Context The genetic basis of human sex development is slowly being elucidated, and >40 different genetic causes of differences (or disorders) of sex development (DSDs) have now been reported. However, reaching a specific diagnosis using traditional approaches can be difficult, especially in adults where limited biochemical data may be available. Objective We used a targeted next-generation sequencing approach to analyze known and candidate genes for DSDs in individuals with no specific molecular diagnosis. Participants and Design We studied 52 adult 46,XY women attending a single-center adult service, who were part of a larger cohort of 400 individuals. Classic conditions such as17β-hydroxysteroid dehydrogenase deficiency type 3, 5α-reductase deficiency type 2, and androgen insensitivity syndrome were excluded. The study cohort had broad working diagnoses of complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25), a group that included partial gonadal dysgenesis and those with a broad “partial androgen insensitivity syndrome” label. Targeted sequencing of 180 genes was undertaken. Results Overall, a likely genetic cause was found in 16 of 52 (30.8%) individuals (22.2% CGD, 40.0% pvDSD). Pathogenic variants were found in sex-determining region Y (SRY; n = 3), doublesex and mab-3–related transcription factor 1 (DMRT1; n = 1), NR5A1/steroidogenic factor-1 (SF-1) (n = 1), and desert hedgehog (DHH; n = 1) in the CGD group, and in NR5A1 (n = 5), DHH (n = 1), and DEAH-box helicase 37 (DHX37; n = 4) in the pvDSD group. Conclusions Reaching a specific diagnosis can have clinical implications and provides insight into the role of these proteins in sex development. Next-generation sequencing approaches are invaluable, especially in adult populations or where diagnostic biochemistry is not possible.

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Hyperoxaluria is a well-recognised risk factor for urolithiasis and patients with primary hyperoxaluria (PH) gradually build up calcium oxalate deposits leading to chronic kidney disease. Efforts to improve treatment for PH have focused on reducing urine oxalate excretion and thus decreasing lithogenesis. To determine the efficacy of treatments designed to alter a biochemical parameter it is necessary to know the biological and analytical variation of that parameter. In this study, we estimated the intra-individual biological variation of urine oxalate excretion in patients with PH, and from this determined what would constitute a significant change in the form of a reference change value (RCV). Each patient collected four 24-h urines on consecutive weeks. The intra-individual biological variation of oxalate excretion calculated from these samples ranged from 0 to 36 % with a mean of 14 %. The corresponding RCVs were 4-84 % with a mean of 32 %. This result implies that, on average, a reduction of almost one-third in urine oxalate excretion is required to prove an effect from treatment. The wide range of biological variation between individuals may reflect other, as yet unknown, determinants of oxaluria in PH, as well as inaccuracies in urine collection. The data suggest that it is more appropriate to use individual RCVs established prior to treatment to determine its efficacy: a relatively small fall in urine oxalate excretion may be outside the biological variation of some patients but not of others.

Oxalate:creatinine ratio and oxalate excretion were discordant in many patients, which is likely to be a result of intra-individual variation in creatinine output and imprecision in the collection itself. Some PH patients had urine oxalate within the reference range on occasion, and therefore it is not possible to exclude PH on the finding of a single normal result. A significant number of individuals had urine oxalate results well above the reference range who potentially have undiagnosed PH and are consequently at risk of renal failure.