Association between Down Syndrome and Disorders of Sex Development: Report of Three Cases and Review of 188 Cases in the Literature

2021 ◽  
pp. 1-9
Author(s):  
Octavio O. Santos-Neto ◽  
Marina H. Mariano ◽  
Antonia P. Marques-de-Faria ◽  
Juliana G. R. Andrade ◽  
Tarsis A. P. Vieira ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Male Genitalia ◽  
Gonadal Dysgenesis ◽  
Sex Chromosome ◽  
Klinefelter Syndrome ◽  
Disorders Of Sex Development ◽  
Androgen Insensitivity ◽  
Mixed Gonadal Dysgenesis ◽  
Sex Development ◽  
Complete Gonadal Dysgenesis

In this study, we present 3 cases of Down syndrome (DS) associated with disorders/differences of sex development (DSD) and review the literature on this topic. Case 1: 1-year-old child with male genitalia and DS phenotype, 47,XX,+21 karyotype and testicular DSD. Case 2: 11-month-old child with male genitalia and few DS dysmorphisms, 45,X/47,XY,+21 karyotype, and mixed gonadal dysgenesis. Case 3: 4-month-old child with female genitalia and DS phenotype, 47,XY,+21 karyotype and XY complete gonadal dysgenesis. In the literature, among 188 patients, 107 (57%) had Klinefelter syndrome and 61 (33%) Turner syndrome, 12 (6%) had mixed gonadal dysgenesis, 2 (1%) had partial androgen insensitivity, 2 (1%) ovotesticular DSD, and the others had congenital adrenal hyperplasia, XY partial gonadal dysgenesis, XY complete gonadal dysgenesis, and complete androgen insensitivity (1 case each). A typical DS phenotype was found in all individuals of the revision, with the exception of one case, but DSD features were not always reported. In conclusion, the association of DS with sex chromosome DSD is the most frequently observed, whereas associations with 46,XX and 46,XY DSD is extremely rare.

scholarly journals Disorders of sex development: a study of 194 cases

2018 ◽  
Vol 7 (2) ◽  
pp. 364-371 ◽  
Author(s):  
R Walia ◽  
M Singla ◽  
K Vaiphei ◽  
S Kumar ◽  
A Bhansali
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Sex Chromosome ◽  
Tertiary Care ◽  
Disorders Of Sex Development ◽  
Androgen Insensitivity Syndrome ◽  
North India ◽  
Care Hospital ◽  
Adrenal Hyperplasia ◽  
Androgen Insensitivity ◽  
Sex Development

Objective To study the clinical profile and the management of patients with disorders of sex development (DSD). Design and setting Retrospective study from a tertiary care hospital of North India. Methods and patients One hundred ninety-four patients of DSD registered in the Endocrine clinic of Postgraduate Institute of Medical Education and Research, Chandigarh between 1995 and 2014 were included. Results One hundred and two patients (52.5%) had 46,XY DSD and seventy-four patients (38.1%) had 46,XX DSD. Sex chromosome DSD was identified in seven (3.6%) patients. Of 102 patients with 46,XY DSD, 32 (31.4%) had androgen insensitivity syndrome and 26 (25.5%) had androgen biosynthetic defect. Of the 74 patients with 46,XX DSD, 52 (70.27%) had congenital adrenal hyperplasia (CAH) and eight (10.8%) had ovotesticular DSD. Five patients with sex chromosome DSD had mixed gonadal dysgenesis. Excluding CAH, majority of the patients (90%) presented in the post-pubertal period. One-fourth of the patients with simple virilising CAH were reared as males because of strong male gender identity and behaviour and firm insistence by the parents. Corrective surgeries were performed in twenty patients (20%) of 46,XY DSD without hormonal evaluation prior to the presentation. Conclusion Congenital adrenal hyperplasia is the most common DSD in the present series. Most common XY DSD is androgen insensitivity syndrome, while CAH is the most common XX DSD. Delayed diagnosis is a common feature, and corrective surgeries are performed without seeking a definite diagnosis.

