The laboratory in the multidisciplinary diagnosis of differences or disorders of sex development (DSD): III) Biochemical and genetic markers in the 46,XYIV) Proposals for the differential diagnosis of DSD.

Maria Luisa Granada,Laura Audí

doi:10.1515/almed-2021-0043

Abstract

46,XY differences/disorders of sex development (DSD) involve an abnormal gonadal and/or genital (external and/or internal) development caused by lack or incomplete intrauterine virilization, with or without the presence of Müllerian ducts remnants. Useful biochemical markers for differential diagnosis of 46,XY DSD include hypothalamic-pituitary-gonadal hormones such as luteinizing and follicle-stimulating hormones (LH and FSH; in baseline or after LHRH stimulation conditions), the anti-Müllerian hormone (AMH), inhibin B, insulin-like 3 (INSL3), adrenal and gonadal steroid hormones (including cortisol, aldosterone, testosterone and their precursors, dihydrotestosterone and estradiol) and the pituitary ACTH hormone. Steroid hormones are measured at baseline or after stimulation with ACTH (adrenal hormones) and/or with HCG (gonadal hormones). Different patterns of hormone profiles depend on the etiology and the severity of the underlying disorder and the age of the patient at diagnosis. Molecular diagnosis includes detection of gene dosage or copy number variations, analysis of candidate genes or high-throughput DNA sequencing of panels of candidate genes or the whole exome or genome. Differential diagnosis of 46,XX or 46,XY DSD requires a multidisciplinary approach, including patient history and clinical, morphological, imaging, biochemical and genetic data. We propose a diagnostic algorithm suitable for a newborn with DSD that focuses mainly on biochemical and genetic data.

Highlights

46,XY differences/disorders of sex development (DSD) involve an abnormal gonadal and/or genital development caused by lack or incomplete intrauterine virilization, with or without the presence of Müllerian ducts remnants
We propose a diagnostic algorithm suitable for a newborn with DSD that focuses mainly on biochemical and genetic data
Blood concentrations of T, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are low in males, higher than in females, which progressively increase from the end of the first week, peak by the 3rd month, and thereafter decrease gradually to reach low levels by 6 months, and continue to be low until the onset of puberty [3]

Summary

This work is licensed under the Creative Commons

Granada and Audí: Differences/disorders of sex development (DSD) 46,XY evaluate the HPT axis or Leydig cell capacity to synthesize T, it is necessary to stimulate the pituitary gland with the gonadoliberin (GnRH) or its analogs, or the testes with chorionic gonadotropin (HCG). AMH concentrations are decreased or even undetectable in patients with gonadal dysgenesis, they are preserved in patients with interstitial compartment disorders (isolated deficiency of androgen synthesis or action). In 46,XY DSD, abnormal gonadal development may result in partial or complete gonadal dysgenesis (PGD or CGD) or even lead to ovotesticular (testicular and ovarian tissues in the same or separate gonads) or ovarian gonads (Table 1). Subjects develop a hypergonadotropic hypogonadism with increased LH and FSH concentrations, T deficiency, and undetectable AMH and INHB. Persistence of Müllerian structures reflects a deficiency of AMH secretion, a sign of Sertoli cell dysfunction. Abnormal genital development secondary to deficient androgen synthesis or action. . Abnormal genital development secondary to defective anti-Müllerian (AMH) hormone synthesis or action. Table : Clinical diagnoses and genes involved in disorders or differences of sex development (DSD) of monogenic etiology

Clinical diagnosis

AMH deficiency Insensitivity to AMH