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The Laboratory in the Multidisciplinary Diagnosis of Differences Or Adv Lab Med 2021; ▪▪▪(▪▪▪): 1–11 Review Maria Luisa Granada* and Laura Audí The laboratory in the multidisciplinary diagnosis of differences or disorders of sex development (DSD) III) Biochemical and genetic markers in the 46,XY IV) Proposals for the differential diagnosis of DSD https://doi.org/10.1515/almed-2021-0043 history and clinical, morphological, imaging, biochemical Received December 14, 2020; accepted February 20, 2021; and genetic data. We propose a diagnostic algorithm suit- published online July 5, 2021 able for a newborn with DSD that focuses mainly on biochemical and genetic data. Abstract Keywords: 46,XY DSD; biochemical diagnosis; diagnostic Objectives: 46,XY differences/disorders of sex develop- algorithm; differences/disorders of sex development (DSD); ment (DSD) involve an abnormal gonadal and/or genital genetic diagnosis. (external and/or internal) development caused by lack or incomplete intrauterine virilization, with or without the presence of Müllerian ducts remnants. III. Biochemical and genetic Content: Useful biochemical markers for differential diag- nosis of 46,XY DSD include hypothalamic-pituitary-gonadal markers in 46,XY differences/ hormones such as luteinizing and follicle-stimulating hor- disorders of sex development mones (LH and FSH; in baseline or after LHRH stimulation conditions), the anti-Müllerian hormone (AMH), inhibin B, (46,XY DSD) insulin-like 3 (INSL3), adrenal and gonadal steroid hor- mones (including cortisol, aldosterone, testosterone and Biochemical work-up in patients with a 46,XY karyotype their precursors, dihydrotestosterone and estradiol) and the and discordances in gonadal and/or genital development pituitary ACTH hormone. Steroid hormones are measured at should include measurements of the hormones involved in baseline or after stimulation with ACTH (adrenal hormones) testicular development and an evaluation of androgen and and/or with HCG (gonadal hormones). anti-Müllerian hormone (AMH) synthesis and action [1]. The Summary: Different patterns of hormone profiles depend hypothalamus-pituitary-testicular (HPT) axis is very active on the etiology and the severity of the underlying disorder during fetal development. The follicle-stimulating hormone and the age of the patient at diagnosis. Molecular diagnosis (FSH) controls the proliferation of Sertoli cells, determining includes detection of gene dosage or copy number varia- the increase of testicular volume and the secretion of AMH tions, analysis of candidate genes or high-throughput DNA and inhibin B (INHB); the luteinizing hormone (LH) regu- sequencing of panels of candidate genes or the whole lates Leydig cells, stimulating the secretion of androgens, exome or genome. mainly testosterone (T), and insulin-like 3 (INSL3), involved Outlook: Differential diagnosis of 46,XX or 46,XY DSD re- in the descent of testes to scrotal pouches [2]. At birth, blood quires a multidisciplinary approach, including patient concentrations of T, LH and FSH are low in males, although higher than in females, which progressively increase from the end of the first week, peak by the 3rd month, and *Corresponding author: Dr. Maria Luisa Granada, MD, PhD, Department of Clinical Biochemistry, Hospital Germans Trias i Pujol, thereafter decrease gradually to reach low levels by Autonomous University of Barcelona, Crta. Canyet s/n, 08916 6 months, and continue to be low until the onset of puberty Badalona, Spain, E-mail: [email protected]. https://orcid. [3]. This physiological activation of the HPT axis is called org/0000-0002-6816-7566 “minipuberty” and is an optimal period to study infants with Laura Audí, Growth and Development Research Group, Vall d’Hebron differences/disorders of sex development (DSD) during the Research Institute (VHIR), Center for Biomedical Research on Rare fi fi Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, rst months of life. From the end of the rst semester of life, Catalonia, Spain serum levels of gonadotropins and T are very low; hence, to Open Access. © 2021 Maria Luisa Granada and Laura Audí, published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0 International License. 