Search

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.

Duplications of dosage sensitive sex-locus Xp21.2 including NR0B1 have been linked to 46,XY gonadal dysgenesis (GD) and their effects are attributed merely to increase gene dosage of NR0B1 (DAX1). Here we present a general mechanism how deletions, duplications, triplications or inversions with or without NR0B1 at Xp21.2 can lead to partial or complete GD by disrupting the cognate topological associated domain (TAD) in the vincinity of NR0B1. Our model is supported by three unrelated patients: two showing a 287kb overlapping duplication at the Xp21.2 locus upstream of NR0B1 containing CXorf21 and GK and one patient having a large new triplication of Xp21.2 as the most likely cause of GD. Whole Genome sequencing uncovered the exact structural rearrangements of the duplications and the triplication. Comparison with a previously published deletion upstream of NR0B1 revealed a common 35kb overlap between the deletion, our newly reported NR0B1 upstream duplications and the triplication as well as all other copy number variations (CNVs) at Xp21.2 reported so far. This overlap contains a strong CCCTC-binding factor (CTCF) binding site representing one boundary of the NR0B1 TAD. All three CNVs at Xp21.2 most likely disrupt this TAD boundary, which isolates NR0B1 from CXorf21 and GK and putatively results in GK and CXorf21 enhancer adoption and ensuing ectopic NR0B1 expression. As a result, the patients’ transcriptomes developed an intermediate expression pattern with both ovarian and testicular features and greatly reduced expression of spermatogenesis-related genes. This model not only allows better diagnosis of GD displaying CNVs at Xp21.2, but also gives deeper insight how spatiotemporal activation of developmental genes can be disrupted by reorganized TADs also in other rare diseases.

A retrospective cross-sectional study was performed in a DSD clinic at a tertiary service (University Hospital) to estimate the frequency of disorders of sex development (DSD) among men who seek medical care because of infertility. The sample included 84 men >20 years of age referred from 2010-2017 due to oligozoospermia or nonobstructive azoospermia of unknown etiology. Twelve cases (14%) were diagnosed as DSD, including Klinefelter Syndrome, 46,XX testicular DSD, and mild androgen insensitivity syndrome. Y chromosome microdeletions were detected in 2 patients. Among the remaining 70 cases there were patients with chromosome abnormalities which are not included in the DSD classification as well as rare NR5A1 variants of uncertain significance and hypergonadotropic hypogonadism and microorchidism in 46,XY subjects. In conclusion, the frequency of DSD in this study was 14%, consisting mainly of sex chromosome abnormalities but also 46,XX and 46,XY DSD. However, this figure may increase as further investigations are conducted in idiopathic cases with signs of primary testicular failure, which may present partial gonadal dysgenesis.

Nuclear receptor subfamily 5 group A member 1 (NR5A1), also named steroidogenic factor 1, is an essential transcription factor that regulates a number of target genes crucial for normal reproductive physiology and endocrine function. It is encoded by NR5A1 gene and is expressed in high doses mainly in steroidogenic tissues, where it controls several steps of adrenal and gonadal development. NR5A1 mutations are associated with a wide phenotypic spectrum of disorders/differences of sex development (DSD), a group of conditions in which development of chromosomal, gonadal, or anatomic sex is atypical. Here, we reviewed 188 NR5A1 mutations from 238 cases reported in literature so far. Additionally, we report the variations p.Ser4*, p.(Cys55Ser), p.(Met78Leu), and p.Met98Glyfs*45, which have not been annotated for NR5A1 before and were identified in some of the 205 46,XY patients of our own cohort. This is the first NR5A1 mutation review which includes both 46,XX and 46,XY karyotype, with the purpose of discussing the complexity of genotype-phenotype correlations among DSD and infertile male patients and also females with primary ovarian failure.