Illness46XX - disorders of sex development, differential diagnosis

NGS +

[Sanger]

Phenotypic sex is the result of the differentiation of the internal ducts and external genitals under the hormonal influence of the differentiated gonad when the gonad has lost its bipotent state under the influence of sex-determining genes. Disorders of sexual development (DSDs) are defined as congenital conditions in which the development of chromosomal, gonadal and anatomical sex is atypical. Clinical classification in patients is difficult because phenotypes are similar or almost identical, although they may have several etiologies. These conditions can be identified at different lifetimes in foetuses or newborns with unclear external genitalia, gonadal dysgenesis and internal genitalia that are discordant in terms of sex chromosome constitution, and they can also be diagnosed subsequently in people with late puberty, unexpected virilization or gynecomastia, infertility or gonadal tumours. Occasionally DSDs can be part of a genetic syndrome, demonstrating the complexity of sexual development and the effect of multiple genes. DSDs are classified according to changes in the levels of sex determination: Genetic, chromosomal, gonadal, hormonal, ductal sex, external genitals, secondary characteristics, legally assigned sex and psychological characteristics. Molecular genetic analysis currently clarifies little more than half of the DSD problems. All inheritance patterns occur with variable expressivity. An inconspicuous genetic finding does not therefore mean that the clinical suspected diagnosis can be excluded with certainty.

