Illness46XY - disorders of testes development, non-syndromic; differential diagnosis

NGS +

Disturbed testis development can lead to complete 46XY gonadal dysgenesis (Swyer syndrome), in which affected individuals have female reproductive structures in terms of external and also some internal genitalia. Therefore, patients usually grow up as girls and have female gender identity. In most of the patients, the cause remains unknown, but variants in the SRY gene are found in about 15% of cases. Impaired testicular development is also observed in the presence of other gene variants, e.g. in the MAP3K1 gene (in up to 18% of cases), in the DHH, NR0B1, NR5A1 and less frequently in other genes. Most cases of Swyer syndrome are not inherited but arise from de novo gene variants that occur during oocyte or sperm formation or in early embryonic development. SRY-related disorders are usually caused by a new variant. Yet, some individuals with Swyer syndrome inherit an altered SRY gene from the unaffected father, who has a mosaic for the variant. When the syndrome is associated with a MAP3K1 or NR5A1 gene variant, the disease is also usually caused by a novel variant, rarely by an autosomal dominant inheritance pattern. Variants in the DHH gene can transmit the disease in an autosomal recessive manner. Variants in the above and many other genes can also cause other 46XY disorders of sex development, syndromal or non-syndromal with all known classical inheritance patterns. MAP3K1 and NR5A1 mutations are comparatively more frequently observed in this regard (10-15% or more), while all other causes are rare. The diagnostic yield of molecular genetics is still largely unknown, so that a negative result by no means excludes the clinical diagnosis.

Reference: https://www.ncbi.nlm.nih.gov/books/NBK1547/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182188/

• Alias: 46XY complete gonadal dysgenesis
• Alias: 46XY disorder of sex development (DSD)
• Allelic: 46XX sex reversal 1 (SRY)
• Allelic: 46XX sex reversal 4 (NR5A1)
• Allelic: Acampomelic campomelic dysplasia (SOX9)
• Allelic: Adrenal hypoplasia, congenital (NR0B1)
• Allelic: Adrenocortical insufficiency (NR5A1)
• Allelic: Alpha-thalassemia myelodysplasia syndrome, somatic (ATRX)
• Allelic: Atrial septal defect 2 (GATA4)
• Allelic: Atrioventricular septal defect 4 (GATA4)
• Allelic: Campomelic dysplasia (SOX9)
• Allelic: Developmental + epileptic encephalopathy 1 (ARX)
• Allelic: Hypospadias 1, XL (AR)
• Allelic: Leydig cell adenoma, somatic, with precocious puberty (LHCGR)
• Allelic: Lissencephaly, XL 2 (ARX)
• Allelic: Luteinizing hormone resistance, female (LHCGR)
• Allelic: Mental retardation, XL 29 + others (ARX)
• Allelic: Mental retardation-hypotonic facies syndrome, XL (ATRX)
• Allelic: Mesothelioma, somatic (WT1)
• Allelic: Nephrotic syndrome, type 4 (WT1)
• Allelic: Partington syndrome (ARX)
• Allelic: Precocious puberty, male (LHCGR)
• Allelic: Premature ovarian failure 7 ((NR5A1)
• Allelic: Prostate cancer, susceptibility to (AR)
• Allelic: Spinal + bulbar muscular atrophy of Kennedy (AR_CAG)
• Allelic: Tetralogy of Fallot (GATA4)
• Allelic: Ventricular septal defect 1 (GATA4)
• Allelic: Wilms tumor, type 1 (WT1)
• 17,20-lyase deficiency, isolated (CYP17A1)
• 17-alpha-hydroxylase/17,20-lyase deficiency (CYP17A1)
• 46XY gonadal dysgenesis with minifascicular neuropathy (DHH)
• 46XY sex reversal 1 (SRY)
• 46XY sex reversal 2, dosage-sensitive (NR0B1)
• 46XY sex reversal 3 (NR5A1)
• 46XY sex reversal 5 (CBX2)
• 46XY sex reversal 6 (MAP3K1)
• 46XY sex reversal 7 (DHH)
• 46XY sex reversal 8 (AK1C2)
• 46XY sex reversal 8, modifier of (AKR1C4)
• Adrenal hyperplasia, congenital, due to 3-beta-hydroxysteroid dehydrogenase 2 deficiency (HSD3B2)
• Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete (CYP11A1)
• Alpha-thalassemia/mental retardation syndrome (ATRX)
• Androgen insensitivity (AR)
• Androgen insensitivity, partial, with/-out breast cancer (AR)
• Antley-Bixler syndrome with genital anomalies + disordered steroidogenesis (POR)
• Campomelic dysplasia with autosomal sex reversal (SOX9)
• Denys-Drash syndrome (WT1)
• Disordered steroidogenesis due to cytochrome P450 oxidoreductase (POR)
• Frasier syndrome (WT1)
• Hydranencephaly with abnormal genitalia (ARX)
• Hypogonadotropic hypogonadism 1 with/-out anosmia [Kallmann syndrome 1] (ANOS1)
• Leydig cell hypoplasia with hypergonadotropic hypogonadism (LHCGR)
• Leydig cell hypoplasia with pseudohermaphroditism (LHCGR)
• Lipoid adrenal hyperplasia (STAR)
• Meacham syndrome (WT1)
• Proud syndrome (ARX)
• Pseudohermaphroditism, male, with gynecomastia (HSD17B3)
• Pseudovaginal perineoscrotal hypospadias (SRD5A2)
• Smith-Lemli-Opitz syndrome (DHCR7)
• Spermatogenic failure (DMRT1)
• Spermatogenic failure 8 (NR5A1)
• Testicular anomalies with/-out congenital heart disease (GATA4)