,XY disorder of sex development. Deficiency of 17α-hydroxylase/17,20-lyase due to a homozygous CYP17A1 gene mutation was the underlying cause. Laboratory, imaging, and genetic features are herein reported and discussed.

scholarly journals Comprehensive Evaluation of Non-invasive Prenatal Screening to Detect Fetal Copy Number Variations

2021 ◽  
Vol 12 ◽  
Author(s):  
Jing Wang ◽  
Bin Zhang ◽  
Lingna Zhou ◽  
Qin Zhou ◽  
Yingping Chen ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Pregnant Women ◽  
Copy Number ◽  
Prenatal Screening ◽  
Comprehensive Evaluation ◽  
Copy Number Variations ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Non Invasive ◽  
Pathogenic Cnvs

ObjectiveTo evaluate the effectiveness of non-invasive prenatal screening (NIPS) in prenatal screening of fetal pathogenic copy number variants (CNVs).Materials and MethodsWe evaluated the prenatal screening capacity using traditional and retrospective approaches. For the traditional method, we evaluated 24,613 pregnant women who underwent NIPS; cases which fetal CNVs were suggested underwent prenatal diagnosis with chromosomal microarray analysis (CMA). For the retrospective method, we retrospectively evaluated 47 cases with fetal pathogenic CNVs by NIPS. A systematic literature search was performed to compare the evaluation efficiency.ResultsAmong the 24,613 pregnant women who received NIPS, 124 (0.50%) were suspected to have fetal CNVs. Of these, 66 women underwent prenatal diagnosis with CMA and 13 had true-positive results. The positive predictive value (PPV) of NIPS for fetal CNVs was 19.7%. Among 1,161 women who did not receive NIPS and underwent prenatal diagnosis by CMA, 47 were confirmed to have fetal pathogenic CNVs. Retesting with NIPS indicated that 24 of these 47 cases could also be detected by NIPS, representing a detection rate (DR) of 51.1%. In total, 10 publications, namely, six retrospective studies and four prospective studies, met our criteria and were selected for a detailed full-text review. The reported DRs were 61.10–97.70% and the PPVs were 36.11–80.56%. The sizes of CNVs were closely related to the accuracy of NIPS detection. The DR was 41.9% (13/31) in fetuses with CNVs ≤ 3 Mb, but was 55.0% (11/20) in fetuses with CNVs &gt; 3 Mb. Finally, to intuitively show the CNVs accurately detected by NIPS, we mapped all CNVs to chromosomes according to their location, size, and characteristics. NIPS detected fetal CNVs in 2q13 and 4q35.ConclusionThe DR and PPV of NIPS for fetal CNVs were approximately 51.1% and 19.7%, respectively. Follow-up molecular prenatal diagnosis is recommended in cases where NIPS suggests fetal CNVs.

scholarly journals 220 46,XY disorder of sex development – partial gonadal dysgenesis – case report

2021 ◽  
Author(s):  
Matea Melša ◽  
Miram Pasini ◽  
Nevena Krnić ◽  
Marija Mikloš ◽  
Kristina Crkvenac Gornik ◽  
...  
Keyword(s):  
Case Report ◽  
Gonadal Dysgenesis ◽  
Disorder Of Sex Development ◽  
Sex Development ◽  
Partial Gonadal Dysgenesis

scholarly journals Delayed Puberty in Girls with Primary Amenorrhea: A Report of Cases

2021 ◽  
Vol 7 (2) ◽  
pp. 92-96
Author(s):  
Fatinah Shahab ◽  
Inu Mulyantoro ◽  
Hary Tjahjanto ◽  
Tri Indah Winarni ◽  
Sultana MH Faradz
Keyword(s):  
Gonadal Dysgenesis ◽  
Follicle Stimulating Hormone ◽  
Breast Development ◽  
Delayed Puberty ◽  
Primary Amenorrhea ◽  
Pituitary Hormone ◽  
Germ Cell Differentiation ◽  
First Case ◽  
Pelvic Imaging ◽  
Hormonal Assay

Background:Female puberty starts when the pituitary hormone producing follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which will stimulate the ovaries to produce estrogen. Delayed puberty with primary amenorrhea in female is the lack of breast development followed by the absence of menses 3 years after the initiation of breast development. Sex chromosomes have an important role in determining the sex, germ cell differentiation of foetus, and reproductive functions of an offspring, thus, sex chromosomal aberrations frequently cause primary amenorrheaCase presentation: We report two delayed puberty cases with the chief complain of primary amenorrhea. Both cases showed hypoplasia of uterus and ovaries on pelvic imaging and hormonal assay showed low of FSH. The first case was gonadal dysgenesis with 46,XX karyotype and low level of estrogen and the second case was a turner syndrome with 45,X karyotype and normal level of estrogen. Conclusion:This study reported delayed puberty with primary amenorrhea cases due to different chromosomal aberration pattern which have similar clinical features. Therefore, cytogenetic examination is needed for any primary amenorrhea cases in order to accomplish the confirmatory diagnosis and for the clinicians to make a correct intervention and treatment. 