2 Granada and Audí: Differences/disorders of sex development (DSD) 46,XY evaluate the HPT axis or Leydig cell capacity to synthesize T, Table : Classification of disorders or differences of sex develop- it is necessary to stimulate the pituitary gland with the ment (DSD) based on the XY sex chromosomes present in the gonadoliberin (GnRH) or its analogs, or the testes with karyotype. chorionic gonadotropin (HCG). However, there are two DSD with ,XY karyotype peptide hormones produced by Sertoli cells (AMH and INHB) that are excellent markers of seminiferous tubule . Abnormal gonadal a. Partial (PGD) or complete (CGD) development gonadal dysgenesis function during infancy, childhood and puberty [4]. b. Ovotesticular DSD AMH is exclusively secreted by Sertoli cells, and is a c. Ovarian DSD good marker of primary testicular dysfunction [5]. AMH . Abnormal genital develop- Disorders of androgen synthesis: concentrations are very high in infants and prepubertal ment secondary to deficient a. Insensitivity to LH (Leydig cell children and decrease at onset of puberty, whereas T androgen synthesis or action aplasia/hypoplasia) concentrations increase. AMH concentrations must be b. -Dehydrocholesterol reductase deficiency (Smith–Lemli–Opitz interpreted according to age and pubertal stage [6]. AMH syndrome) concentrations are decreased or even undetectable in c. Star protein deficiency (lipoid patients with gonadal dysgenesis, although they are congenital adrenal hyperplasia) preserved in patients with interstitial compartment dis- d. Cholesterol desmolase deficiency β orders (isolated deficiency of androgen synthesis or e. -Hydroxy steroid dehydroge- nase type deficiency action). f. α-Hydroxylase/- desmo- INHB is also primarily secreted by Sertoli cells, though lase deficiency not exclusively. It is the main inhibitor of pituitary FSH g. P oxidoreductase deficiency secretion. Although it does not have a specific role in fetal h. Cytochrome b deficiency sex differentiation, it is a useful marker of testicular func- i. Defective backdoor steroidogene- tion. INHB concentrations are low in the newborn and in- sis pathway j. β-Hydroxy steroid dehydroge- crease throughout the first month of life, peaking at two nase type deficiency years. From that moment on, INHB concentrations decrease k. α-Reductase type deficiency progressively until the onset of puberty, remaining at low l. Isolated hypospadias and/or but detectable concentrations during adult life [7, 8]. cryptorchidism Disorders of androgen action: a. Complete or partial androgen insensitivity 1) Abnormal gonadal development b. Therapeutic agents or endocrine disrupting contaminants In 46,XY DSD, abnormal gonadal development may . Abnormal genital develop- Persistent Müller ducts: result in partial or complete gonadal dysgenesis (PGD or ment secondary to defective a. Anti-Müllerian hormone fi CGD) or even lead to ovotesticular (testicular and ovarian anti-Müllerian (AMH) hormone de ciency synthesis or action b. Resistance to anti-Müllerian tissues in the same or separate gonads) or ovarian go- hormone nads (Table 1). Complex malformation a. Malformative syndromes with CGD patients present female internal and external syndromes abnormal genital development genitalia. Bilateral streak gonads develop instead of normal (cloacal malformations, Aarskog gonads, which are unable to secrete androgens or AMH. At syndrome, Robinow syndrome, among others) biochemical level, subjects develop a hypergonadotropic b. Severe, early-onset, intrauterine hypogonadism with increased LH and FSH concentrations, growth retardation T deficiency, and undetectable AMH and INHB. In PGD, the degree of masculinization is determined by the mass of functional testicular tissue. Persistence of Müllerian structures reflects a deficiency of AMH secretion, DMRT1, DMRT2, EMX2, FANCAFGFR2, GATA4, HHAT, LHX9, a sign of Sertoli cell dysfunction. MYRF, NR5A1, PBX1, PPP2R3C, SAMD9, SOX9, TSPYL1, WT1. Thanks to massive sequencing techniques, an increasing In others, no associations had been described (Table 2): DAX1 number of genes involved in PGD and CGD have been iden- duplications, dominant mutations in DHX37, MAP3K1, tified (see Table 2). The firstgenetobedescribedwasSRY. WWOX or ZNRF3, recessive mutations in EFCAB6,mono- Many of these genes are associated with disorders in other allelic or biallelic mutations in ESR2 or SOX8,X-linkedmu- tissues or systems (Table 2): ARX, ATRX, CDKN1C, DHH, tations in FTHL17, MAMLD1 or STARD8. Granada and Audí: Differences/disorders of sex development (DSD) 46,XY 3 Table : Clinical diagnoses and genes involved in disorders or differences of sex development (DSD) of monogenic etiology. DSD with ,XY karyotype Clinical diagnosis Gene (locus) OMIM (inheritance) (additional phenotype) . ,XY DSD secondary to impaired gonadal development: complete gonadal dysgenesis (CGD) or partial gonadal dysgenesis (PGD), ovotesticular DSD, ovarian DSD PGD ARX (Xp.) (XL:D) (lissencephaly, epilepsy, mental retardation) PGD ATRX (Xq.) (D: del) (mental retardation, α-thalassemia) PGD/CGD/ovarian DSD CBX (q.) (RA) (RA) CBX./(DA) CBX. PGD/CGD CDKNC (p.) (DA)/ (IMaGE syndrome: intrauterine growth retarda- tion, metaphyseal dysplasia, congenital adrenal hypoplasia, genital abnormalities) PGD/CGD DAX (NRB) (Xp.) (XL:dup) PGD/CGD DHH (q.) / (RA/DA) (minifascicular neuropathy) PGD/CGD DHX
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