scholarly journals PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans

2019 ◽  
Vol 180 (5) ◽  
pp. 291-309 ◽  
Author(s):  
Tulay Guran ◽  
Gozde Yesil ◽  
Serap Turan ◽  
Zeynep Atay ◽  
Emine Bozkurtlar ◽  
...  
Keyword(s):  
Gonadal Dysgenesis ◽  
Clinical Laboratory ◽  
Disorders Of Sex Development ◽  
Cell Types ◽  
Regulatory Subunit ◽  
Cone Dystrophy ◽  
Molecular Characteristics ◽  
Multiple Organs ◽  
Sex Development ◽  
Complete Gonadal Dysgenesis

Context Most of the knowledge on the factors involved in human sexual development stems from studies of rare cases with disorders of sex development. Here, we have described a novel 46, XY complete gonadal dysgenesis syndrome caused by homozygous variants in PPP2R3C gene. This gene encodes B″gamma regulatory subunit of the protein phosphatase 2A (PP2A), which is a serine/threonine phosphatase involved in the phospho-regulation processes of most mammalian cell types. PPP2R3C gene is most abundantly expressed in testis in humans, while its function was hitherto unknown. Patients and methods Four girls from four unrelated families with 46, XY complete gonadal dysgenesis were studied using exome or Sanger sequencing of PPP2R3C gene. In total, four patients and their heterozygous parents were investigated for clinical, laboratory, immunohistochemical and molecular characteristics. Results We have identified three different homozygous PPP2R3C variants, c.308T>C (p.L103P), c.578T>C (p.L193S) and c.1049T>C (p.F350S), in four girls with 46, XY complete gonadal dysgenesis. Patients also manifested a unique syndrome of extragonadal anomalies, including typical facial gestalt, low birth weight, myopathy, rod and cone dystrophy, anal atresia, omphalocele, sensorineural hearing loss, dry and scaly skin, skeletal abnormalities, renal agenesis and neuromotor delay. We have shown a decreased SOX9-Phospho protein expression in the dysgenetic gonads of the patients with homozygous PPP2R3C variants suggesting impaired SOX9 signaling in the pathogenesis of gonadal dysgenesis. Heterozygous males presented with abnormal sperm morphology and impaired fertility. Conclusion Our findings suggest that PPP2R3C protein is involved in the ontogeny of multiple organs, especially critical for testis development and spermatogenesis. PPPR3C provides insight into pathophysiology, as well as emerging as a potential therapeutic target for male infertility.

Novel pathogenic mutations in disorders of sex development associated genes cause 46,XY complete gonadal dysgenesis

Gene ◽  
2019 ◽  
Vol 718 ◽  
pp. 144072
Author(s):  
Mei Xue ◽  
Xiang Wang ◽  
Cui Li ◽  
Minggang Zhao ◽  
Fang He ◽  
...  
Keyword(s):  
Gonadal Dysgenesis ◽  
Disorders Of Sex Development ◽  
Sex Development ◽  
Pathogenic Mutations ◽  
Complete Gonadal Dysgenesis

Imaging Findings of Septooptic Dysplasia and Joubert's Syndrome in A Patient with Mixed Gonadal Dysgenesis: A New Coexistence?

2020 ◽  
Author(s):  
Merter Keçeli
Keyword(s):  
Gonadal Dysgenesis ◽  
Sex Chromosome ◽  
Karyotype Analysis ◽  
Ambiguous Genitalia ◽  
Total Testosterone ◽  
Resonance Imaging ◽  
Disorders Of Sexual Development ◽  
Laboratory Findings ◽  
Mixed Gonadal Dysgenesis ◽  
Motor Retardation

AbstractAmbiguous genitalia is a common feature in most disorders of sexual development. These disorders can be evaluated within three groups: sex chromosome disorders, 46,XY disorders, and 46,XX disorders. Except for Turner's syndrome, these anomalies are not related to neurological developmental anomalies. A 6-month-old patient presenting with ambiguous genitalia had developmental and motor retardation with nystagmus. In karyotype analysis, 45,X/46,XY sequences were found, compatible with mixed gonadal dysgenesis (GD). Laboratory findings were normal except for low serum total testosterone level. The uterus and left adnexal structures were seen in imaging. There were no gonads in the labial/scrotal regions. Septooptic dysplasia (SOD) and Joubert's syndrome (JS) were detected in cranial magnetic resonance imaging. This presentation reports rare association of SOD and JS in a child with mixed GD.

