Prevalence of endocrine and genetic abnormalities in boys evaluated systematically for a disorder of sex development

Abstract

STUDY QUESTIONWhat is the likelihood of identifying genetic or endocrine abnormalities in a group of boys with 46, XY who present to a specialist clinic with a suspected disorder of sex development (DSD)?SUMMARY ANSWERAn endocrine abnormality of the gonadal axis may be present in a quarter of cases and copy number variants (CNVs) or single gene variants may be present in about half of the cases.WHAT IS KNOWN ALREADYEvaluation of 46, XY DSD requires a combination of endocrine and genetic tests but the prevalence of these abnormalities in a sufficiently large group of boys presenting to one specialist multidisciplinary service is unclear.STUDY, DESIGN, SIZE, DURATIONThis study was a retrospective review of investigations performed on 122 boys.PARTICIPANTS/MATERIALS, SETTING, METHODSAll boys who attended the Glasgow DSD clinic, between 2010 and 2015 were included in the study. The median external masculinization score (EMS) of this group was 9 (range 1–11). Details of phenotype, endocrine and genetic investigations were obtained from case records.MAIN RESULTS AND THE ROLE OF CHANCEAn endocrine abnormality of gonadal function was present in 28 (23%) with a median EMS of 8.3 (1–10.5) whilst the median EMS of boys with normal endocrine investigations was 9 (1.5–11) (P = 0.03). Endocrine abnormalities included a disorder of gonadal development in 19 (16%), LH deficiency in 5 (4%) and a disorder of androgen synthesis in 4 (3%) boys. Of 43 cases who had array-comparative genomic hybridization (array-CGH), CNVs were reported in 13 (30%) with a median EMS of 8.5 (1.5–11). Candidate gene analysis using a limited seven-gene panel in 64 boys identified variants in 9 (14%) with a median EMS of 8 (1–9). Of the 21 boys with a genetic abnormality, 11 (52%) had normal endocrine investigations.LIMITATIONS, REASONS FOR CAUTIONA selection bias for performing array-CGH in cases with multiple congenital malformations may have led to a high yield of CNVs. It is also possible that the yield of single gene variants may have been higher than reported if the investigators had used a more extended gene panel.WIDER IMPLICATIONS OF THE FINDINGSThe lack of a clear association between the extent of under-masculinization and presence of endocrine and genetic abnormalities suggests a role for parallel endocrine and genetic investigations in cases of suspected XY DSD.STUDY FUNDING/COMPETING INTEREST(S)RN was supported by the James Paterson Bursary and the Glasgow Children's Hospital Charity Summer Scholarship. SFA, RM and EST are supported by a Scottish Executive Health Department grant 74250/1 for the Scottish Genomes Partnership. EST is also supported by MRC/EPSRC Molecular Pathology Node and Wellcome Trust ISSF funding. There are no conflicts of interest.TRIAL REGISTRATION NUMBERNone.

Association Between Extra-Genital Congenital Anomalies and Hypospadias Outcome

“…Whilst the prevalence of extra-genital anomalies in hypospadias has been previously reported to range from 12-46% [Schneuer et al, 2015;Fernandez et al, 2016;Lu et al, 2017], the prevalence rate of 22% reported in this study is similar to that in other large cohort studies where information on associated congenital anomalies was systematically collected [Ahmed et al, 2004;Cox et al, 2014;Nixon et al, 2017]. The pattern of extra-genital anomalies that were encountered in this cohort was also similar to that reported before with a disorder of intrauterine growth manifested as being small for gestational age [Ahmed et al, 2004;Nordenvall et al, 2014;Poyrazoglu et al, 2017].…”

Clinical genetic testing in endocrinology: Current concepts and contemporary challenges

“…For example, DSDs may arise from either single-gene defects (>50 genes implicated) or from larger chromosomal abnormalities and combining genetic testing approaches can establish a genetic diagnosis in 40%-60% of cases. 47,57 Whole-Exome Sequencing (WES)/ Whole-Genome Sequencing (WGS). In contrast to disease-targeted gene panels, where prior knowledge of the likely causative gene is required, WES or WGS is suited to the investigation of individuals or kindreds suspected of genetic disease of unknown aetiology (ie "gene discovery" approach).…”

“…In some clinical settings, gene‐panel testing is used in combination with other platforms including aCGH. For example, DSDs may arise from either single‐gene defects (>50 genes implicated) or from larger chromosomal abnormalities and combining genetic testing approaches can establish a genetic diagnosis in 40%‐60% of cases …”

The evaluation and management of the boy with DSD

“…Although XY DSD can be broadly categorised into disorders of gonadal development, androgen synthesis and androgen action ( Table 1), around 70% of boys who present to a specialist clinic with suspected DSD do not fit into any of these categories and are classed as a non-specific disorder of undermasculinisation [2]. It is possible that environmental factors may also play a role [3,4] and interfere with the normal development of the penis.…”

“…Interestingly, a genetic abnormality was detected in 20% of the boys with normal endocrine biochemistry [2]. Increasingly, it is therefore likely that biochemical investigations will in future be paired with molecular genetic analysis to provide a more comprehensive opportunity to offer boys a definitive diagnosis.…”