Klinische Fragestellung46XX - Störungen der Geschlechtsentwicklung, Differentialdiagnose

NGS +

[Sanger]

Das phänotypische Geschlecht ist das Ergebnis der Differenzierung der inneren Gänge und äußeren Genitalien unter dem hormonellen Einfluss der differenzierten Keimdrüse, wenn die Keimdrüse unter der Einwirkung geschlechtsbestimmender Gene ihren bipotenten Zustand verloren hat. Störungen der sexuellen Entwicklung (DSD) sind definiert als angeborene Zustände, bei denen die Entwicklung von chromosomalem, gonadalem und anatomischem Geschlecht atypisch ist. Die klinische Klassifikation bei Patienten ist schwierig, weil die Phänotypen ähnlich oder fast identisch sind, obwohl sie mehrere Ursachen haben können. Diese Zustände können zu verschiedenen Lebenszeiten bei Föten oder Neugeborenen mit unklaren äußeren Genitalien und Gonadendysgenesie identifiziert werden sowie bei inneren Genitalien, die bzgl. der Geschlechtschromosomen-Konstitution diskordant sind. Weiterhin können DSDs auch nachträglich bei Personen mit später Pubertät, unerwarteter Virilisierung oder Gynäkomastie, Unfruchtbarkeit oder Gonadentumoren diagnostiziert werden. Gelegentlich sind DSDs Teil eines genetischen Syndroms, was die Komplexität der sexuellen Entwicklung und die Wirkung multipler Gene belegt. DSDs werden nach den Veränderungen in den Ebenen der Geschlechtsbestimmung klassifiziert: Gen-, Chromosomen-, Gonaden-, Hormon-, Duktus-Geschlecht, äußere Genitalien, sekundäre Merkmale, gesetzlich zugewiesenes Geschlecht und psychologische Merkmale. Die molekulargenetische Analytik klärt gegenwärtig wenig mehr als die Hälfte der DSD-Fragestellungen. Alle Erbgänge kommen vor mit variabler Expressivität. Ein unauffälliger genetischer Befund bedeutet daher keinen sicheren Ausschluss der klinischen Verdachtsdiagnose.

Referenz: 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)