Reference: https://www.karger.com/Article/FullText/499274

• Alias: DSD, disorders of sex determination; Genetic 46XX DSD
• Alias: Genetic female pseudohermaphroditism
• Alleic: Progressive external ophthalmoplegia, AR 1 (POLG)
• Allelic: Acampomelic campomelic dysplasia (SOX9)
• Allelic: Aldosteronism, glucocorticoid-remediable (CYP11B1)
• Allelic: Alpha-thalassemia myelodysplasia syndrome, somatic (ATRX)
• Allelic: Alpha-thalassemia/mental retardation syndrome (ATRX)
• Allelic: Atrial septal defect 2 (GATA4)
• Allelic: Atrioventricular septal defect 4 (GATA4)
• Allelic: Beckwith-Wiedemann syndrome (CDKN1C)
• Allelic: Blepharophimosis, epicanthus inversus, ptosis, type 1 (FOXL2)
• Allelic: Blepharophimosis, epicanthus inversus, ptosis, type 2 (FOXL2)
• Allelic: Brachydactyly, type B2 (NOG)
• Allelic: Campomelic dysplasia (SOX9)
• Allelic: Combined oxidative phosphorylation deficiency 5 (MRPS22)
• Allelic: D-bifunctional protein deficiency (HSD17B4)
• Allelic: Diaphragmatic hernia 3 (ZFPM2)
• Allelic: Disordered steroidogenesis due to cytochrome P450 oxidoreductase (POR)
• Allelic: Encephalocraniocutaneous lipomatosis, somatic mosaic (FGFR1)
• Allelic: Galloway-Mowat syndrome 7 (NUP107)
• Allelic: Guttmacher syndrome (HOXA13)
• Allelic: Hartsfield syndrome (FGFR1)
• Allelic: Hydrops, lactic acidosis + sideroblastic anemia (LARS2)
• Allelic: Hypospadias 2, XL (MAMLD1)
• Allelic: Jackson-Weiss syndrome (FGFR1)
• Allelic: Leukoencephalopathy with vanishing white matter (EIF2B5)
• 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-hypotonic facies syndrome, XL (ATRX)
• Allelic: Mesothelioma, somatic (WT1)
• Allelic: Mitochondrial DNA depletion syndrome 4A [Alpers type] (POLG)
• Allelic: Mitochondrial DNA depletion syndrome 4B [MNGIE type] (POLG)
• Allelic: Mitochondrial DNA depletion syndrome 7 [hepatocerebral type] (TWNK)
• Allelic: Mitochondrial recessive ataxia syndrome [includes SANDO + SCAE] (POLG)
• Allelic: Monosomy 7 myelodysplasia and leukemia syndrome 2 (SAMD9)
• Allelic: Multiple synostoses syndrome 1 (NOG)
• Allelic: Nephrotic syndrome, type 11 (NUP107)
• Allelic: Nephrotic syndrome, type 4 (WT1)
• Allelic: Non-obstructive azoospermia [panelapp] (MSH4)
• Allelic: Osteoglophonic dysplasia (FGFR1)
• Allelic: Ovarian hyperstimulation syndrome (FSHR)
• Allelic: Ovarian response to FSH stimulation (FSHR)
• Allelic: PCWH syndrome (SOX10)
• Allelic: Pfeiffer syndrome (FGFR1)
• Allelic: Precocious puberty, male (LHCGR)
• Allelic: Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD 3 (TWNK)
• Allelic: Progressive external ophthalmoplegia, AR 1 (POLG)
• Allelic: Pseudovaginal perineoscrotal hypospadias (SRD5A2)
• Allelic: Spermatogenic failure 28 (FANCM)
• Allelic: Spermatogenic failure 32 (SOHLH1)
• Allelic: Spermatogenic failure 8 (NR5A1)
• Allelic: Stapes ankylosis with broad thumbs + toes (NOG)
• Allelic: Symphalangism, proximal, 1A (NOG)
• Allelic: Tarsal-carpal coalition syndrome (NOG)
• Allelic: Tetralogy of Fallot (GATA4)
• Allelic: Tetralogy of Fallot (ZFPM2)
• Allelic: Trigonocephaly 1 (FGFR1)
• Allelic: Tumoral calcinosis, familial, normophosphatemic (SAMD9)
• Allelic: Ventricular septal defect 1 (GATA4)
• Allelic: Waardenburg syndrome, type 4C (SOX10)
• Allelic: Wilms tumor, type 1 (WT1)
• Allelic:Mitochondrial DNA depletion syndrome 4A, Alpers type (POLG)
• 17,20-lyase deficiency, isolated (CYP17A1)
• 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 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 (AKR1C2)
• 46XY sex reversal 8, modifier of (AKR1C4)
• 46XY sex reversal 9 (ZFPM2)
• 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/complete (CYP11A1)
• Adrenocortical insufficiency (NR5A1)
• Allelic: Charcot-Marie-Tooth disease, demyelinating, type 1I (POLR3B)
• Allelic: Precocious puberty, central, 1 (KISS1R)
• Allelic: Spastic paraplegia 39, AR (PNPLA6)
• Antley-Bixler syndrome with genital anomalies + disordered steroidogenesis (POR)
• Aromatase deficiency (CYP19A1)
• Aromatase excess syndrome (CYP19A1)
• Boucher-Neuhauser syndrome (PNPLA6)
• CHARGE syndrome (CHD7)
• CHARGE syndrome (SEMA3E)
• Campomelic dysplasia with autosomal sex reversal (SOX9)
• Cerebellar ataxia and hypogonadotropic hypogonadism (RNF216)