scholarly journals Functional analysis of novel desert hedgehog gene variants improves the clinical interpretation of genomic data and provides a more accurate diagnosis for patients with 46,XY differences of sex development

2019 ◽  
Vol 56 (7) ◽  
pp. 434-443 ◽  
Author(s):  
Katie Ayers ◽  
Jocelyn van den Bergen ◽  
Gorjana Robevska ◽  
Nurin Listyasari ◽  
Jamal Raza ◽  
...  
Keyword(s):  
Gonadal Dysgenesis ◽  
Disorders Of Sex Development ◽  
Culture Method ◽  
Significant Loss ◽  
Subcellular Localisation ◽  
Gene Variants ◽  
Gene Variant ◽  
Clinical Interpretation ◽  
Sex Development ◽  
Desert Hedgehog

BackgroundDesert hedgehog (DHH) gene variants are known to cause 46,XY differences/disorders of sex development (DSD). We have identified six patients with 46,XY DSD with seven novel DHH gene variants. Many of these variants were classified as variants of uncertain significance due to their heterozygosity or associated milder phenotype. To assess variant pathogenicity and to refine the spectrum of DSDs associated with this gene, we have carried out the first reported functional testing of DHH gene variant activity.MethodsA cell co-culture method was used to assess DHH variant induction of Hedgehog signalling in cultured Leydig cells. Protein expression and subcellular localisation were also assessed for DHH variants using western blot and immunofluorescence.ResultsOur co-culture method provided a robust read-out of DHH gene variant activity, which correlated closely with patient phenotype severity. While biallelic DHH variants from patients with gonadal dysgenesis showed significant loss of activity, variants found as heterozygous in patients with milder phenotypes had no loss of activity when tested with a wild type allele. Taking these functional results into account improved clinical interpretation.ConclusionOur findings suggest heterozygous DHH gene variants are unlikely to cause DSD, reaffirming that DHH is an autosomal recessive cause of 46,XY gonadal dysgenesis. Functional characterisation of novel DHH variants improves variant interpretation, leading to greater confidence in patient reporting and clinical management.

scholarly journals Shifting syndromes: Sex chromosome variations and intersex classifications

2018 ◽  
Vol 48 (1) ◽  
pp. 125-148 ◽  
Author(s):  
David Andrew Griffiths
Keyword(s):  
Lived Experience ◽  
Classification System ◽  
Consensus Statement ◽  
Sex Chromosome ◽  
Disorders Of Sex Development ◽  
Current Drive ◽  
Medical Community ◽  
New Classification ◽  
Sex Development

The 2006 ‘Consensus statement on management of intersex disorders’ recommended moving to a new classification of intersex variations, framed in terms of ‘disorders of sex development’ or DSD. Part of the rationale for this change was to move away from associations with gender, and to increase clarity by grounding the classification system in genetics. While the medical community has largely accepted the move, some individuals from intersex activist communities have condemned it. In addition, people both inside and outside the medical community have disagreed about what should be covered by the classification system, in particular whether sex chromosome variations and the related diagnoses of Turner and Klinefelter’s syndromes should be included. This article explores initial descriptions of Turner and Klinefelter’s syndromes and their subsequent inclusion in intersex classifications, which were increasingly grounded in scientific understandings of sex chromosomes that emerged in the 1950s. The article questions the current drive to stabilize and ‘sort out’ intersex classifications through a grounding in genetics. Alternative social and historical definitions of intersex – such as those proposed by the intersex activists – have the potential to do more justice to the lived experience of those affected by such classifications and their consequences.

