Illness46XX - indifferent genitals, differential diagnosis

NGS +

[Sanger]

Female and male sex characteristics are determined during fetal life by complex biological processes involving cascades of gene expression. The encoded proteins have highly specific functions in relation to the place and time of development. Genetic sex is determined at conception. Differentiation into internal and external genitalia depends on the secretion of specific factors/hormones by the testes in sufficient quantity and according to a defined schedule. In the absence of AMH and low androgen concentrations, internal and external female genitalia develop. Female differentiation of the internal genital tract is characterised by the disappearance of Wolffian ducts. The Müllerian ducts remain and form the endometrium, while the surrounding mesenchyme differentiates into the utrine myometrium and the fallopian tube. The upper part of the vagina is formed by the Müllerian ducts and the lower part by the sinovaginal bulbs. The female orientation of the urogenital sinus is characterised by the absence of prostatic differentiation and the acquisition of a separate vaginal opening on the surface of the perineum. Any alteration in the individual developmental stages can disrupt normal sex development and lead to differences in sex development in which genital development is atypical or different from the most common developmental forms. All inheritance patterns for monogenic defects are observed. The molecular genetic yield is commonly unknown. Therefore, a negative DNA test result may not exclude the clinical diagnosis.

Reference: https://www.ncbi.nlm.nih.gov/books/NBK279001/

• Alias: Genetic 46XX disorder of sex development - DSD; Genetic female pseudohermaphroditism
• Allelic: 46XY sex reversal 1 (SRY)
• Allelic: Acampomelic campomelic dysplasia (SOX9)
• Allelic: Beckwith-Wiedemann syndrome (CDKN1C)
• Allelic: Campomelic dysplasia (SOX9)
• Allelic: D-bifunctional protein deficiency (HSD17B4)
• Allelic: Disordered steroidogenesis due to cytochrome P450 oxidoreductase (POR)
• Allelic: Hydrops, lactic acidosis, and sideroblastic anemia (LARS2)
• Allelic: Leydig cell adenoma, somatic, with precocious puberty (LHCGR)
• Allelic: Leydig cell hypoplasia with hypergonadotropic hypogonadism (LHCGR)
• Allelic: Leydig cell hypoplasia with pseudohermaphroditism (LHCGR)
• Allelic: Mental retardation, XL, with isolated growth hormone deficiency (SOX3)
• Allelic: Ovarian hyperstimulation syndrome (FSHR)
• Allelic: Ovarian response to FSH stimulation (FSHR)
• Allelic: Precocious puberty, male (LHCGR)
• Allelic: Spinal and bulbar muscular atrophy of Kennedy (AR)
• Allelic: Testicular anomalies with or without congenital heart disease (GATA4)
• Allelic: Tetralogy of Fallot (GATA4)
• 17-alpha-hydroxylase/17,20-lyase deficiency (CYP17A1)
• 46XX sex reversal 1 (SRY)
• 46XX sex reversal 4 (NR5A1)
• 46XY gonadal dysgenesis with minifascicular neuropathy (DHH)
• 46XY sex reversal 2, dosage-sensitive (NR0B1)
• 46XY sex reversal 3 (NR5A1)
• 46XY sex reversal 6 (MAP3K1)
• 46XY sex reversal 7 (DHH)
• Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency (CYP11B1)
• Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency (CYP21A2)
• Adrenal hyperplasia, congenital, due to 3-beta-hydroxysteroid dehydrogenase 2 deficiency (HSD3B2)
• Adrenal hypoplasia, congenital (NR0B1)
• Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete (CYP11A1)
• Adrenocortical insufficiency (NR5A1)
• Aldosteronism, glucocorticoid-remediable (CYP11B1)
• Androgen insensitivity (AR)
• Androgen insensitivity, partial, with/-out breast cancer (AR)
• Antley-Bixler syndrome with genital anomalies + disordered steroidogenesis (POR)
• Aromatase deficiency (CYP19A1)
• Aromatase excess syndrome (CYP19A1)
• CHARGE syndrome (CHD7)
• Campomelic dysplasia with autosomal sex reversal (SOX9)
• Denys-Drash syndrome (WT1)
• Frasier syndrome (WT1)
• Hyperandrogenism, nonclassic type, due to 21-hydroxylase deficiency (CYP21A2)
• Hypogonadotropic hypogonadism 5 with/-out anosmia (CHD7)
• Hypospadias 1, XL (AR)
• Hypospadias 2, XL (MAMLD1)
• IMAGE syndrome (CDKN1C)
• Lipoid adrenal hyperplasia (STAR)
• Luteinizing hormone resistance, female (LHCGR)
• MIRAGE syndrome (SAMD9)
• Meacham syndrome (WT1)
• Mental retardation, XL, syndromic 15 [Cabezas type] (CUL4B)
• Mullerian aplasia + hyperandrogenism (WNT4)
• Ovarian dysgenesis 1 (FSHR)
• Palmoplantar hyperkeratosis + true hermaphroditism (RSPO1)
• Palmoplantar hyperkeratosis with squamous cell carcinoma of skin + sex reversal (RSPO1)
• Panhypopituitarism, XL (SOX3)
• Perrault syndrome 1 (HSD17B4)
• Perrault syndrome 2 (HARS2)
• Perrault syndrome 3 (CLPP)
• Perrault syndrome 4 (LARS2)
• Proud syndrome (ARX)
• Pseudohermaphroditism, male, with gynecomastia (HSD17B3)
• Pseudovaginal perineoscrotal hypospadias (SRD5A2)
• SERKAL syndrome (WNT4)
• Smith-Lemli-Opitz syndrome (DHCR7)
• Testicular anomalies with/-out congenital heart disease (GATA4)