46, XY complete gonadal dysgenesis with pubertal virilisation due to dysgerminoma/gonadoblastoma

2020 ◽  
Vol 13 (7) ◽  
pp. e235501
Author(s):  
Sarah Alam ◽  
Hiya Boro ◽  
Alpesh Goyal ◽  
Rajesh Khadgawat
Keyword(s):  
Germ Cell ◽  
Gonadal Dysgenesis ◽  
Germ Cell Tumour ◽  
Rare Condition ◽  
Cell Tumour ◽  
Breast Development ◽  
Primary Amenorrhea ◽  
Rare Presentation ◽  
Phenotypic Female ◽  
Complete Gonadal Dysgenesis

Complete gonadal dysgenesis (CGD) or Swyer syndrome is characterised by sexual infantilism in a phenotypic female with 46, XY karyotype. Patients with gonadal dysgenesis and Y-chromosome material are at a high risk of developing gonadoblastoma and dysgerminoma. A 16-year-old girl presented with progressive virilisation, poor breast development and primary amenorrhea. On evaluation, she was found to have male-range serum testosterone, large abdominopelvic mass lesion, elevated germ cell tumour markers and 46, XY karyotype. She underwent surgical excision of left gonadal mass and right streak gonad, histopathology of which revealed dysgerminoma and gonadoblastoma, respectively. A diagnosis of virilising germ cell tumour arising in the setting of 46, XY CGD was, therefore, made. This case highlights a rare presentation of 46, XY CGD and the need to consider early prophylactic gonadectomy in patients affected with this rare condition. The presence of dysgerminoma/gonadoblastoma should be suspected if a hitherto phenotypic female with CGD undergoes virilisation.

scholarly journals Phenotypic and Molecular Cytogenetic Analysis of a Case of Monosomy 1p36 Syndrome due to Unbalanced Translocation

2020 ◽  
Vol 11 (5-6) ◽  
pp. 284-295
Author(s):  
Dalia F. Hussen ◽  
Alaa K. Kamel ◽  
Mona K. Mekkawy ◽  
Engy A. Ashaat ◽  
Mona O. El Ruby
Keyword(s):  
Intellectual Disability ◽  
Microarray Analysis ◽  
Cytogenetic Analysis ◽  
Copy Number ◽  
Clinical Manifestations ◽  
Copy Number Variations ◽  
Chromosomal Microarray Analysis ◽  
Fish Analysis ◽  
Unbalanced Translocation ◽  
Genotype Correlation

Monosomy 1p36 syndrome is one of the most common submicroscopic deletion syndromes, which is characterized by the presence of delayed developmental milestones, intellectual disability, and clinically recognizable dysmorphic craniofacial features. The syndrome comprises 4 cytogenetic groups including pure terminal deletions, interstitial deletions, complex rearrangements, and derivative chromosomes 1 due to unbalanced translocations, where unbalanced translocations represent the least percentage of all cases of monosomy 1p36 (7%). Most patients with monosomy 1p36 due to an unbalanced translocation can be cytogenetically diagnosed using conventional techniques. However, chromosomal microarray analysis is mandatory in these cases to detect copy number variance and size of the deletion and allows for setting a phenotype-genotype correlation. Here, we studied a 1.5-year-old female patient who showed intellectual disability, delayed milestones, hypotonia, seizures, and characteristic dysmorphic features including brachycephaly, straight eyebrows, deep-set eyes, downslanting palpebral fissures, midface hypoplasia, depressed nasal bridge, long philtrum, and pointed chin. Conventional cytogenetic analysis (CCA), microarray study, and fluorescence in situ hybridization (FISH) analysis were performed. CCA showed a translocation involving chromosomes 1 and 21, 45,XX,der(1)t(1;21)(p36.32;q21.1)dn. Microarray analysis revealed copy number losses at both 1p36 and proximal 21q. FISH confirmed the presence of the 1p36 deletion, but was not performed for 21q. We have concluded that phenotype-genotype correlation for monosomy 1p36 syndrome can be performed for the fundamental clinical manifestations; however, the final aspect of the syndrome depends on composite factors. Monosomy 1p36 due to unbalanced translocation may present either classically or with additional altered features of various severity based on the copy number variations involving different chromosomes.

scholarly journals Application of Chromosome Microarray Analysis in the Investigation of Developmental Disabilities and Congenital Anomalies: Single Center Experience and Review of NRXN3 and NEDD4L Deletions

2020 ◽  
Vol 11 (4) ◽  
pp. 197-206
Author(s):  
Alper Han Çebi ◽  
Şule Altıner
Keyword(s):  
Developmental Disabilities ◽  
Microarray Analysis ◽  
Congenital Anomalies ◽  
Copy Number Variations ◽  
Step Test ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Multiple Congenital Anomalies ◽  
Single Center Experience ◽  
Genome Wide