Observational study of disorders of sex development in Yaounde, Cameroon

2020 ◽  
Vol 33 (3) ◽  
pp. 417-423
Author(s):  
Suzanne Ngo Um Sap ◽  
Ritha Mbono Betoko ◽  
Martine Etoa Etoga ◽  
Pierre Yves Mure ◽  
Yves Morel ◽  
...  
Keyword(s):  
Sex Chromosome ◽  
Disorders Of Sex Development ◽  
Central Africa ◽  
Main Diagnosis ◽  
Pediatric Endocrinology ◽  
Endocrine Society ◽  
Sex Development ◽  
Mother And Child ◽  
Study Population ◽  
Sub Saharan

AbstractIntroductionAccording to the current classification of the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Pediatric Endocrinology (ESPE) of Disorders of Sex Development (DSD), etiologies vary around the world. Ethnic or genetic diversity probably explains this variability. We therefore conducted the present study on etiologies of DSDs in a country from central Africa.MethodsWe carried out an observational retrospective study at the Pediatric Endocrinology Unit of the Mother and Child Centre of the Chantal Biya Foundation in Yaounde, Cameroon from May 2013 to December 2019. All patients diagnosed with a DSD were included, and incomplete files excluded.ResultsWe included 80 patients diagnosed with DSD during the study period. The 46,XX DSD were the most frequent in our study population (n = 41, 51.25%), with congenital adrenal hyperplasia (CAH) as the main diagnosis. The 46,XY DSD accounted for 33.75% and sex chromosome DSD group represented 15% of the study population.ConclusionsDSDs are not an exceptional diagnosis in a Sub-Saharan context. 46,XX DSD are the most prevalent diagnosis in our setting. The diagnosis of all these affections is late compared to other centers, justifying advocacy for neonatal screening of DSDs in our context.

scholarly journals Etiology and Clinical Presentation of Disorders of Sex Development in Kenyan Children and Adolescents

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Prisca Amolo ◽  
Paul Laigong ◽  
Anjumanara Omar ◽  
Stenvert Drop
Keyword(s):  
Children And Adolescents ◽  
Sex Chromosome ◽  
Clinical Laboratory ◽  
Molecular Genetic ◽  
Management Strategies ◽  
Disorders Of Sex Development ◽  
Ambiguous Genitalia ◽  
Molecular Genetic Analysis ◽  
High Rate ◽  
Sex Development

Objective. The purpose of this study was to describe baseline data on etiological, clinical, laboratory, and management strategies in Kenyan children and adolescents with Disorders of Sex Development (DSD). Methods. This retrospective study included patients diagnosed with DSD who presented at ages 0–19 years from January 2008 to December 2015 at the Kenyatta National (KNH) and Gertrude’s Children’s (GCH) Hospitals. After conducting a search in the data registry, a structured data collection sheet was used for collection of demographic and clinical data. Data analysis involved description of the frequency of occurrence of various variables, such as etiologic diagnoses and patient characteristics. Results. Data from the records of 71 children and adolescents were reviewed at KNH (n = 57, 80.3%) and GCH (n = 14, 19.7%). The mean age at the time of diagnosis was 2.7 years with a median of 3 months. Thirty-nine (54.9%) children had karyotype testing done. The median age (IQR) of children with reported karyotypes and those without was 3.3 years (1.3–8.9) and 8.3 years (3.6–12.1), respectively (p=0.021). Based on karyotype analysis, 19 (48.7%) of karyotyped children had 46,XY DSD and 18 (46.2%) had 46,XX DSD. There were two (5.1%) children with sex chromosome DSD. Among the 71 patients, the most common presumed causes of DSD were ovotesticular DSD (14.1%) and CAH (11.3%). Majority (95.7%) of the patients presented with symptoms of DSD at birth. The most common presenting symptom was ambiguous genitalia, which was present in 66 (93.0%) patients either in isolation or in association with other symptoms. An ambiguous genitalia was initially observed by the patient’s mother in 51.6% of 62 cases despite the high rate (84.7%) of delivery in hospital. Seventeen (23.9%) of the cases had a gender reassignment at final diagnosis. A psychologist/psychiatrist or counselor was involved in the management of 23.9% of the patients. Conclusion. The commonest presumed cause of DSD was ovotesticular DSD in contrast to western studies, which found CAH to be more common. Investigation of DSD cases is expensive and needs to be supported. We would have liked to do molecular genetic analysis outside the country but financial challenges made it impossible. A network for detailed diagnostics in resource-limited countries would be highly desirable. There is a need to train health care workers and medical students for early diagnosis. Psychological evaluation should be carried out for all patients at diagnosis and support given for families.

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