• Congenital disorder of glycosylation, type Ia (PMM2)
• Denys-Drash syndrome (WT1)
• Disorders of sex development [panelapp] (ATRX)
• Frasier syndrome (WT1)
• Galactosemia (GALT)
• Gordon-Holmes syndrome [GeneReviews] (OTUD4, PNPLA6, RNF216, STUB1)
• Hand-foot-uterus syndrome (HOXA13)
• Hyperandrogenism, nonclassic type, due to 21-hydroxylase deficiency (CYP21A2)
• Hypogonadotropic hypogonadism 1 with/-out anosmia; Kallmann syndrome 1 (ANOS1)
• Hypogonadotropic hypogonadism 10 with/-out anosmia (TAC3)
• Hypogonadotropic hypogonadism 11 with/-out anosmia (TACR3)
• Hypogonadotropic hypogonadism 12 with/-out anosmia (GNRH1)
• Hypogonadotropic hypogonadism 13 with/-out anosmia (KISS1)
• Hypogonadotropic hypogonadism 14 with/-out anosmia (WDR11)
• Hypogonadotropic hypogonadism 15 with/-out anosmia (HS6ST1)
• Hypogonadotropic hypogonadism 16 with/-out anosmia (SEMA3A)
• Hypogonadotropic hypogonadism 16 with/-out anosmia (SEMA3A)
• Hypogonadotropic hypogonadism 17 with/-out anosmia (SPRY1)
• Hypogonadotropic hypogonadism 18 with/-out anosmia (IL17RD)
• Hypogonadotropic hypogonadism 19 with/-out anosmia (DUSP6)
• Hypogonadotropic hypogonadism 2 with/-out anosmia (FGFR1)
• Hypogonadotropic hypogonadism 20 with/-out anosmia (FGF17)
• Hypogonadotropic hypogonadism 21 with anosmia (FLRT3)
• Hypogonadotropic hypogonadism 22, with/-out anosmia (FEZF1)
• Hypogonadotropic hypogonadism 23 with/-out anosmia (LHB)
• Hypogonadotropic hypogonadism 24 without anosmia (FSHB)
• Hypogonadotropic hypogonadism 3 with/-out anosmia (PROKR2)
• Hypogonadotropic hypogonadism 4 with/-out anosmia (PROK2)
• Hypogonadotropic hypogonadism 5 with/-out anosmia (CHD7)
• Hypogonadotropic hypogonadism 6 with/-out anosmia (FGF8)
• Hypogonadotropic hypogonadism 7 without anosmia (GNRHR)
• Hypogonadotropic hypogonadism 8 with/-out anosmia (KISS1R)
• Hypogonadotropic hypogonadism 9 with/-out anosmia (NSMF)
• IMAGE syndrome (CDKN1C)
• Isolated gonadotropin-releasing hormone deficiency [GeneReviews] (AXL, CCDC141)
• Laurence-Moon syndrome (PNPLA6)
• Leukodystrophy, hypomyelinating, 8, +/- oligodontia +/- hypogonadotropic hypogonadism (POLR3B)
• Lipoid adrenal hyperplasia (STAR)
• Luteinizing hormone resistance, female (LGCGR)
• MIRAGE syndrome (SAMD9)
• Marinesco-Sjogren syndrome (SIL1)
• Mayer-Rokitansky-Kuster-Hauser syndrome (LHX1)
• Meacham syndrome (WT1)
• Mental retardation, XL, with isolated growth hormone deficiency (SOX3)
• Methemoglobinemia + ambiguous genitalia (CYB5A)
• Mullerian aplasia + hyperandrogenism (WNT4)
• Oliver-McFarlane syndrome (PNPLA6)
• Ovarian dysgenesis 1 (FSHR)
• Ovarian dysgenesis 2 (BMP15)
• Ovarian dysgenesis 3 (PSMC3IP)
• Ovarian dysgenesis 4 (MCM9)
• Ovarian dysgenesis 5 (SOHLH1)
• Ovarian dysgenesis 6 (NUP107)
• Ovarian dysgenesis 7 (MRPS22)
• Ovarian dysgenesis 8 (ESR2)
• Ovarioleukodystrophy (EIF2B5)
• Palmoplantar hyperkeratosis + true hermaphroditism (RSPO1)
• Palmoplantar hyperkeratosis, 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)
• Perrault syndrome 5 (TWNK)
• Perrault syndrome 6 (ERAL1)
• Persistent Mullerian duct syndrome, type I (AMH)
• Persistent Mullerian duct syndrome, type II (AMHR2)
• Premature ovarian failure 10 (MCM8)
• Premature ovarian failure 14 (GDF9)
• Premature ovarian failure 15 (FANCM)
• Premature ovarian failure 2A (DIAPH2)
• Premature ovarian failure 3 (FOXL2)
• Premature ovarian failure 4 (BMP15)
• Premature ovarian failure 5 (NOBOX)
• Premature ovarian failure 7 (NR5A1)
• Premature ovarian failure 8 (STAG3)
• Premature ovarian failure 9 (HFM1)
• Primary ovarian failure [MONDO:0005387] (MSH4)
• Primary ovarian insufficiency (POU5F1)
• Primary ovarian insufficiency (SOHLH2)
• Primary ovarian insufficiency [panelapp] (NANOS3)
• Primary ovarian insufficiency [panelapp] (NOG)
• Primary ovarian insufficiency [panelapp] (POLG)
• Pseudohermaphroditism, male, with gynecomastia (HSD17B3)
• SERKAL syndrome: 46,XX SEx Reversal with dysgenesis of Kidney, Adrenals, Lungs (WNT4)
• Smith-Lemli-Opitz syndrome (DHCR7)
• Spinocerebellar ataxia 48 (STUB1)
• Spinocerebellar ataxia, AR 16 (STUB1)
• Testicular anomalies with/-out congenital heart disease (GATA4)
• Waardenburg syndrome, type 2E, with/-out neurologic involvement (SOX10)
• Woodhouse-Sakati syndrome (DCAF17)