Chromosomal microarray analysis (CMA) is a first step test used for the diagnosis of patients with developmental delay, intellectual disability, autistic spectrum disorder, and multiple congenital anomalies. Its widespread usage has allowed genome-wide identification of copy number variations (CNVs). In our study, we performed a retrospective study on clinical and microarray data of 237 patients with developmental disabilities and/or multiple congenital anomalies and investigated the clinical utility of CMA. Phenotype-associated CNVs were detected in 15.18% of patients. Besides, we detected submicroscopic losses on 14q24.3q31.1 in a patient with speech delay and on 18q21.31q21.32 in twin patients with seizures. Deletions of <i>NRXN3</i> and <i>NEDD4L</i> were responsible for the phenotypes, respectively. This study showed that CMA is a powerful diagnostic tool in this patient group and expands the genotype-phenotype correlations on developmental disabilities.

scholarly journals Simultaneous Detection of CNVs and SNVs Improves the Diagnostic Yield of Fetuses with Ultrasound Anomalies and Normal Karyotypes

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1397
Author(s):  
Qingwei Qi ◽  
Yulin Jiang ◽  
Xiya Zhou ◽  
Hua Meng ◽  
Na Hao ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Diagnostic Yield ◽  
Simultaneous Detection ◽  
Genetic Diagnosis ◽  
Copy Number Variations ◽  
Molecular Diagnostic ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Single Nucleotide Variants ◽  
Sequential Approach

The routine assessment to determine the genetic etiology for fetal ultrasound anomalies follows a sequential approach, which usually takes about 6–8 weeks turnaround time (TAT). We evaluated the clinical utility of simultaneous detection of copy number variations (CNVs) and single nucleotide variants (SNVs)/small insertion-deletions (indels) in fetuses with a normal karyotype with ultrasound anomalies. We performed CNV detection by chromosomal microarray analysis (CMA) or low pass CNV-sequencing (CNV-seq), and in parallel SNVs/indels detection by trio-based clinical exome sequencing (CES) or whole exome sequencing (WES). Eight-three singleton pregnancies with a normal fetal karyotype were enrolled in this prospective observational study. Pathogenic or likely pathogenic variations were identified in 30 cases (CNVs in 3 cases, SNVs/indels in 27 cases), indicating an overall molecular diagnostic rate of 36.1% (30/83). Two cases had both a CNV of uncertain significance (VOUS) and likely pathogenic SNV, and one case carried both a VOUS CNV and an SNV. We demonstrated that simultaneous analysis of CNVs and SNVs/indels can improve the diagnostic yield of prenatal diagnosis with shortened reporting time, namely, 2–3 weeks. Due to the relatively long TAT for sequential procedure for prenatal genetic diagnosis, as well as recent sequencing technology advancements, it is clinically necessary to consider the simultaneous evaluation of CNVs and SNVs/indels to enhance the diagnostic yield and timely TAT, especially for cases in the late second trimester or third trimester.

scholarly journals Molecular Characterization of Mosaicism for a Small Supernumerary Marker Chromosome Derived from Chromosome Y in an Infertile Male with Apparently Normal Phenotype: A Case Report and Literature Review

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Na An ◽  
Yang Yu ◽  
Qi Xi ◽  
Fagui Yue ◽  
Ruizhi Liu ◽  
...  
Keyword(s):  
Marker Chromosome ◽  
Normal Chromosome ◽  
Chromosomal Microarray ◽  
Banding Technique ◽  
Chromosomal Microarray Analysis ◽  
Infertile Male ◽  
Chromosome Y ◽  
Molecular Cytogenetic ◽  
Banding Analysis

Small supernumerary marker chromosomes (sSMCs), equal in size or smaller than chromosome 20 of the same metaphase, can hardly be identified through traditional banding technique. They are usually associated with intelligent disability, growth retardation, and infertility, but the genotype-phenotype correlations are still complicated for their complex origins and constitutions. Herein, we identified a 26-year-old Chinese infertile male who carried a mosaic sSMC and was diagnosed as severe oligospermia. The G-banding analysis initially described his karyotype as mos 47, XY, +mar[32]/46, XY[18]. The chromosomal microarray analysis results showed a 25.5 Mb gain in Yp11.31q11.23 and a 0.15 Mb loss in Yq12. Two SRY signals were discovered in the “seemingly” normal chromosome Y in both cell lines using SRY probe: one normal SRY was located on the distal tip of the short arm of chromosome Y while the other SRY was located on the terminal of long arm in the same chromosome Y. The sSMC(Y) was finally identified as der(Y) (pter ⟶ q11.23) (SRY-). To our knowledge, the chromosomal Y anomalies, SRY gene translocated from der(Y) (pter ⟶ q11.23) to qter of normal chromosome Y, were not reported before. Our findings indicated that the mosaic presence of sSMC(Y) may be the main cause of severe oligospermia although no other apparent abnormalities were observed in the proband. Further research on association between sSMC(Y) and spermatogenesis impairment should be investigated. It is recommended measures of traditional and molecular cytogenetic analysis should be taken to determine the origins and constitutions of sSMC so as to offer more appropriate genetic counseling for the infertile sSMC carriers.

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